Autocrine activity of soluble Flt-1 controls endothelial cell function and angiogenesis.
The negative feedback system is an important physiological regulatory mechanism controlling angiogenesis. Soluble vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), acts as a potent endogenous soluble inhibitor of VEGF- and placenta growth factor (PlGF)-mediated biological function and can also form dominant-negative complexes with competent full-length VEGF receptors. Systemic overexpression of VEGF-A in mice resulted in significantly elevated circulating sFlt-1. In addition, stimulation of human umbilical vein endothelial cells (HUVEC) with VEGF-A, induced a five-fold increase in sFlt-1 mRNA, a time-dependent significant increase in the release of sFlt-1 into the culture medium and activation of the flt-1 gene promoter. This response was dependent on VEGF receptor-2 (VEGFR-2) and phosphoinositide-3'-kinase signalling. siRNA-mediated knockdown of sFlt-1 in HUVEC stimulated the activation of endothelial nitric oxide synthase, increased basal and VEGF-induced cell migration and enhanced endothelial tube formation on growth factor reduced Matrigel. In contrast, adenoviral overexpression of sFlt-1 suppressed phosphorylation of VEGFR-2 at tyrosine 951 and ERK-1/-2 MAPK and reduced HUVEC proliferation. Preeclampsia is associated with elevated placental and systemic sFlt-1. Phosphorylation of VEGFR-2 tyrosine 951 was greatly reduced in placenta from preeclamptic patients compared to gestationally-matched normal placenta. These results show that endothelial sFlt-1 expression is regulated by VEGF and acts as an autocrine regulator of endothelial cell function.


Microcanonical replica exchange molecular dynamics simulation of proteins.
We present microcanonical replica exchange molecular dynamics simulations as an alternative to canonical ones. Its advantage is the easily tunable high acceptance rate for replica exchange. We present the theory, comment on its actual implementation, and demonstrate its application for a common test case, the trp-cage protein.


Familial unipolar depressive illness: a pedigree study.
The author reports a study of five generations of a family in which several members had unipolar depression responsive to tricyclic medication. He concludes that genetic factors play an important role in this disorder and emphasizes the need for pharmacogenetic studies in psychiatry.


History-adjusted marginal structural models for estimating time-varying effect modification.
Much of epidemiology and clinical medicine is focused on estimating the effects of treatments or interventions administered over time. In such settings of longitudinal treatment, time-dependent confounding is often an important source of bias. Marginal structural models (MSMs) are a powerful tool for estimating the causal effect of a treatment using observational data, particularly when time-dependent confounding is present. In recent statistical work, van der Laan et al. presented a generalized form of MSMs called "history-adjusted" MSMs (Int J Biostat 2005;1:article 4). Unlike standard MSMs, history-adjusted MSMs can be used to estimate modification of treatment effects by time-varying covariates. Estimation of time-dependent causal effect modification is frequently of great practical relevance. For example, clinical researchers are often interested in how the prognostic significance of a biomarker for treatment response can change over time. This article provides a practical introduction to the implementation and interpretation of history-adjusted MSMs. The method is illustrated using a clinical question drawn from the treatment of human immunodeficiency virus infection. Observational cohort data from San Francisco, California, collected between 2000 and 2004, are used to estimate the effect of time until switching antiretroviral therapy regimens among patients receiving a non suppressive regimen and how this effect differs depending on CD4-positive T-lymphocyte count.


On the genetic polymorphism of the serum alpha-amylase in the population of the south western Bulgaria (second communication).
The paper presents data on population distribution of individual phenotypes and gene frequencies of alpha-amylase in random serum samples from the population of the South-Western regions of Bulgaria. We studied 1939 individuals of both sexes aged between 18 and 45 years from the South-Western regions of Bulgaria. They were clinically healthy and without kinship ties. The blood was obtained by venous puncture. The amylase phenotypes were established by horizontal electrophoresis of blood serum on agar gel (1%) after the J. Kompf's method with some modification made in our laboratory. In the Bulgarian population of the South-Western regions of Bulgaria the most frequent alpha-amylase phenotype is Amy1A Amy2A--1603 (82.67) followed by AmylA Amy2A2B--162 (8.35%); Amy1 A1 B Amy2 A--92 (4.74%); AmylA1B Amy2A2B--58 (2.99%); AmylA Amy2B--17 (0.88%); Amy1c Amy2A--5 (0.26%); and Amy1c Amy2A2B--2 (0.11%). The revealed genetic frequencies are as follows: 1a = 0.9577, 1b = 0.0398, 1 degrees = 0.0025 and 2a = 0.9340 and 2b = 0.0660. The difference between the observed theoretically expected types of amylase is not significant so the population studied is in genetic balance regarding the enzyme system. This population does not differ significantly from other populations in gene frequency. A tendency of West-Eastern geographical distribution is evident. Allele frequencies of 1a and 2a tend to increase in that direction. Isoenzyme frequencies in the studied Bulgarian population do not differ significantly from those of the European populations.


Three-dimensional tracking of occluded objects using integral imaging.
We present experiments to illustrate tracking of occluded objects using three-dimensional (3D) integral imaging (II). Tracking of heavily occluded objects by conventional two-dimensional (2D) image processing may be difficult owing to the superposition of occlusion noise and object details. The effects of occlusion are remedied by 3D computational II reconstruction. We use a summation of absolute difference (SAD) algorithm between pixels of consecutive frames of a moving object for 3D tracking. SAD algorithm is not robust for 2D images of occluded objects; 3D computation reconstruction of the scene allows implementation of a SAD algorithm by reducing occlusion effects. Experimental results demonstrate 3D tracking of occluded objects. To the best of our knowledge, this is the first report on 3D tracking of objects using II.


Granzyme A Deficiency Breaks Immune Tolerance and Promotes Autoimmune Diabetes Through a Type I Interferon-Dependent Pathway.
Granzyme A is a protease implicated in the degradation of intracellular DNA. Nucleotide complexes are known triggers of systemic autoimmunity, but a role in organ-specific autoimmune disease has not been demonstrated. To investigate whether such a mechanism could be an endogenous trigger for autoimmunity, we examined the impact of granzyme A deficiency in the NOD mouse model of autoimmune diabetes. Granzyme A deficiency resulted in an increased incidence in diabetes associated with accumulation of ssDNA in immune cells and induction of an interferon response in pancreatic islets. Central tolerance to proinsulin in transgenic NOD mice was broken on a granzyme A-deficient background. We have identified a novel endogenous trigger for autoimmune diabetes and an in vivo role for granzyme A in maintaining immune tolerance.


Biopolymer elasticity: Mechanics and thermal fluctuations.
We present an analytical study of the role of thermal fluctuations in shaping molecular elastic properties of semiflexible polymers. Our study interpolates between mechanics and statistical mechanics in a controlled way and shows how thermal fluctuations modify the elastic properties of biopolymers. We present a study of the minimum-energy configurations with explicit expressions for their energy and writhe and plots of the extension versus link for these configurations and a study of fluctuations around the local minima of energy and approximate analytical formulas for the free energy of stretched twisted polymers. The central result of our study is a closed-form expression for the leading thermal fluctuation correction to the free energy around the nonperturbative writhing family solution for the configuration of a biopolymer. From the derived formulas, the predictions of the wormlike chain model for molecular elasticity can be worked out for a comparison against numerical simulations and experiments.


The forensic investigation of propane gas asphyxiation.
Two unusual suicides of a 19-year-old white man and a 47-year-old white man, involving propane inhalation and plastic bag suffocation, are described. The special characteristics of propane gas as an asphyxiant agent are discussed, as well as its effect on the human body. The discussion emphasizes the postmortem examination and the collection of samples for toxicologic analysis.


Basics of US patents and the patent system.
The patent system plays an important role in stimulating the economy and advancing the quality of life in the United States. It serves as an incentive for innovation by giving inventors an exclusive right to their inventions for a limited period of time. It also increases and hastens the publication of useful knowledge by requiring inventors to disclose their invention to the public. Patents are particularly important in the pharmaceutical and biotechnology industries because they provide a mechanism by which the extremely high product development costs may be recouped. The United States Patent and Trademark Office acts as a gatekeeper in the patent system to prevent patents that do not meet the legal requirements from being thrust on the public. The legal requirements for obtaining a patent are discussed, particularly as they relate to pharmaceutical and biotechnological inventions. The process of examining an application for a patent is briefly described, along with some of the burdens faced by examiners when deciding the patentability of therapy-related inventions.


Segmental Defect-Bridging Intramedullary Knee Arthrodesis for Osseous Hydatidosis of the Distal Femur: A Case Report.
Hydatid cyst is a condition endemic to many parts of the world and is mainly caused by Echinococcus granulosus ( E. granulosus). It rarely affects the bone tissue, with the most commonly impacted sites being the vertebrae and the pelvis. Preoperative diagnosis is challenging and very rarely possible because of its similarities with other pathologies. In this report, we present the case of a 64-year-old patient with osseous hydatidosis of a pathological distal femur fracture. The fracture pattern was not recognized on the initial operation and multiple serial debridements were required to control the disease, leading to a large bone defect and a weakened extensor mechanism. A knee arthrodesis with a segmental defect-bridging intramedullary system was eventually performed, which led to satisfying outcomes. Osseous hydatidosis very often presents itself as a pathological fracture and is difficult to diagnose preoperatively with plain radiographs. Orthopedic surgeons are advised to maintain a high index of suspicion and to test for this disease when cystic bone lesions are detected at fracture sites, especially in patients from endemic regions.


Bending the Curve: A Community-Based Behavioral Parent Training Model to Address ADHD-Related Concerns in the Voluntary Sector in Denmark.
Limited access to evidence-based behavioral parent training (BPT) for addressing attention deficit/hyperactivity disorder (ADHD) has been a growing concern internationally. Models to improve access to BPT are needed, particularly those that can be readily implemented in community settings and that leverage the potential workforce to increase capacity to deliver BPT. The purpose of this study was to evaluate a BPT model which included oft-used content, methods, processes of BPT (common-elements), non-professionally delivered (task-shifted/shared) BPT intervention, and an efficient ancillary support system (training, fidelity, and supervision methods) for families of youth with parental concerns about ADHD. In a randomized controlled trial of 161 families of children (79% male; mean age 7.04 [1.55]), the Caring in Chaos (CiC) BPT model, delivered by community volunteers across 12 community-based sites in Denmark, was compared to a wait-list control condition on key child and parent outcomes at immediate post-treatment and 4-month follow-up assessment points. Results suggested that the CiC model led to significantly greater improvement in parenting behavior, parenting sense of competence, child functional impairment, parental stress and parental depressive symptoms compared to the wait list condition at immediate post-treatment, with maintenance of gains in most of these areas at follow-up assessment. No effect of intervention was found on ADHD symptoms. The results of this study suggest that developing efficient BPT intervention models, such as the CiC model, can result in readily implemented interventions by a variety of individuals in community settings. Such models are necessary to bend the curve on addressing unmet needs of families of youth with concerns about ADHD.


Nanomedicine and Cardiovascular Disease.
Nanomedicine has become an important tool in the imaging and therapy of numerous diseases. This is due, in large part, to the ability to generate multifunctional nanoagents bearing combinations of targeting, diagnostic, and therapeutic moieties, allowing for the tailoring of the properties of the synthesized nanomaterials. With respect to cardiovascular disease and its sequelae, nanomedicine has the potential to detect and treat some of the leading causes of death and disability in the developed world, including atherosclerosis, thrombosis, and myocardial infarction. As such, this review focuses on some of the most poignant examples of the utility of nanomedicine in the detection and treatment of cardiovascular disease that have been recently reported.


Dysfunction of endocytic kinase AAK1 in ALS.
Mechanisms of human mutant superoxide dismutase 1 (SOD1)-induced toxicity in causing the familial form of amyotrophic lateral sclerosis (ALS) remain elusive. Identification of new proteins that can selectively interact with mutant SOD1s and investigation of their potential roles in ALS are important to discover new pathways that are involved in disease pathology. Using the yeast two-hybrid system, we identified the adaptor-associated kinase 1 (AAK1), a regulatory protein in clathrin-coated vesicle endocytic pathway that selectively interacted with the mutant but not the wild-type SOD1. Using both transgenic mouse and rat SOD1-linked familial ALS (FALS) models, we found that AAK1 was partially colocalized with the endosomal and presynaptic protein markers under the normal physiological condition, but was mislocated into aggregates that contained mutant SOD1s and the neurofilament proteins in rodent models of ALS in disease. AAK1 protein levels were also decreased in ALS patients. These results suggest that dysfunction of a component in the endosomal and synaptic vesicle recycling pathway is involved in ALS pathology.


Factors associated with early-stage pulmonary fibrosis as determined by high-resolution computed tomography among persons occupationally exposed to asbestos.
Asbestosis remains difficult to diagnose, particularly in its early stages. The aim of this study was to determine criteria for independently associated features of pulmonary fibrosis in high-resolution computed tomograms among persons occupationally exposed to asbestos. Retired persons with documented occupational asbestos exposure and no known asbestos-related diseases were assessed for occupational, clinical, functional respiratory, and chest X-ray criteria. In addition, they all underwent high-resolution computed tomography (HRCT) in the prone position. Altogether 51 (7.2%) of the 706 enrolled participants had features of pulmonary fibrosis consistent with asbestosis in the HRCT. Among those with small irregular opacities of <1/0 according to the 1980 International Labour Office Classification (ILO-C) in their X-rays, 5% had asbestosis in the HRCT. In a multivariate analysis, only age [odds ratio (OR) per year 1.08, 95% confidence interval (95% CI) 1.02-1.14], cumulative-exposure index (CEI) for asbestos (OR 6.4, 95% CI 1.5-28.4 for a CEI of > or =100 fibers/ml x years), and the presence of small irregular X-ray opacities of > or =1/0 ILO-C (OR 3.0, 95% CI 1.6-6.0) were independently associated with HRCT asbestosis. No combinations of these criteria simultaneously yielded high sensitivity and specificity for the diagnosis of early-stage HRCT asbestosis. Moreover, only 2% of the persons with a CEI of <25 fibers/ml x years had HRCT asbestosis, the finding confirming the low incidence of asbestosis for such low exposure, as previously reported on the basis of X-ray data. Additional research is needed to better identify the persons most likely to benefit from HRCT screening for asbestosis.


Factors influencing the use of single vs multiple fractions of palliative radiotherapy for bone metastases: a 5-year review.
Evidence from a number of randomised trials and meta-analyses supports the use of single-fraction radiotherapy for the palliation of painful bone metastases. This study explores patient and treatment factors that influence the choice of single compared with multiple-fraction radiotherapy for the treatment of bone metastases in clinical practice. The Princess Margaret Hospital Palliative Radiation Oncology Program Database served as the basis for our report. All courses of treatment delivered for bone metastases were extracted. Courses were classified into single or multiple fractions. Clinical characteristics were compared between the two groups. Between 1998 and 2002, 882 courses of radiotherapy were delivered for the treatment of bone metastases, of which 283 (32%) were a single fraction. The proportion of single-fraction treatments was 37% in 1998, 30% in 1999 and 43% in 2000, but dropped to 26% and 28% in 2001 and 2002, respectively (P = 0.02). Patients treated with single fractions were significantly older (68 +/- 12 years vs 64 +/- 12 years), and had more weight loss and poor performance status. Single fractions included 20% of treatments in palliative irradiation of the spine, 36% in the pelvis and long bones, and 59% in the chest wall (P < 0.001). There was no significant difference in patients' gender, primary cancers, number of metastatic sites, treating physicians, enrollment in a clinical trial and general radiotherapy waiting time in our department. Multivariate analysis indicated age (P = 0.001), performance status (P < 0.001), anatomical site (P < 0.001) and year of radiotherapy (P = 0.006) as significant. One-third of palliative radiotherapy courses for bone metastases in our programme were given as single fractions. Performance status, age and anatomical site were significant factors affecting single compared with multiple fractionation. The variation in the use of single fractions over time may reflect the dynamic process of interpretation and application of evidence from clinical trials to practice.


The Boom in 3D-Printed Sensor Technology.
Future sensing applications will include high-performance features, such as toxin detection, real-time monitoring of physiological events, advanced diagnostics, and connected feedback. However, such multi-functional sensors require advancements in sensitivity, specificity, and throughput with the simultaneous delivery of multiple detection in a short time. Recent advances in 3D printing and electronics have brought us closer to sensors with multiplex advantages, and additive manufacturing approaches offer a new scope for sensor fabrication. To this end, we review the recent advances in 3D-printed cutting-edge sensors. These achievements demonstrate the successful application of 3D-printing technology in sensor fabrication, and the selected studies deeply explore the potential for creating sensors with higher performance. Further development of multi-process 3D printing is expected to expand future sensor utility and availability.


The Dizziness Handicap Inventory does not correlate with vestibular function tests: a prospective study.
The Dizziness Handicap Inventory (DHI) is believed to quantitate the handicap related to the presence or severity of underlying vestibular dysfunction. However, patients with chronic vestibular diseases may manifest various degrees of behavioural and physiological adaptation resulting in variances of the DHI. Our primary study objective is to evaluate the correlation between the DHI and measurable vestibular parameters. Secondarily, we compared DHI among different vestibular disorders (central, peripheral and functional), and different types of anatomic deficits (semicircular canal vs otolithic). We also correlated the DHI and posturography. We prospectively evaluated 799 patients with precise vestibular diagnoses using video head impulse testing (vHIT), caloric irrigation, and cervical/ocular vestibular-evoked myogenic potentials (c/oVEMP). Posturography was done for 84 patients. All participants completed the DHI. No significant correlation was found between DHI and (1) vestibulo-ocular reflex parameters: unilateral weakness r = - 0.018, total calorics r = 0.055, vHIT right r = 0.007, vHIT left r = - 0.091, vHIT asymmetry r = 0.013; (2) otolith parameters: cVEMP amplitude right r = - 0.034, amplitude left r = - 0.004, asymmetry r = 0.016; oVEMP amplitude right r = 0.044, amplitude left r = - 0.007, asymmetry r = - 0.008. Patients with central vestibular disorders had higher DHI than those with peripheral (z = - 4.743, p = 0.001) or functional disorders (z = - 2.902, p = 0.004). DHI of patients with deficits of canal or otolith function did not differ significantly from those with no deficits (z = 2.153, p = 0.541). There was no significant correlation between DHI and postural sway on posturography. Therefore, the DHI does not correlate with vestibular tests, and neither reflects the presence nor severity of peripheral vestibular deficits.


Synchronous differentiation of Trypanosoma brucei from bloodstream to procyclic forms in vitro.
The differentiation of mammalian stage Trypanosoma brucei bloodstream forms comprising predominantly parasites of intermediate and stumpy morphology to the procyclic forms characteristic for the insect midgut stage was studied in vitro. Differentiation of the cell population occurred synchronously as judged by the synthesis of the surface glycoprotein, procyclin, characteristic of the arising procyclic forms and the loss of the membrane-form variant surface glycoprotein, the coat protein of bloodstream forms. The change in surface antigens took place within 12 h in the absence of cell growth; subsequently, the procyclic cells divided exponentially. As defined in this study, T. brucei may be a useful model to follow other changes in gene expression, metabolism or ultrastructure during differentiation of a unicellular eucaryote.


Deep Sequencing Reveals Novel Genetic Variants in Children with Acute Liver Failure and Tissue Evidence of Impaired Energy Metabolism.
The etiology of acute liver failure (ALF) remains elusive in almost half of affected children. We hypothesized that inherited mitochondrial and fatty acid oxidation disorders were occult etiological factors in patients with idiopathic ALF and impaired energy metabolism. Twelve patients with elevated blood molar lactate/pyruvate ratio and indeterminate etiology were selected from a retrospective cohort of 74 subjects with ALF because their fixed and frozen liver samples were available for histological, ultrastructural, molecular and biochemical analysis. A customized next-generation sequencing panel for 26 genes associated with mitochondrial and fatty acid oxidation defects revealed mutations and sequence variants in five subjects. Variants involved the genes ACAD9, POLG, POLG2, DGUOK, and RRM2B; the latter not previously reported in subjects with ALF. The explanted livers of the patients with heterozygous, truncating insertion mutations in RRM2B showed patchy micro- and macrovesicular steatosis, decreased mitochondrial DNA (mtDNA) content <30% of controls, and reduced respiratory chain complex activity; both patients had good post-transplant outcome. One infant with severe lactic acidosis was found to carry two heterozygous variants in ACAD9, which was associated with isolated complex I deficiency and diffuse hypergranular hepatocytes. The two subjects with heterozygous variants of unknown clinical significance in POLG and DGUOK developed ALF following drug exposure. Their hepatocytes displayed abnormal mitochondria by electron microscopy. Targeted next generation sequencing and correlation with histological, ultrastructural and functional studies on liver tissue in children with elevated lactate/pyruvate ratio expand the spectrum of genes associated with pediatric ALF.


Correlation between focal lesion sites and language deficits in the acute phase of post-stroke aphasia.
Focal lesion sites can predict the language function of patients with aphasia during the subacute or chronic phases. However, the relationship between focal lesion sites and language deficits in the acute phase remains unclear. Therefore, our study aimed to investigate the relationship between focal lesion sites and fluency, auditory comprehension, repetition and naming deficits in patients with acute aphasia to further understand the pathophysiological mechanism of aphasia. We included a total of 52 patients with acute aphasia who had their first-ever stroke between June 2018 and June 2021 to investigate the association between focal lesion sites and fluency, auditory comprehension, repetition and naming deficits. Language function was assessed by the Western Aphasia Battery scale within one month of onset. The lesion sites were independently assessed by three professional speech and language pathologists according to the main sulcus of the brain within 1-2 days after stroke. Lesions involving the superior temporal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, postcentral gyrus, supramarginal gyrus, angular gyrus and insula were significantly associated with low fluency. Lesions involving the superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, middle frontal gyrus, inferior frontal gyrus, supramarginal gyrus and angular gyrus significantly resulted in auditory comprehension impairment. Lesions involving the superior temporal gyrus, middle temporal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, postcentral gyrus, supramarginal gyrus, angular gyrus and insula significantly resulted in repetition and naming deficits. Our study suggests that focal lesion sites could lead to different language function impairments in the acute phase of post-stroke aphasia, which adds to our understanding of speech pathology and provides a direction for future research and treatment.


Effects of must concentration techniques on wine isotopic parameters.
Despite the robustness of isotopic methods applied in the field of wine control, isotopic values can be slightly influenced by enological practices. For this reason, must concentration technique effects on wine isotopic parameters were studied. The two studied concentration techniques were reverse osmosis (RO) and high-vacuum evaporation (HVE). Samples (must and extracted water) have been collected in various French vineyards. Musts were microfermented at the laboratory, and isotope parameters were determined on the obtained wine. Deuterium and carbon-13 isotope ratios were studied on distilled ethanol by nuclear magnetic resonance (NMR) and isotope ratio mass spectrometry (IRMS), respectively. The oxygen-18 ratio was determined on extracted and wine water using IRMS apparatus. The study showed that the RO technique has a very low effect on isotopic parameters, indicating that this concentration technique does not create any isotopic fractionation, neither at sugar level nor at water level. The effect is notable for must submitted to HVE concentration: water evaporation leads to a modification of the oxygen-18 ratio of the must and, as a consequence, ethanol deuterium concentration is also modified.


Evaluation of a home-based intervention program to reduce infant passive smoking and lower respiratory illness.
We conducted a randomized controlled trial to determine whether a home-based intervention program could reduce infant passive smoking and lower respiratory illness. The intervention consisted of four nurse home visits during the first 6 months of life, designed to assist families to reduce the infant's exposure to tobacco smoke. Among the 121 infants of smoking mothers who completed the study, there was a significant difference in trend over the year between the intervention and the control groups in the amount of exposure to tobacco smoke; infants in the intervention group were exposed to 5.9 fewer cigarettes per day at 12 months. There was no group difference in infant urine cotinine excretion. The prevalence of persistent lower respiratory symptoms was lower among intervention-group infants of smoking mothers whose head of household had no education beyond high school: intervention group, 14.6%; and controls, 34.0%.


Natural orbital functional for spin-polarized periodic systems.
Natural orbital functional theory is considered for systems with one or more unpaired electrons. An extension of the Piris natural orbital functional (PNOF) based on electron pairing approach is presented, specifically, we extend the independent pair model, PNOF5, and the interactive pair model PNOF7 to describe spin-uncompensated systems. An explicit form for the two-electron cumulant of high-spin cases is only taken into account, so that singly occupied orbitals with the same spin are solely considered. The rest of the electron pairs with opposite spins remain paired. The reconstructed two-particle reduced density matrix fulfills certain N-representability necessary conditions, as well as guarantees the conservation of the total spin. The theory is applied to model systems with strong non-dynamic (static) electron correlation, namely, the one-dimensional Hubbard model with periodic boundary conditions and hydrogen rings. For the latter, PNOF7 compares well with exact diagonalization results so the model presented here is able to provide a correct description of the strong-correlation effects.


Orbital optic nerve gliomas in children with neurofibromatosis type 1.
To describe the clinical course and treatment of symptomatic orbital optic nerve gliomas in children with neurofibromatosis type-1 (NF-1). A retrospective review of the records of patients with NF-1 and symptomatic orbital optic nerve gliomas seen in a large multidisciplinary NF-1 clinic of a tertiary care children's hospital. The main outcome measures included presenting symptoms and signs, ophthalmologic examination at diagnosis, the presence of progressive disease following diagnosis, type of therapy, and the reasons therapy was instituted. Twelve patients with symptomatic orbital optic nerve gliomas, all of which led to proptosis (eight girls, four boys), were identified. The mean age of diagnosis of NF-1 was 20 months; the mean age of diagnosis of the orbital optic nerve glioma was 26 months. At the time of diagnosis of the tumor, 10 of 12 patients (83%) had decreased visual acuity in the affected eye. Three patients underwent optic nerve resection; eight received chemotherapy, and one was observed without therapy. Of the eight children who received chemotherapy, progressive disease prior to treatment could be documented in only three; none of these eight children had a reproducible improvement in vision following chemotherapy. There was no demonstrable improvement in vision in any treated patient with NF-1-associated orbital optic nerve gliomas. Although not definitively proven, our data and previous studies suggest that NF-1-associated orbital optic nerve gliomas should not be treated unless there is clear evidence of either ophthalmologic or radiographic progression. Surgical excision of tumors which have led to proptotic eyes without functional vision should be reserved for cosmetic purposes or to treat complications of exposed globes.


Molecular Mechanisms behind the Physiological Resistance to Intense Transient Warming in an Iconic Marine Plant.
The endemic Mediterranean seagrass Posidonia oceanica is highly threatened by the increased frequency and intensity of heatwaves. Meadows of the species offer a unique opportunity to unravel mechanisms marine plants activate to cope transient warming, since their wide depth distribution impose divergent heat-tolerance. Understanding these mechanisms is imperative for their conservation. Shallow and deep genotypes within the same population were exposed to a simulated heatwave in mesocosms, to analyze their transcriptomic and photo-physiological responses during and after the exposure. Shallow plants, living in a more unstable thermal environment, optimized phenotype variation in response to warming. These plants showed a pre-adaptation of genes in anticipation of stress. Shallow plants also showed a stronger activation of heat-responsive genes and the exclusive activation of genes involved in epigenetic mechanisms and in molecular mechanisms that are behind their higher photosynthetic stability and respiratory acclimation. Deep plants experienced higher heat-induced damage and activated metabolic processes for obtaining extra energy from sugars and amino acids, likely to support the higher protein turnover induced by heat. In this study we identify transcriptomic mechanisms that may facilitate persistence of seagrasses to anomalous warming events and we discovered that P. oceanica plants from above and below the mean depth of the summer thermocline have differential resilience to heat.


[Simultaneous determination of bensulfuron-methyl and mefenacet residues in paddy field using high performance liquid chromatography].
An analytical method of high performance liquid chromatography (HPLC) was established for the simultaneous determination of bensulfuron-methyl and mefenacet residues in paddy field (paddy water, soil and rice plant). The residues in the paddy water was extracted with methylene chloride, and the soil with alkaline mixed solution of acetonitrile-methylene chloride (1:1, v/v). The rice plant was extracted with alkaline methylene chloride which was cleaned up by a Florisil column. The separation was performed on a stainless steel C18 column (150 mm x 4.6 mm, 5 microm) at 30 degrees C by HPLC with an ultraviolet detector (UVD) at 238 nm, and water-methanol (30:70, v/v) as the mobile phase at a flow rate of 0.5 mL/min. The quantification was performed by external standard. The calibration curves were linear between the peak area and the concentration in the range of 0.05-5.00 mg/L for bensulfuron-methyl and mefenacet, and the correlation coefficients were more than 0.999 9. The average recoveries of the two herbicides spiked in the paddy water, soil and rice plant at the three concentration levels of 0.05, 0.10 and 1.00 mg/kg ranged from 85.39% to 113.33% with the relative standard deviations of 0.91%-10.24%. The method is characterized by simplicity, sensitivity and accuracy.


Taste-evoked responses to sweeteners in the nucleus of the solitary tract differ between C57BL/6ByJ and 129P3/J mice.
C57BL/6ByJ (B6) and 129P3/J (129) mice have different alleles of Tas1r3, which is thought to influence gustatory transduction of sweeteners, but studies have provided conflicting results regarding differences in sweetness perception between these strains. Single-unit taste-evoked activity was measured in the nucleus of the solitary tract (NST) in anesthetized B6 and 129 mice to address this controversy and to provide the first electrophysiological characterization of this nucleus in mice. Neurons had properties similar to those of NST cells in other species, including mean breadth-of-tuning of 0.8 +/- 0.0. There were no strain differences in neural responses at 600 or 900 ms after onset, but, with a 5 s evoked period, responses to the sweeteners sucrose, maltose, acesulfame-K, SC-45647, and D-phenylalanine were significantly larger in B6 relative to 129 mice. The strains did not differ in their mean response to NaSaccharin, but it evoked an across-neuron pattern of activity that was more similar to that of sucrose and less similar to that of NaCl in B6 mice compared with 129 mice. Neurons were classified as sucrose, NaCl, or HCl responsive, with the former more common in B6 than 129 mice. Relative to other neurons, sucrose-responsive cells had delayed but more sustained sweetener responses in both strains. The results suggest that B6 mice perceive some sweeteners as more intense, but NaSaccharin as sweeter and less salty, relative to 129 mice. Furthermore, activity evoked by sweeteners includes a phasic response sent to different NST cells than a later tonic response, and only the latter differs between B6 and 129 mice.


Cutaneous Bacteria of Confiscated Telmatobius culeus in Lima, Peru.
The Lake Titicaca frog is endangered due to threats such as water pollution, introduced species, and overharversting for markets, where people consume them as frog juice. This study, conducted June to November 2012, aimed to determinate the bacteria microflora living on the skin of frogs confiscated from the La Parada market, Lima, Peru, and housed individually in the Laboratory of Wildlife at the Faculty of Veterinary Medicine and Zootechnic of the Universidad Peruana Cayetano Heredia in Lima, Peru. Samples collected with sterile swabs and cultured on blood, tryptic soy, and MacConkey agars were investigated using commercially available test kits, to investigate the commonly encountered bacterial and potentially zoonotic microorganisms associated with their consumption. We found three species of zoonotic concern in the genus Vibro: Vibrio alginolyticus, Vibro cholerae, and Vibro fluvialis. Other Gram-negative species cultured included two different colonies of Aeromonas hydrophila, or Aeromonas caviae or Aeromonas sobria; Pseudomona luteola; one example of Weeksella virosa or Empedobacter brevis; and Citrobacter freundii. Gram-positive bacteria detected were Staphylococcus spp., Micrococcus spp., and Erysipelothrix rhusiopathiae. We recommend against the consumption of this frog due to the pathogens it may carry that could cause serious illness among consumers and in vendors who handle animals.


Synaptojanin 1 mutation in Parkinson's disease brings further insight into the neuropathological mechanisms.
Synaptojanin 1 (SYNJ1) is a phosphoinositide phosphatase highly expressed in nerve terminals. Its two phosphatase domains dephosphorylate phosphoinositides present in membranes, while its proline-rich domain directs protein-protein interactions with synaptic components, leading to efficient recycling of synaptic vesicles in neurons. Triplication of SYNJ1 in Down's syndrome is responsible for higher level of phosphoinositides, enlarged endosomes, and learning deficits. SYNJ1 downregulation in Alzheimer's disease models is protective towards amyloid-beta peptide (Aβ) toxicity. One missense mutation in one of SYNJ1 functional domains was recently incriminated in an autosomal recessive form of early-onset Parkinson's disease (PD). In the third decade of life, these patients develop progressive Parkinsonism with bradykinesia, dystonia, and variable atypical symptoms such as cognitive decline, seizures, and eyelid apraxia. The identification of this new gene, together with the fact that most of the known PD proteins play a role in synaptic vesicle recycling and lipid metabolism, points out that synaptic maintenance is a key player in PD pathological mechanisms. Studying PD genes as a network regulating synaptic activity could bring insight into understanding the neuropathological processes of PD and help identify new genes at fault in this devastating disorder.


Left ventricular hypertrophy and abnormal ventricular geometry in children and adolescents with obstructive sleep apnea.
Obstructive sleep apnea (OSA) has been shown to be an independent risk factor for cardiovascular disease in adults. However, there are severe limitations in the extent to which the cardiovascular consequences of OSA are being studied in children. To investigate the echocardiographic changes in children with OSA, right and left ventricular (RV, LV) dimensions and LV mass index and geometry were measured in 28 children with OSA and 19 children with primary snoring (PS). The study showed that LV mass index and relative wall thickness were greater in the OSA group compared with those with PS (p = 0.012 and p < 0.0001, respectively). An apnea-hypopnea index of more than 10 per hour was significantly associated with RV dimension above the 95th percentile (odds ratios, 6.7; 95% confidence interval, 1.4-32) and LV mass index above the 95th percentile (odds ratios, 11.2; confidence interval, 1.9-64). Abnormality of LV geometry was present in 15% of children with PS compared with 39% of children with OSA. We conclude that OSA in children is associated with increased LV mass.


Combination of flecainide and mexiletine for the treatment of ventricular tachyarrhythmias.
A combination of oral flecainide and mexiletine was given to 11 patients in whom monotherapy with one of these drugs was ineffective for the suppression of inducible ventricular tachycardia or fibrillation. In eight of 11 studies, combination therapy prevented inducibility of a sustained ventricular tachycardia or resulted in induction of only nonsustained tachycardia (P = 0.0003, when compared to monotherapy). In one patient, a slow ventricular tachycardia was induced. During exercise testing ventricular tachycardia occurred in two of these nine patients, and ventricular fibrillation in another patient. Seven patients received combination on the long term, for a mean of 18 months. One patient had recurrences of ventricular tachycardia which was well tolerated. Another patient had a recurrent episode of ventricular fibrillation, but was successfully resuscitated. Severe congestive heart failure occurred in two patients. ACE inhibitors were given to them and to another four patients. No other important unwanted effects occurred. The combination of mexiletine and flecainide is very effective in suppressing inducible sustained ventricular tachycardia. The efficacy of this combination to prevent recurrences of ventricular tachyarrhythmias is acceptable. Exercise testing is of importance to unmask proarrhythmic effects before discharge from hospital.


[Filariasis control: entry point for other helminthiasis control programs?].
Filariasis control programs are based on a decentralized drug distribution strategy known as "community-directed". This strategy could also be applied to the control of schistosomiasis and intestinal nematode infections. Integration of these control programs could be highly cost-effective. However, as a prerequisite for integration, it would be necessary to identify zones where these helminthic infections co-exist, specify the population categories that should receive each medication (ivermectin, albendazole, mebendazole, and praziquantel), check that combined administration of these drugs is safe and ensure that an integrated program would have no detrimental effect on the health care system and on the efficacy of ongoing programs.


Layered wrapping technique combined with oxidized cellulose and vascular prosthesis for effective haemostasis in aortic surgery.
Bleeding from anastomotic sites is one of the major complications of aortic surgery. We describe a novel double-layer wrapping technique using a combination of oxidized cellulose and a vascular prosthesis to effectively achieve haemostasis. The anastomotic site is surrounded by a prosthetic graft inlaid with a strip of Nu-Knit. These are fixed by horizontal mattress and over-and-over sutures. Nu-Knit acts as an ideal cushion to achieve haemostasis, because it has a haemostatic effect and fills the space between the anastomotic site and wrapping graft. This technique is simple, and facilitates adequate haemostasis without complications.


Rural and urban substance use differences: Effects of the transition to college.
With approximately 20% of Americans residing in rural communities, substance use differences is an important topic for appropriate use of resources, policy decisions, and the development of prevention and intervention programs. The current study examined differences in alcohol, tobacco, and marijuana use among students from rural and urban backgrounds across the transition to college. Participants were 431 (48% male) undergraduate students from a large, public southeastern university who provided yearly alcohol, tobacco, and marijuana use data during freshman, sophomore, and junior years. Prevalence of alcohol, tobacco, and marijuana use was lower during early college years, and females were less likely to use tobacco and marijuana. Results indicated that rural individuals were less likely to use alcohol and marijuana than their urban counterparts as freshmen, but rose to meet the rates of urban students by junior year. In contrast, no rural/urban differences in tobacco were noted, although rural minorities were more likely to endorse tobacco use across all years. Finally, perceived peer use of each substance was a significant predictor of future use of that substance for all years. This is the first study to explore rural/urban, gender, and racial differences in substance use across the college transition. Results suggest that there are subgroups of individuals at specific risk who may benefit not only from feedback regarding the influence of perceived peer use in college, but also from a deeper understanding of how cultural norms maintain their substance use behaviors over time.


Innovative approaches in public health research: applying life course epidemiology to aboriginal health research.
A life course epidemiology approach embraces the complexity of disease risk and acknowledges the long-term effects of physical, social, psychological, and behaviour pathways, operating across an individual's life, a community's generation, and a population's development, on health and well-being. Researchers who adopt a life course epidemiology approach broaden their ability to understand, explain, and prescribe ways to mitigate the effects of chronic diseases and reduce risk factor development and interaction. Although there are many diseases that explicate the importance and usefulness of a life course approach for Aboriginal health research, this commentary focuses on the benefits for understanding chronic respiratory diseases in Aboriginal populations. The hope is that this will expose the benefits of a life course approach for the study of Aboriginal health research and draw attention to the need for well-rounded, high-quality Aboriginal respiratory health research.


Epichloë typhina from toxic tall fescue grasses.
Epichloë typhina, a clavicipitaceous systemic phytopathogen, was isolated from two varieties and three hybrids of tall fescue (Festuca arundinaceae). The morphology of the fescue isolates was compared with E. typhina isolated from bent grass (Agrostis perennans). In all isolates, conidia were identical and were typical of E. typhina. In fescue grasses the endophyte failed to produce stromata, but on bent grass the fungus seasonally produced stromata, typical of the genus. Cattle grazing the fescue grasses showed signs of the fescue toxicity syndrome, the E. typhina was found in frequencies of 100%; in grasses from pastures in which cattle showed no signs of the syndrome, frequencies were 0 to 50%. Nutritional factors in vitro were more complex for the isolates from fescue than for the isolate from bent grass. These studies suggested that E. typhina includes biotypes that might be involved in the toxicity syndrome. The fescue biotypes grew poorly on media, and yields were inadequate for toxicity studies. However, the bent grass isolate grew well on three media, and extracts from two of these were toxic to chicken embryos. All isolates produced in vitro the nontoxic fungal steroid tetraenone [ergosta-4,6,8(14),22-tetraen-3-one], which has been isolated from toxic fescue grasses.


5-Hydroxytryptamine1A receptor occupancy by novel full antagonist 2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzdioxyn-5-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide: a[11C][O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635) positron emission tomography study in humans.
5-Hydroxytryptamine(1A) (5-HT(1A)) receptors have been implicated in the pathophysiology and treatment of anxiety and depression, and are a target for novel drug development. This is the first study examining the human brain in vivo occupancy by a novel, selective, silent 5-HT(1A) antagonist. 2-[4-[4-(7-Chloro-2,3-dihydro-1,4-benzdioxyn-5-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide (DU 125530), a compound in clinical development, has potential applications in the treatment of anxiety and mood disorders. Positron emission tomography (PET) and [(11)C][O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635), were used to assess 5-HT(1A) autoreceptor and postsynaptic receptor occupancy in 12 healthy male volunteers. Over a 10- to 40-mg daily dose range, DU 125530 was well tolerated, and exhibited a dose-dependent occupancy from 0 to 72% at 2 h post the last dose. Occupancy correlated significantly with plasma levels of DU 125530, and a fitting of the data to a standard single-site binding model gave a maximum occupancy of approximately 80%, and a half-saturation concentration (ED(50)) of approximately 7 ng/ml. At 24 h after the last dose 5-HT(1A) occupancy was approximately 50% of that achieved at 2 h. This study demonstrates that high occupancy of the human brain 5-HT(1A) receptor can be achieved at doses producing minimal acute side effects.


Morphometry-based radiomics for predicting therapeutic response in patients with gliomas following radiotherapy.
Gliomas are still considered as challenging in oncologic management despite the developments in treatment approaches. The complete elimination of a glioma might not be possible even after a treatment and assessment of therapeutic response is important to determine the future course of actions for patients with such cancers. In the recent years radiomics has emerged as a promising solution with potential applications including prediction of therapeutic response. Hence, this study was focused on investigating whether morphometry-based radiomics signature could be used to predict therapeutic response in patients with gliomas following radiotherapy. 105 magnetic resonance (MR) images including segmented and non-segmented images were used to extract morphometric features and develop a morphometry-based radiomics signature. After determining the appropriate machine learning algorithm, a prediction model was developed to predict the therapeutic response eliminating the highly correlated features as well as without eliminating the highly correlated features. Then the model performance was evaluated. Tumor grade had the highest contribution to develop the morphometry-based signature. Random forest provided the highest accuracy to train the prediction model derived from the morphometry-based radiomics signature. An accuracy of 86% and area under the curve (AUC) value of 0.91 were achieved for the prediction model evaluated without eliminating the highly correlated features whereas accuracy and AUC value were 84% and 0.92 respectively for the prediction model evaluated after eliminating the highly correlated features. Nonetheless, the developed morphometry-based radiomics signature could be utilized as a noninvasive biomarker for therapeutic response in patients with gliomas following radiotherapy.


Effects of different attentional cues on responding to joint attention in younger siblings of children with autism spectrum disorders.
We compared responding to joint attention (RJA) in younger siblings of children with ASD (SIBS-ASD; n = 46) and younger siblings of children developing typically (SIBS-TD; n = 35). Children were tested between 12 and 23 months of age in a situation in which an experimenter directed the child's attention to one of 8 targets. Each child responded to 10 different combinations of verbal and nonverbal cues containing varying levels of attention-specifying information. SIBS-ASD had significantly lower overall RJA scores than SIBS-TD. Moderately redundant cues were most difficult for SIBS-ASD relative to SIBS-TD; adding a point to moderately redundant cues improved RJA for SIBS-ASD, bringing them to a level of RJA commensurate with SIBS-TD.


Glutamatergic neurometabolites during early abstinence from chronic methamphetamine abuse.
The acute phase of abstinence from methamphetamine abuse is critical for rehabilitation success. Proton magnetic resonance spectroscopy has detected below-normal levels of glutamate+glutamine in anterior middle cingulate of chronic methamphetamine abusers during early abstinence, attributed to abstinence-induced downregulation of the glutamatergic systems in the brain. This study further explored this phenomenon. We measured glutamate+glutamine in additional cortical regions (midline posterior cingulate, midline precuneus, and bilateral inferior frontal cortex) putatively affected by methamphetamine. We examined the relationship between glutamate+glutamine in each region with duration of methamphetamine abuse as well as the depressive symptoms of early abstinence. Magnetic resonance spectroscopic imaging was acquired at 1.5 T from a methamphetamine group of 44 adults who had chronically abused methamphetamine and a control group of 23 age-, sex-, and tobacco smoking-matched healthy volunteers. Participants in the methamphetamine group were studied as inpatients during the first week of abstinence from the drug and were not receiving treatment. In the methamphetamine group, small but significant (5-15%, P<.05) decrements (vs control) in glutamate+glutamine were observed in posterior cingulate, precuneus, and right inferior frontal cortex; glutamate+glutamine in posterior cingulate was negatively correlated (P<.05) with years of methamphetamine abuse. The Beck Depression Inventory score was negatively correlated (P<.005) with glutamate+glutamine in right inferior frontal cortex. Our findings support the idea that glutamatergic metabolism is downregulated in early abstinence in multiple cortical regions. The extent of downregulation may vary with length of abuse and may be associated with severity of depressive symptoms emergent in early recovery.


Durability of Telbivudine-Associated Improvement of Renal Function Following Withdrawal or Switching of Antivirals in Chronic Hepatitis B Patients.
Besides antiviral activities against hepatitis B virus (HBV), telbivudine has an extrahepatic pharmaceutical effect: to improve renal function assessed by estimated glomerular filtration rate (eGFR). However, the durability of this effect after withdrawal of telbivudine or switching to other antivirals has never been investigated. We conducted a postmarketing, real-world observation study for telbivudine treatment. The durability of telbivudine-associated renal function improvement was examined following withdrawal/switching of antivirals. Of 160 telbivudine-treated, chronic hepatitis B patients, 21, 6, and 2 patients were loss to follow-up, dead, and pregnant during the study, respectively. Of the remaining 131 patients, 26, 47, 28, and 30 patients experienced telbivudine withdrawal, continuous use of telbivudine, switching to entecavir, or switching to tenofovir, respectively. During the first 2 years, eGFR in telbivudine-treated patients significantly improved before withdrawal/switching of antivirals (P = .009). Thereafter, eGFR remained unchanged for >1 year in the withdrawal (P = .100) and continuous use (P = .517) subgroups, but decreased significantly in the switching to entecavir (P = .002) and switching to tenofovir (P < .001) subgroups. Multivariate logistic regression analysis revealed that switching to tenofovir and poor liver functional reserve were predictors for eGFR deterioration. Telbivudine-associated renal function improvement was durable after withdrawal or continuous use of telbivudine. However, renal function deteriorated if patients were switched to entecavir or tenofovir.


Structure and DNA sequence of the tropomyosin I gene from Drosophila melanogaster.
The muscle tropomyosin I gene of Drosophila melanogaster undergoes alternative splicing in different muscles of the fly to generate two isoforms of the same protein. We report here the structural analysis and DNA sequence of the tropomyosin I gene. The gene spans 5 kilobase of DNA and is comprised of five exons and four introns. Exon 4 is alternatively spliced in RNA of different muscle, resulting in two isoforms of the same protein. The gene lacks a "TATA" box homology at the map position; it is usually found in the vast majority of eukaryotic genes characterized thus far. Instead, a series of three alternating TG stretches are located upstream from the site of initiation of transcription. The gene encodes a 5' untranslated leader of 103 base pairs, and the 3' untranslated region comprises between 30 and 50% of the transcripts. The DNA sequence is extremely G + C rich in the protein coding regions of the gene, and A + T rich in the non-coding, flanking, and intron regions. The DNA sequence upstream of the acceptor sites in the two introns which are subject to alternative splicing displays a stretch of homology which is noted. The 3' untranslated region of the fifth exon contains multiple polyadenylation sites. The 284 amino acid protein encoded by the gene is split by introns between residues 198/199 and 257/258. These sites correlate closely with two important functional domains in the tropomyosin molecule. A comparison of the first 257 amino acids and the carboxyl-terminal 27 amino acids of the Drosophila and vertebrate tropomyosins together, shows two distinct and mutually exclusive classes for these domains. The functional significance of the Drosophila tropomyosin isoforms is discussed.


Photostimulation effects on chicken egg development: Perspectives on human newborn treatment.
It is well known that, under exposure to bright light, eggs tend to hatch earlier than control, without any damage to the birds. This report aims to systematically show the effect and establishes a proposal for a possible application to accelerate chicken egg formation, which could be extrapolated or adapted as a great advance in premature human newborns. Comparing several protocols, the experiments show that lower doses of light slowly delivered for 24 h promote higher efficiency in embryo development, increasing on average 25% of its size and more than 70% in weight when compared to the control. This weight difference shows promising results compared to rates of up to 17% found in the literature. These results can be a first step to reduce the stay of premature human infants in hospitals because light, when applied in very low doses, can accelerate the natural biological processes without risks.


Genetic Environment of blaTEM-1, blaCTX-M-15, blaCMY-42 and Characterization of Integrons of Escherichia coli Isolated From an Indian Urban Aquatic Environment.
The presence of antibiotic resistance genes (ARGs) including those expressing ESBLs and AmpC-β-lactamases in Escherichia coli inhabiting the aquatic environments is a serious health problem. The situation is further complicated by the fact that ARGs can be easily transferred among bacterial species with the help of mobile genetic elements - plasmids, integrons, insertion sequences (IS), and transposons. Therefore, the analysis of genetic environment and mobile genetic elements associated with ARGs is important as these provide useful information about the epidemiology of these genes. In our previous study, we had reported presence of various β-lactam resistance genes present in E. coli strains inhabiting the river Yamuna traversing the National Capital Territory of Delhi (India). In the present study, we have analyzed the genetic environment of three ARGs blaTEM-1, blaCTX-M-15, and blaCMY -42 of those E. coli strains. The structure of class 1 integrons and their gene cassettes was also analyzed. Insertion sequence IS26 was present upstream of blaTEM-1, ISEcp1 was present upstream of blaCTXM-15 gene and orf477 was present downstream of blaCTXM-15. ISEcp1 was also present upstream of blaCMY -42 and, blc and sugE genes were present in the downstream region of this gene. Thus, the overall genetic environment surrounding these genes was similar to that reported from E. coli strains isolated globally. Conjugation assays, isolation and analysis of plasmid DNA of the transconjugants indicated that blaTEM-1, blaCTX-M-15, blaCMY -42 and class 1 integron were plasmid-mediated and possibly transmit between genera through horizontal gene transfer (HGT). This might lead to dissemination of antimicrobial resistance genes in aquatic environment. The work embodied in this paper is the first describing the genetic environment of bla and integrons in aquatic E. coli isolated from India.


Effect of endurance training on the VO2-work rate relationship in normoxia and hypoxia.
We postulated that the relationship between VO2 and work rate (VO2-WR relationship) during incremental exercise is dependent on O2 availability, and that training-induced adaptations alter this relationship. We therefore studied the effect of endurance training on VO2 response during incremental exercise in normoxia and hypoxia (FIO2=0.134). Before and after training (6 d.wk, 4 wk), eight subjects performed incremental exercises under normoxia and hypoxia and one constant-work rate exercise in normoxia at 80% of pretraining VO2max. The slopes of the VO2-WR relationship during incremental exercise were calculated using all the points (whole slope) or only points before the lactate threshold (pre-LT slope). The difference between VO2max measured and VO2max expected from the pre-LT slope (DeltaVO2) was determined, as was the difference between VO2 at minute 10 and VO2 at minute 4 during the constant-work rate exercise (DeltaVO2(10'-4')). In normoxia, training induced a significant decrease in the whole slope (11.0+/-1.0 vs 9.9+/-0.4 mL.min.W, P<0.05). In hypoxia, training induced a significant increase in the pre-LT slope (8.7+/-1.2 vs 9.8+/-0.7 mL.min.W; P<0.05) and the whole slope (8.5+/-1.2 vs 9.4+/-0.5 mL.min.W; P<0.05). A significant correlation between the decrease of DeltaVO2 and the decrease of DeltaVO2(10'-4') with training was found in normoxia (P<0.01, r=0.79). Taken together, these results indicate that adaptations induced by endurance training are associated with more efficient incremental and constant-workload exercise performed in normoxia. Moreover, training contributes to improved O2 delivery during moderate exercise performed in hypoxia, and to enhanced near-maximal exercise tolerance.


Syntheses, structure, some band gaps, and electronic structures of CsLnZnTe3 (Ln=La, Pr, Nd, Sm, Gd, Tb, Dy, Ho, Er, Tm, Y).
Eleven new quaternary rare-earth tellurides, CsLnZnTe3 (Ln=La, Pr, Nd, Sm, Gd, Tb, Dy, Ho, Er, Tm, and Y), were prepared from solid-state reactions at 1123 K. These isostructural materials crystallize in the layered KZrCuS3 structure type in the orthorhombic space group Cmcm. The structure is composed of LnTe6 octahedra and ZnTe4 tetrahedra that share edges to form [LnZnTe3] layers. These layers stack perpendicular to [010] and are separated by layers of face- and edge-sharing CsTe8 bicapped trigonal prisms. There are no Te-Te bonds in the structure of these CsLnZnTe3 compounds so the formal oxidation states of Cs/Ln/Zn/Te are 1+/3+/2+/2-. Optical band gaps of 2.13 eV for CsGdZnTe3 and 2.12 eV for CsTbZnTe3 were deduced from single-crystal optical absorption measurements. A first-principles calculation of the density of states and the frequency-dependent optical properties was performed on CsGdZnTe3. The calculated band gap of 2.1 eV is in good agreement with the experimental value. A quadratic fit for the lanthanide contraction of the Ln-Te distance is superior to a linear one if the closed-shell atom is included.


Interlaced CNT Electrodes for Bacterial Fouling Reduction of Microfiltration Membranes.
Interlaced carbon nanotube electrodes (ICE) were prepared by vacuum filtering a well-dispersed carbon nanotube-Nafion solution through a laser-cut acrylic stencil onto a commercial polyvinylidene fluoride (PVDF) microfiltration (MF) membrane. Dead-end filtration was carried out using 107 and 108 CFU mL-1 Pseudomonas fluorescens to study the effects of the electrochemically active ICE on bacterial density and morphology, as well as to evaluate the bacterial fouling trend and backwash (BW) efficacy, respectively. Finally, a simplified COMSOL model of the ICE electric field was used to help elucidate the antifouling mechanism in solution. At 2 V DC and AC (total cell potential), the average bacterial log removal of the ICE-PVDF increased by ∼1 log compared to the control PVDF (3.5-4 log). Bacterial surface density was affected by the presence and polarity of DC electric potential, being 87-90% lower on the ICE cathode and 59-93% lower on the ICE anode than that on the PVDF after filtration, and BW further reduced the density on the cathode significantly. The optimal operating conditions (2 V AC) reduced the fouling rate by 75% versus the control and achieved up to 96% fouling resistance recovery (FRR) during BW at 8 V AC using 155 mM NaCl. The antifouling performance should mainly be due to electrokinetic effects, and the electric field simulation by COMSOL model suggested electrophoresis and dielectrophoresis as likely mechanisms.


[Surgical treatment of hepatic metastatic tumor from gastric cancer].
To assess the long- term efficacy of surgical treatment of hepatic metastases from gastric adenocarcinoma. Clinical data of 938 cases with primary gastric cancer from January 1993 to October 2001 were analyzed retrospectively. Thirty- two cases received resection of hepatic metastases from gastric adenocarcinoma. Metachronous hepatic metastasis occurred in 24 cases(2.6% ),and 14 cases(58.3% ) underwent resection of hepatic metastases, while synchronous hepatic metastasis occurred in 90 cases(9.6% ) and 18 cases(20% ) underwent resection of hepatic metastases. The 1- 3- 5- year survival rates of hepatic resection for metachronous hepatic metastases were 73% 37% 25% respectively; while for synchronous hepatic metastases 68% 24% and 17% respectively. There were no significant differences between the two groups (P> 0.05). Synchronous and metachronous hepatic metastases from gastric cancer should be treated by surgical resection to confirm a better prognosis.


A culturally adapted depression intervention for African American adults experiencing depression: Oh Happy Day.
The purpose of this article is to describe development of a culturally adapted depression intervention (Oh Happy Day Class, OHDC) designed for African American adults experiencing major depressive disorder (MDD). This project included 2 pilot studies testing the feasibility and acceptability of the OHDC and examining short-term effects of the OHDC in reducing symptoms of MDD. The OHDC is a 2.5-hr weekly, culturally specific, cognitive behavioral, group counseling intervention for 12 weeks. Cultural adaptations of the OHDC are based on the ecological validity and culturally sensitive framework, along with an Afrocentric paradigm. Fifty African American participants with MDD were enrolled (15 in Pilot I and 35 in Pilot II). All participants in Pilots I and II received the 12-week intervention and completed assessments at baseline, mid-intervention, end-intervention, and 3 months postintervention. General linear mixed modeling for assessment of pre-post longitudinal data analysis was conducted. Results for Pilot I showed 73% of participants completed the full OHDC, a statistically significant decline in depression symptoms from pre- to postintervention, and a 0.38 effect size. Participants were very satisfied with the OHDC. In Pilot II, 66% of participants completed the full OHDC, and there was a significant pre-post intervention decrease in depression symptoms. For men, the OHDC showed a 1.01 effect size and for women, a 0.41 effect size. Both men and women were very satisfied with the OHDC based on the satisfaction measure. These promising findings are discussed with a focus on future plans for examining efficacy of the OHDC in a large-scale, randomized, control trial.


Early versus delayed antiretroviral therapy based on genotypic resistance test: Results from a large retrospective cohort study.
Rapid start of antiretroviral therapy (ART) pending genotypic resistance test (GRT) has been recently proposed, but the effectiveness of this strategy is still debated. The rate of virological success (VS), defined as HIV-RNA < 50 copies/ml, with and without GRT was compared in drug-naïve individuals enrolled in the Italian ARCA cohort who started ART between 2015 and 2018. 521 individuals started ART: 397 without GRT (pre-GRT group) and 124 following GRT (post-GRT group). Overall, 398 (76%) were males and 30 (6%) were diagnosed with AIDS. In the pre-GRT group, baseline CD4+ cell counts were lower (p < 0.001), and viral load was higher (p < 0.001) than in the post-GRT group. The estimated probability of VS in pre-GRT versus post-GRT group was 72.54% (CI95 : 67.78-76.60) versus 66.94% (CI95 : 57.53-74.26) at Week 24 and 92.40% (CI95 : 89.26-94.62) versus 92.92% (CI95 : 86.35-96.33) at Week 48, respectively (p = 0.434). At Week 48, VS was less frequent among individuals with baseline CD4+ cell counts <200 versus >500 (90.33% vs. 97.33%), log viral load <5.00 versus >5.70 log10 cps/ml (97.17% vs 78.16%; p < 0.001), and those treated with protease inhibitors or non-nucleoside reverse transcriptase inhibitors versus those treated with integrase strand transfer inhibitors (p < 0.001). The rate of VS does not seem to be affected by an early ART initiation pending GRT results, but it could be influenced by the composition of the ART regimen, as well as immuno-virological parameters.


Role of dorsomedial hypothalamic neuropeptide Y in energy homeostasis.
Hypothalamic neuropeptide Y (NPY) is primarily expressed in the arcuate nucleus (Arc) and the dorsomedial hypothalamus (DMH). Although Arc NPY gene expression is responsive to circulating leptin, the regulation of DMH NPY expression is leptin-independent. DMH NPY expression is increased in response to chronic food restriction, but not acute food deprivation. DMH NPY expression is elevated in pair-fed OLETF rats lacking cholecystokinin (CCK)-1 receptors. A role for CCK in controlling DMH NPY expression is demonstrated by the down-regulation of DMH NPY by parenchymal DMH CCK administration in intact rats. Moreover, access to running wheels normalizes body weight and prevents altered DMH NPY expression of OLETF rats. Together, these data suggest that DMH NPY plays an important role in feeding and body weight control.


[Environmental factors in the etiopathology of inflammatory bowel syndrome].
Inflammatory bowel syndrome (IBS) mainly includes ulcerative colitis (UC) and Crohn's disease (CD). UC and CD are chronic and recurrent conditions, with a tendency to exacerbations and remissions. The incidence of diseases worldwide has increased over the last years. Although the etiology of inflammatory bowel syndrome has been studied intensively it still remains unclear. The development and persistence of inflammation is an effect of numerous factors: proinflammatory (aggressive), regulating bowel mucosa homeostasis and protective factors. Proinflammatory factors include intestinal bacteria, bile acids, digestive enzymes, lipopolysaccharides and peptidoglycans. Protective mechanisms are impermeability of mucosa barrier, presence of intestinal mucus, activity of secretive immunoglobulins, some prostaglandins and interleukins, glutamine, somatostatin, cortisol and short-chain fatty acids. Factors modifying intestinal mucosa homeostasis consist of genetically determined immunoregulators and activity of intestinal mucosa barrier and some environmental factors (diet, smoking, infections, stress, antibiotics and others). Environmental factors are jointly responsible for IBS occurrence in case of genetically determined dysregulation leading to proinflammatory cytokines overproduction or disturbances in synthesis of cytokines regulating intestinal mucosa homeostasis.


Energy expenditure across immune challenge severities in a lizard: consequences for innate immunity, locomotor performance and oxidative status.
Reptiles, like other vertebrates, rely on immunity to defend themselves from infection. The energetic cost of an immune response is liable to scale with infection severity, prompting constraints on other self-maintenance traits if immune prioritization exceeds energy budget. In this study, adult male side-blotched lizards (Uta stansburiana) were injected with saline (control) or high (20 µg g-1 body mass) or low (10 µg g-1 body mass) concentrations of lipopolysaccharide (LPS) to simulate bacterial infections of discrete severities. The costs and consequences of the immune response were assessed through comparisons of change in resting metabolic rate (RMR), energy metabolites (glucose, glycerol, triglycerides), innate immunity (bactericidal ability), sprint speed and oxidative status (antioxidant capacity, reactive oxygen metabolites). High-LPS lizards had the lowest glucose levels and greatest sprint reductions, while their RMR and bactericidal ability were similar to those of control lizards. Low-LPS lizards had elevated RMR and bactericidal ability, but glucose levels and sprint speed changes between those of high-LPS and control lizards. Levels of glycerol, triglycerides, reactive oxygen metabolites and antioxidant capacity did not differ by treatment. Taken together, energy expenditure for the immune response varies in a non-linear fashion with challenge severity, posing consequences for performance and self-maintenance processes in a reptile.


Azithromycin to prevent bronchopulmonary dysplasia in ureaplasma-infected preterm infants: pharmacokinetics, safety, microbial response, and clinical outcomes with a 20-milligram-per-kilogram single intravenous dose.
Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)(0.75); central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥ 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined.


The extreme insular adaptation of Garganornis ballmanni Meijer, 2014: a giant Anseriformes of the Neogene of the Mediterranean Basin.
New skeletal elements of the recently described endemic giant anseriform Garganornis ballmanni Meijer, 2014 are presented, coming from the type-area of the Gargano and from Scontrone, southern and central Italy, respectively. The new remains represent the first bird remains found at Scontrone so far, and another shared element between these two localities, both part of the Apulia-Abruzzi Palaeobioprovince. The presence of a very reduced carpometacarpus confirms its flightlessness, only previously supposed on the basis of the very large size, while the morphologies of tarsometatarsus and posterior phalanges clearly indicate the adaptation of G. ballmanni to a terrestrial, non-aquatic, lifestyle. Its very large body size is similar to that observed in different, heavily modified, insular waterfowl and has been normally interpreted as the response to the absence of terrestrial predators and a protection from the aerial ones. The presence of a carpal knob in the proximal carpometacarpus also indicates a fighting behaviour for this large terrestrial bird species.


Prevalence of paroxysmal atrial fibrillation in Brugada syndrome: a case series and a review of the literature.
The present study aimed at investigating the incidence of paroxysmal atrial fibrillation in 10 patients with spontaneous or induced type 1 electrocardiographic pattern of Brugada syndrome (three with syncopal episodes and seven asymptomatic). Both clinical entities are closely associated with changes in autonomic modulation and, particularly, with increased vagal tone. Transthoracic echocardiography, exercise treadmill test and 24-h Holter recordings were performed to all patients. Episodes of atrial fibrillation were recorded in 2/10 patients (20%). These patients suffered from syncopal episodes, exhibited a positive electrophysiological study, and finally received an implantable cardioverter-defibrillator. The present case series points out a high incidence of paroxysmal atrial fibrillation predominantly in symptomatic patients with type 1 electrocardiographic pattern of Brugada syndrome, indicating that the presence of atrial tachyarrhythmias may reflect an advanced stage of the disease. The prognostic significance of paroxysmal atrial fibrillation, particularly in asymptomatic patients with an electrocardiographic pattern consistent with Brugada syndrome requires further evaluation. Physicians should always be aware of Brugada syndrome in young patients with lone atrial fibrillation, especially in those with a history of syncope.


[Chronological age for the spontaneous resolution of vesicoureteral reflux].
Vesicoureteral reflux (VUR) may have medical management, which implies prophylactic antibiotic therapy, control with serial urine cultures and imaging tests, such as annual voiding cystourethrogram (VCUG) or direct isotopic cystogram (DIC); or it may be surgical, when medical treatment fails, due to recurrent UTI or renal damage. We analyze the chronological age of the patient at which VUR resolve spontaneously, so that we know when we should have a more precise control with VCUG, avoiding a traumatic test and irradiation, but also avoiding to give prophylactic antibiotic without real need. We aim to associate age of resolution with VUR grade and side, and patient's gender. Retrospective study of patients with VUR under control at the Hospital Clinico of the Catholic University of Chile between 1996 and 2004. patients with the diagnosis of VUR grades I, II, and III obtained by VCUG, and spontaneous resolution of VUR on control VCUG or DIC, with no urological surgery, without bladder dysfunction or other urinary tract disorders. 156 patients were included. 73.5% are females, with a mean age at the time of resolution of 52.7 +/- 36 months. 74.3% of the patients had unilateral VUR. There were not statistically significant differences in the age of resolution between unilateral or bilateral VUR, or between different grades. There is a statistically significant difference in the age of resolution comparing gender (p < 0.0001), resolving between 12 and 17 months before in males. VUR improves earlier in males than females, without differences between unilateral-bilateral, or VUR grade I, II and III. The control VCUG or DIC should be indicated in relation to the most probable chronological age of resolution, generally around 4 years of age, and not once a year, so avoiding irradiation and trauma, with a special consideration to the child gender.


Assessment and management of cardiovascular urgencies and emergencies: cognitive and technical considerations.
Cardiovascular emergencies represent the most feared complications in dental practice. Not only do they present the greatest possibility for morbidity and mortality, but their pathogenesis and treatment are poorly understood. This article reviews fundamental physiologic and pathological concepts that will guide the clinician toward a more cognitive approach to patient assessment and management. The treatment algorithms presented develop rationally from these fundamental scientific principles.


Modulation of soft glassy dynamics in aqueous suspensions of an anisotropic charged swelling clay through pH adjustment.
Sodium-montmorillonite (Na-Mt) particles are geometrically anisometric that carry a pH dependent anisotropic surface charge. Therefore, it should be possible to manipulate the particle-particle interaction of colloidal range Na-Mt suspensions through pH changes which in turn should alter the soft glassy dynamics of Na-Mt suspensions. Rheological experiments were used to probe the impact of pH mediated colloidal particle-particle interaction on the physical aging, linear viscoelastic response, and yield stress behavior of Na-Mt suspension. The temporal evolution of the storage modulus (G') was stronger in the acid regime (pH < 9.5) than the base (pH ≥ 9.5) pH regime. Horizontal shifting of the aging curves in the acid and base regimes led to aging time-H+ concentration and aging time-OH- concentration superposition. An aging time-Na-Mt concentration superposition was also observed in both pH regimes. The critical stress associated with the viscosity bifurcation behavior increased linearly with G' but with different slopes for acid and base regime. We propose that positively charged patches on the Na-Mt particle edge merge with the characteristic surface as a function of H+ ions in the system. This leads to a strongly associated microstructure at low pH and a relatively weak but associated microstructure at natural pH, hence confirming the hypothesis.


The efficacy of cap-assisted colonoscopy in polyp detection and cecal intubation: a meta-analysis of randomized controlled trials.
The role of cap-assisted colonoscopy (CAC) in polyp detection and cecal intubation is unclear. We conducted a meta-analysis to compare the efficacy of CAC vs. standard colonoscopy (SC). Publications in English and non-English literatures (OVID, MEDLINE, and EMBASE) and abstracts in major international conferences were searched for controlled trials comparing CAC and SC. Outcome measures included the proportion of patients with polyps or adenomas detected, cecal intubation rate, cecal intubation time, and total colonoscopy time. The statistical heterogeneity of trials was examined and the effects were pooled by random-effects model. The risk of bias was evaluated by the assessment tool from the Cochrane Handbook. Subgroup analyses were performed for possible clinical and methodological heterogeneities. From 2,358 citations, 16 randomized controlled clinical trials were included consisting of 8,991 subjects (CAC: 4,501; SC: 4,490). Mean age of subjects was 61.0 years old and 60% were males. CAC detected a higher proportion of patients with polyp(s) (relative risk (RR): 1.08; 95% confidence interval (CI): 1.00-1.17) and reduced the cecal intubation time (mean difference: -0.64 min; 95% CI: -1.19 to -0.10). Cecal intubation rate (RR: 1.00; 95% CI: 0.99-1.02) and total colonoscopy time (mean difference: -0.97 min; 95% CI: -2.33 to 0.40) were comparable between the two groups. In subgroup analyses, a short cap (≤4 mm) was associated with improved polyp detection, whereas a long cap (≥7 mm) was associated with a shorter cecal intubation time. CAC demonstrated marginal benefit over SC for polyp detection and shortened the cecal intubation time.


[Evaluation of the edge enhancement effect of phase contrast imaging using newly-developed photostimulable phosphor plate].
We investigated whether the use of a newly developed columnar-crystal-type photostimulable-phosphor plate (CP1M200, referred to as system C) helps to provide improved edge-enhanced effect in phase contrast imaging. Physical characteristics of 2 conventional particulate-crystal-type photostimulable-phosphor plates (RP-5PM, referred to as system A and RP-6M, referred to as system B) and system C were measured. Then, an acrylic plate phantom and RMI152 phantom were imaged using 3 types of plates, and the edge-enhancement effects were evaluated based on the profile curve of the acrylic plate phantom. Visual evaluation of the RMI152 phantom images was conducted. The results showed that the modulation transfer function (MTF) of system C was superior to those of the other systems. The WS of system C was superior to those of the other systems in the low frequency band region, and inferior to those of the other systems in the high frequency band region. The presence of an edge-enhanced image was not detectable in the profile curve of the acrylic plate in system A, although that was shown in systems B and C due to their excellent sharpness. In the visual image evaluation of the RMI152 phantom, image quality of system C was superior to those of the other systems. Phase contrast imaging with a digital detector of a columnar-crystal-type photostimulable-phosphor plate is considered to provide improved edge-enhancement over that of conventional plates.


Duration of neutralizing antibody persisting in Thai individuals after childhood vaccination against smallpox.
Although smallpox was completely eliminated by 1980, it remains possible that variola virus could be intentionally released in an act of bioterrorism. Thus, several studies have been performed to detect antibody levels after smallpox vaccination of the current population in various countries to indicate the duration of maintenance of immunological memory. Our study endeavored to investigate the level of neutralizing (Nt) antibody responses of Thai individuals who had been immunized with smallpox vaccine during childhood. The plaque reduction neutralization test (PRNT) was used to study vaccinia Nt antibody responses in sera of individuals ranging in age from 35-4, 45-54, 55-64, 65-74, 75-84 and > 84 years old, referred to as groups 1-6, respectively. Each group included 200 sera: 100 male sera and 100 female sera. An incubation time of 15 hours for sera and vaccinia virus was confirmed to be the optimal incubation period for PRNT. Positive Nt antibody titers (≥32) were detected in 135 (11.25%) of 1,200 sera: 81 (6.75%) male sera and 54 (4.5%) female sera. There were 4 (2%), 11 (5.5%), 19 (9.5%), 16 (8%), 33 (16.5%), and 52 (26%) positive sera in groups 1-6, respectively. Interestingly, the oldest individual with positive Nt antibody was a 98-year-old female. Two males aged 96 and 91 years old had the highest Nt antibody titers. Our data suggests that the vaccinia-specific Nt antibody response in the current Thai population could be maintained for more than 90 years after vaccination. However, the majority of the Thai population aged ≥35-74 years old is still highly susceptible to infection.


Effect of antihypertensive treatment on the behavioral consequences of elevated blood pressure.
It was shown in a prior study that mildly hypertensive patients performed significantly less effectively on several sensory-perceptual, cognitive, and psychomotor tests than did matched normotensive controls. To determine whether these deficits are attributable to elevated blood pressure per se, hypertensive and control subjects were recalled for reexamination 15 months after the original tests. Results indicated that those hypertensives in whom blood pressure had been lowered with antihypertensive drugs showed significant restoration of performance scores toward the levels of normotensive subjects. Hypertensives who had not received active treatment remained deficient as compared with controls. These results indicated that behavioral deficits in mild hypertension may be reversible consequences of the effects of elevated blood pressure on the central nervous system.


Hashimoto's thyroiditis and breast cancer.
The question of a possible association between Hashimoto's thyroiditis and breast cancer was evaluated in (1) an autopsy series and (2) a follow-up of a cohort of patients with Hashimoto's thyroiditis at the Mayo Clinic. In the autopsy study, 174 subjects with histologic diagnosis of Hashimoto's thyroiditis were matched with a control group. There was no significant difference in the frequency of a history of breast cancer in the two groups. In the cohort of Olmsted County residents with a clinical or histologic diagnosis of Hashimoto's thyroiditis for whom there was a substantial period of follow-up, no excess frequency of breast cancer was note. These results contrast with those of a recent study reporting that Japanese women with Hashimoto's thyroiditis were a high risk group for breast cancer.


Deaths occurring during the first year after treatment onset for polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: a retrospective analysis of causes and factors predictive of mortality based on 595 patients.
Although combining corticosteroids and cyclophosphamide has greatly improved the prognoses of severe necrotizing vasculitides, some patients continue to have fulminating disease and die within the first year of diagnosis. To evaluate the characteristics of these patients, we retrospectively studied the files of 60 patients who died within the first year (20 patients with hepatitis B virus-associated polyarteritis nodosa [HBV-PAN], 18 with non-HBV PAN, 13 with microscopic polyangiitis [MPA], and 9 with Churg-Strauss syndrome [CSS]) and 535 first-year survivors (89 patients with HBV-PAN, 182 with non-HBV PAN, 140 with MPA, and 124 with CSS), 85 of whom died during a mean follow-up of 6.4 years. The 2 groups were compared for prognostic factors defined by the five-factor score (FFS) and Birmingham Vasculitis Activity Score at baseline, clinical signs, treatment, outcome, and causes of death. For first-year nonsurvivors, the clinical signs predictive of death were as follows: renal involvement (hazard ratio [HR], 1.6; 95% confidence intervals [CI], 1.09-2.3) or central nervous system involvement (HR, 2.3; 95% CI, 1.5-3.7), and a trend toward cardiomyopathy (HR, 1.4; 95% CI, 1.000-2.115). Older patients died earlier (HR, 1.04; 95% CI, 1.023-1.051). Gastrointestinal symptoms were most frequently associated with early death from HBV-PAN, while 83% of CSS patients died of cardiac involvement. Treatment had no significant impact on early death, except for patients with FFS > or = 2, for whom steroids alone were associated (p < 0.05). The major cause of early death was uncontrolled vasculitis (58%), followed by infection (26%). Cyclophosphamide-induced cytopenia and infection were responsible for 2 deaths. Despite these iatrogenic complications, early deaths were more frequently the consequence of insufficient or inappropriate therapy.


Functional Protein Dynamics in a Crystal.
Proteins are molecular machines and to understand how they work, we need to understand how they move. New pump-probe time-resolved X-ray diffraction methods open up ways to initiate and observe protein motions with atomistic detail in crystals on biologically relevant timescales. However, practical limitations of these experiments demands parallel development of effective molecular dynamics approaches to accelerate progress and extract meaning. Here, we establish robust and accurate methods for simulating dynamics in protein crystals, a nontrivial process requiring careful attention to equilibration, environmental composition, and choice of force fields. With more than seven milliseconds of sampling of a single chain, we identify critical factors controlling agreement between simulation and experiments and show that simulated motions recapitulate ligand-induced conformational changes. This work enables a virtuous cycle between simulation and experiments for visualizing and understanding the basic functional motions of proteins.


The LRR receptor Islr2 is required for retinal axon routing at the vertebrate optic chiasm.
In the visual system of most binocular vertebrates, the axons of retinal ganglion cells (RGCs) diverge at the diencephalic midline and extend to targets on both ipsi- and contralateral sides of the brain. While a molecular mechanism explaining ipsilateral guidance decisions has been characterized, less is known of how RGC axons cross the midline. Here, we took advantage of the zebrafish, in which all RGC axons project contralaterally at the optic chiasm, to characterize Islr2 as an RGC receptor required for complete retinal axon midline crossing. We used a systematic extracellular protein-protein interaction screening assay to identify two Vasorin paralogs, Vasna and Vasnb, as specific Islr2 ligands. Antibodies against Vasna and Vasnb reveal cellular populations surrounding the retinal axon pathway, suggesting the involvement of these proteins in guidance decisions made by axons of the optic nerve. Specifically, Vasnb marks the membranes of a cellular barricade located anteriorly to the optic chiasm, a structure termed the "glial knot" in higher vertebrates. Loss of function mutations in either vasorin paralog, individually or combined, however, do not exhibit an overt retinal axon projection phenotype, suggesting that additional midline factors, acting either independently or redundantly, compensate for their loss. Analysis of Islr2 knockout mice supports a scenario in which Islr2 controls the coherence of RGC axons through the ventral midline and optic tract. Although stereotypic guidance of RGC axons at the vertebrate optic chiasm is controlled by multiple, redundant mechanisms, and despite the differences in ventral diencephalic tissue architecture, we identify a novel role for the LRR receptor Islr2 in ensuring proper axon navigation at the optic chiasm of both zebrafish and mouse.


MicroRNA-574 is involved in cognitive impairment in 5-month-old APP/PS1 mice through regulation of neuritin.
Alzheimer's disease (AD) is the most common form of dementia in the elderly. The recent evidence in AD research suggests that alterations in the microRNA (miRNA) could contribute to risk for the disease. However, little is understood about the roles of miRNAs in cognitive impairment of early Alzheimer's disease (AD). Here, we used 5-month-old APP/PS1 mice, which mimic many of the salient features of the early stage of AD pathological process, to further investigate the roles of miRNAs in synaptic loss involved in learning and memory. We used miRNA expression microarrays on RNA extracted from the hippocampus of 5-month-old APP/PS1 mice and wild type mice. Real-time reverse transcription PCR was conducted to verify the candidate miRNAs discovered by microarray analysis. The data showed that miR-574 was increased significantly in the hippocampus of 5-month-old APP/PS1 mice, which were concomitant with that APP/PS1 mice at the same age displayed a significant synaptic loss and cognitive deficits. Bioinformatic analysis predicted that neuritin (Nrn1) mRNA is targeted by miR-574. Overexpression of miR-574 lowers the levels of neuritin and synaptic proteins expression in primary hippocampal neurons damage induced by Aβ25-35. And the expression of miR-574 was also up-regulated in the hippocampal neurons from APP/PS1 mice compared with WT littermates. In contrast, suppression of miR-574 by miR-574 inhibitor significantly results in higher levels of neuritin and synaptic proteins expression. Taken together, miR-574 is involved in cognitive impairment in 5-month-old APP/PS1 mice through regulation of neuritin.