Propagation of neocortical inputs in the perirhinal cortex.
The perirhinal area is a rostrocaudally oriented strip of cortex in which lesions produce memory and perceptual impairments. It receives topographically organized transverse projections from associative neocortical areas and is endowed with intrinsic longitudinal connections that could distribute neocortical inputs in the rostrocaudal axis. In search of distinguishing network properties that might support perirhinal involvement in memory, we have performed whole-cell recordings in horizontal perirhinal slices with preserved transverse neocortical links and intrinsic longitudinal connections. Neocortical stimulation sites in rostrocaudal register with regular spiking perirhinal neurons elicited a sequence of excitatory and inhibitory synaptic potentials. In contrast, apparently pure excitatory responses were observed when the stimulating and recording sites were separated by >/=1 mm in the rostrocaudal axis. This suggested that adjacent and distant neocortical stimuli influence regular spiking perirhinal neurons by pathways that respectively form and do not form synapses with inhibitory interneurons. In keeping with this, presumed interneurons did not respond to distant neocortical stimuli. These results suggest that neocortical inputs recruit perirhinal inhibitory interneurons located at the same transverse level, limiting the depolarization of principal perirhinal cells. In contrast, distant neocortical inputs only evoke excitation because longitudinal perirhinal pathways do not engage inhibitory interneurons. This leads us to suggest that the perirhinal network is biased to favor Hebbian-like associative interactions between coincident and spatially distributed inputs.


Methylprednisolone applied directly to the round window reduces dizziness after cochlear implantation: a randomized clinical trial.
This prospective, double-blind controlled, randomized clinical trial of 43 adults showed that topical methylprednisolone applied to the round window during cochlear implantation was effective in protecting inner ear function. Postoperative vestibular disturbance was significantly lower in the steroid group (5%) than the control group (29%). Electrode impedances from the middle portion of the electrode array (electrodes 10-13) were significantly reduced in steroid-treated recipients compared to controls. Hearing and vestibular function analyses were under-powered to detect any drug changes due to limited participant data.


Multiplexing Engineered Receptors for Multiparametric Evaluation of Environmental Ligands.
Engineered cell-based therapies comprise a promising, emerging biomedical technology. Broad utilization of this strategy will require new approaches for implementing sophisticated functional programs, such as sensing and responding to the environment in a defined fashion. Toward this goal, we investigated whether our self-contained receptor and signal transduction system (MESA) could be multiplexed to evaluate extracellular cues, with a focus on elucidating principles governing the integration of such engineered components. We first developed a set of hybrid promoters that exhibited AND gate activation by two transcription factors. We then evaluated these promoters when paired with two MESA receptors and various ligand combinations. Unexpectedly, although the multiplexed system exhibited distinct responses to ligands applied individually and in combination, the same synergy was not observed as when promoters were characterized with soluble transcription factors. Therefore, we developed a mechanistic computational model leveraging these observations, to both improve our understanding of how the receptors and promoters interface and to guide the design and implementation of future systems. Notably, the model explicitly accounts for the impact of intercellular variation on system characterization and performance. Model analysis identified key factors that affect the current receptors and promoters, and enabled an in silico exploration of potential modifications that inform the design of improved logic gates and their robustness to intercellular variation. Ultimately, this quantitative design-driven approach may guide the use and multiplexing of synthetic receptors for diverse custom biological functions beyond the case study considered here.


[Resistance to UV radiation of microorganisms isolated from the rock biotopes of the Antarctic region].
Microbiological analysis of terrestrial biotopes of the Antarctic Region has shown, that vertical rocks of the Antarctic islands open for the Sun were characterized by special microcenoses. The wide distribution of pigmented microorganisms in the rock Antarctic samples, a higher frequency of their occurrence, the total number and biologic diversity, than in other Antarctic biotopes, has been demonstrated. For the first time the presence of bacteria and yeast, resistant to high doses of UV radiation on the vertical rocks in the Antarctic Region was shown. The lethal doze of UV radiation for the Antarctic pink pigmented Methylobacterium strains exceeded 200-300 J/m2, for coal-black yeast--500-800 J/m2, for red yeast--1200-1500 J/m2. The distinctions in lethal UV effect against strains of Methylobacterium isolated from the regions with different climate have not been found. Probably, adaptation of the rock microcenosis to extreme factors of the environment proceeds by natural selection of microorganisms, which resistance to this factor is genetically determined.


A review and analysis of the components of potentially effective perinatal mental health interventions for infant development and mother-infant relationship outcomes.
Children of mothers with serious mental health difficulties are at increased risk of developing mental health difficulties themselves in their own lifetime. Specialist interventions delivered in perinatal mental health services offer an opportunity to support the infant's development and long-term mental health. This review aimed to systematically evaluate the shared elements of successful perinatal mental health interventions that underpin improved outcomes for infants whose mothers experience perinatal mental health difficulties. Nine electronic databases were searched comprehensively for relevant controlled studies of perinatal mental health interventions, and a narrative synthesis undertaken to assess whether statistically significant benefits were noted. Sixteen studies, trialing 19 interventions, were analyzed using a narrative approach and grouped according to reported effectiveness. Eight interventions demonstrated significant improvements in infant outcomes and/or mother-infant relationship outcomes and were used to inform the analysis of the included interventions' components. While the interventions identified were diverse, there were common components which potentially underpin successful interventions for infants whose mothers are experiencing mental health difficulties, including: facilitation of positive Mother×Infant interactions; helping mothers to understand their infant's perspective or inner world; and the use of video feedback.


Perceptual size discrimination requires awareness and late visual areas: A continuous flash suppression and interocular transfer study.
We applied continuous flash suppression (CFS) during an interocular transfer paradigm to evaluate the importance of awareness and the contribution of early versus late visual structures in size recognition. Specifically, we tested if size judgements of a visible target could be influenced by a congruent or incongruent prime presented to the same or different eye. Without CFS, participants categorised a target as "small" or "large" more quickly when it was preceded by a congruent prime - regardless of whether the prime and target were presented to the same or different eye. Interocular transfer enabled us to infer that the observed priming was mediated by late visual areas. In contrast, there was no priming under CFS, which underscores the importance of awareness. We conclude that awareness and late visual structures are important for size perception and that any subconscious processing of the stimulus has minimal effect on size recognition.


The Ccr4-Not complex interacts with the mRNA export machinery.
The Ccr4-Not complex is a key eukaryotic regulator of gene transcription and cytoplasmic mRNA degradation. Whether this complex also affects aspects of post-transcriptional gene regulation, such as mRNA export, remains largely unexplored. Human Caf1 (hCaf1), a Ccr4-Not complex member, interacts with and regulates the arginine methyltransferase PRMT1, whose targets include RNA binding proteins involved in mRNA export. However, the functional significance of this regulation is poorly understood. Here we demonstrate using co-immunoprecipitation approaches that Ccr4-Not subunits interact with Hmt1, the budding yeast ortholog of PRMT1. Furthermore, using genetic and biochemical approaches, we demonstrate that Ccr4-Not physically and functionally interacts with the heterogenous nuclear ribonucleoproteins (hnRNPs) Nab2 and Hrp1, and that the physical association depends on Hmt1 methyltransferase activity. Using mass spectrometry, co-immunoprecipitation and genetic approaches, we also uncover physical and functional interactions between Ccr4-Not subunits and components of the nuclear pore complex (NPC) and we provide evidence that these interactions impact mRNA export. Taken together, our findings suggest that Ccr4-Not has previously unrealized functional connections to the mRNA processing/export pathway that are likely important for its role in gene expression. These results shed further insight into the biological functions of Ccr4-Not and suggest that this complex is involved in all aspects of mRNA biogenesis, from the regulation of transcription to mRNA export and turnover.


Recent advances in understanding bile duct remodeling and fibrosis.
Cholestatic liver disease encompasses a detrimental group of diseases that are non-discriminatory in nature. These diseases occur over every age range from infancy (biliary atresia) to geriatrics (hepatitis). They also cover both genders in the form of primary sclerosing cholangitis in men and primary biliary cholangitis in women. Oftentimes, owing to the disease progression and extensive scarring, the treatment of last resort becomes a liver transplant. In this review, we will briefly discuss and explore new avenues of understanding in the progression of cholestatic liver disease and possible therapeutic targets for intervention. The greater our understanding into the idiopathic nature of cholestatic liver disease, the better our chances of discovering treatment options to halt or reverse the progression, reducing or eliminating the need for expensive and risky transplants.


Analysis of Serum Markers with Regard to Treatment Procedures in Advanced Stage Prostate Cancer Patients.
BACKGROUND Biomarkers predicting the efficacy of treatment for locally limited prostate cancer are greatly needed. This knowledge could improve the classification of patients for different methods of treatment and enable better recognition of groups with higher risk of biological recurrence. We prospectively assessed serial blood levels of apoptotic biomarkers and correlated them with response to treatment and clinical factors. MATERIAL AND METHODS Blood was collected from 25 patients with prostate cancer before and after surgery, 16 healthy volunteers with benign prostatic hyperplasia (BPH), and 14 patients with metastasized disease. Immunoenzymatic methods were used to determine circulating apoptotic and inflammatory mediators, including tumor necrosis factor alpha (TNF-alpha), type I receptor (TNFRI), and type II receptor (TNFRII); FAS ligand (FasL); TNF-related apoptosis-inducing ligand (TRIAL); caspase 8 (Cas8); caspase 9 (Cas9); DNA methylation (metDNA); P-selectin; and high-sensitivity C-reactive protein. The total circulating fragments of cell-free DNA (cfDNA) were measured directly in serum. RESULTS Peripheral serum prostate-specific antigen increased rapidly together with cfDNA. A negative correlation was noted between tumor volume and TNFRI and TNFRII. Postsurgery P-selectin level was decreased, and metDNA and TNFRII levels were increased. Three comparisons were made between patient groups: surgical vs. BPH; surgical vs. palliative; and palliative vs. BPH. TNFRI, TNFRII, metDNA, P-selectin, Cas8, and FasL were shown to have significant roles. CONCLUSIONS The study indicated significant roles for cfDNA, both TNF receptors, metDNA, and P-selectin as serum biomarkers in patients with prostate cancer.


A new method to track seed dispersal and recruitment using 15N isotope enrichment.
Seed dispersal has a powerful influence on population dynamics, genetic structuring, evolutionary rates, and community ecology. Yet, patterns of seed dispersal are difficult to measure due to methodological shortcomings in tracking dispersed seeds from sources of interest. Here we introduce a new method to track seed dispersal: stable isotope enrichment. It consists of leaf-feeding plants with sprays of 15N-urea during the flowering stage such that seeds developed after applications are isotopically enriched. We conducted a greenhouse experiment with Solanum americanum and two field experiments with wild Capsicum annuum in southern Arizona, USA, to field-validate the method. First, we show that plants sprayed with 15N-urea reliably produce isotopically enriched progeny, and that delta 15N (i.e., the isotopic ratio) of seeds and seedlings is a linear function of the 15N-urea concentration sprayed on mothers. We demonstrate that three urea dosages can be used to distinctly enrich plants and unambiguously differentiate their offspring after seeds are dispersed by birds. We found that, with high urea dosages, the resulting delta 15N values in seedlings are 10(3) - 10(4) times higher than the delta 15N values of normal plants. This feature allows tracking not only where seeds arrive, but in locations where seeds germinate and recruit, because delta 15N enrichment is detectable in seedlings that have increased in mass by at least two orders of magnitude before fading to normal delta 15N values. Last, we tested a mixing model to analyze seed samples in bulk. We used the delta 15N values of batches (i.e., combined seedlings or seeds captured in seed traps) to estimate the number of enriched seeds coming from isotopically enriched plants in the field. We confirm that isotope enrichment, combined with batch-sampling, is a cheap, reliable, and user-friendly method for bulk-processing seeds and is thus excellent for the detection of rare dispersal events. This method could further the study of dispersal biology, including the elusive, but critically important, estimation of long-distance seed dispersal.


Clinical features, functional consequences, and rescue pharmacology of missense GRID1 and GRID2 human variants.
GRID1 and GRID2 encode the enigmatic GluD1 and GluD2 proteins, which form tetrameric receptors that play important roles in synapse organization and development of the central nervous system. Variation in these genes has been implicated in neurodevelopmental phenotypes. We evaluated GRID1 and GRID2 human variants from the literature, ClinVar, and clinical laboratories and found that many of these variants reside in intolerant domains, including the amino terminal domain of both GRID1 and GRID2. Other conserved regions, such as the M3 transmembrane domain, show different intolerance between GRID1 and GRID2. We introduced these variants into GluD1 and GluD2 cDNA and performed electrophysiological and biochemical assays to investigate the mechanisms of dysfunction of GRID1/2 variants. One variant in the GRID1 distal amino terminal domain resides at a position predicted to interact with Cbln2/Cbln4, and the variant disrupts complex formation between GluD1 and Cbln2, which could perturb its role in synapse organization. We also discovered that, like the lurcher mutation (GluD2-A654T), other rare variants in the GRID2 M3 domain create constitutively active receptors that share similar pathogenic phenotypes. We also found that the SCHEMA schizophrenia M3 variant GluD1-A650T produced constitutively active receptors. We tested a variety of compounds for their ability to inhibit constitutive currents of GluD receptor variants and found that pentamidine potently inhibited GluD2-T649A constitutive channels (IC50 50 nM). These results identify regions of intolerance to variation in the GRID genes, illustrate the functional consequences of GRID1 and GRID2 variants, and suggest how these receptors function normally and in disease.


Super-Strong, Super-Stiff Macrofibers with Aligned, Long Bacterial Cellulose Nanofibers.
With their impressive properties such as remarkable unit tensile strength, modulus, and resistance to heat, flame, and chemical agents that normally degrade conventional macrofibers, high-performance macrofibers are now widely used in various fields including aerospace, biomedical, civil engineering, construction, protective apparel, geotextile, and electronic areas. Those macrofibers with a diameter of tens to hundreds of micrometers are typically derived from polymers, gel spun fibers, modified carbon fibers, carbon-nanotube fibers, ceramic fibers, and synthetic vitreous fibers. Cellulose nanofibers are promising building blocks for future high-performance biomaterials and textiles due to their high ultimate strength and stiffness resulting from a highly ordered orientation along the fiber axis. For the first time, an effective fabrication method is successfully applied for high-performance macrofibers involving a wet-drawing and wet-twisting process of ultralong bacterial cellulose nanofibers. The resulting bacterial cellulose macrofibers yield record high tensile strength (826 MPa) and Young's modulus (65.7 GPa) owing to the large length and the alignment of nanofibers along fiber axis. When normalized by weight, the specific tensile strength of the macrofiber is as high as 598 MPa g-1 cm3 , which is even substantially stronger than the novel lightweight steel (227 MPa g-1 cm3 ).


Coronary microvascular adaptations distal to epicardial artery stenosis.
Until recently, epicardial coronary stenosis has been considered the primary outcome of coronary heart disease, and clinical interventions have been dedicated primarily to the identification and removal of flow-limiting stenoses. However, a growing body of literature indicates that both epicardial stenosis and microvascular dysfunction contribute to damaging myocardial ischemia. In this review, we discuss the coexistence of macro- and microvascular disease, and how the structure and function of the distal microcirculation is impacted by the hemodynamic consequences of an epicardial, flow-limiting stenosis. Mechanisms of endothelial dysfunction as well as alterations of smooth muscle function in the coronary microcirculation distal to stenosis are discussed. Risk factors including diabetes, metabolic syndrome, and aging exacerbate microvascular dysfunction in the myocardium distal to a stenosis, and our current understanding of the role of these factors in limiting collateralization and angiogenesis of the ischemic myocardium is presented. Importantly, exercise training has been shown to promote collateral growth and improve microvascular function distal to stenosis; thus, the current literature reporting the mechanisms that underlie the beneficial effects of exercise training in the microcirculation distal to epicardial stenosis is reviewed. We also discuss recent studies of therapeutic interventions designed to improve microvascular function and stimulate angiogenesis in clinically relevant animal models of epicardial stenosis and microvascular disease. Finally, microvascular adaptation to removal of epicardial stenosis is considered.


Improved tomographic reconstruction in seven-pinhole imaging.
Cardiac emission tomography using a seven-pinhole collimator has received only little appreciation as a diagnostic imaging technique. The main reasons are the limited angular sampling of the seven-pinhole device and the difficulties encountered in properly positioning the patient relative to the collimator/camera system. In order to overcome these problems, we have developed a modified ART3 algorithm for reconstruction of the radioactivity distribution in the heart. The method is very appropriate for seven-pinhole tomography, as demonstrated by the quality of the reconstructions, by the excellent point source resolution of the system response, and by a comparison to two other suitable reconstruction techniques, viz., SMART and SIRT.


Idiopathic pigmented purpuric eruption with palmar-plantar involvement.
A case of generalized idiopathic pigmented purpuric eruption with distinctive and rare palmar-plantar involvement is presented. The clinical and histopathologic features, differential diagnosis, and nosology of the idiopathic pigmented purpuric eruptions are presented.


Prolonged infusion antibiotics for suspected gram-negative infections in the ICU: a before-after study.
ß-Lactam antibiotics demonstrate time-dependent killing. Prolonged infusion of these agents is commonly performed to optimize the time the unbound concentration of an antibiotic remains greater than the minimum inhibitory concentration and decrease costs, despite limited evidence suggesting improved clinical results. To determine whether prolonged infusion of ß-lactam antibiotics improves outcomes in critically ill patients with suspected gram-negative infection. We conducted a single-center, before-after, comparative effectiveness trial between January 2010 and January 2011 in the intensive care units at Barnes-Jewish Hospital, an urban teaching hospital affiliated with the Washington University School of Medicine in St. Louis, MO. Outcomes were compared between patients who received standardized dosing of meropenem, piperacillin-tazobactam, or cefepime as an intermittent infusion over 30 minutes (January 1, 2010, to June 30, 2010) and patients who received prolonged infusion over 3 hours (August 1, 2010, to January 31, 2011). A total of 503 patients (intermittent infusion, n = 242; prolonged infusion, n = 261) treated for gram-negative infection were included in the clinically evaluable population. Approximately 50% of patients in each group received cefepime and 20% received piperacillin-tazobactam. More patients in the intermittent infusion group received meropenem (35.5% vs 24.5%; p = 0.007). Baseline characteristics were similar between groups, with the exception of a greater occurrence of chronic obstructive pulmonary disease (COPD) in the intermittent infusion group. Treatment success rates in the clinically evaluable group were 56.6% for intermittent infusion and 51.0% for prolonged infusion (p = 0.204), and in the microbiologically evaluable population, 55.2% for intermittent infusion and 49.5% for prolonged infusion (p = 0.486). Fourteen-day, 30-day, and inhospital mortality rates in the clinically evaluable population for the intermittent and prolonged infusion groups were 13.2% versus 18.0% (p = 0.141), 23.6% versus 25.7% (p = 0.582), and 19.4% versus 23.0% (p = 0.329). Routine use of prolonged infusion of time-dependent antibiotics for the empiric treatment of gram-negative bacterial infections offers no advantage over intermittent infusion antibiotic therapy with regard to treatment success, mortality, or hospital length of stay. These results were confirmed after controlling for potential confounders in a multivariate analysis.


Fermentation performance of engineered and evolved xylose-fermenting Saccharomyces cerevisiae strains.
Lignocellulose hydrolysate is an abundant substrate for bioethanol production. The ideal microorganism for such a fermentation process should combine rapid and efficient conversion of the available carbon sources to ethanol with high tolerance to ethanol and to inhibitory components in the hydrolysate. A particular biological problem are the pentoses, which are not naturally metabolized by the main industrial ethanol producer Saccharomyces cerevisiae. Several recombinant, mutated, and evolved xylose fermenting S. cerevisiae strains have been developed recently. We compare here the fermentation performance and robustness of eight recombinant strains and two evolved populations on glucose/xylose mixtures in defined and lignocellulose hydrolysate-containing medium. Generally, the polyploid industrial strains depleted xylose faster and were more resistant to the hydrolysate than the laboratory strains. The industrial strains accumulated, however, up to 30% more xylitol and therefore produced less ethanol than the haploid strains. The three most attractive strains were the mutated and selected, extremely rapid xylose consumer TMB3400, the evolved C5 strain with the highest achieved ethanol titer, and the engineered industrial F12 strain with by far the highest robustness to the lignocellulosic hydrolysate.


Adverse events of tumor necrosis factor inhibitors.
Adverse events in anti-TNF treatment can be divided into allergic reactions with an acute and delayed onset, infectious complications in relation to the underlying disease, and without. Last but not least, there is the unresolved question of tumor induction and propagation. All of these may account for morbidity and eventually mortality. Literature-based review to update current knowledge about safety and adverse events of TNF blockers. Major drawbacks are infectious complications with the use of anti-TNF-α antibodies. The risk is increased in inflammatory bowel disease in general and in the perioperative setting of Crohn's disease patients. The number of tuberculosis cases has decreased since meticulous testing prior to treatment start is mandatory. An excess mortality that has been reported from referral centers is neither documented in randomized controlled trials nor in real-life settings. Regarding malignancies, lymphoma and skin cancer are a concern. The incidence of lymphoma may be raised, but this has also been debated with the use of thiopurines. Skin cancer, especially melanoma, is more common in inflammatory bowel disease and may be associated with the use of biologics. Overall, most studies do not address the influence of active inflammation or co-administration of other drugs. Hence, the risk attributable to TNF blockers alone is currently ill-defined. Treatment with anti-TNF-α antibodies is an option with substantial risks. Most problems can be prevented by thorough workup of the patient.


The FE-lspd model for electron beam dosimetry.
The FE-lspd model is a two-component electron beam model that distinguishes between electrons that can be described by small-angle transport theory and electrons that are too widely scattered for small-angle transport theory to be applicable. The two components are called the primary beam and the laterally scattered primary distribution (lspd). The primary beam component incorporates a simple version of the Fermi-Eyges model and dominates dose calculations at therapeutic depths. The lspd component corrects erros in the lateral spreading of the primary beam component, thereby improving the accuracy by which the FE-lspd model calculates dose distribution in blocked fields. Comparisons were made between dose profiles and central-axis depth dose distributions in small fields calculated by the FE-lspd, Fermi-Eyges and EGS4 Monte Carlo models for a 10 MeV beam in a homogeneous water phantom. The maximum difference between the dose calculated using the FE-lspd model and EGS4 Monte Carlo is about 6% at a field diameter of about 1 cm, and less than 2% for field sizes greater than 3 cm diameter. The maximum difference between the Fermi-Eyges and Monte Carlo calculations is about 18% at a field diameter of about 2.5 cm. A comparison was made with the central-axis depth dose distribution measured in water for a 3 cm diameter field in a 10 MeV clinical electron beam. The errors in the dose distribution were found to be less than 2% using the FE-lspd model but almost 18% using the Fermi-Eyges model. A comparison was also made with pencil beam profiles calculated using the second-order Fermi-Eyges transport model.


Diverse Basis of β-Catenin Activation in Human Hepatocellular Carcinoma: Implications in Biology and Prognosis.
β-catenin signaling is a major oncogenic pathway in hepatocellular carcinoma (HCC). Since β-catenin phosphorylation by glycogen synthase kinase 3β (GSK3β) and casein kinase 1ε (CK1ε) results in its degradation, mutations affecting these phosphorylation sites cause β-catenin stabilization. However, the relevance of missense mutations in non-phosphorylation sites in exon 3 remains unclear. The current study explores significance of such mutations in addition to addressing the clinical and biological implications of β-catenin activation in human HCC. Gene alteration in exon3 of CTNNB1, gene expression of β-catenin targets such as glutamate synthetase (GS), axin2, lect2 and regucalcin (RGN), and protein expression of β-catenin were examined in 125 human HCC tissues. Sixteen patients (12.8%) showed conventional missense mutations affecting codons 33, 37, 41, and 45. Fifteen additional patients (12.0%) had other missense mutations in codon 32, 34, and 35. Induction of exon3 mutation caused described β-catenin target gene upregulation in HCC cell line. Interestingly, conventional and non-phosphorylation site mutations were equally associated with upregulation of β-catenin target genes. Nuclear localization of β-catenin was associated with poor overall survival (p = 0.0461). Of these patients with nuclear β-catenin localization, loss of described β-catenin target gene upregulation showed significant poorer overall survival than others (p = 0.0001). This study suggests that both conventional and other missense mutations in exon 3 of CTNNB1 lead to β-catenin activation in human HCC. Additionally, the mechanism of nuclear β-catenin localization without upregulation of described β-catenin target genes might be of clinical importance depending on distinct mechanism.


Usability of a Novel Enteral Feeding System: A Summative Study.
Utilization of long-term home enteral nutrition (HEN) for nutrition therapy is increasing across the world. However, HEN can be a mobility-limiting experience affecting quality of life (QoL). Improvement of QoL for patients receiving HEN is a universal goal within the nutrition community. This study evaluated usability of Mobility+®, a novel enteral feeding system (EFS). A summative study evaluating usability of the novel EFS was conducted with novices (NV), non-novices (NN), and healthcare professionals (HCP). Subjects in NV and NN groups received familiarization training where they were introduced to the novel EFS and walked through steps to fill pouch, simulate feeding, flush (rinse), and wear the system, using the Instructions for Use (IFU) booklet, followed by a testing session where they simulated system use on their own. HCP self-trained using the IFU and instructional videos. A fill from ready-to-hang (RTH) formula bag method was also tested in HCP. Participants' ability to loosely coil the tubing and sit, stand, and move around wearing a filled feeding pouch inside a crossbody bag was also evaluated. Forty-five participants completed the study. All participants successfully and safely simulated use of the novel EFS, with 97.8% (44/45) doing so on first attempt. All participants could wear the novel EFS in crossbody bag and move around without any use errors or safety issues. The examined novel EFS can be safely used in intended use population, with or without previous experience with enteral nutrition, on provision of basic familiarization training and written IFU. Additionally, HCP can successfully self-train on this system with instructional videos.


Effects of mercury on reproduction, avoidance, and heat shock protein gene expression of the soil springtail Folsomia candida.
Based on the Cambisols of Beijing (used as agricultural soils), toxicity tests were conducted to investigate the effects of mercury (Hg) on reproduction and avoidance of Folsomia candida (Hexapoda: Collembola), as well as the transcriptional responses of the hsp70 gene, under different Hg concentrations and at different exposure times. Results showed that the hsp70 gene of the springtail was the most sensitive parameter to soil Hg stress, with a half-maximal effective concentration (EC50) of 0.42 mg/kg. The EC50 values based on reproduction and avoidance tests were 9.29 and 3.88 mg/kg, respectively. The expression level of the hsp70 gene was significantly up-regulated when soil Hg concentration was over 0.25 mg/kg (lowest-observed-effect concentration [LOEC]). In addition, responses of this gene expression were strongly induced after 48 h exposure under 1 mg/kg soil Hg, which probably was due to the fast and sensitive response of the gene transcription to Hg stress. Thus, the results suggested that the responses of the hsp70 gene and individual-level effects (reproduction and avoidance) could be integrated to provide helpful information for environmental monitoring and assessment of contaminated soils.


Comparison and development of advanced machine learning tools to predict nonalcoholic fatty liver disease: An extended study.
Nonalcoholic fatty liver disease (NAFLD) is a public health challenge and significant cause of morbidity and mortality worldwide. Early identification is crucial for disease intervention. We recently proposed a nomogram-based NAFLD prediction model from a large population cohort. We aimed to explore machine learning tools in predicting NAFLD. A retrospective cross-sectional study was performed on 15 315 Chinese subjects (10 373 training and 4942 testing sets). Selected clinical and biochemical factors were evaluated by different types of machine learning algorithms to develop and validate seven predictive models. Nine evaluation indicators including area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), accuracy, positive predictive value, sensitivity, F1 score, Matthews correlation coefficient (MCC), specificity and negative prognostic value were applied to compare the performance among the models. The selected clinical and biochemical factors were ranked according to the importance in prediction ability. Totally 4018/10 373 (38.74%) and 1860/4942 (37.64%) subjects had ultrasound-proven NAFLD in the training and testing sets, respectively. Seven machine learning based models were developed and demonstrated good performance in predicting NAFLD. Among these models, the XGBoost model revealed the highest AUROC (0.873), AUPRC (0.810), accuracy (0.795), positive predictive value (0.806), F1 score (0.695), MCC (0.557), specificity (0.909), demonstrating the best prediction ability among the built models. Body mass index was the most valuable indicator to predict NAFLD according to the feature ranking scores. The XGBoost model has the best overall prediction ability for diagnosing NAFLD. The novel machine learning tools provide considerable beneficial potential in NAFLD screening.


Promoting evidence based medicine in preclinical medical students via a federated literature search tool.
Medical educators are increasingly faced with directives to teach Evidence Based Medicine (EBM) skills. Because of its nature, integrating fundamental EBM educational content is a challenge in the preclinical years. To analyse preclinical medical student user satisfaction and feedback regarding a clinical EBM search strategy. The authors introduced a custom EBM search option with a self-contained education structure to first-year medical students. The implementation took advantage of a major curricular change towards case-based instruction. Medical student views and experiences were studied regarding the tool's convenience, problems and the degree to which they used it to answer questions raised by case-based instruction. Surveys were completed by 70% of the available first-year students. Student satisfaction and experiences were strongly positive towards the EBM strategy, especially of the tool's convenience and utility for answering issues raised during case-based learning sessions. About 90% of the students responded that the tool was easy to use, productive and accessed for half or more of their search needs. This study provides evidence that the integration of an educational EBM search tool can be positively received by preclinical medical students.


Cholinesterase inhibitors in Alzheimer's disease: efficacy in a non-selected population.
This paper presents preliminary results on the efficacy of acetyl-cholinesterase inhibitors (ChE-I) administered in a population of patients with mild-to-moderate Alzheimer's disease (AD), recruited in the context of an Italian Department of Health supported project (Progetto Cronos). The patients were followed up for a maximum of 21 months. Around 45% of the subjects responded well to the treatment (i.e., stable or improved Mini Mental State) at the end of the 9th month. Thereafter, a global cognitive and functional decline was reported, more marked in basic daily activities. No factors (age, sex, disease duration, family history for AD, cognitive impairment at baseline) emerged as predictors of outcome.


(Re)criminalizing Abortion: Returning to the Political with Stories.
Abortion stories have always played a powerful role in advancing women's rights. In the abortion sphere particularly, the personal is political. Following the Court's reversal of Roe v. Wade, abortion politics, and abortion storytelling, take on an even deeper political role in challenging the bloodless judicial language of Dobbs with the lived experience of women.


Can oral anaerobic bacteria cause adverse pregnancy outcomes?
Maternal periodontal infection has been recognized as a risk factor for premature and low birthweight infants. It is suspected that pathogens causing periodontal disease may translocate to the amniotic cavity and so contribute to triggering an adverse pregnancy outcome. The aim of this study was to evaluate whether the presence of specific periodontal pathogens may influence the incidence of preterm labor and premature birth. This study was designed as a hospital-based case-control study. A total of 70 pregnant women, aged 18-40 with single live pregnancy were recruited from the Departement of Gynecolgy and Obstetrics at a General hospital in Sibenik, Croatia, between March 2013 to March 2014. The case group: 30 pregnant women who were hospitalised with signs of premature labor. 40 patients with normal pregnancy post-delivery up to 48 hrs, who had given birth at term, and the baby had a weight of more than 2500 gr. These women had undergone microbiological examination at the time of recruitment, microbial samples, paper point subgingival swabs were obtained in both groups and processed by anaerobic culturing. Standard procedures were used for culture and identification of bacteria. Information was collected on demographics, health behaviors, and obstetric and systemic diseases that may have influence the premature delivery. The levels of periodontal pathogens tended to be higher in the premature (case group) labor compared to the term deliveries (control group). Levels of Porphyromonas gingivalis, Fuscobacterium nucleatum, Actinomyces actinomycetecomitans were statistically significantly higher in premature births as compared to term deliveries, adjusting for baseline levels. The joint effects of red and orange microbial clusters were significantly higher in the premature group compared to the term group. The study shows a significant association betwen periodontal anaerobic infection and adverse pregnancy outcome. High levels of periodontal pathogens during pregnancy are associated with an increased risk for preterm delivery. Further studies elucidating the role of the microbial load and maternal immune response as related to pregnancy outcome seem merited.


A cluster randomized trial of standard quality improvement versus patient-centered interventions to enhance depression care for African Americans in the primary care setting: study protocol NCT00243425.
Several studies document disparities in access to care and quality of care for depression for African Americans. Research suggests that patient attitudes and clinician communication behaviors may contribute to these disparities. Evidence links patient-centered care to improvements in mental health outcomes; therefore, quality improvement interventions that enhance this dimension of care are promising strategies to improve treatment and outcomes of depression among African Americans. This paper describes the design of the BRIDGE (Blacks Receiving Interventions for Depression and Gaining Empowerment) Study. The goal of the study is to compare the effectiveness of two interventions for African-American patients with depression--a standard quality improvement program and a patient-centered quality improvement program. The main hypothesis is that patients in the patient-centered group will have a greater reduction in their depression symptoms, higher rates of depression remission, and greater improvements in mental health functioning at six, twelve, and eighteen months than patients in the standard group. The study also examines patient ratings of care and receipt of guideline-concordant treatment for depression. A total of 36 primary care clinicians and 132 of their African-American patients with major depressive disorder were recruited into a cluster randomized trial. The study uses intent-to-treat analyses to compare the effectiveness of standard quality improvement interventions (academic detailing about depression guidelines for clinicians and disease-oriented care management for their patients) and patient-centered quality improvement interventions (communication skills training to enhance participatory decision-making for clinicians and care management focused on explanatory models, socio-cultural barriers, and treatment preferences for their patients) for improving outcomes over 12 months of follow-up. The BRIDGE Study includes clinicians and African-American patients in under-resourced community-based practices who have not been well-represented in clinical trials to improve depression care. The patient-centered and culturally targeted approach to depression care is a relatively new one that has not been tested in most previous studies. The study will provide evidence about whether patient-centered accommodations improve quality of care and outcomes to a greater extent than standard quality improvement strategies for African Americans with depression. ClinicalTrials.gov NCT00243425.


Developmental Idealism and Migration: Theorizing their Relationship and an Empirical Example from Nepal.
This paper brings together both theoretically and empirically two strands of social science research: migration and developmental idealism. The paper is motivated by the fact that there are extensive bodies of research about migration and about developmental idealism, but almost no discussion in the literature about how they might be interconnected. We present theoretical arguments concerning the influence of migration in distributing developmental idealism around the world and in developmental idealism being a force influencing the migration decisions of people. We also provide an empirical investigation of how variation in developmental idealism may have been an influence on migration and choice of migration destinations in Nepal. Thus, we extend the developmental idealism literature to include migration and the migration literature to include developmental idealism.


[The doctor-patient relationship in history].
In the final decades of the XX century the way doctors and patients related to each other changed more than in the twenty-five preceding centuries. The change from a paternalistic to an autonomous model represented a transformation with few historical precedents. The evolution of this phenomenon over time affected the three elements involved: 1. The patient, who had traditionally been considered as a passive receiver of the decisions that the doctor took in his name and for his benefit, was transformed at the end of the XX century into an agent with well-defined rights and a broad capacity for autonomous decision-making on the diagnostic and therapeutic procedures, which were offered to him and no longer imposed on him. 2. The doctor, from being a priestly father-figure (as corresponded to the traditional role of his profession) was transformed into a technical adviser to his patients, to whom he offered his knowledge and advice, but whose decisions were no longer taken for granted. 3. The clinical relationship, from being bipolar, vertical and infantilising, became more collective (with the involvement of numerous health professionals), more horizontal and better adapted to the type of relationship appropriate to adult subjects in democratic societies.


Acetaldehyde self-administration by a two-bottle choice paradigm: consequences on emotional reactivity, spatial learning, and memory.
Acetaldehyde, the first alcohol metabolite, is responsible for many pharmacological effects that are not clearly distinguishable from those exerted by its parent compound. It alters motor performance, induces reinforced learning and motivated behavior, and produces different reactions according to the route of administration and the relative accumulation in the brain or in the periphery. The effective activity of oral acetaldehyde represents an unresolved field of inquiry that deserves further investigation. Thus, this study explores the acquisition and maintenance of acetaldehyde drinking behavior in adult male rats, employing a two-bottle choice paradigm for water and acetaldehyde solution (from 0.9% to 3.2% v/v), over 8 weeks. The behavioral consequences exerted by chronic acetaldehyde intake are assessed by a set of different tests: trials in an open-field arena and elevated-plus maze provided information on both general motor and explorative activity, and anxiety-driven behavioral responses. The Morris water maze allowed the exploration of cognitive processes such as spatial learning and memory. Determination of acetaldehyde levels in the brain was carried out at the end of the drinking paradigm. Our results indicate that rats exposed for the first time to acetaldehyde at 0.9% displayed a regular and stable daily drinking pattern that reached higher values and a "peaks and drops" shaped-trend when acetaldehyde concentration was increased to 3.2%. Accordingly, an increase in acetaldehyde levels in the brain was determined compared to non-acetaldehyde drinking rats. Acetaldehyde intake during the free-choice paradigm exerted an anxiogenic response in the open-field arena and elevated-plus maze, which in turn correlates with an enhancement in cognitive flexibility and spatial orientation skills, when an adaptive response to a stressful environmental challenge was required. These findings further support the idea that acetaldehyde is indeed a centrally active and behaviorally relevant metabolite of alcohol.


Race and ethnicity, mental health services and cultural competence in the criminal justice system: are we ready to change?
By the end of 2003, 3.2% of the U.S. adult population or 6.9 million adults were incarcerated, on probation or on parole. While non-whites constitute approximately 25% of the general U.S. population, they represent the majority of the prison (62%) and jail population (57%), a 33% increase since 1980. Approximately 15% of this prison and jail population has active symptoms of serious mental illness with two-thirds likely to have a co-occurring substance use disorder diagnosis. Meanwhile, the lack of adequate mental health and substance abuse treatment within all levels of the criminal justice system continues to exist. This is further exaggerated by the dearth of evidence showing appropriate cultural awareness and competence in delivery of these much needed services to a majority non-white population. This article will review the existing racial disparities present in the criminal justice system, the lack of appropriate psychiatric services, and the effect of cultural dissonance in service provision when services do exist. Policy implications and recommendations are included in the conclusion with a call for action to all agencies directly and indirectly affected by this multifaceted problem.


Audit and feedback: effects on professional practice and health care outcomes.
Audit and feedback has been identified as having the potential to change the practice of health care professionals. To assess the effects of audit and feedback on the practice of health professionals and patient outcomes. We searched MEDLINE up to June 1997, the Research and Development Resource Base in Continuing Medical Education, and reference lists of related systematic reviews and articles. Randomised trials of audit and feedback (defined as any summary of clinical performance of health care over a specified period of time). The participants were health care professionals responsible for patient care. Two reviewers independently extracted data and assessed study quality. Thirty-seven studies were included, involving more than 4977 physicians. The reporting of study methods was inadequate for almost all studies. In 31 out of 37 studies the randomisation process could not be determined. Information regarding data analysis was also lacking. For example, power calculations were not mentioned in 27 out of 37 studies. A variety of behaviours were targeted including the reduction of diagnostic test ordering, prescribing practices, preventive care, and the general management of a problem, for example hypertension. Twenty-eight studies measured physician performance, one study targeted patient outcomes in diabetes and the remaining eight studies measured both physician performance and patient outcomes. The relative percentage differences ranged from -16% to 152%. The clinical importance of the changes was not always clear. Audit and feedback can sometimes be effective in improving the practice of health care professionals, in particular prescribing and diagnostic test ordering. When it is effective, the effects appear to be small to moderate but potentially worthwhile. Those attempting to enhance professional behaviour should not rely solely on this approach.


Human herpesvirus 6 open reading frame U12 encodes a functional beta-chemokine receptor.
Human herpesvirus 6 (HHV- 6), which belongs to the betaherpesvirus subfamily and infects mainly T cells in vitro, causes acute and latent infections. HHV- 6 contains two genes (U12 and U51) that encode putative homologs of cellular G-protein-coupled receptors (GCR), while three other betaherpesviruses, human cytomegalovirus, murine cytomegalovirus, and human herpesvirus 7, have three, one, and two GCR-homologous genes, respectively. The U12 gene is expressed late in infection from a spliced mRNA. The U12 gene was cloned, and the protein was expressed in cells and analyzed for its biological characteristics. U12 functionally encoded a calcium-mobilizing receptor for beta-chemokines such as regulated upon activation, normal T expressed and secreted (RANTES), macrophage inflammatory proteins 1alpha and 1beta (MIP-1alpha and MIP-1beta) and monocyte chemoattractant protein 1 but not for the alpha-chemokine interleukin-8, suggesting that the chemokine selectivity of the U12 product was distinct from that of the known mammalian chemokine receptors. These findings suggested that the product of U12 may play an important role in the pathogenesis of HHV- 6 through transmembrane signaling by binding with beta-chemokines.


Mitochondrial calcium uniporter in Drosophila transfers calcium between the endoplasmic reticulum and mitochondria in oxidative stress-induced cell death.
Mitochondrial calcium plays critical roles in diverse cellular processes ranging from energy metabolism to cell death. Previous studies have demonstrated that mitochondrial calcium uptake is mainly mediated by the mitochondrial calcium uniporter (MCU) complex. However, the roles of the MCU complex in calcium transport, signaling, and dysregulation by oxidative stress still remain unclear. Here, we confirmed that Drosophila MCU contains evolutionarily conserved structures and requires essential MCU regulator (EMRE) for its calcium channel activities. We generated Drosophila MCU loss-of-function mutants, which lacked mitochondrial calcium uptake in response to caffeine stimulation. Basal metabolic activities were not significantly affected in these MCU mutants, as observed in examinations of body weight, food intake, body sugar level, and starvation-induced autophagy. However, oxidative stress-induced increases in mitochondrial calcium, mitochondrial membrane potential depolarization, and cell death were prevented in these mutants. We also found that inositol 1,4,5-trisphosphate receptor genetically interacts with Drosophila MCU and effectively modulates mitochondrial calcium uptake upon oxidative stress. Taken together, these results support the idea that Drosophila MCU is responsible for endoplasmic reticulum-to-mitochondrial calcium transfer and for cell death due to mitochondrial dysfunction under oxidative stress.


A combined molecular dynamic and quantum mechanic study of the solvent and guest molecule effect on the stability and length of heterocyclic peptide nanotubes.
Molecular dynamic simulations were performed to investigate the stability of heterocyclic peptide nanotubes composed of 1,4-disubstituted-1,2,3-triazol ε-amino acid. 45 ns MD simulations were conducted on the cyclic peptide nanotube (CPNT) and cyclic peptide dimer in methanol, chloroform, and water and revealed that these structures are more stable in nonpolar solvents. MM-PBSA and MM-GBSA calculations were employed to analyze the solvent effect on the stability and length of the CPNT. These calculations showed that CPNT in chloroform was more stable and longer as compared to other solvents. In addition, the effect of the guest molecule (ethanol) inside the dimer and CPNT was investigated. The obtained results confirmed that guest molecule(s) stabilized the dimer and CPNT in all solvents. Quantum chemistry calculations on the cyclic peptide dimer were performed at the M06-2X/6-31G(d) level in the gas phase and three solvents. The obtained results from the quantum chemistry study were in good agreement with the MD simulation results. DFT calculations showed that the guest molecule stabilized the dimer structure and electrostatically interacted with the cyclic peptide dimer. Finally, for investigation of the solvent effects on the hydrogen bonds of the cyclic peptide dimer, NBO and AIM analysis were performed.


Is Variety the Spice of Life? An Experimental Investigation into the Effects of Species Richness on Self-Reported Mental Well-Being.
Losses in biodiversity and trends toward urbanisation have reduced people's contact with biodiverse nature, yet the consequences for mental well-being are not well understood. Here, we demonstrate that greater plant and animal species richness in isolation causes an improvement in mental well-being. To do so, the present research experimentally manipulated species richness and assessed widely-used indicators of mental well-being. Participants viewed short videos of either high or low tree (Study 1) or bird (Study 2) species richness and reported on positive (i.e., vitality, positive affect) and negative (i.e., anxiety) indicators of mental well-being. Building on Study 1, Study 2 included an urban environment as a reference treatment and explored the role of giving participants information on the presented environment. We find that, in line with expectations, watching videos containing greater species richness consistently leads to higher mental well-being. We discuss findings in light of the importance of connecting people to biodiverse environments.


Modelling Ebola.
This paper is the combination of a review on the problems of data collection and modelling efforts of the recent Ebola epidemics. After a brief review of data availability, the modelling frameworks have been discussed. Both deterministic and stochastic models have been reviewed and supplemented with a short discussion of some problems of parameter estimation. The methods have been illustrated by a realistic case study. A hint is given for the scope and limits of prediction and control.


Fructose use in clinical nutrition: metabolic effects and potential consequences.
The current article presents recent findings on the metabolic effects of fructose. Fructose has always been considered as a simple 'caloric' hexose only metabolized by splanchnic tissues. Nevertheless, there is growing evidence that fructose acts as a second messenger and induces effects throughout the human body. Recent discoveries made possible with the evolution of technology have highlighted that fructose induces pleiotropic effects on different tissues. The fact that all these tissues express the specific fructose carrier GLUT5 let us reconsider that fructose is not only a caloric hexose, but could also be a potential actor of some behaviors and metabolic pathways. The physiological relevance of fructose as a metabolic driver is pertinent regarding recent scientific literature.


Relationships between urethrovesical angles and urinary incontinence due to urethral sphincter mechanism incompetence in bitches.
In women, the posterior urethrovesical angle is thought to be an important factor in the aetiology of stress urinary incontinence. This form of incontinence has many similarities to urethral sphincter mechanism incompetence (SMI) in the bitch. The role of the ventral and dorsal urethrovesical angles in the aetiology of SMI in the incontinent bitch has yet to be established. Positive-contrast retrograde vagino-urethrograms from 30 incontinent bitches with a diagnosis of SMI and 30 continent bitches were retrieved and the angles between the urethra and dorsal and ventral bladder walls were measured. No relationship was shown to exist between the dorsal urethrovesical angle (the equivalent of the posterior urethrovesical angle in women) and urinary incontinence due to SMI in bitches. Differences in ventral urethrovesical angles were considered to be associated with differences in bladder neck position between the two groups of bitches.


Is Ahmed valve superior to Baerveldt implant as an aqueous shunt for the treatment of glaucoma?
Aqueous shunt has emerged as an alternative technique to trabeculectomy, considered the standard for glaucoma surgery. Currently, it is mainly indicated after failure of trabeculectomy or in glaucoma with high risk of failure. The Ahmed valve and the Baerveldt implant are the most commonly used aqueous shunts. However, it is not clear whether there are differences between them. To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We identified five systematic reviews including 10 studies overall, of which two were randomized trials. We concluded the Ahmed valve probably achieves a lower decrease in intraocular pressure, might lead to less qualified success and probably needs more reinterventions than the Baerveldt implant. Regarding safety profile, the Ahmed valve is not clearly superior or inferior to the Baerveldt implant.


Predictive Value of a Thyroid-Absorbed Dose with a Shorter Effective Half-Life on Efficacy in Graves Disease Patients Receiving Iodine-131 Therapy.
BACKGROUND Although radioiodine therapy (RIT) efficacy is thoroughly validated for Graves disease (GD), there is a lack of research on the predictive factors of RIT, especially the optimal thyroid-absorbed dose (TD) with a shorter effective half-life (Teff ≤5 days). The goal of this study was to explore the predictive value of TD in GD patients receiving RIT with a shorter Teff. MATERIAL AND METHODS We studied 208 GD patients receiving RIT with a shorter Teff. Plotting the receiver-operating characteristic (ROC) curve verified the accuracy of TD for predicting RIT efficacy in GD patients. In addition, we conducted univariate and multivariate analyses to investigate the influence of 14 factors, including thyroid weight, TD, 24-h radioiodine uptake rate (RAIU), the highest RAIU, thyrotrophin receptor antibody level, thyroglobulin antibody level, thyroid peroxidase antibody level, and others, on curative effects of RIT. RESULTS Of the 208 study participants, complete remission and the total effectiveness rates were 68.3% and 92.3%, respectively. The threshold value of TD to predict RIT efficacy was 70.2 Gy, based on ROC analysis. Univariate analysis showed that 24-h RAIU, Teff, total iodine dose, iodine dose per gram of thyroid tissue, TD, and thyrotropin receptor antibody level were significantly associated with RIT efficacy. Multivariate analysis indicated that 24-h RAIU, total iodine dose, iodine dose per gram of thyroid tissue, and TD were significant independent predictors of RIT efficacy. CONCLUSIONS Predicting RIT efficacy from TD with a shorter Teff was feasible in GD patients, and TD above 70.2 Gy had an especially high predictive accuracy.


H2S promotes developmental brain angiogenesis via the NOS/NO pathway in zebrafish.
Hydrogen sulphide (H2S) is considered as the third member of the gasotransmitter family, along with nitric oxide (NO) and carbon monoxide. H2S has been reported to induce angiogenesis by promoting the growth, migration and tube-like structure formation of endothelial cells. Those studies were conducted in conditions of cell culture, mouse Matrigel plug assay model, rat wound healing model or rat hindlimb ischaemia model. Recent in vivo studies showed the physiological importance of H2S in muscle angiogenesis. However, the importance of endogenous H2S for brain angiogenesis during development remains unknown. We therefore aimed at determining the role of H2S in brain vascular development. Both knockdown and knockout of H2S-producing enzymes, cystathionine β-synthase (cbs) and cystathionine γ-lyase (cth), using morpholino oligonucleotides and clustered regularly interspaced short palindromic repeats/Cas9-mediated mutation, impaired brain vascular development of larval zebrafish. Incubation with the slow-releasing H2S donor GYY4137 alleviated the defects of brain vascular development in cbs and cth morphants. Quantitative analysis of the midbrain vascular network showed that H2S enhances angiogenesis without affecting the topological structure of the brain vasculature. Mechanically, nitric oxide synthase 2a (nos2a) expression and NO production were decreased in both cbs and cth morphants. Overexpression of nos2a by coinjection of cbs or cth MO with full-length zebrafish nos2a mRNA alleviated the brain vascular developmental defects in cbs and cth morphants. We conclude that H2S promotes brain developmental angiogenesis via the NOS/NO pathway in zebrafish.


False-susceptible results from the MS-2 system used for testing resistant Pseudomonas aeruginosa against two third-generation cephalosporins, moxalactam and cefotaxime.
The MS-2 system (Abbott Laboratories) was used for cefotaxime and moxalactam susceptibility testing of 111 Pseudomonas aeruginosa isolates collected from our burn treatment center. The frequency of very major errors was 52% for moxalactam and 32% for cefotaxime for all isolates requiring a minimal inhibitory concentration of greater than or equal to 64 micrograms/ml. For isolates requiring a minimal inhibitory concentration of 64 micrograms/ml, the very major errors were 78% for moxalactam and 57% for cefotaxime. Testing of an additional 44 isolates collected from another hospital confirmed that these results were not unique to nosocomial strains from within the burn center. The ratio of errors did not change when MS-2 results were compared with disk diffusion results. Colony count testing done on cuvettes which produced false-susceptible results indicated that little numerical change occurred during the 5- to 6-h test cycle, whereas microscopy of cuvette contents revealed metabolically active filamentous bacilli. The high frequency of false-susceptible results indicated that the MS-2 should not be used for testing clinical P. aeruginosa isolates for resistance to the two third-generation cephalosporins currently available for the MS-2. A comparison of the disk diffusion results indicated that neither moxalactam nor cefotaxime could be reliably used for predictive, class-concept testing of P. aeruginosa.


Novel feature for catalytic protein residues reflecting interactions with other residues.
Owing to their potential for systematic analysis, complex networks have been widely used in proteomics. Representing a protein structure as a topology network provides novel insight into understanding protein folding mechanisms, stability and function. Here, we develop a new feature to reveal correlations between residues using a protein structure network. In an original attempt to quantify the effects of several key residues on catalytic residues, a power function was used to model interactions between residues. The results indicate that focusing on a few residues is a feasible approach to identifying catalytic residues. The spatial environment surrounding a catalytic residue was analyzed in a layered manner. We present evidence that correlation between residues is related to their distance apart most environmental parameters of the outer layer make a smaller contribution to prediction and ii catalytic residues tend to be located near key positions in enzyme folds. Feature analysis revealed satisfactory performance for our features, which were combined with several conventional features in a prediction model for catalytic residues using a comprehensive data set from the Catalytic Site Atlas. Values of 88.6 for sensitivity and 88.4 for specificity were obtained by 10-fold cross-validation. These results suggest that these features reveal the mutual dependence of residues and are promising for further study of structure-function relationship.


RAISIN - a national programme for early warning, investigation and surveillance of healthcare-associated infection in France.
Surveillance is a key component of the French plan for prevention of healthcare-associated infection (HAI) and has progressively evolved in the past decades. We describe the development and current organisation of surveillance of HAI in France and summarise key achievements and results. Surveillance of HAI is under the auspice of the national institute for public health surveillance through a central coordinating structure, the Reseau d alerte, d investigation et de surveillance des infections nosocomiales (RAISIN), which consists of five regional coordinating structures, two national advisory committees of the Ministry of Health and public health agencies. Surveillance includes the performance of national prevalence surveys every five years (latest in 2006), specific surveillance networks to follow trends and characterise HAI that are national priority, and mandatory reporting of HAI that meet specific criteria for alert purposes. RAISIN prioritises activities, defines technical specifications of surveillance systems, coordinates their implementation, and supports response to alerts, emergences or outbreaks of HAI. We demonstrate that the French surveillance program of HAI has become comprehensive and contributes to evaluating the impact of control and prevention of HAI. Data from RAISIN indicate a general decrease in the risk of HAI in acute care in France. They show a decrease in HAI during recent years, particularly of those related to methicillin-resistant Staphylococcus aureus (MRSA) for which a drop of 38% was documented between 2001 and 2006. RAISIN is also integrated into European surveillance of HAI coordinated by the European Centre for Disease Control.


Patient counseling program to improve the compliance to imatinib in chronic myeloid leukemia patients.
To achieve successful therapeutic outcomes in chronic myeloid leukemia (CML), continuous and adequate imatinib (Gleevec(®), Glivec(®), Novartis Pharmaceuticals, Basel, Switzerland) dosing is essential. Here, we report a patient counseling program ("Care club", "Happy club" in Korea) performed to improve patient compliance with imatinib. From January 2006 to December 2008, patients diagnosed with chronic phase CML and taking imatinb were eligible for this retrospective study. A total of 114 patients from 4 centers in Korea were recruited at a 50:50 ratio for Happy club group versus non-Happy club group at each center. During 36-month follow-up, persistency (the number of days of imatinib prescribed versus 1 year) was higher in the Happy club group (98.2 ± 0.03%) than in the non-Happy club group (79.3 ± 0.16%, P = 0.001), whereas dose compliance (miligrams of imatinib that were actually taken versus miligrams that should have been taken) was not different between two groups; 96.5 ± 0.6% and 96.6 ± 0.7% in the Happy club and non-Happy club (P = 0.958). Overall compliance (the product of persistency and dose compliance) improved in the Happy club group (93.0 ± 2.3%) compared with the non-Happy club group (76.2 ± 7.4%, P = 0.001). The patient counseling program was efficient especially in patients who needed high-dose imatinib (>400 mg/day), and overall compliance was 87.8 ± 6.0% in the Happy club group versus 65.5 ± 16.1% in the non-Happy club group (P = 0.017). In conclusion, the patient counseling program was effective in persisting imatinib medication, resulting in the improvement of overall compliance.


Is Physical Activity Causally Associated With Symptoms of Attention-Deficit/Hyperactivity Disorder?
Emerging evidence suggests that physical activity (PA) enhances cognition and may be a protective factor for attention-deficit/hyperactivity disorder (ADHD). Yet the impact of PA on ADHD symptoms has been investigated only in a few undersized, nonrandomized, and retrospective studies. We examined the effect of PA during late adolescence on ADHD symptoms in early adulthood while controlling for unmeasured genetic and shared environmental confounding. The effect of PA at age 16 to 17 years (baseline) on ADHD symptoms at age 19 to 20 years (follow-up) was examined using a within-monozygotic (MZ) twins fixed-effects model in 232 MZ twin pairs born in Sweden between May 1985 and December 1986. Parents rated their children's DSM ADHD symptoms at baseline and follow-up. Participants' weekly energy expenditure (in metabolic equivalent task minutes per week) was based on self-reports at baseline of PA frequency, intensity, and duration. Greater weekly energy expenditure in adolescence was significantly associated with reduced ADHD symptom levels in early adulthood, even when controlling for unmeasured confounding (all genetic and environmental factors shared within MZ twin pairs) as well as ADHD symptoms and body mass index (BMI) at baseline, β = -0.21, p = .013 (95% CI = -0.38 to -0.05). Similar results were observed for the 2 ADHD subcomponents: hyperactivity/impulsivity, β = -0.21, p = .022 (95% CI = -0.39 to -0.03), and inattention, β = -0.19, p = .049 (95% CI = -0.36 to -0.0005). In line with a causal hypothesis, PA was inversely associated with ADHD symptoms, even after adjusting for unmeasured confounding. These findings suggest that PA in adolescence might decrease ADHD symptoms in early adulthood. However, given the size of the effect, the clinical value of this intervention needs to be explored further.


2021 World Health Organization Classification of Brain Tumors.
The classification of brain tumors is a rapidly evolving field that requires extensive integration of molecular diagnostic findings from an expanding set of platforms and assays. This article summarizes the schema presented in the 5th edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors while highlighting diagnostic molecular findings and discussing the strengths and weaknesses of commonly available testing modalities. Several major changes in practice were introduced with the 5th edition of the CNS WHO classification, including molecular grading of adult diffuse gliomas, the introduction of many new entities within the spectrum of pediatric gliomas and glioneuronal tumors, and the widespread adoption of methylation classes as useful or even necessary diagnostic criteria. Additionally, several revisions to nomenclature (eg, IDH-mutant gliomas) were introduced for simplicity and to disambiguate from other tumor types. The classification of brain tumors continues to grow in complexity alongside our improved understanding of their nuanced molecular underpinnings.


Insights on aerosol properties using two decades-long ground-based remote sensing datasets in Moldova, Eastern Europe.
Aerosol optical properties were studied over Chisinau in Moldova, one of the longest running AERONET sites in Eastern Europe. During two decades (September 1999-November 2018), the mean aerosol optical depth (AOD) and Angstrom exponent (AE) were observed as 0.21 ± 0.13 and 1.49 ± 0.29, respectively. The highest AOD (0.24 ± 0.13) and AE (1.60 ± 0.26) were observed during the summer. More than half (∼55%) of the share was occupied by clean continental aerosols with seasonal order of winter (74.8%) > autumn (62%) > spring (48.9%) > summer (44.8%) followed by mixed aerosols with a respective contribution of 30.7% (summer), 28.4% (spring), 22.5 (autumn) and 16.4% (winter). A clear dominance of volume size distribution in the fine mode indicated the stronger influence of anthropogenic activities resulting in fine aerosol load in the atmosphere. The peak in the fine mode was centered at 0.15 μm, whereas that of the coarse mode was centered either at 3.86 μm (summer and autumn) or 5.06 μm (spring and winter). 'Extreme' aerosol events were observed during 21 days with a mean AOD (AE) of 0.99 ± 0.32 (1.43 ± 0.43), whereas 'strong' events were observed during 123 days with a mean AOD (AE) of 0.57 ± 0.07 (1.44 ± 0.40), mainly influenced by anthropogenic aerosols (during 19 and 101 days of each event type) from urban/industrial and biomass burning indicated by high AE and fine mode fraction. During the whole period (excluding events days), the fine and coarse mode peaks were observed at the radius of 0.15 and 5.06 μm, which in the case of extreme (strong) events were at 0.19 (0.15) and 3.86 (2.24) μm respectively. The fine mode volume concentration was 4.78 and 3.32 times higher, whereas the coarse mode volume concentration was higher by a factor of 1.98 and 2.27 during extreme and strong events compared to the whole period.


Characterization and construction of functional cDNA clones of Pariacoto virus, the first Alphanodavirus isolated outside Australasia.
Pariacoto virus (PaV) was recently isolated in Peru from the Southern armyworm (Spodoptera eridania). PaV particles are isometric, nonenveloped, and about 30 nm in diameter. The virus has a bipartite RNA genome and a single major capsid protein with a molecular mass of 39.0 kDa, features that support its classification as a Nodavirus. As such, PaV is the first Alphanodavirus to have been isolated from outside Australasia. Here we report that PaV replicates in wax moth larvae and that PaV genomic RNAs replicate when transfected into cultured baby hamster kidney cells. The complete nucleotide sequences of both segments of the bipartite RNA genome were determined. The larger genome segment, RNA1, is 3,011 nucleotides long and contains a 973-amino-acid open reading frame (ORF) encoding protein A, the viral contribution to the RNA replicase. During replication, a 414-nucleotide long subgenomic RNA (RNA3) is synthesized which is coterminal with the 3' end of RNA1. RNA3 contains a small ORF which could encode a protein of 90 amino acids similar to the B2 protein of other alphanodaviruses. RNA2 contains 1,311 nucleotides and encodes the 401 amino acids of the capsid protein precursor alpha. The amino acid sequences of the PaV capsid protein and the replicase subunit share 41 and 26% identity with homologous proteins of Flock house virus, the best characterized of the alphanodaviruses. These and other sequence comparisons indicate that PaV is evolutionarily the most distant of the alphanodaviruses described to date, consistent with its novel geographic origin. Although the PaV capsid precursor is cleaved into the two mature capsid proteins beta and gamma, the amino acid sequence at the cleavage site, which is Asn/Ala in all other alphanodaviruses, is Asn/Ser in PaV. To facilitate the investigation of PaV replication in cultured cells, we constructed plasmids that transcribed full-length PaV RNAs with authentic 5' and 3' termini. Transcription of these plasmids in cells recreated the replication of PaV RNA1 and RNA2, synthesis of subgenomic RNA3, and translation of viral proteins A and alpha.


Primary cilia utilize glycoprotein-dependent adhesion mechanisms to stabilize long-lasting cilia-cilia contacts.
The central tenet of cilia function is sensing and transmitting information. The capacity to directly contact extracellular surfaces would empower primary cilia to probe the environment for information about the nature and location of nearby surfaces. It has been well established that flagella and other motile cilia perform diverse cellular functions through adhesion. We hypothesized that mammalian primary cilia also interact with the extracellular environment through direct physical contact. We identified cilia in rod photoreceptors and cholangiocytes in fixed mouse tissues and examined the structures that these cilia contact in vivo. We then utilized an MDCK cell culture model to characterize the nature of the contacts we observed. In retina and liver tissue, we observed that cilia from nearby cells touch one another. Using MDCK cells, we found compelling evidence that these contacts are stable adhesions that form bridges between two cells, or networks between many cells. We examined the nature and duration of the cilia-cilia contacts and discovered primary cilia movements that facilitate cilia-cilia encounters. Stable adhesions form as the area of contact expands from a single point to a stretch of tightly bound, adjacent cilia membranes. The cilia-cilia contacts persisted for hours and were resistant to several harsh treatments such as proteases and DTT. Unlike many other cell adhesion mechanisms, calcium was not required for the formation or maintenance of cilia adhesion. However, swainsonine, which blocks maturation of N-linked glycoproteins, reduced contact formation. We propose that cellular control of adhesion maintenance is active because cilia adhesion did not prevent cell division; rather, contacts dissolved during mitosis as cilia were resorbed. The demonstration that mammalian primary cilia formed prolonged, direct, physical contacts supports a novel paradigm: that mammalian primary cilia detect features of the extracellular space, not just as passive antennae, but also through direct physical contact. We present a model for the cycle of glycoprotein-dependent contact formation, maintenance, and termination, and discuss the implications for potential physiological functions of cilia-cilia contacts.


Recent evidence for the effects of nonnutritive sweeteners on glycaemic control.
By replacing sugar, nonnutritive sweeteners (NNSs) are thought to aid in weight management and decrease insulin resistance. We reviewed the latest randomized clinical trials (RCTs) investigating the effects NNSs on glycaemic control. Six RCTs addressed this topic between 2017 and 2018; the majority tested artificial NNS (sucralose or aspartame), with only one testing natural NNS (stevia and monk fruit extract). Most found no effect of NNS on blood glucose, insulin, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) levels; however, two trials showed an effect of sucralose on the acute insulin response. We are still incapable of reaching a definite judgement on which types of NNS, if any, impact glycaemic control. There is a need for more research to overcome the limitations of recent RCTs, related to sample size, intervention duration, dose, form of NNSs used, and inclusion of males or female participants only. Future studies should also compare different NNS types with each other, and include the increasingly popular 'natural' NNS.


Is rationing the inevitable consequence of medical advance?
The past decades have seen an impressive advance in medical technology. However, there are concerns about the growing costs of medical technology and the need to ration health care services. Some economists argue that the use of technology might be expensive now but that it would be unwise to ration technological advances as they will save money in the long-term. The author argues that increased productivity in health care does not necessarily lead to reduction of costs. In fact, it has often resulted in increased costs because such innovations made possible a widening of the indications for the treatment. Rationing of medical technology is inevitable, as further advances of technology will lead to higher pressures on the financing of the public health care system and the increased removal from the basic package of long-term care services for chronic conditions, the provision of which is an important responsibility of our society.


Negative regulation of mitogen-activated protein kinase activation by integrin alphaIIbbeta3 in platelets.
Activation of the mitogen-activated protein (MAP) kinase pathway in nucleated cells is dependent on both growth factor receptors and integrins engaged in cell adhesion. Human platelets are an interesting model for studying cell adhesion and the involvement of integrin engagement on extracellular signal-regulated kinase (ERK) activation, independently from the nuclear-DNA signal pathway. Maximal phosphorylation and activity of ERK2 occurred late during thrombin-induced platelet aggregation (90 s and later), an alphaIIbbeta3 integrin-dependent event. Surprisingly, alphaIIbbeta3 inhibition by the RGDS ligand peptide, or (Fab')2 fragments of the AP-2 monoclonal antibody, resulted in a 2-fold enhancement in ERK2 phosphorylation and activity. A similar 2-fold enhancement of ERK2 activation was observed in thrombasthenic platelets which are defective in alphaIIbbeta3 and do not aggregate. This suggests that ERK2 activation in thrombin-induced platelet aggregation is dependent on thrombin rather than on alphaIIbbeta3 and is down-regulated by alphaIIbbeta3 engaged in ligand (fibrinogen) binding and/or aggregation. Finally, in the absence of stirring which allows fibrinogen binding to alphaIIbbeta3 but prevents aggregation, ERK2 was again overactivated. This overactivation appears to be consecutive to inhibition of aggregation itself and to alphaIIbbeta3 ligand binding. We conclude that in platelets, alphaIIbbeta3 engaged in aggregation down-regulates thrombin-induced ERK2 activation. To our knowledge, this is the first report of a down-regulation of the MAP kinase pathway by integrin engagement.


Calculation of metabolic fluxes with anatomically separated sources of tracer and tracee.
Traditional calculations of metabolic fluxes using isotope dilution are based on the assumption that tracer and tracee enter the distribution space through effectively identical ports. If the tracer infusion site is not identical with the site of endogenous release of the tracee, the traditional equations for calculating rate of appearance (Ra) of a metabolite may give rise to appreciable errors due to the presence of gradients in specific activity. When tracer and tracee enter by means of anatomically disparate sites, such as may be encountered in the study of metabolite (e.g., lactate, alanine, and glycerol) or free fatty acid turnover, one must employ a modification of the traditional specific activity. This modified specific activity is obtained as the ratio of tracer concentration "near" (in the same compartment as) the source of tracee to the concentration of tracee near the source of tracer infusion. This concept is employed to derive equations for calculating metabolic turnover in both steady- and non-steady-state conditions when entry sites of tracer and tracee are dissimilar.


Long-term survival following aortocoronary artery bypass. Analysis of 4,522 consecutive patients.
At the Texas Heart Institute, from October 1969 through December 1974 a consecutive series of 4,522 patients who underwent aortocoronary bypass procedures was analyzed. Our experience with this procedure over a 5-year period demonstrated a decreasing operative and long-term mortality. This included patients who had aortocoronary bypass alone or in combination with other procedures such as resection of a left ventricular aneurysm or aortic and mitral valve procedures. Actuarial follow-up during the 5 years revealed mortality to be approximately 2.5% per year. Current operative mortality is less than 3.5% regardless of the number of grafts implanted. The rate of late myocardial infarction was only 4% for the entire series. Coronary artery bypass can be safely performed with minimal mortality and increased long-term survival.


Spontaneous abortions among women working in the pharmaceutical industry.
A register based study was conducted on the pregnancy outcome of female workers in eight Finnish pharmaceutical factories to determine whether they had a higher risk of spontaneous abortion than the general population or matched controls. Information about all female workers who had been employed in the factories during the years 1973 or 1975 (four factories) to 1980 was obtained from the employers. The workers' pregnancy data were collected from the nation wide hospital discharge register and polyclinic data of hospitals from 1973 to 1981. The total number of 1795 pregnancies included 1179 deliveries, 142 spontaneous abortions, and 474 induced abortions. The spontaneous abortion rate (the number of spontaneous abortions X 100, divided by the number of spontaneous abortions plus the number of births) during employment was 10.9% and before/after employment 10.6%. The rate for all the women in the corresponding central hospital districts was 11.3% [corrected] during the study period. A case-control study was also carried out in which the cases were 44 women who had a spontaneous abortion during employment in the pharmaceutical factory. Three age matched female pharmaceutical factory workers who had given birth to a child were chosen as controls for every case. The information about occupational exposures was collected from questionnaires completed by the occupational physician or nurse at the factory. The response rate was 93%. Exposure to chemicals was more common among the cases than among the controls. For methylene chloride, a solvent commonly used in the pharmaceutical industry, the increase in odds ratio of borderline significance (odds ratio 2.3, p = 0.06). In a logistic regression model (which included oestrogen exposure, solvent exposure frequency of the usage, and heavy lifting) the odds ratio was increased for oestrogens (odds ratio 4.2, p = 0.05) and for continuous heavy lifting (odds ratio 5.7, p = 0.02). The odds ratio for spontaneous abortions was greater among those exposed to four or more solvents (odds ratio 3.5, p=0.05) than among those exposed to one to three solvents (odds ration 0.8, p=0.74).


Relationship between Structural and Intermediary Determinants of Health and Preterm Delivery.
Preterm birth is a major health problem that leads to infant morbidity and mortality. The main goal of this study was to find the relationship between social determinants of health and preterm delivery. A prospective longitudinal cohort study was carried out on 500 pregnant women in their 24th to 28th gestational weeks in 2012. The pregnant women filled out a self-report questionnaire on the structural determinant, perceived stress, and perceived social support. The participants were followed up until labor and the data about mother and the newborn were collected after labor. The data were analyzed by SPSS 21 and Lisrel 8.8 software programs using pathway analysis. The final path model fit well (CFI=0.96; RMSEA=0.060). Path analysis showed that among structural factors, income had a direct effect (β=0.06) and the factors of income (β=0.00594), number of children (family size) (β=-0.024), as well as mother's education (β=-0.0084) had the greatest overall effect on gestational age at birth respectively. Also, the results showed that among intermediate factors of social determinants of health, stress in the direct path (β=-0.12) and among the overall effects, the perceived stress (β=-0.12) and perceived social support (β=0.0396) affected the gestational age at birth. The current study showed that some structural and intermediary determinants such as income and perceived stress had an effect on preterm labor.


Improvement of Legionnaires' disease diagnosis using real-time PCR assay: a retrospective analysis, Italy, 2010 to 2015.
AimTo evaluate real-time PCR as a diagnostic method for Legionnaires' disease (LD). Detection of Legionella DNA is among the laboratory criteria of a probable LD case, according to the European Centre for Disease Prevention and Control, although the utility and advantages, as compared to culture, are widely recognised.MethodsTwo independent laboratories, one using an in-house and the other a commercial real-time PCR assay, analysed 354 respiratory samples from 311 patients hospitalised with pneumonia between 2010-15. The real-time PCR reliability was compared with that of culture and urinary antigen tests (UAT). Concordance, specificity, sensitivity and positive and negative predictive values (PPV and NPV, respectively) were calculated.ResultsOverall PCR detected eight additional LD cases, six of which were due to Legionella pneumophila (Lp) non-serogroup 1. The two real-time PCR assays were concordant in 99.4% of the samples. Considering in-house real-time PCR as the reference method, specificity of culture and UAT was 100% and 97.9% (95% CI: 96.2-99.6), while the sensitivity was 63.6% (95%CI: 58.6-68.6) and 77.8% (95% CI: 72.9-82.7). PPV and NPV for culture were 100% and 93.7% (95% CI: 91.2-96.3). PPV and NPV for UAT were 87.5% (95% CI: 83.6-91.4) and 95.8% (95% CI: 93.5-98.2).ConclusionRegardless of the real-time PCR assay used, it was possible to diagnose LD cases with higher sensitivity than using culture or UAT. These data encourage the adoption of PCR as routine laboratory testing to diagnose LD and such methods should be eligible to define a confirmed LD case.


Effects of diuretic hormone 31, drosokinin, and allatostatin A on transepithelial K⁺ transport and contraction frequency in the midgut and hindgut of larval Drosophila melanogaster.
Recent studies have identified paracrine and endocrine cells in the midgut of larval Drosophila melanogaster as well as midgut and hindgut receptors for multiple neuropeptides implicated in the control of fluid and ion balance. Although the effects of diuretic factors on fluid secretion by isolated Malpighian tubules of D. melanogaster have been examined extensively, relatively little is known about the effects of such factors on gut peristalsis or ion transport across the gut. We have measured the effects of diuretic hormone 31 (DH31), drosokinin and allatostatin A (AST-A) on both K(+) transport and muscle contraction frequency in the isolated gut of larval D. melanogaster. K(+) absorption across the gut was measured using K(+) -selective microelectrodes and the scanning ion-selective electrode technique. Allatostatin A (AST-A; 1 μM) increased K(+) absorption across the anterior midgut but reduced K(+) absorption across the copper cells and large flat cells of the middle midgut. AST-A strongly inhibited gut contractions in the anterior midgut but had no effect on contractions of the pyloric sphincter induced by proctolin. DH31 (1 μM) increased the contraction frequency in the anterior midgut, but had no effect on K(+) flux across the anterior, middle, or posterior midgut or across the ileum. Drosokinin (1 μM) did not affect either contraction frequency or K(+) flux across any of the gut regions examined. Possible functions of AST-A, DH31, and drosokinin in regulating midgut physiology are discussed.


Effects of vector backbone and pseudotype on lentiviral vector-mediated gene transfer: studies in infant ADA-deficient mice and rhesus monkeys.
Systemic delivery of a lentiviral vector carrying a therapeutic gene represents a new treatment for monogenic disease. Previously, we have shown that transfer of the adenosine deaminase (ADA) cDNA in vivo rescues the lethal phenotype and reconstitutes immune function in ADA-deficient mice. In order to translate this approach to ADA-deficient severe combined immune deficiency patients, neonatal ADA-deficient mice and newborn rhesus monkeys were treated with species-matched and mismatched vectors and pseudotypes. We compared gene delivery by the HIV-1-based vector to murine γ-retroviral vectors pseudotyped with vesicular stomatitis virus-glycoprotein or murine retroviral envelopes in ADA-deficient mice. The vesicular stomatitis virus-glycoprotein pseudotyped lentiviral vectors had the highest titer and resulted in the highest vector copy number in multiple tissues, particularly liver and lung. In monkeys, HIV-1 or simian immunodeficiency virus vectors resulted in similar biodistribution in most tissues including bone marrow, spleen, liver, and lung. Simian immunodeficiency virus pseudotyped with the gibbon ape leukemia virus envelope produced 10- to 30-fold lower titers than the vesicular stomatitis virus-glycoprotein pseudotype, but had a similar tissue biodistribution and similar copy number in blood cells. The relative copy numbers achieved in mice and monkeys were similar when adjusted to the administered dose per kg. These results suggest that this approach can be scaled-up to clinical levels for treatment of ADA-deficient severe combined immune deficiency subjects with suboptimal hematopoietic stem cell transplantation options.


Influence of human T lymphotropic virus type I infection on the etiology of community-acquired pneumonia.
Human T lymphotropic virus type I (HTLV-I), the cause of human T cell leukemia, is associated with a high incidence of several other infectious diseases. However, the relationship between pulmonary infections and HTLV-I infection is still unclear. A large-scale retrospective study was conducted on hospital inpatients to evaluate the relationship between community-acquired pneumonia (CAP) and HTLV-I infection. The present study included 4,666 hospitalized patients during 1991-2007. Three hundred and thirteen of them were diagnosed as CAP. The presence of serum HTLV-I antibody was determined in all patients on admission. Prevalence of HTLV-I infection was analyzed between CAP patients and all inpatients. We also compared HTLV-I-positive CAP patients and HTLV-I-negative CAP patients for severity and manifestation of pneumonia. The prevalence of HTLV-I was higher in CAP patients than in all inpatients (18.9%: 13.7%, p=0.011). The rates of renal diseases and collagen vascular disorders were higher in the HTLV-I-positive CAP patients than in the HTLV-I-negative CAP patients. Multivariate analysis revealed that HTLV-I infection, gender, COPD and collagen vascular disorders were all independent risk factors for CAP. The severity indices of CAP, the PORT score and the CURB-65 score, were higher in the HTLV-I-positive patients than in the HTLV-I-negative patients. This study demonstrates that HTLV-I infection might be an independent risk factor for CAP and that HTLV-I-infected patients tend to demonstrate a relatively severe form of pneumonia.


Parvimonas micra Causing Emphysematous Osteomyelitis: A Case Report.
We present an interesting case of femoral emphysematous osteomyelitis (EO) in a 67-year-old patient with the offending pathogen to be Parvimonas micra. Two knee arthrotomies with lateral thigh exploration were performed to debride and irrigate the bone and compartments. Although the patient initially improved, definitive treatment with an antibiotic intramedullary rod was necessary and resulted in complete resolution. We present the first case of EO secondary to P. micra described in the literature and recommend aggressive surgical management for complete resolution and preserved functional outcome.


Magnesium sulfate for persistent pulmonary hypertension of the newborn.
Persistent pulmonary hypertension of the newborn (PPHN) occurs in approximately 1.9 per 1000 newborns and may be more frequent in developing countries. There is strong evidence for the use of inhaled nitric oxide (iNO) and extra corporeal membrane oxygenation (ECMO) in the treatment of PPHN. However, many developing countries do not have access or the technical expertise required for these expensive therapies. Magnesium sulfate is a potent vasodilator and hence has the potential to reduce the high pulmonary arterial pressures associated with PPHN. If magnesium sulfate were found to be effective in the treatment of PPHN, this could be a cost effective and potentially life-saving therapy. To evaluate the use of magnesium sulfate compared with placebo or standard ventilator management alone, sildenafil infusion, adenosine infusion, or inhaled nitric oxide on mortality or the use of backup iNO or ECMO in term and near-term newborns (> 34 weeks gestational age) with PPHN. The standard search strategy of the Cochrane Neonatal Review Group (CNRG) was used. No language restrictions was applied. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006) and MEDLINE (1966 to April 20, 2007) were searched for relevant randomized and quasi-randomized trials. In addition the reference lists of retrieved articles were reviewed and known experts were contacted to obtain unpublished data. All randomised or quasi-random studies were eligible where one of the treatment groups received magnesium sulfate for PPHN. Standard methods of the Cochrane Collaboration and the CNRG were used, including independent assessment of trial quality and extraction of data by each author. No eligible trials were found On the basis of the current lack of evidence, the use of magnesium sulphate cannot be recommended in the treatment of PPHN. Randomised controlled trials are recommended.