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Despite improvements in definitive therapy, many patients with gastrointestinal malignancies experience local recurrences or have unresectable disease making subsequent management often challenging and morbid. Although higher doses of radiation may offer improved local control, the ability for dose escalation of external beam radiation therapy is often limited by adjacent radiosensitive structures. Intraoperative radiation therapy allows for additional radiotherapy to be delivered directly to the tumor or areas at highest risk for local recurrence while minimizing toxicity to adjacent structures, offering potentially improved outcomes for patients with unresectable disease or those with a high risk of local recurrence. | Gastrointestinal Neoplasms |
The therapeutic approaches used against scrofula in the 19th Century in Ferrara are discussed. In the manuscripts and treatises of the time treasured in the town's libraries, hygienic and dietetic rules and treatment of this illness were described. In particular, baths and mineral water spas (sulphurous, ferruginous and other mineral waters, such as a bromo-iodine-salt water) and the sea-bathing establishment were recommended. The remedies reported in Campana's Pharmacopoeia ferrarese and the efficacious treatments employed in St Anna Hospital are discussed. The Committee and its President, Marquis Giovanni Manfredini, decided to cure the scrofulous in bathing establishments. | King's Evil |
This study aimed at enhancing alpha-ketoglutaric acid (alpha-KG) production by Yarrowia lipolytica WSH-Z06. Batch culture experiments demonstrated that CaCO(3) and a relatively low pH (3.0) in the alpha-KG production phase contributed to alpha-KG synthesis. Using a two-stage pH control strategy, in which pH was buffered by CaCO(3) in the growth phase and then maintained at 3.0 in the alpha-KG production phase, the yield of alpha-KG reached 53.4 g L(-1). In the later phase of batch fermentation, the glycerol was exhausted but synthesis of alpha-KG did not cease. Therefore, glycerol was fed with an integrated fed-batch mode, and alpha-KG production increased to 66.2 g L(-1) with a productivity of 0.35 g L(-1) h(-1). Compared to optimal batch culture, alpha-KG production and productivity were enhanced by 23.9% and 16.7%, respectively. The two-stage pH control strategy, constant feeding approach and lower pH in later phase would be useful for alpha-KG industrial production. | Ketoglutaric Acids |
BACKGROUND: The mechanisms underlying rupture of a coronary atherosclerotic plaque and development of myocardial ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI) remain unresolved. Increased arginase 1 activity leads to reduced nitric oxide (NO) production and increased formation of reactive oxygen species due to uncoupling of the NO-producing enzyme endothelial NO synthase (eNOS). This contributes to endothelial dysfunction, plaque instability and increased susceptibility to ischemia-reperfusion injury in acute myocardial infarction. OBJECTIVE: The purpose of this study was to test the hypothesis that arginase gene and protein expression are upregulated in patients with STEMI. METHODS: Two cohorts of patients with STEMI were included. In the first cohort (n = 51), expression of arginase and NO-synthases as well as arginase 1 protein levels were determined and compared to a healthy control group (n = 45). In a second cohort (n = 68), plasma arginase 1 levels and infarct size were determined using cardiac magnetic resonance imaging. RESULTS: Expression of the gene encoding arginase 1 was significantly elevated at admission and 24-48 h after STEMI but not 3 months post STEMI, in comparison with the control group. Expression of the genes encoding arginase 2 and endothelial NO synthase (NOS3) were unaltered. Arginase 1 protein levels were elevated at admission, 24 h post STEMI and remained elevated for up to 6 months. No significant correlation between plasma arginase 1 protein levels and infarct size was observed. CONCLUSION: The markedly increased gene and protein expression of arginase 1 already at admission indicates a role of arginase 1 in the development of STEMI. | Arginase |
Male C57BL/6 mice of 12, 19, and 24 months of age received injections of low (25 micrograms 100 g-1 body weight) or high (50 micrograms 100 g-1 body weight) doses of Salmonella typhosa endotoxin and were exposed to ambient temperatures below (24 degrees C) or within (30 degrees C) the thermoneutral zone. Old mice (19 and 24 months) developed initial fevers followed by hypothermia in response to endotoxin challenge at 24 degrees C, irrespective of dose; 12-month-old-mice became hypothermic at 24 degrees C following injection of the high dose of endotoxin only. At 30 degrees C, 12- and 19-month-old mice developed and maintained fever over 4 hr in response to endotoxin compared with the 24-month-old mice who were unable to maintain fevers. Logistic regression analysis showed that age, ambient temperature, and body temperature responses were significant predictors of survival outcome in endotoxin-treated mice; of these, age and ambient temperature had the strongest effects. | Mice, Inbred C57BL |
Intramural pseudodiverticulosis of the esophagus is a rare benign disease of the eosphageal wall, with dilation of the submucosal glands, and the predominant symptom is dysphagia. This disorder may be associated with gastroesophageal reflux, motility disorders, candidiasis and alcoholism. Inflammation, resulting in periductal fibrosis and compression of the duct orifices, may be a causative factor. Good and long-lasting therapeutic success can be achieved by bouginage of the stenosis with concomitant treatment of the associated esophageal diseases. Esophageal intramural pseudodiverticulosis is a differential diagnosis in cases of dyspagia and/or esophageal strictures if no other causes are found. | Diverticulosis, Esophageal |
128 patients with acute myocardial infarction of duration 6 h or less were randomised in double-blind fashion to receive 30 U anistreplase over 5 min or 1.5 MU streptokinase over 1 h, both intravenously. Angiographic patency was assessed 90 min and 24 h from the start of therapy. 55% of patients who received anistreplase and 53% of patients who received streptokinase had patent infarct-related arteries (TIMI grade 2-3) at 90 min (95% CI 42-68% and 40-66%, respectively). At 24 h 81% and 87.5% of arteries were patent respectively (95% CI, 71-91% and 83.5-91.5%). Time to therapy had no significant effect on patency rates. There was one early reocclusion within 24 h in each treatment group and clinical evidence of reocclusion was recorded between 24 h and hospital discharge in a further 5 patients (streptokinase 3, anistreplase 2). With these regimens, therefore, anistreplase and streptokinase gave the same patency rates. | Anistreplase |
The anterior cruciate ligament (ACL) is a dynamic structure composed of distinct bundles that function synergistically to facilitate normal knee kinematics in concert with bony morphology. Characterized by individual uniqueness, the ACL is inherently subject to both anatomic and morphological variations as well as physiologic aging. No locus on the lateral wall of the intercondylar notch is truly isometric through full range of motion, suggesting the ACL is a dynamic structure. Future studies should explore dynamic ACL behavior in vivo. | Skeleton |
This work highlights the use of push-pull hydroxylphenylpolyenylpyridinium fluorophores coupled with trimethyl lock quinone to engineer the ratiometric two-photon probes for cellular and intravital imaging of mitochondrial NAD(P)H:quinone oxidoreductase 1 (NQO1), a critical antioxidant enzyme responsible for detoxifying quinones. As a typical representative, QBMP showed favorable binding with NQO1 with a Michaelis constant of 12.74 muM and exhibited a suite of superior properties, including rapid response (4 min), large Stokes shift (162 nm), ultralow detection limit (0.9 nM), favorable two-photon cross section for the released fluorophore (70.5 GM), and deep tissue penetration (225 mum) in fixed brain tissues. More importantly, this probe was successfully applied for distinguishing different NQO1-expressing cancer and normal cells, revealing decreased NQO1 activity in a cellular Parkinson's disease model, screening NQO1 inducers as neuroprotective agents, and imaging of NQO1 in live mouse brain." | NAD(P)H Dehydrogenase (Quinone) |
Biological molecular machines use thermal activation energy to carry out various functions. The process of thermal activation has the stochastic nature of output events that can be described according to the laws of thermodynamics. Recently developed single molecule detection techniques have allowed each distinct enzymatic event of single biological machines to be characterized providing clues to the underlying thermodynamics. In this study, the thermodynamic properties in the stepping movement of a biological molecular motor have been examined. A single molecule detection technique was used to measure the stepping movements at various loads and temperatures and a range of thermodynamic parameters associated with the production of each forward and backward step including free energy, enthalpy, entropy and characteristic distance were obtained. The results show that an asymmetry in entropy is a primary factor that controls the direction in which the motor will step. The investigation on single molecule thermodynamics has the potential to reveal dynamic properties underlying the mechanisms of how biological molecular machines work. | Molecular Motor Proteins |
BACKGROUND AND AIM: Stump healing is critical to post amputation management. When healing is not optimal, immobility is prolonged and patients risk hospital acquired deconditioning. Two clinical cases with unhealed trans-femoral stump wounds are described. Vacuum assisted closure (VAC) dressing with concurrent prosthetic utilisation was undertaken successfully in both cases. TECHNIQUE: Fitting of the prosthetic socket included space for VAC dressing with modifications to allow the suction piping to exit the prosthesis. With VAC application, timely rehabilitation and mobility was enabled despite incomplete wound healing. DISCUSSION: The two clinical cases described made excellent progress. Discharge home was expedited with the provision of portable VAC pumps. Wounds healed fully without infection. Both patients were able to mobilise sooner than if they had to wait for complete wound closure and, importantly, the consequences of prolonged immobility were minimised. No extra costs were incurred using this novel therapy. CLINICAL RELEVANCE: Guidance for early mobilisation of trans-femoral amputees with open wounds is limited. These cases provide examples utilising VAC dressings with concurrent prosthetic rehabilitation, facilitating prompt ambulatory retraining, minimising deconditioning and optimising outcomes." | Negative-Pressure Wound Therapy |
LncRNAs represent an abundant group of noncoding transcripts, some of which carry out important regulatory functions. To survey the biological and molecular roles of lncRNAs, reliable strategies for their genetic inactivation are required. Several lncRNA features make them challenging to target by genome editing. First, lncRNA loci often span large genomic distances. As such, full or partial deletion alleles are not always easy to generate and interpret as they might affect DNA regulatory elements. Second, in contrast to proteins, lncRNA transcripts are usually resistant to the minimally invasive approach of point substitutions. Third, lncRNA sequences exhibit rapid evolutionary turnover, impeding prediction and targeting of the specific functional sequence elements. Nonetheless, advances in genome editing and comparative genomics have expanded the repertoire of genetic strategies to dissect lncRNA functions in model organisms and cell lines. In this review, we discuss several approaches that have been used to generate lncRNA mutant alleles, focusing on vertebrate lncRNAs. We also briefly highlight comparative genomics approaches to identify conserved lncRNA sequence motifs, which represent attractive target sequences to abrogate lncRNA functions and to pinpoint functional contributions of these elements. | RNA, Long Noncoding |
BACKGROUND: Because the varicella incidence has declined following varicella vaccine licensure, herpes zoster (HZ) cases may play a larger role in varicella zoster virus (VZV) transmission. We investigated how HZ and varicella cases contribute to the varicella incidence in schools and day care centers. METHODS: Surveillance data collected in Philadelphia during September 2003-June 2010 were analyzed. A varicella case was considered to be sporadic if it was reported from a school or day care facility >6 weeks after or >/=10 days before other reports of VZV transmission. A varicella case was considered to be secondary if it occurred 10-21 days after report of a case of HZ or sporadic varicella. Analysis compared VZV transmission from individuals with HZ or sporadic varicella, stratified by varicella vaccination status and disease severity. RESULTS: Of 290 HZ cases reported, 27 (9%) resulted in 84 secondary varicella cases. Of 1358 sporadic varicella cases reported, 205 (15%) resulted in 564 secondary varicella cases. Approximately half of the HZ and sporadic varicella cases resulted in single secondary cases. The proportion of individuals who had secondary cases with mild disease was similar for those exposed to HZ and those exposed to varicella (70% and 72%, respectively). VZV transmission was highest from unvaccinated individuals with sporadic varicella (P < .01). CONCLUSIONS: VZV transmission from individuals with HZ contributes to varicella morbidity. More research is needed to understand risk factors and guide recommendations for preventing VZV transmission from individuals with HZ." | Varicella Zoster Virus Infection |
Pedestrian safety is a serious concern at busy intersections and pedestrian campuses across the nation. Although crosswalks and signs inform pedestrians where to cross, there is no standard protocol for pedestrians to signal drivers that they wish to use the crosswalks, except to stand in or at the crosswalk. We examined the effects of two pedestrian prompts, a raised hand and extended arm, on motorist yielding at uncontrolled crosswalks. The two prompts were effective at increasing yielding. | Accidents, Traffic |
An increasing number of media reports on patient safety risks arising from office-based surgery procedures, as well as growing concerns about patient safety issues in general, have brought office-based surgery as well as its practitioners into focus and placed this very cost-effective medical practice in the eye of the media and regulators. Concerted efforts are now being made to understand the causes and true incidence of patient safety risk associated with office-based surgery and to find ways to minimize this risk. | Lipectomy |
The organization of genomic DNA into nucleosomes profoundly affects all DNA-related processes in eukaryotes. The histone chaperone known as 'facilitates chromatin transcription' (FACT(1)) (consisting of subunits SPT16 and SSRP1) promotes both disassembly and reassembly of nucleosomes during gene transcription, DNA replication and DNA repair(2). However, the mechanism by which FACT causes these opposing outcomes is unknown. Here we report two cryo-electron-microscopic structures of human FACT in complex with partially assembled subnucleosomes, with supporting biochemical and hydrogen-deuterium exchange data. We find that FACT is engaged in extensive interactions with nucleosomal DNA and all histone variants. The large DNA-binding surface on FACT appears to be protected by the carboxy-terminal domains of both of its subunits, and this inhibition is released by interaction with H2A-H2B, allowing FACT-H2A-H2B to dock onto a complex containing DNA and histones H3 and H4 (ref. (3)). SPT16 binds nucleosomal DNA and tethers H2A-H2B through its carboxy-terminal domain by acting as a placeholder for DNA. SSRP1 also contributes to DNA binding, and can assume two conformations, depending on whether a second H2A-H2B dimer is present. Our data suggest a compelling mechanism for how FACT maintains chromatin integrity during polymerase passage, by facilitating removal of the H2A-H2B dimer, stabilizing intermediate subnucleosomal states and promoting nucleosome reassembly. Our findings reconcile discrepancies regarding the many roles of FACT and underscore the dynamic interactions between histone chaperones and nucleosomes." | Transcriptional Elongation Factors |
Bone loss in the oral cavity may occur due to many causes, including infection, systemic or local alterations in the host response, or multifactorial causes. The purpose of this article is to review our present understanding of the major causes of oral bone loss in adults, with special emphasis on two major oral diseases: periodontitis and residual ridge resorption. Periodontitis is characterized by resorption of the alveolar bone as well as loss of the soft tissue attachment to the tooth. Progressive periodontitis will result in continued alveolar bone loss and may result in tooth mobility, abscesses, and ultimately tooth loss. Although the reported prevalence may vary according to the epidemiologic study design, the 1985 National Survey of Oral Health of United States Adults indicated that 94% of female senior citizens examined demonstrated at least one site with at least 2 mm loss of attachment. Resorption of alveolar bone that occurs following tooth extraction is termed residual ridge resorption. In many cases, the denture will loosen because of the inability of the resorbed ridge to stabilize the prosthesis. In the most severe cases, the denture may impinge on the exposed mandibular nerve, resulting in pain or total inability to tolerate the prostheses. Although clear statistics on the prevalence of residual ridge resorption are not available, this boss loss may result in the need for new dentures to replace ill-fitting prostheses. | Periodontal Atrophy |
The most common arrhythmia requiring drug treatment is atrial fibrillation (AF), which affects 2 to 5 million Americans and continues to be a major cause of morbidity and increased mortality. Despite recent advances in catheter-based and surgical therapies, antiarrhythmic drugs continue to be the mainstay of therapy for most patients with symptomatic AF. However, many antiarrhythmics block the rapid component of the cardiac delayed rectifier potassium current (IKr) as a major mechanism of action, and marked QT prolongation and pause-dependent polymorphic ventricular tachycardia (torsades de pointes) are major class toxicities. | Potassium Channel Blockers |
Idiopathic Parkinson's disease is the second most common neurodegenerative disease and is estimated to be approximately 30% heritable. Genome wide association studies have revealed numerous loci associated with risk of development of Parkinson's disease. The majority of genes identified in these studies are expressed in glia at either similar or greater levels than their expression in neurons, suggesting that glia may play a role in Parkinson's disease pathogenesis. The role of individual glial risk genes in Parkinson's disease development or progression is unknown, however. We hypothesized that some Parkinson's disease risk genes exert their effects through glia. We developed a Drosophila model of alpha-synucleinopathy in which we can independently manipulate gene expression in neurons and glia. Human wild type alpha-synuclein is expressed in all neurons, and these flies develop the hallmarks of Parkinson's disease, including motor impairment, death of dopaminergic and other neurons, and alpha-synuclein aggregation. In these flies, we performed a candidate genetic screen, using RNAi to knockdown 14 well-validated Parkinson's disease risk genes in glia and measuring the effect on locomotion in order to identify glial modifiers of the alpha-synuclein phenotype. We identified 4 modifiers: aux, Lrrk, Ric, and Vps13, orthologs of the human genes GAK, LRRK2, RIT2, and VPS13C, respectively. Knockdown of each gene exacerbated neurodegeneration as measured by total and dopaminergic neuron loss. Knockdown of each modifier also increased alpha-synuclein oligomerization. These results suggest that some Parkinson's disease risk genes exert their effects in glia and that glia can influence neuronal alpha-synuclein proteostasis in a non-cell-autonomous fashion. Further, this study provides proof of concept that our novel Drosophila alpha-synucleinopathy model can be used to study glial modifier genes, paving the way for future large unbiased screens to identify novel glial risk factors that contribute to PD risk and progression. | Auxilins |
Bdellovibrio and like organisms are abundant environmental parasitoids of prokaryotes that show diverse predation strategies. The vast majority of studied Bdellovibrio bacteria and like organisms deploy intraperiplasmic replication inside the prey cell, while few isolates with smaller genomes consume their prey from the outside in an epibiotic manner. The novel parasitoid Candidatus Bdellovibrio qaytius" was isolated from a eutrophic freshwater pond in British Columbia, where it was a continual part of the microbial community. "Ca Bdellovibrio qaytius" was found to preferentially prey on the betaproteobacterium Paraburkholderia fungorum without entering the periplasm. Despite its epibiotic replication strategy, "Ca Bdellovibrio" encodes a large genomic complement more similar to that of complex periplasmic predators. Functional genomic annotation further revealed several biosynthesis pathways not previously found in epibiotic predators, indicating that "Ca Bdellovibrio" represents an intermediate phenotype and at the same time narrowing down the genomic complement specific to epibiotic predators. In phylogenetic analysis, "Ca Bdellovibrio qaytius" occupies a widely distributed, but poorly characterized, basal cluster within the genus Bdellovibrio This suggests that epibiotic predation might be a common predation type in nature and that epibiotic predation could be the ancestral predation type in the genus.IMPORTANCEBdellovibrio and like organisms are bacteria that prey on other bacteria and are widespread in the environment. Most of the known Bdellovibrio species enter the space between the inner and outer prey membrane, where they consume their prey cells. However, one Bdellovibrio species has been described that consumes its prey from the outside. Here, we describe "Ca Bdellovibrio qaytius," a novel member of the genus Bdellovibrio that also remains outside the prey cell throughout its replication cycle. Unexpectedly, the genome of "Ca Bdellovibrio" is much more similar to the genomes of intracellular predators than to the species with a similar life cycle. Since "Ca Bdellovibrio" is also a basal representative of this genus, we hypothesize that extracellular predation could be the ancestral predation strategy." | Bdellovibrio |
The genomes of all retroviruses contain sequences near their 5' ends that interact with the nucleocapsid domains (NC) of assembling Gag proteins and direct their packaging into virus particles. Retroviral packaging signals often occur in non-contiguous segments spanning several hundred nucleotides of the RNA genome, confounding structural and mechanistic studies of genome packaging. Recently, a relatively short, 82 nucleotide region of the Rous sarcoma virus (RSV) genome, called muPsi, was shown to be sufficient to direct efficient packaging of heterologous RNAs into RSV-like particles. We have developed a method for the preparation and purification of large quantities of recombinant RSV NC protein, and have studied its interactions with native and mutant forms of the muPsi encapsidation element. NC does not bind with significant affinity to truncated forms of muPsi, consistent with earlier packaging and mutagenesis studies. Surprisingly, NC binds to the native muPsi RNA with affinity that is approximately 100 times greater than that observed for other previously characterized retroviral NC-RNA complexes (extrapolated dissociation constant K(d)=1.9 nM). Tight binding with 1:1 NC-muPsi stoichiometry is dependent on a conserved UGCG tetraloop in one of three predicted stem loops, and an AUG initiation codon controvertibly implicated in genome packaging and translational control. Loop nucleotides of other stem loops do not contribute to NC binding. Our findings indicate that the structural determinants of RSV genome recognition and NC-RNA binding differ considerably from those observed for other retroviruses. | Nucleocapsid Proteins |
This symposium focuses on exertional heatstroke, with emphasis on predisposing factors, clinical observations, diagnosis, treatment and recovery. The serious challenge to cardiovascular stability presented by exercise hyperthermia and some aspects of regulatory failure was reviewed in the introduction. The intent of this review, to understand how heat stress is translated into heat strain at the cellular level, is not to downplay the seriousness of the systemic condition. If we are successful, this may stimulate further interest on the impact of heat on the cell as a model for other factors which alter membrane integrity and permeability, lead to new experimental paradigms, and improve the diagnosis and treatment of other disorders such as toxic, hypovolemic, or ischemic shock. This review may also stimulate interesting research regarding more subtle threats to homeostasis such as chronic exercise, hypohydration and thirst, ion imbalance, and sleep deprivation. Since the original article on heat stroke pathophysiology was published (39), we have discussed the relationship of this concept to carbohydrate metabolism (40), thirst (41), and the cellular aspects of heat illness treatment (99). This article will attempt to integrate and extend some of those ideas. | Heat Exhaustion |
BACKGROUND: For a significant subset of agricultural products, including coffee, wine and tea, sensory perceptions of terroir (i.e., characteristic flavors imparted by the growing environment) are tightly linked to the product's value. With increasing climate change, it is critical to understand how shifts in climate, such as changes in precipitation, may interact with management practices (e.g., cultivar selection) to impact sensory quality in terroir-driven crops, and what biochemical compounds may be associated with those impacts. Here, sensory quality and volatile profile composition were assessed for four Arabica coffee (Coffea arabica) cultivars grown in a field experiment where precipitation was reduced by rainout shelters, resulting in 14% lower soil moisture on average. RESULTS: Our results indicate an overall increase in yield coincident with a moderate decrease in sensory quality in response to reduced precipitation. The presence and magnitude of the sensory quality shift varied by cultivar and sensory attribute, though the Acidity attribute was consistently negatively impacted across cultivars, albeit with a high degree of uncertainty. Additionally, 31 volatile compounds were identified across green coffee samples that were variably impacted by reduced precipitation. Hierarchical clustering analysis identified patterns in volatile clustering associated with sensory attributes suggesting that reduced precipitation effects on sensory attributes may depend on nonlinear combinations of secondary metabolites. CONCLUSION: Ultimately, our results advance efforts to improve predictions of climate impacts on coffee-growing landscapes and communities and highlight the value of considering indicators of harvest value beyond yield to improve economic forecasts for agroecosystems under climate change. | Coffee |
Site-directed spin labeling has become a popular biophysical tool for the characterization of protein structure, dynamics and conformational change. This method is well suited and widely used to study small soluble proteins, membrane proteins and large protein complexes. Recent advances in site-directed spin labeling methodology have occurred in two areas. The first involves an understanding of the conformations and local dynamics of the spin-labeled sidechain, including the features of proteins that influence electron paramagnetic resonance lineshape. The second advance is the application of pulse techniques to determine long-range distances and distance distributions in proteins. During the past two years, these technical developments have been used to address several important problems concerning the molecular function of proteins. | Spin Trapping |
A fluorometric assay avoiding the use of radioactivity has been developed for detecting cytotoxic T lymphocytes (Tc cells). The method involves labelling targets with Hoechst dye no. 33342 (H33342) which becomes brightly fluorescent on binding to DNA. Lysis of target cells by Tc cells is quantified by measuring the release of fluorescent H33342 into the supernatant of culture wells. The fluorescence is measured using an automated Microfluor reader which allows results to be obtained rapidly. The assay has been used to detect alloreactive Tc cells and H-2 restricted Tc cells against influenza virus in a short-term 6 h assay using P815 and L929 as targets with comparable results to those obtained with 51Cr labelling. In contrast, lymphocyte blasts were found to be less sensitive in 6 h fluorometric assays when compared with the 51Cr assay. In long-term overnight assays (possible because of the low spontaneous release of H33342 from targets) lymphocyte blasts gave high specific lysis and some anti-self reactivity. The cause of the anti-self reactivity may reflect fundamental differences between the H33342 and 51Cr release assays." | Cytotoxicity Tests, Immunologic |
Toxoplasma gondii is a ubiquitous, obligate intracellular protozoan parasite in human and animals. Chronic infection with this parasite is likely one of the most common infection in human. Following invasion of host cells T gondii resides within membrane-bound vacuoles known as parasitophorous vacuole (PV), which can protect the parasite from the endosomal acidification and lysosomal fusion of host cells. It plays an essential role in the whole parasitic process of T. gondii. This review summarizes the mechanism of PV formation and its function in the host cells. | Eimeriida |
Biodegradation of glyphosate in sod-podzol soil by both the indigenous micro flora and the introduced strain Ochrobactrum anthropi GPK 3 was studied with respect to its sorption and mobility. The experiments were carried out in columns simulating the vertical soil profile. Soil samples studied were taken from soil horizons 0-10, 10-20, and 20-30 cm deep. It was found out that the most of the herbicide (up to 84%) was adsorbed by soil during the first 24 h; the rest (16%) remained in the soluble fraction. The adsorbed glyphosate was completely extractable by alkali. No irreversible binding of glyphosate was observed. By the end of the experiment (21st day), glyphosate was only found in extractable fractions. The comparison of the effect of the introduced O. anthropi GPK 3 and indigenous microbial community on the total toxicant content (both soluble and absorbed) in the upper 10 cm soil layer showed its reduction by 42% (21 mg/kg soil) and 10-12% (5 mg/kg soil), respectively. Simultaneously, 14-18% glyphosate moved to a lower 10-20 cm layer. Watering (that simulated rainfall) resulted in a 20% increase of its content at this depth; 6-8% of herbicide was further washed down to the 20-30 cm layer. The glyphosate mobility down the soil profile reduced its density in the upper layer, where it was available for biodegradation, and resulted in its concentration in lower horizons characterized by the absence (or low level) of biodegradative processes. It was shown for the first time how the herbicide biodegradation in soil can be increased manifold by introduction of the selected strain O. anthropi GPK 3. | Ochrobactrum anthropi |
11 patients (9m, 2f, median age 59 years) with ventricular ectopic activity of at least Lown grade III received 20 mg N-Propyl-ajmaline-bitartrate (N-PAB) p.o. Plasma concentrations of N-PAB were determined with HPLC from blood samples within 26 hours after administration. An open two-compartment model was used. In 8 patients with normal function of the liver and the kidneys, the median clearance of N-PAB was 6.86 ml/min/kg and the median volume of distribution was 1.56 l/kg. Two patients had a clearly diminished clearance of 1.58 ml/min/kg without obvious impairment of liver or renal function. One patient with chronic glomerulonephritis (plasma creatinine 3.4 mg/dl) had a N-PAB clearance of 2.79 ml/min/kg. None of the Spearman rank correlation coefficients between the pharmacokinetic parameters of N-PAB with age, plasma albumin/globulin-quotient, plasma creatinine and cholin-esterase were significant. All calculated parameters were in the range determined in young subjects. It is concluded that physiological changes with age do not lead to significant changes of the pharmacokinetics of N-PAB. On the other hand in patients with increased levels of plasma creatinine a diminished clearance of N-PAB can be expected. It is also possible that patients without an obvious impairment of liver or renal function may have diminished N-PAB clearance. | Prajmaline |
n-Pentyl ether of damavaricin Fc (n-pentyl DvFc) preferentially killed human T-cell lymphotropic virus type I (HTLV-I)-transformed cell lines. The mechanism of action of the drug was investigated using MT-4 cells. Cytotoxic action was diminished by the removal of n-pentyl DvFc from the culture or by the addition of sulfhydryl compounds such as 2-mercaptoethanol and dithiothreitol. The killing activity of n-pentyl DvFc was also diminished by membrane-acting agents including quinidine and diphenylhydantoin. Influx and subsequent efflux of Ca2+ were observed when either HTLV-I infected (MT-4 cells) or uninfected cells were treated with n-pentyl DvFc. An efflux of K+ was observed in HTLV-I infected MT-4 cells immediately after the exposure of the cells to n-pentyl DvFc. The K+ efflux, however, was not observed in the uninfected T cells. n-Pentyl DvFc seems to act primarily on the cell surface of MT-4 cells, leading to the perturbation of membrane function. The restoration of cell growth, however, is critically dependent on the presence of dithiothreitol and 2-mercaptoethanol, implying a role for a free sulfhydryl group in the killing activity. | Streptovaricin |
After increasing for nearly two decades, rates of neonatal abstinence syndrome have recently leveled off, reaching a plateau as early as 2014. These findings may represent successful efforts to prevent and treat opioid use before and during pregnancy. | Neonatal Abstinence Syndrome |
PURPOSE OF REVIEW: Invasive pulmonary aspergillosis (IPA) can affect patients with severe coronavirus disease 2019 (COVID-19), but many questions remain open about its very variable incidence across the world, the actual link between the viral infection and the fungal superinfection, the significance of Aspergillus recovery in a respiratory sample, and the management of such cases. This review addresses these questions and aims at providing some clues for the practical diagnostic and therapeutic approaches of COVID-19-associated pulmonary aspergillosis (CAPA) in a clinical perspective. RECENT FINDINGS: Definitions have been proposed for possible/probable/proven CAPA, but distinction between colonization and invasive fungal infection is difficult and not possible in most cases in the absence of histopathological proof or positive galactomannan in serum. Most importantly, the recovery of an Aspergillus by a direct (culture, PCR) or indirect (galactomannan) test in a respiratory sample is an indicator of worse outcome, which justifies a screening for early detection and initiation of preemptive antifungal therapy in such cases. SUMMARY: The COVID-19 pandemic has increased our awareness of IPA among ICU patients. Although current recommendations are mainly based on experts' opinions, prospective studies are needed to get more evidence-based support for the diagnostic approach and management of CAPA." | Invasive Pulmonary Aspergillosis |
Office of Management and Budget (OMB) Circular A-110 provides standards for obtaining consistency and uniformity among Federal agencies in the administration of grants and agreements with institutions of higher education, hospitals, and other non-profit organizations. On September 13, 1994, the Department published a final rule which adopted the revised circular as it pertains to HUD. However, the September 13, 1994 rule contained, in subpart E, special provisions relating to the use of lump sum grants. Therefore, subpart E was treated as an interim rule, and the public was invited to submit comments on subpart E. This final rule addresses the public comments received on subpart E and makes final the provisions of subpart E. | Organizations, Nonprofit |
BACKGROUND: Rhythm disruption is a core feature of bipolar disorder and it has been hypothesized that disturbances of the circadian timing system play a fundamental role in the etiology of the disorder. OBJECTIVE: We sought to investigate (1) theoretical models for biological rhythm disruptions in bipolar disorder, (2) physiological disturbances of biological rhythms in bipolar disorder, (3) clinical and therapeutic implications of biological rhythm disturbances in bipolar disorder, and (4) associations between circadian gene variations and bipolar disorder. DATA SOURCES: PubMed database was searched systematically for articles that were published on or before May 5, 2013, and were written in English using the terms bipolar disorder, clock genes, endogenous clock, molecular clock, biological rhythms, circadian, suprachiasmatic nucleus, circadian rhythm, melatonin, and sleep. STUDY SELECTION: Seventy-four articles highlighting the objectives were included in the review. DATA EXTRACTION: Data regarding exploring the association between bipolar disorder and circadian and chronobiological phenomena were reviewed and findings summarized. RESULTS: The literature reviewed suggests that circadian rhythm disturbance may be a feature of bipolar disorder. CONCLUSIONS: In toto, the literature suggests that circadian rhythm disturbances may be a feature of bipolar disorder. This area of research has received theoretical consideration as playing a significant role in the pathophysiology of the illness but has been understudied to this point. Further research in the field is warranted. | Chronobiology Disorders |
Like many other schools, the faculty of the University of Oklahoma College of Nursing (OUCN) recently revised its baccalaureate and master's curricula to prepare students better for the evolving changes in the nursing profession and the health care job market. Our personal visions of needed changes, reviews of the literature, and feedback from nursing leaders and community employers supported the need for four significant changes. First, students needed more experiences in the community and clients' homes, with the aged, the chronically ill, and the disabled in all age brackets. Second, students needed greater familiarity with Medicare, Medicaid, and managed care, and more active involvement in the wise use of limited resources. Third, they needed more experience with interdisciplinary teams and with the management of care across sites and levels of acuity. Fourth, there was a need for more consistent integration of health promotion and research content into student learning related to emerging trends in health care and nursing practice. | Nursing Faculty Practice |
Initiation of transcription is the first step in gene expression and a major point of regulation. Recent structural studies reveal the nature of the initiating complex and suggest new ways of accomplishing the processes required for initiation. | Transcription Initiation Site |
Transgenerational inheritance requires mechanisms by which epigenetic information is transferred via gametes. Canonical thought holds that mammalian sperm chromatin would be incapable of carrying epigenetic information as post-translational modifications of histones because of their replacement with protamine proteins. Furthermore, compaction of the sperm genome would hinder DNA accessibility of proteins involved in transcriptional regulation and genome architecture. In this Minireview, we delineate the paternal chromatin remodeling events during spermatogenesis and fertilization. Sperm chromatin is epigenetically modified at various time points throughout its development. This allows for the addition of environment-specific modifications that can be passed from parents to offspring. | Paternal Inheritance |
A substantial proportion of fractures can present with nonunion, and the management of nonunion continues to present a challenge for orthopaedic surgeons. A variety of biological, mechanical, patient, and injury factors can contribute to the occurrence of nonunion, and often the cause of nonunion may be multifactorial. Successful management often requires assessment and treatment of more than one of these factors. This article reviews common factors that may contribute to nonunion including infection, impaired biology, and metabolic disorders. In addition, new and evolving strategies for diagnosing the cause and effectively treating nonunion including the diagnosis of infection, metabolic workup, bone grafting, cell-based therapies, and biological adjuvants are reviewed and discussed. | Fractures, Ununited |
At the Surgical Department of the University of Cologne, a system has been developed for transanal endoscopic surgery, which allows all the conventional surgical techniques within the rectal cavity. The clinical and long-term results regarding local excision of broad based adenomas and small (< 4 cm) carcinomas of the rectum were the subject of the study. The main indication was the removal of sessile adenomas. Early rectal carcinomas with favourable histological grading (Grade 1 and 2) and staging (Mason I and II) were also suitable for endorectal therapeutical approach. Infiltrative cancers can be removed endoscopically in one session, but the authors performed local excisions of these cancers only in cases where the patient was unwilling to undergo extensive surgery or due to medical reasons. Nevertheless several Dukes B carcinomas were removed locally. Most of the histological findings of the subsequent radical operations (rectum resection, rectum extirpation) revealed that the carcinoma had already been totally removed. During the period July 1983 to December 1992, the techniques have been employed on 313 patients in 348 cases. Early postoperative complications consisted of intraperitoneal perforations (five cases); rectovaginal fistulae (four cases); haemorrhages (four cases), death due to cardiopulmonary failure (two cases). All the complications occurred within the first three years of the learning phase. The recurrence rate of adenomas amounted to 5%. The technique allows accurate endoscopic microsurgical excision of giant adenomas and early cancers with minimal morbidity and excellent presentation of specimens for complete histological analysis. Open invasive surgery can thus be avoided. | Proctoscopes |
Laryngopharyngeal reflux (LPR) occurs when gastric contents pass the upper esophageal sphincter, causing symptoms such as hoarseness, sore throat, coughing, excess throat mucus, and globus. The pattern of reflux is different in LPR and gastroesophageal reflux. LPR usually occurs during the daytime in the upright position whereas gastroesophageal reflux disease more often occurs in the supine position at night-time or during sleep. Ambulatory 24-h double pH-probe monitoring is the gold standard diagnostic tool for LPR. Acid suppression with proton pump inhibitor on a long-term basis is the mainstay of treatment. Helicobacter pylori (H. pylori) is found in many sites including laryngeal mucosa and interarytenoid region. In this paper, we aim to present the relationship between LPR and H. pylori and review the current literature. | Laryngopharyngeal Reflux |
Frequency of the 4-bp deletion mutant in canine mdr1 gene was examined in 193 dogs of eight breeds in Japan. The mutant allele was found in Collies, Australian Shepherds, and Shetland Sheepdogs, where its respective frequencies were 58.3%, 33.3%, and 1.2%. The MDR1 protein was detected on peripheral blood mononuclear cells (PBMC) from a MDR1/MDR1 dog, but not on PBMC from a mdr1-1Delta/mdr1-1Delta Collie. Rhodamine 123 was extruded from MDR1/MDR1 lymphocytes. That excretion was inhibited by a MDR1 inhibitor, verapamil. On the other hand, Rh123 excretion was not observed from lymphocytes derived from a mdr1-1Delta/mdr1-1Delta Collie. These results indicated that the mutant mdr1 allele also existed in Collie-breed dogs in Japan at high rates and that mdr1-1Delta /mdr1-1Delta dogs have no functional MDR1. | Genes, MDR |
Entomotoxicology allows the detection and analysis of substances such as poisons, drugs, and metals in necrophagous insects using analytical protocols. In a forensic situation related to death by gunshot, the gunshot residue (GSR) is dispersed at the crime scene and may be consumed by necrophagous insects. Lead (Pb) is the most abundant metal in GSR samples and it can be determined using non-portable methods. However, the toxicity effects of GSR samples on Lucilia cuprina (Diptera: Calliphoridae) and the detection of Pb via portable electrochemical methods have not been investigated. This study describes for the first time the toxicity analysis of Pb on immature L. cuprina through their survival rate and influence of Pb on immature development. In addition, the bioaccumulation of Pb in the larvae samples was determined based on square wave anodic stripping voltammetry (SWASV) measurements. The results revealed a low limit of detection to Pb (6.5 mug L(-1)) and the analytical performance was satisfactory because it measures Pb levels in larvae exposed to a diet containing 50 mug Pb g(-1). Furthermore, the levels of Pb influenced the survival rate and development time of the immature L. cuprina. Larvae exposed to a high concentration of the metal (50 mug Pb g (-1)) showed statistically significant changes (p < 0.05). The presence of Pb in immature L. cuprina can be used to estimate the post-mortem interval; thus, the present study provides important information in forensic entomology. | Calliphoridae |
The trade-off between a machine learning (ML) and deep learning (DL) model's predictability and its interpretability has been a rising concern in central nervous system-related quantitative structure-activity relationship (CNS-QSAR) analysis. Many state-of-the-art predictive modeling failed to provide structural insights due to their black box-like nature. Lack of interpretability and further to provide easy simple rules would be challenging for CNS-QSAR models. To address these issues, we develop a protocol to combine the power of ML and DL to generate a set of simple rules that are easy to interpret with high prediction power. A data set of 940 market drugs (315 CNS-active, 625 CNS-inactive) with support vector machine and graph convolutional network algorithms were used. Individual ML/DL modeling methods were also constructed for comparison. The performance of these models was evaluated using an additional external dataset of 117 market drugs (42 CNS-active, 75 CNS-inactive). Fingerprint-split validation was adopted to ensure model stringency and generalizability. The resulting novel hybrid ensemble model outperformed other constituent traditional QSAR models with an accuracy of 0.96 and an F1 score of 0.95. With the power of the interpretability provided with this protocol, our model laid down a set of simple physicochemical rules to determine whether a compound can be a CNS drug using six sub-structural features. These rules displayed higher classification ability than classical guidelines, with higher specificity and more mechanistic insights than just for blood-brain barrier permeability. This hybrid protocol can potentially be used for other drug property predictions. | Machine Learning |
A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, an H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabolites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically. We conducted a randomized crossover study in 11 healthy subjects to characterize the involvement of CYP2C8 in desloratadine metabolism and to compare the CYP2C8 inhibitory strength of clopidogrel (300 and 75 mg on two following days) with that of gemfibrozil (600 mg BID for 5 days). Compared with placebo (control), clopidogrel increased the area under the plasma concentration-time curve (AUC(0-infinity)) and peak plasma concentration (C (max)) of desloratadine to 280% (P = 3 x 10(-7)) and 165% (P = 0.0006), respectively. The corresponding increases by gemfibrozil were to 462% (P = 4 x 10(-7)) and 174% (P = 0.0006). Compared with placebo, clopidogrel and gemfibrozil decreased 3-hydroxyloratadine AUC(0-71h) to 52% (P = 5 x 10(-5)) and 6% (P = 2 x 10(-8)), respectively. Moreover, the 3-hydroxydesloratadine:desloratadine AUC(0-71 h) ratios were 21% (P = 7 x 10(-10)) and 1.7% (P = 8 x 10(-11)) of control during the clopidogrel and gemfibrozil phases. Our results confirm that CYP2C8 plays a critical role in the formation of 3-hydroxydesloratadine in humans, making desloratadine a potential CYP2C8 probe substrate. Furthermore, the findings corroborate the previous estimates that clinically relevant doses of clopidogrel cause strong CYP2C8 inhibition, whereas those of gemfibrozil almost completely inactivate the enzyme in humans." | Cytochrome P-450 CYP2C8 Inhibitors |
Cytoplasmic polyadenylation element binding protein 1 (CPEB1) regulates the translation of numerous mRNAs. We previously showed that AU-rich binding factor 1 (AUF1) regulates Cpeb1 expression through the 3' untranslated region (3'UTR). To investigate the molecular basis of the regulatory potential of the Cpeb1 3'UTR, here we performed reporter analyses that examined expression levels of Gfp reporter mRNA containing the Cpeb1 3'UTR. Our findings indicate that CPEB1 represses the translation of Cpeb1 mRNA and that miR-145a-5p and let-7b-5p are involved in the reduction in Cpeb1 expression in the absence of AUF1. These results suggest that Cpeb1 expression is post-transcriptionally regulated by AUF1, CPEB1, and microRNAs. | 3' Untranslated Regions |
The effect of colchicine, Nocodazole, and dibucaine on the assembly of Semliki Forest virus was investigated. Colchicine, Nocodazole, and dibucaine reduced the production of extracellular virus by 75 to 90%. Lumicolchicine had no effect on virus growth. Other control experiments showed no effect by these drugs on the incorporation of [3H]leucine into material precipitated by trichloroacetic acid. Colchicine (100 micron) disrupted the microtubles of the baby hamster kidney cells (BHK-21), whereas dibucaine did not alter microtubule polymerization. The stage of virus assembly inhibited by colchicine and dibucaine was studied by experiments with [3H]-leucine or [35S]methionine. At various times after addition of one of these drugs, the incorporation of the labeled precursors into viral proteins associated with fractions enriched for endoplasmic reticulum or plasma membrane from the cell was evaluated. The results clearly show that the envelope and nucleocapsid proteins of the virus move to the plasma membrane of the cell where they accumulate. The studies strongly suggest that the cytoskeletal system is involved in the final stages of morphogenesis of Semliki Forest virus from the plasma membrane. | Dibucaine |
Dysregulation in the gamma motoneuron circuitry is proposed as one mechanism to explain the development of trigger point activity in myofascial pain syndrome. Dysregulation in this context is defined operationally as significantly (and functionally) different levels of electrical activity detected in the same muscle on the left and right sides of the body that is persistently present with movement of that muscle. Neurophysiological concepts as they pertain to muscles and motor control principles are reviewed. Research is integrated that ties together material from diverse fields of psychology and medicine. Dysregulation in the gamma motoneuron circuitry may lead to disinhibition of muscle that causes it to remain hyperactive after contraction, generate excessive electrical activity during movement, and/or inappropriately coactivate with other muscles during movement. Any or all of these phenomena may occur with dysregulation. Such dysregulation may be corrected by learning. Immediate clinical implications are discussed, including the addition of specifically targeted neuromuscular retraining procedures via surface electromyography, as well as some conceptual and research issues that require further clarification. | Motor Neurons, Gamma |
BACKGROUND: Although complications such as blister formation, erosion, and post-inflammatory hypo- and hyperpigmentation are well-known side effects of intense pulsed light (IPL) photoepilation, little is known about the paradoxical hypertrichosis after therapy. OBJECTIVE: To report the paradoxically increased hair density and coarseness after IPL photoepilation. METHODS: Within a period of 23 months, a total of 991 hirsute female patients were treated with IPL for photoepilation. The IPL system used was the Vasculight-SR, a multifunctional laser and IPL system (Lumenis Inc., Santa Clara, CA, USA). The cut-off filters frequently used were 695, 755 and 645 nm. RESULTS: Paradoxical hypertrichosis and terminal hair change were detected after a few sessions of IPL therapy among 51 out of 991 patients. Our serial digital photographs, schematic diagrams, and hair counts before and after treatment confirmed the patients' claims. The other more commonly seen complications were epidermal burning with blisters, erosion, and crust formation followed by post-inflammatory hypo- and/or hyperpigmentation. CONCLUSION: Paradoxical hypertrichosis and terminal hair change is a common complication of IPL photoepilation. | Hypertrichosis |
The southern white-cheeked gibbon Nomascus siki is endemic to Indochina and is classified as critically endangered on the International Union for Conservation of Nature (IUCN) Red List. The most updated information on the status of this species dates back to a decade ago. As hunting has tremendous impacts on wildlife in Southeast Asia, the population of N. siki might have changed a lot in the last decade. Updated information on the status and potential distribution of this species is critically important for conservation and prioritization, especially for N. siki because of its undefined distribution range. The goal of this study was to review the population status of N. siki in Vietnam and Lao People's Democratic Republic (PDR) and to model its potential distribution. In Vietnam, this species has been intensively surveyed in all major areas of occurrence from 2016 to 2021. The total number of N. siki groups recorded and estimated in Vietnam were 324 and 483, respectively. In Lao PDR, the occurrence of N. siki has been confirmed in Nam Kading, Nakai Nam Theun, Hin Nam No, and Phou Hinpoun national protected areas. However, population estimates are generally lacking. The suitable habitat of N. siki was predicted from about 105.00 degrees to 106.80 degrees E longitude and from about 16.60 degrees to 17.90 degrees N latitude located in Quang Binh and Quang Tri provinces (Vietnam), and Khammounan and Savannakhet provinces (Lao PDR). The area of the potential distribution range is about 9894.15 km(2), both in Vietnam and Lao PDR. Particularly, the high, medium, and low suitable habitats were estimated at around 1229.58 km(2), 3019.68 km(2), and 5644.89 km(2), respectively. The area of suitable habitat of N. siki in Vietnam was predicted to be 4151.25 km(2), of which only 1257.93 km(2) (30.30%) is in the protected area network. Dong Chau-Khe Nuoc Trong and Bac Huong Hoa Nature Reserves, and Phong Nha-Ke Bang National Park should receive priority for conservation of N. siki in Vietnam. Improving conservation beyond the protected areas' boundaries or transforming the forest enterprises and watershed protection forests into protected areas should also be considered as an alternative for the conservation of N. siki. In Lao PDR, surveys of the species in its entire distribution range should be the first priority. | Hylobatidae |
Bullous Pemphigoid (BP) is an inflammatory rare autoimmune bullous dermatosis, which outcome cannot be predicted through clinical investigations. Eosinophils are the main immune infiltrated cells in BP. However, the release of Major Basic Protein (MBP), Eosinophil Derived Neurotoxin (EDN), and Eosinophil Cationic Protein (ECP) upon eosinophil activation has still not been evaluated with respect to BP development. MBP, EDN and ECP were measured by ELISA in serum (n = 61) and blister fluid (n = 20) of patients with BP at baseline, and in serum after 2 months of treatment (n = 41). Eosinophil activation in BP patients was illustrated at baseline by significantly higher MBP, EDN and ECP serum concentrations as compared with control subjects (n = 20), but without distinction according to disease severity or outcome. EDN and ECP values were even higher in the blister fluids (P < 0.01 and P < 0.05, respectively), whereas MBP values were lower (P < 0.001). ECP serum concentration decreased after 60 days of treatment in BP patients with ongoing remission but not in patients who later relapsed (P < 0.05). A reduction of at least 12.8 ng/mL in ECP concentrations provided a positive predictive value for remission of 81%, showing that ECP serum variation could be a useful biomarker stratifying BP patients at risk of relapse. | Eosinophil Cationic Protein |
Recent developments in long-term central venous access devices, access techniques, and the management of complications are described. Factors used in selecting a device include the intensity and frequency of therapy and the preferences of the patient. Implantable ports and external catheters are available with valved (Groshong) and nonvalved catheters and with single or multiple lumens. Single- or dual-lumen, peripherally inserted central catheters and ports provide a smaller and less invasive alternative to central access. Sonographic guidance during central catheterization allows detection of venous abnormalities, increases the success rate, and decreases the number of complications. When occlusion of the jugular veins, subclavian veins, or superior vena cava prevents routine access, alternatives include translumbar or transhepatic cannulation of the inferior vena cava. Common complications of long-term access are catheter and venous thrombosis and catheter infection. Catheter thrombosis is treated by fibrinolysis. Daily administration of 1 mg of warfarin reduces the risk of thrombosis. An infected catheter can be diagnosed without catheter removal by comparison of quantitative blood cultures from the catheter and peripheral vein. Early recognition of catheter-related infection may save the catheter. Removal of an infected catheter depends on the nature of the offending agent, severity of infection, success of treatment, and degree of difficulty in obtaining alternative access." | Catheterization, Central Venous |
BACKGROUND: Collaborative care (CC) is a well-established approach for the delivery of accessible behavioral health services in integrated health care settings. Substantial evidence supports its effectiveness in improving the quality and outcomes of adult services, and growing research indicates utility with child and adolescent populations. METHODS: To date, studies examining CC models for youth have focused exclusively on primary-care settings. Nevertheless, as the most common integrated service delivery setting for youth, the education sector is an equally important context for improving access to behavioral health services for children and adolescents. RESULTS: We provide a narrative review of the literature on CC, describes the relevance of CC to schools, and details its alignment with contemporary movements in education and school-based behavioral health. CONCLUSIONS: Potential adaptations of the CC model for use in schools are detailed to improve: (1) behavioral health service accessibility, (2) the capacity of schools to provide behavioral health services, and (3) school service effectiveness through use of evidence-based practices. Although little research has explored the applicability of CC in the education sector, the model holds potential promise to improve the quality and efficiency of school-based behavioral health services. | School Mental Health Services |
About 70% of C. elegans mRNAs are trans-spliced to one of two 22 nucleotide spliced leaders. SL1 is used to trim off the 5' ends of pre-mRNAs and replace them with the SL1 sequence. This processing event is very closely related to cis-splicing, or intron removal. The SL1 sequence is donated by a 100 nt small nuclear ribonucleoprotein particle (snRNP), the SL1 snRNP. This snRNP is structurally and functionally similar to the U snRNAs (U1, U2, U4, U5 and U6) that play key roles in intron removal and trans-splicing, except that the SL1 snRNP is consumed in the process. More than half of C. elegans pre-mRNAs are subject to SL1 trans-splicing, whereas ~30% are not trans-spliced. The remaining genes are trans-spliced by SL2, which is donated by a similar snRNP, the SL2 snRNP. SL2 recipients are all downstream genes in closely spaced gene clusters similar to bacterial operons. They are transcribed from a promoter at the 5' end of the cluster of between 2 and 8 genes. This transcription makes a polycistronic pre-mRNA that is co-transcriptionally processed by cleavage and polyadenylation at the 3' end of each gene, and this event is closely coupled to the SL2 trans-splicing event that occurs only ~100 nt further downstream. SL2 trans-splicing requires a sequence between the genes, the Ur element, that likely base pairs with the 5' splice site on the SL2 snRNP, in a manner analogous to the interaction between the 5' splice site in cis-splicing with the U1 snRNP. The key difference is that in trans-splicing, the snRNP contains the 5' splice site, whereas in cis-splicing the pre-mRNA does. Some operons, termed hybrid operons", contain an additional promoter between two genes that can express the downstream gene or genes with a developmental profile that is different from that of the entire operon. The operons contain primarily genes required for rapid growth, including genes whose products are needed for mitochondrial function and the basic machinery of gene expression. Recent evidence suggests that RNA polymerase is poised at the promoters of growth genes, and operons allow more efficient recovery from growth-arrested states, resulting in reduction in the need for this cache of inactive RNA polymerase." | Trans-Splicing |
Hydrolysates of lignocellulosic biomass contain glucose, xylose, arabinose, cellobiose, among other sugars. Effective utilization of these sugars remains challenging for microbial conversion, because most microorganisms consume such sugars sequentially with a strong preference for glucose. In the present study, the oleaginous yeast, Lipomyces starkeyi, was shown to consume cellobiose and xylose simultaneously and to produce intracellular lipids from cellobiose, xylose and glucose. In flask cultures with glucose, cellobiose or a mixture of cellobiose/xylose as carbon sources, overall substrate consumption rates were close to 0.6 g/L/h, and lipid coefficients were 0.19 g lipid/g sugar, respectively. This cellobiose/xylose co-fermentation strategy provides an opportunity to efficiently utilize lignocellulosic biomass for microbial lipid production, which is important for biorefinery and biofuel production. | Lipomyces |
Sequential administration of alpha-difluoromethyl ornithine and methylglyoxal bis(guanylhydrazone), two differently acting inhibitors of the biosynthesis of natural polyamines, produced a rapid and distinct therapeutic response in four children with advanced lymphoblastic and in one with myeloblastic leukemia. The synergism between the action of the two compounds was based upon a unique drug interaction; a preceding treatment with difluoromethyl ornithine greatly increased the uptake of subsequently administered methylglyoxal bis(guanylhydrazone) as verified by the actual determinations of the latter drug in the circulating leukemia cells. The side-effects associated with the combined drug regiment were either absent or mild. | Mitoguazone |
BACKGROUND: Family planning is regarded as an important preventive measure against maternal and child morbidity and mortality. This study was aimed at determining the knowledge, attitude and use of family planning methods among women attending antenatal clinic in Jos; factors that militates against use of contraceptive methods and their contraceptive intentions following the index pregnancy. METHOD: This was a cross-sectional study involving 420 women who attended the antenatal clinic. The respondents were interviewed by the use of structured interviewer administered questionnaire. RESULTS: Knowledge (88.1%) and acceptability (75.4%) of family planning methods were high, while modern family planning methods use was 44.0%. More women 39.3% were aware of oral contraceptive pills. Common methods used were male condom (59.5%), oral contraceptive pills (47.0%) and injectables (27.1%) among others. Most of the women (60.0%) received their family planning information in the hospital. Seventy five percent of the women agreed that both husband and wife should jointly decide for a family planning method. Sixty eight percent of women would like to use contraceptive methods after delivery of the index pregnancy. The desire for more children accounted for 36.5% among those that refused use of contraceptive method after delivery. CONCLUSION: Despite the high educational status, knowledge and acceptability of family planning methods observed in this study, the practice of these methods is still relatively low. More targeted and well-organized educational campaigns are needed to improve this trend. | Family Planning Services |
Immunomodulation activity-guided fractionation of ethanol extract of Brugmansia suaveolens leaves was carried out to isolate a novel compound SUPH036-022A (1) by co-culturing the test fraction/compound activated PBMC with MCF7 and A549 cancer cell lines. Assessment of immune markers in PBMC, and analysis of apoptosis markers and cell cycle was carried out for cancer cells. The structure of the isolated compound was elucidated by spectral analysis. Compound 1 enhanced the secretion of immune markers, IL-2 and IFN-gamma, from PBMC. Further, compound 1 treated PBMC increased cell death in MCF7 and A549 cell lines and induced ROS production and mitochondrial membrane perturbation, leading to apoptosis. Flow cytometry analysis revealed; compound 1 stimulated PBMC to cause a five-fold increase in cell cycle perturbations in the sub-G1 stage of cancer cells as compared to the negative control. The compound, in the absence of PBMC, only had a weak cytotoxic activity against these cell lines. Thus, compound 1 is a novel lead for immunomodulation-mediated anticancer activity. | Brugmansia |
Bacteria of the species Aerococcus urinae are Gram-positive, catalase-negative cocci that are arranged in pairs, tetrads, or clusters resembling enterococci or staphylococci. They are rare causative agents of infective endocarditis. Repetitive urinary tract infections based upon underlying genitourinary tract abnormalities could involve these bacteria. Due to their similarity to other Gram-positive cocci misinterpretation may occur along the line of microbiologic differentiation, which could potentially lead to a fatal outcome. We herein report on the clinical course of a 68 year-old male patient who in the setting of an embolic stroke was initially diagnosed with a culture-negative acute infective endocarditis of the aortic valve. | Aerococcus |
The facilitative transport of glucose across the plasma membranes of mammalian cells is catalyzed by a family of glucose transport proteins (GLUT). Four glucose transport proteins and a fructose transport protein have been identified. These transport proteins have unique tissue distributions and biochemical properties under- lying specific physiologic functions. GLUT1, the first GLUT isoform identified, is expressed at highest levels in the endothelial of barrier tissues such as blood vessels and the blood-brain barrier. GLUT2, found predominantly in liver, intestine, kidney, and pancreatic beta-cells, is a low-affinity glucose transport protein that is part of the glucose sensor in pancreatic beta-cells and facilitates either glucose uptake or efflux from the liver depending on the nutritional state. GLUT3 is the glucose transporter responsible for maintaining an adequate glucose supply to neurons. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues, heart muscles, and skeletal muscles that is responsible for insulin-regulated glucose disposal." | Monosaccharide Transport Proteins |
BACKGROUND AND OBJECTIVE: An animal model for bile duct stenosis using intraductal thermal injury has not yet been established. The aims of the current study were to develop biliary stenosis in a swine model by inducing intraductal thermal injury using a heat probe or radiofrequency ablation electrode and to investigate an effective and safe energy dose. METHODS: Intraluminal thermal injury was applied to the common bile duct with a heat probe in three swines and a radiofrequency ablation electrode in the other three swines by either endoscopic retrograde cholangiography or open laparotomy. Cholangiography and histologic evaluation of common bile duct were taken 2 weeks after thermal injury. RESULTS: Thermal injury with a heat probe at 25 J for 40 seconds produced a stricture in all three animals. Application of a radiofrequency ablation electrode produced a stricture in two of three animals. An energy dose of 40 W at 80 degrees C for 30 seconds produced biliary stenosis without any complications initially and 2 weeks after thermal injury. CONCLUSIONS: The application of a heat probe and a radiofrequency ablation electrode for intraductal thermal injury resulted in a reproducible animal model of biliary stenosis. | Common Bile Duct |
PURPOSE: To determine common mechanisms of anterior cruciate ligament (ACL) injury in baseball players and to quantify the rate of return to play after primary surgical reconstruction and review intermediate clinical outcomes. METHODS: Surgical injuries involving the ACL in youth, high school, collegiate, and professional baseball players were queried for an 11-year period (2001 to 2011). Over the study period, 42 baseball players were identified who had undergone arthroscopically assisted primary ACL reconstruction by 1 of 3 attending surgeons. Retrospective chart review was performed for all 42 patients to evaluate variables of age, level of competition, position, mechanism of injury, graft choice, and associated meniscal injuries. Twenty-six patients were reached for telephone survey and International Knee Documentation Committee questionnaire and they answered questions about their original injury and playing history. RESULTS: The most common mechanism of injury was fielding, followed by base running. Infielders and outfielders (32% each) were the most commonly injured position, followed by pitchers (29%). Among the 32 players for whom it could be determined, 30 (94%) were able to return to playing baseball at a mean follow-up of 4.2 years (range 1.0 to 9.9 years). The mean International Knee Documentation Committee score was 84.0 (range 63 to 91). Among the 26 patients contacted for telephone interview, no one required revision ACL surgery, but 3 required a subsequent procedure for meniscal tear. Twenty-five patients (96%) denied any episodes of instability in the knee after reconstruction. CONCLUSIONS: The overwhelming majority of baseball players that sustain ACL injuries do so while fielding or base running. Outfielders are significantly more likely than infielders to suffer ACL injuries while fielding versus base running. The results with respect to return to play are promising, as nearly all patients were able to return to baseball and none required a revision ACL surgery at a mean follow-up of 4.2 years. LEVEL OF EVIDENCE: Level IV, therapeutic case series." | Anterior Cruciate Ligament Injuries |
The breeding of male layer chickens is currently considered to be highly uneconomical. In Germany alone, 40 to 50 million newly hatched male chickens were killed annually immediately after hatching. Therefore, it is necessary to find a method for sexing chickens early in the embryonic development, preferably before incubation. The genotypic sex of an egg can be determined using information found in the germinal disc, so knowledge of the exact position of the germinal disc is essential for further sexing, or for other actions such as the in ovo injection of agents. Previous studies have shown that the germinal disc is located somewhere on top of the yolk. However, no studies have yet been performed that investigate the influence of time spent in horizontal storage on the position of the germinal disc. Magnetic resonance imaging was chosen to determine this influence on the position of the germinal disc. It was found that eggs placed horizontally for long periods of time before scanning had significant changes in the positions of their germinal discs compared with those of eggs scanned minutes after positioning. The position of the germinal disc in eggs, minutes after horizontal positioning, deviated 14.7 +/- 0.6 mm from the maximum vertical plane of the egg (zero position) in the z-direction; eggs scanned after 96 h of horizontal positioning showed a deviation of only 4.9 +/- 1.6 mm. The x-axis also exhibited changes in the position of the germinal disc over time. Immediately after horizontal positioning, the eggs showed a deviation of 0.4 +/- 0.4 mm in the x-direction, whereas the deviation after 96 h was 2.9 +/- 0.5 mm. These results show that horizontal positioning of the egg hours before the measurement is necessary. | Blastodisc |
In most surgeries, the primary aim, for both surgeons and patients, is the success of the operation being undertaken. A secondary aim is for optimal wound healing with minimal scar formation. The normal wound-healing process involves four distinct but overlapping stages: haemostasis, inflammation, proliferation and remodelling. In some patients, the cellular process involved in the proliferation and remodelling stages can be deranged, resulting in the formation of hypertrophic or keloid scars, a phenomenon more frequently seen in skin of colour. The first report of excessive scarring is thought to be the Smith papyrus about 1700 BC. In the 20th century, both Mancini and Quaife (in 1962) and Peacock et al. (in 1970) classified excessive scarring into hypertrophic and keloid scar formation. Clinicians can minimize the risk of these pathological scars developing by using good preoperative, perioperative/intraoperative and postoperative surgical practices. This paper reviews the wound-healing processes in association with good surgical principles and practice, discusses how implementing these principles in practice helps in this prevention and management of pathological surgical scars such as hypertrophic scars and keloid scars. and offers a practical step-by-step clinical guide that can be used by any clinician. | Granulation Tissue |
CONTEXT: Tripleurospermum disciforme (C.A. Mey) Schultz Bip. (Asteraceae) is a widespread biennial species which also has traditional medicinal uses. According to the few recent studies, essential oils of this species exhibit anti-inflammatory, antispasmodic, antiseptic, antifungal, antiulcer, and antioxidant activity. OBJECTIVE: The chemical compositions of the hydrodistilled oils of T. disciforme of Iranian origin are studied in the stages of prior to flowering, flowering, and post flowering, for the first time. Also, we investigated the antibacterial activities of the oils. MATERIALS AND METHODS: The essential oils of air-dried T. disciforme were obtained by hydrodistillation in three different developmental stages and analyzed by gas chromatography-mass spectrometry (GC-MS). The antimicrobial activity of the isolated essential oil, in the three stages, was also investigated against four Gram-positive and four Gram-negative bacteria. RESULTS: Twenty-one components were identified in the essential oils of T. disciforme, and the highest amount of oil was extracted at the flowering stage. The main component of the species in the flowering stage was beta-farnesene (22.46%) and the other major components were beta-sesquiphellandrene (17.85%), p-methoxy-beta-cyclopropylstyrene (16.64%), heptadecane (10.6%), p-methoxy-humulene oxide (6.88%) and benzene acetaldehyde (9.3%). The MIC of essential oil was evaluated from 4 microL ml(-1) against Staphylococcus subtilis and Bacillus cereus to 22 microL ml(-1) against Citrobacter amalonaticus. DISCUSSION AND CONCLUSION: This study demonstrates the occurrence of beta-farnesene/beta-sesquiphellandrene chemotype of T. disciforme in western regions of Iran that are different from previous reports. The findings also showed that the essential oils T. disciforme have excellent antibacterial activities and thus have great potentiality to be used as a resource for natural health products. | Tripleurospermum |
BACKGROUND AND PURPOSE: Middle ear adenomatous tumors (MEAT) are rare tumors which can be begin or malignant and can present a neuroendocrine differentiation. Their radiological aspect is very similar to glomus tympanicum (GT) which are the most common tumoral lesions of the middle ear. We present several radiological and clinical findings that could help radiologists to accurately identify MEAT. MATERIAL AND METHODS: We retrospectively reviewed the radiological and clinical findings of three patients with MEAT and of eight patients with GT. Diagnostic was obtained after surgical resection in all cases. All patients had high resolution CT and MR of the middle ear associated with a subtracted digital carotid angiography. Tumor location, size, extension, signal intensity, and enhancement were analysed. From the medical records of the patients, clinical manifestations (hearing loss, tinnitus), evolution length and recurrences were noted. RESULTS: MEAT and GT appeared as tissular lesion with significant enhancement on CT and MR. A vascular blush was present on angiography in all cases of GT and absent from all cases of MEAT. A close relationship between the tumor and the Jacobson's nerve or its branches was identified in all cases of GT. Pulsatile tinnitus was present in all patients with GT and absent in all patients with MEAT. CONCLUSION: A middle ear tissular lesion clearly separated from the Jacobson nerve or its branches, showing significant enhancement after contrast medium injection but with a normal angiography, should make one suspicious for MEAT. | Glomus Tympanicum Tumor |
The localization, release, and effects of substance P and neurokinin A were studied in the porcine pancreas and the localization of substance P immunoreactive nerve fibers was examined by immunohistochemistry. The effects of electrical vagus stimulation and capsaicin infusion on tachykinin release and the effects of substance P and neurokinin A infusion on insulin, glucagon, somatostatin, and exocrine secretion were studied using the isolated perfused porcine pancreas with intact vagal innervation. NK-1 and NK-2 receptor antagonists were used to investigate receptor involvement. Substance P immunoreactive nerve fibers were localized to islets of Langerhans, acini, ducts, and blood vessels. Vagus stimulation had no effect on substance P and neurokinin A release, whereas capsaicin infusion stimulated release of both. Substance P and neurokinin A infusion increased release of insulin, glucagon, and exocrine secretion, whereas somatostatin secretion was unaffected. The effect of substance P on insulin, glucagon, and exocrine secretion was blocked by the NK-1 receptor antagonist. The effect of electrical stimulation of vagus nerves on insulin and exocrine secretion was not influenced by tachykinin receptor antagonists. We conclude that tachykinins stimulate both endocrine and exocrine pancreatic functions through NK-1 receptors. Tachykinins are not involved in vagal regulation of pancreatic secretion in pigs but could constitute part of an alternative stimulatory system. | Tachykinins |
Neurons and synapses in the mammalian brain exhibit plastic changes, which occur not only during development and under physiological conditions, but also under pathological conditions. One major cellular hypothesis is that activity-dependent changes in synaptic strength may contribute to the formation of memory and the expression of persistent inflammatory pain. Recently, the anterior cingulate cortex (ACC) has been proposed to play an important role for learning, memory and chronic pain. Long-term potentiation (LTP) and long-term depression (LTD) are well-studied phenomena which may be related to learning and memory. NMDA receptors are the most important trigger for LTP and LTD of synaptic strength. Here, we review recent studies and present new experimental data on the roles of NMDA receptors during synaptic depression in the ACC. Furthermore, we consider the physiological and pathological significance of LTD in the ACC. | Long-Term Synaptic Depression |
Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis and tumor invasion. We have described, for the first time, that pancreatic ductal adenocarcinomas (PDACs) with an aggressive behavior and a poor outcome expressed MUC1 (pan-epithelial membrane-associated mucin) but did not express MUC2 (intestinal-type secreted mucin), whereas intraductal papillary mucinous neoplasms (IPMNs) with indolent behavior and a favorable outcome did not express MUC1 but did express MUC2. These expression profiles of MUC1 and MUC2 related to the prognoses of the patients were also observed in biliary neoplasms such as intrahepatic cholangiocarcinoma (ICC)-mass-forming type (MF), mucin-producing bile duct tumor (MPBT), and extrahepatic bile duct carcinoma (EHBDC). We also found recently that high expression of MUC4 (tracheobronchial membrane-associated mucin) in PDACs, ICCs-MF, and EHBDCs was a new independent poor prognostic factor, although MUC4 was not expressed in normal pancreatobiliary tissue. High de novo expression of MUC5AC (gastric-type secreted mucin) was observed in many types of pancreatobiliary neoplasms, including all grades of pancreatic intraepithelial neoplasia (PanIN) and biliary intraepithelial neoplasia (BilIN), and all types of IPMNs and MPBTs, as well as PDACs and ICCs-MF, although MUC5AC was not expressed in normal pancreatobiliary tissue. The combined status of MUC1, MUC2, MUC4, and MUC5AC expression may be useful for the early detection of pancreatobiliary neoplasms and evaluation of their malignancy. In regard to the mechanism of mucin expression, we have recently reported that MUC1, MUC2, MUC4, and MUC5AC gene expression is regulated by epigenetics (DNA methylation and histone H3 lysine 9 modification) in cancer cell lines, including PDAC cells. Translational research of mucin gene expression mechanisms, including epigenetics, in pancreatobiliary neoplasms may give us new tools for the early and accurate detection of these neoplasms. | Mucin-2 |
Malaria causes every year over half-a-million deaths. The emergence of parasites resistant to available treatments makes the identification of new targets and their inhibitors an urgent task for the development of novel anti-malaria drugs. Protein kinase CK2 is an evolutionary-conserved eukaryotic serine/threonine protein kinase that in Plasmodium falciparum (PfCK2) has been characterized as a promising target for chemotherapeutic intervention against malaria. Here we report a crystallographic structure of the catalytic domain of PfCK2alpha (D179S inactive single mutant) in complex with ATP at a resolution of 3.0 A. Compared to the human enzyme, the structure reveals a subtly altered ATP binding pocket comprising five substitutions in the vicinity of the adenine base, that together with potential allosteric sites, could be exploited to design novel inhibitors specifically targeting the Plasmodium enzyme. We provide evidence for the dual autophosphorylation of residues Thr(63) and Tyr(30) of PfCK2. We also show that CX4945, a human CK2 inhibitor in clinical trials against solid tumor cancers, is effective against PfCK2 with an IC(50) of 13.2 nM. | Casein Kinase II |
Next-generation sequencing (NGS), also known as massively parallel sequencing, has revolutionized genomic research. The current advances in NGS technology make it possible to provide high resolution, high throughput HLA typing in clinical laboratories. The focus of this review is on the recent development and implementation of NGS in clinical laboratories. Here, we examine the critical role of NGS technologies in clinical immunology for HLA genotyping. Two major NGS platforms (Illumina and Ion Torrent) are characterized including NGS library preparation, data analysis, and validation. Challenges of NGS implementation in the clinical laboratory are also discussed, including sequencing error rate, bioinformatics, result interpretation, analytic sensitivity, as well as large data storage. This review aims to promote the broader applications of NGS technology in clinical laboratories and advocate for the novel applications of NGS to drive future research. | Laboratories, Clinical |
Perioperative myocardial infarction is a serious complication affecting a significant portion of patients undergoing coronary artery bypass graft surgery. This may arise due to coronary graft thrombosis, a rare but potentially fatal phenomenon associated with both congenital and acquired risk factors. Multiple case reports implicate the role of protamine in the development of such thromboses. The role of protamine in facilitating the regulation of hemostasis by reversing the anticoagulant effects of heparin in patients undergoing cardiopulmonary bypass is well-recognized. However, discussion of its potential contribution to coronary graft thrombosis and mechanisms by which this may occur is lacking. Furthermore, its narrow therapeutic index and side effect profile are such that its appropriateness as a universal reversal agent to heparin requires reconsideration. This article reviews the current body of evidence regarding the use of protamine in cardiac surgery and the limited case reports pertaining to its potential role in the pathophysiology of coronary graft thrombosis. | Heparin Antagonists |
External auditory canal stenosis, although uncommon, is a condition that is sometimes encountered by otolaryngologists. This condition has been shown to result from inflammatory changes that may be incited by many different causes. Various methods of stenting the canal open postoperatively have been described. We describe a readily accessible and inexpensive method of stenting the canal open postoperatively. The technique presented has been used effectively in all age groups at our institution, in cases ranging from trauma to postmastoidectomy procedures. | Otologic Surgical Procedures |
The most widely accepted and propagated theory of neurotrophic joint pathogenesis is the neurotraumatic one. Seldom published and little known is the neurovascular theory. To gain better understanding of the pathogenesis, we reviewed radiographs of 91 neurotrophic joints with attention to the particular joint affected, the type of changes present (resorptive vs. productive), and the time sequence involved. The pathological findings, when available, were also reviewed. While many joint changes could not be explained on a traumatic basis alone, all could be explained by a vascular mechanism. | Tabes Dorsalis |
The interferon-regulatory factor (IRF) family comprises nine members in mammals. Although this transcription factor family was originally thought to function primarily in the immune system, contributing to both the innate immune response and the development of immune cells, recent advances have revealed that IRFs plays critical roles in other biological processes, such as metabolism. Accordingly, abnormalities in the expression and/or function of IRFs have increasingly been linked to disease. Herein, we provide an update on the recent progress regarding the regulation of immune responses and immune cell development associated with IRFs. Additionally, we discuss the relationships between IRFs and immunity, metabolism, and disease, with a particular focus on the role of IRFs as stress sensors. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. | Interferon Regulatory Factors |
Nipah virus and Hendra virus are related, highly pathogenic paramyxoviruses with unusually broad host ranges. Henipaviruses encode several proteins that block innate immune responses, and these are likely to serve as virulence factors. Specfically, four virus-encoded proteins, the phosphoprotein (P), the V protein, the W protein, and the C protein have each been demonstrated to counteract aspects of the interferon (IFN)-alpha/beta response, a key component of the innate immune response to virus infection. The available data indicate that V and W can inhibit the production of IFNalpha/beta in response to various stimuli, while the P, V, and W proteins also block the ability of IFNs to signal and induce an antiviral state in cells. The C protein also inhibits the antiviral effects of IFNalpha/beta by a poorly characterized mechanism. Reverse genetics systems, which allow the generation of recombinant viruses bearing specific mutations, have demonstrated the importance of the viral IFN-antagonists for replication. With these systems in hand, the field is now poised to define how specific viral IFN-antagonist functions influence viral pathogenesis. | Nipah Virus |
X-ray photoelectron spectroscopy (XPS) is harnessed as an in situ efficient characterization technique for monitoring chemical bond transformation in DNA and cisplatin-DNA complexes under synergic X-ray irradiation. By analyzing the variation of relative peak area of core elements of DNA as a function of irradiation time, we find that the most vulnerable scission sites in DNA are those containing phosphate and glycosidic bonds. Compared to DNA, the effective rate constants of the corresponding phosphodiester and glycosidic bond cleavages for cisplatin-DNA complexes are 1.8 and 1.9 folds larger. These damages and their enhancements are similar to those induced by low energy electrons (LEE). Consistently, the magnitude of the secondary electron distribution produced by the X-rays on the cisplatin-DNA complexes is considerably increased compared to that of pristine DNA. The data suggest that DNA radiosensization by cisplatin results not only from the sensitization of DNA to the action of LEE, but also from an increase the production of LEE at the site of binding of the cisplatin. The results provide new insights into the mechanisms of cisplatin-induced sensitization of DNA under X-ray irradiation, which could be helpful in the design of new cisplatin-based antitumor drugs. | DNA Cleavage |
As photoreceptor cells die during retinal degeneration, the surrounding microenvironment undergoes significant changes that are increasingly recognized to play a prominent role in determining the efficacy of therapeutic interventions. Chondroitin Sulphate Proteoglycans (CSPGs) are a major component of the extracellular matrix that have been shown to inhibit neuronal regrowth and regeneration in the brain and spinal cord, but comparatively little is known about their expression in retinal degeneration. Here we provide a comprehensive atlas of the expression patterns of four individual CSPGs in three models of inherited retinal degeneration and wildtype mice. In wildtype mice, Aggrecan presented a biphasic expression, while Neurocan and Phosphacan expression declined dramatically with time and Versican expression remained broadly constant. In degeneration, Aggrecan expression increased markedly in Aipl1(-/-) and Pde6b(rd1/rd1), while Versican showed regional increases in the periphery of Rho(-/-) mice. Conversely, Neurocan and Phosphacan broadly decrease with time in all models. Our data reveal significant heterogeneity in the expression of individual CSPGs. Moreover, there are striking differences in the expression patterns of specific CSPGs in the diseased retina, compared with those reported following injury elsewhere in the CNS. Better understanding of the distinct distributions of individual CSPGs will contribute to creating more permissive microenvironments for neuro-regeneration and repair." | Chondroitin Sulfate Proteoglycans |
OBJECTIVE: Unique to individuals with insulin-dependent diabetes mellitus is a disordered eating behaviour whereby insulin is deliberately restricted or omitted. Despite growing research in this area, experiential perspectives of individuals remain understudied. Therefore, this meta-synthesis sought to explore the experiences of individuals with Type 1 Diabetes Mellitus by identifying, analysing and synthesising existing knowledge concerning this misuse of insulin. DESIGN: Meta-aggregative techniques were employed to generate synthesised findings related to individuals' understanding and experience, physical and psychological impacts, support and treatment-related needs, noted in twelve studies. RESULTS: A multifaceted relationship with insulin misuse, beyond weight control was identified. Many individuals experienced diabetes-related complications alongside increased distress, loss of control and feelings of regret, guilt, and shame. Almost all individuals valued support from those who shared a 'diabulimic' identity; peer support appeared more conducive to recovery than support from others including formal support services. CONCLUSIONS: This meta-synthesis highlights the need for empathic, collaborative care, and proactive prevention and intervention. The findings highlight the value of peer support, the need for increased knowledge among informal supports, training among multidisciplinary teams and support services, and crucially the development of evidence-based treatments informed by the behaviour as a unique distinct construct. | Diabulimia |
A series of new visnagin and benzofuran scaffold-based molecules was designed and synthesized as anti-inflammatory and analgesic agents. Biological screening of these compounds showed that they exhibit potent anti-inflammatory/analgesic activity with a safer side effect profile in in vivo mouse models. In vitro cyclooxygenase (COX) inhibition assay showed that the compounds elicit their function through selective COX-2 inhibition. Molecular docking study also revealed the ability of the compounds to correctly recognize the active site and achieve noncovalent binding interactions with key residues therein. The best combined profile of anti-inflammatory, analgesic and COX-2 selective inhibition properties in association with low gastrotoxicity was displayed by the analogs 8, 11b and 19d, which can be considered as promising leads for further future optimization. | Khellin |
Conformational change and protein-protein interactions are two major mechanisms of membrane protein signal transduction, including G protein-coupled receptors (GPCRs). Upon agonist binding, GPCRs change conformation, resulting in interaction with downstream signaling molecules such as G proteins. To understand the precise signaling mechanism, studies have investigated the structural mechanism of GPCR signaling using X-ray crystallography, nuclear magnetic resonance (NMR), or electron paramagnetic resonance. In addition to these techniques, hydrogen/deuterium exchange mass spectrometry (HDX-MS) has recently been used in GPCR studies. HDX-MS measures the rate at which peptide amide hydrogens exchange with deuterium in the solvent. Exposed or flexible regions have higher exchange rates and excluded or ordered regions have lower exchange rates. Therefore, HDX-MS is a useful tool for studying protein-protein interfaces and conformational changes after protein activation or protein-protein interactions. Although HDX-MS does not give high-resolution structures, it analyzes protein conformations that are difficult to study with X-ray crystallography or NMR. Furthermore, conformational information from HDX-MS can help in the crystallization of X-ray crystallography by suggesting highly flexible regions. Interactions between GPCRs and downstream signaling molecules are not easily analyzed by X-ray crystallography or NMR because of the large size of the GPCR-signaling molecule complexes, hydrophobicity, and flexibility of GPCRs. HDX-MS could be useful for analyzing the conformational mechanism of GPCR signaling. In this chapter, we discuss details of HDX-MS for analyzing GPCRs using the beta2AR-G protein complex as a model system." | Deuterium Exchange Measurement |
BACKGROUND AND OBJECTIVE: Loss of intermediolateral nucleus (IML) neurons is considered to play a major role in orthostatic hypotension (OH) of multiple system atrophy (MSA). In Parkinson disease (PD) and dementia with Lewy bodies (DLB), autonomic phenomena such as OH are common and attributed to dysfunction of sympathetic, parasympathetic, and visceral autonomic neurons. However, apart from MSA, few reports have focused on the neuropathologic aspects in PD and DLB. Here we assessed IML degeneration as well as the fine myelinated fibers (FFs; maximum diameter less than 3 mum) considered to be preganglionic sympathetic nerve fibers derived from IML neurons in PD, DLB, MSA, and age-matched normal controls (NC). METHODS: We counted IML neurons and measured the diameter and number of myelinated fibers of the ventral root at the level of the 12th thoracic segment. RESULTS: Compared to NC, number of IML neurons and density of FF were significantly reduced in PD (53% and 67%), DLB (47% and 71%) and MSA (27% and 42%). Compared to combined group of PD and DLB without OH (OH-), IML neurons in combined group of PD and DLB with OH (OH+) were significantly reduced (77%). Compared to NC, FF densities in OH-, OH+ were significantly reduced (74% and 59%). The mean ratio of small to large myelinated fibers in OH+ (1.18), but not that in OH-(1.58), was significantly lower than that in NC (3.17). CONCLUSIONS: We present neuropathological evidence that IML neurons and FFs in the ventral root are reduced in PD and DLB and that the reduction was more severe in the combined group of OH+ than in OH-. | Spinal Cord Lateral Horn |
In this study, we evaluated the experience of a single center pediatric intensive care unit in pediatric bedside tracheostomies performed during a six-year period. Thirty-one bedside tracheostomies were performed on 31 patients aged 2 months to 18 years. The major indication for tracheostomy was prolonged ventilator dependence. Twenty-two complications, 6 major and 16 minor, were observed in 18 patients. Early complications were observed in 5 patients and all were managed immediately without serious outcomes. Ten patients died during the study period and only one death was directly related to the tracheostomy; the remaining 9 patients died due to their underlying disease. Eleven patients were successfully decannulated, 12 patients were discharged home with their tracheostomies and 5 of these 12 patients required home ventilation. Although children who required tracheostomy had a high overall mortality (32.3%), the prognosis of these patients depends primarily on the underlying medical condition. | Tracheostomy |
BACKGROUND: Grafting is a horticultural practice used widely across woody perennial crop species to fuse together the root and shoot system of two distinct genotypes, the rootstock and the scion, combining beneficial traits from both. In grapevine, grafting is used in nearly 80% of all commercial vines to optimize fruit quality, regulate vine vigor, and enhance biotic and abiotic stress-tolerance. Rootstocks have been shown to modulate elemental composition, metabolomic profiles, and the shape of leaves in the scion, among other traits. However, it is currently unclear how rootstock genotypes influence shoot system gene expression as previous work has reported complex and often contradictory findings. RESULTS: In the present study, we examine the influence of grafting on scion gene expression in leaves and reproductive tissues of grapevines growing under field conditions for three years. We show that the influence from the rootstock genotype is highly tissue and time dependent, manifesting only in leaves, primarily during a single year of our three-year study. Further, the degree of rootstock influence on scion gene expression is driven by interactions with the local environment. CONCLUSIONS: Our results demonstrate that the role of rootstock genotype in modulating scion gene expression is not a consistent, unchanging effect, but rather an effect that varies over time in relation to local environmental conditions. | Gene-Environment Interaction |
Current views of plant communities emphasize the importance of competition for resources and colonization ability in determining seedling establishment and plant distributions. Many desert shrubs are surrounded by bare zones that lack other plants or have different suites of species beneath them compared with the open desert surrounding them. Releases of biochemicals as volatiles from leaves, leachates from litter, or exudates from roots have been proposed as mechanisms for this pattern, but such phytotoxicity has been controversial. I tested the hypothesis that experimental clipping of sagebrush foliage enhances its effect as a germination inhibitor. Germination of native forbs and grasses was reduced in association with clipped, compared with unclipped, sagebrush foliage in lath house and field experiments. Sagebrush seeds were not significantly affected. Air contact was required for this inhibition of germination. Soil contact and leaf litter were not required and added little inhibition of germination. These results suggest a potentially large, indirect, and previously overlooked role for interactions between herbivory and germination that could affect plant community structure. | Eriogonum |
BACKGROUND: Symptomatic infection with pinworm (Enterobius vermicularis), a human pathogen, is clinically relevant in Germany, with an estimated prevalence in childhood of 2-20%. Enterobiasis can cause major mental distress. There is little systematically verified knowledge on the treatment of this condition, and there is no corresponding German guideline. This review is, therefore, intended as a summary of the current state of knowledge. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed for literature appearing from 1 January 1990 to 5 February 2019 and containing the search terms enterobiasis," "oxyuriasis," "Enterobius vermicula- ris," "pinworm," and "threadworm." RESULTS: More than one billion people worldwide are thought to be infected with pinworm. Estimates of its prevalence among kindergarten and primary-school pupils in Europe are generally near 20%. Infants (<2 years of age), adolescents (>14 years of age), and adults are only sporadically affected. The main risk factors are age 4-11 years, uncontrolled anus-finger-mouth contact, nail-biting (onychophagia/peri- onychophagia), unsupervised body hygiene, and poor compliance with basic hand hygiene. No large-scale, randomized, controlled trials of treatment are available. The approved antihelminthic agents are mebendazole, pyrantel embonate, and pyrvinium embonate (success rates up to >90%). For recurrent infections, prolonged treatment for up to 16 weeks (a "pulse scheme") is recommended. CONCLUSION: In nearly all cases, antihelminthic treatment along with attention to hygienic measures can successfully eradicate pinworm infection and prevent recurrence and autoinfection. The involvement of all persons living in the patient's house- hold, including sexual partners, is a prerequisite to the lasting success of treatment." | Oxyurida Infections |
The formation of an unexpected heterocyclic scaffold, a benzoxazole, in a three-component reaction between a ketone, isocyanide, and 2-aminophenol was encountered. This reaction involved a benzo[b][1,4]oxazine intermediate resulting from intramolecular attack of the aminophenol hydroxyl group on the nitrilium ion. Unlike previous literature examples, the trapped nitrilium benzo[b][1,4]oxazine could readily be subjected to ring opening with bis-nucleophiles. The reaction scope includes simple linear as well as complex cyclic ketones and substituted 2-aminophenols. A representative benzoxazole product could be further diversified to yield drug-like compounds. | Nitriles |
There is global concern about acid rain and other pollution which is caused by the consumption of oil. By decreasing sulfur content in the oil, we can reduce unwanted emissions and acid rain. Shale was used which is a solid waste generated in the pyrolysis of shale, impregnated with Zn as an adsorbent which removes sulfur present in fuels from the hexane/toluene model solution. An influence of the agitation time (60-180 min), temperature (25-35 degrees C), adsorbent mass (0.1-0.25 g), and initial sulfur concentration (100-250 ppm) factorial 24 with three central points totaling 19 experiments was applied to investigate the effect of the variables on the efficiency of sulfur removal in fuels. The values of the parameters tested for maximum sulfur removal were obtained as follows: contact time = 180 min, temperature = 35 degrees C, adsorbent mass = 0.25 g, and initial sulfur concentration = 100 ppm. The mathematical model proposed with R(2) 99.97% satisfied the experimental data. This may provide a theoretical basis for new research and alternative uses for tailings of schist industrialization in order to evaluate its potential. | Sulfur |
Ingestion of plant and fungal glucosylceramides is known to reduce colon carcinogenesis and skin barrier damage in mice and humans. However, such effects in animal experiments have not been revealed for plant and fungal ceramides because the content of ceramides contained in plants and fungi is so low that the large amount required for animal experiments is difficult to obtain. Noting that the fungus shiitake mushroom (Lentinula edodes) is rich in a glucosylceramide, (4E,8E)-N-d-2'-hydroxypalmitoyl-1-O-beta-d-glucopyranosyl-9-methyl-4,8-sphingadienine [Glc-d19:2(4E,8E,9Me)-h16:0], we developed a new method to purify this fungal glucosylceramide using ethanol precipitation and high-performance liquid chromatography. We also developed a new method to produce large amounts of a ceramide [d19:2(4E,8E,9Me)-h16:0] from this purified glucosylceramide using human glycoside hydrolase family 30 glucocerebrosidase (imiglucerase). These methods will be useful for elucidating the physiological function by ingestion of fungal ceramides in animal experiments. | Glucosylceramides |
OBJECTIVE: This study aimed to describe and compare patients' consumption of dental services and dentists' productivity in a university campus clinic before and after changing from a time-based to an item-based fee-paying system. METHOD: Data were collected from the University of Hong Kong dental clinic which serves all university students and staff. A time-based fee-paying system had been in use up to February 1999 when it was switched to an item-based system. Computerised records of all patients in two 1-year periods starting from February 1996 and February 1999 were analysed. RESULTS: The percentages of eligible users who attended the University dental clinic were similar in the two study periods (30% in 96/97 vs 29% in 99/00). However, on average, patients consumed more dental service items in a year after the switch in fee-paying system (3.2 vs 4.1). There was also an increase in the mean number of dental service items provided by a dentist per working week after the change in fee-paying system (71.5 vs 99.4). CONCLUSION: On switching from a time-based to an item-based fee-paying system, dentists in the UHS dental clinic became more productive and the consumption of dental services per patient also increased. | Fee-for-Service Plans |
This literature review includes all reports from 1993 to 2000 concerning the use of aprotinin in children undergoing cardiopulmonary bypass (CPB) for congenital cardiac surgery. This review examined a nonhomogeneous pediatric patient population ranging from neonates to children up to 18 years of age, presenting many challenges. There have been publications advocating its use and those that have found no significant difference between the control group and those receiving aprotinin. The literature suggests that there is improvement in post-operative blood loss in pediatric patients undergoing redo cardiac surgery, but no significant difference in blood loss in those undergoing primary surgical repair. There is some evidence in the neonatal study groups that with high-dose aprotinin the inflammatory response is attenuated, leading to a reduction in inotropic support, earlier extubation, a tendency toward reduced post-operative blood loss and a reduced hospital stay. In most of the studies, the actual dose of aprotinin has varied with high-dose aprotinin" demonstrating the most significant differences. To achieve an adequate dose of aprotinin, the dose must be calculated on either the patient's weight or their body surface area, and must include an appropriate dose in the prime of the cardiopulmonary bypass circuit, to achieve a plasma concentration between 200 KIU/mL to 400 KIU/mL. The incidence of anaphylactic reactions reported in the literature range from 0.3 to 0.6%. To date, there is no evidence to indicate any contraindication related to the use of aprotinin in the pediatric population." | Aprotinin |
Phosphate-dependent glutaminase (L-glutamine amidohydrolase, EC 3.5.1.2) from rat liver was found to be strongly activated by phosphoribosylpyrophosphate (P-rib-PP), the substrate of amidophosphoribosyltransferase (EC 2.4.2.14). Since the assay of the latter is based on the P-rib-PP-dependent conversion of glutamine to glutamate, the amidotransferase activities determined in crude tissue preparations were found to be too high. The interference of glutaminase, however, could be completely eliminated by its inactivation at 50 degrees C. Amidotransferase was not affected by the heat treatment. Because of the increased rate of the glutamate formation at this temperature, the incubation time of the assay could be significantly reduced." | Amidophosphoribosyltransferase |
N-linked protein glycosylation follows a conserved pathway in eukaryotic cells. The assembly of the lipid-linked core oligosaccharide Glc3Man9GlcNAc2, the substrate for the oligosaccharyltransferase (OST), is catalyzed by different glycosyltransferases located at the membrane of the endoplasmic reticulum (ER). The substrate specificity of the different glycosyltransferase guarantees the ordered assembly of the branched oligosaccharide and ensures that only completely assembled oligosaccharide is transferred to protein. The glycosyltransferases involved in this pathway are highly specific, catalyzing the addition of one single hexose unit to the lipid-linked oligosaccharide (LLO). Here, we show that the dolichylphosphomannose-dependent ALG9 mannosyltransferase is the exception from this rule and is required for the addition of two different alpha-1,2-linked mannose residues to the LLO. This report completes the list of lumen-oriented glycosyltransferases required for the assembly of the LLO." | Polyisoprenyl Phosphate Monosaccharides |
It is well established that stimulant medication improves classroom manageability and attention in terms of time on task, but does stimulant medication improve learning or long-term academic achievement in children with ADHD? There is no clear evidence that it does, but there are at least two reasons why beneficial effects may be obscured in research studies and clinical practice: (1) Higher-than-optimal doses may be prescribed if behavioral response (rather than cognitive response) is used to titrate the dose, and (2) treatment may be overinclusive if diagnostic groups are targeted in which a significant proportion of cases do not have favorable cognitive responses to medication. This article addresses these two issues and describes a large clinical series of patients who were evaluated using a double-blind medication assessment protocol designed to overcome some of the theoretical deficiencies suggested by these issues. | Pemoline |
The protein NAMPT (nicotinamide phosphoribosyltransferase, encoded by the NAPMT gene) is present in two forms. The intracellular form of NAMPT (iNAMPT) is the rate-limiting enzyme in a major nicotinamide adenine dinucleotide (NAD) biosynthetic pathway and regulates cellular metabolism. NAMPT is also secreted by cells in the extracellular milieu, and referred to as extracellular NAMPT (eNAMPT or visfatin). In mammals, visfatin has been linked to various metabolic disorders. However, the role of visfatin in regulating energy homeostasis in fish is not known. In this study, we assessed the effects of nutritional status on NAMPT mRNA expression and the effects of visfatin peripheral injections on food intake and the expression of appetite regulators in goldfish. Our results show that NAMPT is widely expressed in peripheral tissues and brain. Fasting induced increases in NAMPT expression in liver but had no effect on either brain or intestine NAMPT expression levels. Intraperitoneal injections of visfatin (400 ng/g) induced an increase in food intake and in expression levels of hepatic leptin and sirtuin1. Visfatin injections decreased intestine CCK and PYY, and telencephalon (but not hypothalamic) orexin and NPY expression levels. Visfatin did not affect plasma glucose levels, intestine ghrelin or brain CART, POMC and AgRP expressions. These data suggest that visfatin/NAMPT might be involved in the regulation of feeding and energy homeostasis in goldfish. | Goldfish |
This study aims to evaluate the anti-caries effect of a mouthwash containing Lespedeza cuneata extract by confirming its effect on acid-producing capacity and bacteria causing dental caries in the oral cavity. For the same oral environments of 95 subjects who agreed to participate in this study, scaling was performed one week before the experiment. The final number of subjects included in the analysis was 82, excluding those who dropped out during the study period. A randomized placebo-controlled trial was conducted by dividing the subjects into the Lespedeza cuneata extract gargle group (n = 42) and the saline gargle group (n = 40). Participants in each group gargled once every day before going to bed for 5 days, and data were collected by measuring 3 times: before gargling (Baseline), immediately after gargling (Treatment), and 5 days after gargling (After 5 Days). Two trained dental hygienists confirmed the dental caries activity through the Cariview test under the guidance of a dentist. Microbiological analysis was performed to evaluate the changes in bacteria causing dental caries. By confirming the anti-caries effect in the oral environment according to the application of Lespedeza cuneata extract gargle, dental caries activity was found to be significantly lower from Treatment to After 5 Days (p < 0.05). Dental caries-causing bacteria in the upper and lower jaws were also significantly reduced (p < 0.05). These results confirm that Lespedeza cuneata extract is a natural substance with an anti-caries effect. Gargling with a mouthwash containing Lespedeza cuneata extract is useful in preventing dental caries and inhibiting its progression. The same mouthwash can also be used as an effective formulation for maintaining and promoting oral health. | Lespedeza |
Background Children with congenital hypothyroidism (CH) are at risk for preventable intellectual disability without adequate medical management. The purpose of this manuscript is to discuss quality improvement (QI)-based processes for improving provider adherence to practice guidelines and ultimately identifying at-risk patients with chronic illness prior to the occurrence of adverse events. Methods Our study population included patients ages </=3 years diagnosed with CH; lost to follow-up was defined as >180 days since last evaluation by an endocrinology provider. Iterative testing of interventions focused on establishing standardized care through (1) registry-based identification, (2) scheduling future appointments during current visits, (3) outreach to patients lost to follow-up and (4) provider and family education of current practice guidelines. Results A population-validated, electronic medical registry identified approximately 100 patients ages </=3 years diagnosed with CH; initially, 12% of patients met criteria for lost to follow-up. Through serial testing of interventions, the rate of loss to follow-up declined to the goal of <5% within 8 months. Additional measures showed improvement in provider adherence to standard of care. All patients identified as lost to follow-up initially were seen within the first 3 months of intervention. Conclusions Applying QI methodology, a multidisciplinary team implemented a process to identify and contact high-risk CH patients with inadequate follow-up. Focused interventions targeting population management, scheduling and patient/provider education yield sustained improvement in the percentage of patients with a chronic condition who are lost to follow-up. | Lost to Follow-Up |
PURPOSE OF REVIEW: Leptospirosis, a spirochaetal zoonotic disease, has been recognized as an important emerging infectious disease in the last 10 years. This review addresses the issues in the epidemiology, diagnosis and clinical management which confront public health responses, and highlights the progress made towards understanding the Leptospira genome, biology and pathogenesis. RECENT FINDINGS: Leptospirosis has spread from its traditional rural base to become the cause of epidemics in poor urban slum communities in developing countries. Mortality from severe disease forms, Weil's disease and severe pulmonary haemorrhage syndrome, is high (>10% and >50%, respectively) even when optimal treatment is provided. Moreover, the overall disease burden is underestimated, since leptospirosis is a significant cause of undifferentiated fever and frequently not recognized. Barriers to addressing this problem have been the lack of an adequate diagnostic test and effective control measures. China and Brazil, countries in which leptospirosis is a major health problem, have completed the sequence of the Leptospira interrogans genome. Together with new genetic tools and proteomics, new insights have been made into the biology of Leptospira and the mechanisms used to adapt to host and external environments. Surface-exposed proteins and putative virulence determinants have been identified which may serve as sub-unit vaccine candidates. SUMMARY: Major progress has been made in the basic research of leptospirosis. Future challenges will be to translate these advances into public health measures for developing countries. Yet the most effective responses may be interventions that directly address the determinants of poverty, such as poor sanitation, which are often responsible for transmission. | Leptospiraceae |
Frontotemporal lobar degenerations are clinically, genetically, and molecularly heterogeneous diseases characterized by mainly frontal and temporal atrophy and affecting behavioral, language, cognitive, and motor functions. The term frontotemporal dementia incorporates 3 distinct clinical syndromes seen in frontotemporal degenerations: behavioral variant of frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia. Progressive supranuclear palsy syndrome, corticobasal syndrome, and motor neuron disease syndrome are also associated with frontotemporal lobar degenerations. The neuropathologic hallmark of frontotemporal lobar degenerations is accumulation of abnormal proteins in the cytoplasm and nuclei of neurons and glial cells. Proteins involved in pathologic processes that represent the basis for frontotemporal lobar degeneration classification are tau protein, transactive response DNA-binding protein of 43 kDa, and "fused in sarcoma" protein. The aim of this review is to provide a summary of practical approaches for neuropathologic diagnostics of the rapidly evolving classifications of frontotemporal lobar degenerations." | Frontotemporal Lobar Degeneration |
Human fascioliasis is a zoonosis caused by Fasciola hepatica, and this is a trematode that infests cattle and sheep. Humans are accidental hosts in the life cycle of this parasite. People are infected by ingestion of the water or the raw aquatic vegetables that are contaminated with the metacercaria. This fluke's worldwide distribution occurs in areas where sheep, cattle and goats are raised, and there is a life-cycle niche for this fluke in lymnaeid snails. However, it is a rare disease in Korea. We experienced four human fascioliasis which were difficult to differentiate from hepatic malignancy in three patients, and this was misdiagnosed as common hepatic duct tumor in one patient. The patients manifested only vague abdominal symptoms. Intrahepatic fascioliasis showed multiple ill-defined hypoattenuating lesions and filling defects of the lesion lumens on radiologic study. A striking eosinophilia from the patients' blood was identified and a positive finding of a serum enzyme linked immunosorbent assay for the Fasciola hepatica was also noted in three of four patients. The therapeutic trial with triclabendazole and praziquantel was not successful. | Liver Diseases, Parasitic |
Most well-known restriction endonucleases recognize palindromic DNA sequences and are classified as Type IIP. Due to the recognition and cleavage symmetry, Type IIP enzymes are usually found to act as homodimers in forming 2-fold symmetric enzyme-DNA complexes. Here we report an asymmetric complex of the Type IIP restriction enzyme MspI in complex with its cognate recognition sequence. Unlike any other Type IIP enzyme reported to date, an MspI monomer and not a dimer binds to a palindromic DNA sequence. The enzyme makes specific contacts with all 4 base pairs in the recognition sequence, by six direct and five water-mediated hydrogen bonds and numerous van der Waal contacts. This MspI-DNA structure represents the first example of asymmetric recognition of a palindromic DNA sequence by two different structural motifs in one polypeptide. A few possible pathways are discussed for MspI to cut both strands of DNA, either as a monomer or dimer. | Deoxyribonuclease HpaII |
Despite the presence of beta-1,2-glucan in nature, few beta-1,2-glucan degrading enzymes have been reported to date. Recently, the Lin1839 protein from Listeria innocua was identified as a 1,2-beta-oligoglucan phosphorylase. Since the adjacent lin1840 gene in the gene cluster encodes a putative glycoside hydrolase family 3 beta-glucosidase, we hypothesized that Lin1840 is also involved in beta-1,2-glucan dissimilation. Here we report the functional and structural analysis of Lin1840. A recombinant Lin1840 protein (Lin1840r) showed the highest hydrolytic activity toward sophorose (Glc-beta-1,2-Glc) among beta-1,2-glucooligosaccharides, suggesting that Lin1840 is a beta-glucosidase involved in sophorose degradation. The enzyme also rapidly hydrolyzed laminaribiose (beta-1,3), but not cellobiose (beta-1,4) or gentiobiose (beta-1,6) among beta-linked gluco-disaccharides. We determined the crystal structures of Lin1840r in complexes with sophorose and laminaribiose as productive binding forms. In these structures, Arg572 forms many hydrogen bonds with sophorose and laminaribiose at subsite +1, which seems to be a key factor for substrate selectivity. The opposite side of subsite +1 from Arg572 is connected to a large empty space appearing to be subsite +2 for the binding of sophorotriose (Glc-beta-1,2-Glc-beta-1,2-Glc) in spite of the higher Km value for sophorotriose than that for sophorose. The conformations of sophorose and laminaribiose are almost the same on the Arg572 side but differ on the subsite +2 side that provides no interaction with a substrate. Therefore, Lin1840r is unable to distinguish between sophorose and laminaribiose as substrates. These results provide the first mechanistic insights into beta-1,2-glucooligosaccharide recognition by beta-glucosidase. | beta-Glucosidase |
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