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pmc-6282134-1
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A 83-year-old Caucasian male with a past medical history of TIA and nephrolithiasis initially presented for hematologic evaluation of persistent leukocytosis with immature cells on peripheral smear found on routine office visit. On initial evaluation, peripheral smear showed a leukocytosis of 17,500, with neutrophil predominance of 72%, lymphocytes 10%, monocytes 13%, eosinophils 1%, myelocytes 1%, and blasts 3 %. Absolute neutrophil count (ANC) was 2600 cells/mcL, along with mild anemia, hemoglobin of 11.6 mg/dl, and thrombocytopenia 90,000. His metabolic profile was within normal limits. The patient was asymptomatic except for easy fatigability for few months. No B symptoms were present on initial evaluation.
Initial evaluation with ANA, RA factor, ESR, CRP, iron, ferritin, thyroid function tests, vitamin B12, folate, copper serum, and urine immunofixation tests was normal.
Bone marrow biopsy was done due to suspicion for CML vs. MDS which showed hypercellular marrow (80% cellularity) with granulocytic hyperplasia and trilineage dyspoiesis with <5% blasts. Fluorescence in situ hybridization (FISH) performed on bone marrow was negative for BCR-ABL fusion gene—p190 and p230 isoforms—and was negative for MDS/ AML probes—PDGFRA/ PDGFRB/ FIP1L1/ CHIC2 negative. Cytogenetics was normal with analysis showing 46,XY with no evidence for any clonal structural or numerical abnormality.
Blood CML PCR quantitative panel was negative for b2a2 and b3a2 (p210) and E1a2 (p190) transcripts along with JAK2V617F mutation.
The patient was diagnosed as low-grade (IPSS-R score 2.5, low risk) myelodysplastic syndrome (MDS) and was monitored as he was mostly asymptomatic and had been doing well. 10 months later, he developed progressive symptomatic anemia, with hemoglobin drop to 8.8 from a baseline of 11.6. Meanwhile, his leukocytosis resolved and thrombocytopenia seemed to improve to >100,000. The patient was started on weekly Epoetin alfa with improvement in his anemia. Leukocytosis resolved, but 8 months later, the patient developed significant thrombocytopenia with platelet count drop from 121,000 to 64,000 in 1 week. Workup for thrombocytopenia was initiated with slightly elevated prothrombin time 11.8 sec, INR 1.2, and normal PTT. Von Willebrand Factor antigen and Factor III activity were normal. A repeat bone marrow biopsy showed hypercellular marrow for age (approx 80% cellularity), with trilineage hematopoiesis with significant dysmegakaryopoiesis and mild dyserythropoiesis. No evidence of T or B cell lymphoma or acute leukemia was found.
Flow cytometry on bone marrow specimen revealed neutrophil predominant specimen with 74% neutrophils, monocytes 3%, lymphocytes 10% with normal subtypes, and 2.9% blasts. Cytogenetics on bone marrow with analysis of 100 interphase cells revealed new BCR-ABL1 fusion gene t(9; 22)(q34; q11.2) with translocation between 22q11.2 and 9q34 in 79% of cells. Peripheral blood RT PCR for BCR-ABL was positive for BCR-ABL p210 transcript (b2a2 at 11.042%). Pt was diagnosed as Ph+ve MDS/MPN, intermediate risk and was started on tyrosine kinase inhibitor imatinib which was discontinued 7 months later due to lack of significant decrease in Ph+ve clone on repeat marrow biopsy. He was instead started on dasatinib which was discontinued 1 week later due to development of right sided heart failure. He did not have a T315I mutation and was not a candidate for ponatinib. He is currently doing well, 30 months after diagnosis, not requiring transfusion support and is currently waiting for nilotinib approval. His last BCR-ABL level was 9.9% in peripheral blood at last check 1 month ago.
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pmc-6282140-1
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A 54-year-old Caucasian male with a past medical history of treated rhabdomyolysis, COPD, and occasional methamphetamine use presented to the emergency department for severe right pectoral pain that began 5 days prior. He reported coming to the emergency department 3 days prior to presentation with right pectoral pain and was put on sulfamethoxazole/trimethoprim for suspected cellulitis, but reported worsening of symptoms. Pain radiated from his right pectoral muscle to his right shoulder. He characterized the pain as severe, constant, sharp, and pleuritic.
He reported minor superficial abrasions from steel to his right superior lateral chest while working odd jobs one week prior to onset of symptoms, but denied any blunt trauma, intravenous drug use, recent travel, sick contacts, weight loss, or shortness of breath. He endorsed a fever the night prior to admission, nonproductive chronic cough, and red, swollen skin changes on his right chest.
Upon initial presentation, the patient was febrile and tachycardic, but stable. Patient's right chest was erythematous and tender to palpation along the distal right pectoral insertion and right shoulder, with 4/5 right shoulder strength and sensitivity to light touch along the right arm. His right chest was 3 times the size of his left chest. Nontender induration of the right flank was present. No discrete mass or abscess was palpable; however, a fluid collection was present in the posterior scapula region on the right. Lab results showed elevated levels of procalcitonin, c-reactive protein, and white blood cell count. The creatinine kinase level was not suspicious for rhabdomyolysis.
Chest x-ray was unremarkable. Initial ultrasound of his right pectoral muscle showed an area of skin induration with tiny anechoic areas compatible with cellulitis. Computed tomography (CT) scan of his chest showed fat stranding of the right pectoral, but no abscess ().
Upon admission, the patient was placed on piperacillin/tazobactam and vancomycin. However, after ten days on the new antibiotic regimen, his clinical presentation failed to improve. Blood cultures were positive for S. aureus that was susceptible to vancomycin. Repeat ultrasonography was performed and showed interval development of abscess in the pectoral muscle body. Surgery was consulted, and they proceeded with incision and drainage. Surgical exploration revealed a large amount of purulent fluid in between the pectoralis minor and major muscles, and the diagnosis of pyomyositis was reached. Wound cultures were consistent with methicillin-resistant S. aureus (MRSA). The patient had improvement with serial drainages. In preparation for discharge, the patient's antibiotic regimen was switched to clindamycin for MRSA coverage and a nonparenteral route for administration. The patient was discharged in stable condition on oral clindamycin and a wound vacuum.
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pmc-6282142-1
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An 8-year-old girl, from a rural area in Choco (Colombian Pacific Coast), presented with 20 days of fever, hiporexia, asthenia, and arthralgias, associated with emesis and diarrhea. She was found to have anemia and was prescribed ferrous bisglycinate without improvement. The fever was persistent and was associated with chills, abdominal pain, and dark urine; she was admitted to a rural hospital and diagnosed with pancytopenia; 2 units of packed red blood cells were transfused; and she was transferred to our hospital with a clinical suspicion of lymphoproliferative disorder. Her vital signs showed tachycardia (131 bpm), tachypnea (45 per min), and limit-low oxygen saturation (91%). Physical examination revealed jaundice and hepatosplenomegaly of 6 cm and of 2 cm below the costal margin, respectively; fine right basal crackles and a soft systolic heart murmur were heard at the left sternal border and the third intercostal space. Her past medical history was relevant for posttraumatic osteomyelitis of the right humerus and septic arthritis of the right elbow; her parents were not consanguineous, and she did not have pseudoalbinism.
Test results revealed thrombocytopenia and lymphopenia (Hg 11.5 g/dL, WBCs 4600/µL, neutrophils 3404/µL, lymphocytes 1058/µL, and platelets 59000/µL), elevated C-reactive protein (21.57 mg/dL), and altered liver function tests (ALT 349 U/L, AST 135 U/L, total bilirubin 6.67 mg/dL, direct bilirubin 5.3 mg/dL, LDH 1376 IU/L, and albumin 2.1 g/dL). Infectious workup was negative for HIV, dengue, malaria, Hepatitis B, Hepatitis C, CMV, EBV, and Mycoplasma. Additional laboratory tests showed hypertriglyceridemia (787 mg/dL) and hyperferritinemia (>2000 ng/mL) with normal fibrinogen (311 mg/dL). Echocardiogram showed minimal pericardial effusion and preserved ventricular function without anatomic defects or signs of endocarditis. Abdominal ultrasound showed a small right pleural effusion, hepatomegaly, splenomegaly, and retroperitoneal and hepatic hilar lymphadenopathies. Abdominal computed tomography showed the same findings, with hypodensity areas corresponding to splenic infarcts. She was diagnosed with hemophagocytic lymphohistiocytosis and started on piperacillin-tazobactam and intravenous immunoglobulin (1 g/kg/d for 2 days); while waiting for blood cultures and bone marrow analysis, CSF was within normal limits. On her third hospital night, she presented hematemesis and rectorrhagia with hypovolemic shock that required fluid resuscitation, intravenous infusion of omeprazole, tranexamic acid, phytomenadione, packed red blood cell, and platelets transfusion. She was stabilized; upper and lower endoscopies did not show signs of active bleeding, but just some residual melena. On the fourth day of hospitalization, both blood and bone marrow cultures were positive for Salmonella typhi; and the antibiotic regimen was changed to ciprofloxacin; bone marrow specimen showed hematopoietic precursors with no signs of malignancy; and no hemophagocytosis was appreciated. Repeated blood cultures were negative; during the hospital stay, she was started on enalapril to maintain a tight control on blood pressure. She completed 14 days of antibiotic treatment with resolution of the fever, hepatomegaly, splenomegaly, and the abdominal pain. Laboratory investigations before discharge showed resolution of the cytopenias, down trending of liver function tests and triglycerides levels, and ferritin was still elevated.
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pmc-6282241-1
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At the end of 2015, a 3-year-old girl, with B-cell acute lymphocytic leukaemia with TEL-AML1 fusion and profound neutropenia, was started treatment with EORTC 58081 protocol (NCT01185886), medium risk AR1. After 19 days of prednisolone (60 mg/m2/day), two doses of vincristine (1.5 mg/m2), one dose of daunorubicin (30 mg/m2) and one dose of asparaginase (10,000 IU/m2), she developed febrile neutropenia with digestive problems. Procalcitonin and serum C-reactive protein (CRP) levels were 1.85 ng/mL and 91 mg/L, respectively. Chemotherapy was discontinued and antibiotherapy was started with ceftriaxone. Due to persistence of fever, ceftriaxone was switched on Day 3 to piperacillin-tazobactam for 14 days and amikacin for 3 days. At that time, neutrophil count was 0.5 × 109/L. Increasing CRP (350 mg/L) prompted the addition of caspofungin on Day 6 (70 mg/m2 day 1, followed by 50 mg/m2/day) following a local protocol established according to international guidelines []. Twice weekly screening for serum mannan, galactomannan (Platelia™; Bio-Rad Laboratories) and (1,3)-β-D-glucan (Fungitell™; Associates of Cape Cod, Inc.) remained negative. On Day 10 of fever, a chest computed tomography (CT) scan showed condensation in the left lower lobe associated with right pleural effusion evocative of invasive aspergillosis. Treatment with intravenous voriconazole was started (9 mg/kg bid day 1, then 8 mg/kg bid) and caspofungin was stopped. An abdominal ultrasound showed bilateral nephromegaly. Direct microscopic examination, culture, galactomannan detection and Aspergillus q-PCR in bronchoalveolar lavage were negative. All blood cultures remained sterile.
On Day 21 of fever, neutrophil count was 11.2 × 109/L. Fundoscopy was performed because of a reduction in visual acuity, revealing multiple subretinal foci suspected to be fungal in origin. Direct microscopy of vitreous humour revealed large, aseptate, ribbon-like hyphae. Among the different mycological techniques used, only Mucorales q-PCR was positive for Lichtheimia spp. (Cq 31) in vitreous humour, but was negative in serum. Magnetic resonance imaging (MRI) showed two abscess-like cerebral lesions and confirmed the kidney infiltration (Fig. a). A diagnosis of disseminated mucormycosis was established.
Despite limited experience in children, voriconazole was switched to isavuconazole (ISAV) (compassionate off-label use) instead of liposomal amphotericin B (L-AmB), because of renal impairment. Each dose (70 mg every 8 h for 48 h, then 70 mg/day IV) was infused over 1 h. Plasma drug monitoring was implemented from Day 3 after ISAV introduction (AISAVI) and was repeated regularly up to Day 150 (Fig. a). Considering a target trough plasma level (TPL) of 2000–4000 ng/mL (approximate average adult TPL observed in Phase 3 studies) [, ], low TPL on Day 5 AISAVI prompted an increase in dose to 90 mg/day. A pharmacokinetic profile (Fig. b) obtained on Day 7 AISAVI showed that TPL decreased to 1110 ng/mL at 24 h. The ISAV dosage was changed to 90 mg twice daily and L-AmB (10 mg/kg/day) was added despite renal impairment because of the cerebral lesions and difficulties in achieving the ISAV TPL target. The TPL target was reached on Day 17 AISAVI and levels were stable by Day 24. In order to facilitate home nursing care, the route of administration was changed to capsules (100 mg bid). Due to difficulties in swallowing, the capsules were opened and the contents dissolved in an acidic beverage. After 1 week, the mixture was introduced via a nasogastric tube because of vomiting. Median TPL was 4890 ng/mL from Day 66 AISAVI and remained stable over time, while the maximum concentration was obtained between 1 or 2 h after administration, with values varying between 4200 and 4690 ng/ml (Fig. b).
With the exception of slight nausea/vomiting during the first 2 months after initiation, no adverse effects were noted with ISAV, and liver enzymes were in the range of normal values observed in healthy subjects. The patient was in complete cytological and molecular remission and was chemotherapy-free for 7 months, until her leukaemia relapsed at 8 months. The patient was treated with the first-line CAALL-F01 protocol (NCT02716233), medium risk, and was in complete remission 4 months after relapse. Because of the risk of drug interactions, L-AmB (7 mg/kg/day) was continued alone for 4 months and was then replaced with ISAV (50 mg twice daily). Antifungal treatment was maintained during maintenance chemotherapy. The size of the cerebral abscesses decreased between the first and last MRI (at 16 months) from 55 × 37 and 45 × 38.4 mm to 23.5 × 18 and 17 × 17 mm with persistence of hypometabolism on a fluorodeoxyglucose-positron emission tomography scan (FDG PET/CT). Renal insufficiency was stable with clearance of 78 ml/min/m2 according to the Schwartz formula. The loss of left-sided vision was irreversible. After 24 months of treatment, the patient was still alive without further damage. The treatment timeline is shown in the Table .
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pmc-6282261-1
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An 11-year-old, intact male German Shepherd dog (GSD) was referred to the emergency service of the Department of Clinical Sciences of Companion Animals of the Faculty of Veterinary Medicine of Utrecht University with a 2-day history of acute onset dyspnea and generalized weakness. Vaccination and deworming were performed regularly. The dog had visited Southern Europe 6 months before presentation. No drugs were administered prior to the development of the clinical signs and no environmental circumstances that could cause dyspnea (e.g. tobacco, organic solvent exposure, dust) were reported.
Physical examination showed a responsive but lethargic dog with generalized weakness, severe dyspnea, cyanotic mucous membranes, prolonged capillary refill time, weak peripheral pulses, tachycardia (heart rate 180 beats/min) and a grade one out of six systolic murmur with the point of maximal intensity over the right cardiac apex. Harsh lung sounds were heard on lung auscultation. Complete blood count (CBC) showed a mild mature leukocytosis (white blood cells: 18.9 × 109/L; reference interval 4.5–14.6 × 109/L) and a haematocrit of 56% (reference interval 42–61%). Biochemistry did not show any abnormalities. Arterial blood gas analysis showed a severe hypoxemia (PaO2: 48.5 mm Hg; reference interval 85–103 mm Hg) and mild hypocapnia (PaCO2: 27.0 mm Hg; reference interval: 32–43 mm Hg). The suspected cause for the hypocapnia was hyperventilation. D-dimer and antithrombin concentrations were within the reference intervals. Dirofilaria immitis antigen snap test (SNAP® Heartworm RT Test, IDEXX Laboratories) and faecal examination (flotation and Baermann larval isolation technique) were both negative.
Thoracic radiographs showed a dilation of the pulmonary artery trunk and right-sided cardiomegaly (Fig. ). Echocardiography was severely complicated due to the severe anxiety and panting of the dog and was therefore limited. It showed severe right ventricular dilation, mild uniform dilation of the main pulmonary artery, systolic flattening of the interventricular septum and moderate tricuspid regurgitation (Fig. a). Application of the modified Bernoulli equation to the velocity of the tricuspid regurgitation jet showed an estimated systolic pulmonary artery pressure of 77 mm Hg, graded as severe PH (reference < 25 mm, severe > 75 mm Hg) []. The left ventricular dimensions were markedly reduced, consistent with left-sided volume depletion. A saline contrast echocardiography was performed, which was negative, thereby excluding intra- and extra-cardiac right-to-left shunting. To address the severe hypoxemia and PH the dog was placed in an oxygen cage with an inspired concentration of oxygen between 40 and 50%. Furthermore, 1.5 mg/kg/8 h oral sildenafil (Viagra®, Pfizer, New York, USA) and 0.25 mg/kg/12 h oral pimobendan (Vetmedin®, Boehringer Ingelheim, Germany) were administered. This therapy did not significantly affect the clinical condition of the dog. However, the arterial hypoxemia mildly improved after the first day of therapy (PaO2 increased from 48.5 to 53 mm Hg, reference interval 85–103 mm Hg). The echocardiogram was repeated on the third day of therapy and the echocardiographic changes and the severity of the PH were markedly reduced. The right ventricular dilation had dramatically decreased, the interventricular septum was no longer flattened, and the pressure gradient of the tricuspid regurgitation was reduced from 77 mm Hg to 41 mm Hg (reference < 25 mm Hg) (Fig. b). Therefore, therapy with pimobendan and sildenafil was continued during the hospitalized period (7 days).
As further diagnostic steps a (pre-and post-contrast) computed tomography (CT) scan with an apnoea, followed by a surgical lung biopsy in the same anaesthetic session were performed 4 days after the initial presentation. A single slice helical CT scanner (Philips Secura, Philips NV, Eindhoven, the Netherlands) was used. Technical settings included 3 mm helical slices, 120 kV, 200 mA, 292 mm field of view, 512 × 512 matrix and a high spatial frequency algorithm. On CT images, the lung parenchyma showed subtle centrilobular ground glass nodules and an enlarged pulmonary artery. Septal lines, pleural effusion and lymphadenopathy were absent (Fig. a, b). CT findings were compatible with PH without a conclusive diagnosis. Following the CT scan, a lung biopsy from the left cranial lung lobe (3 × 2 cm) was taken for histopathological examination with a mini-thoracotomy. Directly after this procedure a therapy with dexamethasone (0.25 mg/kg q24 h I.V., Rapidexon ®, Eurovet Animal Health, Bladel, the Netherlands) was initiated as a last resort while histopathological results were pending (3 days).
Histopathology of the surgical lung biopsy showed a moderate chronic interstitial histiocytic pneumonia of unknown aetiology and atelectasis by haematoxylin and eosin, periodic acid–Schiff, and Van Gieson’s stainings. Vascular changes were initially not clearly identified. Because of the poor response to the initiated treatment and the suspected poor prognosis based on the histopathologic results, the dog was euthanized. Autopsy was performed with the owner’s informed consent.
Gross pathology of the lungs showed moderately collapsed firm lungs with a diffuse mottled appearance with multiple dark red foci of 1 × 1 × 3 mm, and small numbers of white foci of 1 × 1 × 1 mm, often surrounded by a dark red zone (demarcation) randomly distributed throughout all lung lobes (Fig. ). Routine histopathology of the lungs showed multifocal vascular remodelling. In order to differentiate between small arteries and veins, essential to diagnose PVOD, an additional stain visualising elastic fibers and collagen (Weigert’s Resorcin Fuchsin) was added to identify elastic laminae. In this dog, like in people with PVOD, all three compartments (arteries, veins and capillaries) of the pulmonary microcirculation were affected, although the changes in the pulmonary venous system were the most pronounced. Venular lesions included severe concentric intimal proliferation, partial to complete obliteration of the lumina (Figs. , ) and post-thrombotic recanalization (Fig. c). Capillary lesions were organized in foci, most obvious adjacent to remodelled venules and were characterized by proliferation of plumb endothelial cells (similar to PCH) (Figs. , b, d). Segmental congestion of alveolar capillaries was also regularly associated with the foci of PCH (Fig. ). Arterial lesions resembled those of PAH with concentric intimal thickening by increased extracellular matrix and medial hypertrophy, but complex plexiform lesions were absent (Fig. ). These findings were consistent with the findings described by Williams et al. [] and therefore the human equivalent of PVOD.
The genomic DNA of the case was isolated from EDTA-blood using a semi-automated Chemagen extraction robot (PerkinElmer Chemagen Technologie GmbH) and was stored at − 20 °C. Approximately 6 years later, the genomic DNA of the case and an unrelated healthy GSD were analysed by whole genome sequencing. Integrity of DNA was checked on a Bioanalyzer (Agilent, Santa Clara, USA) and quantified using Qubit dsDNA HS (Thermo Fisher Scientific, Waltham, USA). DNA libraries were prepared using TruSeq Nano library prep kit (TruSeq Nano library prep kit, Illumina, San Diego CA, USA) using 200 ng gDNA input. Whole genome sequencing information at 30× coverage was obtained using a HiSeqX Ten instrument (HiSeqX Ten instrument, Illumina, San Diego CA, USA) and 2 × 150 base pair paired-end reads.
Data was processed with our in-house developed pipeline v1.2.1 () including somatic mutation analysis (Strelka, VarScan, FreeBayes, and MuTect) and a genome analysis toolkit (GATK v. 3.2.2) [] according to best practices guidelines []. Sequence reads were mapped against the Canine Reference Genome (CanFam 3.1) using Burrows-Wheeler alignment with maximal exact matches (BWA-MEM) v0.7.5a [] followed by marked duplicates, merging of lanes, and realignment of indels. Base recalibration was not performed. In human medicine, mutations in BMPR2, ACVRL1, ENG, KCNK3, CAV-1, and SMAD9 have been suggested to be causative for an autosomal dominant form of PAH []. These genes were included in analyses to prevent missing candidate mutations due to phaenotypical misclassification. Comparing the case and control, analysis of these genes revealed 196 unique intronic variants. Comparing the sequence of EIF2AK4 in the case and the healthy GSD revealed 124 unique variants, of which 9 were located in the 3`-UTR, 112 were intronic and 3 were exonic variants. The case was homozygous mutant for c.2961T>C and c.1266G>A, a heterozygous variation was found at c.2092G>A. Variant validation was performed by Sanger sequencing on amplified polymerase chain reaction products from genomic DNA using Platinum Taq Polymerase (Invitrogen). After exonuclease I treatment DNA sequence reactions were performed using BigDye v3.1 on, sequenced on an ABI3130XL and analyzed in Lasergene (version 12.0 DNASTAR). Four of the five additional GSD's, unknown for any form of respiratory stress and aged ≥ 10 years revealed the identical genotype as the case and therefore excluded these as causal variants for PVOD.
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pmc-6282289-1
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A 25-year-old white woman presented to our Emergency Department (ER) in October 2014 with a 2-month history of headaches, morning vomiting, memory deficits, and sleepiness, followed by psychomotor retardation, reduced vision, and progressive loss of autonomy in daily activities during the preceding week. Her first menstruation occurred when she was 13-years old and her periods were regular until 15-years old, when she developed secondary amenorrhea and galactorrhea. She reported that in a previous evaluation she had high PRL levels and was submitted to pituitary imaging. These complementary studies were performed at another hospital and these results were not available. She was treated with bromocriptine for 2 years (from 15-years to 17-years old) with clinical improvement. Since then, she maintained oligomenorrhea without galactorrhea recurrence, but she missed the follow-up appointment. She also had grade 2 obesity with a body mass index (BMI) of 35.3 kg/m2 and was treated with fluoxetine and loflazepate ethyl for a severe depression since her mother’s death 4 years earlier. She was an asymptomatic BRCA1 mutation carrier with heterozygous mutation c.2906delA (p.Asn969fs) in intensive cancer screening, because her family history was relevant for premature mortality due to breast cancer (mother and maternal aunt). At admission in our ER, she was hemodynamically stable, although a physical examination highlighted a depressive mood, marked psychomotor retardation, ataxia, and bilateral papilledema.
Laboratory assessment at admission revealed normal values for the blood count (except mild leukocytosis), coagulation, liver and renal function tests, and electrolytes. There were no other signs of infection and urinary drug screening was negative. She underwent an urgent cerebral computed tomography (CT) scan, which revealed a giant pituitary lesion, with a cystic/necrotic component, extending to her sphenoid and cavernous sinuses (causing internal carotid artery compression) and suprasellar, prepontine, and interpeduncular cisterns. The lesion compressed her optic chiasma, basilar trunk, protuberance, and mesencephalon and obliterated the third ventricle, leading to obstructive hydrocephalus (Fig. ). The results of a hormonal study were only available on the next day and revealed marked hyperprolactinemia (7615 ng/mL), central hypocortisolism, GH deficiency, normal thyroid function, and serum/urinary osmolality (Table ).
Despite the probable pituitary etiology, endocrine assessment was in progress and our patient had a space-occupying brain lesion of still unknown origin and an acute hydrocephalus with rapid deterioration of consciousness. She was submitted to surgery for insertion of a right frontal external ventricular drain (EVD), but the early postoperative period was complicated by sudden-onset anisocoria and left upper limb paresis. A CT scan revealed a de novo large frontal extradural hematoma (Fig. ), as a result of rapid decompression of the hydrocephalus. The hematoma was successfully removed by a new surgical procedure. Postoperatively, there was reversal of the new neurological deficits, without relapse or development of new symptoms.
When she was observed by an endocrinology physician, she had already been started on intravenously administered dexamethasone 4 mg twice a day for cerebral edema. It was decided to keep this long-acting systemic corticosteroid and to switch to an orally administered hydrocortisone as soon as possible. Given the diagnosis of a large pituitary lesion with marked hyperprolactinemia, our patient was given orally administered cabergoline 0.5 mg twice a week. One week after admission, the EVD was substituted with a medium-pressure ventriculoperitoneal shunt, leading to an additional slight reduction in the dimensions of the lateral ventricles. After stabilization and 12 days of cabergoline, pituitary magnetic resonance imaging (MRI) confirmed a giant prolactinoma (52 × 30 × 33 mm in dimensions) with solid and cystic components, maintaining moderate residual supratentorial enlargement and confirming the massive invasion previously described in the CT scan (Fig. ). During the in-patient management, short-term memory (assessed by Mini Mental State Examination) improved but our patient’s depressive mood was maintained. She was discharged on the 16th day under treatment with cabergoline 1 mg/week, hydrocortisone 30 mg/day in three divided doses (and progressive down-titration to 15 mg/day), fluoxetine 20 mg/day, and alprazolam 0.5 mg/day. She was referred to Endocrinology, Neurosurgery, and Neurophthalmology out-patient clinics.
One month after treatment with cabergoline, there was a 99.8% reduction in serum PRL levels (from 7615.0 ng/mL to 12.2 ng/mL). An ophthalmological examination performed only after discharge showed visual fields without signs of chiasmal compression. Two months after discharge, she underwent an ACTH stimulation test. Serum cortisol was 14.1 μg/dL and 43.9 μg/dL at baseline and after 60 minutes, respectively, excluding adrenal insufficiency; accordingly, hydrocortisone was withdrawn. Regarding the remaining pituitary hormonal profile, she had persistent GH deficit and central hypogonadism. Restoration of regular periods was achieved with an oral contraceptive pill. A mild elevated parathyroid hormone (PTH) level of 71.6 pg/mL (reference range 10–65) evoked the possibility of multiple endocrine neoplasia type 1 (MEN1). Bone densitometry revealed marked osteopenia of the lumbar spine with Z-score ≤ 2.0 (31% lower than expected). Total and ionized serum calcium levels were normal and PTH was normalized after vitamin D supplementation. However, genetic analysis was performed given the presence of an isolated sporadic giant prolactinoma in a young adult. AIP (encoding aryl-hydrocarbon receptor-interacting protein) and MEN1 (encoding menin) sequencing (without multiplex ligation-dependent probe amplification) did not detect a pathogenic mutation.
Our patient’s depressive syndrome progressively improved and psychiatric drugs were withdrawn after 3 months of cabergoline treatment. She also lost 20 kg with lifestyle modification during the last 3 years (current BMI of 27.9 kg/m2), contributing to an improvement in overall wellbeing. Given the detection of a pathogenic BRCA1 mutation, she started cancer screening at a young age in a breast cancer unit. Her screening combines breast self-examination, clinical breast examination and breast ultrasound, a mammography, and a transvaginal ultrasound. Up until now, the screening has been negative. Her sister is also a BRCA1 mutation carrier under cancer screening. Currently, there is no familial history of hyperprolactinemia or pituitary lesions.
Treatment with cabergoline 0.5 mg twice a week was continued. The drug was well-tolerated and cardiac safety was assured by a transthoracic echocardiogram without evidence of valvular heart disease or any other heart dysfunction. The last pituitary MRI revealed a tumor measuring 20 × 15 × 20 mm (Fig. ). She currently attends regular follow-up visits, with normal PRL levels and significant tumor shrinkage during this 3-year follow-up period.
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pmc-6282338-1
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Patient 1 is a 72-year-old female who was initially diagnosed in 1997 with a well differentiated G3 (Ki-67 20%) metastatic jejunal NET. Her primary tumor was resected after diagnosis and a liver transplant was performed in 1998 for bulky symptomatic liver metastases. She has received a series of therapies including octreotide, lanreotide, and everolimus for her carcinoid syndrome (CS) and disease control. In May 2017, a 68Ga-DOTATATE PET-CT revealed somatostatin receptor (SSTR) avidity in bilateral orbits although she was asymptomatic from a visual symptom standpoint (Fig. a and b). In March 2018, the patient was hospitalized for preseptal cellulitis. During the hospitalization, she underwent a CT scan which revealed focal thickening of the right medial rectus and left lateral rectus muscles. Opthalmology evaluated her and felt the cellulitis was unrelated to her orbital masses. Once her infection resolved she underwent biopsy of a rectus muscles mass which confirmed orbital metastases from her NET primary. Patient did not have any worsening visual symptoms or signs (limited extraocular motility, visual field deficits or proptosis).
177Lu-DOTATATE PRRT was initially recommended; however, this was not pursued due to the patient’s poor renal function. Radiation therapy was then considered but given the proximity of the lesions to other critical structures and her lack of symptoms, this too was deferred in favor of close surveillance. In July 2018, she started on capecitabine and temozolomide for better systemic control of her NET, which also involved her liver, pancreas, bone and intra-abdominal lymph nodes. On a follow-up orbital MRI in July 2018, her lesions were noted to be stable.
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pmc-6282338-2
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Patient 2 is a 68-year-old male who was initially diagnosed with a well-differentiated G2 (Ki-67 10%) metastatic ileal NET in 2012. Post-resection of his primary, the patient began treatment with octreotide. Eventually, he enrolled on a clinical trial with 177Lu-DOTATATE PRRT. During a hospitalization in November 2017, while admitted for abdominal pain, he developed left peri-orbital swelling. This prompted an orbital MRI which demonstrated bilateral extraocular masses in his recti muscles (Fig. a). A subsequent biopsy confirmed metastatic NET. To manage his acute periorbital swelling, he was first treated with corticosteroids and later completed image-guided radiation therapy (IGRT) to 44 Gy to bilateral orbits in December 2017. The patient had a post-treatment MRI scan which demonstrated a decrease in signal abnormality and enhancement in the previously visualized lesions (Fig. b). Post-radiation, patient continued octreotide until his death in February 2018 due to progressive disease.
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pmc-6282338-3
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Patient 3 is a 63-year-old female who was initially diagnosed with a well differentiated metastatic ileal NET in 1994. She was found to have G3 (Ki-67 22%) disease on later biopsies. She had stable disease controlled on octreotide until 2014 when she had disease progression which required everolimus, multiple hepatic artery embolizations and debulking of bulky adenopathy in her right paratracheal region. She underwent her first 68Ga-DOTATATE PET-CT in April 2015 which revealed bilateral extraocular masses in her right medial and left infraorbital rectus muscles. She was asymptomatic initially from these lesions; however, during her initial visit at VUMC in June 2018 for consideration of 177Lu-DOTATATE PRRT, due to persistent CS, she mentioned worsening diplopia and visual acuity. A pre-treatment 68Ga-DOTATATE PET-CT was repeated which revealed increased SSTR avidity in the recti at the site of the previously known lesions (Fig. a and b). Although she was planned for earlier, in the setting of disease-related complications, her anticipated start date for 177Lu-DOTATATE PRRT is December 2018.
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pmc-6282338-4
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Patient 4 is a 72-year-old gentleman who was diagnosed with a well differentiated G2 metastatic ileal NET in 2006. He started monthly octreotide shortly thereafter in 2007. He was incidentally noted to have a left lateral rectus mass in March 2007 during a brain MRI. This lesion was monitored with serial MRI and remained stable until 2015 when it began to grow (Fig. c). The patient developed progressive diplopia and proptosis in 2015 which prompted an evaluation by radiation oncology. He received stereotactic radiosurgery (SRS) administered over 5 fractions to the site in February 2015 at VUMC and his diplopia and proptosis resolved within several months of treatment completion. He has unfortunately developed complications from his other sites of metastatic involvement including right sided nephrostomy tube placement from ureteral obstruction and an end colostomy due to recurrent small bowel obstructions from mesenteric tethering. His disease remains radiographically stable on his 68Ga-DOTATATE PET-CT from August 2018 (Fig. a and b).
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pmc-6282338-5
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Patient 5 is a 61-year-old female who was diagnosed with a well differentiated G2 (Ki-67 5%) metastatic small intestine (not otherwise specified) NET in February 2010. She remained symptom free until April 2014 when she was started on monthly octreotide. In the setting of progressive disease, she subsequently received sunitinib and everolimus. She began to develop progressive diplopia and right ocular pain in August 2016. This prompted an orbital MRI which revealed bilateral recti masses in the right lateral and superior left medial muscles. She was evaluated by radiation oncology shortly thereafter and was treated with IGRT to 52Gy, which completed in October 2016. Although her right ocular pain improved, she had persistent diplopia. Her post-treatment orbital MRI in January 2017 revealed a mild increase in size of her right lateral rectus mass (Fig. a). She was then started on capecitabine in January 2017 on a two week on, one week off regimen schedule. Patient also established care with ophthalmology at this time. She achieved stable disease in her orbits with symptomatic improvement and did not demonstrate any evidence of visual field deficits. She continues capecitabine and her last MRI in July 2018 revealed ongoing shrinkage of her right lateral rectus mass (Fig. b); her recent 68Ga-DOTATATE PET/CT from October 2018 shows residual SSTR avidity within her bilateral recti muscles (Fig. c and d).
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pmc-6282365-1
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A 57-year-old woman visited our clinic complaining of blurred vision in both eyes that had started 4 months previously. She had been diagnosed with SLE and had been on HCQ therapy (200 mg/d) for the past 20 years. The cumulative dose of HCQ was approximately 2190 g. She did not report any history of systemic diseases that could be associated with ME, such as diabetes and hypertension. Her best-corrected visual acuity (BCVA) was 20/50 in both eyes and fundus examination showed midperipheral pigmentary changes in both eyes (Fig. a). Visual field (VF) examination showed field constriction on the grayscale map at baseline (Fig. b). Fundus autofluorescence (FAF) showed bilateral pericentral hypo-autofluorescence (Fig. c). Optical coherence tomography (OCT) revealed photoreceptor defects (yellow arrowheads) in the pericentral area and cystoid spaces (red arrowhead) in the macula of both eyes (Fig. d). Based on her medical history, characteristic photoreceptor defects on OCT, and corresponding findings on FAF and VF examination, she was diagnosed with HCQ retinopathy associated with CMO. Accordingly, HCQ treatment was discontinued by the prescribing physician.
Oral acetazolamide (250 mg once a day) therapy was started. One month later, OCT revealed partial resolution of CMO in the right eye, as demonstrated by decrease in the size of cystoid spaces (Fig. ) and in central foveal thickness (CFT) from 418 to 335 μm, and complete resolution of CMO in the left eye (CFT decreased from 338 to 255 μm). Her BCVA was 20/50 in the right eye and 20/30 in the left. However, her rheumatologist recommended discontinuation of oral acetazolamide due to the risk of aggravation of the patient’s underlying renal issue, lupus nephritis, as her renal function, as measured by glomerular filtration rate, had decreased from 70 to 56 mL/min/1.73 m2 during the one-month period. We discontinued systemic acetazolamide accordingly; topical dorzolamide 2%/timolol maleate 0.5% fixed combination (Cosopt; MSD Korea) twice daily was started in its stead.
Three months later, she complained of worsening of blurred vision. Her BCVA was 20/50 in both eyes, and OCT revealed aggravated CMO, as demonstrated by an increase in CFT, to 427 and 348 μm in the right and left eyes, respectively (Fig. ). After explaining to her the possible therapeutic options, we treated her with intravitreal injection of 0.7 mg dexamethasone implant (Ozurdex) and discontinued topical dorzolamide in the right eye.
One month after the therapy, the patient reported that her blurred vision had improved; her BCVA was 20/30 in the right eye and 20/40 in the left. Fluorescein angiography (FA) showed decreased leakage in the right eye in the late phase compared to the untreated, fellow eye (Fig. ). The OCT also revealed regression of CMO in the right eye. CFT in the right eye was decreased to 284 μm, whereas that in the left showed no remarkable change (from 348 to 347 μm). The resolution of CMO persisted up to the last visit, 2 months after the dexamethasone implant was placed. Her intraocular pressure was 15 and 11 mmHg in the right and left eye, respectively, and no other ocular complication was noted at the last visit.
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pmc-6282367-1
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A 6-year old intact male Plott hound dog was presented to a veterinarian on September 18, 2014 with severe self-induced facial trauma including unilateral periocular swelling, and intense pruritus. The dog had participated in a benefit wild hog rodeo in Wilcox County, Alabama from September 11–13, 2014. During the course of the three-day spectator event that included dog, trapping, and stalk hunting categories, the dog was involved in the capture and removal of 13 feral swine. On September 19, 2014, the dog had further self-induced trauma, intense pruritus, erythema, and vomited blood. The animal was vocalizing and self-mutilation of the facial region resulted in severe and diffuse lacerations and bleeding. The attending veterinarian administered morphine, but the clinical presentation including facial self-mutilation remained unaltered. By the next day (September 20th- Day 9 or 10), the dog was dead.
Fresh and 10% formalin-fixed sections of cerebrum, cerebellum, brainstem, liver, spleen and tonsil from the dog were submitted to Iowa State University Veterinary Diagnostic Laboratory (ISUVDL) in Ames, Iowa for testing. Histopathologic examination was performed on all formalin-fixed tissues. Fresh tissue sections of cerebrum, cerebellum, and brainstem were submitted for real-time polymerase chain reaction (PCR) testing for PRV, and virus isolation [, ].
A direct fluorescent antibody test was also conducted on brain tissue for detection of rabies antigen []. Though no antigen was detected, rabies testing was considered inconclusive because the cerebellum and brainstem, which are the preferred tissues for rabies testing, were unavailable because they had been used for PRV testing. Histopathologic examination of the liver and spleen did not reveal any significant lesions, but moderate lymphoplasmacytic encephalitis was detected in the brainstem. Virchow-Robin spaces were often infiltrated and expanded by low to moderate numbers of lymphocytes, plasma cells, and rare macrophages (Fig. ); multifocal areas of gliosis were also observed. Endothelial cells within affected vessels were moderately enlarged (hypertrophied). Occasionally neurons and astrocytes contained an intranuclear eosinophilic inclusion that often peripheralized the chromatin (Fig. ). Tonsil was negative but brain tissue tested positive (cycle threshold (Ct) = 30; value < 40 considered positive) for PRV by PCR. Pseudorabies virus was isolated from central nervous system tissue in porcine kidney-15 cells, and confirmed by immunofluorescence staining (Fig. ). Based on the clinical presentation, histologic lesions, PCR results, and virus isolation, the dog was diagnosed with PRV.
Two hunters (Hunters A and B) used nine mixed breed dogs (six belonging to Hunter A, and three to Hunter B) to hunt feral swine in Sevier county, Arkansas on December 13, 2014 (Day 0). According to the hunters, the six dogs owned by Hunter A caught and bit a young female feral swine multiple times on the face and body prior to the animal being dispatched. Hunter B’s three dogs did not have direct contact with the feral swine during the hunt. However, the three dogs along with the hunter’s three other dogs (six total) reportedly consumed the offal once he finished butchering the animal at his house. On December 17, 2014 (Day 4), one of Hunter A’s dogs refused to eat, scratched its head profusely, and was whining and moaning. By December 18, 2014 (Day 5), three of Hunter A’s dogs had swollen heads and appeared to have vomited prior to dying. Two more of Hunter A’s dogs had diarrhea. Two of Hunter B’s dogs were dead and one was sick. On December 19, 2014 (Day 6), Hunter A had one dog that started vomiting, and another that was salivating excessively and then died a few hours later. Hunter B’s sick dog was euthanized because its symptoms were so severe. Two more of Hunter B’s dogs died on December 20, 2014 (Day 7), and another one was sick and then died on December 21, 2014 (Day 8). One of Hunter A’s dogs (directly exposed) was sick, but recovered by December 29th (Day 16). Hunter A had one dog that was directly exposed but failed to develop clinical signs. In the end, Hunter A lost four of six dogs that were directly exposed to the feral swine, and Hunter B lost all six of his dogs that consumed the offal.
Samples from one each of the two hunter’s dogs (one male and one female) that displayed compatible signs of PRV on December 19th and 20th respectively, and the feral swine that had been hunted were initially submitted to the Arkansas Livestock and Poultry Commission Veterinary Diagnostic Laboratory (ARVDL) in Little Rock, Arkansas. Specifically, a fecal swab, nasal swab, and serum sample from the female dog as well as the carcasses of both dogs, and the head, first cervical vertebra, and some muscle tissue from the feral swine were submitted for examination. The brain (except the frontal lobe), a section of spinal cord, and skeletal muscle tissue were fixed in formalin for histopathology. The frontal lobe and muscle tissue from the feral swine, the brain stem, trigeminal nerve, and serum from the female dog, and a sagittal section of the brain and the trigeminal nerve of the male dog were forwarded to ISUVDL for real-time PCR testing, and virus isolation. Serology was conducted with the PRV gB enzyme-linked immunosorbent assay (ELISA; HerdCheck, IDEXX Laboratories, Inc. Westbrook Maine, USA) at ISUVDL.
Histopathology conducted on the feral swine tissues was consistent with PRV. Attempts to identify unequivocal viral inclusions bodies were unsuccessful, likely due to the subjective and multifocal nature of such findings. One of the dogs had encephalitic lesions that were compatible with PRV. The other dog did not have lesions, but had inflammation in the intestine and the liver. However, multifocal areas of necrosis or eosinophilic intranuclear inclusions were not observed. The PCR results for the brain tissue from both dogs (Ct =40.0, 40.8 respectively) and the feral swine (Ct = 38.7) were close to the cut-off value, and consequently were considered suspect positive. The single serum sample was antibody negative.
The U.S. Department of Agriculture’s Wildlife Services (WS) collects blood from approximately 3000 feral swine annually across the U.S. for wildlife damage management purposes. A subset of these are tested for exposure to various pathogens. Due to funding, samples are collected based on a fiscal year from October 1st to September 30th of the following year. Sera are tested routinely for exposure to PRV due to the economic and regulatory concerns related to a detection in the commercial swine industry. We examined the antibody results of 1965 feral swine sera collected in Alabama (n = 755) and Arkansas (n = 1210) from 2010 to 2017 to determine PRV serologic status of feral swine in those states.
Sera were tested at the Washington Animal Disease Diagnostic Laboratory in Pullman, Washington, the Wisconsin Veterinary Diagnostic Laboratory in Madison, Wisconsin, or the Kentucky Federal Brucellosis Laboratory in Frankfort, Kentucky using the PRV gB ELISA (HerdCheck, IDEXX Laboratories, Inc. Westbrook Maine, USA). Testing was performed according to the manufacturer’s instructions.
Maps of feral swine serology results were created in ArcGIS version 10.5 (ESRI, Redlands, California, USA). The PRV antibody prevalence for each county in Alabama (Fig. ) and Arkansas (Fig. ) was calculated, and then color coded by the following categories: no samples collected, no positive samples, 1–5%, 6–10%, 11–15%, 16–20% or > 20%. The cases described herein where dogs died from PRV after direct or indirect exposure to feral swine are marked with a star on the maps (Figs. and ).
The PRV antibody prevalence in feral swine from 2010 to 2017 in Alabama was 13.9% (95% confidence interval (CI): 11.6–16.6), and 13.1% (95% CI: 11.3–15.1) in Arkansas. There was wide-ranging variation in antibody prevalence between counties (Figs. and ) and years (Table ).
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pmc-6282376-1
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The patient was a 79-year-old Japanese woman, who provided informed consent for publication of anonymized case details. She had a history of high blood pressure, which had been treated with 80 mg/day valsartan and 5 mg/day amlodipine since the age of 55. No family history of epilepsy or movement disorders was noted. She was diagnosed with bipolar disorder when she was 64 years of age, and treatment was started with 200 mg/day lithium carbonate and 400 mg/day sodium valproate. At least four depressed and five manic phases appeared between ages 64 and 79 years. At 79 years of age, she was admitted to the authors’ hospital with serious depression. Three months before the admission at 79 years of age for severe depression, olanzapine was used to treat mania for 6 weeks with a maximum dose of 12.5 mg/day. Two weeks before the admission, 12.5 mg/day quetiapine was added to treat depression. There were no adverse effects including extrapyramidal symptoms during her previous treatment. Once 15 mg/day MTZ was administered, quetiapine was tapered off within 7 days. Three days after administration of 15 mg/day MTZ, she exhibited symptoms of parkinsonism including short-step gait, rigidity, and tremor. Moreover, 12 days after initiation of MTZ administration, when the dose level had been raised to 22.5 mg/day for 5 days, she presented with an abnormal maintained posture of the trunk, which had a lateral deviation to the right side. No other localizing signs were found, and no changes had been made to her usual medication after the introduction of MTZ. Blood and biochemical screening, and brain computed tomography were normal. Although her cognitive function was preserved (Mini-Mental State Examination score 22/30), the possibility of developing Parkinson’s disease or Lewy body disease was considered. Brain perfusion single-photon emission computed tomography with 99mTc-ethyl cistainate dimer revealed mild decreases in cerebral blood flow in both sides of the frontal lobe. Myocardial metaiodobenzylguanidine (MIBG) scintigraphy revealed no dysfunction in the sympathetic nerves. Dopamine transporter imaging with 123I ioflupane did not reveal nigrostriatal degeneration. From the results of these imaging tests, the possibility of idiopathic Parkinson’s disease or Lewy body disease was ruled out. The patient was diagnosed with Pisa syndrome and the MTZ was quickly tapered off; 3 days later, dystonia completely disappeared.
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pmc-6283093-1
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A 75-year-old nonsmoking woman presented to our emergency department due to progressive shortness of breath for 3 days. She denied fever, abdominal pain, diarrhea, bloody stool, or tenesmus. She had been diagnosed with ulcerative colitis at our hospital and received mesalazine 2 g per day for 2 years and 8 months.
Her initial vital signs were a blood pressure of 131/79mm Hg, pulse rate of 80 bpm, respiratory rate of 28/min and body temperature of 36.0°C. On physical examination, chest auscultation revealed coarse breathing sounds with bilateral crackles. Laboratory investigations revealed a white blood cell count of 10,600/μL with 79% neutrophils, hemoglobin level of 9.7 g/dL, and platelet count of 464,000/μL. Biochemistry profile showed an elevated level of C-reactive protein (79.7 mg/L), mildly impaired renal function (blood urea nitrogen level of 21.2 mg/dL and creatinine level of 1.23 mg/dL), and a normal alanine aminotransferase level (13 U/L).
Electrocardiography showed a normal sinus rhythm, and echocardiography of her heart was normal (left ventricular ejection fraction of 77%). Chest radiography revealed increased infiltration with patchy consolidations in both lungs and lower lobe predominance (Fig. A). She was then given oxygen via a nasal cannula. Under the impression of community-acquired pneumonia, she received antibiotic treatment and was admitted to our chest ward.
Episodic high fever was noted since admission, and chest radiography showed progression of bilateral infiltrates. Further investigations were thus warranted, and a computed tomography (CT) scan showed diffuse peribronchial and subpleural consolidations in bilateral lungs with minimal interstitial thickening. The differential diagnosis included cryptogenic OP, acute interstitial pneumonia, and metastasis (Fig. A). In the following days, her respiratory condition deteriorated, and she was given noninvasive ventilator support (bi-level positive airway pressure, BiPAP) (Fig. B). Under the consideration of mesalazine-induced OP, mesalazine was discontinued on the 8th day of admission, and intravenous hydrocortisone 100 mg Q6H was started. She was then transferred to our medical intensive care unit.
We performed infection surveys for viruses, fungi, and mycobacteria. Due to positive cytomegalovirus (CMV) serologic tests including both IgM and IgG, intravenous ganciclovir was given for 7 days until the results of CMV antigenemia assays and qualitative CMV polymerase chain reaction (PCR) assays were negative. We also surveyed her autoimmune condition and vasculitis markers, and positive results of antinuclear antibodies and p-ANCA (antineutrophilic cytoplasmic antibodies, perinuclear pattern) were attributed to ulcerative colitis.
Her respiratory condition improved in the following days, although only a mild improvement was shown on serial chest plain films (Fig. C). Hydrocortisone 100 mg Q6H was maintained for 8 days and then tapered. BiPAP was shifted to an oxygen mask in the 2nd week of ICU admission.
Bronchoscopy with bronchoalveolar lavage (BAL) was performed, and a specimen was sent for bacterial, fungal, and viral cultures, PCR testing of tuberculosis and Pneumocystis jirovecii, galactomannan, total and differential cell counts, CD4/CD8 ratio, and cytology. The results showed 81% macrophages, 10% lymphocytes, 8.2% neutrophils, and 0% eosinophils, with CD4 and CD8 counts of 24.6% and 22.7%, respectively (CD4/CD8 ratio: 1.08). The BAL culture showed growth of Actinomyces odontolyticus, which may have been caused by aspiration of oropharyngeal secretion. A transbronchial lung biopsy was done, and the pathology report showed mild chronic inflammation with OP (Fig. ). There was no evidence of granuloma, malignancy, or vasculitis.
The patient was discharged on the 28th day of hospitalization with oral prednisolone 20 mg per day. She was regularly followed up at our chest out-patient department. One month after discharge, she had greatly reduced exertional dyspnea, and a chest plain film showed substantial improvements (Fig. D). A follow-up chest CT scan 3 months after disease onset showed resolution of most of the infiltration (Fig. B).
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pmc-6283186-1
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In spring of 2013, a 32-year-old woman sought medical attention at the Jilin University First Bethune Hospital with complaints of intermittent pruritus and fatigue. Liver function tests revealed significantly increased levels of γ-glutamyltransferase (γ-GT, 468 U/L) and alkaline phosphatase (ALP, 968 U/L). The patient was diagnosed with hypothyroidism 3 years ago due to the use of I31I therapy and was treated with euthyrox (250 mg/d). She had no hypertension, diabetes, special drug, hepatitis, or consumption of alcohol history, as well as no any family history. No positive signs were observed on physical examination. Serology for hepatitis virus A, B, or C was negative. Immunologic tests showed that serum antinuclear antibodies were positive (1:640), accompanied by increased concentrations of serum immunoglobulin M (IgM, 5.01 g/L) and the presence of an anti-mitochondrial M2 antibody (AMA-M2, >200 RU/mL); however, the anti-Ro (SS-A) and anti-La (SS-B) antibodies were negative. A liver biopsy showed stage II PBC (Fig. A and B). The patient was eventually diagnosed with PBC and was treated with ursodeoxycholic acid (UDCA, 250 mg/d). The cholestatic enzyme levels and symptoms of pruritus were significantly improved.
In April 2016, the patient visited our hospital because of repeated fatigue for 2 years. Liver and kidney function, serum glucose levels, and blood routine tests were normal. Laboratory tests mainly revealed that the level of serum potassium (2.42 mmol/L) was low. The patient was treated intermittently with potassium citrate. However, the therapeutic effect was not satisfactory, and the cause of low potassium was unknown.
In July 2016, the patient visited the superior hospital for further treatment. She weighed 43 kg, and her height was 155 cm. Blood tests showed the following: pH, 7.347; PaCO2, 33.1 mm Hg; HCO3−, 17.7 mmol/L; PaO2, 103 mm Hg; Na+, 141 mmol/L; K+, 3.4 mmol/L; Cl−, 113 mmol/L; Mg2+, 0.94 mmol/L; serum creatinine, 70 μmol/L. In addition, the plasma anion gap (AG) was normal: AG = [Na+] – [Cl− + HCO3−] = 141 – (113 + 17.7) = 10.3 mmol/L (normal, 10–14 mmol/L). Urine routine showed a pH of 7.5, and 24-hour urine analysis demonstrated that the urine potassium concentration was 94 mmol/24 h. The aldosterone renin ratio was normal. Baseline data of the patient are summarized in Table . An abdominal ultrasound showed evidence of cirrhosis and gallstones. Adrenal CT showed bilateral nephrocalcinosis and no tumor. Whole-body bone mineral density was 0.99 g/cm2 with a T score of −1.3. According to the patient's history and related test results, she was finally diagnosed with RTA in PBC and was then treated with a combination of UDCA, potassium citrate, calcium supplements and activated vitamin D. One year after the treatment, the patient's liver function remained stable, and the clinical symptoms were significantly improved.
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pmc-6283190-1
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A 57-year-old man underwent gastroscopy because of eating obstruction. He had history of surgery for gastric cancer. The esophagus computed tomography (CT) scan (Fig. ) was normal before gastroscopy. Laboratory analysis revealed the following: serum RBC 4.7cell/L; Hgb 138 g/L; HCT 42.8% when just hospitalized. On the 6th day after admission, the endoscopic jejunal tube placement was performed under the gastroscope, and parenteral nutrition was performed. There was no discomfort after operation. After 25 days of operation, the nutrient tube was blocked and removed. It is planned to further perform gastroscopy jejunal tube placement.
During the gastroscopy process, the patient suddenly suffered from nausea and vomiting, felt severe pain in the chest and lower back, and felt a compression pain in the neck. A physical examination revealed subcutaneous emphysema in the thoracolumbar segment and face and neck, with a crepitus. An emergency CT scan of the chest and neck showed extensive subcutaneous emphysema in the chest and back, a large amount of emphysema in the mediastinum, a small amount of left pleural effusion, no pneumothorax (Fig. ). Spontaneous esophageal rupture was diagnosed. Laboratory analysis revealed that serum RBC 3.3cell/L; Hgb 100 g/L; HCT 28.5% after spontaneous esophageal rupture.
Due to the poor general condition of the patient, the risk of surgery was high, and endoscopic treatment was preferred. A long strip rupture in esophagus which was 28–34 cm away from the incisors was seen by endoscope. A small amount of blood stasis was applied, and a hemostatic clip was placed from the anal side to the mouth side and a large Boston's clip was stitched. A total of 14 titanium clips were used for suturing the split (Fig. ). Postoperative fasting and strong anti-infection treatment were performed. Esophageal angiography was performed on the 11th day after operation. No contrast agent leakage or exacerbation of emphysema was observed (Fig. ).
Recheck chest CT was performed after the operation. 17 days later, emphysema and subcutaneous emphysema disappeared (Fig. ). Laboratory analysis revealed serum RBC 3.98cell/L; Hgb 113 g/L; HCT 33.6% 20 days later after the operation. Recovery was complicated by renal failure, leading to death 61 days after admission.
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pmc-6283191-1
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A 51-year-old man presented with hematochezia, thin and frequent defecation for 2 months before being admitted to the hospital. Colonoscopy showed a cauliflower-like mass in the rectum 5 cm above the anus, occupying 4/5 of the rectal circle. The biopsy pathology suggested “adenocarcinoma”. The patient had no medical or familial history. He had smoked 20 cigarettes daily for 30 years and drank white wine 100 g daily for 2 years. He was admitted with normal vital signs and a BMI (Body Mass Index) of 20.6 kg/m2. Digital palpation found a hard mass 5 × 5 cm in size and slight intestinal stenosis. Routine blood, biochemical test, blood gas analysis, and blood coagulation function found no obvious abnormality. His CEA level was 2.34 ng/mL and CA19–9 10.27 U/ml. Chest high-resolution computed tomography (HRCT) found a localized emphysema in bilateral lungs. Abdominal enhanced computed tomography (CT) revealed non-homogeneous thickening and enhancement of the rectal wall in the middle and lower segment with no enlarged peripheral mesenteric lymph nodes or distant metastases.
The patient was diagnosed as cT4aN0M0 rectal cancer. Multiple disciplinary team (MDT) was held to discuss whether neoadjuvant therapy should be performed. In the view of incomplete intestinal obstruction, the patient′s suffering and his insistence to receive operation as soon as possible, laparoscopic radical resection of rectal cancer (Dixon) and protective end ileostomy was carried out 4 days after his admission. The operation was successful with only 10 ml of blood loss recorded during the procedure. The patient returned to ground activity in 24 h, exhausted and defecated from the orifice in 48 h. His temperature remained within normal range; his white blood cell (WBC) and C-reactive protein returned to normal in 5 days. The incision, as well as the stoma and its surrounding skin, healed well 3 days after operation.
On day 7, the drain pipe was removed after CT scan showing no evidence of leakage or infection. On day 8, routine blood test showed the WBC count jumped to 20.1 × 109/L, with neutrophil ratio up to 82.5%; no fever or pain occurred. Only a tiny skin irritation on the upper side of stoma was found, where the supporting plastic loop was located (Fig. ). The patient was diagnosed with peristomal dermatitis. The loop was adjusted, and the ostomy bag model was changed (from Alterna 02833 + 01698 Coloplast into 05985 Coloplast) in order to increase the frequency of stoma observation. No obvious abnormality in nutritional status or electrolyte balance occurred. On day 10, both upper and lower side of the stoma saw red and edema skin with deep ulcer and pus (Fig. ). The supporting loop was removed immediately and pus was cleared until fresh tissue emerged. The patient was told to take food with less liquid and montmorillonite powder was also prescribed to make the fecal less watery. At daytime, the stoma was kept uncovered and cleaned as long as any fecal fluid outflew from the orifice. Ostomy bag was only used at night to guarantee adequate sleep time. Zinc oxide ointment, Coloplast Brava 1907 skin care powder and Prep Barrior Film 62041 were also used to isolate the skin from the irritant. The upper side wound ulcerated to an area of 4 cm in diameter but the lower one healed 6 days later (Fig. ). Besides, the skin 1–2 cm peripheral to the margin of the ulceration showed a color of dark red. A catheter was inserted to the proximal end of the ileostomy, and then connected to the vacuum aspiration with continuous low negative pressure. The temperature of the patient remained normal and the pain from the wound was slight except when we cleared the necrotic tissue. WBC count declined to 12.0 × 109/L, with neutrophil ratio 80.7% after mezlocillin was used for 7 days. One more week later the ulcer area increased, taking up almost the whole area around the orifice (Fig. ). A lot of pus moss covered the surface and obvious purulent drainage exuded from the wound edge. Debridement of the involved abdominal wall was performed under general anesthesia. Infective tissue surrounding the ileostoma was completely resected deep into the fascia superficialis layer, paving with vacuum sealing draina (VSD) (Figs. and ). On day 37, when the VSD was removed, the wound came to us with fresh granulation tissue as well as some purulent secretion. The lower left side of the wound saw a small area of pus moss again, and necrosis in the upper right side (Fig. ). On day 41, the same situation happened as we had seen before (Fig. ). So the burn surgery specialist suggested closure of the stoma before doing dermatoplasty. Considering it had been 40 days since LAR and the patient recovered well except for the peri-stoma dermatitis, we did an operation to close the ileostoma and debride the infected abdominal wall again under general anesthesia (Fig. ). After that, the wound healed rapidly without any signs of infection. Burn surgery specialist then performed harvesting grafts from the scalp and abdominal autologous skin transplantation on day 55. The patient was discharged 60 days after the first surgery and 5 days after the last one (Fig. ). After 18 months of follow-up, the skin graft healed well without any infection, and the tumor did not recur or metastasize.
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pmc-6283199-1
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A 48-year-old premenopausal woman was referred to local hospital for the presence of a left breast mass. Needle biopsy analysis was performed and an infiltrating ductal carcinoma with ER-negative, PgR-negative, and HER2-negative was diagnosed. The clinical examination showed giant tumor of the left breast and chest wall metastasis, together with ulcer and infection (Fig. A). Multiple metastases were detected in left supraclavicular fossa, bilateral axilla, anterior abdominal wall lymph node and left cervical lymph node in positron emission tomography/computed tomography. The tumor stage was cT4N1M1. Considering both the histologic characteristics and disease burden, chemotherapy and anti-angiogenesis therapy were performed. The treatment was initiated with 4 courses of bevacizumab 7.5 mg/kg q2w + paclitaxel 80 mg/m2 q3w followed by 2 courses docetaxel 35 mg/m2 q3w + bevacizumab 7.5 mg/kg q2w. The investigations showed a remarkable tumor regression. However, Grade 3 hematological toxicities were recorded and the treatment was stopped. Then, bevacizumab 7.5 mg/kg q2w and carboplatin 550 mg q3w was administered for 6 cycles. After that, a significant improvement of the cutaneous lesion was observed while the treatment was interrupted for the patient's poor compliance treatment due to the grade 3 leucopenia (Fig. B). Taking her leucopenia into consideration, 7.5 mg/kg q2w bevacizumab and cisplatin 70 mg/m2 q3w were administered. The skin involvement showed signs of aggression after 1 cycle. Radiotherapy was then performed to achieve local control. Xeloda 1 g bid was given for 2 weeks followed by bevacizumab 400 mg q2w and xeloda 1 g q3w from the next 1 year. Considering the patient's response to bevacizumab, 7.5 mg/kg q2w bevacizumab and gemcitabine 1000 mg/m2 q3w were given. A rapid improvement of the skin involvement was then observed. At the most recent follow-up (46 months from the start of treatment), a remarkable improvement of the chest wall cutaneous lesion was observed (Fig. C).
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pmc-6283207-1
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The patient was a 22-year-old unmarried man who worked in construction. He had lived in a basement for a long time before developing his symptoms. The patient began experiencing coughing and expectoration that did not resolve through self-medication; he thus visited Xuzhou Central Hospital on June 29, 2017. Chest computed tomography (CT) showed inflammation in both lungs. The patient then visited the Hai’an County People's Hospital, where he was diagnosed with lung infection and was prescribed moxifloxacin. No significant improvements in cough and expectoration were observed, and the patient developed a fever (his highest temperature was 39.3 °C) along with bloody sputum, and his eosinophil count continuously increased to a maximum of 7.47 × 109/L. Cytological examination of his bone marrow indicated HES (Fig. ); no fusion gene detection was performed, and examinations of extractable nuclear antibody series, vasculitis, nephropathy-related antibodies, immunoglobulins, and complement showed no abnormal results. After ruling out allergic pneumonia and vasculitis-related pneumonia caused by drugs and parasites, the patient was deemed to have acute eosinophil-associated pneumonia, and was thus treated with additional methylprednisolone starting on July 14, 2017. His coughing and expectoration improved while his body temperature decreased. On July 17, the patient experienced abdominal distension and periumbilical pain with persistent colic that progressively worsened; he also had nausea and vomiting of the contents of the stomach. Physical examination indicated periumbilical tenderness as well as rebound tenderness. Plain abdominal radiography in an upright position showed no obvious abnormalities, and the patient was treated with acid suppression, spasmolysis, and induced defecation. The patient also had elevated D-dimer, and mesenteric arteriovenous thrombosis could not be ruled out; hence, he was administered low molecular weight heparin for anticoagulant treatment, but no significant improvements of his abdominal symptoms were observed. On July 19, the patient experienced palpitations, nausea, hematemesis, and hematochezia combined with decreased blood pressure and a heart rate of 179 beats/min (the latter were evidence of hemorrhagic shock caused by gastrointestinal bleeding). The patient was treated with blood transfusion, fluid infusion, and norepinephrine to maintain his blood pressure. Blood examinations showed that fibrinogen levels decreased to 0.18 g/L and D-dimer levels were 40 mg/L; abdominal CT indicated thrombosis in the portal and superior mesenteric veins.
As the patient was now in critical condition, he was admitted to our hospital for treatment on July 19. The patient's test indicators before his admittance are shown in Table . He had previously been healthy, and had no history of diseases such as allergic rhinitis, urticaria, or bronchial asthma nor of allergies to drugs or foods. He also had no family history of thrombotic diseases. Upon admission, he had a body temperature of 37.4 °C, heartrate of 140 beats/min, respiratory rate of 38 breaths/min, blood pressure of 130/80 mmHg (with norepinephrine 10 μg/min, dopamine 7 μg/kg min, vasopressin 2 U/h), and peripheral capillary oxygen saturation of 96%. The superficial lymph nodes were normal, and there was no obvious skin rash anywhere on his body. However, he had an obvious abdominal bulge, and the abdomen itself was soft with periumbilical tenderness, no rebound pain, positive mobility dullness, and weak bowel sounds. On post-admission examination, the patient's tumor markers were negative; moreover, all rheumatoid factors as well as anti-nuclear, anti-histone, anti-double strand DNA, anti-nucleosomal, anti-Sjogren syndrome, anti-scleroderma, anti-phospholipid, and anti-neutrophil cytoplasmic antibodies were negative. A fecal test (performed at another hospital) was negative for parasites and eggs. The results of a coagulation test were as follows: prothrombin time, 63.0 seconds; international normalized ratio, 5.48; activated partial thromboplastin time, 303.70 seconds; antithrombin 3, 69.8%; fibrin degradation products, 137.3 mg/L; and D-dimer, 67.55 mg/L. Enhanced abdominal CT showed multiple emboli in the portal, right hepatic, splenic, and superior mesenteric veins. Furthermore, a portion of the small intestine was enlarged, and the intestinal wall was thickened due to edema (Fig. ). Chest CT revealed low perfusion zones in pulmonary tissue and bilateral atelectasis of the lower lobes with possible pulmonary infarction. His preliminary diagnoses at admission was HES; thrombosis in the portal, superior mesenteric, right hepatic, and splenic veins; gastrointestinal bleeding; and hemorrhagic shock.
The patient's treatment regimens after admission were as follows:
Methylprednisolone was intravenously injected at an initial dose of 40 mg q6 hours; however, after blood tests revealed a low eosinophil count, the methylprednisolone dose was gradually reduced to 20 mg/d.
Plasma exchange and hemofiltration was performed. The plasma exchange treatment was performed once, where 3000 mL of plasma was replaced within 3 hours; continuous veno-venous hemofiltration was performed 4 times for a total of 85 hours with the blood flow volume set at 180 mL/min. The pre-dilution volume was 2000 mL, the post-dilution volume was 500 mL, and the ultrafiltration volume was 100 to 300 mL.
Anticoagulant and thrombolytic treatments were administered; the patient received unfractionated heparin and argatroban as anticoagulants as well as alteplase and urokinase as thrombolytic agents. Both anticoagulant and thrombolytic drugs were continuously pumped through the deep vein. From July 19 to July 23, the patient was administered unfractionated heparin (200–1000 U/h) combined with argatroban (0.2–0.8 mg/h). However, after his platelet counts decreased, argatroban at the same dose was administered alone from July 24 to July 26 and was discontinued from July 27 to August 2, during which unfractionated heparin (maintained at 200–1000 U/h) was continuously administered as an anticoagulant. Alteplase (50–100 mg/d) was used for thrombolysis from July 21 to July 25. After 5 days of treatment, the patient's vital signs stabilized although he still had nausea, vomiting, bloating, abdominal pain, and intermittent bloody stool. Both axial and reconstructed images from a whole abdominal enhanced CT scan performed on July 25 showed extensive venous filling defects that suggested extensive venous thrombosis. This thrombosis had not significantly improved since July 21, and was accompanied by partial small intestine dilatation, intestinal wall edema, and decreased renal perfusion; moreover, renal artery thrombosis was not ruled out (Fig. ). Alteplase was discontinued and replaced by urokinase (the initial dose was 200,000 U as a bolus injection, after which 50,000–100,000 U/h for 24 h was continuously pumped for maintenance) combined with unfractionated heparin (the dose of which [200–1000 U/h] was adjusted to maintain an activated partial thromboplastin time of 60–80 s) for enhanced anticoagulation. The levels of fibrinogen degradation products and D-dimer were continuously monitored during treatment (Fig. ) to evaluate the thrombolytic effect. Starting on July 26, the patients symptoms, including vomiting and abdominal distension, began to improve, and his ascites gradually became lighter in color and decreased in volume (Fig. ). At the same time, his bloody stool significantly abated, and his hemoglobin levels did not decrease significantly after intermittent blood transfusion (Fig. ). As the patient had severe intestinal edema, small intestinal clearance, and a high risk for abdominal puncture at the time of his admission, abdominal puncture, and drainage were performed once his condition started to improve to reduce intraperitoneal pressure and enhance renal perfusion. After receiving anticoagulant and thrombolytic treatments, the patient's portal venous pressure was reduced, and his intestinal edema and exudate gradually decreased. Bedside abdominal ultrasonography indicated intestinal canal expansion and decreased edema (see Fig. ). Moreover, an enhanced abdominal CT scan on July 31 showed that, while there remained no significant improvement in the right hepatic vein thrombosis and small emboli in the left branch of the portal vein, the remaining veins were essentially unobstructed and the small intestine was expanded and effused. A portion of the small intestine was severely expanded with decreased perfusion (Fig. ); the urokinase was discontinued and heparin continuously administrated at 200–1000 U/h for 24 h) for anticoagulation.
Meanwhile, the patient also received a blood transfusion, fluid infusion, and vasoactive drugs to maintain blood pressure; the patient also received anti-infection agents, somatostatin, and hypophysin to reduce portal pressure as well as symptomatic and supportive treatments. On August 12, the patient was found to have dark red bloody stools, decreased hemoglobin, right mid-abdominal pain, and board-like rigidity of the abdomen suggesting intestinal necrosis. The patient underwent emergency partial small intestine resection, following which his adverse abdominal symptoms improved. Enhanced whole abdominal CT on August 21 revealed that the right hepatic vein had less thrombosis than before and was completely unobstructed; meanwhile, the intestinal expansion and effusion were relieved. The patient was discharged on September 1, 2017. He was prescribed warfarin 2.5 mg/d orally after discharge. His prothrombin time/international normalized ratio was maintained between 1.5 and 2.5, and prednisone 5 mg/d was administered. During regular follow-up, this patient reported no discomfort, and his eosinophil levels were normal.
The study was approved by the Nantong Third People's Hospital Ethics Committee. The patient provided written informed consent for the publication of his details.
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pmc-6283229-1
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A 69-year-old Asian male was suffered severe burn injury that caused by flame. The patient had no known comorbidity but had drunk much alcohol every day. The patient has second to third-degree burns on face, chest, abdomen, both arms, and both buttocks that affected 37.5% TBSA. Second-degree burn was estimated 9.5% TBSA and third-degree burn was estimated 28% so that Burn Index was 32.75. Upon admission and after cleaning the fresh burn and removing blisters, we changed dressing every day. We harvested full-thickness normal skin from right groin area in order to manufacture JACE on next day. We performed debridement all eschar on 7 days from admission. And we implanted artificial dermis on the all ulcer to manage the good wound bed. At last, we applied JACE on meshed 3:1 split-thickness dermis graft or meshed 6:1 split-thickness autograft for covering all wound. All skin graft take rate was 90% at four post-operative weeks. And this patient was transferred to a rehabilitation hospital on 101 days from admission.
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pmc-6283229-2
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A 51-year-old Asian male was suffered severe burn injury with inhalation injury that caused by flame. The patient had no known comorbidity. The patient has second to third-degree burns on face, chest, abdomen, right side of the back, both arms, right thigh and left lower leg that affected 44.0% TBSA. Second-degree burn was estimated 34% TBSA and third-degree burn was estimated 10% so that Burn Index was 27. We harvested full-thickness normal skin from right groin area in order to manufacture JACE on 2 days from admission. And we performed debridement all eschar and we implanted artificial dermis on the all ulcer on the same day. We implanted meshed split thickness skin graft on back in advance on 17 days from admission. This is because the patient will need absolute rest after using JACE and generally CEA take rate on back is very low. We finally applied JACE on meshed 3:1 split-thickness dermis graft or meshed 6:1 split-thickness autograft on chest and abdomen and implanted only meshed 3:1 split-thickness autograft for upper and lower limbs wound on 24 days from admission. All skin graft take rate was 95% at four post-operative weeks. And this patient was transferred to a rehabilitation hospital on 77 days from admission.
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pmc-6283229-3
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A 55-year-old Asian male was suffered severe burn injury with inhalation injury that caused by flame. The patient had no known comorbidity. The patient has second to third-degree burns on face, chest, abdomen, back, both upper and lower limbs that affected 69.0% TBSA. Second-degree burn was estimated 48% TBSA and third-degree burn was estimated 21% so that Burn Index was 45. Upon admission and after cleaning the fresh burn and removing blisters, an escharotomy was performed. We harvested full-thickness normal skin from right groin area in order to manufacture JACE on the next day from admission. And we performed debridement all eschar and we implanted artificial dermis on the all ulcer on 6 days from admission. We applied JACE on meshed 3:1 split-thickness dermis graft on both upper limb and chest and implanted only meshed 3:1 split-thickness autograft for the rest wound on 27 days from admission. All skin graft take rate was 85% at four post-operative weeks. And this patient was transferred to a rehabilitation hospital on 86 days from admission.
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pmc-6283378-1
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A 39-year-old G6P3 with an unspecified inherited bleeding disorder presented at 37-6/7 weeks gestational age for a fourth repeat scheduled CD in the setting of fetal macrosomia. The patient had a diagnosis of an unspecified bleeding disorder. Prior to diagnosis, her bleeding history consisted of easy bruising, gingival bleeding, heavy menstrual bleeding, and multiple post-operative hemorrhagic complications after previous surgeries. These complications included hemorrhagic compartment syndrome after an ankle surgery and bleeding complications with all three prior deliveries including persistent vaginal bleeding after her first two CDs and intra-abdominal hemorrhage after her third CD. Although she reported having had epidurals during her prior pregnancies, these anesthetic records were unavailable. Her family history is positive for mucocutaneous bleeding including maternal heavy menstrual bleeding and death of her maternal grandmother secondary to postpartum hemorrhage. Prior to this pregnancy, she was referred for evaluation of a bleeding disorder in advance of cervical spine surgery. Her extensive coagulation laboratory evaluation was unremarkable, including normal complete blood count and smear, activated partial thromboplastin time, prothrombin time, thrombin time, von Willebrand factor (VWF) parameters, fibrinogen activity, platelet aggregation studies (including ristocetin-induced platelet aggregation), platelet function assay, factor XIII level, and rotational thromboelastography. There was good documentation of her prior bleeding and no suspicion for other disorders, such as endocrine or connective tissue disorders. She was diagnosed with an unspecified inherited bleeding disorder. The differential diagnosis for her hemostatic defect included rare congenital bleeding disorders such as undetected VWF qualitative dysfunction or undetected defects in fibrin, fibrinolysis, or platelet function. She received prophylactic fresh frozen plasma (FFP), cryoprecipitate, platelets, and anti-fibrinolytic treatment as prophylaxis for her cervical spine surgery and achieved good hemostasis without complication.
Upon presentation for delivery, her laboratory values were unremarkable: hematocrit (Hct) 30%, platelets 169 × 10
3/ml, international normalized ratio (INR) 1.1, partial thromboplastin time (PTT) 30 s, fibrinogen activity 461 mg/dl, and a thromboelastogram (TEG) within normal parameters. Prior to her delivery, a multi-disciplinary care plan, including hematology, anesthesiology, and obstetric services was established and a delivery plan that balanced patient safety and birthing preferences agreed upon; contingency plans for transfusion and anatomic control of bleeding were in place in the event of obstetric hemorrhage. The risks and benefits of regional anesthesia in the setting of a unremarkable airway exam (Mallampati Score 2, normal head flexion and extension, and normal mouth opening), were discussed at length with the patient, acknowledging the diagnostic challenges and lack of a useful laboratory monitoring test.
The patient prophylactically received 2 units of FFP, 10 units of cryoprecipitate within 4 hours prior to CD, and 2 units of platelets immediately before the placement of her routine single shot spinal anesthetic (consisting of 12.5 mg hyperbaric bupivacaine, 10 mcg fentanyl, and 100 mcg preservative-free morphine). Following the delivery of a healthy infant, intravenous aminocaproic acid was immediately started and routine oxytocin was infused (at an approximate rate of 15 IU per hour). Poor uterine tone was noted after delivery, which improved after single dose of 200 ug IM methylergonovine and 800 mg buccal misoprostol administration. The estimated blood loss was 1.5 liters. In response to her higher-than-average blood loss, 2 additional units of platelets were given in the immediate postoperative period. Deep venous thrombosis prophylaxis consisted of sequential compression devices until ambulation; low molecular weight heparin was avoided. The patient was closely monitored for neuraxial hematoma. Her postoperative labs were notable for Hct 22%, platelets 175 × 10
3/ml, INR 1.1, PTT 28 s, and fibrinogen activity 462 mg/dl. Additionally, TEG results during and after the CD remained normal. The patient continued intravenous aminocaproic acid therapy postpartum, and transitioned to oral tranexamic acid for 5 days. She had an uneventful recovery and was discharged 3 days after surgery. The case management timeline and dosing regimen are shown in
.
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pmc-6283806-1
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A 75-year-old male taxi driver was referred with a diagnosis of severe AS and moderate pericardial effusion. He had a history of ESRD of unknown origin and had been on hemodialysis for 4 years. His primary complaint was dyspnea on effort that had gradually worsened in the previous 3 months. Electrocardiography revealed sinus rhythm, and chest radiography showed cardiomegaly with a cardiothoracic ratio of 68% (Fig. a). Transthoracic echocardiography (TTE) showed pericardial effusion and severe AS with peak and mean pressure gradients of 89 and 48 mmHg, respectively, and an aortic valvular area of 0.86 cm2. A medium volume of pericardial effusion was also observed on computed tomography (CT) (Fig. b). The estimated volume of the pericardial effusion was 700 mL. An aortic valve replacement (AVR) was scheduled. When he was admitted for the AVR 4 weeks after the initial outpatient counseling, he suffered from cough and fever. His white blood cell (WBC) count was 7700/μL and serum C-reactive protein (CRP) level was 9.0 mg/dL. Thus, the operation was postponed. When he was readmitted 2 weeks later, he had general fatigue and persistent inflammation was observed (WBC, 6250/μL; CRP, 6.84 mg/dL). Hepatic dysfunction (aspartate transaminase, 624 U/L; alanine transaminase, 1072 U/L) was newly detected. Electrocardiography revealed paroxysmal atrial fibrillation. The cardiothoracic ratio increased to 71% on chest radiography (Fig. c). Massive pericardial effusion was observed on chest CT (Fig. d). The estimated pericardial effusion volume was 1300 mL. A diagnosis of cardiac tamponade was made. We decided to abort the operation and started the administration of oral loxoprofen at 300 mg/day. Pericardiocentesis was performed, and a total of 1084 mL of bloody pericardial effusion was successfully drained. Examination of the fluid revealed antibody titers to coxsackievirus A4 and B4 elevated 256 times above the normal range. Several tumor marker levels in the pericardial effusion were also elevated (carcinoma antigen-125, 384.9 U/mL; cytokeratin 19 fragment, 43.5 ng/mL); however, cytology of the fluid revealed no malignancy. No abnormal accumulation of fluorodeoxyglucose was detected on positron emission tomography–CT. The inflammation improved immediately. During a 2-month outpatient observation, the inflammation was well-controlled and no recurrence of the pericardial effusion was observed. Thus, the AVR was rescheduled.
The elective operation was performed. The pericardium was thickened and showed almost complete adherence to the heart. Following meticulous dissection of the adhesions, isolation of the right pulmonary veins was performed with a radiofrequency ablator (Isolator Synergy Clamp OSL2; AtriCure Inc., West Chester, OH, USA) before the initiation of cardiopulmonary bypass (CPB). After the establishment of CPB, dissection of the adhesion around the left pulmonary veins was performed and the left pulmonary veins were similarly isolated. Myocardial protection was achieved using intermittent antegrade and retrograde cold blood cardioplegia. The aortic valve was exposed via an aortotomy. A visual inspection revealed calcified cusps and annulus. The cusps were resected, and the calcifications on the annulus were gently removed using an ultrasonic aspirator (Sonopet UST-2001; Stryker Japan Inc., Tokyo, Japan). A 23-mm stentless bioprosthesis (Solo Smart; Sorin Group, Milan, Italy) was implanted with three continuously running 4–0 monofilament polypropylene sutures. Aortic cross-clamp time and CPB time were 72 and 127 min, respectively. The patient tolerated the procedure well and had an uncomplicated postoperative course. Postoperative TTE showed no aortic regurgitation. The effective orifice area (EOA) and indexed EOA of the bioprosthesis were calculated as 1.73 cm2 and 1.08 cm2/m2, respectively, and mean pressure gradient across the prosthetic valve was 10 mmHg. Anti-platelet therapy (aspirin 100 mg/day) was initiated on the first postoperative day. The patients had no adverse events during 1 year and 9 months of follow-up, and his sinus rhythm has been maintained.
Pathological examination of the pericardium (Fig. ) showed fibrous pericarditis without active inflammation. There was no malignancy in the immune-stained specimen. We could not detect the specific cause of the pericarditis in the pathological specimen.
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pmc-6284006-1
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A 27-year-old man was admitted to our Emergency Department for a 3-days-history of blurry vision in his left eye. His medical history included CVID: during early childhood, he experienced multiple respiratory tract infections and selective IgA deficiency was diagnosed. At the age of 11, he developed splenomegaly and multiple abdominal and thoracic lymphadenopathies. At the age of 14, histological analysis of an inguinal lymph node was performed, showing reactive lymphadenopathy and no evidence of lymphoproliferative disease. Serum IgG were 593 mg/dL, IgM 50 mg/dL, IgA 6 mg/dl. Few months later he developed severe immune thrombocytopenic purpura (ITP), successfully treated with a course of intravenous immunoglobulins. Autoimmune/lymphoproliferative syndrome (ALPS) was excluded based on negative molecular analysis for TNFRSF6. No further investigations for lymphoproliferation and hypogammaglobulinemia were done at that time. At the age of 21, he experienced recurrent prostatic infections and Herpes Zoster reactivation on the trunk. After a long delay, at the age of 23, diagnosis of CVID was made according to the criteria developed by the European Society for Immune Deficiencies (ESID) and the International Consensus on CVID (, ). He presented recurrent sinusitis, splenomegaly, laterocervical, axillary, and inguinal lymphoadenopathy. Total IgG, IgM, and IgA count at diagnosis was 150 mg/dL, 6 mg/dl, and 0, respectively. Lymphocytes immunophenotyping and maturative analysis revealed normal levels of circulating B cells (341/μL), failure of B lymphocytes maturation with reduced levels of switched memory B cells (0.6%), and increase in CD21 low subpopulation (22%). T and NK cell subsets were in normal range. Serum β2-microglulin was 3.54 mg/dL (n.r. 0.8–2.2). Molecular analyses for HIV, EBV, CMV, Toxoplasma were negative. Lymphoma was ruled out by bone marrow trephine biopsy and total body Computed Tomography (CT)-scans showed no change in previously described thoracic and abdominal lymphadenopathies and splenomegaly. Other causes of secondary hypogammaglobulinemia were excluded. Therefore, replacement therapy with intravenous immunoglobulins (0.4 g/kg every 3 weeks) was started and the patient was addressed to CVID protocol for follow up since then.
At presentation, the patient reported decreased visual acuity and partial loss of color vision on his left eye. Neurologic examination showed reduced visual acuity, relative paracentral scotoma and red desaturation in the left eye, moderate pain on pressure of the ipsilateral ocular bulb, but no pain on ocular movements. Pupillary light reflex was reduced on the same side, and relative afferent pupillary defect or Marcus-Gunn pupil was present. The right eye was unaffected and the remaining neurological examination was unremarkable. Fundoscopic evaluation revealed a sharp-edged optic disk in absence of stasis signs and retinal lesions. Optical coherent tomography (OCT) showed normal retinal morphology and thickness. Brain and spinal cord Magnetic Resonance Imaging (MRI) demonstrated enlargement and hyperintensity of the left optic nerve in its posterior portion, with intense enhancement after the administration of gadolinium (Figure ). Pattern shift visual evoked potentials showed a marked delay of the P100 component with an attenuation of the P100 wave amplitude in the left eye (Figure ). Cerebral spinal fluid (CSF) analysis revealed marked pleocytosis (200 cells/ul) with lymphocyte prevalence, and mildly elevated protein level (56 mg/dl). Oligoclonal bands were absent. PCR for HIV, HSV 1, HSV2, HHV6, HHV8, EBV, VZV, Parvovirus, Adenovirus, Enterovirus, BKV, Pneumococcus, Streptococcus group B, Cryptococcus, and Toxoplasma did not detect any infection. CSF cultures were negative. Serum anti-AQP4 and anti-MOG antibodies were absent. Likewise, anti-nuclear antibodies, anti-extractable nuclear antigens antibodies, anti-double strand DNA antibodies, and anti-tireoperoxidase antibodies turned out negative.
Routine blood examination showed mild leukopenia (3,250/ul) and low platelet count (72,000/uL). Serum IgG and IgM levels were, respectively, 764 mg/dL and 8 mg/dL, while serum IgA were undetectable. Circulating lymphocytes were 1463/μL, (CD3+ 835/μL, CD4+ 559/μL, CD8+ 240/μL, CD19+ 536/μL, CD16+56+ 84/μL). Lymphocytes immunophenotyping and maturative analysis showed decreased NK cells (84/uL), failure of maturation of B lymphocytes with markedly reduced switched memory B cells (0.6%), transitional B cells (0.1%) and plasmablasts (0.2%), and further increased CD21 low subpopulation (36.7%). Infection markers resulted within normal range. Serum β2-microglulin was slightly increased compared to baseline (4.09 mg/dL; n.r. 0.8–2.2). Serum PCR for HIV, HSV 1, HSV2, HHV6, HHV8, EBV, VZV, Parvovirus, Adenovirus, Enterovirus, BKV, Pneumococcus, Streptococcus group B, Cryptococcus, and Toxoplasma were negative. Serum serologies for Treponema pallidum, Borrelia burgdorferi, Bartonella henselae, and Brucella were negative, as well as QuantiFERON gold test for Mycobacterium tubercolosis and serum galactomannan assay for Aspergillus detection.
Given the higher susceptibility of CVID patients to lymphoproliferative diseases, cytological and radiological examinations were carried out in order to exclude CNS lymphoma. No malignant cells were detected in the CSF. Total body Positron Emission Tomography (PET)/CT study with 18-FDG did not show any focal increase in glucose metabolism.
As soon as viral infections were excluded, our patient was treated with an empiric course of IV methylprednisolone (1 g/die for 5 days) and a tapering course of prednisone, as early IV steroidal therapy was shown to accelerate clinical resolution in patients with autoimmune ON. IV ceftriaxone and oral Bactrim were added while waiting for microbial cultures results. Given the history of Zoster reactivation, prophylactic therapy with oral Acyclovir was administered to the patient in concomitance with steroidal therapy. The patient reported a rapid clinical improvement following the administration of the first methylprednisolone dose, with complete regression of symptoms in 4 days, and remained asymptomatic at 6-month follow-up.
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pmc-6284021-1
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The proband is a 3 year-old girl born at 38 weeks by vaginal delivery after an uneventful pregnancy, second child of healthy non-consanguineous Caucasian parents with an uneventful family history. At birth, weight was 3,050 g (−0.09 SDS), length 49 cm (−0.1 SDS), and occipitofrontal circumference (OFC) 32.5 cm (−0.94 SDS). Neonatal SDSs were calculated according to the Italian Neonatal Study (INeS) charts (). Feeding difficulties and delayed growth were recorded during the perinatal period and first months of life. At 8 months (preverbal age), she was diagnosed with bilateral SNHL, and mutations in both GJB2 and GJB4 genes were ruled out. Magnetic resonance revealed a bilateral dilatation of both the vestibular aqueduct and the membranous labyrinth. Upon PS suspicion, appropriate genetic analysis was requested. At 26 months, weight was 9.2 kg (−2.09 SDS), height 79.5 cm (−2.51 SDS), and OFC 46.5 cm (−0.64 SDS), while at the last visit (34 months) weight 10.5 Kg (−2.09 SDS), height 86.5 cm (−2.20 SDS), and OFC was 47 cm (−0.98 SDS). Post-natal SDS were calculated according to the WHO Child Growth Standard (). Cranio-facial dysmorphic features included high forehead, mild frontal bossing, low-set posteriorly rotated ears, and thin lips. The patient also displayed brachydactyly of both hands and feet and clinodactyly of the V finger (Figure ). Thyroid function was normal, as found in most PS cases during infancy, as well as ophthalmological evaluation, heart and abdominal ultrasounds. Bone age corresponded to chronological age. Neuropsychiatric assessment showed a mild intellectual disability with expressive language delay. Neuropsychomotor evaluation at 34 months showed (Bayley scales): (a) cognitive scale: 25.15 months; (b) language scale: receptive communication subtest 14.15 months, expressive communication subtest 24.15 months; (c) motor scale: fine motor subtest 31.15 months, gross motor subtest 28.15 months. Social-emotional and adaptive behavior subscales were according to age. The study was approved by Ethical Clinical Research Committee of IRCCS Istituto Auxologico Italiano. Written informed consents to participate in the study and for publication were obtained from patients' parents.
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pmc-6284267-1
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A 9-year-old male English Setter presented with a 6-month history of ulceration of the left upper eyelid as the only clinical finding (Fig. a). On examination, the lesion was round, elevated, and well circumscribed. A malignant eyelid tumour was suspected, and the lesion was excised for histopathological examination. A fine-needle aspirate was obtained from a popliteal lymph node from the left side. The popliteal lymph node was chosen, as the owner did not want any expensive diagnostic procedures and the popliteal lymph node was the easiest accessible. The dog was doing well and presented without fever, clinical signs of anaemia, or weight loss. A routine blood profile was unremarkable except for a haematocrit (packed cell volume, PCV) of 37%, which is borderline low. The blood test also showed a serum calcium: 2.43 mmol/L (ref 1.98–3.0 mmol/L), serum albumin: 31 g/L (ref 23–40 g/L), serum alkaline phosphatase: 53 U/L (ref 23–213 U/L), and serum creatinine: 91 µmol/L (ref 44–159 µmol/L). Serum sodium, potassium, chloride, and glucose were also within normal limits. C-reactive protein (CRP) was < 10 mg/L, which is also normal. The owner did not want additional examinations or treatments other than excision of the tumour and for this reason, a thoracic radiograph, abdominal ultrasound, and a full haematological profile were not performed. No systemic treatment was initiated, and 2 months after surgery an unremarkable full haematological profile was obtained. 19 months after the diagnosis the dog was still alive and doing well with no signs of relapse.
The specimen was fixed in 10% neutral buffered formalin immediately after surgical excision, processed and embedded in paraffin. Sections (4 µm) were prepared and stained with haematoxylin and eosin according to standard protocols. Furthermore, sections were routinely stained with periodic acid-Schiff (PAS), Gram stain, and Gomori’s methenamine silver stain (GMS) to detect microorganisms. Giemsa staining was performed to visualize the blood derived cells in the specimen.
Immunohistochemical stainings were performed on a Ventana Benchmark Ultra Platform (Ventana Medical Systems, Tucson, AZ, USA) according to manufacturer’s instructions. The following antibodies were used: CD3 [clone 2GV6, code 790-4341, rabbit anti-human, ready-to-use (RTU), Roche (Hvidovre, Denmark)], PAX-5 [clone SP34, code 790-4420, rabbit anti-human, RTU, Roche (Hvidovre, Denmark)], vimentin [clone V9, code 790-2917, mouse anti-human, RTU, Roche (Hvidovre, Denmark)], and Ki-67 (clone MIB-1, code M724001, mouse anti-human, 1:100, Dako). Positive and negative controls were performed according to the manufacturers’ instructions.
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pmc-6284286-1
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A 16-year-old Mexican girl presented with a 4-day history of epigastric abdominal pain that radiated to the left hypochondrium and was accompanied by abdominal bloating. She reported vomiting approximately 30 times 24 hours after symptom onset. Oral intake of fluids and solid food was impaired, and both flatus and bowel movements were absent. She had no history of prior surgical interventions and did not have a history of fever, hematemesis, jaundice, chyluria, or acholic stools.
She was hemodynamically stable on room air with a mild tachycardia of up to 140 beats per minute (bpm). On physical examination she presented no neurological alterations or alopecia. An abdominal examination revealed distention, borborygmi, painful palpation, and involuntary resistance in upper quadrants with rebound tenderness.
She was hemoconcentrated with a hematocrit of 40 and had leukocytosis of 17,560/mm3. A computed tomography of her abdomen and pelvis with intravenously and orally administered contrast showed dilatation of the gastric chamber with a hyperdense beehive pattern (Fig. , ). Dilated small intestine loops with fluid levels and a target image in the jejunum were suggestive of intussusception. Furthermore, findings were compatible with a trichobezoar.
She underwent an exploratory laparotomy. Findings included gastric distention (Fig. ), a palpable mass that extended from the gastric lumen to the first duodenum section, and a jejuno-jejunal intussusception (Fig. ), which was liberated through manual revision. The jejunum showed macroscopic signs of inflammation 110 cm away from the ligament of Treitz. The mass was manually dragged into the duodenum.
A 10 cm gastrotomy was performed on the anterior portion of the gastric body and a 20 cm-long continuous conglomerate of hair was extracted followed by four smaller fragments which extended to the site of the intussusception (Figs. and ). After gastric lavage with saline solution, a first intention closure was performed in two layers: first with polyglactin 00 using the Connell technique and then with gastric silk 00 using the Lembert technique. A 19 Fr closed system drainage was placed in her peritoneal cavity.
She had no immediate complications. Enteral nutrition was tolerated during the third postoperative day. Before hospital discharge she was evaluated by an in-house psychiatrist and was discharged during the fifth day of hospital admission.
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pmc-6284379-1
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We present the case of a 76-year-old man with no pathological history. admitted in the emergency room due to a 5-day evolution fever associated with abdominal distension and a palpable mass in the hypogastrium. Hemodynamic instability with BP of 90/50 and tachycardia with good response to initial resuscitation with 2000 ml of physiological solution and antibiotic therapy (Metronidazole+Ceftriaxone). The exploration showed indurated and mobile formation in hypogastrium, without signs of peritoneal irritation. Blood analysis showed leukocytosis with immature cells, and CRP increased with normal lactate.
Abdominal CT presented large supra-bladder pelvic mass of 12 cm with central necrosis and hydro-aerial level compatible with abscess formation in the tumor, presence of hepatic intra-portal gas in relation to the patient’s septic process (Figure1).
Pig tail drainage was placed obtaining purulent liquid, admission to the intensive care unit requiring noradrenaline (0.15 μg/kg/min). Improvement of the septic pattern occurred in the first 48 h with withdrawal of vasoactive drugs and decrease in inflammatory parameters. Cultures of blood and abscess liquid were positive for Streptococcus anginosus associated with mixed anaerobic flora. Percutaneous biopsy was negative for malignant cells; acute inflammatory component was associated with intestinal perforation.
At 72 h, orotracheal intubation was required due to progressive respiratory insufficiency, without any increase in inflammatory parameters. Thoracoabdominal CT demonstrated respiratory distress, abdominapelvic free fluid and completely drained intra-tumoral abscess.
Urgent surgical intervention showed a large tumor of 15x15 cm affecting the jejunum (20 cm from the duodenojejunal angle); intestinal resection was performed with free margins and lateral-lateral mechanical anastomosis was done. During the post-operative period, the patient recovered progressively and was discharged after 13 days.
Anatomopathological examination revealed mesenchymal proliferation on the intestinal wall without mucosa infiltration, constituted by a proliferation of elongated cells without pleomorphisms arranged forming bundles.
Immunohistochemical analysis was negative for CD117, DOG1, ALK1, S100, CD34, desmin and actin and positive for vimentin and beta-catenin, desmoid tumor dependent on the jejunal wall, free neoplasic intestinal margins ().
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pmc-6284393-1
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A 15-year-old caucasian male, with non-relevant past medical history. He had no prior history of change in bowel habits or gastrointestinal bleeding and was admitted to the emergency department after an episode of lipothymy. He complained of asthenia and hematochezia since the day before. The laboratory tests showed hemoglobin of 10.8 g/dl. The upper endoscopy was normal and the ileocolonoscpy showed ileal nodular hyperplasia with blood and clots in the ileum. Twenty-four hours later the hemoglobin dropped to 7.9 g/dl and on physical examination he was pale, diaphoretic and hypotensive. VCE (Endocapsule Olympus®) performed 24 h after admission identified the bleeding source as an active bleeding (oozing) from a small diverticulum like orifice in the middle ileum.
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pmc-6284393-2
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A 16-year-old caucasian female had past medical history irrelevant. She was admitted due to melena lasting for 24 h. On admission she initiated hematochezia and pale but normotensive. The hemoglobin was 12.9 g/dl on admission but dropped to 7.1 g/dl 24 h later, requiring blood transfusions. Also the upper endoscopy was normal and on the ileocolonoscpy she had fresh clots in the ileum, without other relevant lesions. Then a VCE (PillCam SB 2®) was used revealing a luminal duplication on the terminal ileum ().
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pmc-6284393-3
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A 14-year-old caucasian male was admitted due to melena. He had melena six months previously, but endoscopy and ilecolonoscopy performed at that time did not showed lesions with active bleeding. On admission, he was pale and hypotensive and laboratory workup revealed hemoglobin of 7.0 g/dl. After hemodynamic resuscitation, an upper endoscopy was performed but, also, did not showed any relevant alterations. The abdominal computer tomography (CT) and the Meckel scan with 99mTc-Na-pertechnetate also did not show relevant findings. At this time a VCE (PillCam SB 2®) was performed and luminal duplication in the terminal ileum, with signs of active bleeding, was visualized ().
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pmc-6284393-4
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A 17-year-old caucasian male was admitted in hypovolemic shock and rectal bleeding. He had hemoglobin of 4.9 g/dl on admission. After blood transfusions and hemodynamic resuscitation and upper endoscopy followed by ileocolonoscopy were performed, which did not showed lesions with active bleeding. The CT scan also did not showed any relevant lesions. VCE (PillCam SB 2®) was performed and identified a diverticular ulcerated lesion on the middle ileum with active bleeding.
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pmc-6284393-5
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A 19-year-old caucasian man was admitted with melena, that also have occurred two days previously. In that time, he had hemoglobin of 13.9 g/dl and was discharged with indication for symptoms surveillance. In admission laboratory workup performed revealed hemoglobin of 7.3 g/dl. After two blood transfusions, upper endoscopy and colonoscopy were performed without identification of any bleeding lesions. Abdominal-CT scan also did not showed anything relevant. Meckel scan with 99mTc-Na-pertechnetate was negative for heterotopic gastric tissue in the small bowel area. Due to hemodynamic instability an angiography was performed, also without identifying the source of bleeding. VCE (PillCam SB 3®) revealed a luminal duplication consistent with MD, but without active bleeding
All five patients were submitted to surgical excision of the MD and the histological examination confirmed the diagnosis. All of them presented good outcome without bleeding recurrence
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pmc-6284869-1
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A 64-year-old female with a past medical history of CLL being treated with ibrutinib, presented with fever, chills, night sweats, productive cough and lower back pain. She had been diagnosed with CLL (Rai stage I) five years prior, along with 17p deletion, and was initially treated with bendamustine and rituximab, with an excellent response. Two years later, she became symptomatic with generalized lymphadenopathy and was started on ibrutinib 420 mg daily.
Upon presentation to our clinic, the patient had a temperature of 101.8 degrees Fahrenheit, heart rate greater than 90 beats per minute and blood pressure of 86/53, which responded to a one-liter bolus of intravenous fluids. Physical exam was significant for a solid subcutaneous mass measuring 2 x 3 cm. An ultrasound of the mass revealed a 2.4 x 3.0 x 2.8 cm avascular abnormality with lobulated and irregular margins. Subsequent computed tomography (CT) of the abdomen and pelvis divulged two additional masses, one in the right lower rib measuring 36 mm and the other at the diaphragmatic hiatus, which appeared necrotic. A CT of the chest was significant for a patchy area of consolidation in the right lower lobe with several lung nodules measuring up to 1.6 cm in size in both lungs, as well as extensive mediastinal, sub-carinal, hilar and axillary adenopathy (Figure ). These findings correlated to hypermetabolic areas on a position emission tomography-computed tomography (PET/CT) scan completed a few days prior to her presentation (Figures -). Laboratory data revealed a normocytic anemia (hemoglobin 7.6 g/dL) but otherwise was unremarkable.
She was started on broad-spectrum antibiotics with vancomycin and piperacillin-tazobactam while infectious workup was pending. Ibrutinib was held due to concern for infection. A sputum culture showed the presence of Aspergillus. Due to her immune suppression, voriconazole was initiated. Fine needle aspirate was obtained from the rib lesion and subcutaneous lesions. Additionally, bronchoscopy was performed to evaluate the subcarinal lymph nodes and subsequently revealed Staphylococcus auricularis on cultures. Flow cytometry from endoscopic biopsy was consistent with her prior diagnosis of CLL, with a monoclonal population of kappa restricted B cells which co-expressed CD5 and CD23. The fungal cultures obtained from the rib, subcarinal lymph node and subcutaneous lesion revealed Nocardia species of no specific type. She was transitioned to trimethoprim-sulfamethoxazole, ceftriaxone and imipenem-cilastatin. Immunoglobulin levels were measured, with IgG, IgA and IgM at 1,390, 183 and 18 mg/dL, respectively. Due to IgG level >500 mg/dL, no intravenous immunoglobulin was administered.
The patient then developed a headache and had subsequent magnetic resonance imaging of the brain revealing a solitary enhancing lesion in the anterior limb of the internal capsule with surrounding vasogenic edema. Neurology believed these findings on imaging were likely consistent with CNS involvement from disseminated Nocardia. Her hospital course was prolonged and complicated by multiple events, including acute kidney injury and thrombocytopenia felt to be secondary to trimethoprim use. This was discontinued and amikacin was started. She also had development of a transient third-degree heart block and pericardial effusion with resultant pericardiocentesis. Pericardial fluid cultures were without growth and cytology was unremarkable. Subsequently, she developed progressive altered mental status with hypercapnia requiring non-invasive airway support. Workup for etiologies of her altered mental status was non-revealing, including CT of the head. Her clinical status continued to deteriorate. Her family decided to transition her to inpatient hospice care where she died a few days later.
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pmc-6284871-1
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A 41-year-old female presented to our clinic as a new patient for excision of a previously diagnosed right heel leiomyoma. Six months prior, she had consulted a dermatologist for a painful area on her right heel that had been present for approximately three to six months. The area was raised, tender, firm, and was increasing in size. Physical exam at that time revealed a 2 cm raised, firm, noncompressible nodule on the posterior right heel, which was tender to palpation without any redness or streaking. X-rays were nonspecific and revealed that the soft tissue shadow was “not connecting to bone.” A punch biopsy taken at a follow-up visit with the dermatologist revealed a leiomyoma of the heel. She continued to experience pain (8/10 in severity) and was seen in our clinic for evaluation six months later. She had no other areas of bleeding, itching, or pigment changes of the skin. Physical exam revealed a palpable 2 cm x 1 cm nodule on the posterior aspect of the right heel which was freely mobile and tender to palpation (Figure ). Pulses and sensation were normal throughout in both lower extremities and no other gross abnormalities were noted.
The patient did not have a history of frequent running, gout, diabetes, constitutional symptoms, or weight loss. Due to the unusual location of this leiomyoma, Reed’s syndrome was considered in the differential diagnosis, and the patient was referred for a gynecological oncology appointment. However, because she had no personal or family history of other similar soft tissue masses, uterine fibroids, renal cell carcinoma, or skin cancer, there was a low index of suspicion. Her past medical history was nonspecific for any condition predisposing to cancer.
She was scheduled for surgery two weeks later. The tumor was excised (Figures -) and sent for pathology confirming cutaneous leiomyoma (Figure ). Follow-up visit at two weeks status post-excision showed a well-healing incision with no signs of infection, erythema, or discharge, and no signs of any nodule remaining.
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pmc-6284872-1
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A 72-year-old Caucasian male with no significant past medical history presented with fatigue, shortness of breath, and malaise for a couple of weeks. He had paroxysmal nocturnal dyspnea, leg swelling and gained 26 pounds in two weeks. Physical exam was positive for crackles at bilateral lung bases and bilateral pedal edema. His home medications included only BC powder (high-dose aspirin with caffeine) on a daily basis for headaches for few months.
His blood urea nitrogen (BUN) and creatinine levels on admission were 25 and 1.62 mg/dl. Lower extremity ultrasound showed a right popliteal vein deep venous thrombosis. Ventilation/perfusion scan of lungs was of intermediate probability. He was started on an anticoagulation regimen. His low density lipoprotein (LDL) was 233 mg/dl. Progressive elevation was noticed in his BUN and creatinine during the hospital stay despite institution of protective therapies including fluids. Urinalysis showed proteinuria with no hematuria or pyuria. His 24-hour urine protein was 16.3 g and urine protein/creatinine ratio was 10.2. Renal ultrasound was unremarkable. Urine sodium was 14. Serum protein electrophoresis showed low serum protein and albumin with high alpha-2 globulin and low gamma globulin. Urine protein electrophoresis showed a total protein concentration of 1414.6 mg/dl. Anti-phospholipase A2 receptor antibody was negative. Anti-nuclear antibody, hepatitis B surface antigen and antibody, hepatitis C antibody, and human immunodeficiency virus (HIV) test were negative. Complement C3 and C4 levels were normal. Beta-2-microglobulin was high. Kappa and lambda chains were both high and the ratio was 1.73. Abdominal fat pad biopsy was negative for amyloidosis. The patient was later started on hemodialysis due to worsening renal function. Renal biopsy was done. Light microscopy showed severe acute tubular injury with tubular dilatation, epithelial simplification, cytoplasmic vacuolization, nuclear reactive changes, mild interstitial edema, and mild interstitial fibrosis (Figure ). Electron microscopy showed diffuse effacement of podocyte foot processes (Figure ). Thus, the diagnosis of MCD with severe acute tubular necrosis was made based on the biopsy results. The patient was started on prednisone. At discharge, patient was instructed to stop using BC powder. The kidney function improved within six weeks of treatment institution and dialysis was stopped.
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pmc-6284875-1
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Case 1 - infected diabetic foot
A 41-year-old male, known case of complicated type 2 DM and left diabetic foot with big toe amputation, was admitted on 23/7/2018 with wet gangrene of the left second toe and infected forefoot. His blood workup showed severe leukocytosis of 42 x 109/L and mild renal impairment with uncontrolled blood sugar of 19 mmol/L. The patient was started on intravenous (IV) antibiotics and insulin infusion and underwent surgical debridement and left second toe amputation. He needed three more surgical debridement followed by amputation of left third toe (on 2/8/2018, 12/8/2018 and 20/8/2018). Six days after last debridement (Figure ) decision was made to fix CLEANSE CHOICE™ Dressing with V.A.C. VERAFLO™ Therapy. We used MicroSafe® (Sonoma Pharmaceuticals, Petaluma, CA) as instillation fluid, 20 cc with soak time of 15 minutes every four hours with V.A.C pressure of 75 mm Hg. Three days later, the wound bed showed dramatic improvement (Figure ), so a second application of the CLEANSE CHOICE™ dressing for another three days was done with reducing the frequency of instillation to six hourly. Figure showed the wound bed of the second application and Figure showed necrotic slough attached to the sponge of CLEANSE CHOICE™. Since the remaining necrotic and infected tissue was significantly less, we used the usual foam dressing for V.A.C. VERAFLO™ Therapy for four days. Figure is the end result. So, in total of nine days we were able to clean the wound bed and produce clean and healthy granulation without taking the patient to OR since he already had four times OR visits. The plan is to obtain wound closure by secondary intention healing.
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pmc-6284875-2
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Case 2 - abdominal wall
A 31-year-old male, victim of road traffic accident, admitted to surgical intensive care unit (ICU) intubated with severe head injury in the form of multiple facial fractures and brain contusions. He had multiple bilateral flail rib fractures, lung contusions and pneumothorax for which bilateral chest tubes were fixed. He had five laparotomies during first 10 days for liver injury (segment IV B & V resection), hepatobiliary anastomosis for bile leak. We were consulted on hospital day 60 for a large full thickness abdominal skin loss with necrotic slough post-surgical debridement for gangrenous skin patch with methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter (Figure ). He was a poor surgical candidate, so a decision was made to place V.A.C. VERAFLO CLEANSE CHOICE™ Dressing (Figure ). The settings were 50 cc of MicroSafe solution with a 20-minute dwell time, followed by six hours of NPWT at -100 mm Hg. After four days, half of necrotic slough was removed (Figure ) and almost 90% after the second application (Figure ). New cultures were collected and appeared negative. The wound was then fixed to the simple V.A.C for another four days. The final wound was ready for skin grafting but because the patient was poor surgical candidate and developed biliary fistula, decision was taken to leave the wound to heal by secondary intention (Figure ).
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pmc-6284875-3
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Case 3 - dehiscence of amputation stump
A 63-year-old man, known case of DM type II, hypertension and peripheral vascular disease, developed right forefoot dry gangrene. He underwent right femoroperoneal bypass and the gangrenous forefoot was treated conservatively. Six months later, he was admitted with wet gangrene of the forefoot for which he underwent right trans-metatarsal amputation. He developed wound dehiscence and gangrene of the skin of the amputation stump, for which he underwent surgical debridement. We were consulted for wound coverage; the wound bed was not yet ready. Figure shows the necrotic bed with ischemic skin edges. V.A.C.VERAFLO CLEANSE CHOICE™ Dressing was fixed with installation of 15 cc of MicroSafe® and soak time of 15 minutes every six hours with V.A.C pressure of 75 mm Hg (Figure ). After four days, more than 50% necrotic slough was removed (Figure ) and almost all after the second application (Figure ). He was transitioned to V.A.C. VERAFLO™ without the cleanse dressing and after two applications was ready for grafting (Figure ), and the skin graft take was 100% (Figure ). The patient was able to be discharged with covered and stable amputation stump in two weeks with only single visit to OR.
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pmc-6284877-1
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A 62-year-old white female with a known history of rheumatoid arthritis, pancreatitis, migraine, fibromyalgia, cervical disc diseases, asthma, general anxiety disorder, and unspecified depressive disorder was admitted to hospital with complaints of chest pain, extreme weakness of legs, diffuse body tremors, aches, worsening of anxiety, insomnia, and increased fearfulness. She described her chest pain as "floating" from the left to the right side with radiation into her right arm, jaw, and right upper back associated with occasional dyspnea, palpitations, and dizziness. These symptoms started after the patient was going through the pregabalin taper. She also reported suicidal ideations at the night of admission. She was given after an intravenous push of lorazepam 1 mg to help with anxiety and was admitted to telemetry unit. Cardiology and psychiatry were consulted. On cardiology consultation, all cardiogenic causes of chest pain were excluded, and electrocardiogram (EKG), cardiac enzymes, and positron emission tomography-myocardial perfusion imaging were normal. The initial EKG was of poor quality and it was repeated. The repeat EKG was done, and the cardiac causes for the chest pain were ruled out (Figure ).
During her visit with the psychiatrist, she denied any suicidal ideations and reported that this extremely worsening of anxiety, fearfulness, and somatic symptoms started after pregabalin taper was initiated about three months ago. Pregabalin taper was initiated by her outpatient rheumatologist because she was concerned about the long-term effects of pregabalin on brain waves. She was previously taking pregabalin 150 mg three times a day which was tapered at 150 mg intervals every month. In the last month of pregabalin taper when the dose was 150 mg daily, she started to have discontinuation symptoms which she described as “feeling of going crazy.” Bupropion extended-release (XL) 150 mg in the morning was started in outpatient a week before admission to address possible worsening of anxiety and depression based on the past history of a favorable response. She was already taking sertraline 100 mg in the morning, trazodone 100 mg at night, and alprazolam 0.5 mg three times a day. Her bupropion XL was discontinued considering its adverse effect on anxiety and lack of evidence for anxiety disorders. Alprazolam 0.5 mg was increased to every six hours as needed with a recommendation of considering duloxetine in future to address both anxiety and fibromyalgia. Subsequently, the patient continued to report an improvement in her chest pain, somatic symptoms, anxiety, and diffuse body tremors. Her symptoms eventually resolved and the patient was discharged. She was advised to schedule a follow-up visit with her outpatient physicians.
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pmc-6286527-1
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One month following cadaveric kidney transplantation a 45-year-old Caucasian man, under tacrolimus, micophenolate mofetil (MMF) and steroids immunosuppression developed PTDM. Thirty months after transplantation histological graft changes characterized by mesangial sclerosis, mesangiolysis with glomerular capillary ectasia and microaneurysms appeared (Additional file ). Diagnostic criteria for PDTM were consistent with current American Diabetes Association (ADA) clinical practice recommendation to diagnose diabetes in the general population [].
The deceased donor was a 58-year-old man whose cause of death was cerebral hemorrhage. The cold storage time was 12 h. The recipient’s cause of end stage renal disease (ESRD) was autosomal polycystic kidney disease. Non-modifiable recipient risk factors for diabetes were, excluding polycystic kidney disease, male gender and family history for diabetes, while donor non-modifiable risks included male gender, deceased donor. The donor history was negative for diabetes or insulin resistance. A week after transplantation, the recipient developed a moderate hypertension (Fig. ) requiring doxazosin treatment resulting in good blood pressure control. The patient‘s BMI was always within normal range values. Basiliximab was used as induction therapy. The maintenance immunosuppressive regimen included tacrolimus, MMF, and methylprednisolone. To treat the PTDM, repaglinide was introduced with a poor glycemic control; consequently it was substituted with insulin followed by acceptable glycemic levels: HbA1c 6.7% (52 mmol/mol). At time of PTDM diagnosis creatinine serum level (SCr) was 1.5 mg/dL and 24-h proteinuria was 300 mg (Fig. ). Glycosuria was detected persistently in the first six months after transplantation and the basal glucose monitoring showed glycemia levels that didn’t exceed 180 mg/dL. To achieve further improvement in diabetes management, tacrolimus was replaced with cyclosporine (CyA). Steroids were rapidly tapered and stopped. To minimize calcineurin inhibitors (CNI) toxicity, which was revealed in a 1-year-protocol biopsy, everolimus was introduced thereby lowering CyA through levels. A mild mixed dyslipidemia was controlled with atorvastatin and omega-3 fatty acid. A second graft biopsy was performed 30 months after transplantation due to renal function decline, SCr was 2.2 mg/dL, 24-h 200 mg microalbuminuria appeared, and BMI was 21. Although treatment with doxazosin and bisoprolol were titrated at each follow-up control, blood pressure always ranged between 140 and 160/90–100 mmHg (Fig. ). The patient did not accept angiotensin-converting enzyme inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARBs) because of associated side effects, cough and erectile dysfunction respectively. The main clinical and laboratory data are shown in Fig. . At this point Donor Specific Antibodies, serum C3 and C4 levels and autoimmunity tests were negative, microalbuminuria/creatininuria ratio was 56.82 mg/g. Histological analysis surprisingly showed mesangiolysis, glomerular capillary ectasia and microaneurysms (Fig. panel a). It was observed in about 30% of glomeruli; moreover sclero-hyalinosis, basal membranes thickness in 20% of glomeruli and typical nodular glomerulosclerosis as showed in Fig. panel b, in few glomeruli. C4d staining was negative and no evidence of immune deposits was detected. According to our post-transplant biopsy protocol, sample collection for electronic microscopy was not performed. After transplantation glycosylated hemoglobin never exceeded 6.9% (52 mmol/mol). A serial Ultrasound Doppler performed on kidney transplant every six months showed Renal Resistive Index (RRI) that didn’t exceed 0.65. A retrospective re-analysis of pre-implant donor biopsy confirmed no diabetic injury (Fig. panel c).
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pmc-6286540-1
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A 32-year-old, previously healthy, African American man presented to an emergency department 45 minutes after the acute onset of left facial droop and right-sided weakness (Fig. ). A thorough history confirmed an episode 1-week prior, during which he developed sudden onset of dizziness associated with nausea and vomiting that resolved within hours. He denied any past medical or surgical history and was taking no medications. He has no family history of tumors. In the emergency room, his vital signs were within normal limits. His physical examination was significant for a left facial droop and right hemiparesis. Auscultation of his chest revealed a regular rate and rhythm with no appreciable murmur. No additional significant findings were noted. Stroke protocol was initiated. A chest X-ray was normal and an electrocardiogram showed normal sinus rhythm. A head computed tomography (CT) scan was negative for signs of intracranial hemorrhage. He was subsequently started on tissue plasminogen activator (tPA) therapy. Magnetic resonance imaging (MRI) of his brain demonstrated a right basal ganglia infarct and an old left cerebral infarct. A carotid ultrasound was negative. TTE demonstrated a 1 cm by 1 cm mass on the posterior leaflet of the mitral valve with a moderate mitral regurgitation In addition, TTE revealed a questionable mass on the left coronary cusp of the aortic valve. These findings were confirmed with TEE (Fig. ), which verified no sign of endocarditis and no atrial septal defect. A complete hypercoagulable workup was negative. Stroke protocol continued with the working diagnosis of cerebrovascular accident secondary to emboli from the mitral valve mass. Within 24 hours, he regained function of the right side of his body and had complete resolution of symptoms. He was diagnosed as having transient ischemic attack (TIA) and discussion was undertaken regarding surgical excision of his mitral valve mass.
A median sternotomy was performed and cardiopulmonary bypass was employed via aortic and bicaval cannulation with full anticoagulation. His aorta was cross-clamped and his heart arrested with retrograde cardioplegia. The aortic valve was examined through an ascending aortotomy and all three valve leaflets appeared normal. A left atriotomy was made and the mass was easily identified on the posterior mitral valve leaflet adjacent to the mitral valve annulus (Fig. ). The mass was excised and a frozen section confirmed globular myxoma cells with abundant eosinophilic cytoplasm consistent with myxoma. The valve leaflet was reconstructed with an autologous pericardium patch and the annulus was supported using a running DeVega-type suture. The valve appeared normal and was tested; no regurgitation was noted. His left atrium and aorta were closed. His aorta was unclamped, after aggressive venting and de-airing maneuvers, and his heart returned to normal sinus rhythm with successful weaning from cardiopulmonary bypass. Anticoagulation was reversed with protamine and his chest was closed after placement of drains and pacing wires. At the conclusion of the operation, TEE confirmed appropriate mitral valve function and normal aortic valve with no evidence of a mass and no regurgitation at either location.
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pmc-6286565-1
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A 60-year-old male patient (height: 170 cm, weight: 60 kg) diagnosed with type 1 DM was scheduled for dental implant primary surgery in the right mandibular first and second molar region. The present patient, who had diabetic nephropathy and retinopathy as secondary complications, was prescribed intensification therapy of subcutaneous injection of insulin (ultra-rapid-acting insulin aspart/long-acting insulin glargine). The patient’s glycated hemoglobin (HbA1c) level was 6.4%, but he exhibited large and irregular diurnal variations in blood glucose values. Preoperative blood biochemistry examination revealed elevated alkaline phosphatase (492 U/L) and creatine kinase (282 U/L) and decreased albumin (3.6 g/dL) and glucose (39 mg/dL), accompanied by few subjective hypoglycemic symptoms such as nausea, malaise, and drowsiness. Urinary ketone bodies were negative, and an electrocardiogram indicated normal sinus rhythm (84 bpm).
Premedication with peroral antibiotics was carried out to prevent systemic infections that can be derived as a complication of DM. The patient’s initial postprandial blood glucose value just before surgery was 90 mg/dL. Preoperative cardiorespiratory parameters showed systolic/diastolic blood pressure of 162/93 mmHg, heart rate of 90 bpm, and oxygen saturation (SpO2) of 98%. Owing to the high blood pressure, the patient was treated to control intraoperative hypertension, with diligent attention to cardiovascular conditions; this was performed under the auspices of the first author, who is a certified dental anesthesiology specialist. An intravenous line with saline fluid was inserted for intravenous administration of nicardipine and/or diltiazem as antihypertensive agents to control blood pressure with noninvasive monitoring, including a lead II electrocardiogram. Local anesthesia with 3% prilocaine containing felypressin (0.03 IU/mL) as a vasoconstrictor for surgical procedures was applied to avoid unstable hemodynamics. Intravenous nicardipine (0.4 mg) and diltiazem (5 mg) were intermittently administered via a bolus injection to achieve a systolic blood pressure level lower than 150 mmHg with good control and stability of hemodynamics.
During surgery, the patient abruptly complained of discomfort such as malaise that seemed to be a symptom of hypoglycemia. At that time, neither conscious nor cardiorespiratory disturbance was confirmed, with blood pressure of 160/75 mmHg, heart rate of 75 bpm, and SpO2 of 96%. Blood glucose was promptly measured at 32 mg/dL and recognized as severe hypoglycemia. Oral glucose and an electrolyte-combined infusion of glucose were administered, and he immediately recovered, with blood glucose increasing to 65 mg/dL 15 min after glucose administration and to 127 mg/dL by the end of the surgical procedure.
The present surgery, involving the placement of a screw-shaped endosseous implant fixture made of titanium in the lower jaw, was smoothly performed precisely as planned. There was no implant placement supplemented by various guided bone regeneration, and no other issues occurred. The surgical procedure resulted in less invasion, limited to the area of implant fixture placement within the right mandibular region of the two molars, compared to commonly performed dental implant surgery that spans the entire lower jaw and is likely to be relatively highly-invasive. The durations of surgery and systemic management were 85 min and 140 min, respectively (Fig. ).
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pmc-6286575-1
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A 52-year-old HIV positive patient presented to the Prosthetics Clinic of the Department of Dentistry at Makerere University College of Health Sciences in March 2017 with a desire to replace her missing teeth and remove the broken ones so that she could look aesthetically pleasing as well as improve her nutrition. She had been taking Tenofovir, Lamivudine and Efavirenz since 2014; and cotrimoxazole prophylaxis since 2004. She was generally in good health with no other chronic systemic illnesses. She reported having lost her first three teeth as a young girl resulting from tooth decay in the early 1980s’. Between that time and 2008, she lost two more teeth as a result of tooth decay. In 2008, she reported suffering from a severe febrile illness that left her bed ridden for two weeks, during which time she was unable to perform proper oral hygiene measures. Upon recovery, she noticed that her gums were bleeding and some of her teeth were loose and a number were lost (See Table below).
Between 2014, when ART was initiated until she presented to our clinic, she reported suffering from extensive tooth decay that caused more loss of teeth leaving her with just four teeth and four retained roots (Figs. & ). There is no history of smoking or alcohol consumption and a diet rich in refined sugars. Table shows her CD4 and viral load measurements, as shown in her records at the HIV treatment centre.
Her diet consisted of predominantly high fiber carbohydrates including plantain, cassava, potatoes, rice, maize flour bread (posho) with fish, meat, beans, groundnut paste sauce and vegetables. As regards oral hygiene, she reported brushing twice a day using warm salt rinses.
On general examination, she was in fairly good general health condition without pallor of the mucous membranes, yellowing of the sclera or palpable cervical lymphadenopathy. The face was symmetrical with prominence of the zygomatic bones, sunken cheeks and mandibular prognathism, features associated with tooth loss. Temporomandibular joint (TMJ) examination showed no signs and symptoms of dysfunction.
Intraorally, there were light to moderate plaque deposits on the remaining dentition with diffuse blackish-purple pigmentation on the hard palatal surface and dorsum of the tongue probably secondary to ART or Kaposi’s sarcoma (Fig. ). In the maxillary arch, tooth # 12, 15 and 25 were present with a peculiar type of cervical caries (caries affecting a significant portion of the cervix/neck of the tooth). There were also retained roots of tooth # 11, 13, and 22. In the mandibular arch, only tooth # 34 with the same peculiar cervical caries and retained root of tooth # 35 were present.
A diagnosis of partially edentulous maxillary and mandibular arches, retained roots of tooth # 11, 13, 22 and 35, as well as cervical caries of 12, 15, 25 and 34 was made. Following oral health education and mouth preparation, this patient received a set of removable acrylic full upper and lower dentures, which has significantly improved her feeding abilities and cosmetic concerns. (Fig. ).
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pmc-6286578-1
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The study was approved by the Cyprus National Bioethics Committee and informed, written consent was obtained from all participants.
The patient under discussion is a 30 year old male, weight lifter with hyper-acute onset chest and back pain. Upon initial evaluation, the patient did not have any manifestation of any phenotypic findings (i.e. iris flocculi, livedo reticularis, aortic valve abnormalities) hinting towards connective tissue disorders or aortic pathology. Based on echocardiography and chest CT findings the patient was diagnosed with a Type A Aortic Dissection with severe aortic valve regurgitation. The patient was then emergently intubated and was transferred to the American Medical Center (AMC) in Nicosia, Cyprus where he had emergency aortic surgery and Bentall procedure. No angiography was performed due to the fact that the patient had aortic dissection and was an emergency. Intraoperative findings showed a 70 mm diameter aortic root aneurysm with dissection extending from the sinotubular junction to the aortic root. The aortic annulus was extensively dilated and the aortic dissection extended down the origin of the left main coronary artery involving also the aortic valve commissures that resulted in severe aortic valve regurgitation. There was no evidence of involvement of the distal ascending aorta and the aortic arch.
Further evaluation of the patient’s family showed that several family members had ascending aortic aneurysms. The patient’s father, a 60-year-old male had an asymptomatic aortic root and ascending aortic aneurysm of 52 mm that also required aortic valve, aortic root and ascending aortic replacement (Bentall procedure). Pre-operatively thefather had CT chest coronary angiography that confirmed the presence and dimensions of the aneurysm and coronary angiography did not show any coronary artery disease. The patient’s mother, a 56-year-old female was also screened with echocardiography that showed ascending aortic dilatation, 42 mm in diameter. Subsequent screening of the siblings, two sisters at the ages of 22 and 34 respectively did not show any abnormalities. Following the genetic screening of the index patient, his parents and his siblings, a follow-up was recommended for both his sisters. Six years after the initial screening of the sisters, the 34-year-old was found to have a mild dilation of the ascending aorta (39 mm) by echocardiography with a 4–5 mm increase in diameter in comparison with the previous echocardiography results. The pedigree of the family is demonstrated in Fig. . The index patient’s and the family’s medical diagnosis and interventions are shown in Table .
To understand any genetic implication in the cause of TAA of this family, targeted sequencing was performed on DNA samples from the father and the son. Whole blood samples were used to extract DNA using the QIAamp Blood Midi Kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions.
The TruSight Cardio Sequencing panel (Illumina, San Diego, CA, USA) which includes 16 genes, the most predominant, with known association to familial aortic aneurysm was initially used and paired-end sequencing was performed on an Illumina Miseq platform at our Institute. Our results showed that the two samples (son and father) had an average depth of coverage of 117x and 108x respectively for the MYH11 region and an average depth of coverage of 135x and 125x for the ACTA2. Raw variants were filtered to include only those variants with a coverage depth greater than 20× and a Quality score greater than 30. The Illumina run generated 94.8% of base calls having >Q30. We followed the Genome Analysis Toolkit (GATK) best practices for variant calling. Sequencing reads were aligned to the human reference genome build GRCh37/hg19 using Burrows Wheeler Aligner (BWA) software. Different GATK programs were used for local realignment and base recalibration and the SAMtools (Sequence Alignment/Map) pipeline was used to retrieve per-base read depth information. Calling was performed using Haplotype Caller from the GATK. The called Small Nucleotide Variants (SNVs) and Insertions and Deletions (InDels) were annotated using the Annotate Variation (ANNOVAR) [] software. The variants were then filtered using the GATK best practices (), focusing on rare (minor allele frequency < 0.05) and known pathogenic variants. MPS results identified a frameshift deletion c.363_367del GAGTC, p.Met121Ilefs*5 in the ACTA2 gene (Genbank transcript ID: NM 001613) and a non-synonymous variant c.3234C > G, p.Ile1078Met in the MYH11 gene (Genbank transcript ID: NM 001040114). In order to predict the pathogenicity of the novel variants, the in silico software of the computational algorithms SIFT (Sorting Intolerant from Tolerant) [] (), PolyPhen2 (Polymorphism Phenotyping) [] (), Mutation Taster [] (), PROVEAN (Protein Variation Effect Analyzer) [] () and VEP (Variant Effect Predictor) [] () were used. All five different prediction tools (SIFT: Deleterious PolyPhen2: Probably Damaging, Mutation Taster: Disease causing, PROVEAN: Deleterious, VEP: High) presented a consistent result describing the p.Met121Ilefs*5 (c.363_367delGAGTC) variant as having a detrimental/deleterious effect. These predictions, suggest that this variant has a significant effect on the function of ACTA2 and the development of TAA. Regarding the p.IIe1078Met (c.3234C > G) variant in the MYH11 gene, PolyPhen2 and PROVEAN prediction tools presented it as being a benign and neutral variant respectively while, VEP, SIFT and Mutation Taster suggested it as being a moderate, deleterious and disease causing variant respectively In addition, Iterative Threading ASSEmbly Refinement (I-TASSER) modeling [–], a protein structure prediction tool, was used to predict the secondary structure of the ACTA2 and MYH11 proteins. The results showed the presence of the amino acids Met121 and Ile1078 respectively, on a helix structure motif (Fig. ). It is difficult to describe the protein function of the regions where these variants occur as the protein structure of ACTA2 and MYH11 is not completely known as yet after performing a search in UniProtKB and Protein Data Bank (PDB).
It is noteworthy that no known pathological sequence variants were identified in the affected individuals we studied. The TruSight Cardio sequencing panel led to the identification of a 5 bp frameshift deletion in the ACTA2 gene (c.363_367del, p.Met121Ilefs*5) which results in a premature stop codon as well as a non-synonymous variant in the MYH11 gene (c.3234C > G:p.I1078M) predicted as deleterious and disease causing by the in silico software of the computational algorithms used. Both variants were absent from public variant databases, such as the dbSNP (), 1000 genome dataset (), Genome Aggregation Database (), and Human Genetic Variation Browser () databases. With respect to the MYH11 (c.3234C > G:p.I1078M) it is noteworthy that (c.3234C > T:p.I1078I) has been detected four times in the Genome Aggregation Database (GnomAD) and it is however synonymous (GnomAD, n = 282,728). Both the affected father and son displayed the novel heterozygous p.Ile1078Met variant in the MYH11 gene while the son was also identified with the novel heterozygous p.Met121Ilefs*5 (c.363_367delGAGTC) variant in the ACTA2 gene.
The identified variants were verified in the proband and other consenting family members (father, mother and two sisters) were screened by Sanger sequencing. PCR amplification was performed using 5 Units AmpliTaq DNA polymerase (Applied Biosystems, Foster City, CS). The ACTA2 gene was initially amplified by PCR at 55 °C annealing temperature using the ACTA2-Forward: 5’ CTTTCAAGCTGTTCCTGTC 3′ and the ACTA2-Reverse: 5’ TGTGTTTCTCCTCTGTCC 3′ primers. The MYH11 gene was amplified by PCR at 55 °C annealing temperature using the MYH11-Forward: 5’ AGTGAACAGGGTCGAGAAG 3′ and the MYH11-Reverse: 5’ TTTGCAGTGCGGCTAAAG 3′ primers. Amplified products were cleaned using QIAquick PCR Purification Kit (Qiagen, Hilden, Germany) and subjected to cycle sequencing according to the manufacturer’s instructions [BigDye Terminator v1.1 Cycle Sequencing Kit (Applied Biosystems]. The reactions were run on a 3130xL Genetic Analyzer (Applied Biosystems, Foster City, CA, USA) with the results analyzed via the Sequencing Analysis 5.2 Software (Applied Biosystems).
Sanger sequencing analysis of the patients’ ACTA2 and MYH11 genes revealed that the p.IIe1078Met variant was inherited from the father and the p.Met121Ilefs*5 variant from the mother (Fig. ). Results showed that the mother, the son and the 34-yo daughter had the p.Met121Ilefs*5 variant whereas the father, the son and the same daughter had the p.Ille1078Met variant. Overall, results showed that the affected son and the one daughter are carriers of both variants inherited one from each parent. The second daughter did not show any variants in either of the two genes.
In order to evaluate evidence for a sequence variant we followed the guidelines of the American College of Medical Genetics and Genomics (ACMG) []. The two variants (chr10:90703556_90703560delGAGTC and chr16:15831386 G > C) of ACTA2 and MYH11 genes are a deletion which results in a truncated transcript in exon 4 (c.363_367del GAGTC, p.Met121Ilefs*5) and a single base substitution in exon 26 (c.3234C > G, p.Ile1078Met), respectively. Combining the PVS1 criterion (predicted as a null variant) with 1 Moderate (PM2: Absence in population databases) classifies the ACTA2 variant as “likely pathogenic”. The MYH11 variant was interpreted as “variant of uncertain significance (VUS)” based on the following criteria: Absent in population databases (PM2), and computational evidence by different in silico tools applied supported a deleterious effect on the gene (PP3). For the p.Ile1078Met of MYH11, the small number of affected individuals (meiosis) was not enough to use the PP1 criteria. Although this variant is not found in GnomAD controls and is located on coiled-coil myosin heavy chain tail region, the evidence at this point is not enough to indicate that p.Ile1078Met is pathogenic according to ACMG standards. Therefore, we concluded that the variant in ACTA2 is more likely to contribute to the TAA phenotype.
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pmc-6286606-1
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In November 2007, a 51 year-old man was admitted to the Centre Hospitalier Universitaire Vaudois in Switzerland for observation due to leucocytosis. His white blood cell (WBC) count was 232,000/μL, with 130,000/μL neutrophils (69.8%), 2300/μL basophils (1%), 7000/μL eosinophils (3%), 140 × 109/L platelets, 9.5 g/dL hemoglobin, and 2% peripheral blood blasts. He had no liver or spleen enlargement. The calculated Sokal, EUTOS and ELTS scores were low (0.64), low (7), and intermediate (1.639), respectively. A bone marrow aspirate showed marked hypercellularity and myelogenous hyperplasia without an increase in the blast ratio. Cytogenetic analysis showed the presence of a 46,XY,t(9;22)(q34;q11.2),+der(22)t(9;22) karyotype in 25 metaphases, and the presence of a BCR-ABL1 gene fusion was confirmed by FISH analysis. Molecular analysis revealed the presence of an e19a2 BCR-ABL1 transcript and the patient was diagnosed with an e19a2-positive chronic phase CML. The detection of an additional Ph+, a major route abnormality that has been reported as an adverse prognostic factor, does not mandate in daily practice a different initial treatment approach [], therefore imatinib 400 mg QD was started. The patient rapidly achieved an haematological response and, after 3 months of treatment, a partial cytogenetic response (PCyR) was observed (28% Ph + metaphases), corresponding to an optimal response according to the ELN guidelines []. After 6 months of imatinib therapy, he lost his cytogenetic response (CyR), with all the metaphases analysed showing the same karyotype detected at diagnosis, which suggested treatment failure []. At this point, the patient interrupted the treatment and was lost to follow-up. In May 2010, the patient presented with hyperleukocytosis (300,000/μL), left abdominal pain and malaise. A CT scan revealed a splenomegaly of 20 cm and karyotype analysis showed the presence in 25 metaphases of the same karyotype observed at diagnosis. In view of the patient’s previous history, it was decided to initiate treatment with imatinib 600 mg QD. After 4 months of therapy, he was in haematological remission, but karyotype analysis showed only a minimal cytogenetic response (75% Ph + metaphases). In December 2010, 6 months after starting therapy, his cytogenetic response improved to a minor response (45% Ph + metaphases), corresponding to a sub-optimal response []. In February 2011, by decision of the patient, he was transferred to our institute (Additional file : Table S1). At the time of admission, he was in complete haematological response. Molecular analysis showed the presence of an e19a2 BCR-ABL1 transcript, but no cytogenetic analysis was performed. In order to quantitate the e19a2 BCR-ABL1 transcript and monitor response to treatment, a BCR exon 19 forward primer was designed (ENF007; 5′- CACTGAAGGCAGCCTTCGA-3′) and used with reverse primer ENR561 and probe ENP541 (7). A standard curve was established by tenfold dilutions of patient cDNA. Control ABL1 transcripts were detected as previously described []. At this point, 9 months after restarting imatinib therapy, the BCR-ABL1/ABL1 ratio was 40.258% (Fig. ). Three months later, at the 12-month evaluation, the patient finally achieved a complete cytogenetic response (CCyR), with a BCR-ABL1 level of 0.846% (Fig. ). At this point, and taking into account the good response to treatment, the patient was switched to imatinib 400 QD. However, 6 months later, karyotype analysis showed loss of CCyR (40% Ph + metaphases; minor CyR), with a concomitant rise in BCR-ABL1 levels (6.070%). Two months later, an additional rise in BCR-ABL1 levels to 15.820%, confirmed loss of molecular response and prompted search for mutations in the ABL1 kinase domain as previously reported []. Sanger sequencing allowed identification of an E255V mutation (Fig. ), leading to start of second line dasatinib therapy (140 mg QD), and prompting search for an unrelated stem cell donor. Three months after start of dasatinib therapy, the patient achieved a CCyR with a BCR-ABL1 level of 0.365% and 5 months later, the patient maintained a CCyR, with a BCR-ABL1 level of 0.671%. However, in the following months, the patient showed a progressive loss of cytogenetic response: PCyR (17% Ph + metaphases), minor CyR (38% Ph + metaphases), and minor CyR (63% Ph + metaphases), 14 months, 17 months and 21 months after starting second-line dasatinib therapy, respectively. At this time, dasatinib therapy was stopped and the patient underwent allogeneic haematopoietic stem cell transplant (HSCT) from a 9/10 matched HLA unrelated donor (one HLA-B mismatch), after a non-myeloablative reduced-intensity conditioning (RIC) regimen that included busulfan, fludarabine and antithymocyte globulin (ATG). The graft-versus host disease (GVHD) prophylaxis consisted of the association of tacrolimus with mycophenolate mofetil (MMF). Neither acute GVHD nor other significant clinical complications were observed. One month after transplant, cytogenetic analysis showed persistence of disease (10% Ph + metaphases; PCyR), with a BCR-ABL1 level of 1.229%, which prompted start of nilotinib therapy (400 mg BID). Two months later, his BCR-ABL1 level rose to 8.132% with 23% Ph + metaphases (PCyR), suggesting resistant disease. Mutational analysis by Sanger sequencing revealed the presence of a T315I mutation, which led to the interruption of both nilotinib therapy and immunosuppression. Four months after transplant the patient lost his PCyR (70% Ph + metaphases; minor CyR) and his BCR-ABL1 levels increased to 12.477%. The patient showed mixed chimerism predominantly donor-derived. Since ponatinib was not available at the time at our institution and approval was pending, nilotinib therapy (400 mg BID) was restarted. One month later, karyotype analysis showed a minimal CyR (97% Ph + metaphases) and the patient was submitted to donor lymphocyte infusion (DLI), which resulted only in a minor CyR (90% Ph + metaphases) that nevertheless was maintained in the following months. This was, however, accompanied by increasing BCR-ABL1 levels to a maximum of 32.879%, 10 months after HSCT. The patient also showed progressive loss of donor chimerism (mixed chimerism with < 5% donor cells). At this point ponatinib approval was granted, nilotinib therapy was interrupted and ponatinib was started at the standard dose of 45 mg QD. Before ponatinib initiation, and considering its well-known cardiovascular toxicity profile, a comprehensive cardiologic and metabolic evaluation was performed. The only cardiovascular risk-factors identified were dyslipidaemia and arterial hypertension (AHT), which were already present since the beginning of the disease and were easily manageable with lifestyle modifications and therapy (enalapril/hydrochlorothiazide 20/12.5 mg, ½ tablet QD), respectively. Two months later, karyotype analysis showed a PCyR (17% Ph + metaphases) and a reduction of BCR-ABL1 levels (10.940%) was observed. Subsequently, four months later, the patient achieved a CCyR associated with a BCR-ABL1 level of 0.213%. In the following months a progressive decline in BCR-ABL1 levels was documented: 0.029% at 6 months (equivalent to a Major Molecular Response; MMR), 0.005% at 9 months (equivalent to a MR4.0), 0.001% at 12 months (equivalent to a MR4.5), and 0.000% at 15 months (equivalent to a MR5.0). The patient maintained ponatinib 45 mg QD treatment during an additional 16 months and, since a persistent and sustained MR5.0 with no detectable disease was documented, dosage was reduced to 15 mg QD. Treatment with ponatinib was well tolerated since the beginning of therapy with no evidence of toxicity. At the time of the last evaluation, 15 months after ponatinib dose reduction, the patient maintained a sustained MR5.0 with no detectable disease. No evidence of cardiovascular toxicity was observed at the last observation. Under ponatinib treatment, the patient maintained a mixed chimerism with < 5% donor cells. To evaluate if the T315I clone was present at low-levels in the earlier phases of the disease, we used CastPCR (Competitive Allele-Specific TaqMan PCR™, Applied Biosystems) specific for the T315I mutation in all the available RNA patient samples collected since he was admitted to our institution. For the T315I mutation detection, each sample was run in real-time PCR with the assay targeting both the mutation and the corresponding reference gene, according to the manufacturer’s instructions. After amplification, data files containing the samples Ct values were imported into Life Technologies Mutation Detector™ Software for post-PCR data analysis. CastPCR is highly specific and sensitive and can detect and quantitate rare amounts of mutated DNA/cDNA in a sample that contains large amounts of normal, i.e., non-mutated, DNA/cDNA, with a sensibility up to 0.1%. Using this approach, we could trace back the presence of the T315I mutation to all the RNA samples up to the detection of T315 mutation by Sanger sequencing shortly after HSCT.
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pmc-6286608-1
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A 33-year-old Chinese female complained of sudden onset of a para-central large scotoma in her left eye seven days after the third intramuscular administration of rabies vaccine (Rabipur, Novartis) according to standard vaccine time schedule (days 0, 3, 7, 14 and 28) for a stray cat scratch. The type of the rabies vaccine is embryonated-egg vaccine. She has not been administered with other vaccines recently and it was the first time she had symptoms after vaccination. The stray cat was not available for observation of rabies symptoms. Otherwise healthy, the patient has no remarkable medical history or underlying pathology. Her best-corrected visual acuity (BCVA) at the time was 20/20 in both eyes with − 9.0 D right eye and − 8.5 D left eye. An ophthalmoscopic examination of the left eye revealed nothing to explain her complaints. During the follow-up, she developed photopsia in the left eye.
Visual field testing showed an enlarged blind spot and decreased sensitivity superiorly and nasally (Fig. a). Fundus fluorescence angiography (FFA) and autofluorescence (AF) revealed hyperfluorescence corresponding to the area of the retina in the region of ellipsoid zone abnormalities. FFA showed right eye the normal appearances in arteriovenous phase (Fig. a) and late phase (Fig. b), and early choroidal background hyperfluorescence (Fig. c) and mild diffuse leakage of fluorescein was noted in the late phase (Fig. d) of the left eye. Optical coherence tomography (OCT) demonstrated disruptions in the ellipsoid zone of the posterior retina (Fig. a). Fundus AF demonstrated multiple ill-defined spots of markedly increased AF in the posterior pole (Fig. a).
Initial work-up for a complete blood cell count, immunological test, syphilis, human immunodeficiency virus (HIV), and brain computed tomography (CT) were all negative. MEWDS was high in the differential diagnosis. As the patient refused to take oral steroid, she received local steroid injection (retrobulbar injection of triamcinolone acetonide 40 mg). At the follow-up examination 2 months after the initial evaluation, symptoms, OCT (Fig. b), Fundus AF (Fig. b), and the visual field (Fig. b) were partially resolved. Three years later, the patient was examined again, the fundus was completely restored to normal both on fundus photograph and OCT (Fig. a&b) and the BCVA was 20/20 and all symptoms disappeared.
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pmc-6286736-1
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A 35-year-old male presented to a regional urban hospital two days following an assault-related blunt traumatic injury. The evening before arrival at the emergency department, he noticed swelling around his chest and neck. It was worse the next morning, precipitating his presentation to hospital. On initial assessment, the patient had a Glasgow Coma Scale of 15, and vital signs were BP 125/66, HR 92, and SpO2 95% on oxygen at 5 litres per minute via nasal cannulas. At the time of presentation, the patient displayed moderate subcutaneous emphysema on physical examination and subcutaneous emphysema on chest X-ray ().
Computed tomography of the chest, abdomen, and pelvis revealed a left-sided pneumothorax and subcutaneous emphysema (Figures and ). Significant laryngeal swelling was also noted (). The patient was found to have multiple rib fractures, a lacerated scalp, and a Grade 1 liver laceration. A chest tube was not inserted at this time, after consultation with a thoracic surgeon at the nearby Level 1 trauma hospital. Upon reviewing the CT, it was suggested that the relatively small amount of pneumothorax for the degree of subcutaneous emphysema indicated potential pleural adhesions. The view of the thoracic surgery service and trauma was that an incorrectly placed chest tube at the regional centre may have risked entering the lung parenchyma. The patient was transferred to a Level 1 trauma centre 4 and 1/2 hours after presentation arriving 30 min later.
The extent of the subcutaneous emphysema was such that the patient could not be placed in a cervical spine collar for transport to the referral facility. His cervical spine was instead immobilized with towel rolls. Vital signs remained stable in transit, and the patient arrived at the trauma centre awake, alert, and breathing spontaneously on supplemental oxygen. The patient was assessed by the trauma service and thoracic surgery.
Over the next two hours, the patient's condition deteriorated. While the patient had been ordered to get admitted to the trauma nursing unit, the emergency room physician wisely held the patient in the high observation area of the emergency department. Seven hours after initial presentation to the regional hospital and two hours after arrival at the trauma centre, the patient demonstrated altered phonation in addition to yet greater swelling around the neck. In order to obtain a definitive airway in a controlled environment, the patient was taken to the operating room for intubation with surgical standby.
In the operating room, the patient's oxygen requirements increased, with desaturation on 10 litres per minute, now via facemask. The patient was also becoming increasingly agitated. An attempt was made at awake fiber-optic intubation, but the posterior oropharyngeal anatomy, glottis, and larynx could not be visualized. Given the increasing oxygen demands and the challenging airway, after considering all options, an awake tracheostomy was performed with a Shiley XLT extended-length tracheostomy appliance. A left thoracostomy tube was then placed. Bronchoscopy in the OR did not reveal proximal tracheobronchial injury.
The patient was transferred to the intensive care unit where he remained for 21 days. He had complications of ventilator-associated pneumonia and delirium due to substance withdrawal. A repeat bronchoscopy on day 18 was normal, and he was successfully weaned from the ventilator that day.
Subcutaneous decompression was achieved with continued suction via the thoracostomy tube inserted in the operating room at the time of the tracheostomy. Considerable subcutaneous air was also seen escaping from the tracheostomy incision. The subcutaneous emphysema had resolved by day 14. He was transferred to the trauma ward on day 21 and decannulated on day 22. A normal CXR was performed on day 23 (), and he was discharged on day 28.
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pmc-6286739-1
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An eight-year-old girl presented to the emergency department (ED) with cervical spine (C-spine) pain post a fall from a climbing frame approximately 4 ft off the ground. The patient had a fall from 5 ft backwards with a hyperextension injury to the neck. The patient stood from the ground holding her neck. The patient denied any weakness or paraesthesia of the upper limbs or lower limbs. No evidence of a head injury was noted, including no loss of consciousness, vomiting, or visual disturbance. The patient was immobilized by the local family practitioner and transferred to the emergency department.
An isolated cervical spine injury was identified after initial assessment. On examination, the young girl had midline C2-C5 cervical spine tenderness with associated paraspinal muscle tenderness. Neurological examination was normal.
Initial imaging included primary C-spine radiographs showing no bony injury (). A computed tomography scan was also obtained, confirming no bony injury (). The patient was admitted overnight in cervical spine immobilization for magnetic resonance imaging (MRI) due to the persistent midline tenderness.
An MRI obtained revealed disruption of the posterior atlantoaxial ligament. No other injuries were noted including no injury to the posterior longitudinal ligament or posterior annulus fibrosus of C1-2 (Figures and ). The patient was treated in soft collar immobilization and followed up in the outpatient clinic. Follow-up cervical radiographs including flexion and extension views revealed no abnormality. Week 6 post injury, no midline tenderness was elicited on examination. Repeat radiographic imaging was normal, but static and dynamic views of the C-spine were normal with no evidence of instability. The soft C-spine immobilization was removed, and physical therapy was initiated.
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pmc-6286740-1
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A 4-year-old girl was previously diagnosed with asplenia, single right ventricle, and supracardiac TAPVC. She underwent pulmonary artery banding at the age of 1 month, followed by a bidirectional Glenn procedure and TAPVC repair at the age of 5 months. She did not demonstrate symptoms of PVO, and there was no evidence of delay in the excretion of contrast media in cardiac catheter examination before Fontan procedure. Extracardiac Fontan palliation was subsequently performed at the age of 19 months. At the age of 3 years, although right lower PVO occurred because of the compression of the vertebra, she did not demonstrate symptoms of PVO (). At the age of 4 years, she underwent a cardiac catheterization to evaluate her hemodynamic parameters after Fontan procedure (). She was taking oral aspirin, warfarin, and enalapril. After a routine hemodynamic assessment, NO and oxygen tests were performed. A pigtail catheter was placed in the single ventricle, and a wedge catheter was positioned in the pulmonary artery. We performed the pulmonary vasodilator examination in the same way as when doing the examination in patients with pulmonary hypertension []. Subsequently, 20 ppm NO was administered via face mask. After 5 minutes of NO administration, her hemodynamic parameters were measured. Following a washout period of 5 minutes, 100% oxygen was administered, and after 5 minutes of oxygen administration, her hemodynamic parameters were again measured. To measure the pulmonary arterial wedge pressure and pulmonary arterial pressure accurately, the waveform was monitored carefully (Figures and ). After the administration of NO, the single-ventricle end-diastolic pressure, bilateral mean pulmonary arterial pressure, and cardiac index did not change. Oxygen saturation did not change at 95%, and pulmonary resistance index decreased from 2.1 to 1.0 Um2. However, the right lower pulmonary arterial wedge pressure increased from 8 to 12 mmHg, and the left lower pulmonary arterial wedge pressure increased from 7 to 9 mmHg. The cardiac index remained almost the same. Similarly, following the administration of oxygen, the single-ventricle end-diastolic pressure did not change; however, the right lower pulmonary arterial wedge pressure increased from 8 to 14 mmHg and the left lower pulmonary arterial wedge pressure increased from 7 to 12 mmHg. The bilateral mean pulmonary arterial pressure increased from 13 to 15 mmHg. Although angiography was performed after the inhalation of NO and oxygen, there was no evidence of left pulmonary venous obstruction or delay in the excretion of contrast media (Figures and ). A systemic-to-pulmonary shunt was also nonexistent. On echocardiography, there was no acceleration of blood flow at the left pulmonary vein or surgical anastomosis between the pulmonary venous confluence and the atrium. There was also no stenosis of the atrioventricular valve. Despite the inhalation of NO and oxygen, there was no acceleration of blood flow, and stenosis was not identified at the surgical anastomosis between the pulmonary venous confluence and the atrium ().
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pmc-6286750-1
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A 62-year-old female with a past medical history of hypertension presented to the emergency department with worsening left flank pain associated with nausea and subjective fevers. Physical examination findings included left lower quadrant tenderness and left sided costovertebral angle tenderness. The patient had no history of nephrolithiasis.
The patient was afebrile, but her initial vital signs were significant for hypertension (182/95)/MAP (124), tachycardia (109 beats per minute), and tachypnea (20 breaths per minute). The patient's complete blood count (CBC) and serum chemistry panel showed a leukocytosis of 16,500/μL and a creatinine of 1.36 mg/dL. Urinalysis found 44 white blood cells (WBCs) and 16 red blood cells (RBCs) per high-power field (HPF), with positive leukocyte esterase (500/μL), negative nitrites, and no bacteria, and initial urine culture was contaminated. Initial CT scan showed obstructing left sided stones (1 cm calcified stone within the proximal left ureter and a 2.2 cm stone below the ureteropelvic junction) causing hydronephrosis.
The patient was then started on levofloxacin at the time of admission and subsequently underwent a left ureteral stent placement. During stent placement, purulent discharge was noted after cannulation with a guidewire. Postoperative course was unremarkable. The urine culture showed no growth or presence of bacteria after 24 hours. Considering the patient was afebrile, hemodynamically stable, and labs were within normal limits, the patient underwent URS-LL one day following stent placement. The duration of the procedure was 94 minutes. An access sheath was placed and a flexible ureteroscope was advanced into the kidney. A single stone was encountered in the lower pole of the kidney and was fragmented to dust then extracted with a zero-tip basket. Following removal of the stones, the patient clinically improved and was discharged the next day with a stent in place.
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pmc-6286750-2
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A 49-year-old female with a past medical history of a solitary right kidney presented with right lower quadrant pain associated with nausea, vomiting, decreased urination, and dysuria. Physical exam findings included right lower quadrant tenderness and right costovertebral angle tenderness. The patient had no history of stones.
During the initial evaluation, the patient's vital signs were significant for hypotension (77/46), tachycardia (117 beats per min), tachypnea (22 breaths per min). She was afebrile; however, had leukocytosis of 24,190/μL, creatinine of 3.90 mg/dL, and lactic acid of 7.49 mg/dL. There was concern for sepsis due to a sequential (sepsis related) organ failure assessment (SOFA) score >2 []. Urinalysis found 30 WBCs and 6 RBCs per HPF, positive leukocyte esterase, and negative nitrites. Urine culture grew Klebsiella pneumoniae. Initial CT scan showed an atrophic left kidney and a 4 mm stone in the right ureterovesical junction causing mild hydroureteronephrosis with findings suggestive of pyelonephritis ().
The patient underwent an emergent cystoscopy with right ureteral stent placement and was started on piperacillin-tazobactam. Intraoperatively, purulent discharge emitted from the right ureteral orifice after cannulation with a guidewire. Her postoperative course was complicated by persistent hypotension requiring vasopressors. Blood cultures revealed Klebsiella and antibiotics were tailored accordingly.
Three days following decompression and continued IV antibiotics, repeat blood and urine cultures were negative for bacteria. On the fifth day, with no obvious signs or symptoms of persistent infection, the patient underwent a URS-LL and right ureteral stent placement with a string. A rigid ureteroscope was introduced into the ureter and a stone was encountered in the distal ureter. Laser lithotripsy was performed, and the stone was obliterated into small fragments which were extracted with a wire basket. Laser lithotripsy was performed instead of a simple extraction to safely extract the stone without causing damage to the ureter. Subsequently, an access sheath was then placed and a flexible ureteroscope was advanced into the kidney. Randall plaques were encountered in the upper pole and were removed using laser lithotripsy. The duration of the procedure was 108 minutes. Following URS-LL, the patient recovered without complications and was discharged on the same day with a completion course of PO antibiotics. The patient was at high risk to be lost to follow up, so was instructed to pull the string to remove the stent on postoperative day 3. Given what was essentially a solitary kidney and the patient's social circumstances, the risk of a retained ureteral stent in this setting outweighed the risks of premature stent removal; thus the stent was left attached to the string to facilitate self-removal of the stent.
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pmc-6286750-3
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A 59-year-old female with no significant past medical history presented to the emergency department with acute onset right flank pain radiating to the right lower quadrant. The pain was described as stabbing and constant and associated with nausea and vomiting. She had no prior history of nephrolithiasis. The patient's CBC and serum chemistry were within normal limits. Urinalysis was positive for nitrite, leukocyte esterase (500/μL), 27 WBC per HPF, 23 RBC per HPF, and moderate bacteria. Urine culture revealed the presence of >100,000 CFU/mL Escherichia coli. Initial CT scan showed a 6 mm obstructing right proximal ureteral stone causing mild hydronephrosis and a 2 cm left inferior pole partial staghorn calculus causing calyceal dilatation ().
The patient was then started on IV levofloxacin and underwent bilateral ureteral stent placement the following day without complication. Urine culture collected during stent placement showed resolution of bacteriuria. Five days after stent placement and continued antibiotic therapy, the patient underwent bilateral URS-LL, complicated by left ureteral perforation upon guidewire placement. The perforation occurred due to a technical error where the stiff end of the PTFE wire was advanced up the ureter and was seen perforating the ureter on fluoroscopy. The wire was removed and then advanced correctly. An access sheath was placed past the perforation and a flexible ureteroscope was advanced. One stone was encountered in the left inferior pole of the kidney and another was encountered in the right proximal ureter. They were both fragmented then extracted with a zero-tip basket. The duration of the procedure was 60 minutes. The patient was discharged after two days of hospitalization. The stents were removed in clinic three weeks postoperatively without complication.
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pmc-6286750-4
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A 62-year-old female with a past medical history of hypertension, poorly controlled diabetes, and nephrolithiasis presented to our hospital's emergency department three days after receiving a diagnosis of UTI with multiple nonobstructive renal stones. The patient was found to have right sided abdominal pain radiating to her right flank with fevers, nausea and vomiting, and endorsed dysuria. CBC and serum chemistry panel showed a leukocytosis of 13,740/μL, and creatinine of 1.06 mg/dL. Urinalysis was positive for ketones, proteinuria, urobilin, nitrite, leukocyte esterase, 146 RBC per HPF, over 182 WBC per HPF, and many bacteria. Urine culture was positive for Escherichia coli. CT scan performed at our institution showed an 8 mm right obstructive proximal ureteral stone as well as bilateral nonobstructive stones ().
The patient was given ceftriaxone and underwent right ureteral stent placement. The patient tolerated the procedure well. Intraoperative urine culture was positive for E. coli and she was started on piperacillin-tazobactam. Four days after decompression, she underwent uncomplicated URS-LL. A rigid cystoscope was introduced into the bladder and a flexible grasper was used to grasp and remove the retained ureteral stent. A ureteral access sheath was placed over a guidewire before a flexible ureteroscope was introduced into the ureter through the access sheath. An 8 mm stone was encountered in an interpolar calyx. Laser lithotripsy was performed to obliterate the stone into small fragments which were then extracted with a wire basket. No stent was placed after procedure. The duration of the procedure was 43 minutes. Postoperative course was uneventful, and the patient was discharged later that day.
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pmc-6286763-1
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In February 2008, a 26-year-old female patient consulted us for a second opinion before surgery on a suspected ME cholesteatoma. She had been complaining for several months about right aural fullness and otalgia.
The otoscopy revealed a posterosuperior reddish retrotympanic mass without retraction pockets accompanied by a subnormal audiometry. The well-defined soft tissue mass density observed on the CT scan close to the ossicles but without any bone erosion did not support a diagnosis of cholesteatoma (cf. ). A surgical exploration was performed, and the tumor easily resected through an ossicle preservation transmastoïd tympanoplasty.
Histological examination revealed an epithelial proliferation with architecture sometimes trabecular, sometimes glandular, embedded in a dense fibrous stroma. The tumor was composed of uniform cuboidal or cylindrical cells with round to oval nuclei and a plasmacytoid morphology. No necrosis or mitotic activity was identified (cf. ). Periodic acid Schiff (PAS) staining revealed the presence of mucin in some cytoplasms.
Immunohistochemical staining was strongly positive for synaptophysin (cf. ), focally positive for chromogranin (cf. ) and neuron-specific enolase (NSE), reactive for epithelial membrane antigen (EMA) and cytokeratin (AE1/AE3) but was negative for S100 protein. The Ki67 cells proliferation index of 2% was weak. The tumor had the histological and immunohistochemical profile of a “carcinoid tumor.”
Two years after the tumor resection, the patient presented an intense right otalgia and a neurosensorial hearing loss. 111Indium-pentetreotide scintigraphy showed an intense activity in the right ME (cf. ), and the CT scan revealed a soft tissue density mass in the attic of the ME, which confirmed the MEANT recurrence (cf. ). During a revision surgery, a yellowish tissue was resected by removing the ossicular chain. No adherence or bone erosion was noted. Function was restored by a total ossicular replacement prosthesis (TORP) ossiculoplasty. Histopathology disclosed the neuroendocrine (NE) nature of the tumor.
Scintigraphy and CT scan were free of recurrence two years after the revision surgery. The patient came for her follow-up check 10 years later without any complaint, and follow-up CT scan was negative.
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pmc-6286767-1
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A 19-year-old woman was referred and admitted to our hospital because of a progressive fever and persistent cough. The patient was a university student who lived with her parents, brother, and grandmother. Her medical history was uninformative regarding risk factors; the patient had no smoking history. She had not received influenza vaccination during the season. Six days prior to admission, she experienced fever and visited a clinic. There had been an outbreak of influenza A and B virus infections in the area during that time. Aside from this, she had no episodes of exposure to pathogens causing acute fever. The nasopharyngeal swab sample was analyzed using a rapid test kit and did not indicate the presence of either type A or B influenza virus antigen. Repeated examination of a nasopharyngeal swab sample on the following day did not indicate any influenza virus antigen. Clarithromycin was administered based on a diagnosis of acute upper respiratory infection. As there was no clinical improvement in spite of five days of treatment, the patient was referred to our hospital.
At admission, a physical examination indicated that the patient was a well-developed and well-nourished woman. Her body temperature was 39.6°C, blood pressure was 108/65 mm Hg, pulse was 106 beats/min, respiratory rate was 24 breaths/min, and room air percutaneous oxygen saturation (SpO2) was 95%. The physical examination was unremarkable, and her respiratory sound was normal.
An initial laboratory examination showed a white blood cell count of 5,200/µL (70% neutrophils), C-reactive protein level of 18.58 mg/dL, and procalcitonin level of 0.63 ng/mL (normal range <0.5 ng/mL). A nasopharyngeal swab sample analyzed using a rapid test kit (Quick Chaser Flu A, B; Mizuho Medy Co., Saga, Japan) indicated the presence of influenza B virus antigen. Stained sputum smears revealed Gram-positive cocci and Gram-negative rods. No pathogenic bacteria were cultured form repeated blood or sputum cultures. Chest radiography and CT scan () showed dense consolidation in the left upper lobe, indicating the presence of lobar pneumonia. The patient was diagnosed with influenza B virus infection accompanied by community-acquired pneumonia. The patient was treated with peramivir (600 mg/day) and sulbactam/ampicillin (SBT/ABPC; 12 g/day).
Following admission, the patient's fever persisted, and her respiratory condition worsened. The course of the patient's illness is shown in . On day 3 after admission, her body temperature was 40.0°C, and a laboratory examination showed no improvement. Therefore, ciprofloxacin (CPFX; 600 mg/day) was added. On day 5, the high fever persisted, and the room air SpO2 was 88%. A chest CT scan revealed extension of the consolidation areas with air bronchogram in the left upper lobe and opacities in the right lung (). On day 6, the SBT/ABPC and CPFX treatment was changed to meropenem (MEPM; 3 g/day) and levofloxacin (LVFX; 500 mg/day). On day 8, the patient's physical condition gradually improved, and the SpO2 recovered to >95% without oxygen administration. The sputum sample analyzed using a loop-mediated isothermal amplification assay (Mitsubishi Chemical Medience Co., Tokyo, Japan) revealed the presence of M. pneumoniae-specific DNA. There was no outbreak of M. pneumoniae infection in the area at the time. On day 13, the patient became afebrile and was discharged. The serum antibody titer against M. pneumoniae was 1 : 160 on admission and 1 : 10,240 on day 18 using the particle agglutination method and 1 : 32 on admission and 1 : 1024 on day 18 using the complement fixation test. In addition, the serum antibody titer against influenza B virus, measured using the complement fixation test, was <4 on admission and 1 : 128 on day 18. The serum antibody titer against influenza A virus did not increase throughout the clinical course.
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pmc-6286771-1
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A 42-year-old woman, in the 34th week of pregnancy, was admitted to the obstetrics unit of the university hospital with premature rupture of membranes. Her past medical history was negative. On admission, physical examination was unremarkable. Arterial blood pressure (ABP) was 110/70 mmHg, and temperature was normal. Complete blood cell count showed leukocytosis (12,430 cells/mmc) and severe microcytic hypochromic anaemia (Hb=6.9 mg/dL, Hct=25.2%, MCV=70.8 fL, and MCHC=27.4 g/dL). Anaemia was deemed chronic and was attributed to multiple uterine myomas. On admission, the patient was transfused with 4 units of blood. The following day, she underwent caesarian section. Therapy after surgery included hydration, low molecular weight heparin, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), ranitidine, calcium gluconate, cabergoline, and methylergometrine. After transfusion, Hb levels raised (Hb=9.3 mg/dL) and remained stable during the hospital stay. Arterial blood pressure values increased after blood transfusion (165/90 mmHg). On the third day after surgery, she presented a generalized tonic-clonic seizure which was treated with intravenous diazepam. Electroencephalogram registered after treatment showed rapid low amplitude waves without other relevant abnormalities. Neurologic examination revealed a lethargic status, with a mild right hemiparesis. Brain MRI showed multiple cortical and subcortical bilateral areas with hyperintense signal in T2, DWI, and Flair sequences, which did not show contrast-enhancement, involving not only posterior areas but also frontal lobes and right thalamus [Figures and ]. The last arterial blood pressure measurement was taken 4 hours before seizure (170/90 mmHg). The patient was transferred to the Neurology Department. The following day, the patient worsened, developing severe right hemiparesis. Blood pressure values were moderately high (160/100 mmHg). Transthoracic echocardiogram was normal. The patient was treated with antihypertensives (amlodipine, ramipril, amiloride, and hydrochlorothiazide), antiepileptics (levetiracetam 1000 mg bid), and osmotic therapy. Osmotic therapy was continued for 3 days. Three days after the reported seizure, the patient had improved and was alert and able to move right limbs against gravity. Brain CT showed widespread hypodensities in the same areas showing signal alterations in MRI imaging. Fundoscopy examination revealed an acute isolated retinal haemorrhage in left eye. Twelve days after the onset of symptoms, the patient had only a residual mild right hemiparesis. After 19 days, a control brain CT showed complete resolution of brain alterations.
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pmc-6286771-2
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A 59-year-old woman, with a history of hypertension complicated with 2nd stage retinopathy and treated with bisoprolol, olmesartan, and amlodipine, was admitted to Emergency Department because of headache and transient loss of vision. Arterial blood pressure was 140/80 mmHg. Brain CT scan, visual field test, and neurological examination were normal. The patient improved quickly and was discharged to home the same day. After seven days, she presented with progressive confusion, loss of consciousness, and postural instability, with frequent falls. The patient was unable to maintain the standing position without support. She had also aimless movements, with repetitive, involuntary, purposeless, and slow movements of superior limbs. Neurologic examination revealed lethargy, impaired consciousness, loss of verbal comprehension, poor and inadequate verbal production, and dysphagia. Brain CT was normal. On admission, the patient had severe metabolic abnormalities including hypoglycaemia (49 mg/dL), hypokalemia (3.0 mEq/L), hypocalcemia (6.3 mg/dL), hypophosphoremia (1.3 mg/dL), hypomagnesemia (1.3 mg/dL), and hypoalbuminemia (3.38 g/dL). BP was 110/65 mmHg. Temperature was normal. Treatment was aimed at correcting metabolic imbalances and psychomotor agitation. The day after admission, the patient had two generalized tonic-clonic seizures. The last arterial blood pressure measurement was taken 6 hours before the first seizure (100/60 mmHg). After the crisis, arterial blood pressure was 140/90 mmHg. EEG showed widespread theta and delta subcontinuous activity. MRI showed hyperintensities in T2 and DWI sequences, localized in the white matter and cortex of the right temporal lobe and in both parietal and occipital lobes together with mild cerebral oedema. MR-Angiography did not show vascular abnormalities []. Brain CT performed after 48 hours showed hypodensity in the same brain areas. CSF examination was normal. The patient was treated with osmotics (mannitol 150 mL four times a day) and antiepileptics (levetiracetam 1000 mg bid). After 21 days from onset, verbal comprehension and consciousness considerably improved; the patient was alert and well oriented to space and people, though disoriented to time; she showed good verbal comprehension and answered appropriately to questions. She had motor slowing and difficulty in naming objects. One month after admission, brain MRI showed a partial regression of signal alterations in T2 and Flair sequences, with persisting hyperintensities only in left temporal and occipital lobes and, to a lesser extent, in the right occipital lobe [].
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pmc-6286773-1
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A 64-year-old male with chronic low back pain presented to the emergency department with a new onset, severe mid back pain radiating to bilateral shoulders. CT scan, performed to rule out aortic dissection, demonstrated multiple lytic lesions throughout the bony skeleton and a compression fracture at T7 vertebral body with epidural extension of the soft tissue. A bone survey confirmed CT scan findings, and subsequent bone marrow biopsy confirmed the diagnosis of MM. He received radiation therapy to the thoracic spine and completed 2 cycles of CyBorD regimen (cyclophosphamide 300 mg/m2 by mouth, BTZ 1.5 mg/m2 subcutaneous, and dexamethasone 40 mg by mouth each on days 1, 8, 15, and 22). Three days after the completion of the second cycle, he was admitted to hospital with respiratory distress. CT chest () showed new interval appearance of bilateral perihilar ground-glass opacities and peribronchial and interstitial thickening predominantly in the upper lobes not seen in prior scan (). There were no other signs or symptoms of pneumonia such as leukocytosis, fever, or cough. After some benefit from oral prednisone, he was discharged with a tapering dose of the same. Unfortunately, the patient was readmitted with worsening respiratory distress 4 days later. A repeat CT scan of the chest showed resolution of previously well-defined areas of perihilar ground-glass opacities but development of hazy areas of ground-glass opacification throughout both lungs with more confluent abnormalities in bilateral lower lobes (). The patient was treated with high-dose methylprednisone and noninvasive positive pressure ventilation without any improvement. The family requested do-not-resuscitate and do-not-intubate status. The patient died on the 10th day of the admission.
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pmc-6286777-1
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A 19-year-old girl was admitted to our hospital for surgery with a 15-year history of GI bleeding associated with BRBNS. She had repeated episodes of resections of hemangiolymphangiomas on the right thoracic wall from 3 months to 3 years of age. At 4 years of age, she presented with a few cutaneous small VMs on the feet; hematological examination revealed persistent anemia and positive fecal occult blood. Colonoscopy revealed a VM on the right colon. She underwent an exploratory laparotomy at 5 years of age. Multiple VMs were identified (): 1 on the lesser curvature of the stomach, 7 on various parts of the small intestine, 1 on the hepatic flexure of the colon, and 1 on the liver. Intestinal lesions were resected, and gastric and hepatic lesions were left untreated to avoid injury to surrounding organs. The pathological finding was cavernous hemangioma, so she was diagnosed with BRBNS. Four months later, she suffered superior mesenteric artery thrombosis and underwent partial resection of the small intestine. Since then, although mild anemia persisted, it was treatable by oral iron replacement therapy, and the clinical course was uneventful for 10 years.
At 15 years of age, the anemia got slightly worse. Hematological examination revealed that Hemoglobin (Hb) level was 7–8 mg/dL. GI endoscopy, including transanal double-balloon endoscopy and capsule endoscopy, and contrast-enhanced computed tomography (CT) revealed multiple VMs on almost the entire GI tract, including the stomach, duodenum, jejunum, ileum, and colon (Figures and ). VMs were also found in the right pleural space, hepatic hilum, liver, and spleen. An additional finding was a right ovarian cyst. Anemia and GI bleeding became more severe despite the administration of a β-blocker since she was 18. Hematological examination revealed that Hb level was 4 mg/dL. Frequent blood transfusion was prescribed. At 19 years of age, CT revealed an increase in the size of known lesions. In order to control GI bleeding, she underwent the second surgery for GI VMs. We performed resection of all lesions on the stomach and the intestine, partial resection of the small intestine, appendectomy, splenectomy, and right ovarian cystectomy. Enteric lesions were removed through a gastrotomy, 11 enterotomies, and a sigmoid colotomy. Palpation of a lesion on the posterior gastric corpus revealed the absence of transmural involvement, so the lesion was resected above the proper muscular layer. Palpable lesions on the small intestine () were marked with serosal sutures and were exposed by intussuscepting the bowel through enterotomies (). For transmural lesions, wedge resection was performed. For the lesions grossly localized in the mucosal layer, small or polypoid lesions were ligated and resected, and elevated lesions were treated with argon plasma coagulation (APC). Intraoperative endoscopy was performed through enterotomies to detect the remaining lesions (). The number of the lesions on the small intestine was > 350. Localized dilatation of the small intestine caused by adhesion of the mesentery was found and resected partially to avoid involvement of an adhesive bowel obstruction. A palpable lesion on the sigmoid colon was ligated and resected through colotomy. Although preoperative colonoscopy revealed several other small lesions from the cecum to the sigmoid colon, they were left untreated because colonoscopic treatment would be possible at a later date. The splenic lesion was suspected to invade the tail of the pancreas, so the pancreatic parenchyma was also resected with splenectomy. Operative duration was 11.5 hours. Intraoperative blood loss was 325 mL. Postoperative pancreatic fistula was observed but successfully managed by conservative treatment. Pathology of surgical specimens revealed VMs in the stomach, small intestine, sigmoid colon, and spleen. The splenic lesion was found to invade pancreatic tissue. The right ovarian cyst was found to be a mature teratoma. Postoperative GI endoscopies revealed the remaining VMs on the duodenum and colon. The patient had no bleeding or anemia for 5 years after the surgery.
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pmc-6286778-1
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The patient, 47 years old, female, systemically healthy, and nonsmoker, presented in the Laerte Schenkel Residency Course of Dentistry, a private clinic, where the case was carried out, requiring the rehabilitation of MultiPlus implants already installed in the posterior region of the mandible corresponding to the dental elements 35, 36, 37, 46, and 47. The main complaint focused on masticatory difficulty in the already-existing crowns, frequent mobility of these crowns, absence of aesthetics, and difficulty in sanitizing. At the time of the anamnesis, screwed metal-ceramic crowns joined in the implant region, mucositis, food retention, and degradable odor were found.
Before the planning of the new prosthetic rehabilitation, a working protocol was established with diagnostic tools: initial photographic documentation (Figures –) of the patient, work models mounted on a semiadjustable articulator (), and evaluation of panoramic radiography (). With the articulated work models, the unevenness of the occlusal plane was evaluated (Monson's plaque-Monson's theory []); alteration of vertical dimension and crowns outside the dental arch were found. In the radiographic evaluation, the inadequate angulation of the implants and the connection of the installed implants were verified: external hexagons which were screwed directly on the implant.
In the first stage of the treatment, the installation of minipillars (Neodent brand) on the implants (posterior region right and posterior region left) was chosen, with the proposal to remove the prosthetic connection from intimate contact with the gingiva, thus providing a better hygiene condition and improvement with the mucositis. In the posterior region of the mandible, a lack of keratinized gingiva is common so the installation of minipillars favors gingival health in this region. It was not possible to maintain the most posterior implant of the left side in the planning of the new crowns since it was very vestibularized and outside the patient's dental arch, jeopardizing the hygiene of the new crowns so it was decided to bury it (). The model obtained from regions 46 and 47 can be seen in and the model obtained from regions 35 and 36 can be seen in .
The laboratory phase was performed by a dental technician, and each step was rigorously followed, from the conference of the moldings and models obtained (), diagnostic waxing (Figures and ), maintenance of the occlusal plane, and sanitation planning of the crowns ().
The authors' project for a new prosthesis treatment plan consisted of joining in one study the main advantages of cemented prosthesis: aesthetics and passivity and the main advantage of screw prosthesis: reversibility. The proposal to perform cemented-retained and screw-retained crowns in multiple prostheses began by making a waxing of the future alloy primary structure framework (), predicting the insertion of the key. Then the alloy framework (cobalt-chromium) was casted according to the waxing (). New waxing of the crowns and gingiva was performed (Figures and ).
The aesthetic necessity of the final work resembled the rest of the lower arch, which was being rehabilitated with IPS e.max crowns (Ivoclar Vivadent), lithium disilicate, and the laboratory was asked to apply feldspathic ceramics to the metal structure in the region where the crowns would later be cemented. In the same way, the application of a ceramic gingiva—a secondary structure—was also necessary to restore any soft tissue lost (Figures and ). Figures and show the gold bath in the connection and Figures and the space for insertion of the key. The primary and secondary structure in the mouth can be seen in Figures and .
The implant-supported ceramic crowns were confectioned in e.max lithium disilicate (Ivoclar Vivadent), and Figures – refer to finished crowns prior to installation in the mouth—in plaster models and outside them.
Fixation of crowns on the implant right side and left side followed the same protocol: the primary structure was screwed to a minipillar bolt with the manufacturer's established torque (foundry occurred in calcinable UCLAs with chromium-cobalt termination), and the secondary structure was cemented with Ultimate resin cement (3 M). During the cementation of the crowns, the occlusal orifices were protected with seal tape (polymer-polytetrafluoroethylene, patented by the commercial name Teflon, DuPont) so that the cement did not obstruct the existing space for a possible reintervention. After polymerization of the cement, the sealing tapes were maintained and the occlusal holes were restored with resin (3M Z-350). The final result can be seen in Figures – and achieved function and expected aesthetic. shows the comparison of the initial clinical case and the final results.
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pmc-6286784-1
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A 55-year-old woman with a medical history of cystitis and anaphylactic shock ingested about 110 tablets of antidiabetics and antihypertensives (Lipitor®: atorvastatin calcium hydrate; Lasix® [furosemide] 20 mg; Diart® [azosemide] 60 mg; amlodipine 5 mg; Inhirokku® [cilazapril hydrate] 1 mg; and glibenclamide 2.5 mg; and Bratogen, among others.) that had been prescribed for her husband at 15:00 on November 18. At 05:00 on November 19, she had complaints of chest pain and was taken by ambulance to the hospital. She conveyed to the ambulance crew that she had consumed a large quantity of medications. The ambulance crew confirmed finding a number of empty drugs packets, including those for 10 tablets of Lipitor®, 10 tablets of Lasix®, 16 tablets of Diart®, 17 tablets of amlodipine, 27 tablets of Inhirokku®, and 21 tablets of glibenclamide. In the hospital, her blood glucose level was 36 mg/dL and her blood pressure was 80/38 mmHg. The doctor carried out an endoscopy, but found her stomach was empty. Therefore, gastric irrigation was not performed. The doctor prescribed Takepron® (lansoprazole) and Malfa® gel (aluminum hydroxide and magnesium hydroxide). After treatment, her consciousness became clear. She refused hospitalization and returned home. However, at 06:00 on November 20, about 40 h after consuming the medications, she went into cardiopulmonary arrest in her home. She was transported to the hospital by ambulance, and could not be resuscitated. A forensic autopsy was carried out to determine the cause of death about 18 h after death.
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pmc-6286906-1
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A 55-year-old man with a past history of ITP and hypertension visited a local dental clinic. Four years earlier, the patient had undergone knee joint surgery and was diagnosed with ITP. Because his platelet count was maintained at 35,000/μL thereafter and no spontaneous bleeding occurred, the patient attended periodic follow-up visits to check his platelet level but was not treated with any medication. The patient underwent extraction of the left mandibular first molar because of chronic periodontitis. Post-extraction bleeding occurred for 1 week after the procedure, but the hemorrhage gradually decreased and was finally controlled by a suture at the extraction site. After the extraction, the patient’s platelet count was evaluated and maintained at 35,000/μL.
One month after the extraction, the patient underwent dental implant surgery at the same site (the left mandibular first molar) at the same local dental clinic. Bleeding started immediately after fixture installation and the mouth floor began to swell. Therefore, the patient visited the emergency room (ER) of the authors’ hospital. The patient was prescribed medication to control hypertension but no medication for ITP. The patient complained of severe swelling on the mouth floor and shortness of breath accompanied by marked dysphagia, which had also occurred immediately after the surgery. Bilateral submandibular swelling and mouth-closing difficulty were present (Fig. ).
Regarding vital signs, his blood pressure was 173/108 mmHg and the respiratory rate was 22/min. A laboratory blood workup revealed a white blood cell count of 4.38 × 103/μL, a hemoglobin (Hb) level of 11.7 g/dL, and an initial platelet count of 22,000/μL. Coagulation studies revealed that fibrinogen levels (114 mg/dL) were lower than normal, and D-dimer levels were elevated at 31.91 μg/mL. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were within normal limits. A diagnosis of exclusion for ITP was made by the hematologist after ruling out other conditions that may cause symptoms similar to those of thrombocytopenic purpura. Because the patient had no past history of other contributing medication or medical condition and the results of laboratory tests showed a low platelet count and normal PTT and aPTT values, he was diagnosed with refractory ITP.
Facial-enhanced computed tomography revealed severe narrowing of the pharyngeal airway space. Marked soft tissue swelling was observed with isodensity in the left masticatory and submandibular spaces and hypopharynx. The patient complained of worsening respiration in the ER. The expanding hemorrhage was deemed to potentially result in a compromised airway with a life-threatening outcome. Therefore, the surgical wound from the dental implant was opened to evacuate the hematoma and an emergency tracheostomy was performed under local anesthesia and intravenous sedation to maintain airway patency. The patient was then admitted to the intensive care unit (ICU).
After tracheostomy, the intubation site also bled heavily. The patient was treated with antibiotics, high-dose steroids, and intravenous (IV) immunoglobulin O with a platelet infusion (platelet concentration 11 pints, 3600 mL) continuously for 3 days. The aim was to elevate the platelet level to 80,000/μL. To compensate for the blood loss (Hb 8.7) associated with constant severe bleeding from a gingival surgical wound and tracheostomy site, a transfusion of filtered red blood cells and IV saline was performed.
Laboratory data after 3 days in the ICU showed a platelet count of 129,000/μL and other complete blood count (CBC) values within normal ranges. Follow-up CT 3 days later revealed that the hemorrhage had not expanded further. Moreover, diminished soft tissue swelling was noted along the superficial and deep neck spaces compared with the swelling shown on the previous CT images (Fig. ). Therefore, the patient was extubated without dyspnea. The patient showed resolution of the mouth floor swelling, and no additional bleeding was detected; thus, he was discharged 9 days after admission.
A follow-up visit 1 week after discharge revealed complete resolution of intra-oral and extra-oral swelling without superficial or deep neck infection. However, despite medication for ITP, the patient’s platelet count decreased after 1 and 3 weeks (Table , Fig. ). Four months later, final prosthetic implant restoration was performed in the prosthetic department.
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pmc-6286975-1
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A 67-year-old female lifelong non-smoker with a history of scoliosis and early osteoporosis developed a non-productive cough for 6 months, an unintentional weight loss, and daytime fatigue. She had experienced a seven-pound weight loss over 6 months, to a body mass index (BMI) of 17.5 kg/m2 (normal: 19–24 kg/m2). An avid swimmer and jogger, she had also noticed a gradual decline in her stamina, with an increase in shortness of breath with moderate exercise. Her primary care provider ordered a chest radiograph, which showed possible right middle lobe pneumonia. She was prescribed 10 days of levofloxacin, which did not improve her respiratory symptoms. She developed severe diarrhea, and on the seventh day of levofloxacin, her husband took her to the emergency department, where she was admitted for dehydration secondary to Clostridium difficile colitis. Because the cough had not improved with antibiotics, a CT of the chest was performed, showing right middle lobe and lingula bronchiectasis, nodularity, and mucus impaction (Figure ). She was placed on airborne isolation for possible pulmonary tuberculosis. MTB PCR probe was negative on an induced sputum sample, so she was taken for bronchoscopy with lavage. These samples were smear positive for AFB, and 10 days later, grew M. avium. She was discharged from the hospital on a combination of ethambutol, rifampin, and azithromycin three times weekly, and after 3 months of treatment, her cough resolved and she began to gain weight. Repeat CT imaging at 6 months demonstrated fewer lung nodules, with less mucus impaction.
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pmc-6287048-1
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A 61 years old post-menopausal woman was admitted to our hospital for a locally advanced tumor in the left breast, with clinical involvement of axillary nodes (cT3N3). Pathological evaluation of a core needle biopsy revealed the presence of HR-/HER2+ invasive ductal carcinoma (IDC). The patient received neoadjuvant CT with 12 cycles of weekly paclitaxel plus trastuzumab followed by 4 cycles of cyclophosphamide, epirubicin, and fluorouracil (FEC). She then underwent left mastectomy plus axillary node dissection (AND). Pathological study of the surgical specimen showed scattered foci of ductal carcinoma in situ, with no residual disease on axillary nodes (ypTisN0). The patient also underwent radiotherapy (RT) to the chest wall and supra-clavicular fossa. In addition, she received trastuzumab to complete 1 year.
Unfortunately, while being treated with trastuzumab, a red wide cutaneous rash appeared on her left chest wall. A biopsy of such lesions confirmed the presence of HER2+ skin recurrence. A restaging CT scan did not show any other sign of distant metastasis. TDM1 was therefore initiated. Over the course of 4 weeks, the rash completely resolved. It has been 45 cycles of TDM1 and the patient is still disease-free (Figure ).
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pmc-6287048-2
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A 39 years old pre-menopausal woman came to our attention with a locally advanced BC. The pathological evaluation revealed the presence of HR-/HER2+ IDC (cT3N2). The patient initially received 3 cycles of neoadjuvant FEC followed by docetaxel concurrent with trastuzumab; docetaxel was discontinued due to anaphylactic reaction. She then underwent left mastectomy plus AND. The pathological study of the surgical specimen reported the presence of scattered foci of residual IDC in the breast and the presence of metastasis in four axillary nodes (ypT1micN2).
After surgery, 1 year of trastuzumab treatment was completed. The patient also underwent RT to the chest wall and sovra-clavicular fossa. After 12 months from the end of adjuvant trastuzumab, the patient experienced isolated skin relapse. In particular, she presented with itchy erythematous skin lesions on her left chest wall. Since a restaging PET did not reported any sign of distant metastatic disease, a wide cutaneous surgical excision was performed. Pathological study of the surgical specimen confirmed the presence of HR-/HER2+ skin recurrence.
The patient was then offered systemic therapy with CT plus an anti HER2 agent. However, she refused treatment. The patient was therefore strictly followed-up.
However, after a disease-free interval (DFI) of 4 months, the patient experienced a second skin relapse, with a wide erythematous rash appearing on her trunk. Systemic therapy with trastuzumab plus vinorelbine was therefore administered. Unfortunately, 5 months later, the patient experienced a cutaneous disease progression, consisting in an increasing in size of pre-existing skin lesions and appearance of new skin lesions on the antero-lateral abdominal wall. TDM1 was then initiated. Two months later, a complete response was achieved. After 17 cycles of TDM1, the patient decided to stop treatment. After 9 months since TDM1 had been discontinued the patient was still disease free (Figure ).
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pmc-6287080-1
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In september2017, an 18-month-old male admitted in endocrine department with symptoms of moon face, general weakness, central obesity, growth arrest and short stature of 5 months duration. On physical exam, the patient was noted to have 1 + pitting edema on his lower extremities bilaterally and hirsutism in back of trunk. At the time of presentation, he did not appear severely cushingoid appearance and his blood pressure was (115/61 mm Hg). Laboratory results revealed highly elevated ACTH and cortisol levels (ACTH = 731 pg/mL; AM cortisol = 142.8 μg/dL; 24-h urine cortisol 12743.5μg/24 hours total volume). In addition, the patient was also hypokalemic (3.0 mEq/L) and had a metabolic alkalosis (pH = 7.89, HCO3 = 41 mEq/L). Dexamethasone suppression test was considered: however, in the presence of very high ACTH and cortisol levels, hypokalemia, and metabolic alkalosis, as well as clinical findings, a primary pituitary tumor or an ectopic ACTH syndrome was suspected. Brain MRI was negative for primary pituitary tumor. Abdominal ultrasonography (USG) showed a solid, calcified heterogeneous mass measuring 57 × 46 × 36 mm in front of anteromedial of right kidney near to inferior pole. A Doppler ultrasound test showed the blood flow through inferior vena cava (IVC) restricted by pressure effect of tumor. Contrast-enhanced computed tomography abdomen showed large lobulated, necrotic and calcified hypodense enhancing mass measuring 47.6 × 44.3 mm in the largest diameters that extending from anterior of right kidney to retroperitoneum and involving retroperitoneal space. The lesion was abutting the IVC, displacing it laterally () The USG/CT appearance of the mass, in combination with the clinical and laboratory findings, was suspicious for neuroblastoma or pPNET. Informed consent was obtained from parents prior to surgery. Total resection of mass was performed by laparoscopic abdominal surgery. After surgery, his metabolic abnormalities were controlled. Grossly, the tumor was brownish, soft and multilobulated. Gross examination of the specimen sent to us revealed a soft tissue mass measuring about 47 × 42 × 37 mm, cut surface of which revealed an encapsulated creamy to brownish mass with lobulated and variegated appearance with solid and necrotic areas with foci of calcification (). On microscopic examination, there were lobules of tumor cells separated by fibrous septa. The tumor cells comprised of small cells with round vesicular nuclei, inconspicuous nucleoli, scanty eosinophilic cytoplasm with frequent homer wright rosettes and pseudorosettes (). The immunohistochemical evaluation revealed a diffuse CD99 and vimentin positivity in the cytoplasm of the neoplastic cells. Pan keratin, cytokeratin AE1/AE3, myogenin and CD45 were negative. The S-100 protein was weakly positive in tumor cells. Ki67 immunostain shows about 65% immunoreactivity. Also, there were focal expression of synaptophysin and ACTH (). These findings represent an ACTH-secreting PNET. Following the operation, his ACTH level decreased to 22 pg/mL. Ki67 immunostain shows about 65% immunoreactivity. He was discharged on hydrocortisone 5 mg in the morning and 5mg in the evening for secondary glucocorticoid deficiency because of prolonged ectopic ACTH secretion. When the patient finished the hydrocortisone course, he maintained a normal ACTH, morning plasma cortisol, and urine cortisol levels. Furthermore, his Cushing's syndrome symptoms completely resolved.
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pmc-6287087-1
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A 15-year-old boy presented with multiple asymptomatic cutaneous white patches, noticed by his mother 4 years before presentation. The mother's pregnancy and patient's birth history were unremarkable. The patient had difficulty feeding since birth, laryngomalacia requiring gastric tube placement, and recurrent hospitalizations for aspiration pneumonia.
His clinical features of bushy arched eyebrows, thick everted lips, broad nasal bridge, facial nevi, and developmental delay prompted metabolic and genetic testing. At 11 years old, a diagnosis of CSS was established via whole-exome sequencing, revealing a de novo mutation (c.4202G>T, p.E1402X) in the ARID1B gene, a premature stop codon mutation leading to a truncated protein. This mutation was not found in either parent or his 2 unaffected older sisters.
Clinical examination showed distinctive coarse facial features (), fifth finger hypoplasia, first metatarsal hypermobility, and hypertrichosis characteristic of CSS. There were depigmented macules and patches on the elbows and knees () and malleoli, clinically characteristic of vitiligo. He had over 60 brown macules consistent with melanocytic nevi (under 5 mm) on the face (), neck, abdomen, trunk (), extremities, palms, and soles (up to 1.0 cm). Halo nevi were not present. The parents noted the onset of nevi around age 3 years, and neither had multiple nevi.
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pmc-6287126-1
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A 45-year old male presented at our clinic with right hip pain of five months duration and the pain had worsened since the last two months with a visual analog scale (VAS) score of 7. The pain was localised to the hip and it occurred especially during movement and weight bearing. There was no history of trauma, alcohol abuse, steroid use, metabolic disorder, and any associated chronic disease. His height was 161cm, body weight was 63kg, and body mass index was 24.3 kg/m. Physical examination revealed a positive Patrick’s test. Range of movement at the right hip joint was flexion 100 degrees, abduction 40 degrees, adduction 10 degrees, external rotation 40 degrees, and internal rotation 10 degrees. Several bony lumps were found at various periarticular sites on the upper and lower extremities. Preoperative functional activity score based on Harris Hip score (HHS) was 40. A plain anteroposterior pelvic radiograph showed right femoral head flattening with subchondral sclerosis and a cyst. Joint space obliteration and joint subluxation were also observed.
Exostoses were found at the inferomedial site of the base of femoral neck on both sides, and on the superolateral side of the left femoral neck (). Proximal femoral geometrical measurements on both anteroposterior hip radiographs revealed the following findings (right/left): femoral head width 66.8 mm/74 mm, widest femoral neck width 79.5 mm/74.5 mm, bilateral coxa valga with a neck-shaft angle 157 degrees/157 degrees, bilateral acetabular dysplasia with Sharp’s angle 43 degrees/43 degrees, right hip joint subluxation of 48% and left femoral head coverage of 69% without any sign of joint subluxation. Radiographic limb length discrepancy was 17mm. Femoral head width on the lateral femoral head radiograph was 59.6 mm/59.7 mm with femoral neck width 57.1mm/53.6mm (). The anteroposterior teleroentgenogram of the lower extremity showed multiple exostoses on both distal femoral, proximal tibial, and distal tibial regions (). Pelvic computed tomography confirmed the exact position of proximal femoral exostosis (). Based on the physical and radiographic findings, this patient was diagnosed as having right coxarthrosis associated with HME. The patient was scheduled for THA surgery.
Details of MIS-2 incision THA have been provided in a previous publication. Briefly, the patient was positioned in the lateral decubitus position. The hip joint was approached via two incisions. The first incision was part of Watson-Jones anterolateral approach with muscle interval between the gluteus medius and tensor fascia lata. This incision started from a point approximately one finger breadth posterior to the anterior border of the greater trochanter, just distal to the vastus ridge, and extended cranially and anteriorly at an angle of 30 degrees to the long axis of the femoral shaft. The length of the incision was 7cm (). Through this incision, femoral head extraction was performed (), acetabular reaming and insertion of the acetabular cup. Excision of proximal femoral exostosis was also performed through the anterolateral incision. The second incision of 4cm length () was performed through part of the posterolateral incision with the hip flexed to 90 degrees. After dissecting through the muscle fibers of gluteus maximus and fat excision, the piriformis tendon was exposed and used as a landmark. Intermuscular dissection with interval between gluteus medius and piriformis muscle was performed to expose and incise the posterosuperior capsule. Femoral canal broaching and stem position was confirmed by fluoroscopy. The femur was then brought anteriorly by applying traction, external rotation and extension of the hip. The femoral head trial and head implant were inserted through the anterolateral incision after fluoroscopic confirmation of leg length discrepancy. The femoral component was cementless Master-SL® [Lima Corporate, Udine, Italy]. The acetabular component was cementless Delta-PF ® cup [Lima Corporate, Udine, Italy] with a diameter of 50mm. Ceramic-on-ceramic bearing was used with a head diameter of 36mm. The posterior and anterior joint capsule, fascia lata, and subcutaneous tissue were repaired; and the skin closed. The total skin-to-skin operation time was 55 minutes.
A postoperative hip radiograph showed satisfactory femoral and acetabular component placement with an equal limb length compared to the contralateral side (). Postoperative protocol which included an abduction pillow between the two legs and elastic stockings to prevent deep vein thrombosis were applied. Early hip range of motion exercise was allowed on the first day after surgery. Walking with tolerable weight bearing with crutches was started on the second postoperative day. Range of movement at the right hip joint had improved: flexion 120 degrees, abduction 40 degrees, adduction 30 degrees, external rotation 40 degrees, and internal rotation 30 degrees. No complication occurred after surgery. At two years follow-up, the patient had an excellent hip function with a HHS of 96.
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pmc-6287128-1
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A 53-year old man was admitted to our emergency unit with low back pain (Visual Analog Scale VAS 7), bilateral leg pain (VAS 9) and acute paraparesis with leg extension and bilateral hip flexion deficit without trauma. A neurological examination found that the strength in the right hip flexion and the right knee flexion was grade 2 with bilateral hypoesthesia in the L4 and L5 region. No other neurologic abnormalities were found. Blood tests revealed no alterations. CT scan of lumbar spine did not reveal any significant findings. Therefore, an MRI of the lumbar spine was performed. MRI images showed a mass in the dorsal epidural space with compression of the epidural sac at the L3-L4 level (). Fifteen hours after admission the patient underwent surgery through a posterior approach and right hemi-laminectomy at the L3 level. After the removal of the ligamentum flavum, a disc material was found, which was responsible for compression and displacement of the dural sac. A disc inspection at L3-L4 level revealed a tear of the disc's annulus. Two days after surgery the patient experienced significant pain relief (VAS back 3, VAS leg 2), and recovery of the right hip flexion and right knee flexion strength. At the one month follow-up, patient had complete neurological recovery.
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pmc-6287128-2
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A 49-year old man was admitted to our emergency unit for acute dorsal pain experienced during driving. He had no trauma. The patient had bilateral hypoesthesia in the L2-L3-L4-L5 region and VAS for back pain was 9. A neurologic examination revealed a condition of paraparesis. The strength of knee flexion and extension was grade 3 bilaterally, the hip flexion was grade 3 bilaterally and the ankle flexion and extension was grade 4. The blood test revealed no alterations. MRI of the thoracic spine revealed a wide lesion in the dorsal epidural space with compression of the epidural sac at the T6-T7 level (). Twelve hours after admission the patient underwent decompression surgery, through a posterior approach with laminectomy at T7 level. After removing the ligamentum flavum, a large amount of disc material migrated into the dorsal epidural space was found (). After the removal of herniated fragment (), the dural sac showed no more signs of compression (). In the first post-operative day, the patient had good pain relief (VAS back 3) and showed prompt neurological recovery. The patient was discharged five days after surgery and at the one-month follow-up evaluation he was pain-free, with no hypoesthesia or motor weakness.
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pmc-6287130-1
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A 9 year-old male child was referred to us for right radial clubhand-like deformity and limitation in performing daily activities. He was forced to modify his hand dexterity due to weak grip and pinch strength. He had previous history of extensive radius osteomyelitis that was treated by sequestrectomy. As a result of the extensive sequestrectomy, the child developed manus valgus deformity.
Examination revealed no signs of infection in the forearm. His right wrist was deviated 60 degrees radially (). The forearm was pronated 90 degrees. Ulnar head was prominent. Grip and wrist strength were markedly reduced. Forearm rotation was absent. Wrist dorsiflexion and palmar flexion were restricted to approximately 0 to 10 degrees. There was no neurovascular impairment. He had full range of elbow and hand movements.
Pre-operative radiographs () revealed remnant distal radial epiphysis with intact distal radial physeal plate and part of the metaphysis. The distal radioulnar joint was dislocated and the radial head was hypoplastic. There was ulna overgrowth and bowing. Blood investigations including white cell count, erythrocyte sendimentation rate and C-reactive protein confirmed the absence of active infection. Taking into account the child’s extensive radial loss and the available surgical expertise in our centre, the patient was offered single-bone forearm salvage procedure.
The patient was operated under general anaesthesia, in a supine position, with the forearm on a radiolucent table. An incision was made over the previous scar on the dorsal aspect of the forearm. The distal right radius and ulna were approached through the same incision. Radial metaphyseal end was freshened until bleeding. The right ulna was osteotomised at the level corresponding to the remaining right radius epiphysis. As there was overgrowth of the ulna, it was impossible to reduce the distal radio-ulnar joint without sacrificing 2cm of the ulna shaft. Care was also taken to avoid excessive ulna shortening, as this would cause loss of tendon tension. The distal radius was moved ulnar-wards and distally until the distal radioulnar joint was reduced. Then, the proximal segment of the ulna was radialised and the distal radius was impacted into the proximal ulna medullary cavity. Once the desired rotational alignment and length were achieved, the new distal radius-on ulnar shaft-composite was fixed with 1.6mm Kirschner wires (). Following wound closure, a full-length cast was applied. The Kirschner wires were removed on the 6th post-operative week.
At 12 months post-surgery, the child had normal use of his right hand and was pleased with the cosmetic appearance. The wrist was pain free with full range of motion. There was no forearm rotation () but the child had learned to overcome this by compensatory shoulder rotation. Radiographs revealed solid union at the fusion site. The distal ulna had developed osseous bridge with the adjacent proximal ulna, creating a Y-shaped single bone forearm. Long-term follow-up is needed to monitor for recurrence of the deformity and limb length discrepancy.
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pmc-6287132-1
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We present a case of a 25 year-old man who complained of worsening back pain and left lower limb weakness and radiculopathy for two weeks. He was unable to walk due to the pain and weakness. There was no bowel or bladder incontinence but he had loss of appetite and significant weight loss.
He had history of fall and sustained a stable burst fracture of T12. He was treated with an extension body cast at that time as there was no suspicious lesion on the radiographs. During follow-up, he developed a kyphotic deformity of which we performed pedicle subtraction osteotomy of T12 a year after the primary injury. He defaulted the follow-up after surgery.
Examination revealed a posterior midline surgical scar measuring 12cm. There was a mild kyphotic deformity. His hip and knee flexion were weak with a medical research council (MRC) muscle power grading of 3. The ankle and toes had MRC muscle power grading of zero. Magnetic resonance imaging (MRI) was suggestive of an aggressive spinal tumour over T12 with extension to T11 and L1 (). Computed tomography of the lungs revealed no lung metastasis.
He underwent posterior extension of fusion from T8-L4 with total vertebrectomy of T11, T12 and L1. Excision of the posterior elements of T11 and L1 then removal of the pedicles of T11 and L1 was done. En bloc tumour removal was attempted but scarring and adhesions to the diaphragm prevented an en bloc removal, so piecemeal vertebrectomy of T11, T12 and L1 and excision of tumour was performed. Three segmental arteries were ligated on the right side to facilitate cage insertion and the bone gap reconstructed with a titanium mesh cage filled with bone cement (). The reconstructed mesh was shorter than the total height of the removed vertebral bodies, as we shortened the spinal column, but not exceeding one vertebral body and two discs height to prevent cord buckling. Intra-operatively there was adhesions due to the previous scarring causing dura and diaphragm tear during excision of the tumour, which we could not repair. A dura sealing agent was used to seal the tears. He lost 7.7 litres of blood during the surgery requiring massive blood transfusion.
Post-operatively, his neurological deficit improved to MRC muscle grade 5 and he was able to walk with a single crutch with minimal back pain. The wound healed well. At the last follow-up at one and a half years post-operatively, there was complete neurological recovery with good functional outcome. Histopathological examination confirmed the diagnosis of GCT of the spine ().
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pmc-6287146-1
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An 86-year-old man with a medical history of coronary artery disease and severe aortic stenosis presented with fatigue, shortness of breath, and chest pain. The patient had undergone aortic valve replacement with a bioprosthetic Intuity valve 25 days prior to presentation. His postoperative course was complicated by excessive bleeding from chest tubes that necessitated a mediastinal washout and mild volume overload treated with diuretics. His chest tubes and pacing wires were removed on postoperative day (POD) 5 without issue, and he was discharged on POD 7.
The patient was noted to be doing well at follow-up appointments with his geriatrician on POD 13 and with the cardiothoracic surgery clinic on POD 20. However, on POD 24, the patient presented to the emergency department with several days of fatigue, subjective shortness of breath, and chest pain. He described his chest pain as worse at night and when lying flat. He complained of associated confusion and weakness, both of which were unusual for him. The patient's review of systems was otherwise negative, and he denied any other constitutional, respiratory, gastrointestinal, urinary, rheumatologic, or dermatologic symptoms.
In the emergency department, he was febrile to 102 degrees Fahrenheit, and his exam was notable for a warm, erythematous, and tender epigastrium without obvious wound dehiscence (). Notable labs included sodium 124 mmol/L, creatinine 1.5 mg/dL (baseline 1.2–1.3 mg/dL), AST 47 U/L, ALT 31 U/L, alkaline phosphatase 87 U/L, total bilirubin 1.1 mg/dL, and white blood cell count 6.4 × 109 cells/L. Because of concern for wound infection, as well as his hypovolemic hyponatremia, he was admitted to the hospital.
Computed tomography of the chest demonstrated a 13.6-centimeter rim-enhancing fluid collection in the anterior mediastinum with multiple small foci of gas, an additional 2.5-centimeter collection between the clavicular heads, and new skin thickening and soft-tissue stranding in the anterior chest wall concerning for soft-tissue infection (). Blood cultures were drawn, and treatment was initiated with intravenous vancomycin and piperacillin-tazobactam. He was admitted to the cardiothoracic surgery service, and on hospital day two, underwent washout of the collection, during which time his midline incision was reopened, and two pockets of pus were identified and evacuated. A wound vacutainer system was placed. On hospital day three, one of the two sets of admission blood cultures and two intraoperative wound cultures grew Gram-negative rods. Vancomycin was discontinued, and the patient was maintained on piperacillin-tazobactam. On hospital day 4, the organism was identified as Salmonella group D. Susceptibility testing showed that the isolate was susceptible to ampicillin (MIC < 8 μg/mL), ceftriaxone (MIC < 0.5 μg/mL), and trimethoprim-sulfamethoxazole (MIC < 2 μg/mL) but had intermediate susceptibility to ciprofloxacin (MIC 0.12 μg/mL). The infectious disease service was consulted and recommended switching piperacillin-tazobactam to ceftriaxone.
The patient had no personal or family history of unusual infections. He was a 30 pack-year former smoker (quit in 1980), drank alcohol in moderation, and had no history of illicit substance use. He had traveled to Switzerland several years prior and had remote travel to Southeast Asia. He reported consumption of raw fish, raw beef, and incompletely cooked eggs. The patient had a dog, but no exposure to chickens or other birds. Notably, the patient's son had recently returned from college to help his father during the postoperative period and had brought with him a pet snake. Although the patient did not specifically interact with the snake, he reported that his son had prepared food for him after handling the animal.
The patient required two additional debridements, and during the final procedure, the sternum was reopened to confirm no further infection of the mediastinum by direct visualization. Transthoracic and transesophageal echocardiography were performed and showed no evidence of valvular infection or involvement of the aorta. His wound was closed, and he was discharged in good clinical condition to continue his antibiotic therapy as an outpatient, with a planned course of intravenous ceftriaxone 2 grams daily for a total of six weeks. A repeat chest CT after completion of therapy showed no evidence of aortic involvement, a small amount of residual fluid, and sternal bony changes concerning for remodeling versus infection (). Because of the remaining fluid and concern for possible sternal osteomyelitis, he was treated with oral amoxicillin consolidation therapy for an additional 4 weeks, although ultimately the CT findings were thought to be more likely related to poststernotomy changes. Due to intolerance, amoxicillin was changed to cefixime; his course was complicated by an episode of mild Clostridium difficile infection. A C-reactive protein downtrended from 190 mg/L to 5.5 mg/L. At the time of writing, the patient has been off antibiotic therapy for four months and continues to do well.
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pmc-6287168-1
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A 13-year-old boy with no past medical history presented with six months of progressive left knee pain. He denied any trauma or constitutional symptoms. On physical exam, the patient had a moderate left knee effusion with some warmth and no erythema. There was tenderness to palpation along the medial joint line and a marked decreased passive range of motion, 40-90 degrees. His neurovascular exam was intact with no signs of lymphedema, adenopathy, or instability.
Computed tomography (CT) revealed a mixed radiolucent and sclerotic permeative lesion within the left posterior medial epiphysis with medial cortical destruction (). There was an associated suprapatellar effusion without evidence of infiltration through the physis.
Magnetic resonance imagining (MRI) demonstrated a nonspecific infiltrative process involving the left distal medial femoral epiphysis, extending proximally along the posterior femoral cortical surface, appearing dark on T1 and bright on STIR and T2 weighted images (). The radiographic differential diagnosis included chondroblastoma, osteomyelitis and eosinophilic granuloma.
Metastatic workup including CT chest, abdomen, and pelvis, three phase bone scintigraphy, and fludeoxyglucose-positron emission tomography scans (FDG-PET) were all otherwise unremarkable (Figures and ).
Fluoroscopic guided core biopsy was performed (). Histologic analysis revealed a round cell tumor (). Immunohistochemistry was positive for CD20 and CD79a, confirming diffuse large B-cell lymphoma (). Further analysis revealed positivity for BCL-6 and CD10, and negativity for MUM1, confirming a germinal center phenotype (GC type).
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pmc-6287239-1
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A 49 year old woman, very symptomatic, suffering high quadrant abdominal pain, nausea, dyspepsia, dorsal pain and constant episodes of cough leading to impossibility to sleep and rest, conducing to a very decreased quality of life. Cysts were discover by ultrasound and patient was then referred to our service. CT-Scan was later performed (). CT showed grade II APLD compromising left lateral segment entirely and big sized cyst located mostly in posterior right segments of the liver. Patient wanted to be operated as soon as possible. Laparoscopic approach was elected and planned surgery was left lateral sectionectomy and fenestration of posterior right cysts. Laparoscopic liver resection and fenestration combined was performed in order to reduce liver mass and relief symptoms.
Laparoscopic left lateral sectionectomy associated with fenestration and partial resection of giants cysts located in right lobe was performed. A very low debit and auto-limited biliary leak was observed and patient was discharged at 8th post-operative day with no further complications.
After more than five years of follow up patient remains without related symptoms and CT-Scan shows only few cysts and hypertrophy of the remanent liver parenchyma. Blood test and liver function were normal.
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pmc-6287239-2
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Woman 46 year old with grade III APLD went for consultation as soon as her sister was discharged. She already knew having the same liver condition. CT-Scan and MRI showed more aggressive disease in segments 2 to 8, leaving a portion of caudate lobe with visible parenchyma (). Physical exam showed huge palpable mass involving almost all abdominal quadrants. Patient suffered weight loss, nausea and signs of gastric compression. Open liver resection was offered in order to reduce mass but patient refused operation.
Further regular controls showed increasing of weight loss, abnormal low BMI, and severe bilateral lower limb varicose veins and edema due to IVC compression. Patient still refuse to surgical treatment.
Few months later was admitted in emergency room due to double incarcerated hernia due to intra-abdominal hypertension and both hernias were successfully repaired urgently. Patient then accepted go through liver surgery.
Regarding complete compromise of left lobe and most of the symptoms were related to gastric compression, left open liver resection was planned in association with several non anatomic resection and fenestration in order to make space for the future remanent parenchyma to grow.
Bilateral sub-costal incision was elected and open left lateral sectionectomy associated with several non anatomic resections and fenestration were performed.
Patient underwent re-laparotomy for lavage due to hemorrhagic liquid in the abdomen causing acute abdominal pain. Then was discharged with no other complications.
After more than three years follow up, she remains without digestive symptoms. She gained weight and has no longer palpable abdominal mass. Inferior members edema disappeared. CT-Scan showed huge hypertrophy of remanent liver and small sized remaining cysts ()
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pmc-6287239-3
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Woman 52 year old with severe grade III APLD came in consultation. She was also aware of her familiar condition. Liver transplantation was offered to her in another center but she refused. Previous MRI from another center showed multiple giants cysts compromising the whole abdominal cavity. Cysts reached hypogastric area and both inferior quadrants. Higher segments of the liver seemed to be respected. Globulous deformation of the abdomen was clearly observed. Despite aesthetic and mild abdominal pain symptoms were not as significant as they were in her two sister so she did not want to underwent liver resection too. However she kept coming to consultation every six months.
Two years later she came back presenting jaundice with serum levels of FAL>1700 mg/dl. Bilirrubin 9,8/7,9 mg/dl. New MRI showed cyst compression of the hepatic pedicle including common bile duct and portal vein ( A and 3B)
Surgery was soon programed and approach was discussed. We decided laparoscopic approach but being aware room will be very reduced even after pneumoperitoneum. We decided to start by performing aspiration and evacuation of the big lower and anterior cysts to intend reducing the mass and make new space for the laparoscopic procedure. By performing this gesture followed by several fenestration and partial cysts resections space was increased within the abdominal cavity so laparoscopic liver resection could be then performed. Once gallbladder was located, we then identified two cysts that seemed to be responsible for hepatic pedicle compression. Fenestration was done and, then, intra-operative cholangiogram showed no further compression of the common bile duct with adequate passage of contrast to duodenum. Standard cholecystectomy was completed and later laparoscopic left lateral sectionectomy was done in association with several more cyst fenestration. Post-operative course was un-eventful and patient was discharged at 6th day with decreasing levels of FAL and bilirubin. Late follow up imaging control are still to come.
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pmc-6287356-1
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A 31-year-old Mestizo-Mexican woman presented to our emergency department (ED) with DKA. She did not have a family history of diabetes or previous autoimmune diseases. She mentioned multiple hospitalizations due chronic idiopathic pancreatitis between 12 and 16 years of age. At that time, laboratory tests ruled out the presence of gallstones, tumors, autoimmune diseases, or metabolic diseases. Her pancreatic exocrine and endocrine functions were completely normal after each episode. Fifteen years after the last episode of pancreatitis, she presented with alopecia, malar rash, and oral ulcers. She was initially diagnosed as having discoid lupus with the skin biopsy results. However, a week later, she developed severe neuropsychiatric manifestations of SLE, including focal motor seizures, with a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of 18 points. Rheumatologists prescribed methylprednisolone (three doses of 1 g daily by intravenous injection) with improvement of neurological symptoms. Her treatment at hospital discharge was: chloroquine (225 mg/day), levetiracetam (1.5 g twice a day), phenytoin (100 mg twice a day), lorazepam (1 mg/day), and a monthly bolus of CY. In addition, she was treated with weekly down-titrating doses of prednisone (initial dose of 1 mg/kg).
Seven days after administration of the sixth dose of CY (cumulative dose of 6.25 g), she presented with asthenia, adynamia, polydipsia, nausea and vomiting, food intolerance, impaired visual acuity, and abdominal pain. The physical examination at our ED revealed tachycardia (125 beats per minute), tachypnea (27 breaths per minute), drowsiness, and dehydration. She presented with a normal body mass index and no stigmata associated with insulin resistance. Laboratory tests reported: serum glucose of 1240 mg/dl, sodium of 127 mEq/L, potassium of 5.56 mEq/L, chlorine of 86 mEq/L, arterial pH of 7.07, bicarbonate of 3.00 mmol/L, and ketonuria (80 mg/dl) with effective serum osmolarity of 322.8 mOsm/kg and total osmolarity of 334.1 mOsm/kg, with an anion gap of 43.56, urea 63 mg/dl, and creatinine of 1.58 mg/dl. Liver tests, amylase, and lipase were normal. After the diagnosis of a mixed hyperglycemic state with predominance of severe DKA, she was started on an aggressive intravenously administered fluid schedule with saline solution 0.9% and intravenous continuous insulin infusion (CII). During the first day she required a total of 165 units of insulin per day (2.75 U/kg per day). Table shows the clinical and biochemical evolution from first evaluation to resolution of DKA.
During the first hours, traditional precipitant factors for DKA, such as infections or cardiac ischemia were ruled out. With an aliquot from the first serum sample in the ED, we measured anti-insulin, anti-GAD65, and anti-IA2 antibodies that were reported as negative; C-peptide was determined to be 0.5 ng/ml and the glycated hemoglobin (HbA1c) was 12.0%. The diagnostic consideration was of T1DM, so once DKA remission was achieved, she was prescribed an intensive insulin scheme at a dose of 1.09 IU/kg per day with 70% of basal insulin glargine daily and 30% of lispro boluses divided in three doses.
With the multi-drug immunosuppressive treatment her symptoms improved and 3 months after discharge the CY was switched to azathioprine and then to chloroquine. Three weeks after the switch from CY to other immunosuppressive therapies, she presented with symptomatic hypoglycemia and insulin doses were tapered down. Five months after the switch, insulin was completely withdrawn. At last follow up, 1 year after the hyperglycemic crisis, she had no symptoms related to hyperglycemia and her blood glucose remains under 100 mg/dl. She continues to have a well-balanced, low-carbohydrate diet and her last HbA1c was 5.2% and C-peptide was 1.8 ng/ml without any antidiabetic drugs.
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pmc-6287602-1
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A 79-year-old man was admitted to the Department of Nephrology, Kansai Electric Power Hospital on January 14, 2014, for proteinuria. He had been followed up for hypertension and dyslipidemia in a local clinic since the age of 50. He had experienced several vascular events, such as total occlusion in the common iliac artery at the age of 63 and two histories of cerebral infarction at the ages of 70 and 77. He had 30 years of smoking history but no alcohol habit. He had no family history of kidney disease except for one cousin showing end-stage renal disease of unknown etiology. During his initial admission to our hospital, his urine protein level was 5.4 g/g Cr, and serum albumin was 3.2 g/dL; he was discharged because his condition was stable. Ten months later, edema of his lower limbs worsened, and renal biopsy was performed on his second admission.
On the second hospitalization, physical examination showed the following: height of 169 cm, weight of 70 kg, body mass index of 24.5, and blood pressure of 180/88 mmHg. Laboratory findings revealed a nephrotic range of urine protein, 9.15 g/g Cr accompanying microscopic hematuria of dysmorphic 10 – 19 RBC/HPF, and total serum protein and albumin of 4.8 and 1.8 g/dL, respectively. Serum creatinine was 0.95 mg/dL, AST was 29 IU/L, ALT was 14 IU/L, and ALP was 188 IU/L. Serological examination revealed serum IgG, IgA, and IgM of 875, 344, and 52 mg/dL, respectively. Antinuclear and antineutrophil cytoplasmic antibodies were negative.
Lipid analysis revealed elevated total cholesterol (259 mg/dL), triglyceride (376 mg/dL), and LDL cholesterol (167 mg/dL) levels, and a low HDL cholesterol level (45 mg/dL). The serum ApoE level was 13.6 mg/dL (normal range: 2.8 – 4.6 mg/dL). An oral glucose tolerance test showed no abnormality, and his hemoglobin A1c was 5.7%. Although hypertriglyceridemia was marked, systemic abnormalities characteristic of hyperlipidemia, such as corneal opacities, xanthoma, and Achilles tendon hypertrophy, were not found. Moreover, the patient had no family history of hyperlipidemia and diabetes mellitus.
Light microscopy (LM) revealed that the specimens contained 27 glomeruli, 8 of which showed global sclerosis (29.6%). Most glomeruli showed segmental sclerosis, infiltration of foam cells containing lipid deposits in capillary lumen (a). In periodic methenamine silver (PAM)-stained sections, spike formation and bubbling were detected on the glomerular basement membrane (GBM) (c, d). Mild to severe arteriosclerosis and arteriolosclerosis were also seen. Fibrosis was observed in ~ 20% of the whole interstitial area. Intriguingly, Sudan III staining was strongly positive not only in the mesangial and infiltrating foam cells but also in the focal capillary lumen in the glomerulus (b). Immunofluorescence (IF) studies demonstrated subtle granular staining for IgG along the capillary wall; however, C3 was not detected (data not shown). Electron microscopic (EM) findings analysis showed electron-dense deposits (EDDs) with a variety of densities and distributions. Highly-dense deposits accompanied by spike formation identical to MN were seen in the subepithelial area (a, b). In the subendothelial area, highly dense EDDs were detected but in higher magnification, and microbubbles were contained (a, b). Effacement of foot process was also accompanied with these depositions. In addition, EM findings demonstrated that the capillary lumina was filled with lipid deposits that did not show lamellar formation similar to “lipid thrombi” in LPG.
Plasma ApoE phenotypes were analyzed by isoelectric focusing in polyacrylamide gel electrophoresis and immunoblotting analysis as previously reported [, ]. The patient’s sample showed the position of ApoE2/2 (a, Lane 1).
The APOE genotype was determined by restriction fragment length polymorphism (RFLP) analysis as described previously [, ]. The PCR products were digested with the restriction enzyme HhaI. Genotype ε2/2 in the patient was identified by 91- and 83-bp fragments (b, Lane 1). The ApoE Toyonaka (Ser197Cys) as shown in d was also confirmed by RFLP analysis digested with SacI (c). Genomic DNA was amplified by polymerase chain reaction (PCR) using oligonucleotide primers, sense 5′-CGTGCGGGCCGCCACTGTGAGCT-3′ and antisense 5′-TCGCATGGCTGCAGGCTTCGGCGTTC-3′. The 335-bp fragment after cleavage by SacI suggested normal c.644C of ApoE in codon 197 (Lane 3). The 358- and 335-bp fragments after cleavage by SacI showed a heterozygous novel mutation of ApoE Toyonaka (Lane 2). Direct sequencing of APOE DNA was performed as described previously []. Based on the results, we identified a homozygous polymorphism at codon 158 (e2/2: c.526 C>T: Arg158Cys) (data not shown) and a heterozygous missense mutation (C to G) in exon 4 leading to an amino acid substitution Cys (TGC) for Ser (TCC) at codon 197 (c.644 C>G: p.S215C: Ser197Cys) (d). All these findings were the same as that of a previous case of ApoE2/2 and ApoE Toyonaka showing MN-like glomerular histology [6].
For hypertriglyceridemia, fibrate 400 mg/day was started. Obtaining the results of the IF and EM studies, which did not deny immune-related MN like lesions, PSL 10 mg/day and cyclosporine (CyA) 75 mg/day for NS were started. These treatments brought about a substantial improvement of hypertriglyceridemia and complete remission of NS by 300 days after admission. During maintenance therapy with oral PSL 5 mg and CyA 75 mg/day, he had cerebral infarction and aspiration pneumonia. After withdrawal of CyA, his NS relapsed with an increase of proteinuria more than 1 g/day.
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pmc-6288365-1
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The P+ patient was a right-handed (), seventy-two years old man. In January 2017, he suffered from a right ischemic stroke and was admitted to San Camillo Hospital in Turin, for a neurorehabilitation program. He had no previous history of psychiatric disorders. Before starting the experimental procedures, he provided written informed consent to participate in the study, which was designed in accordance with the Declaration of Helsinki (BMJ 1991; 302: 1194) and approved by the Ethical Committee of the ASL TO 1 of Turin. Written informed consent was obtained from the P+ patient for the publication of this case report and their indirectly identifiable information. At the time of this study (March 2017), he was assessed using common neuropsychological tests (see Table for details). At the evaluation, he appeared awake, cooperative and with an adequate mood level. Visual, motor and tactile functions were evaluated by the responsible neurologist and by a standardized neurological protocol. In this protocol, scores range from 0 (no deficit) to 3 (severe deficit) and are carried out in accordance with the procedure outlined in previous studies (e.g., ; ; ,; , ). According to these evaluations, the P+ patient did not show signs of hemianopia () or a contralesional upper limb motor deficit (i.e., he was able to perform both distal and proximal movements requested by the examiner with the contralesional upper limb). However, he showed signs of extra-personal neglect [assessed by means of the Diller Letter H Cancellation Test () and the Behavioral Inattention Test – BIT ()], personal neglect [assessed by means of the Fluff Test ()] and of tactile extinction (; ). What is more crucial for this study, is that he showed a selective proprioceptive impairment of the contralesional upper limb. Proprioception, as in previous studies (, ; ), was assessed by means of two techniques for testing the limb localization: the Contralateral Limb Matching Task (CLMT) (; ; ) and the Finger Localizing Test (FLT) (; ; ). Both procedures were performed with the patient’s eyes closed. It should be noted that prior to the test, we instructed the patient in how to complete the task to ensure the correct performance of it (i.e., with his eyes open). In the CLMT, the patient’s affected contralesional arm was passively moved in a reference joint angle (i.e., target position) by the examiner and the patient was asked to recreate such a target position by matching it with the contralateral intact arm. In the FLT, the examiner positioned the patient’s contralesional affected limb (fixed limb) and asked him to pinch a target finger of that limb with the thumb and index finger of the opposite hand (reaching limb). For the CLMT, a correct response was designated when the difference of joint angles between the affected limb and the unaffected limb was less than 10° as judged by visual estimation. While a difference of more than 10° was designated as an incorrect response. For the FLT, a correct response was designated when the patient reached the target finger with reasonable accuracy. While an incorrect response was assigned when the patient was unable to reach the target finger. Each test consisted of a total of 10 trials. The score was calculated as percentage of accuracy. It should be noted that when the P+ patient had to reproduce (CLMT test) or to reach (FLT test) the position of the affected limb with the intact limb, his performance was never correct (0% of accuracy). Therefore, his proprioception was considered impaired. However, because of the patient’s spared motor ability, one of the two tests (namely the FLT) was also performed on the ipsilesional side of the body. That is, the patient’s ipsilesional intact limb (fixed limb) was passively moved by the examiner and the patient was asked to pinch it with the affected hand (reaching limb). In this case, the patient’s performance was always correct (100% of accuracy) (see Discussion).
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pmc-6288563-1
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A 71-year-old woman was referred for evaluation of back pain and worsening left lower extremity pain, which included neurogenic claudication. She gave a history of a fall from standing height, with onset of low back pain. Around a month later, her left leg pain became a prominent feature, with a symptom duration of approximately five months at the time of injury. She did not experience lumbar epidural or intrathecal injections. She reported no history of fever and no difficulty passing urine. Significant medical history included mild hypertension, of note, and there was no history of malignancy and no history of use of anticoagulant drugs. Both platelet count and prothrombin time were in the normal range. On examination, there was full power and symmetrical reflexes in both lower extremities. Patchy reduction in sensation to the left lower limb was noted. She was given a left L5 nerve root block which was only effective for 3 days. The patient and/or her families were informed that data from the case would be submitted for publication and gave their consent.
A lumbar MRI without gadolinium (Gd) had been performed prior to evaluation (4 months after symptom onset) in a previous hospital (). The MRI showed a posterior mass at L4/5. On T1-weighted images (), the mass was isointense, with a few hyperintense areas within. On T2-weighted images, the mass was hyperintense in the center and hypointense in the periphery (). We suspected the spinal tumour and carried out a 2nd MRI with Gd. On the 2nd MRI of the same area (Figures –), after a 2-week interval, a newly isointense mass was present within the anterior part of the previously identified lesion on T1-weighted image () and the hyperintense area in the lesion was a little extended on T2-weighted imaging (). There was no significant enhancement with Gd-based contrast (Figures and ). Her symptoms were not changed between the 1st and 2nd MRI.
The patient underwent surgery for decompression of the spinal canal and resection of the lesion, which at this stage was presumed to be an epidural tumour. After L4/5 partial laminectomy, the solid blackish ligamentum flavum was visible and firmly adherent to the dural sac at L4/5 posteriorly (). After removing the ligament (), both L5 roots were decompressed perfectly. A hematoma was found inside the ligamentum flavum (). After surgery, her symptoms immediately resolved.
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pmc-6288569-1
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A 45-year-old woman G2P0A1 was admitted to the emergency department at 27 weeks of gestation for tonico-clonic seizure. As past medical history, she has a poorly controlled epilepsy diagnosed in childhood, currently on carbamazepine (300 mg twice daily), one unexplained abortion 5 years ago, at 16 weeks of gestation, and gestational diabetes mellitus on metformin (500 mg three times daily) identified 3 weeks prior to presentation. She had recurrent seizure attacks in the past 4 years but this is the first time when it occurs during pregnancy. No calcium level measured prior to the actual admission.
There is no family history of hypoparathyroidism and no surgery of the thyroid or parathyroid glands.
Emergent CT brain revealed no abnormalities. Metabolic workup showed life-threatening hypocalcemia with hyperphosphatemia. Other laboratory data are showed in .
1.25 vitamin D was not measured. Neck ultrasound was normal.
After controlling her seizure with the appropriate antiepileptic drugs, she started complaining of paresthesia all over her body, especially in her extremities. Intravenous calcium gluconate (11 grams), magnesium sulfate (2 grams), and levetiracetam (1 gram twice daily) for her seizure were administered and symptoms rapidly resolved and thereafter switched to oral calcium (600 mg 3 tablets every 6 hours) with calcitriol (2 mcg daily) and vitamin D replacement (10 000 IU daily). Based on these results and in front of the hypocalcemia, hyperphosphatemia, and the inappropriately normal PTH, idiopathic hypoparathyroidism associated with vitamin D deficiency was on the top of the differential diagnosis in this patient. No genetic studies performed. Fetal ultrasound was unrevealing. She was discharged home on oral calcium (600 mg 3 tablets every 8 hours), calcitriol (2 mcg daily), oral magnesium and vitamin D supplementation, and antiepileptic drugs with close monitoring of calcium level in order to keep the level in the lower limit of normal. After 4 weeks, caltrate and calcitriol doses were decreased to 600 mg 2 tablets twice daily and 1 mcg daily, respectively, because corrected calcium level increases to 8.8 mg/dl. Variation of calcium level was reported in . She was followed up clinically and biochemically all her third trimester with a stable calcium level of around 8 mg/dl and without any symptoms.
At 37 weeks of gestation, she presented for delivery, calcium level was 8.5 mg/dl with normal albumin level, and 25-hydroxyvitamin D after 8 weeks of replacement was 20 ng/ml. She gave birth to a baby boy (Apgar score 9/10) with hyperparathyroidism (PTH of 68 pg/ml) and hypercalcemia of 10.7 mg/dl after an uneventful normal vaginal delivery and thereafter she started breastfeeding.
2 weeks postpartum, calcium level increased to 9 mg/dl; therefore calcitriol was given at a dose of 0.5 mcg daily and caltrate at a dose of 1200 mg daily. Oral calcium dose was adjusted every 3 weeks during lactation period, to prevent elevation of calcium level. She had a stable calcium level of around 8.4 mg/dl during the 2 months of lactation. Her baby was followed and monitored for any hypercalcemic side effect by the pediatric team.
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pmc-6288572-1
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A 53-year-old male, smoker (20 pack-years), occasional alcoholic, presented with complaints of blood expectoration of 400 ml in one episode followed by 100–150 ml for 2–3 days. He had 3 episodes of similar history which required hospitalizations and emergency care since 9 months. He denied history of fever, chest pain, and loss of appetite. He underwent cholecystectomy 3 years ago. There was no history of systemic immune suppression like diabetes. He had undergone bronchial artery embolization for massive haemoptysis; however, his haemoptysis persisted and diagnosis remained elusive after evaluation with sputum studies and CT-guided aspiration cytology, biopsy, and bronchoscopic lavage. He was treated for LRTI with multiple courses of antibiotics for more than 9 months.
On examination, vitals were normal with no respiratory distress. Oral hygiene was poor with dental caries. Respiratory examination revealed scattered crackles in the left lower lobe area. Chest X-ray showed an inhomogeneous opacity in the left lower zone with raised left diaphragm (), and CECT (contrast-enhanced computer tomogram) chest showed a hypodense lesion with irregular margins in the anterior segment of the left lower lobe adjacent to the descending aorta and associated subcarinal lymphadenopathy (Figures and ). Image-guided transthoracic biopsy showed type 2 alveolar cell hyperplasia with negative immunohistochemistry. Bronchoscopy confirmed left lower lobe bleed with any endoluminal lesion. Bronchial wash was negative for microbiological and cytological studies including AFB stain, geneXpert for MTB complex, and pyogenic culture. Patient's symptoms of haemoptysis persisted; hence, CT angiogram was performed, which showed dilated vascular channels within the lesion without any obvious extravasations of contrast and no aortic abnormality.
Probable diagnosis of the left intrapulmonary vascular lesion was made and hence the patient underwent left lower lobe lobectomy. Intraoperatively, the left lower lobe was adherent posterolaterally to the aorta and diaphragm. Multiple prominent blood vessels in areas of adhesion were seen. Histopathology was suggestive of chronic inflammatory cells with focal aggregates of lymphocytes with positive GMS staining for actinomycosis (). Postoperatively, the patient received parenteral benzylpenicillin 20 lakh units 6th hourly for 3 months. The patient was in regular follow-up, and no further episodes of haemoptysis and no recent respiratory complaints are reported.
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pmc-6288573-1
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We present a case of a 70-year-old male, who presented with two-week history of perianal pain accompanied by urgency to defecate and anorexia. He was passing small stools with severe pain, sweating, and burning sensation. There was no history of abdominal pain, constipation, rectal bleeding, fever, and diarrhea or weight loss. Past history included coronary artery bypass graft and hiatus hernia repair. He had worked at a cattle farm and was a nonsmoker.
At presentation, he was haemodynamically stable with normal systemic examination. The perineum looked unremarkable with no blood or mucous. Digital examination was aborted due to pain. His hemoglobin was normal with raised inflammatory markers. Liver function tests were mildly elevated. A provisional diagnosis of deep perianal abscess was made.
Following this, magnetic resonance imaging (MRI) was done which demonstrated inflammatory changes involving mucosa of the anus, rectum, and internal sphincter with no definite fistulous tract or collection (see ). His blood film showed marked monocytosis, promonocytes, and some circulating blasts suggesting acute myelomonocytic leukemia (AMML) or chronic myelomonocytic leukemia (CMML) in transformation.
Following admission, he became febrile; hence, full septic screen was done before starting intravenous antibiotics. An examination under anesthesia in theatre showed a generally inflamed, edematous rectum without contact bleeding. There was no mass, fistula, or abscess identified. A rectal polyp found at 5 o'clock position was excised and sent for histology. Several biopsies of the inflamed mucosa were also sent for histological analysis (). Histology of the polyp revealed dense stromal infiltrate of atypical cells with granular eosinophilic cytoplasm, medium-large nuclei with irregular nuclear membrane, and prominent nucleoli, morphology, and immunohistochemical profile consistent with mucosal involvement by myelomonocytic leukemia. Immunoperoxidase stains showed CD4+, CD68+, CD45+, and MPO+ (see Figures and ).
The hematologist performed a trephine bone marrow biopsy that reported markedly hypercellular bone marrow aspirate showing excess blasts consistent with the diagnosis of acute leukemia, morphologically AMML. Flow cytometry showed an increased population detected with the phenotypes CD13+, CD33+, CD34−, CD65+, HLADr+, and CD117+ and aberrant expression of CD7+. His cytogenetic studies showed no molecular evidence of a translocation involving the KMT2A (MLL) gene at 11q23. No molecular/next generation sequencing was performed because of involvement of high cost of the test. Diagnosis of acute myeloid leukemia was hence made. Histology and bone marrow trephine biopsy results showed French American British (FAB) classification [] as AMML-M4 and as World Health Organization (WHO) classification 2008 []. The patient was then transferred to a cancer hospital where he was offered intensive chemotherapy for AMML. He went into remission following chemotherapy, and his GIT symptoms settled subsequently.
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pmc-6288574-1
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A 7-year-old boy was admitted to our hospital with a 4-day history of high fever and scalp swelling with ulcers. Physical examination revealed consciousness (Glasgow Coma Scale/core was 15), pus formation, and fistula with purulent discharge on the scalp, scalp peeling, face swelling, and poor eating (). Laboratory findings exhibited severe neutropenia (white blood cells, 2.39 × 109/l; neutrophils, 0.25 × 109/l; and lymphocytes, 2.1 × 109/l) and increased acute-phase reactants (erythrocyte sedimentation rate 101 mm/hour and C-reactive protein 272 mg/dl). Pus culture exhibited Enterococcus faecalis and Escherichia coli. Blood culture and urine culture were negative. The chest X-ray and urinalysis results were normal. Cerebrospinal fluid (CSF) analysis was normal. Serum titers of IgG, IgM, IgA, and IgE and percentage of CD4+ and CD8+ T cells were normal. Tests of HIV, HBV, HCV, EBV, and CMV were negative. Bone marrow analysis revealed a maturation arrest at the promyelocyte/myelocyte stage with few mature neutrophils; there was no evidence of malignant involvement in the bone marrow. Computed tomography scan of the head and skull showed subcutaneous emphysema of the scalp, neither brain injury nor skull fractures (). Necrotizing fasciitis of the scalp and septicaemia were diagnosed. The patient was treated with pentaglobin (0.5 g/kg) and the combination of three antibiotics: vancomycin, meropenem, and metronidazole, respectively. To maintain the neutrophil count, granulocyte colony-stimulating factor (G-CSF) was administered from 5 to 10 µg/kg/day and 15 µg/kg/day, respectively (). The patient was discharged from our hospital after 46 days of treatment. Now, he is well under regular G-CSF therapy.
Due to severe neutropenia and infections, we analyzed the medical history, family history, and medical records of the patient carefully. The patient is the third child in his family. He has two healthy younger sisters, one older sister who died at the age of 6 months because of meningitis, and one older brother who died at the age of 5 months because of severe pneumonia. No consanguinity was reported among parents, but their origins are from the same commune. From 7 months of age, the patient had recurrent severe infections such as cutaneous abscesses, otitis media, and respiratory infections, which were treated with appropriate antibiotics. In addition, he had neutropenia many times and mental retardation such as developmental delay, dysarthria, and linguistic immaturity.
Considering his past history, family history, and physical examination, SCN associated with ELANE or HAX1 abnormality was suspected. The ELANE gene was analyzed by direct DNA sequencing analysis firstly but the mutation was not found. Due to mental retardation of the patient, the HAX1 gene was analyzed next. In exon 3 of the HAX1 gene, we found a homozygous frameshift mutation (c.423_424insG, p.Gly143fs). This is a novel mutation.
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pmc-6288861-1
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A 47-year-old female patient presented to the dialysis unit with decreased level of consciousness and sleepiness of two days duration. Her past medical history is end stage renal disease and regular hemodialysis 3 times/week for 2.5 years, controlled hypertension. She is non-diabetic. Her past surgical history included arteriovenous fistula before 2.5 years, appendectomy and tonsillectomy long time ago.
The patient was in her usual state of health of moderate exercise tolerance until two days before admission when she started to experience lower back and bilateral knee pain that was vague in nature and associated with insomnia. That time, she received one tablet of baclofen 25 mg from her sister. Her sister used to ingest baclofen for chronic neck pain. The patient fell into a deep sleep throughout that night and entire next day without any wakefulness periods. Two days later, she went to her usual hemodialysis session and there the medical personnel noticed her high blood pressure and a state of unconsciousness for which she was sent back to the emergency department after the hemodialysis session. The family denied any previous similar episodes or limb weakness, numbness, dysarthria, dysphagia or mouth deviation before the event. There is no history of fever, photophobia, neck stiffness, falling down or any psychosocial problems. She had not travelled or had any contact with sick people. She was compliant to her hemodialysis sessions. She is a 20 pack-year smoker but does not use any illegal drugs or consume alcoholic drinks. Her home medications were: Atenolol 50 mg/day, Amlodipine 5 mg/ day, CaCO3 600 mg /day and alfacalcidol 0.25 ugm/day.
On examination, the vital signs were as follows: Temperature: 36.4 °C, Blood pressure: 220/110, pulse: 95 beat/minute, respiratory rate: 14/min, oxygen saturation: 95% on room air. On admission, the Glasgow Coma Scale was 9/15. She was unconscious. Deep tendon reflexes were absent. There was no obvious facial asymmetry, left pupil was round and reactive to light (right eye is artificial due to previous trauma). Gag reflex was intact but the cranial nerves could not be assessed. The fundus was examined and no papilledema or hemorrhage were seen. The breathing sounds were heard bilaterally on the chest with no added sounds. Abdominal examination was unremarkable.
Lab results at admission were: Hemoglobin: 16.1 g/dL, White blood cells: 6.8 K/ul, platelets: 155 K/ul, Sodium: 138 mEq/L, potassium: 4.4 mEq/L, chloride: 95 mEq/L, CRP: 1.6 mg/L, Glucose: 99 mg/dL, ABG’s: pH:7.44, pCO2: 36.6 mmHg, pO2: 88 mmHg, HCO3: 24.4 mEq/L, albumin: 4.4 g/dL, alkaline phosphatase:88, total bilirubin: 0.5 mg/dL, direct bilirubin: 0.2 mg/dL, BUN: 27 mg/dL, Creatinine: 5.5 mg/dL. Liver function tests were within normal ranges. To rule out any brain ischemia or hemorrhage, brain computed topography (CT scan) was done on the day of admission and Magnetic resonance imaging (MRI) of the brain was done on the second day of admission. CT scan showed no significant lesions, no hemorrhage or any other defects. MRI showed no signs of recent ischemic stroke, intracranial hemorrhage, space-occupying lesion or midline shift. The hypertension was controlled by labetalol IV infusion pump.
After ruling out all possible causes of her decreased level of consciousness, including Posterior reversible encephalopathy syndrome (PRES), baclofen toxicity was considered as the cause. She was started on flumazenil 0.25 mg and on intensive daily ultrafiltration hemodialysis sessions since the first day of admission with total of three extra hemodialysis sessions. The improvement started to be noticed at the second day when she was semi-conscious, hallucinating, obeying commands as ordered but still not oriented to time, place or person. GCS was 10/15. The dramatic improvement was on the next day after a total of two extra hemodialysis sessions, she was fully awake, GCS 15/15, able to obey commands but still not well oriented so a third extra session was considered. After three days of admission and a total of five hemodialysis sessions, she was discharged after she had returned to her previous baseline state of health and she was instructed not to receive baclofen again.
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pmc-6288893-1
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A 41-year-old male heavy smoker with no specific medical history was admitted to our hospital with severe chest pain lasting 2 h. His blood pressure was 130/80 mmHg on admission, and he presented with no laterality in the upper extremities. Electrocardiography on arrival showed ST-segment elevation in leads II, III, and aVF. The cardiac troponin I was 0.68 ng/ml. He was diagnosed with inferior ST-segment elevation myocardial infarction (STEMI) in Killip Class I and immediately brought to the cardiac catheterization laboratory. An emergency coronary angiography revealed a large filling defect extending from the distal LM artery into the proximal LCX artery (Fig. a and b). Otherwise, no significant lesions were found and thrombolysis in myocardial infarction (TIMI) III flows were observed in all coronary arteries. Therefore, PCI was performed using a 6Fr guiding catheter (EBU3.5, Medtronic). Unfortunately, while a 0.014-in. guidewire (Runthrough, Terumo) crossed the LM artery, the whole thrombus was extracted from the proximal LCX artery and pushed into the LAD artery. The proximal LAD artery was completely occluded by the thrombus (Fig. c). After crossing the lesion in the LAD artery with the guidewire (Runthrough, Terumo), thrombectomy was attempted several times using an aspiration catheter (Export, Medtronic), and the intracoronary administration of Glycoprotein IIbIIIa inhibitor was slowly infused. However, these treatments did not reduce the thrombus burden in the proximal LAD artery, and no visible thrombus was detected in the aspirate. Then, a 14-atm dilation of a semicompliant balloon (Ryujin 2.5 × 15 mm, Terumo) was performed in the lesion. However, the thrombus moved to the middle LAD artery with TIMI flow 0 (Fig. d). Following the failure of another attempt of aspiration using an Export catheter (Medtronic), thrombus extraction from the LAD artery was considered as impossible. The initial angiogram showed no stenosis in the LAD artery, which had diameters above 2.5 mm and above 1.5 mm at the distal and terminal sites, respectively. To reduce the infarct size, we decided to try a new technique by pushing the thrombus to the terminal LAD artery. A dilated balloon with 6 atm (Ryujin 2.5 × 15 mm, Terumo) was used to push the thrombus carefully toward the distal LAD artery (Fig. a and b). Furthermore, the contracted balloon (Ryujin 2.5 × 15 mm, Terumo) successfully pushed the thrombus to the terminal LAD artery (Fig. c and d). The final angiogram demonstrated no other significant stenosis except the embolization in the terminal site of the LAD artery (Fig. a); thus, stent deployment was not performed.
The patient was transferred to the coronary intensive care unit in a hemodynamically stable condition, while his ST elevation subsided. He was started on low-molecular-weight heparin in addition to regular aspirin, ticagrelor and rosuvastatin. Glycoprotein IIbIIIa inhibitor administration was continued for 24 h. The immunological screen results were unremarkable. A follow-up coronary angiography was performed 1 week later, which revealed the restoration of TIMI 3 flow and the complete resolution of thrombus in the left coronary artery (Fig. b). Intravascular ultrasound (IVUS) showed nonsignificant residual stenosis of the LM artery (Fig. c). Echocardiography revealed the left ventricular ejection fraction (EF) was 61% with a slight apex hypokinesis, and the bubble study showed a negative result. The patient had an uncomplicated recovery and was discharged after 2 days. No adverse events occurred during a 12-month follow-up period.
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pmc-6288932-1
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A 19-year-old Hispanic female with a past medical history of acne, asthma, and extensive psychosocial distress but no psychiatric diagnoses, presented to the ED with complaints of an episode of lightheadedness, generalized weakness, diaphoresis, diarrhea, and vomiting. Previously, she presented to the hospital with similar complaints two other times; however, she was not seen by our team until the third visit. On this first visit she stated that she used the blood glucose monitor of her girlfriend/roommate, who is a type 1 diabetic, and that her blood sugar reading was 53 mg/dL and later rose to 80 mg/dL after she ate two sandwiches and some chocolate. Upon arriving to the ED, the patient’s symptoms had improved. Vital signs obtained at the time of triage were: blood pressure (BP) 98/65 mmHg, heart rate 81 beats per minute (bpm), respiratory rate 18 breaths per min, oxygen saturation (SpO2) of 100% on room air, and an oral temperature of 37 °C (98.6 °F). The patient reported no pertinent past surgical history. She stated that she was allergic to pineapples and that she does not take any medications. In addition, she did not report any tobacco or alcohol use. Initial examination revealed a well-developed, asymptomatic, obese young female in no acute distress. Her blood glucose according to the glucose monitor was 60 mg/dL, which was confirmed with lab draw. Physical exam and labs were unremarkable, and the patient was discharged after being given intravenous (IV) 0.9% sodium chloride (NaCl) for volume restoration, ondansetron for her nausea and vomiting, further directions on diet for hypoglycemia (i.e. adding protein to each meal and eating small frequent meals), and instructions on follow-up with her primary care provider (PCP) for recommendation on further testing for the cause of her hypoglycemic episode and GI symptoms.
The next day, the patient arrived via emergency medical services (EMS) to the ED after she was found unresponsive. She stated that she was not feeling too well due to a virus and became very lightheaded and passed out. Her blood sugar was 46 mg/dL at home prior to administration of half an ampule of dextrose (D50W). Her family mentioned the patient has a history of her blood sugar dropping rather frequently and that they are unsure what to do for this problem. Vital signs obtained at the time of triage were: BP 122/75 mmHg, heart rate 100 bpm, respiratory rate 18 breaths per minute, SpO2 of 100% on room air, and an oral temperature of 36.7 °C (98 °F). Physical exam and other labs were unremarkable, and the patient was discharged after being given instructions once again on following-up with a PCP.
Three weeks after her initial presentation, she was rushed to the ED via EMS after being found unresponsive at work with a blood glucose level of 23 mg/dL. She was given 1 ampule of IV D50W by EMS at the scene and her blood sugar rose to 172 mg/dL. Upon arrival to the ED, her blood sugar had dropped back down to 61 mg/dL; and she was noted to again have symptoms of dizziness and decreased alertness with her hypoglycemia. Vital signs obtained at the time of triage were: BP 135/78 mmHg, heart rate 108 bpm, respiratory rate 18 breaths per minute, SpO2 of 100% on room air, and an oral temperature of 36.4 °C (97.6 °F). She was given one half of an ampule of D50W IV because of her symptoms of dizziness and evidence of decreased alertness with a decreased blood glucose level, which was suspected to still be dropping. She responded to this treatment with improvement of dizziness and alertness but later had a second hypoglycemic episode in the ED. At this time she was treated with a full ampule of D50W IV and was started on dextrose 5% with 0.45% NaCl (D5 half-normal). Despite a brief improvement a few minutes after starting D5 half-normal, she had a third episode of hypoglycemia in the ED and was treated with another ampule of D50W IV and her IV changed to dextrose 10% in water (D10W) at 100 cm3 (cc’s) an hour. Despite this change, her blood glucose further dropped to 105 mg/dL from 140 mg/dL, so her D10W was increased to 150 cc’s an hour. Detailed glucose readings throughout this time are reported in Table . Her girlfriend/roommate was asked to leave the patient to rest, in order to help determine whether the patient, her roommate, or both might be involved in giving insulin to cause the abrupt hypoglycemic episodes. The patient was weak, confused, profusely sweating with chills, short of breath, nauseated, had heart palpitations, and an altered mental status during all of her hypoglycemic episodes. Of note, once alert, the patient told the charge nurse that her PCP had found a mass in her pancreas that was responsible for her hypoglycemic episodes. Due to the critical nature of her recurrent hypoglycemic episodes in the ED, the patient was admitted to the ICU, where she became more responsive. An electrocardiogram demonstrated normal sinus rhythm, normal axis and intervals, and no acute changes in ST-segment or T wave morphology. The laboratory findings from all three ED visits are reported in Table .
Standard drug screen was done to rule out any symptoms from toxicity; however the results were negative. To determine if factitious use of insulin was the cause for the patient’s presentation, further tests were performed: hemoglobin A1C of 5.1%, C-peptide level of 9.9 ng/mL, free insulin level of 370 mIU/L and a total insulin level of 377 mIU/L.
To rule out any neurological causes, a computed tomography (CT) scan of the head without IV contrast was performed and revealed no evidence of intracranial findings or suspicious intracranial mass. To rule out any pancreatic masses, CT of the abdomen was obtained and showed a 1.8 cm collapsing cyst in the right ovary and trace fluid in the pelvis, which is likely physiological (Fig. ). Otherwise, no acute intra-abdominal or intra-pelvic process was seen.
The patient was interviewed at length by the ED hospital team in the ICU the following day, and the diagnosis of factitious disorder was suggested. The encounter revealed that the patient is an undocumented immigrant from Honduras, who has been in the US since she was 14 years old. She used to reside with foster parents. However, she recently graduated from being a minor and is currently living at a halfway house with four other women. She works full-time at a thrift store. She is unaware of her family history. She states that she was heavily involved with illicit drug use in the past but does not smoke or drink alcohol anymore. When confronted with evidence about no mass found on imaging, the patient did not deny injecting insulin. She had significant knowledge about insulin administration as well as the amount of units her girlfriend/roommate currently injects for her type 1 diabetes management. She mentioned that she frequently checks her blood sugar at home, where her readings range from 30s – 100 s mg/dL. The patient reported missing several meals throughout the day due to time restraints and work. Her caregiver called the hospital to let the hospital staff know that the patient had been taking her girlfriend/roommate’s insulin resulting in her previous ED visits. She has also asked for insulin needles and may have taken insulin to gain attention.
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pmc-6288948-1
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An 86-year-old woman was referred to the emergency department (ED) for unrelieved chest tightness, shortness of breath and back pain for 6 h on November 7, 2016. Three hours before admission, she presented to her local hospital and was newly diagnosed with acute anterior myocardial infarction (MI), loading doses of aspirin and clopidogrel were orally taken but failed to relieve her symptoms. Five days prior, she had experienced chest tightness on exertion with shortness of breath and no back pain, and these symptoms resolved within a few minutes to two hours at rest and failed to draw her attention. Past medical history included previous pulmonary tuberculosis, besides, she had 40 years of smoking history but quit 16 years ago.
Physical examination revealed vital signs as follows: blood pressure 100/76 mmHg, heart rate 82 beats/min, respiratory rate 20/min. The cardiopulmonary examination was unremarkable, and no peripheral edema was present. The routine laboratory tests at ED revealed troponin I (cTnI) was 0.041 ng/ml (normal reference range 0–0.02 ng/ml), and creatine kinase-MB (CK-MB) was 6.54 ng/ml (normal reference range 0–4.99 ng/ml). No abnormalities were observed in complete blood count, renal and liver function tests. Electrocardiogram (ECG) showed abnormal Q-waves in leads I, aVL and V2-V9, ST-segment elevation in leads V2-V9, biphasic T-waves in V2-V9 and negative T-wave in V1 (Fig. ).
Echocardiogram was performed at ED admission, showing normal tricuspid annular plane systolic excursion and right ventricular diameter of 19 mm, an enlarged left ventricle (LV) of 53 mm at end-diastole with a reduced ejection fraction (EF) of 36% and decreased motion of the left ventricular anterior, anteroseptal, anterolateral wall and apex, and mild tricuspid regurgitation was observed with an estimated pulmonary artery systolic pressure (PASP) of 51 mmHg. Acute anterior wall and high lateral wall MI was initially diagnosed, thus emergency coronary angiography (CAG) was performed (Additional file : Video 1–2). Stable coronary plaques without signs of acute plaque rupture or coronary dissection were seen in the left anterior descending branch and right coronary artery. She was then sent to and managed in the coronary care unit after CAG. Dynamic changes of blood biomarkers and arterial blood gas results were summarized in Table1. Unexpectedly, CAG and dynamic alterations of cardiac biomarkers and ECGs seemed to rule out the initial diagnosis (Fig. , Additional file : Video 1–2, Table ). Repeat echocardiogram on Day 1 displayed a normal-sized LV with left ventricular anterior, anteroseptal and apical hypokinesia and a left ventricular EF of 41%.
By detailly inquiring medical history again, many years of right lower extremity pain, weakness of bilateral lower limbs for half a year and inactivity in the train for 10 h half a month ago were complained of. Since D-Dimer was extremely high, lower extremity venous ultrasound was done on Day 2, indicating multiple thrombi in the right intermuscular vein, dilation of bilateral deep femoral vein and spontaneous echo contrast. The following chest computed tomography (CT) illustrated multiple emboli in bilateral pulmonary arteries, calcified nodules in left upper pulmonary lobe, posterior segment of the right upper lobe and the anterior basement of the lower lobe (Fig. ).
Cardiac magnetic resonance (CMR) (Fig. , Additional file : Video 3–4) on Day 7 demonstrated paradoxical systolic motion of anterior left ventricular wall and akinesis of apex with an EF of 43%, and TTS could not be excluded. Filling defects in the right upper lobe and basal segments of the right lower lobe corresponded with pulmonary thromboembolism.
She received aspirin 100 mg qd, clopidogrel 75 mg qd, isosorbide dinitrate 10 mg tid, atenolol 3.125 mg bid, atorvastatin 20 mg qn, nicorandil 5 mg tid, furosemide 20 mg qd and spironolactone 20 mg qd and enoxaparin 0.3 ml qd on admission. Angiotensin converting enzyme inhibitors were not used due to low blood pressure. Dual antiplatelet therapy was terminated and enoxaparin was changed to 0.3 ml q12h while PE was suspected, and enoxaparin was switched to rivaroxaban 15 mg bid after one week, the latter was used for three weeks and was adjusted to 15 mg qd in consideration of her old age and bleeding risk. She was in a stable condition at 3 months follow-up after discharge, no chest tightness, chest pain or shortness of breath were complained of. Serological biomarkers and blood gas results were within normal ranges (Table ). Echocardiogram revealed normal-sized LV with an EF of 68%, mild aortic valve regurgitation and tricuspid regurgitation, but no regional wall motion abnormalities were detected (Fig. ). No any evidence of PE was spotted in CT. CMR demonstrated improvement in left ventricular systolic function in comparison with the former (Fig. , Additional file : Video 5–6). Hence, her final diagnosis was corrected as TTS with PE and bilateral deep venous thrombosis.
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pmc-6288951-1
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A 25-year-old female presented with heat intolerance, palpitations, weight gain, and goiter. Thyroid function tests showed FT4 at 24.46 pmol/L (normal range, 9.01–19.05), FT3 at 7.31 pmol/L (normal range, 2.63–5.70), and TSH at 8.63 mIU/L (normal range, 0.35–4.94). Radioiodine uptake was 21.95% at 3 h (normal range, 10–30%) and 41.5% at 24 h (normal range, 25–60%). TSH was stimulated from 4.50 to 34.40 mIU/L 15 min after intravenous bolus of thyrotropin-releasing hormone (TRH); liothyronine (L-T3) suppressed TSH from 4.61 mIU/L to 0.21 mIU/L []. Pituitary magnetic resonance imaging (MRI) revealed no abnormality. Gene sequencing identified a heterozygous Y321C substitution mutation in exon 9 of the THRB gene [], thereby confirming the diagnosis of RTHβ. Dual-energy X-ray absorptiometry (DEXA) scan revealed decreased bone mass. The patient was considered as susceptible to Hashimoto’s thyroiditis based on positive thyroid peroxidase antibodies (TPOAb), positive thyroglobulin antibodies (TgAb), and negative thyrotropin receptor antibodies (TRAb). She was given L-T3 to suppress TSH, and a β-blocker to manage tachycardia.
In addition, she had a history of diabetes mellitus without glucose management that resulted in hemoglobin A1c (HbA1c) at 7.1%; oral glucose tolerance test (OGTT) showed basal glucose 7.8 mmol/L (15.2 mmol/L at 120′) and basal insulin 19.47 mIU/L (80.87 mIU/L at 120′), and homeostasis model assessment-estimated insulin resistance (HOMA-IR) was 6.75. Her body mass index (BMI) was 28.3 kg/m2 at 155 cm height. She had liver steatosis and serum triglyceride level was 3.05 mmol/L.
The patient requested ovulation induction after 2 years of irregular menstruation and infertility. The singleton pregnancy was confirmed at 13 weeks gestation, then both LT3 and β-blocker were discontinued. Her thyroid functions and fetal ultrasound morphology were monitored every 1–4 weeks (more frequently during the initial and last month), and revealed no complications. Based on the mild elevation of maternal thyroid hormones and patient preference, fetal THRB gene testing was not performed. The patient also did not require propranolol or propylthiouracil during pregnancy for RTH because she was asymptomatic and had mildly elevated and stable thyroid functions (Fig. ). Since FT4 crosses the placenta, propylthiouracil is recommended by the Endocrine Society to decrease FT4 levels if it is too high. L-T3 was not considered since it does not cross the placenta. However, she did require strict glucose control for previously diagnosed diabetes mellitus with insulin titrated to 52 units daily towards the end of gestation (HbA1c 5.20–5.50%). She was instructed to closely monitor her glucose levels, and she did not experience any hyper- or hypoglycemic symptoms or emergencies during pregnancy. The pregnancy was uneventful until premature rupture of membranes at 37 weeks, which developed to placental abruption during observation, and a healthy neonate of 3210 g was delivered by caesarean. The newborn did not have a THRB mutation. Suppressed TSH and low birth weight commonly seen in unaffected infants born to RTH mothers was not observed. The newborn did not show signs of thyroid dysfunction in the follow-up: FT4 was 14.47 pmol/L with TSH 5.05 mIU/L at one-month-old, and FT4 12.28 pmol/L with TSH 1.20 mIU/L at one-year-old. After delivery, the patient was restarted on L-T3 (low starting dose for titration), and insulin (24–26 units daily) doses were readjusted, but all medications were discontinued 1 month after delivery due to poor compliance.
At 6 months postpartum, the patient showed marked suppression of TSH compared with baseline (0.59 mIU/L vs. 8.63 mIU/L) with elevated FT3 (6.70 pmol/L) and FT4 (24.94 pmol/L), but remained clinically euthyroid. HOMA-IR was 7.97 with fasting glucose at 10.12 mmol/L. Suppressed TSH in RTH followed by exceedingly elevated TSH (> 100 mU/L) at 9 months postpartum indicated the occurrence of PPT, which recovered at 11 months postpartum (Fig. ). Fasting glucose and insulin varied between 8 and 12 mmol/L and 17.5–21.8 mIU/L, respectively. HOMA-IR during the hypothyroid phase could not be calculated from medical charts. Glycemia was managed with diet and exercise, though controlled less ideally compared to prepregnancy.
At 18 months postpartum, the patient was asymptomatic apart from discomfort due to a III degree goiter. TSH were again elevated, but recovered spontaneously after 1 month suggesting an episode of Hashimoto’s thyroiditis. No medication was prescribed for this period.
The index member’s biological mother had a history of poorly-controlled Graves’ disease, and diabetes mellitus. She was later found to carry the same THRB mutation. THRB gene sequencing of the index case’s spouse and father were negative for mutation. Second-degree relatives reported no symptoms related to thyroid dysfunction, and thyroid function screening was normal without inappropriate TSH secretion, however, they declined gene sequencing.
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pmc-6288957-1
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A 33-year-old Japanese woman with a history of IgAN and diabetes mellitus was admitted to our hospital for the initiation of insulin therapy and evaluation of persistent proteinuria in 2015.
She had undergone a renal biopsy for proteinuria and had been diagnosed with IgAN at our hospital in 2009. At the current presentation, she had 0.7–1.0 g/day of urinary protein excretion without significant haematuria. Although her mean blood pressure was 110/60 mmHg, she was treated with an angiotensin receptor blocker (ARB) for IgAN with persistent proteinuria. Her urinary protein excretion levels had been about 0.5 g/day after the initiation of ARB. Two years later, a tonsillectomy for persistent proteinuria was performed. The patient was diagnosed with diabetes mellitus based on the fasting plasma glucose levels and haemoglobin A1c (HbA1c) levels during regular visits and was started on a dipeptidyl peptidase-4 (DPP-4) inhibitor and Pioglitazone in 2012. One year later, she discontinued both the regular visits to our hospital and her medication. Seven days prior to admission at our hospital, she visited a clinic for fatigue. Her random blood glucose level was 375 mg/dL; based on this result and persistent proteinuria, she was referred to our hospital.
Regarding her family history, her younger sister was diagnosed with impaired glucose tolerance, while her maternal grandmother was diagnosed with diabetes (Fig. ). The physical examination was unremarkable; she had a height of 147.0 cm and weight of 46 kg (body mass index [BMI] 21.3). Laboratory testing revealed several abnormal values, including a random blood glucose level of 355 mg/dL, HbA1c level of 10.8%, 95 mmol/mol (reference; 4.6–6.2%, 27–44 mmol/mol), lactic acid level of 19.4 mg/dL (reference, 3.0–17.0 mg/dL), and pyruvic acid level of 1.28 mg/dL (reference, 0.30–0.94 mg/dL). Her renal function was preserved, as her creatinine level was 0.52 mg/dL (reference, 0.47–0.79 mg/dL) and her estimated glomerular filtration rate (eGFR) was 107.5 mL/min/1.73 m2. No antibodies to glutamic acid decarboxylase (GAD) or islet cells were detected. Urinalysis revealed 1+ protein and 4+ glucose without blood by dipstick. A 24-h urine collection test showed a creatinine clearance (CCr) of 175 mL/min, 2.08 g of protein with poor selectivity, and C-peptide immunoreactivity (CPR) of 33.3 μg (reference, 29.2–167 μg). During closer evaluation, the patient recalled having a hearing impairment during her school days. Therefore, audiometry was conducted and revealed mild bilateral sensorineural hearing loss > 4 kHz. Electrocardiography and echocardiography showed no abnormalities. No diabetic changes or macular retinal dystrophy were observed on funduscopic examinations.
Based on the above findings, we suspected mitochondrial disease. A second percutaneous renal biopsy was performed to identify the cause of the persistent proteinuria in 2015 (Fig. d-f). The biopsy specimens for light microscopy contained 25 glomeruli, of which 6 were globally sclerotic. The remaining glomeruli revealed no mesangial hypercellularity or expansion of the matrix (Fig. d). There was no evidence of thickness of the glomerular basement membranes, crescents, necrotising lesions, or lesions of focal segmental sclerosis. Moderate tubular atrophy and interstitial fibrosis involving up to 30 to 40% of the sample were observed (Fig. e). Abnormally distended epithelial cells containing numerous small intracytoplasmic granules that were positive for periodic acid-Schiff staining were present among the collecting ducts (Fig. f, arrowhead). These cells were identical to ‘granular swollen epithelial cells (GSECs)’, which have previously been reported as a morphologic feature of mitochondrial nephropathy. Immunofluorescence staining for IgA and C3 was negative (Fig. d). On ultrastructural examination, no significant deposits were observed in the glomeruli (Fig. b). Podocyte foot processes were globally preserved. No cell type with an abnormal shaped or increased number of mitochondria was observed either in the glomeruli or the tubules. The GSECs that had been observed in the microscopic analysis were not apparent in the specimen for electron microscopy.
A review of the first renal biopsy specimen (Fig. a–c) revealed the presence of 12 glomeruli; of these, none were globally sclerosed (Fig. b). The glomeruli exhibited mild mesangial widening accompanied by IgA deposition (Figs. a, a, and a), but no crescents, mesangial hypercellularity, or segmental sclerosis. These findings correspond to M0, E0, S0, T0, and C0 in the Oxford-MEST-C classification of IgA nephropathy []. IgG was negative, and C3 was dimly positive on immunohistology (data not shown). We stained the first biopsy specimen with a monoclonal antibody (KM55) against Gd-IgA1 (IBL, Gunma, Japan) []; this immunofluorescence analysis revealed that the IgA1 deposits in the patient’s glomeruli consisted of Gd-IgA1 (Fig. a-c). No tubular atrophy or interstitial fibrosis were evident (Fig. b); however, numerous GSECs were present among the distal tubules and collecting ducts (Fig. c, arrowheads). On electron microscopic analysis, cells containing dysmorphic mitochondria were not apparent in the glomeruli or tubules.
Mitochondrial DNA analysis from peripheral blood revealed a m. DNA3243A > G mutation. Therefore, the patient was diagnosed with MIDD. After the initiation of insulin therapy, her blood glucose levels returned to a normal range, and she was discharged.
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pmc-6289061-1
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Patient 1 is an 8-year-old girl who first presented with abdominal pain, an erythematous, vesicular skin rash (Figure ) and subfebrile body temperatures over a 4-day period. In the preceding month, the patient had been referred for a medical workup for persistent warts on the hands and feet. At that time, recurrent furuncles been noted. On admission, the serum AST level was 490 U/l (normal range < 48), the ALT was 374 U/l (normal range < 39), and the LDH was 1619 U/L (normal range < 236). The patient's blood count and prothrombin time (PT), activated Partial Thromboplastin Time (aPTT), bilirubin, fibrinogen, and creatinine levels were all normal. Although the skin rash was not classic for VZV and could thus not be unambiguously assigned to VZV infection, empiric treatment with acyclovir was initiated immediately. A biopsy showed non-specific changes with spongiosis of the epidermis, perivascular lymphocytic infiltrates and rare eosinophilic granulocytes. The patient's mother reported that the patient had chicken pox some years before admission. However, we could not detect anti-VZV antibodies in a serum sample taken 1 month before admission. Varicella zoster virus DNA was detected in the patient's blood (peaking at 537,000 copies/ml) and in the fluid from skin vesicles. HSV-1 and−2 PCR of vesicle fluid as well as HHV6, EBV, and CMV PCR of blood were negative. Mild hypogammaglobulinemia was noted (IgG 6.5 g/l; normal range: 7.6 – 14.5) and intravenous immunoglobulins (0.4 g/kg) were administered on day 2 and 4 as a supportive treatment. Seven days after the onset of illness, the skin rash progressed to targetoid lesions (Figure ) and the patient developed fever and tachy-dyspnoea. Respiratory insufficiency on day 8 after the onset of illness required mechanical ventilation. A miliary pattern of pulmonary opacities was noted on a chest X-ray (Figure ). The patient's laboratory parameters gradually deteriorated with progression to bicytopenia. On day 13, specific laboratory findings were noted: anemia (hemoglobin: 73 g/l), neutropenia (absolute neutrophil count: 710 cells/μL), elevated ferritin (peak value: 7090 μg/L; normal range 7 – 69), elevated triglycerides (peak value: 5.8 mmol/L; normal range 0.5 – 2.2), elevated soluble IL-2 receptor (peak value: 1622 pg/ml; normal range < 477), documentation of haemophagocytosis in a bone marrow aspirate; an elevated platelet count, and elevated fibrinogen. The spleen was not enlarged. Overall, the patient's clinical and laboratory profile met the diagnostic criteria for HLH (Table ), and so treatment with corticosteroids (1.5 mg/kg/d) was initiated on day 13. The patient progressively recovered from hepatitis, pneumonitis and HLH. Leukocyte subpopulations, which had contracted during the VZV illness expanded again thereafter (Supplementary Table ). The rash resolved after having progressed from vesicles to scabbing. Acyclovir was discontinued after 21 days, and corticosteroids were tapered over a total treatment period of 4 weeks.
A history of persistently low cell counts of neutrophilic granulocytes and B cells, hypogammaglobulinaemia, and increased susceptibility to infections (furunculosis and persistent warts) had prompted us to sequence the patient's GATA2 gene. This confirmed the presence of a heterozygous mutation (c.1172_1175del, p.E391Gfs*85) compatible with GATA2-haploinsufficiency.
More than 1 year later, the patient again developed bicytopenia, hyperferritinaemia, hypertriglyceridaemia, hypofibrinogenaemia, an elevated soluble IL-2 receptor level, and transaminitis after an episode of fever of unknown origin. Treatment with corticosteroids (2 mg/kg/day) and a broad-spectrum antibiotic was initiated, and the patient recovered. No pathogen could be identified.
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pmc-6289061-2
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Patient 2 is a 7-year-old boy with known GATA2-haploinsufficiency who presented with fever, skin rash, and cough. Three years earlier, the patient had been treated for recurrent fever, oral aphthosis, and recurrent furunculosis. Together with the observed lymphopenia (affecting CD4 T cells, B cells, and NK cells) and the presence of treatment-resistant warts on the patient's mother's hands, these immunological findings prompted us to sequence GATA2 in the patient and his mother. The diagnosis of GATA2-haploinsufficiency was confirmed by the presence of a c.(16bp tandem repeat in exon 4), p.T347fs) mutation. On admission, the boy was in good general condition. He showed mild fever (38.5°C), hepatosplenomegaly and an erythematous, vesicular skin rash suggestive of chickenpox, prompting empiric intravenous treatment with acyclovir. Mild hypogammaglobulinemia was known in this patient (IgG 6.1 g/l; normal range: 6.7 – 12.1) but was not substituted before. After admission, varicella immunoglobulins (22 IU/kg) and intravenous immunoglobulins (0.4 g/kg) were administred on day 0 and 2, respectively. Diagnosis was confirmed by positive VZV PCR in samples from skin lesions and peripheral blood (peak value: 183,572 copies/ml). CMV PCR of blood was negative. Low EBV DNA load had been detected in this patient 1 month before VZV-infection and EBV DNA load slightly increased during VZV-infection (max 424 copies/ml, normal range < 100) and became negative 2 months thereafter. On day 2, the patient developed pancytopenia (hemoglobin: 95 g/L; absolute neutrophil count: 380 cells/μL; platelet count: 53 G/L). On days 2 and 3, specific laboratory findings were noted: an elevation in serum ferritin (from 820 to 4,510 μg/L within 3 days) and triglycerides (from 0.6 to 2.2 mmol/l within 3 days). The clinical signs and laboratory results were consistent with a diagnosis of developing HLH (Table ), and so treatment with corticosteroids (2 mg/kg/d) was initiated.
Natural killer cell function assays revealed a slight reduction in degranulation (as assessed by CD107a expression) in both patients (9.4% in patient 1 and 8.8% in patient 2; normal range >10%) upon stimulation with K562 target cells. Perforin expression in both GATA2-haploinsufficient patients was within the lower range compared to an adult control and within the range of a control individual with known heterozygous A91V-perforin-mutation. SAP and XIAP expression in patient 2 were normal (Figure ).
Five months before the VZV episode, patient 2 was included, together with two other patients with GATA2-haploinsufficiency (patients 3 and 4), in a pilot study aimed at characterizing the immunological phenotype of this disease using mass cytometry (CyTOF). Patient 3 is the mother of patient 2 with an identical genotype (p.T347fs). In patient 4, a mutation in GATA2 c.593delC was found, which is predicted to result in p.Ala198fs with a premature stop codon 19 positions downstream. To visualize the lymphocyte pattern differences in peripheral blood samples from these three patients and three healthy controls, we used t-Disturbed Stochastic Neighbor Embedding (tSNE) to visualize mass cytometry datasets (Figures ), using the antibody panel shown in Supplementary Table . All patients with GATA2-haploinsufficiency had markedly reduced peripheral blood B cells, NK cells and monocytes (Figure ). The patients furthermore displayed an exceedingly high frequency of a CD3+ CD56+ CD16- CD8- CD4- cell population (“XYZ-population” in Figures ). Although largely different in ratios, this and the monocyte population retained the same phenotype as the ones present in healthy controls (Figure ). A large proportion of the CD3+ CD56+ CD16- CD8- CD4- cell population phenotypically corresponded to TCRγδ+ or NKT lymphocytes. This was confirmed by flow cytometry analysis of samples collected at different time points using a TCRγδ specific antibody (Figure ). A marked accumulation (20% to 30% of lymphocytes) of these TCRγδ+ cells was noted between the age of 4 and 8 years in patient 2. Patient 4 also showed an elevated percentage of these cells (10% to 20% of lymphocytes between the age of 12 and 16 years). On the contrary, TCRγδ+ cells in patient 1 and patient 3 remained below 5% of lymphocytes during the period of monitoring (between the age of 8 and 10 years for patient 1, and 22 and 25 years for patient 3), raising the possibility that populations other than TCRγδ+ T cells are expanded in GATA2-haploinsufficiency (Figure ).
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pmc-6289554-1
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An 18-year-old lady with no medical comorbidities presented to the eye clinic with complaints of left eye redness and pain for three days associated with several small nodular lesions on her left inferior palpebral conjunctiva. However, there was no blurring of vision, eye discharge or itchiness. She is a cat lover and had been caring for her sick cat. Despite veterinary care, her cat subsequently died because of sporotrichosis infection. However, she denied any history of a cat scratch, trauma, or contact with organic matter. She also denied any fever, skin infection, or respiratory symptoms.
On examination, the patient’s visual acuity was found to be 6/9 in both eyes. Her left eye showed conjunctival hyperemia with generalized granulomatous lesions over the superior and inferior palpebral conjunctiva (Figure ). The granulomatous conjunctival lesions were covered with thin whitish discharge. The cornea was normal, as was the anterior chamber. Posterior segment was likewise unremarkable. Systemic examination revealed a swollen and painful left cervical lymph node measuring about 1 x 2 cm. The patient was afebrile. There was no evidence of cutaneous fungal infection. An excisional biopsy of the left eye inferior conjunctival fornix lesion was performed. The patient was started on guttate fluconazole q1h and guttate ciprofloxacin q2h on the left eye while waiting for the tissue histopathology and culture results. Tissue specimen identified numerous granulomas with few fungal yeasts engulfed by histiocytes. Culture of the tissue isolated S. schenckii. The topical fluconazole and ciprofloxacin were stopped and the patient was treated with oral itraconazole 200 mg twice daily for six months. Her condition improved gradually and the conjunctival lesions completely resolved after five months of treatment (Figure ).
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pmc-6289561-1
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A 40-year-old male presented to the surgical emergency with complaints of swelling in the right loin and a dull aching pain that had both been present for a week. He had no complaints of altered bowel habit. There was no history of evening rise in temperature, weight loss, or loss of appetite. The patient did not have any significant medical history. On examination, a swelling (measuring 5×5 cm) was found in the right anterior lumbar region that became less prominent on the leg-raising test. The rest of the abdominal examination showed normal findings. A hematological evaluation revealed features suggestive of anemia with leukocytosis, and all other routine investigations were normal. A contrast-enhanced computed tomography (CECT) scan of the abdomen revealed a 9×6 cm heterogeneous enhancing mass lesion arising from the cecum with hypodense areas abutting the anterior abdominal wall and tracking into the intermuscular plane (Figure ).
Thus, the patient was taken up for an emergency exploratory laparotomy. During operative exploration, we found a 9×6 cm growth arising from the cecum with a localized intraperitoneal abscess that was tracking into the intermuscular plane in the right anterior abdominal wall and forming a subcutaneous abscess. A right hemicolectomy with an end-to-end ileocolic anastomosis was conducted along with external drainage of the subcutaneous abscess. Postoperatively, the patient recovered well and resumed normal diet.
A histopathological specimen examination revealed spindle cells arranged in fascicles with moderate eosinophilic cytoplasm and elongated nuclei with blunt ends suggestive of leiomyoma. There was acute on chronic inflammatory cells suggestive of an abscess (Figure ).
The final diagnosis was leiomyoma of the cecum with abscess formation.
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pmc-6289563-1
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A 23-year-old male patient, a medical student with no previously known co-morbids, presented to emergency room with bilateral chest pain, massive hemoptysis and cough. Vitals at initial assessment were: blood pressure (BP) 130/70 mmHg, pulse 85 beats per minute, temperature 98.6°F, respiratory rate (RR) 18/minute and SpO2 97% at room air. On examination, 15/15 on Glasgow coma scale (GCS), auscultation of lungs revealed decreased breath sounds bilaterally and cardiovascular exam was normal. Electrocardiogram (ECG) was unremarkable except sinus tachycardia. There was no lymphadenopathy or hepatosplenomegaly. Initial investigations showed mild thrombocytopenia 113,000/mL. Coagulation profile including prothrombin time (PT) with international normalized ratio (INR), partial thromboplastin time (PTT), and fibrinogen were within normal range. Hepatitis profile was negative and chest X-ray showed wedge-shaped consolidations.
He had been having exertional dyspnea, right-sided chest pain which aggravated on inspiration and cough for about one month. He developed hemoptysis one week ago. Computed tomography (CT) scan done in another health facility was reported as having multiple peripheral pleural-based consolidation in the apical segment of right upper lobe, lateral basal segment of right lower lobe, lateral segment of right middle lobe, and apical segment of left lower lobe with surrounding halo representing pulmonary hemorrhage. He was being treated initially as pneumonia with antibiotics and pain killers which resolved his symptoms temporarily except exertional dyspnea, three days prior to the presenting episode. He had no history of weight loss, no allergies, no family history of bleeding disorders and no history of illicit drug use.
Workup upon admission revealed lupus coagulant to be strong positive, LA1/LA2 ratio to be 2.6 (less than 1.4), anticardiolipin antibodies IgG > 280 GPL/mL (>80 strong positive) and IgM 4.8 MPL/mL (>80 strong positive). Antinuclear antibody and extractable nuclear antibody (ENA) profiles were negative. Antithrombin III, protein C and protein S, liver function tests were within normal limits. CT pulmonary angiogram showed extensive bilateral pulmonary embolism with resultant lung infarcts more pronounced on right side (Figure ), and a large filling defect in right atrium adjacent to posterior wall and closely abutting right atrioventricular valve (Figure ). Deep venous thrombosis was ruled out by CT venogram of lower extremity from pelvis up to the level of knees. Transthoracic echocardiography followed by transesophageal echo showed a large rounded mass of 28 × 28 mm of heterogeneous consistency attached to right side of the right atrium in fosse ovalis area with dilatation of right atrial chamber. Rest of the echo was normal. It was suspected to be atrial myxoma (Figure ). Normal procalcitonin level 0.09 ng/mL (less than 0.1 ng/mL) and sterile blood and urine cultures made infection less likely. CT scan abdomen and pelvis was done to rule out any metastatic process.
Treatment with therapeutic dose of anticoagulation was initiated. The patient was shifted to critical area and electively intubated following massive hemoptysis and respiratory compromise. Pulmonary angiography and subsequent embolization of right bronchial artery was performed. Excision of intracardiac lesion was done. Intraoperatively, right atrial lesion and fibrous tissue present on the posterior aspect of inferior vena cava orifice were resected and sent for histopathology. Anticoagulation with warfarin was resumed postoperatively with the target INR of 1.5 to 2. The right atrial mass on histopathology was consistent with embolus showing fibrinous tissue with dystrophic calcification. Postoperative extubation was uneventful and the patient was discharged.
The patient presented to emergency room with massive hemoptysis (500 ml) 24 hours after discharge, again intubated due to hypoxia and for airway maintenance. His blood count was within normal range, and INR 2.7. Anticardiolipin antibody was >280 whereas lupus anticoagulant was not significant. Follow-up echocardiography ruled out recurrence of intracardiac thrombus. Pulmonary angiography showed abnormal origin of right bronchial artery from internal thoracic artery with abnormal vascularity and parenchymal blush (Figure ) followed by embolization on the right bronchial artery in the right upper lobe. Considering near catastrophic antiphospholipid syndrome (CAPS), the patient was treated with pulse methylprednisolone, seven sessions of plasma exchange were done with three liters of fresh frozen plasma. Anticoagulation was withheld due to ongoing hemoptysis. Once bleeding stopped and the patient was extubated, intravenous heparin was initiated followed by maintenance with oral vitamin K antagonist. As the patient was hemodynamically stable with no further bleeding, he was discharged with regular follow-up in anticoagulation clinic.
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pmc-6289564-1
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A 34-year-old female with no significant past medical history presented to our clinic after experiencing a left second metatarsal stress fracture (Figure ). One year prior, while running errands around town, she suddenly felt a sharp pain in her left midfoot and promptly consulted an orthopedic surgeon who placed her in a boot. Six months later, after experiencing minimal improvement in her pain, a different orthopedic surgeon performed an open reduction and internal fixation by injecting 1 mL of bone cement into the diaphysis of the second metatarsal.
Over the next six months, she noticed no meaningful improvement in her pain. At this point, she presented to our clinic for a third opinion. During our initial visit with her, she stated that her left foot felt different than her right at baseline.
On physical exam, there was no gross deformity of her left lower extremity. The skin was intact with a healed incision over the dorsal midfoot, and there was point tenderness to palpation over the second metatarsal. Active and passive range of motion of the ankle and transverse tarsal joint was full and painless. Strength was 5/5 in dorsiflexion, plantarflexion, inversion, and eversion. Sensation to light touch was intact, Achilles reflex was present, and dorsalis pedis and posterior tibialis pulses were palpable.
Laboratory work revealed an elevated erythrocyte sedimentation rate of 36 (reference range: 0–20) and C-reactive protein of 34.74 (reference range: 0–10.9). Plain radiographs and a computed tomography (CT) scan of the left foot showed diffuse sclerotic changes and cement within the left second metatarsal (Figures , ). Magnetic resonance imaging (MRI) showed diffuse edema of the left second metatarsal with a non-displaced fracture line (Figure ).
All treatment options were discussed with the patient and she agreed with undergoing operative fixation. In the operating room, cultures and a bone biopsy of the left second metatarsal were taken. After performing an osteotomy, curettage was performed to remove the injected cement. Open reduction and internal fixation was performed utilizing a plate and calcaneal bone graft (Figure ). The patient was discharged home on the same day with adequate pain control and a bone stimulator. X-rays taken at two weeks post-revision surgery are shown in Figure .
At one-month follow-up, her incision was healing well without signs of infection and she had no complaints of pain. At her most recent appointment—three months post-revision surgery—she again reported no pain and good functional recovery with physical therapy. CT scan at three months post-revision surgery showed appropriate alignment of the healing second metatarsal with intact hardware (Figure ).
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