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PURPOSE: Laser prostatectomy has increased in popularity in the last decade. However, traditional transurethral resection of the prostate remains common. To understand decisions about the use of laser prostatectomy vs transurethral prostate resection, we evaluated trends in transurethral surgery for benign prostatic hyperplasia in an all payer data set, focusing on patient and provider factors associated with the receipt of laser prostatectomy. MATERIALS AND METHODS: Using Florida State Inpatient Database and Ambulatory Surgery Database, we identified patients who underwent laser prostatectomy or transurethral prostate resection from 2001 to 2009. We calculated surgery rates with time, stratified by procedure type. We used multilevel regression to examine patient (age, race and comorbidity level) and provider (surgeon volume) factors associated with the receipt of laser prostatectomy vs transurethral prostate resection. RESULTS: While the overall rates of transurethral surgery remained stable during the study period (p = 0.227), laser prostatectomy use increased 400% from 25 to 114 procedures per 100,000 men (p <0.001), replacing about half of all transurethral prostate resections. Patients were less likely to undergo laser prostatectomy if they were older (OR 0.65, 95% CI 0.61-0.70) and less healthy (OR 0.48, 95% CI 0.45-0.51). While these factors were predictive of surgery type, most of the variation in laser prostatectomy use (69%) was determined by the urologist seen by the patient. CONCLUSIONS: Laser prostatectomy use has increased in the last decade at the expense of transurethral prostate resection, driven largely by provider effects. However, elderly and more infirm patients are least likely to undergo it, raising concern about underuse in this population." | Urologic Surgical Procedures, Male |
Mechanisms controlling skin heterogeneity are poorly understood. In this issue of Developmental Cell, Liang et al. show that in chicken, the difference in beta-keratin genes expressed in feathered and scaly skin is regulated via typical enhancers, while differential expression within individual feathers correlates with chromatin looping within the gene cluster. | beta-Keratins |
The crystal structure of the free base of the antidiabetic drug alogliptin [systematic name: 2-(6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl)benzonitrile], C18H21N5O2, displays a two-dimensional N-H...O hydrogen-bonded network. It contains two independent molecules, which have the same conformation but differ in their hydrogen-bond connectivity. In the crystal structure of the benzoate salt (systematic name: (3R)-1-3-[(2-cyanophenyl)methyl]-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylpiperidin-3-aminium benzoate), C18H22N5O2(+).C7H5O2(-), the NH3(+) group of the cation is engaged in three intermolecular N-H...O hydrogen bonds to yield a hydrogen-bonded layer structure. The benzoate salt and the free base differ fundamentally in the conformations of their alogliptin moieties. | Uracil |
Cells from the rat preputial gland--a type of sebaceous gland--exhibited specific responsiveness of cyclic 3',5'-adenosine monophosphate (AMP) dependent protein kinase to stimulation by agents that elevate intracellular cyclic AMP. Electron microscopy shows that the rat preputial gland resembles the human sebaceous gland, not only in terms of containing a sebocyte-like population of cells in an acinar arrangement at different maturational stages, but also in the morphology of its organelles such as abundant and sometimes atypical mitochondria, many perinuclear lysosomes with crystalline inclusions, lipid droplets of various sizes, and peroxisomes. Other cell types, among them duct and inflammatory cells, were evident in the tissue sections, but constituted a minor component. Responses to stimulation of the adenylate cyclase-protein kinase pathways were determined using preputial cells that had been both freshly dispersed and grown in monolayer culture. Stimulation with isoproterenol (IPR) or forskolin (FS) resulted in both cases in an increase of cyclic AMP binding of the regulatory (R) subunits of cyclic AMP-dependent protein kinase, as determined by photoaffinity labeling of R subunits with an azido analog of cyclic AMP ([32P]-8-azido cyclic AMP). Cells from the epidermis under comparable conditions responded to a lesser degree and with a different distribution of R subunit isoforms. There are, therefore, differences in receptor activity as well as in the transduction pathways between the two types of epithelial cell populations. These results indicate that the preputial gland contains precursor cells that differentiate in culture to retain specific molecular mechanisms of action mediated via cyclic AMP. | Receptors, Cyclic AMP |
DRB sensitivity-inducing factor (DSIF) and negative elongation factor (NELF) were originally identified as factors responsible for transcriptional inhibition by 5,6-dichloro-1-beta-d-ribofuranosyl-benzimidazole (DRB) and were later found to control transcription elongation, together with P-TEFb, at the promoter-proximal region. Although there is ample evidence that these factors play roles throughout the genome, other data also suggest gene- or tissue-specific roles for these factors. In this review, we discuss how these apparently conflicting data can be reconciled. In light of recent findings, we also discuss the detailed mechanism by which these factors control the elongation process at the molecular level. This article is part of a Special Issue entitled: RNA polymerase II Transcript Elongation. | Transcription, Genetic |
BACKGROUND: The CLSI breakpoint for micafungin and Candida albicans is 0.25 mg/L, higher than the CLSI epidemiological cut-off value (0.03 mg/L) whereas the EUCAST values are identical (0.016 mg/L). We developed a novel in vitro dialysis-diffusion pharmacokinetic/pharmacodynamic (PK/PD) model, confirmed correlation to in vivo outcome and studied micafungin pharmacodynamics against Canida albicans. METHODS: Four C. albicans isolates, including a weak (F641L) and a strong (R647G) fks1 mutants, were studied using a 104 cfu/mL inoculum and RPMI medium with and without 10% pooled human serum. The exposure-effect relationship fAUC0-24/MIC was described for CLSI and EUCAST methodology. Monte Carlo simulation analysis included standard (100 mg i.v.) and higher (150-300 mg) doses q24h to determine the corresponding probability of target attainment (PTA). RESULTS: The in vitro PK/PD targets for stasis/1-log kill were 36/57 fAUC0-24/MIC in absence and 2.8/9.2 fAUC0-24/MIC in the presence of serum, and similar for wild-type and fks mutant isolates. The PTAs for both PK/PD targets were high (>95%) for EUCAST susceptible isolates but not for CLSI susceptible non-wild-type isolates (CLSI MICs 0.06-0.25 mg/L). 300 mg q24h was needed to attain PK/PD targets for non-wild-type isolates with CLSI MICs 0.06-0.125 mg/L and EUCAST MICs 0.03-0.06 mg/L. CONCLUSION: The in vitro 1-log kill effect corresponded to stasis in animal model and mycological response in patients with invasive candidiasis, thereby validating the model for studying pharmacodynamics of echinocandins in vitro. EUCAST breakpoints were well supported by our findings but our data questions whether the current CLSI breakpoint, which is higher than the epidemiological cut-off values, is appropriate. | Micafungin |
Panretinal photocoagulation has been shown to raise preretinal oxygen tension in cats and monkeys breathing 100% oxygen. However, in normoxia, there is no significant difference between normal and photocoagulated areas. This is thought to be due to autoregulatory vasoconstriction of the retinal circulation. In avascular rabbit retina, photocoagulation effects on retinal oxygenation can be studied without the influence of retinal vascular autoregulation. We measured normoxic preretinal oxygen tension of normal and photocoagulated rabbit retina at 1, 7, 14 and 28 days after photocoagulation using polarographic oxygen electrodes. For all time points, preretinal oxygen tension of photocoagulated retina (42 +/- 14 torr; mean +/- S.D.) was higher than untreated retina (14 +/- 10 torr; mean +/- S.D., P less than 0.001). Light and electron microscopy of lasered retina showed that the improved oxygenation corresponded to loss of mitochondria-rich inner segments of the photoreceptors. | Retina |
Bacteriophages are ubiquitous parasites of bacteria and major drivers of bacterial ecology and evolution. Despite an ever-growing interest in their biotechnological and therapeutic applications, detailed knowledge of the molecular mechanisms underlying phage-host interactions remains scarce. Here, we show that bacteriophage N4 exploits a novel surface glycan (NGR) as a receptor to infect its host Escherichia coli. We demonstrate that this process is regulated by the second messenger c-di-GMP and that N4 infection is specifically stimulated by the diguanylate cyclase DgcJ, while the phosphodiesterase PdeL effectively protects E. coli from N4-mediated killing. PdeL-mediated protection requires its catalytic activity to reduce c-di-GMP and includes a secondary role as a transcriptional repressor. We demonstrate that PdeL binds to and represses the promoter of the wec operon, which encodes components of the enterobacterial common antigen (ECA) exopolysaccharide pathway. However, only the acetylglucosamine epimerase WecB but none of the other ECA components is required for N4 infection. Based on this, we postulate that NGR is an N-acetylmannosamine-based carbohydrate polymer that is produced and exported to the cell surface of E. coli in a c-di-GMP-dependent manner, where it serves as a receptor for N4. This novel carbohydrate pathway is conserved in E. coli and other bacterial pathogens, serves as the primary receptor for various bacteriophages, and is induced at elevated temperature and by specific amino acid-based nutrients. These studies provide an entry point into understanding how bacteria use specific regulatory mechanisms to balance costs and benefits of highly conserved surface structures. IMPORTANCE Because bacterial surface glycans are in direct contact with the environment they can provide essential protective functions during infections or against competing bacteria. But such structures are also Achilles' heels" since they can serve as primary receptors for bacteriophages. Bacteria thus need to carefully control the exposure of conserved surface glycans to balance costs and benefits. Here, we identify a novel exopolysaccharide that is widely conserved in E. coli and is used by N4 and related bacteriophages as primary receptor. We demonstrate that the synthesis of NGR (N4 glycan receptor) is tightly controlled by the second messenger c-di-GMP in a highly specific manner and by a single diguanylate cyclase. These studies provide an example of how bacteria can alleviate the strong selective pressure imposed on them by bacteriophages entering through conserved surface structures by carefully regulating their synthesis and secretion." | Bacteriophage N4 |
BACKGROUND: Among different surgical approaches, dermabrasion and carbon dioxide laser vaporization have been used to treat Hailey-Hailey disease (HHD) (familial benign chronic pemphigus) and Darier disease (DD) (keratosis follicularis), with various results. Because of the erbium: YAG laser's unique absorption characteristics in tissue water, erbium:YAG laser ablation combines the advantages of both techniques, avoiding thermal injury of vaporization and also allowing selectively deeper tissue removal in the follicular lesions of DD. Therefore, good results should be expected in both types of acantholytic disorders. OBSERVATIONS: Four patients (2 with HHD and 2 with DD) with different affected areas were treated with laser ablation. During a follow-up period ranging from 8 to 20 months, complete remission was achieved in 3 patients--2 with DD and 1 with HHD--and significant improvement was achieved in 1 patient with HHD. Histological examination of control biopsy specimens after ablation in 1 patient with DD revealed no signs of the disease and only a slight fibrosis in the papillary dermis. CONCLUSIONS: Erbium:YAG laser ablation effectively removes lesions of both HHD and DD and can also yield excellent long-term results in chronic, recalcitrant cases. | Pemphigus, Benign Familial |
The genetic hallmark of epithelioid hemangioma (EH) is the presence of recurrent gene fusions involving FOS and FOSB transcription factors, which occur in one-third of the cases. Certain clinical, pathologic, and genotypic correlations have been described, with FOS-related fusions being more often detected in skeletal and cellular variants of EH, while FOSB gene rearrangements are more commonly associated with atypical histologic features and penile location. These fusions are infrequently detected in the cutaneous or head and neck EH. Overall, two-thirds of EH lack these canonical fusions and remain difficult to classify, especially when associated with atypical features and/or clinical presentations. Triggered by an index case of an intravascular soft tissue EH with a novel GATA6-FOXO1 gene fusion by targeted RNA sequencing (Archer(R) FusionPlex(R) Sarcoma Panel), we have investigated 27 additional EH cases negative for FOS and FOSB gene rearrangements for this novel abnormality to determine its recurrent potential, and its association with clinical and pathologic features. Four additional EH cases were found to display GATA6-FOXO1 fusions (18%). There were three females and two males, with a mean age of 32 years old. Three lesions occurred in the head and neck (dura, nasopharyngeal, and cheek), one in the back and one in the leg. Two of these lesions were cutaneous and one was intravascular in the subcutis of the leg. Microscopically, the tumors showed a variegated morphology, with alternating vasoformative and solid components, extravasated red blood cells and mild to moderate cytologic atypia. None showed brisk mitotic activity or necrosis. Tumors were negative for FOS and FOSB by immunohistochemistry. In conclusion, we report a new GATA6-FOXO1 fusion in a subset of EH, with a predilection for skin, and head and neck location. The relationship of this novel molecular subset with the more common FOS/FOSB fusion-positive EH remains to be determined. | Forkhead Box Protein O1 |
Secretory carcinoma of the salivary glands is a distinct entity with distinct morphologic features, immunohistochemical profile and molecular alterations. It mainly affects middle aged individuals with slight male predominance and parotid gland is the most common site of involvement. Although ETV6-NTRK3 gene fusion is considered pathognomonic for secretory carcinoma, advances in molecular profiling of this tumor have led to the discovery of novel ETV6 fusion partners and gene mutations. Herein, we describe a case of an adenocarcinoma of intercalated duct origin favor secretory carcinoma, in a unique location of von Ebner's glands of mobile tongue in a 40-year-old Caucasian female. Aside from being in a unique location, the tumor showed somatic mutation for PALB2 gene which has not been described so far in secretory carcinoma. Discovery of novel fusions and mutations have therapeutic implications with respect to targeted therapy. | von Ebner Glands |
Young people's health is giving rise to increasing concern. However, despite recent government emphasis on patient involvement and partnership, little discussion has occurred concerning how this may be achieved with younger age groups in primary care. Here we outline issues relating to adolescents' health and characteristics of current provision. These are considered in the context of innovative services that have incorporated adolescents' views. Finally, we discuss the challenge of establishing a partnership with adolescents and propose strategies for achieving this. | Adolescent Health Services |
BACKGROUND: Genetic variation in monoamine oxidase A (MAOA) and serotonin transporter (5-HTT)-linked polymorphic regions (LPR) is associated with neuropsychiatric behavior. METHODS: We genotyped 37 macaques using conventional PCR product gel fractionation and by capillary electrophoresis of multiplexed amplicons and compared the data. RESULTS: Genotype concordance was 97% and 95% for MAOA-LPR and 5-HTT-LPR, respectively. Capillary electrophoresis was more sensitive and cost-effective. CONCLUSIONS: Multiplexing MAOA-LPR and 5-HTT-LPR will enhance the genotyping of large sample sets. | Genotyping Techniques |
Drug-induced active hepatitis is rare. The three main drugs incriminated are oxyphenisatine, alphamethyldopa and isoniazid. Despite the histological appearance suggestive of chronic active hepatitis, such forms of hepatitis, and in particular those due to alphamethyldopa and isonizid, follow an acute rather than a chronic course. The course is usually rapidly favourable when the responsible drug is stopped, provided the histological lesions are not those of multilobar necrosis or cirrhosis. | Oxyphenisatin Acetate |
The reaction of [Ru(2)Cl(2)(mu-Cl)(2)(eta(6)-p-cymene)(2)] with two thiosemicarbazones obtained by the condensation of N-(4-methoxybenzyl) thiosemicarbazide and 1,4-hydroxy-3-methoxyphenyl)ethan-1-one (HL(1)) or 2-fluoro-4-hydroxybenzaldehyde (HL(2)) was studied. The cationic complexes of formula [RuCl(eta(6)-p-cymene)(HL)](+) were isolated as solid chloride and trifluoromethylsulfate (TfO) salts. A study of the solid state and NMR spectra suggests the presence in the material of two isomers that differ in the configuration in the iminic bond, C2=N3, of the coordinated thiosemicarbazone in the triflate salts and only the E isomer in the chloride. An X-ray study of single crystals of the complexes supports this hypothesis. The thiosemicarbazone ligand coordinates with the ruthenium center through the iminic and sulfur atoms to form a five-membered chelate ring. Furthermore, the isolation of single crystals containing the thiosemicarbazonate complex [Ru(2)(mu-L(2))(2)(eta(6)-p-cymene)(2)](2+) suggests the easy labilization of the coordinated chloride in the complex. The redox behavior of the ligands and complexes was evaluated by cyclic voltammetry. It seems to be more difficult to oxidize the complex derived from HL(1) than HL(2). The ability of the complexes to inhibit cell growth against the NCI-H460, A549 and MDA-MB-231 lines was evaluated. The complexes did not show greater potency than cisplatin, although they did have greater efficacy, especially for the complex derived from HL(1). | Thiosemicarbazones |
BACKGROUND: Alternaria solani is a known air-born deuteromycete fungus with a polycyclic life cycle and is the causal agent of early blight that causes significant yield losses of potato worldwide. However, the molecular mechanisms underlying the conidiation and pathogenicity remain largely unknown. RESULTS: We produced a high-quality genome assembly of A. solani HWC-168 that was isolated from a major potato-producing region of Northern China, which facilitated a comprehensive gene annotation, the accurate prediction of genes encoding secreted proteins and identification of conidiation-related genes. The assembled genome of A. solani HWC-168 has a genome size 32.8 Mb and encodes 10,358 predicted genes that are highly similar with related Alternaria species including Alternaria arborescens and Alternaria brassicicola. We identified conidiation-related genes in the genome of A. solani HWC-168 by searching for sporulation-related homologues identified from Aspergillus nidulans. A total of 975 secreted protein-encoding genes, which might act as virulence factors, were identified in the genome of A. solani HWC-168. The predicted secretome of A. solani HWC-168 possesses 261 carbohydrate-active enzymes (CAZy), 119 proteins containing RxLx[EDQ] motif and 27 secreted proteins unique to A. solani. CONCLUSIONS: Our findings will facilitate the identification of conidiation- and virulence-related genes in the genome of A. solani. This will permit new insights into understanding the molecular mechanisms underlying the A. solani-potato pathosystem and will add value to the global fungal genome database. | Alternaria |
Semicarbazide-sensitive amine oxidase (SSAO) is a copper-containing enzyme that catalyzes the oxidative deamination of endogenous and exogenous primary amines. SSAO exists in mammals both as a plasma-soluble and as a membrane-bound form, and its active site is able to come into contact with numerous xenobiotic, amine-containing compounds. The kinetic studies performed in this work showed that caffeine inhibition of bovine serum amine oxidase was noncompetitive when benzylamine was used as substrate and mixed when the substrate used was methylamine. Since caffeine contains an imidazole ring, it cannot be excluded that it might bind to an inhibitory imidazoline-binding site on SSAO." | Amine Oxidase (Copper-Containing) |
A novel lignan glysocide, namely sagitiside A (1), together with two known ones, (+)-lyoniresinol-2alpha-O-beta-D-glucopyranoside (2) and (+)-5'-methoxyisolariciresinol 3alpha-O-beta-D-glucopyranoside (3), was isolated from the 95% ethanol extract of dry roots of Tinospora sagittata var. yunnanensis. The structure of the new compound (1) was determined based on MS, 1D and 2D NMR spectral data. Compounds 1-3 showed antioxidant activity with EC(50) values 55, 75 and 80 microM by 1,1-diphenyl-2-picryhydrazyl (DPPH) radical-scavenging assay. | Tinospora |
The conversion of glucose and fructose into gluconic acid (GA) and sorbitol (SOR) was conducted in a batch reactor with free (CTAB-treated or not) or immobilized cells of Zymomonas mobilis. High yields (more than 90%) of gluconic acid and sorbitol were attained at initial substrate concentration of 600 g/L (glucose plus fructose at 1:1 ratio), using cells with glucose-fructose-oxidoreductase activity of 75 U/L. The concentration of the products varied hyperbolically with time according to the equations (GA)=t(GA)(max)/(W(GA) +t), (SOR)=t (SOR)(max)/(W(Sor)+t), v(GA)=[W(GA) (GA)(max)]/(W(GA)+t)(2) and V(SOR)=[W(SOR) (SOR)(max)]/(W(SOR)+t)(2). Taking the test carried out with free CTAB-treated cells as an example, the constant parameters were (GA)(max)= 541 g/L, (SOR)(max)=552 g/L, W(GA)=4.8h, W(SOR)=4.9h, upsilon(GA)=112.7 g/L. and upsilon(SOR)=112.7 g/L. | Zymomonas |
BACKGROUND AND PURPOSE: Little is known about the facilitators and barriers to the workforce transition of novice nurse practitioners (NPs) in primary care. This research aimed to identify factors contributing and detracting from a successful initial workforce transition for novice NPs in the primary care setting. METHODS: A descriptive, cross-sectional study was conducted via online survey administered to a national sample of 177 NPs who graduated from an accredited NP program and were practicing in a primary care setting for 3-12 months. Open-ended responses were analyzed using the Krippendorff content analysis method. CONCLUSIONS: This study demonstrated that facilitators of the novice NP transition are the presence of mentorship and social support, finding meaning in their work, job satisfaction, and work-life balance. Barriers to the novice NP transition are lack of support and respect, role ambiguity, and workload. IMPLICATIONS FOR PRACTICE: More mentorship, support, role clarity, and respect are needed to facilitate the novice NP workforce transition. More research is needed on interventions that can be implemented by health care organizations to improve the facilitators of role transition identified in this study. | Workforce |
Chilblains represents an idiopathic vascular cutaneous benign acral syndrome. Epidemiology and basic mechanisms remain hypothetic and the treatment is controversial. The patients exhibit pruritic, redness painful, burning acral patches or plaques on the toes and/or fingers. The disease is bilateral, youthful and influenced by exposure to cold. Spontaneous healing is common when spring arrives and relapse is frequent on the following winters. There is no systemic symptom and laboratory studies are normal. The physical examination is sufficient for diagnosis. Histologic examination shows vascular and perivascular capillary and venular lymphocyte infiltrates without necrosis nor leukocytoclasia. The differential diagnosis includes: lupus, cold urticaria, acrocyanosis, erythermalgia, vasculitis and the Blue Toe Syndrome. Treatment includes prophylactic measures against cold and calcium channel inhibiting drug. In more severe cases thyrocalcitonin and hemodilution might be helpful. | Cold Injury |
Myotonic dystrophy type 1 (DM1, OMIM 160900) is a rare autosomal dominant hereditary disease. A case of DM1 patient with early onset diabetes and decreased muscle strength was treated in the Department of Endocrinology, Third Xiangya Hospital, Central South University. The peripheral blood of the patient was collected to extract DNA for gene detection. It was found that the triple nucleotide CTG repeat in the 3'-untranslated region (3'-UTR) of the dystrophia myotonica protein kinase (DMPK) gene was more than 100 times, and the diagnosis of DM1 was clear. For diabetes patients with multiple system abnormalities such as muscle symptoms, attention should be paid to the screening of DM1, a rare disease. | Myotonic Dystrophy |
Blood product transfusions are an essential component of the practice of emergency medicine. From acute traumatic hemorrhage to chronic blood loss necessitating transfusion for symptomatic anemia, familiarity with individual blood products and their indications for transfusion is an essential tool for every emergency physician (EP). Although the focus of this article is primarily on the transfusion of red blood cells, many of the concepts are applicable to the transfusion of all blood products. EPs must be fully familiar with both the individual blood components and the potential reactions and complications of these transfusions. | Blood Group Incompatibility |
Nutritional support of the burn patient is essential to optimize host immune defenses and to promote prompt wound healing. The interdependent relationship between metabolism, nutrition, and infection is discussed, followed by an extensive description of the various means of determining the appropriate type, form, and amount of nutritional support to provide to patients of various ages and with differing burn sizes. A concise discussion of the role of various growth factors and micronutrients completes this article. | Nutritional Support |
Conventional cancer chemotherapy heavily relies on the use of cytotoxic agents, which typically do not preferentially localize at the tumor site and cause toxicity to normal organs, preventing dose escalation to therapeutically active regimens. In principle, antibodies and other ligands could be used for the selective pharmacodelivery of cytotoxic agents to the neoplastic mass. For many years, the availability of ligands, capable of selective internalization into tumor cells, has been considered to be an essential requirement for the development of targeted cytotoxics. This assumption, however, has recently been challenged on the basis of therapeutic data obtained with noninternalizing drug conjugates. Moreover, quantitative evaluations of the tumor targeting properties of antibodies and of small organic ligands have provided new insights for the implementation of optimal strategies for the development of targeted cytotoxics. In this article, we highlight opportunities and challenges associated with the clinical and industrial development of antibody-drug conjugates and small molecule-drug conjugates for cancer therapy. | Immunoconjugates |
BACKGROUND Karoshi, which is sudden death associated with overwork, has become a serious problem in China. Many studies have examined the relationship between cardiovascular risks and karoshi, but there is little evidence that explains the exact mechanism by which overwork induces sudden death. In these cases, there are few obvious positive findings from forensic autopsies except for histories of overwork prior to death. Therefore, we assume that abnormalities, such as cardiac arrhythmia, rather than organic changes are the cause of karoshi. MATERIAL AND METHODS In the present study, the forced swim test (FST) was used to establish models of overwork. The myocardial tissues of SD rats taking FST (1 h per day, for 30 consecutive days) were collected. The arrhythmia-related molecule CX43 as well as its upstream regulation molecule Cav-1 and cSrc were tested by Western blot (WB) and immunohistochemistry (IHC). HE staining and Masson's staining were performed in the myocardium tissue section. RESULTS We observed downregulation of caveolin-1 (Cav1) followed by cSrc activation, resulting in the decrease of connexin43 (Cx43) levels in overwork models. Myocardial interstitial fibrosis, which is associated with electrophysiological aberrances that result in arrhythmia, was also found in the overwork models. CONCLUSIONS These data provide a mechanistic explanation for the speculated link between karoshi and cardiac arrhythmias. | Karoshi Death |
The general thermodynamic principles behind pH driven conformational transitions of biological macromolecules are well understood. What is less obvious is how they can be used to engineer pH switches in proteins. The acid unfolding of staphylococcal nuclease (SNase) was used to illustrate different factors that can affect pH-driven conformational transitions. Acid unfolding is a structural transition driven by preferential H(+) binding to the acid unfolded state (U) over the native (N) state of a protein. It is the result of carboxylic groups that titrate with more normal pK(a) values in the U state than in the N state. Acid unfolding profiles of proteins reflect a balance between electrostatic and non-electrostatic contributions to stability. Several strategies were used in attempts to turn SNase into an acid insensitive protein: (1) enhancing global stability of the protein with mutagenesis or with osmolytes, (2) use of high salt concentrations to screen Coulomb interactions, (3) stabilizing the N state through specific anion effects, (4) removing Asp or Glu residues that titrate with depressed pK(a) values in the N state, and (5) removing basic residues that might have strong repulsive interactions in the N state at low pH. The only effective way to engineer acid resistance in SNase is not through modulation of pK(a) values of Asp/Glu but by enhancing the global stability of the protein. Modulation of pH-driven conformational transitions by selective manipulation of the electrostatic component of the switch is an extremely difficult undertaking. | Micrococcal Nuclease |
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, capable to degrade the extracellular matrix (ECM) in physiologic conditions. Because of their overexpression and pivotal role in many pathological events, they have been proposed as a therapeutic and prognostic target for a number of diseases. Selectivity among MMPs is essential for realizing the clinical potential of inhibitors. The design of MMP inhibitors (MMPIs) has largely focused on development of various compounds containing a zinc binding group (ZBG) in their structure, with hydroxamate being the most potent one. Due to the high degree of homology in the catalytic domain of all the MMPs, the specificity and selectivity of first generation hydroxamate MMPIs were minimal, with several off-target effects and binding to other metzincins. This review highlights the role of phosphonate as ZBG in the design and development of new MMPIs." | Matrix Metalloproteinase Inhibitors |
Kounis syndrome is defined as the clinical development of acute coronary syndrome caused by the activation of inflammatory cells due to an allergy, hypersensitivity, anaphylaxis, or anaphylactic reaction. Corticosteroids that are used in the treatment of many inflammatory conditions may paradoxically cause allergic reactions and even anaphylaxis. This article is a description of the case of a 52-yearold female patient who had a non-ST elevation myocardial infarction after the administration of triamcinolone that was relieved with antihistaminic treatment. The patient had been diagnosed with dermatitis at another medical center and injected with 40 mg/mL (intramuscular [IM]) of triamcinolone acetonide and developed chest pain 15 minutes after the first dose. Despite a normal physical examination and echocardiogram, laboratory tests revealed troponin positivity and an inferolateral ST depression was present on an electrocardiogram (ECG). The ECG findings and clinical symptoms resolved completely after conservative anti-ischemic treatment and antihistaminic therapy (pheniramine maleate 45.5 mg/2 mL, Avil ampoule, IV; Sanofi-Aventis, Paris, France) and coronary angiography evaluation of the arteries was normal. The heart, and in particular the coronary arteries, are among the organs that are most damaged during hypersensitivity reactions and anaphylaxis. Although Kounis syndrome is not a rare condition, few cases have been reported in clinical practice. The failure to recognize Kounis syndrome due to inadequately defined cases may lead to unwanted medical results. Kounis syndrome should be kept in mind in order to make a rapid and accurate diagnosis. | Kounis Syndrome |
In this work, salicylic acid (SA), a non-steroidal anti-inflammatory, was chemically incorporated into hydrogel systems to achieve sustained SA release profiles. With its anti-inflammatory properties, sustained release of SA would be relevant for treating diseases such as diabetes and cancer. In this work, SA was chemically incorporated into hydrogel systems via covalent attachment to an itaconate moiety followed by UV-initiated crosslinking using acrylic acid and poly(ethylene glycol) diacrylate. The chemical composition of the hydrogel system was confirmed using FT-IR spectroscopy. The SA-based hydrogels were designed as pH-responsive hydrogels, collapsing at acidic pH (1.2) values and swelling at higher pH (7.4) values for gastrointestinal-specific delivery. The hydrogel systems exhibited a pH-dependent SA release profile: SA release was much slower at pH 1.2 compared to pH 7.4. Under acidic pH conditions, 30wt% SA was released after 24h, whereas 100wt% SA was released in a sustained manner within 24h in pH 7.4 PBS buffer. The pore structure of the gel networks were studied using SEM and exhibit appropriate pore sizes (15-60mum) for physically encapsulating drugs. In addition, rheological studies of the hydrogels proved that these systems are mechanically strong and robust. Mucoadhesive behaviors were confirmed using a Texture Analyzer, the work of adhesion for the hydrogels was around 290 g.mm and the maximum detachment force was around 135g. The SA-based hydrogels demonstrate great potential for oral delivery of bioactives in combination with SA to treat serious diseases such as cancer and diabetes. | Salicylic Acid |
We conducted a survey to assess whether current veterinary practices concerning prophylaxis and treatment of canine roundworm (Toxocara canis) infection are adequate to prevent the potential public health risks of visceral larva migrans. We administered a standard questionnaire by telephone to 100 small animal practitioners. Fifty-four veterinarians included health education for the pet's owner as part of their routine care in a case of canine roundworm infection, and 39 recommended prophylactic treatment for this potential zoonosis. Seven veterinarians recommended that pups receive the 1st treatment for roundworm infection before 3 weeks of age, 32 recommended 1st treatment or deworming at 3-4 weeks of age, 39 recommended 5-6 weeks of age, and 22 suggested that it be done at or after 7 weeks of age. Fifteen veterinarians recommended that a nursing bitch be treated for roundworm infection. On the basis of the survey results, we concluded that current veterinary practices concerning the zoonotic aspect of T canis fections are inadequate. We recommend that veterinarians inform their clients that simple hygienic practices are important at avoid the risk of visceral larva migrans. We recommend that deworming programs be started at 2-3 weeks after whelping and include the nursing bitch as well as the pups. | Secernentea Infections |
Ornithine aminotransferase (OAT), a mitochondrial matrix enzyme, is genetically deficient in patients with gyrate atrophy of the choroid and retina. Histologically defined micro-samples (10 ng-6.8 micrograms dry weight) were dissected out from freeze-dried tissue sections of eyeballs of cat and mouse, and the OAT activities were determined by a newly developed microassay method in the ocular tissues and retinal layers. Very high specific activities of OAT, expressed on a dry weight basis, were found in the feline ocular tissues of ectodermal origin, that is, neuroretina, retinal pigment epithelium, ciliary processes and epithelium of iris. In cat and mouse retinas, high OAT activities were distributed in the inner retina with an activity peak in the inner plexiform and ganglion cell layers. Very low activity was present in the outer nuclear layer. The inner segments of photoreceptor cells, which are very rich in mitochondria, contained the highest OAT activity. In contrast, the outer segments of photoreceptor cells contained the low activity resulting from contamination by small pieces of inner segments." | Ornithine-Oxo-Acid Transaminase |
As a pathogenic free-living amoeba, Acanthamoeba is easy to be recognized at the genus level, but difficult to identify at species level on the morphological basis. This review summarizes the methods for Acanthamoeba species classification and identification. | Lobosea |
BACKGROUND & AIMS: Improving clinical management of early stage colorectal cancers (T1CRCs) requires a better understanding of their underlying biology. Accumulating evidence shows that cancer-associated fibroblasts (CAFs) are important determinants of tumor progression in advanced colorectal cancer (CRC), but their role in the initial stages of CRC tumorigenesis is unknown. Therefore, we investigated the contribution of T1CAFs to early CRC progression. METHODS: Primary T1CAFs and patient-matched normal fibroblasts (NFs) were isolated from endoscopic biopsy specimens of histologically confirmed T1CRCs and normal mucosa, respectively. The impact of T1CAFs and NFs on tumor behavior was studied using 3-dimensional co-culture systems with primary T1CRC organoids and extracellular matrix (ECM) remodeling assays. Whole-transcriptome sequencing and gene silencing were used to pinpoint mediators of T1CAF functions. RESULTS: In 3-dimensional multicellular cultures, matrix invasion of T1CRC organoids was induced by T1CAFs, but not by matched NFs. Enhanced T1CRC invasion was accompanied by T1CAF-induced ECM remodeling and up-regulation of CD44 in epithelial cells. RNA sequencing of 10 NF-T1CAF pairs revealed 404 differentially expressed genes, with significant enrichment for ECM-related pathways in T1CAFs. Cathepsin H, a cysteine-type protease that was specifically up-regulated in T1CAFs but not in fibroblasts from premalignant lesions or advanced CRCs, was identified as a key factor driving matrix remodeling by T1CAFs. Finally, we showed high abundance of cathepsin H-expressing T1CAFs at the invasive front of primary T1CRC sections. CONCLUSIONS: Already in the earliest stage of CRC, cancer cell invasion is promoted by CAFs via direct interactions with epithelial cancer cells and stage-specific, cathepsin H-dependent ECM remodeling. RNA sequencing data of the 10 NF-T1CAF pairs can be found under GEO accession number GSE200660. | Cathepsin H |
Mancozeb (manganese/zinc ethylene bis-dithiocarbamate) is an organometallic fungicide that has been associated with human neurotoxicity and neurodegeneration. In a high-throughput screen for modulators of KCNQ2 channel, a fundamental player modulating neuronal excitability, Mancozeb, was found to significantly potentiate KCNQ2 activity. Mancozeb was validated electrophysiologically as a KCNQ2 activator with an EC50 value of 0.92+/-0.23muM. Further examination showed that manganese but not zinc ethylene bis-dithiocarbamate is the active component for the positive modulation effects. In addition, the compounds are effective when the metal ions are substituted by iron but lack potentiation activity when the metal ions are substituted by sodium, signifying the importance of the metal ion. However, the iron (Fe(3+)) alone, organic ligands alone or the mixture of iron with the organic ligand did not show any potentiation effect, suggesting as the active ingredient is a specific complex rather than two separate additive or synergistic components. Our study suggests that potentiation on KCNQ2 potassium channels might be the possible mechanism of Mancozeb toxicity in the nervous system. | KCNQ2 Potassium Channel |
Collagenous sprue (CS) is a severe malabsorption disorder, the etiology of which has not been well defined. Herein, we report the case of a 3-month-old infant with CS who responded to steroid and immunomodulator treatment and presented a thick subepithelial collagen band. A 3-month-old Japanese girl presented with severe watery diarrhea that lasted for 2 weeks. She was admitted to the referring hospital, but symptomatic improvement was not achieved with fasting and rehydration. Gastroduodenal endoscopy showed an edematous duodenal mucosal surface. Duodenal biopsy indicated severe villous atrophy with infiltration of mostly CD8-positive T cells; and deposition of subepithelial collagen was confirmed. The subepithelial collagen deposits, however, had disappeared after treatment. Historically, child-onset CS is extremely rare and this case is likely to be the youngest case of infantile CS. The present case suggests that CS should be considered as a differential diagnosis for intractable diarrhea, even in infants. | Collagenous Sprue |
This paper describes the development and initial validation of the Miller Screening for Preschoolers (MSP). A pilot edition of the test was administered to 174 preschool children in the state of Colorado. Of these, 39 had been previously identified as developmentally delayed. On the basis of preliminary analyses, test items were discarded if they were insensitive to differences between the at-risk group and the not-at-risk group or if they were nonsignificantly related to developmental age trends; if they were only weakly related to the domain total score; if they were redundant with other items within a domain; if they were too easy or too difficult for any given age; if they were rated low by the testers on administration and scoring issues; or if the test materials were deemed to be too expensive. This paper presents final statistics for the selected screening test items and discusses implications for the design, construction, and validation of developmental tests. | Developmental Disabilities |
In four canine Heidenhain pouches the net fluxes of H+ and Na+ have been examined before, during, and after instillation of sodium taurocholate into the pouch. These experiments were conducted in animals given H1 (mepyramine maleate) and H2 (metiamide) histamine antagonists, alone and in combination. Control experiments without antagonists were also conducted. In control experiments, as well as in those using the histamine antagonists separately, the usual sequence of events followed exposure to taurocholate-that is, a gain in the volume of the solution in the pouch and an increase in the fluxes of Na+ and H+ across the mucosa. In experiments in which H1 and H2 histamine antagonists were used in combination, taurocholate had very little effect on the ionic fluxes of H+ and Na+, suggesting that changes in the ionic permeability of the gastric mucosal barrier are mediated by histamine through both H1 and H2 receptor sites. | Metiamide |
Optic pathway gliomas account for 3-5% of all pediatric CNS tumors and represent the most common intrinsic optic nerve tumors. These tumors occur preferentially during the first decade of life and are particularly frequent in children with neurofibromatosis type 1. Although optic pathway gliomas are low-grade tumors, their behavior can be aggressive, and their management is often challenging. Their management includes observation, surgery, chemotherapy and radiation. The role of each modality is discussed as well as current and future developments in treatment, in particular targeted therapies that are currently being investigated. | Optic Nerve Neoplasms |
Rod photoreceptors have been isolated from the adult rabbit retina using enzymatic and mechanical dissociation procedures; their fine structure, synaptic activity, and long-term viability were examined using conventional electron-microscopic, quick-freezing, and cell culture techniques. Freshly dissociated photoreceptors were well-preserved compared to their counterparts in the intact retina. About half of the cells, however, exhibited broad continuity between inner and outer segments. Quick-frozen, freeze-substituted rods differed from chemically fixed cells in 3 respects: (1) there was an increased amount of granular matrix in the cytoplasm, mitochondria, and rough endoplasmic reticulum; (2) branching and anastomosing profiles of smooth endoplasmic reticulum had disappeared from the inner segment; and (3) the number of synaptic vesicles within the spherule was highly variable, in some cases leaving synaptic ribbons completely denuded of their halo of vesicles. Light-adapted, solitary rod cells continued to be synaptically active: their endings were capable of endocytosis when placed in the dark in the presence of extracellular ferritin and tracer was incorporated into vesicles and vacuoles; this uptake was much reduced when the cells were incubated with the tracer in the light. Thus, synaptic vesicle regeneration was stimulated in the dark, suggesting that vesicles underwent exocytosis in the dark. Isolated rod cells adhered poorly to most standard substrates; without proper adhesion, cells deteriorated in 2-4 hr. However, photoreceptors did adhere to glutaraldehyde-fixed Vitrogen gels and could be maintained for over 48 hr on this substrate if kept in a complete medium at 22 degrees C. In contrast, Muller cells adhered quickly to a laminin substrate with their endfoot processes. The differential adhesion properties of Muller and photoreceptor cells may be useful in obtaining pure populations of glial cells or neurons from the adult mammalian retina. | Photoreceptor Cells |
A series of 3-imino-2-indolones are the first published, high-affinity antagonists of the galanin GAL3 receptor. One example, 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (9), was shown to have high affinity for the human GAL3 receptor (Ki=17 nM) and to be highly selective for GAL3 over a broad panel of targets, including GAL1 and GAL2. Compound 9 was also shown to be an antagonist in a human GAL3 receptor functional assay (Kb=29 nM). | Receptor, Galanin, Type 3 |
Contents Summary 505 I. Introduction 505 II. Models of plant cell division 505 III. Establishing the division plane 506 IV. Maintaining the division plane during mitosis and cytokinesis 509 Acknowledgements 510 References 510 SUMMARY: Plants, a significant source of planet-wide biomass, have an unique type of cell division in which a new cell wall is constructed de novo inside the cell and guided towards the cell edge to complete division. The elegant control over positioning this new cell wall is essential for proper patterning and development. Plant cells, lacking migration, tightly coordinate division orientation and directed expansion to generate organized shapes. Several emerging lines of evidence suggest that the proteins required for division-plane establishment are distinct from those required for division-plane maintenance. We discuss recent shape-based computational models and mutant analyses that raise questions about, and identify unexpected connections between, the roles of well-known proteins and structures during division-plane orientation. | Cell Division |
Heparan sulfate is an essential glycosaminoglycan that plays important roles in development, homeostasis, and disease. As a group, the glycosaminoglycans provide mechanical strength to skin, as they can absorb water and occupy the space between elastin fibers and collagen. Heparan sulfate is also a key participant in cell proliferation, cell migration, collagen fiber formation, basement membrane regeneration, granulation tissue formation, and cell adhesion associated with wound healing. A variety of dermatological disorders are associated with changes in glycosaminoglycans or their associated proteoglycans. A new topical formulation of low molecular weight heparan sulfate glycosaminoglycan has been shown to penetrate the epidermis, basement membrane, and dermis within 24 hours of application. In an 8-week study, 15 patients using this new formulation showed improvement in skin hydration, skin firmness, skin elasticity, skin barrier function, and global fine lines and wrinkles. Incorporating low molecular weight heparan sulfate into topically applied formulations may represent a new approach to improving the appearance of photodamaged skin. | Heparitin Sulfate |
In pathogenic Neisseria species the type IV pili (Tfp) are of primary importance in host-pathogen interactions. Tfp mediate initial bacterial attachment to cell surfaces and formation of microcolonies via pilus-pilus interactions. Based on genome analysis, many non-pathogenic Neisseria species are predicted to express Tfp, but aside from studies on Neisseria elongata, relatively little is known about the formation and function of pili in these organisms. Here, we have analysed pilin expression and the role of Tfp in Neisseria cinerea. This non-pathogenic species shares a close taxonomic relationship to the pathogen Neisseria meningitidis and also colonizes the human oropharyngeal cavity. Through analysis of non-pathogenic Neisseria genomes we identified two genes with homology to pilE, which encodes the major pilin of N. meningitidis. We show which of the two genes is required for Tfp expression in N. cinerea and that Tfp in this species are required for DNA competence, similar to other Neisseria. However, in contrast to the meningococcus, deletion of the pilin gene did not impact the association of N. cinerea to human epithelial cells, demonstrating that N. cinerea isolates can adhere to human epithelial cells by Tfp-independent mechanisms. | Neisseria cinerea |
The marshland plant Cyperus articulatus (Cyperaceae) is commonly used in traditional medicine in Africa and Latin America to treat a wide variety of human diseases ranging from headache to epilepsy. We tested the hypothesis that the purported anti-epileptic effect of this plant might be due to a functional inhibition of excitatory amino acid receptors. One or several component(s) contained in the extracts inhibited the binding of [3H]CGP39653 to the NMDA recognition site and of [3H]glycine to the strychnine-insensitive glycine site of the NMDA receptor complex from rat neocortex. Water extracts from rhizomes of Cyperus articulatus dose-dependently reduced spontaneous epileptiform discharges and NMDA-induced depolarizations in the rat cortical wedge preparation at concentrations at which AMPA-induced depolarizations were not affected. We conclude that the purported beneficial effects of Cyperus articulatus might at least partially be due to inhibition of NMDA-mediated neurotransmission. | 2-Amino-5-phosphonovalerate |
A recombinant DNA ribosomal gene spacer of Leishmania braziliensis Y was used as probe to test different Leishmania species. Based on the similarity of their restriction patterns, three groups were distinguished with respect to international Leishmania references: first a group with a similar restriction pattern to L. braziliensis Y and the reference organism L. mexicana garnhami JAP78; a second group with restriction patterns similar to the reference organism L. mexicana mexicana M379; and finally a group where all the restriction patterns were related to the reference organism L. braziliensis braziliensis M2903. These results support the existence of L. garnhami as an independent Leishmania species; they confirm previous studies on L. mexicana and L. braziliensis and open the way for the more exact diagnosis of New World Leishmaniasis. | Leishmania |
A 3-year-old boy presented with severe airway obstruction which was diagnosed as asthma. He improved but had repeated episodes of severe airway obstruction. On clinical examination, he had a tracheal cough and monophonic wheezing. Imaging revealed a large lesion in the distal part of the trachea which was confirmed by bronchoscopy. The lesion was surgically removed. Histology revealed features characteristic of an inflammatory myofibroblastic tumour. Following the resection there is no recurrence of the lesion. | Neoplasms, Muscle Tissue |
Essential hypertension is a complex multifactorial disorder with epigenetic and environmental factors contributing to its prevalence. Epigenetic system is a genetic regulatory mechanism that allows humans to maintain extraordinarily stable patterns of gene expression over many generations. Sympathetic nervous system plays a major role in the maintenance of hypertension and the rostral ventrolateral medulla is the main source of this sympathetic activation. A possible mechanism to explain the sympathetic hyperactivity in the rostral ventrolateral medulla is an action of the area postrema. Area postrema seems to be the region where a shift of the set-point to a higher operating pressure occurs resulting in hypertension. But, how can a shift occur in the area postrema. We propose that melatonin-induced epigenetic modifications in the neurons of area postrema plays a role in this shift. Area postrema is reported to contain high levels of melatonin receptors that play a role in the epigenetic modifications in certain cells. Environmental stressors cause epigenetic modifications in the neurons of area postrema via the pineal hormone melatonin and these changes lead to a shift in the set-point to a higher operating pressure. This signal is then sent via efferent projections to key medullary sympathetic nuclei in rostral ventrolateral medulla resulting in increases in sympathetic nerve activity. This model may explain the long-term alterations in sympathetic activity in essential hypertension. | Area Postrema |
BACKGROUND: Hormonal replacement therapy is administered to many brain-dead organ donors to improve hemodynamic stability. Previous clinical studies present conflicting results with several randomized studies reporting no benefit. METHODS: Consecutive adult donors (N = 199) were randomized to receive high-dose levothyroxine, high-dose methylprednisolone, both (Combo), or no hormonal therapy (Control). Vasopressor requirements using the vasoactive-inotropic score (VIS) were assessed at baseline, 4 h, and at procurement. Crossover to the Combo group was sufficient to require separate intention-to-treat and per-protocol analyses. RESULTS: In the intention-to-treat analysis, the mean (+/-SD) reduction in VIS from baseline to procurement was 1.6 +/- 2.6, 14.9 +/- 2.6, 10.9 +/- 2.6, and 7.1 +/- 2.6 for the levothyroxine, methylprednisolone, Combo, and Control groups, respectively. While controlling for the baseline score, the reduction in VIS was significantly greater in the methylprednisolone and Combo groups and significantly less in the levothyroxine group compared with controls. Results were similar in the per-protocol analysis. CONCLUSIONS: High-dose methylprednisolone alone or in combination with levothyroxine allowed for significant reduction in vasopressor support in organ donors. Levothyroxine alone offered no advantage in reducing vasopressor support. Organ yield, transplantation rates, and recipient outcomes were not adversely affected. | Thyroxine |
Familial hypocalciuric hypercalcemia (FHH) is a lifelong, benign autosomal dominant disease characterized by hypercalcemia, normal to increased parathyroid hormone level, and a relatively low renal calcium excretion. Inactivation of the calcium-sensing receptor in heterozygous patients results in FHH, while in homozygous patients as well as in compound heterozygous or dominant negative heterozygous patients, it may result in neonatal severe hyperparathyroidism (NSHPT). Parathyroid surgery is not indicated in FHH and does not lower plasma calcium unless total parathyroidectomy is performed, in which case hypocalcemia ensues. There is currently no definitive medical treatment available, although pamidronate can be used to stabilize these patients before parathyroidectomy. Some NSHPT patients are asymptomatic subsequently in their lives. In this paper, clinical characteristics of this relatively rare disorder are presented. | Hypercalcemia |
BACKGROUND: Lumbar multifidus (LM) is regarded as the major stabilizing muscle of the spine. The effects of exercise therapy in low back pain (LBP) are attributed to this muscle. A current literature review is warranted, however, given the complexity of LM morphology and the inconsistency of anatomical descriptions in the literature. METHODS: Scoping review of studies on LM morphology including major anatomy atlases. All relevant studies were searched in PubMed (Medline) and EMBASE until June 2019. Anatomy atlases were retrieved from multiple university libraries and online. All studies and atlases were screened for the following LM parameters: location, imaging methods, spine levels, muscle trajectory, muscle thickness, cross-sectional area, and diameter. The quality of the studies and atlases was also assessed using a five-item evaluation system. RESULTS: In all, 303 studies and 19 anatomy atlases were included in this review. In most studies, LM morphology was determined by MRI, ultrasound imaging, or drawings - particularly for levels L4-S1. In 153 studies, LM is described as a superficial muscle only, in 72 studies as a deep muscle only, and in 35 studies as both superficial and deep. Anatomy atlases predominantly depict LM as a deep muscle covered by the erector spinae and thoracolumbar fascia. About 42% of the studies had high quality scores, with 39% having moderate scores and 19% having low scores. The quality of figures in anatomy atlases was ranked as high in one atlas, moderate in 15 atlases, and low in 3 atlases. DISCUSSION: Anatomical studies of LM exhibit inconsistent findings, describing its location as superficial (50%), deep (25%), or both (12%). This is in sharp contrast to anatomy atlases, which depict LM predominantly as deep muscle. Within the limitations of the self-developed quality-assessment tool, high-quality scores were identified in a majority of studies (42%), but in only one anatomy atlas. CONCLUSIONS: We identified a lack of standardization in the depiction and description of LM morphology. This could affect the precise understanding of its role in background and therapy in LBP patients. Standardization of research methodology on LM morphology is recommended. Anatomy atlases should be updated on LM morphology. | Back Muscles |
Although immune mechanisms can suppress tumour growth, tumours establish potent, overlapping mechanisms that mediate immune evasion. Emerging evidence suggests a link between angiogenesis and the tolerance of tumours to immune mechanisms. Hypoxia, a condition that is known to drive angiogenesis in tumours, results in the release of damage-associated pattern molecules, which can trigger the rejection of tumours by the immune system. Thus, the counter-activation of tolerance mechanisms at the site of tumour hypoxia would be a crucial condition for maintaining the immunological escape of tumours. However, a direct link between tumour hypoxia and tolerance through the recruitment of regulatory cells has not been established. We proposed that tumour hypoxia induces the expression of chemotactic factors that promote tolerance. Here we show that tumour hypoxia promotes the recruitment of regulatory T (T(reg)) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs are closely connected and cooperate to sustain tumour growth. | Receptors, CCR10 |
Dependence of the speed of various screen/film systems on x-ray energy was studied using the nearly monoenergetic x rays emitted by a filtered fluorescent source. The results show that response depends on screen phosphor composition and thickness. Barium and rare earth screens having K absorption energies lower than that of calcium tungstate are relatively more sensitive to x rays in the 40-70-keV region. | Technology, Radiologic |
A rapid and simple high performance liquid chromatographic method is described and validated for the determination of lobenzarit disodium (CAS 64808-48-6) in a sustained release tablet formulation. The calibration graph was linear over the range 20-105 micrograms/ml. The sensitivity (discriminator capacity) was 2.079 micrograms/ml. The coefficient of variations for repeatability and reproducibility were less than 1.60% and 1.30%, respectively. The accuracy of the method did not depend on lobenzarit concentration in tablets. The mean recovery was found to be 100.62%. The method was selective, even when degradation products were present. | ortho-Aminobenzoates |
Secretory phospholipase A(2) (sPLA(2)) represents a class of enzymes that hydrolyze phospholipids from cellular membranes and lipoproteins, resulting in multifarious proatherogenic actions in the vessel wall. Proatherogenic actions of sPLA(2) involve lipoprotein remodeling that facilitates proteoglycan binding and formation of lipid aggregates that are rapidly internalized by tissue macrophages. The hydrolysis of phospholipids on cell membranes generates bioactive lipids and lipolipoproteins with increased oxidative susceptibility. These particles and other bioactive lipids activate inflammatory pathways in various cells of the vessel wall. Transgenic mice overexpressing groups IIA, V, and X have increased atherosclerosis formation, whereas mice deficient in these sPLA(2) isoenzymes have less atherosclerosis formation. In apolipoprotein E knockout mice fed an atherosclerotic diet, sPLA(2) inhibition with varespladib reduced atherosclerosis formation. The potential for sPLA(2) inhibitors for preventing cardiovascular events is being investigated. | Phospholipases A2, Secretory |
Pharmaceutical counterfeiting is becoming a serious problem in the world, especially in developing countries including China. Herein an isocratic reversed-phase high performance liquid chromatography (RP-HPLC) method was developed for screening counterfeit medicines and adulterated dietary supplement products. The developed method could be employed to separate and determine simultaneously six anti-diabetic drugs (glipizide, gliclazide, glibenclamide, glimepiride, gliquidone, repaglinide) on an isocratic solvent system using an Alltima C18 column (5 microm, 150 mmx4.6 mm) with an isocratic mobile phase of methanol-phosphate buffer (pH 3.0; 0.01 mol/L) (70:30, v/v), at a flow rate of 1.0 mL/min and at a wavelength of 230 nm. The proposed method was successfully applied to the analysis of medicinal and dietary supplement samples purchased from the local market in China. | Sulfonylurea Compounds |
Research has indicated that the taking and viewing of idealized selfies can result in negative body image outcomes. Given the negative consequences associated with selfie activities, it is important to explore factors that relate to idealized self-presentation on social media. Combining insights of sociocultural, social comparison, and objectification theory, we distinguished and examined four different pathways linking appearance media exposure to selfie-behavior (i.e., selfie taking/posting and selfie-investment and manipulation) via internalization and social media comparison. Additionally, we examined the protective role of positive peer body talk. A sample of 949 Belgian adolescents aged 14-18 (M(age) = 15.45, SD = 1.37) participated in an online survey. Structural equation analyses showed that appearance-related media exposure was positively related to selfie-taking and -posting via internalization and social media comparison. Both internalization and social media comparison were positively related to selfie manipulation and selfie-investment. Additionally, results indicated a protective role of positive peer body talk against thin/athletic-ideal internalization. For adolescents who engaged in more positive body talk, watching appearance-related media content resulted in less thin/athletic-ideal internalization. Overall, the findings emphasize the crucial role of peers -and more specifically peer validation -in reinforcing and criticizing dominant appearance ideals and shaping the way adolescents present themselves online. | Social Comparison |
Using a genetic approach, we assessed the effects of mutations in protein kinase A (PKA) on long-term potentiation (LTP) in the mossy fiber pathway and its relationship to spatial and contextual learning. Ablation by gene targeting of the C beta 1 or the RI beta isoform of PKA produces a selective defect in mossy fiber LTP, providing genetic evidence for the role of these isoforms in the mossy fiber pathway. Despite the elimination of mossy fiber LTP, the behavioral responses to novelty, spatial learning, and conditioning to context are unaffected. Thus, contrary to current theories about hippocampal function, mossy fiber LTP does not appear to be required for spatial or contextual learning. In the absence of mossy fiber LTP, adequate spatial and contextual information might reach the CA1 region via other pathways from the entorhinal cortex." | Cyclic AMP-Dependent Protein Kinase RIbeta Subunit |
OBJECT: Failed back surgery syndrome is defined as persistent chronic low-back pain and/or leg pain lasting more than 1 year, despite of one or more surgical procedures. Instrumented spinal fusion has been offered by surgeons as a potential treatment to recover from pain and functional disability. Factors contributing to good outcome of instrumented spinal fusion have not been investigated extensively. This study evaluated the global perceived recovery and functional status of patients after instrumented fusion for the treatment of failed back surgery syndrome. METHODS: Between January 2004 and September 2007, 100 patients underwent instrumented spinal fusion because of persistent back and/or leg pain lasting more than 1 year despite of one or more previous spine surgeries. The global perceived recovery of the patients was documented on a seven-point Likert scale, in which good outcome was defined as complete recovery" and "almost complete recovery". Pain was evaluated by the 100-mm visual analogue scale (VAS) of back pain and leg pain, and functional disability measured by the Roland Disability Questionnaire for Sciatica (RDQ) and Oswestry Disability Index (ODI). The Hospital Anxiety and Depression Scale (HADS) evaluated psychological co-morbidity. All patients were sent questionnaires by mail. Pearson's correlation coefficient was calculated between outcome measures and preoperative patient characteristics. RESULTS: Eighty-two patients (82% response rate) returned questionnaires that were useful for analysis. After a mean follow-up period of 15 months, 35% of the patients reported good outcome, whereas 65% had unsatisfactory outcome. The mean (+/- SD) score of VAS low-back pain and leg pain was 45.7 +/- 29 and 37.9 +/- 31.9, respectively. The mean (+/- SD) RDQ and ODI score was 11.8 +/- 5.4 and 30.6 +/- 20.3, respectively. HADS score indicated a possible anxiety disorder in 28% of the patients and in 30% a possible underlying depression. Of the patients' baseline characteristics, there was only a significantly negative correlation between level of education and outcome. CONCLUSIONS: The present study showed disappointing outcome of instrumented fusion for the treatment of failed back surgery syndrome in terms of perceived recovery, functional disability and pain. Conservative management is probably more beneficial and, therefore, more selective and careful assessment should be done in order to prevent unnecessary surgery." | Failed Back Surgery Syndrome |
Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood serum or plasma to optimize pharmacological therapy. TDM is an instrument with which the high interindividual variability of pharmacokinetics of patients can be identified and therefore enables a personalized pharmacotherapy. In September 2017 the TDM task force of the Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update of the consensus guidelines on TDM published in 2011. This article summarizes the essential statements for the clinical practice in psychiatry and neurology. | Neuropharmacology |
AIM: The sensitivity of cancer cells which exhibit multi-drug resistance phenotype to A3 adenosine receptor (A3AR) agonist N(6)-(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide (IB-MECA) was studied. METHODS: To establish direct relationship between P-glycoprotein (P-gp, ABCB1 and MDR1) expression and IB-MECA induced cell death, a straightforward method for precise estimation of intracellular level of this A3AR agonist was developed. RESULTS: We subjected three human leukaemia cell lines HL-60, K562 and K562/HHT to treatment with micromolar concentrations of IB-MECA. Although all cell lines used expressed A3AR, there was a large difference in their sensitivity to IB-MECA. While HL-60 and K562 cells were almost equally sensitive, the K562/HHT cells, which exhibit a multi-drug resistance phenotype because of overexpression of P-gp, were significantly more resistant. We found that the intracellular level of IB-MECA in K562/HHT cells was approx. 10 times lower than those in HL-60 or K562 cells. Inhibitors of P-gp, including cyclosporine A (CsA) and verapamil (Vpa), increased the intracellular level of IB-MECA and reversed the resistance of K562/HHT cells to this drug. Accordingly, shRNA-mediated down-regulation of P-gp significantly increased the intracellular level of IB-MECA in K562/HHT cells which simultaneously exhibited reduced resistance to this A3AR agonist. In addition, an in vitro enzyme-based assay provided evidence that IB-MECA might serve as a substrate for P-gp. CONCLUSION: Our results suggest that P-gp overexpression prevents cells from IB-MECA induced apoptosis despite the A3AR expression. Pro-apoptotic effect of IB-MECA seemed to strongly depend on its intracellular accumulation rather than on its interaction with A3AR." | Adenosine A3 Receptor Agonists |
Immunotherapy with intravesical bacillus Calmette-Guerin (BCG) has proved to be more effective than most chemotherapeutic agents in the prophylaxis and treatment of superficial bladder tumours. Side-effects, both local and systemic, are the main limitations against its use. With the aim of lowering the incidence and severity of side-effects, we started to use two vials of BCG, Connaught type, per instillation, instead of three vials, as recommended by the manufacturer. We prospectively reviewed adverse effects of BCG treatment at the lower dosage in 92 patients. Compared with other series, we found a similar incidence of adverse effects except for some local effects as haematuria which showed a higher incidence, but we also found a lower rate of tumour relapse. Four primary tumours were recorded during the study period. In our open study, a lower BCG intravesical dosage is not followed by a reduction in side-effects. | BCG Vaccine |
OBJECTIVE: To quantify by meta-analysis the genetic effect of the HLA-B5 or HLA-B51 (HLA-B51/B5) allele on the risk of developing Behcet's disease (BD) and to look for potential effect modifiers. METHODS: Relevant studies were identified using the PubMed Medline database and manual searches of the literature. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by using the random-effects model. Subgroup meta-analyses and meta-regression analyses were undertaken to investigate the effects of selected study-level parameters on the pooled OR. Heterogeneity was assessed using the I2 statistic. Pooled results were used to calculate population-attributable risks (PAR) for BD in relationship to HLA-B51/B5. RESULTS: A total of 4,800 patients with BD and 16,289 controls from 78 independent studies (published 1975-2007) were selected. The pooled OR of HLA-B51/B5 allele carriers to develop BD compared with noncarriers was 5.78 (95% CI 5.00-6.67), with moderate between-study heterogeneity (I2 = 61%). The subgroup analyses stratifying studies by geographic locations (Eastern Asia, Middle East/North Africa, Southern Europe, Northern/Eastern Europe) yielded consistent OR ranges (5.31-7.20), with I2 ranges of 52-70%. Univariate random-effects meta-regression indicated the percentage of male BD cases (P = 0.008) as a source of heterogeneity. The PAR within the various geographic areas were estimated at 32-52%. CONCLUSION: The strength of the association between BD and HLA-B51/B5, and its consistency across populations of various ethnicities, lends further support to this allele being a primary and causal risk determinant for BD. Variations according to sex support an interaction of this allele with BD characteristics. | HLA-B51 Antigen |
Cistanche deserticola Y. C. Ma, a precious parasitic medicinal herb distributed in desert areas in the Northwest of China, also known as desert ginseng", has been used in China for thousands of years for its nourishing effects. The phenylethanoid glycosides (PeGs) have been proven as the main effective compounds due to their neuroprotective effects and were used for quality control. In this study, echinacoside content, a representative PeG, total phenolic content, DPPH scavenging activity, and PAL activity were determined in different tissues of C. deserticola. Our results showed that most indices had a similar pattern of scale > cambium ring > pith and bottom part > middle part > upper part. Besides, stereomicroscopic observation showed that the scale surface was densely covered with physical wounds formed during vertical and broadwise growth in sand. Thus, wound area was quantified and a linear regression analysis was conducted between wound area and PAL activity, total phenolics, and echinacoside content. Our results suggested that physical wounding caused by sand might play an important role in echinacoside biosynthesis which has never been noticed in C. deserticola development. Furthermore, the coexistence of the highest PAL activity and highest echinacoside accumulation in scale tissue might indicate that the biosynthetic site of echinacoside in C. deseticola Y. C. Ma is mainly in the scale tissue." | Cistanche |
Ets-1 is a transcription factor that plays an important role in various physiological and pathological processes, such as development, angiogenesis, apoptosis and tumour invasion. In the present study, we have demonstrated that Ets-1 p51, but not the spliced variant Ets-1 p42, is processed in a caspase-dependent manner in Jurkat T-leukaemia cells undergoing apoptosis, resulting in three C-terminal fragments Cp20, Cp17 and Cp14 and a N-terminal fragment, Np36. In vitro cleavage of Ets-1 p51 by caspase 3 produces fragments consistent with those observed in cells undergoing apoptosis. These fragments are generated by cleavage at three sites located in the exon VII-encoded region of Ets-1 p51. This region is absent from the Ets-1 p42 isoform, which therefore cannot be cleaved by caspases. In Ets-1 p51, cleavage generates C-terminal fragments containing the DNA-binding domain, but lacking the transactivation domain. The Cp17 fragment, the major cleavage product generated during apoptosis, is devoid of transcriptional activity and inhibits Ets-1 p51-mediated transactivation of target genes by competing with Ets-1 p51 for binding to Ets-binding sites present in the target promoters. In the present study, we have demonstrated that caspase cleavage of Ets-1 within the exon VII-encoded region leads to specific down-regulation of the Ets-1 p51 isoform during apoptosis. Furthermore, our results establish that caspase cleavage generates a stable C-terminal fragment that acts as a natural dominant-negative form of the full-length Ets-1 p51 protein. | Proto-Oncogene Proteins c-ets |
A Prins pinacol type rearrangement followed by C4-OBn participation" in a cascade manner has been observed while probing the fate of carbocation in some carbohydrate derived homoallylic alcohols in the Prins reaction. This has led to an easy access to tetrahydrofuran-fused bridged bicyclic ketals (or tetrahydrofuran-fused 1,6-anhydro-heptopyranose frameworks) which are further converted into some annulated sugars and C2-branched heptoses." | Heptoses |
Magnetic resonance imaging of the brain is invaluable in assessing the neonate who presents with encephalopathy. Successful imaging requires adaptations to both the hardware and sequences used for adults. Knowledge of the perinatal and postnatal details are essential for the correct interpretation of the imaging findings. Perinatal lesions are at their most obvious on conventional imaging between 1 and 2weeks from delivery. Very early imaging is useful to guide management in ventilated neonates but abnormalities may be subtle on conventional sequences. Diffusion-weighted imaging (DWI) is clinically useful for the early identification of ischaemic tissue in the neonatal brain, the pattern of which can predict outcome. DWI may underestimate the final extent of injury, particularly basal ganglia and thalamic lesions. Serial imaging with quantification of both tissue damage and structure size provides invaluable insights into the effects of perinatal injury on the developing brain. | Hypoxia-Ischemia, Brain |
Reconstruction following total vulvectomy is a reconstructive challenge. Previously described techniques typically require bilateral flaps and the associated donor site morbidity. We present a case of reconstruction after radical total vulvectomy using a single split anterolateral thigh (ALT) perforator flap with a design that optimizes perfusion while allowing for primary donor site closure. A 68-year-old female with a history of vulvar squamous cell carcinoma who had previously undergone vulvectomy and radiation therapy presented with local recurrence. The patient required a radical total vulvectomy, resulting in a 12 x 10 cm vulvar defect. A 2-perforator ALT flap (25 x 7 cm) was harvested, split transversely, and then inset in a circumferential manner around the vulva. This approach contrasts with previous reports, which split the ALT flap longitudinally or centrally, and can compromise perfusion and/or preclude primary donor site closure. The patient healed without complication with 6 months of follow-up. The described approach allows for total vulvectomy reconstruction using a single ALT flap with a perforator configuration that maximizes perfusion while obviating the need for donor site grafting. | Vulvectomy |
An 8 wk old female Dalmatian weighing .56 kg presented with growth retardation. The puppy exhibited no abnormalities during physical examination other than significantly reduced growth compared with her littermates. Endocrine results suggested pituitary dwarfism. Two wk later, the puppy returned due to the onset of megaesophagus, but the puppy unfortunately died the following morning. This case report describes the diagnosis of dwarfism in a Dalmatian puppy that was caused by growth hormone (GH) deficiency and describes its early clinical manifestations. | Dwarfism, Pituitary |
BACKGROUND: Factor XI (FXI) is a zymogen in the coagulation pathway that, once activated, promotes haemostasis by activating factor IX (FIX). Substitution studies using apple domains of the homologous protein prekallikrein have identified that FIX binds to the apple 3 domain of FXI. However, the molecular changes upon activation of FXI or binding of FIX to FXIa have remained largely unresolved. OBJECTIVES: This study aimed to gain more insight in the FXI activation mechanism by identifying the molecular differences between FXI and FXIa, and in the conformational changes in FXIa induced by binding of FIX. METHODS: Hydrogen-deuterium exchange mass spectrometry was performed on FXI, FXIa, and FXIa in complex with FIX. RESULTS: Both activation and binding to FIX induced conformational changes at the interface between the catalytic domain and the apple domains of FXI(a)-more specifically at the loops connecting the apple domains. Moreover, introduction of FIX uniquely induced a reduction of deuterium uptake in the beginning of the apple 3 domain. CONCLUSIONS: We propose that the conformational changes of the catalytic domain upon activation increase the accessibility to the apple 3 domain to enable FIX binding. Moreover, our HDX MS results support the location of the proposed FIX binding site at the beginning of the apple 3 domain and suggest a mediating role in FIX binding for both loops adjacent to the apple 3 domain." | Hydrogen Deuterium Exchange-Mass Spectrometry |
OBJECTIVE: The objective of the present study was to assess the prevalence and determinants of preconceptional folic acid supplement use among pregnant women in Lebanon. DESIGN/SETTING/SUBJECTS: The study was a descriptive epidemiological study. Analysis was performed on 5280 deliveries admitted to twelve member hospitals of the National Collaborative Perinatal Neonatal Network during the period September 2003-January 2005. Information on folic acid intake and maternal and neonatal characteristics were obtained from obstetric charts along with direct interviews performed by trained personnel. Logistic regression was performed to determine the predictors of preconceptional folic acid use. RESULTS: The overall use of preconceptional folic acid supplementation was 14.0 % (18.6 % in urban hospitals v. 2.7 % in rural hospitals). Higher socio-economic status, lower parity and having a history of previous spontaneous abortions were significantly associated with preconceptional folic acid use. CONCLUSION: Our study shows that Lebanon currently has a low rate of preconceptional folic acid supplement use. Intervention through the means of awareness campaigns needs to be implemented on a national level. | Preconception Care |
We introduce a novel compartmental model accounting for the effects of vaccine efficacy, deployment rates and timing of initiation of deployment. We simulate different scenarios and initial conditions, and we find that higher abundancy and rate of deployment of low efficacy vaccines lowers the cumulative number of deaths in comparison to slower deployment of high efficacy vaccines. We also forecast that, at the same daily deployment rate, the earlier introduction of vaccination schemes with lower efficacy would also lower the number of deaths with respect to a delayed introduction of high efficacy vaccines, which can however, still achieve lower numbers of infections and better herd immunity. | Immunotherapy, Active |
Objectives The objective was to evaluate a nadir-led protocol for transitioning porcine lente insulin suspension (PLIS)-treated diabetic cats onto human recombinant protamine zinc insulin (PZIR). Methods Recently diagnosed (<5 months) diabetic cats, treated with PLIS q12h for ⩾6 weeks, were recruited. Fructosamine, 24 h blood glucose curve (BGC), quality of life assessment (DIAQoL-pet score) and Diabetic Clinical Score (DCS) were assessed at enrolment (PLIS-treated) and 2, 4 and 12 weeks after transitioning to PZIR (starting dose 0.2-0.7 U/kg q12h). Short duration of insulin action was defined as <9 h. Linear mixed effects modelling assessed for change in fructosamine, mean blood glucose (MBG) during BGCs, DIAQoL-pet score, DCS and q12h insulin dose. McNemar's tests compared the proportion of cats with hypoglycaemia at week 0 (PLIS-treated) and week 4 (PZIR-treated). Results Twenty-two cats were recruited. Median PLIS dose at enrolment was 0.5 U/kg (interquartile range 0.3-0.7 U/kg) q12h, equalling median PZIR starting dose (0.5 U/kg; interquartile range 0.3-0.7 U/kg q12h). Transitioning was followed by significant decreases in fructosamine ( P = 0.00007), insulin dose ( P = 0.02), DCS ( P = 8.1 x 10(-8)) and DIAQoL-pet score ( P = 0.003), indicating improved quality of life. MBG did not alter significantly ( P = 0.1). Five cats (22.7%) achieved remission. Hypoglycaemia was recorded in 30/190 12 h BGCs (15.8%) and five cats experienced clinical hypoglycaemia. The proportion of cats with hypoglycaemia did not differ between PLIS (week 0) and PZIR (week 4) ( P = 1.0). Duration of action was analysed in 19 cats. Six cats (31.6%) showed short duration of action on PLIS, compared with two cats (10.5%) after 4 weeks on PZIR. All six cats with short PLIS duration showed duration of ⩾9 h on PZIR. Conclusions and relevance Used alongside a low-carbohydrate diet, transitioning to PZIR was associated with significantly improved clinical signs and quality of life, with some cats achieving remission. Transition to PZIR should be considered for cats with short duration of action on PLIS. | Insulin, Lente |
Delusional Infestation (DI), represents one of the most difficult patient encounters that dermatology practitioners may experience. It is common for DI patients to doctor shop. Thus, dermatologists are one of several disciplines that may encounter DI patients in their practices. Others include veterinarians, epidemiologists, emergency departments, mental health practitioners, and entomologists. In this article, entomologist, Dr. Gale E. Ridge, with extensive DI experience, was interviewed to find out what an entomologist's perspective has been and what we, the dermatology providers, can learn from that. This is followed by a discussion by the dermatology experts on how the experience of entomologists compares to our experience and what we can learn from them. | Delusional Parasitosis |
INTRODUCTION: The major chemical marker of black pepper (Piper nigrum L) is piperine and its estimation is extremely important for quality assessment of black pepper. The methods for piperine quantification, to date, are laboratory based and use high end instruments like chromatographs, which require tedious sample processing and cause sample destruction. OBJECTIVES: In this article, we present a simple, rapid and green analytical method based on Raman spectroscopy for the quantitative assessment of piperine. MATERIAL AND METHODS: To assess the potential of the technique, we report the complete vibrational characterisation of the piperine with density functional theory (DFT) calculations. RESULTS: The theoretical peaks were obtained at 1097 cm(-1) , 1388 cm(-1) , 1528 cm(-1) , 1578 cm(-1) , and at 1627 cm(-1) , and this result was verified in a Raman spectrometer followed by a preliminary experiment. Twenty black pepper samples were analysed using high-performance liquid chromatography (HPLC) and used as reference data for Raman analysis. The Raman shift spectra were analysed using partial least squares (PLS) and good prediction accuracy with correlation coefficient of prediction (Rp(2) ) = 0.93, root mean square error of prediction (RMSEP) = 0.13 and residual prediction deviation (RPD) = 3.9 obtained. CONCLUSIONS: The results demonstrate the efficacy of the Raman technique for the estimation of piperine in the dry fruit of Piper nigrum. | Benzodioxoles |
Cu-CF3" species have been used historically for a broad spectrum of nucleophilic trifluoromethylation reactions. Although recent advancements have employed ligands to stabilize and harness the reactivity of this key organometallic intermediate, the ability of a ligand to differentiate a regiochemical outcome of a Cu-CF3-mediated or -catalyzed reaction has not been previously reported. Herein, we report the first example of a Cu-catalyzed trifluoromethylation reaction in which a ligand controls the regiochemical outcome. More specifically, we demonstrate the ability of bipyridyl-derived ligands to control the regioselectivity of the Cu-catalyzed nucleophilic trifluoromethylation reactions of propargyl electrophiles to generate (trifluoromethyl)allenes. This method provides a variety of di-, tri-, and tetrasubstituted (trifluoromethyl)allenes, which can be further modified to generate complex fluorinated substructures." | Alkadienes |
OBJECTIVE: This study aims to evaluate ADHD-like symptoms in children with autism spectrum disorder (ASD) based on single-item analysis, as well as the comparison of two ASD subsamples of children with ADHD (ASD+) and without ADHD (ASD-). METHODS: Participants are 83 children with ASD. Dimensional and categorical aspects of ADHD are evaluated using a diagnostic symptom checklist according to DSM-IV. RESULTS: Of the sample, 53% fulfill DSM-IV criteria for ADHD. The comparison of the ASD+ and the ASD- samples reveals differences in age and IQ. Correlations of ADHD and PDD show significant results for symptoms of hyperactivity with impairment in communication and for inattention with stereotyped behavior. Item profiles of ADHD symptoms in the ASD+ sample are similar to those in a pure ADHD sample. CONCLUSION: The results of our study reveal a high phenotypical overlap between ASD and ADHD. The two identified subtypes, inattentive-stereotyped and hyperactive-communication impaired, reflect the DSM classification and may theoretically be a sign of two different neurochemical pathways, a dopaminergic and a serotonergic. | Neurodevelopmental Disorders |
The direct enantiomeric resolution of the racemic herbicide 2-(4-chloro-2-methylphenoxy)propanoic acid (CMPP) was demonstrated on an Enantiopac (alpha 1-acid glycoprotein) chiral high-performance liquid chromatographic (HPLC) column. The HPLC separation of various amide derivatives of CMPP on a chiral "Ionic Pirkle" column comprising of N-(3,5-dinitrobenzoyl) (R)-(-)phenylglycine as chiral ligand, was also accomplished. These amides and racemic ibuprofen, however could not be separated on the Enantiopac system. The performance, stability and cost of the two systems were compared. Using optically pure CMPP enantiomers the elution order was determined and shown to reverse between the two systems. It was also shown that negligible racemisation occurred during derivatization." | 2-Methyl-4-chlorophenoxyacetic Acid |
A nonchordomatous solitary lesion of the clival bone is an exceptionally rare pathological entity, which represents a diagnostic and a therapeutic challenge. Many diseases with extremely different biological behavior, and requiring a dedicated treatment strategy, may result in similar clinical patterns. The approach to a correct differential diagnosis has to consider the specific epidemiological, radiological, and histopathological characteristics of each pathology to minimize the diagnostic bias and to allow the planning of the best treatment strategy. Because of the rarity of these diseases, a systematical review of nonchordomatous lesions of the clival bone still lack in the literature. The purposes of this study are to provide an overview of the epidemiological, clinical, radiological, and histopathological characteristics of nonchordomatous clival lesions, with particular emphasis on diagnostic and therapeutic strategies and related clinical outcome. | Skull Neoplasms |
Acquired thrombocytopenia recognizes a myriad of causes. Among these, infectious diseases play a relevant role since a low platelet count is commonplace along with other abnormal laboratory data. Areas covered: This narrative review, after a brief presentation of the possible pathogenic mechanisms, is focused on the most prevalent infections associated with thrombocytopenia, namely those attributable to hepatitis C virus (HCV), human immunodeficiency virus (HIV) and Helicobacter pylori. Expert commentary: An underlying HCV or HIV infection should always be suspected in patients at risk who present with isolated thrombocytopenia. The eradication of Helicobacter pylori is advisable in infected patients with secondary immune thrombocytopenia, because this will increase the platelet count in a substantial number of cases, thus avoiding more aggressive and prolonged treatments. | Thrombocytopenia |
Five 99mTc-generators, based on fission Mo-99, from five different manufacturers were studied in April and May of 1977 -- with regard to their performance and to the quality of the eluates. The study covers types of generators not already dealt with in a previous publication [5]. One generator was overloaded with Mo-99; one generator had Tc-99m yields below 70%. One generator yielded eluates containing appreciable gamma-emitting impurities other than Mo-99. Two generators yielded eluates containing trace amounts of Al+++. The content of alpha- and pure beta-emitting nuclidic impurities (other than Tc-99) were in all cases below the limits set in the DLS 79 [2] monograph on Tc-99m pertechnetate obtained from fission Mo-99. | Nuclear Fission |
Tension and stiffness of tetanically activated skeletal muscle fibres of the frog were studied at varied tonicity of the extracellular medium (1.7-3.2 degrees C; sarcomere length, 2.13-2.22 microns). The stiffness was measured from the change in peak tension in response to fast (0.2 ms) stretches and releases of small amplitude (0.11-0.15% of the fibre length). The bathing solution was made hypotonic by reduction of NaCl and hypertonic by addition of sucrose. The osmotic strength of the solutions tested varied from 81 to 168% of the isotonic value. Maximum tetanic tension decreased markedly with increased tonicity. The active stiffness, on the other hand, increased as the tonicity was raised, and the tension/stiffness ratio (the total extension of the undamped fibre elasticity) was thus greatly reduced under these conditions. Evidence is presented to show that the change in the tension/stiffness ratio is due neither to the development of rigor cross-bridges nor to the recruitment of passive parallel-elastic elements in response to increased tonicity. Neither are viscous-like components important for explaining the effect. A change in the tension/stiffness ratio, similar to that seen in response to increased tonicity, did not occur as fibre width was reduced by increasing the sarcomere length. This suggests that the changes in the fibre volume affect this ratio mainly by mechanisms that are unrelated to changes in lateral spacing between the myofilaments. | Tensile Strength |
Sequential thymidine radiograms from rats labeled on days E13 and E14, and killed at daily intervals thereafter, were analyzed to trace the migratory route and settling pattern of neurons of the inferior olive. Long-survival thymidine radiograms from perinatal rats injected on day E14 were used to subdivide the inferior olivary complex on the basis of neurogentic criteria. The inferior olivary neurons originate on days E13 and E14 in the primary precerebellar neuroepithelium. The olivary neurons labeled on day E14 (the late generated components) translocate into the inferior olivary premigratory zone on day E15. On day E16 these cells join the olivary migratory stream, which follows an intramural circumferential path between the gray and white matters of the medulla. By day E17 the olivary migratory stream is reduced to a small band near the corpus of the inferior olive, which has been settled by this time by neurons generated on day E13. As a result, the unlabeled cells are situated on day E17 dorsomedially and the labeled cells ventrolaterally. The regional segregation of neurons forming subdivisions of the inferior olive begins on day E18, and by day E19 the major subdivisions are all recognizable. In thymidine radiograms from perinatal rats injected on day E14, four neurogenetic components can be distinguished in the inferior olive, those composed: (1) of unlabeled cells (generated on day E13), (2) of predominantly unlabeled cells, (3) of predominantly labeled cells (generated on day E14), and (4) of labeled cells. By combining these neurogenetic differences with the morphological features of the inferior olivary complex, we propose a modification of the currently accepted classification. The four major divisions of the inferior olive are the successively produced posterodorsal olive, anterolateral (principal) olive, posteroventral olive, and anteroventral olive. The location and configuration of these divisions are illustrated in relation to the traditional classification both in the coronal and the sagittal plane. | Olivary Nucleus |
OBJECTIVE: This study seeks to find out the presentation, management and complications of encephaloceles in an African setting. DESIGN: a retrospective study reviewing the age and sex of the patients, type and contents of encephaloceles, associated anomalies, preoperative evaluation and investigations, surgical approaches, intra- and post-operative complications as well as follow-up outcomes. SETTING: Bethany Crippled Children's centre and Bethanykids at Kijabe Hospital (BKKH), between January 1998 and August 2006. PATIENTS: Of the 53 patients seen, 23 were males and 30 females. The median age at presentation was four months. RESULTS: The follow-up period extended to eight years. Twenty nine patients had occipital encephaloceles, and 39 were operated using the direct external approach. Cererobrospinal fluid leak was the most common post-operative complication. Recurrence occurred in four patients and death in six. CONCLUSIONS: Most of the encephalocele patients manage d at BKKH had good outcomes and proceeded to live normal or near-normal lives. Our study confirms that even in resource-constrained areas, children with encephaloceles can be successfully managed with acceptable outcomes. | Encephalocele |
From each of a group of 217 adult males selected through enzyme-immunoassay or skin-test (Group A), six stool samples were examined by both the Lutz/Hoffman, Pons & Janer (Lutz/HPJ) and Kato/Katz methods. In addition, one oogram of the rectal mucosa was performed. By these methods, schistosomiasis was detected in 44.7%, 47.5% and 40.1% of the individuals respectively. To evaluate the methods in the assessment of cure, the last 40 patients from group A, treated with a single oral dose of oxamniquine at 15 mg/kg were followed up for six months (Group B). The criteria for parasitological cure included three stool examinations by Kato/Katz and Lutz/HPJ methods, one, three and six months post-treatment and a rectal biopsy between the fourth and sixth months post-treatment. The examinations were negative in 87.5%, 90% and 95% of the patients, respectively. The efficacy of oxamniquine was 82.5% when the three methods were considered together and there was no statistically significant difference between the sensitivity of the individual methods. | Schistosomiasis mansoni |
BACKGROUND: Tuberculosis (TB) of posterior pharyngeal wall (PPW), either primary or secondary, is extremely rare and can mimic malignancy in elderly patients. CASE REPORT: A 36-year-old female patient presented with complains of nonhealing ulcer at the back of her throat for 4 months. On examination, there was an ulceroproliferative growth covered with slough over PPW. Positron emission tomography scan showed uptake in PPW. There was no uptake in any other part of body. A biopsy from PPW lesion showed epithelioid cell granulomas with Langhans type giant cells. Auramine-rhodamine staining showed few beaded bacilli consistent with TB. CONCLUSION: Tuberculosis of PPW is an extremely uncommon entity and can mimic malignancy. It should be kept as one of the differential diagnosis as it can be cured solely by giving anti-tubercular therapy. | Benzophenoneidum |
This article examines how one patient and the recent political climate surrounding Planned Parenthood influenced a college graduate with career aspirations in criminology to pursue nursing instead." | International Planned Parenthood Federation |
Heterotopic salivary tissue is a rare lesion, although most authors agree that anomalous embryologic development of salivary tissue is the main cause. One case of cervical tumor by ectopic salivary gland is reported, and existent literature is reviewed. A 26-year-old woman was operated on for a cystic tumor in the midline of the neck diagnosed as thyroglossal cyst in the hyoid region. After Sistrunk operation, the recurrence was immediate. A second operation was performed, and a solid tumor located between muscles of the tongue was resected. A long tract opening in recurrent cervical cystic tumor was also removed. No recurrence was evident at 1 year after surgery. Pathological examination of the excised mass revealed an ectopic salivary gland with serous and mucinous acini located between muscles of the tongue. This is a rare case report of a cervical fistula by ectopic salivary gland surrounded by muscles of the tongue draining into a cystic tumor in the hyoid midline lesion. Recurrence of thyroglossal cyst after a correct surgical resection must be suspected as an ectopic salivary tissue. Also when a cystic neck tumor is present, an ectopic salivary gland must be suspected. | Salivary Gland Fistula |
A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982). | Nuclear Factor 90 Proteins |
Herein, the effects of Agaricus bisporus Polysaccharides (ABPs) on anti-channel catfish virus (CCV) infections to promote their application in channel catfish culture were explored. Transcriptome and metabolome analyses were conducted on the spleen of a CCV-infected channel catfish model fed with or without ABPs. CCV infections upregulated many immune and apoptosis-related genes, such as IL-6, IFN-alpha3, IFN-gamma1, IL-26, Casp3, Casp8, and IL-10, and activated specific immunity mediated by B cells. However, after adding ABPs, the expression of inflammation-related genes decreased in CCV-infected channel catfish, and the inflammatory inhibitors NLRC3 were upregulated. Meanwhile, the expression of apoptosis-related genes was reduced, indicating that ABPs can more rapidly and strongly enhance the immunity of channel catfish to resist viral infection. Moreover, the metabonomic analysis showed that channel catfish had a high energy requirement during CCV infection, and ABPs could enhance the immune function of channel catfish. In conclusion, ABPs can enhance the antiviral ability of channel catfish by enhancing immune response and regulating inflammation. Thus, these findings provided new insights into the antiviral response effects of ABPs, which might support their application in aquaculture. | Ictalurivirus |
Pituitary growth hormone (GH) has considerable potential as an anabolic agent in animal production. For example, pigs treated with GH will grow faster (i.e. deposit protein), require less feed per unit of body weight gain, and will have less carcass fat than untreated animals. Lactating cows will produce more milk with less feed. It is likely, though not completely established, that young cattle will also respond to GH treatments. Most of the information on the mode of action of GH has been obtained with laboratory rather than farm animals. The hormone affects almost all aspects of metabolism although the specific mechanism for these effects is still not understood. Stimulation of protein accretion is reflected by increased nitrogen retention and incorporation of radioactive amino-acids into tissue proteins. An increased rate of protein synthesis is thought to be a result of enhanced ability of ribosomes to translate messenger RNA. GH increases polyamine synthesis by increased ornithine decarboxylase activity; RNA synthesis by increasing RNA polymerase and DNA synthesis by increased DNA polymerase. Cell division is stimulated in several tissues (e.g. muscle and lymphoid tissue). In vivo GH lowers the respiratory quotient indicating an increased oxidation of fatty acids. The numbers of fat cells do not change but the fat cells are reduced in size. The stimulating effects of GH on skeletal tissue, and perhaps other tissues as well, is mediated by the formation of at least three peptides called somatomedins. GH is a protein with a molecular weight of about 22,000 and contains 191 amino-acid residues. The amino-acid sequence varies with the species. GH isolated from one species is not always effective in a different species. Use of GH isolated from pituitaries does not appear to be economically feasible. A chemical synthesis for human GH has been accomplished. However, biological activity equivalent to the native hormone has not been unequivocally established. Synthesis of bovine or porcine GH is feasible but will be expensive. A partial sequence of GH with 39 amino-acid residues has some biological activity. Synthesis of this shorter peptide would be considerably less expensive. Since proteins generally are not active orally, an economic procedure for prolonged parenteral administration would have to be devised. Althernative approaches would be the stimulation of endogeneous production of GH with hypothalmic GH releasing factor. This factor has not been identified but is probably a small peptide. Agents such as arginine, DOPA, and prostaglandins, which are known to stimulate GH release under some conditions, could also be considered. Another approach would be the implantation of sparganum from the spirometra family (a flatworm). This treatment is known to mimic GH effects in the rat. Implantation of a GH producing tumour could also be considered. Clearly these latter suggestions are quite speculative and would present some obvious problems... | Sparganum |
Both acetic acid and acetate catalyze the isomerization of 5-androstene-3,17-dione (1) to its conjugated isomer, 4-androstene-3,17-dione (3), through a dienol(ate) intermediate. The temperature dependence of the overall isomerization rate constants and of the microscopic rate constants for this isomerization was determined, and the Arrhenius plots give the activation enthalpy and entropy for each step. The source of the activation energy for the overall isomerization and for each of the individual steps is predominantly enthalpic, with a moderate to low entropic penalty. Additionally, the entropy and enthalpy for the keto-enol equilibrium of 1 and dienol were determined; this equilibrium is entirely controlled by enthalpy with no entropic contribution. The relevance of these results to the mechanism of the isomerization of 1 catalyzed by the enzyme 3-oxo-Delta(5)-steroid isomerase is discussed. | Androstenedione |
An account is given of the problem of delivery from breech presentation, with reference being made to an analysis of childbirths over the last 14 years (1965 through 1978). -- Since the rate of premature births from breech presentation was found to be much higher than that generally recordable from vertex presentation, the gap being roughly by factor 4, reference in this paper has been restricted to children with birth weights above 2,500 g, defined as mature" in a WHO recommendation, with the view to establish comparability between the data given in this paper, on the one, hand and the birth record on the basis of vertex presentation, on the other. -- Evidence is provided, by the example of 604 newborns delivered from breech presentation, that their intrapartum and postpartum mortality -- generally referred to as "purified" perinatal mortality, does not differ from figures quoted for comparable cases of vertex presentation. -- Another point made is that the vaginal route of delivery, except for complete extraction, is by no means necessarily inferior to caesarean section. Reduction of perinatal mortality, including morbidity, is considered to depend primarily on adequate labour monitoring. -- Taking into due consideration the considerable increase in maternal mortality and morbidity, the authors feel that the indications followed for termination of labour by caesarean section should be identical with those applicable to vertex presentation. -- The conclusion is drawn that delivery from breech presentation is a problem of premature birth rather than of positional abnormality." | Labor Presentation |
Multicolor fluorescence in situ hybridization (mFISH) approaches are routine applications in tumor as well as clinical cytogenetics nowadays. The first approach when thinking about mFISH is multicolor karyotyping using human whole chromosome paints as probes; this can be achieved by narrow-band filter-based multiplex-FISH (M-FISH) or interferometer/spectroscopy-based spectral karyotyping (SKY). Besides, various FISH-based banding approaches were reported in the literature, including multicolor banding (MCB/mBAND) the latter being evaluated by narrow-band filters, and using specific software. Here, we describe the combined application of multicolor karyotyping and MCB/mBAND for the characterization of simple and complex acquired chromosomal changes in cancer cytogenetics. | Spectral Karyotyping |
BACKGROUND: Allelic loss in chromosome 3p is one of the most frequent and earliest genetic events in lung carcinogenesis. We investigated if the loss of microRNA-128b, a microRNA located on chromosome 3p and a putative regulator of epidermal growth factor receptor (EGFR), correlated with response to targeted EGFR inhibition. Loss of microRNA-128b would be equivalent to losing a tumor suppressor gene because it would allow increased expression of EGFR. PATIENTS AND METHODS: We initially showed that microRNA-128b is a regulator of EGFR in non-small-cell lung cancer (NSCLC) cell lines. We tested microRNA-128b expression levels by quantitative RT-PCR, genomic copy number by quantitative PCR, and mutations in the mature microRNA-128b by sequencing. We determined whether microRNA-128b loss of heterozygosity (LOH) in 58 NSCLC patient samples correlated with response to gefitinib and evaluated EGFR expression and mutation status. RESULTS: We determined that microRNA-128b directly regulates EGFR. MicroRNA-128b LOH was frequent in tumor samples and correlated significantly with clinical response and survival following gefitinib. EGFR expression and mutation status did not correlate with survival outcome. CONCLUSION: Identifying microRNA regulators of oncogenes could have far-reaching implications for lung cancer patients including improving patient selection for targeted agents, development of novel therapeutics, or development as early biomarkers of disease. | Genes, erbB-1 |
Canine distemper outbreak and coinfections in three giant anteaters and in a maned wolf has been described. Three giant anteaters developed respiratory and digestive clinical signs after the introduction of a maned wolf to a Wildlife Rehabilitation Center. The maned wolf and two anteaters died, and one anteater was euthanized. Post mortem and histopathologic exams revealed lesions associated with numerous intraepithelial inclusion bodies, mainly in the respiratory and digestive systems. Infection by distemper virus was confirmed in all animals by RT-PCR and gene sequencing, which revealed the Europe 1/ South America 1 strain, closely related to the strain from Canis familiaris. In addition to distemper, the animals had other comorbidities, such as toxoplasmosis and salmonellosis in the maned wolf and cutaneous candidiasis in an anteater. Considering the chronology of clinical manifestation in both species and the viral characterization, it is possible that the maned wolf was the source of infection to the anteaters. This study demonstrates the importance of implementing biosecurity measures in enclosures that house animals of different species, highlighting the importance of quarantine before introduction of new animals into the same environment. | Distemper |
Background: The benefits of performing open versus laparoscopic gubernaculum-sparing second-stage Fowler-Stephens orchiopexy (FSO) remain unclear. We compared the two techniques to answer this question. Methods: We retrospectively studied a cohort of patients who underwent laparoscopic first-stage FSO and open versus laparoscopic gubernaculum-sparing second-stage FSO at our institution between September 2004 and June 2020 (all patients underwent surgery by a single surgeon). We evaluated both procedures based on the incidence of testicular atrophy, testicular ascent, and other complications. Results: The age at initial surgery was 45.7 +/- 28.2 months (median, 39). One hundred nine cases were treated with open second-stage gubernaculum-sparing FSO (OFSO), and 96 cases were treated with laparoscopic second-stage gubernaculum-sparing FSO (LFSO). The mean follow-up period was 59.8 months (median, 54; standard deviation, +35). The overall testicular atrophy rate was 1.5%. Atrophy was observed in 2 and 1 patient in the OFSO and LFSO groups, respectively (1.8% versus 1.0%, P > .05). There was no significant difference in the incidence of testicular ascent between both groups (2.8% versus 3.1%). Five and four complications were noted in the OFSO and LFSO groups, respectively (P > .05). Conclusions: Second-stage gubernaculum-sparing FSO achieved high testicular survival rates and satisfactory testicular positions. Neither the open nor laparoscopic approach appeared superior, because the overall testicular survival rates and incidence of testicular ascent and other complications were equivalent between both groups. | Gubernaculum |
Metabolism cages are designed to conduct absorption, distribution, metabolism and excretion (ADME) studies, enabling an 'excretion balance' scientific objective to be met. Historically, the design of dog metabolism cages has involved single housing. This type of housing has limitations for normal social behaviours and has been largely unchanged for 25-30 years. Improving animal welfare is a focus area for the authorities as well as the industry throughout the European Union. A collaboration was developed between Novo Nordisk and Covance to enhance the design of metabolism cages, allowing dogs to be pair housed. The purpose of the study was to compare excretion balance data from pair-housed and singly housed dogs in order to demonstrate that conducting excretion balance studies with a pair-housing design improves animal welfare without compromising the scientific integrity of the study. A radiolabelled test compound, [(14)C]-Quetiapine, was selected for this investigation based on its excretion profile. The assessment of the dogs' stress levels was investigated by measuring the levels of serum cortisol as an indicative biomarker. Results were inconclusive due to large variations in cortisol levels. However, dogs appeared calmer in the pair-housing setting. The overall mean recovery (+/-standard deviation) for pair-housed animals (94.0 +/- 0.66% of the dose) was equivalent to that from singly housed dogs (93.0 +/- 2.29%). Based on these data, we conclude that pair housing of dogs for future metabolism ADME studies does not compromise the scientific integrity, and therefore is a major progression in the design of these studies, enhancing welfare. | Drug Elimination Routes |
Fasciola hepatica (liver fluke), a significant threat to food security, causes global economic loss for the livestock industry and is re-emerging as a foodborne disease of humans. In the absence of vaccines, treatment control is by anthelmintics; with only triclabendazole (TCBZ) currently effective against all stages of F. hepatica in livestock and humans. There is widespread resistance to TCBZ and its detoxification by flukes might contribute to the mechanism. However, there is limited phase I capacity in adult parasitic helminths with the phase II detoxification system dominated by the soluble glutathione transferase (GST) superfamily. Previous proteomic studies have demonstrated that the levels of Mu class GST from pooled F. hepatica parasites respond under TCBZ-sulphoxide (TCBZ-SO) challenge during in vitro culture ex-host. We have extended this finding by exploiting a sub-proteomic lead strategy to measure the change in the total soluble GST profile (GST-ome) of individual TCBZ-susceptible F. hepatica on TCBZ-SO-exposure in vitro culture. TCBZ-SO exposure demonstrated differential abundance of FhGST-Mu29 and FhGST-Mu26 following affinity purification using both GSH and S-hexyl GSH affinity. Furthermore, a low or weak affinity matrix interacting Mu class GST (FhGST-Mu5) has been identified and recombinantly expressed and represents a new low-affinity Mu class GST. Low-affinity GST isoforms within the GST-ome was not restricted to FhGST-Mu5 with a second likely low-affinity sigma class GST (FhGST-S2) uncovered. This study represents the most complete Fasciola GST-ome generated to date and has supported the potential of subproteomic analyses on individual adult flukes. | Triclabendazole |
Tamoxifen, a triphenylethylene antiestrogen and one of the first-line endocrine therapies used to treat estrogen receptor-positive breast cancer, has a number of interesting, off-target effects, and among these is the inhibition of sphingolipid metabolism. More specifically, tamoxifen inhibits ceramide glycosylation, and enzymatic step that can adventitiously support the influential tumor-suppressor properties of ceramide, the aliphatic backbone of sphingolipids. Additionally, tamoxifen and metabolites N-desmethyltamoxifen and 4-hydroxytamoxifen, have been shown to inhibit ceramide hydrolysis by the enzyme acid ceramidase. This particular intervention slows ceramide destruction and thereby depresses formation of sphingosine 1-phosphate, a mitogenic sphingolipid with cancer growth-promoting properties. As ceramide-centric therapies are becoming appealing clinical interventions in the treatment of cancer, agents like tamoxifen that can retard the generation of mitogenic sphingolipids and buffer ceramide clearance via inhibition of glycosylation, take on new importance. In this review, we present an abridged, lay introduction to sphingolipid metabolism, briefly chronicle tamoxifen's history in the clinic, examine studies that demonstrate the impact of triphenylethylenes on sphingolipid metabolism in cancer cells, and canvass works relevant to the use of tamoxifen as adjuvant to drive ceramide-centric therapies in cancer treatment. The objective is to inform the readership of what could be a novel, off-label indication of tamoxifen and structurally-related triphenylethylenes, an indication divorced from estrogen receptor status and one with application in drug resistance. | Ceramidases |
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