Chromatin accessibility in the Drosophila embryo is determined by transcription factor pioneering and enhancer activation.
Chromatin accessibility is integral to the process by which transcription factors (TFs) read out cis-regulatory DNA sequences, but it is difficult to differentiate between TFs that drive accessibility and those that do not. Deep learning models that learn complex sequence rules provide an unprecedented opportunity to dissect this problem. Using zygotic genome activation in Drosophila as a model, we analyzed high-resolution TF binding and chromatin accessibility data with interpretable deep learning and performed genetic validation experiments. We identify a hierarchical relationship between the pioneer TF Zelda and the TFs involved in axis patterning. Zelda consistently pioneers chromatin accessibility proportional to motif affinity, whereas patterning TFs augment chromatin accessibility in sequence contexts where they mediate enhancer activation. We conclude that chromatin accessibility occurs in two tiers: one through pioneering, which makes enhancers accessible but not necessarily active, and the second when the correct combination of TFs leads to enhancer activation.


A new type of congenital nephrotic syndrome.
Description of a newborn male suffering from hydrops fetalis of unknown cause. Placenta showed multiple chorioangiomata. Coincidence of chorioangiomata of the placenta and hydrops fetalis has not been previously reported. The authors suggest a new kind of glomerulopathy as a cause of congenital nephrotic syndrome.


Alteration of plasma ketamine levels in mice by probenecid.
Probenecid increases plasma ketamine levels in mice concurrently with an enhancement of duration of loss of righting reflex. The magnitude of these changes is directly related to the dose of ketamine and intervals between administration of compounds. Plasma levels of anesthetic are similar for all animals upon termination of hypnosis.


Recurrent thoracic air leak syndrome in patients affected by pulmonary graft-versus-host disease: Surgical strategies and outcome.
Thoracic air leak syndrome (TALS) is a complication related to chronic pulmonary graft-versus-host disease (pGvHD) that affects approximately 0.83%-3.08% patients after allogenic hematopoietic stem cell transplant. Such complication is defined as the occurrence of any form of air leak in the thorax, including spontaneous pneumomediastinum or pneumopericardium, subcutaneous emphysema, interstitial emphysema and pneumothorax and has a negative impact on post-transplant survival. The aim of the present study is to describe a single-center experience in the surgical management of recurrent TALS in adolescents and young adults and its outcome. We retrospectively reviewed the clinical notes of patients with previous allogenic hematopoietic stem cell transplant who underwent surgical procedures for recurrent TALS from January 2016 until March 2021. We analyzed clinical data, number of episodes of thoracic air leak, surgical procedures and relative outcome. In the examined period, four patients, aged 16-25 years, underwent surgical procedures for TALS, including thoracostomy tube placement, thoracoscopic pleurodesis and thoracotomy. All the patients had been diagnosed with pGvHD before the onset of TALS, with a mean time lapse of 276 days (range 42-513). These patients experienced on average 4.5 air leak episodes (range 3-6). All the patients experienced at least two episodes before surgery. One patient underwent emergency tube thoracostomy only, three patients underwent thoracoscopic pleurodesis and two patients underwent thoracotomy. After surgery, patients were free from air leak symptoms for a mean time of 176 days (range 25-477). Pulmonary function progressively deteriorated, and all the patients eventually died because of respiratory failure after a mean time of 483 days (range 127-1045) after the first episode of air leak. Surgery provides temporary relief to symptoms related to TALS but has limited effects on the underlying pathophysiologic process. The development of TALS in a sign of progressive pulmonary function worsening and is associated with high risk of respiratory failure and mortality.


Effects of an Educational Workshop on Pediatric Nurses' Attitudes and Beliefs About Family-Centered Bedside Rounds.
This pilot study evaluated the effects of an educational workshop on nurses' (N=36) attitudes and beliefs toward family-centered bedside rounds (FBR) using a single group, pretest/posttest design on two pediatric inpatient units at an academic tertiary-care center in Western Canada. The theory of planned behavior was used to develop the Nurses Attitudes and Behaviors about Rounds (NABAR) questionnaire. There were statistically significant increases between pretest and posttest scores on nurses' intentions, subjective norms and perceived behavioral control related to FBR, and on providing education to families about FBR. A brief, educational workshop can positively affect nurses' attitudes and beliefs about FBR. Future research should include additional psychometric evaluation of the NABAR.


Influence of apolipoprotein E polymorphism on plasma vitamin A and vitamin E levels.
Plasma concentrations of vitamins A and E are positively correlated with those of concurrent lipids and, on the other hand, lipid levels are influenced by apolipoprotein E polymorphism. Therefore, the effect of this polymorphism on both vitamins was analysed in an adult population. Subjects were recruited from a working population. Their anthropometric, lifestyle and dietary intake variables and menopausal status were recorded. Their apolipoprotein E phenotype and their plasma vitamins A and E (by high-performance liquid chromatography) and lipid (enzymatically) concentrations were determined after an overnight fast. The associations of the phenotype with vitamins and lipids were studied in men and women separately and controlling for significant covariates. The apolipoprotein E phenotype was associated with the concentrations of total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol in women, whereas no associations with lipids were found in men. Vitamin A and vitamin E levels were higher in men than in women, but only the difference in the former persisted after lipid adjustment. Apolipoprotein E2 slightly increased vitamin A levels in women, an effect which was still evident with lipid adjustment. Actually, both the apolipoprotein E phenotype and triglyceride were selected as significant predictors of this vitamin by multiple regression. This phenotype did not affect vitamin E levels in either sex. Lipids do not mediate the effect of gender on vitamin A levels. Apolipoprotein E polymorphism is an independent determinant of vitamin A levels in women. Pending confirmation by others, we propose that enhancement of this vitamin may contribute to the beneficial impact of the epsilon2 allele on human ageing and health.


An early stage in the evolution of Aristotle's physics.
Aristotle's Physics V and VI deal with the same concepts: motion, change and continuity. The two books, however, employ altogether different approaches to the study of these concepts, thus presenting different orders of conceptualization. Abraham Edel (1982, 42) claims that Aristotle is a systematic philosopher "not in the sense of [i] one who pursues a deductive system … but in the sense of [ii] one who has a well-constructed and fairly clearly analyzed conceptual network that he uses with considerable power in field after field of human inquiry." Truly, [ii] is more typical of Aristotle, but in the Physics both approaches are present. Books VI and V (respectively) are good examples. It is commonly taken for granted that Physics V prepares for VI, because of the order in which they appear in the corpus, and because V includes the definitions of the main concepts that are used in VI. A closer look at the texts, however, reveals that the definitions of V are not used in VI. I argue that the definitions of V were not only unknown when VI was written, but are actually incompatible with the spirit of Physics VI and with the main thesis underlying it. Physics VI is close in method, conceptual basis and in its radical formal approach to the Posterior Analytics, and a part of it (the early stratum) looks like a mathematical exercise. The mathematical-logical approach was abandoned, and gave way to the more mature Aristotelian style, which is already dominant in Physics V.


Varicella zoster virus infection occurs at a relatively young age in The Netherlands.
To date, there is no universal varicella vaccination in the Netherlands. We studied the seroprevalence of varicella zoster virus (VZV) specific antibodies and determinants for seropositivity among participants of a serosurveillance study, conducted in 2006/2007 among Dutch inhabitants 0-79 years of age. Serological testing of 6386 blood samples for VZV was performed with a fluorescent bead-based multiplex immunoassay. Seroprevalence and geometric mean concentration (GMC) were weighted for age, sex, ethnicity, and urbanization rate to the total Dutch population. Determinants for VZV seropositivity were identified among children younger than 6 years of age using a logistic regression model. The overall seroprevalence of VZV specific antibodies in the Dutch population was 94.6% (95% CI: 93.2-96.0%). This seroprevalence increased rapidly with age: at 6 years of age, more than 95% were seropositive. Determinants associated with lower VZV seropositivity were: young age, first-generation non-Dutch ethnicity, and low frequency of attendance at a day care center or nursery school. The GMC increased with age and was lower for women than for men from the age of 20 years onwards. This study confirmed that VZV infection occurs at a younger age in the Netherlands compared to other countries, which might explain the low disease burden due to varicella. Introduction of universal varicella vaccination is not a foregone conclusion in the Netherlands. Changes in migration and day care usage will influence the age-specific risk on varicella and should therefore be monitored. Further research might elucidate the sex differences in VZV specific GMC.


Imaging selection for reperfusion therapy in acute ischemic stroke beyond the conventional time window.
Originally, the efficacy of acute ischemic stroke treatment with thrombolysis or thrombectomy was only proven in narrow time windows of, respectively, 4.5 and 6 h after onset. Introducing imaging-based selection beyond non-contrast enhanced computed tomography has expanded the treatment window, focusing on presumed tissue status rather than solely on time after stroke onset. Different mismatch concepts have been adopted in clinical practice to select patients in the extended and unknown time window based on findings from randomized controlled trials. Since various concepts exist that can identify patients likely to benefit from reperfusion strategies, clinicians may wonder which imaging modality may be preferred in the emergency setting. In this review, we will discuss the different mismatch concepts and their practical implementation for patient selection for thrombolysis or thrombectomy, beyond the conventional time window.


A 7/24-GHz CMOS VCO with High Band Ratio Using a Current-Source Switching Topology.
In this paper, a 7/24-GHz dual-band voltage-controlled oscillator (DVCO) using a current-source switching topology is designed, implemented, and verified in a 0.18-μm CMOS technology for C-band and K-band radar applications. The low- and high-frequency bands are obtained by the Colpitts mode oscillation and the cross-coupled pairs (CCP) mode oscillation, respectively. Unlike conventional dual-band VCOs realized by resonator-switching topologies, the proposed VCO is based on the composite Colpitts and CCP architecture to avoid additional losses in the resonator, or lower its power consumption. The fabricated VCO occupies a chip area of 0.95×0.71 mm2 including all testing pads. Measurements show that the VCO operating in the Colpitts mode provides a phase noise of -112.5 dBc/Hz at 1 MHz offset from the 7.4-GHz oscillation frequency under 7.5-mW power consumption. When the VCO operating in the CCP mode, it provides a phase noise of -99.9 dBc/Hz at 1 MHz offset from the 24-GHz oscillation frequency with 9.7-mW power dissipation. Moreover, the DVCO achieves a high band ratio (fH/fL=24/7) of 3.43. To the authors' best knowledge, the design features the highest band ratio, low power dissipation, and comparable electrical performances among previously reported DVCOs.


Characterization of the novel HLA-A*32:172 allele by next generation sequencing.
HLA-A*32:172 differs from HLA-A*32:01:01:01 by one nucleotide substitution at position 1013, codon 314 located in exon 6.


Rearranging Low-Dimensional Phase Distribution of Quasi-2D Perovskites for Efficient Sky-Blue Perovskite Light-Emitting Diodes.
Metal halide perovskites have received much attention for their application in light-emitting diodes (LEDs) in the past several years. Rapid progress has been made in efficient green, red, and near-infrared perovskite LEDs. However, the development of blue perovskite LEDs is still lagging far behind. Here, we report efficient sky-blue perovskite LEDs by rearranging low-dimensional phase distribution in quasi-2D perovskites. We incorporated sodium ions into the mixed-Cl/Br quasi-2D perovskites with phenylethylammonium as the organic spacer and cesium lead halide as the inorganic framework. The inclusion of the sodium ion was found to significantly reduce the formation of the n = 1 phase, which was dominated by nonradiative transition, and increase the formation of other small-n phases for efficient exciton energy transfer. By managing the phase distribution, a maximum external quantum efficiency (EQE) of 11.7% was achieved in the sky-blue perovskite LED, with a stable emission peak at 488 nm. Further optimizing the phase distribution and film morphology with Pb content, we demonstrated the sky-blue devices with the average EQE approaching 10%. This strategy of engineering phase distribution of quasi-2D perovskites with a sodium ion could provide a useful way for the fabrication of high-performance blue perovskite LEDs.


Hepatolienal fusion: case report of an unusual lesion.
A unique fusion of liver and spleen was observed at autopsy between a tongue of hepatic parenchyma and the superolateral aspect of the spleen in an adult Caucasian male. No instance of hepatolineal fusion was found in the literature, prompting this report. An embryologic explanation is offered.


Strong biomass burning contribution to ambient aerosol during heating season in a megacity in Northeast China: Effectiveness of agricultural fire bans?
Sustainable use of crop residues remains a challenge in main agricultural regions of China such as the Northeast Plain. Here we investigated the impacts of biomass burning on fine particle (PM2.5) during a six-month long heating season in the Harbin-Changchun (HC) metropolitan area, China's only national-level city cluster located in the severe cold climate region. Temporal variation of PM2.5 was found to coincide with that of levoglucosan. This was attributed to the strong contribution of biomass burning to organic aerosol (the dominant component in PM2.5), as supported by the source apportionment results and high levoglucosan-to-organic carbon (OC) ratios. Furthermore, the variation of biomass burning contribution was inferred to be driven mainly by agricultural fires with relatively low combustion efficiencies, based on a synthesis of the relationship between OC and elemental carbon (EC), the dependence of EC on carbon monoxide, and the relative abundances of different tracers for biomass burning. Nitrate formation was enhanced during biomass burning episodes whereas no evidence was observed to indicate enhanced sulfate formation or net increase of OC mass due to secondary formation. This study demonstrates the importance of open burning as a source of haze pollution in the HC region.


Association between paraoxonase 2 gene polymorphisms and noise-induced hearing loss in the Chinese population.
The aim of the present study was to investigate whether PON2 gene polymorphisms (rs7493, rs12026, rs12704796, rs7785846 and rs7786401) are associated with susceptibility to noise-induced hearing loss (NIHL) in the Chinese population. A case-control study was conducted using 615 cases selected without any restriction in age or sex and 644 controls who were matched with the cases in terms of age, gender and the intensity and duration of exposure to noise. Information on these subjects was gathered by questionnaires that were administered through face-to-face interviews by trained interviewers. We found that the rs7493 CG + GG genotype (OR=1.36, 95% CI, 1.08-1.72), rs12026 CG + GG genotype (OR=1.34, 95% CI, 1.06-1.70), rs7785846 CT + TT genotype (OR=1.36, 95% CI, 1.07-1.71) and rs7786401 GT + TT genotype (OR=1.33, 95% CI, 1.05-1.68) were risk factors for NIHL. PON2 gene polymorphisms may be associated with susceptibility to NIHL in the Chinese population


The potential role of exposure to environmental toxicants in the pathophysiology of endometriosis.
Humans and animals are exposed daily to a complex mixture of polyhalogenated aromatic hydrocarbons (PHAHs). Previous work has shown that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with a dose-dependent increase in the incidence and severity of endometriosis in the rhesus monkey. Dioxin-like chemicals can also exert effects in combination with TCDD via the aryl hydrocarbon receptor. Using a rhesus model of chronic TCDD exposure and endometriosis, serum concentrations of TCDD and 19 dioxin-like PHAHs were quantified 13 years after termination of exposure to TCDD. In additional studies, the immune status of TCDD-exposed monkeys was evaluated. For TCDD-exposed and unexposed animals, TCDD exposure correlated with an increased serum TCDD concentration. Furthermore, TCDD exposure and an elevated serum TCDD concentration were associated with increased serum levels of triglycerides, 1,2,3,6,7,8-hexachlorodibenzofuran (HxCDF), PCB77, and PCB126. Importantly, the animals with elevated serum levels of PCB77 and PCB126 and increased total serum TCDD equivalents (TEQs) had a high prevalence of endometriosis, and the severity of disease correlated with the serum concentration of PCB77. In immune studies, TCDD exposure correlated with increased tumor necrosis factor alpha (TNFalpha) production by peripheral blood mononuclear cells (PBMC) in response to stimulation by T cell mitogen and decreased NK cytolytic activity. Elevated serum concentrations of TCDD, 1,2,3,6,7,8-HxCDF, and PCB126 correlated with increased numbers of CD3+/CD25- and CD3-/CD25+ leukocytes and enhanced secretion of TNFalpha by mitogen-stimulated PBMC. This evidence suggests that TCDD exposure and endometriosis in the rhesus monkey may be associated with increased serum concentrations of specific coplanar PCB compounds and long-term alterations in systemic immunity. Furthermore, the data suggest a potential involvement of an increased body burden of PCB compounds in the etiology of endometriosis in the rhesus. Recent advances in the detection and assay of individual PHAH congeners in biological samples have made it possible to assess total PHAH body burden in humans and animals. Future studies are expected to exploit this advance to assess the health impact of PHAH body burdens in both exposed individuals and the general population. Serum PHAH concentrations and TEQs in TCDD-exposed monkeys with endometriosis are similar to or lower than blood levels in the general human population; thus, it is important to consider the implications of these findings for human health and the prevalence of endometriosis in humans. Additional studies are warranted, particularly in human subjects, to explore the potential implications of these data.


Uncertainty-informed deep learning models enable high-confidence predictions for digital histopathology.
A model's ability to express its own predictive uncertainty is an essential attribute for maintaining clinical user confidence as computational biomarkers are deployed into real-world medical settings. In the domain of cancer digital histopathology, we describe a clinically-oriented approach to uncertainty quantification for whole-slide images, estimating uncertainty using dropout and calculating thresholds on training data to establish cutoffs for low- and high-confidence predictions. We train models to identify lung adenocarcinoma vs. squamous cell carcinoma and show that high-confidence predictions outperform predictions without uncertainty, in both cross-validation and testing on two large external datasets spanning multiple institutions. Our testing strategy closely approximates real-world application, with predictions generated on unsupervised, unannotated slides using predetermined thresholds. Furthermore, we show that uncertainty thresholding remains reliable in the setting of domain shift, with accurate high-confidence predictions of adenocarcinoma vs. squamous cell carcinoma for out-of-distribution, non-lung cancer cohorts.


The cells of the bovine outflow system in tissue culture.
Meshwork cells from the bovine outflow system were grown in culture and their growth characteristics and behaviour in vitro reported. The cells were studied by inverted phase microscopy and time-lapse cinephotomicrography. It was found that plating efficiency was highest for third and seventh passage cells. These cells reached confluence within 2 weeks when plated out at 7.5 X 10(3) cells cm-2 in a conventional culture medium containing 10% serum. Third passage cells were studied in greatest detail. These cells exhibited postconfluence contact inhibition of division. By 2 weeks postconfluence the division rate decreased 10-fold to a level of less than six divisions per thousand cells per day. The contact inhibition was not overcome by increasing the serum content of the medium. On the other hand, a 30-fold increased division rate could be produced after scratching the culture flask. Postconfluent contact-inhibited cultures were considered to be a better reflection of the behaviour and activities of meshwork cells in vivo than cultures which retain a high level of division.


The mechanism of acute cytotoxicity of triethylphosphine gold(I) complexes. I. Characterization of triethylphosphine gold chloride-induced biochemical and morphological changes in isolated hepatocytes.
Triethylphosphine gold complexes are effective therapeutic agents used for the treatment of rheumatoid arthritis. Many of those molecules are also highly cytotoxic in vitro and can inhibit DNA and protein synthesis. Preliminary experiments have indicated that triethylphosphine gold chloride (TEPAu) may induce the peroxidative decomposition of cellular membrane lipids. The purpose of these investigations therefore was to evaluate the role of lipid peroxidation in the mechanism of acute cytotoxicity of a gold(I) coordination complex, TEPAu, and to examine the early morphological and biochemical changes induced by TEPAu in suspensions of freshly isolated rat hepatocytes. TEPAu caused a rapid loss of cell viability at concentrations above 25 microM which was significantly different from that of control by 60 min and complete by 180 min of incubation. TEPAu also depleted cells of reduced glutathione (GSH) and increased the formation of malondialdehyde (MDA) by 60 min. Incubation of cells with either of the antioxidants, N,N'-diphenyl-p-phenylenediamine (DPPD) or promethazine blocked the formation of MDA but did not alter the time course of cell death or GSH depletion induced by TEPAu. TEPAu also caused a decrease in cellular NADPH and NADH by 10 min. Electron microscopy of hepatocytes exposed to TEPAu revealed early (5 min) formation of flocculent electron-dense precipitates within condensed mitochondria. These changes characteristically preceded cell death. Energy-dispersive electron-probe microanalysis indicated that the electron-dense precipitates did not contain detectable amounts of gold. TEPAu also caused a concentration-dependent decrease in cellular ATP and oxygen consumption in isolated rat hepatocytes. These data suggest that lipid peroxidation, as indicated by the formation of MDA, is probably not a major mechanism by which triethylphosphine gold complexes lethally injure cells. These data, therefore, suggest that mitochondria may be target organelles in TEPAu-induced toxicity to isolated rat hepatocytes.


Women in Hand Surgery: Leadership and Legacy.
Although women have existed in medicine and surgery for thousands of years, challenges continue to persist to date. Despite being discouraged and excluded from training, sponsorship, and opportunities, throughout the history of Hand Surgery, female surgeons have found ways to contribute significantly to science, our organizations, each other, changing the culture, and engaging the next generation of female trainees. This article integrates historical facts with oral history about Hand Surgery training, national societies, interest groups, achievements, and lived experiences to tell the history and legacy of women in Hand Surgery.


Hereditary Gastric Cancer Syndromes.
Hereditary gastric cancer syndromes are a rare but distinct cause of gastric cancers. The genetic mutations underlying most affected families are unknown. Mutations of CDH1 occur in some patients affected by hereditary diffuse gastric cancer, and is the only practical marker for guiding management. Carriers of CDH1 mutations are at risk for a highly penetrant, aggressive and early-onset diffuse-type gastric cancer, and these individuals are usually offered prophylactic total gastrectomy. Further research is required to identify other genetic mutations responsible for these syndromes to improve our understanding of the underlying disease mechanisms and optimize the clinical management of affected individuals.


Multifunctional Au@Pt@Ag NPs with color-photothermal-Raman properties for multimodal lateral flow immunoassay.
Multimodal lateral flow immunoassay (LFIA) has displayed its potential to improve practicability and elasticity of point-of-care testing. Herein, multifunctional core-shell-shell Au@Pt@Ag NPs loaded with dual-layer Raman reporter molecules of 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) with a characteristic combination of color-photothermal-Raman performance were constructed for colorimetric LFIA (CM-LFIA), photothermal LFIA (PT-LFIA) and surface-enhanced Raman scattering-based LFIA (SERS-LFIA), respectively. The highly specific nanoprobes, being obtained through the combination of the resulted dual-layer DTNB modified Au@Pt@Ag NPs with the antibody, were triumphantly utilized in exploring multimodal LFIA with one visual qualitative and two optional quantitative modes with excellent sensing sensitivity. Under optimal conditions, the limit of detection (LOD) for the model hazardous analyte dehydroepiandrosterone (DHEA) were 1.0 ng mL-1 for CM-LFIA, 0.42 ng mL-1 for PT-LFIA, and 0.013 ng mL-1 for SERS-LFIA, three of which were over 100-fold, 200-fold and 7 000-fold more sensitive than conventional visual AuNPs-based LFIA, respectively. In addition, the quantitative PT-LFIA and SERS-LFIA sensors worked well in spiked real samples with acceptable recoveries of 96.2 - 106.7% and 98.2 - 105.2%, respectively. This assay demonstrated that the developed multimodal LFIA had a great potential to be a powerful tool for accurate tracing hazardous analytes in complex samples.


Characterisation of variant alleles at the HumD21S11 locus implies unique Australasian genotypes and re-classification of nomenclature guidelines.
Several variant alleles of the HumD21S11 locus have only been reported in Australasian population samples. Fifteen such alleles were observed in Caucasian and Australian Aborigine sub-population databases compiled from residents of the state of Western Australia. Each variant was sequenced to authenticate the allelic designation and determine the structural conformation. Nine novel structural variants are described. The structure of the repeat region of these rare alleles combined with the STR designation brings aspects of the HumD21S11 nomenclature guidelines into question, in particular the designation of common incomplete repeats (or "0.2's"). The conformation of the sequences provides evidence in support of a genetic relationship between the Australian Aborigine and the Papuan people.


Species differences in the formation of butadiene monoxide from 1,3-butadiene.
When 1,3-butadiene is incubated with liver postmitochondrial fractions from mouse, rat, monkey or man and a NADPH-regenerating system, the formation rate of butadiene monoxide is different in the four species. With the exception of the rhesus monkey, the amount of epoxide is proportional to the monooxygenase activity. The sequence of epoxide formation is B6C3F1 mouse, Sprague Dawley rat, man, rhesus monkey. The ratio between mouse and monkey was about 7:1. When 1,3-butadiene is incubated with homogenates from lung tissue, only tissues from mouse and rat produce measurable butadiene monoxide concentrations. The monooxygenase activity in lung tissue of the mouse was only 1/30 that in mouse liver. By contrast, lung tissue formed epoxide concentrations comparable to those formed by liver tissue, whereas monkey and human lung tissue did not produce any measurable levels of butadiene monoxide. The data might suggest that the results of recent rodent inhalation studies with 1,3-butadiene could not automatically be extrapolated to man.


Severe thrombocytopenia in primary EBV- Infection with no signs of infectious mononucleosis. A case report.
Epstein-Barr virus is a widely spread Herpesvirus. Primary EBV infection affects children and young people, inducing haematological changes, with lymphocytosis being the most common. Moderate symptomless thrombocytopenia is found in 50% of the patients, however, severe thrombocytopenia is exceptionally rare. We present a case report of a 20-year-old man with an acute EBV infection, severe thrombocytopenia, and no signs of infectious mononucleosis.


Molecular developmental neurobiology of formation, guidance and survival of primary vestibular neurons.
Untangling the molecular and physiological interactions that generate the proper connections of the primary vestibular neurons in normal gravity requires two parallel approaches. One approach needs to use mutant mice to delineate the molecular basis of developmental mechanisms that govern ear development, including formation and differentiation of neurons and establishment of their peripheral and central connections. Beyond that and in addition to it, we need physiological investigations using microgravity and/or hypergravity, as well as absence of otoconia, to understand the role played by vestibular stimuli to fine tune connections of primary and secondary vestibular neurons. This paper provides an overview of some of the molecular mechanisms uncovered over the last few years that guide development, differentiation and survival of primary vestibular neurons of the mammalian ear. Briefly, several genes that are essential for primary neuron formation have been identified, all genes that govern embryonic survival are known and the first genes and mechanisms that guide formation of proper connections are being revealed. While still incomplete, the progress has been astounding and the completion of the mouse genome project will further accelerate the pace. Such data pave the way to put the research on the influence of altered gravity stimulation within a molecular framework.


Long-term study of pig carrion entomofauna.
Long-term changes of carrion entomofauna are poorly understood. No single carrion study lasted longer than one year. We studied entomofauna of large pig carcasses in the second and the third year postmortem. Ten carcasses were exposed in xerothermic grasslands of Western Poland in spring, early and late summer of 2012. Entomofauna was monitored until September of 2014. 72 species were found in the second year, and six in the third year. In the second or the third year carcasses from the late summer block revealed larger number of taxa compared to carcasses from the spring or the early summer block. Taxa differed in pattern of multiple larval colonizations. Only necrophagous taxa breeding in long-lasting carrion parts as well as predators feeding on arthropods present in these parts were found to recolonize. Recolonizations were always recorded in the second or the third year after death. Patterns of multiple colonization depended on the time of carcass exposure in the first year. Residencies of larvae were unexpectedly long in the second year. Several forensically important flies overwintered on carcasses in the larval stage. Current results support the view that insect fauna of cadavers with long post-mortem interval (PMI) may be used for PMI estimation.


Identification of cross-linked peptides from large sequence databases.
We describe a method to identify cross-linked peptides from complex samples and large protein sequence databases by combining isotopically tagged cross-linkers, chromatographic enrichment, targeted proteomics and a new search engine called xQuest. This software reduces the search space by an upstream candidate-peptide search before the recombination step. We showed that xQuest can identify cross-linked peptides from a total Escherichia coli lysate with an unrestricted database search.


Space and Bond Synergistic Conjugation Controlling Multiple-Aniline NIR-II Absorption for Photoacoustic Imaging Guided Photothermal Therapy.
Currently, clinical photothermal therapy (PTT) is greatly limited by the poor tissue penetration of the excitation light sources in visible (390-780 nm) and first near-infrared (NIR-I, 780-900 nm) window. Herein, based on space and bond synergistic conjugation, a multiple-aniline organic small molecule (TPD), is synthesized for high-efficiency second near-infrared (NIR-II, 900-1700 nm) photoacoustic imaging guided PTT. With the heterogeneity of six nitrogen atoms in TPD, the lone electrons on the nitrogen atom and the π bond orbital on the benzene ring form multielectron conjugations with highly delocalized state, which endowed TPD with strong NIR-II absorption (maximum peak at 925 nm). Besides, according to the single molecular reorganization, the alkyl side chains on TPD make more free space for intramolecular motion to enhance the photothermal conversion ability. Forming TPD nanoparticles (NPs) in J-aggregation, they show a further bathochromic-shifted absorbance (maximum peak at 976 nm) as well as a high photothermal conversion efficiency (66.7%) under NIR-II laser irradiation. In vitro and in vivo experiments demonstrate that TPD NPs can effectively inhibit the growth of tumors without palpable side effects. The study provides a novel NIR-II multiple-aniline structure based on multielectron hyperconjugation, and opens a new design thought for photothermal agents.


A systematic review and meta-analysis of Listeria monocytogenes isolated from human and non-human sources: the antibiotic susceptibility aspect.
Listeria monocytogenes causes listeriosis with a high mortality rate. This study systematically reviewed the antibiotic susceptibility of L. monocytogenes in the world. A literature search was done and the data of 33 studies that matched with the inclusion criteria, were used for meta-analysis. The random-effect model meta-analysis was applied to determine the frequency of overall L. monocytogenes and its antibiotic non-sensitive isolates. The frequency of L. monocytogenes contamination in non-human sources was 10.3%. The most frequent serotypes were 4b and 4ab in human and non-human isolates, respectively. The resistance of L. monocytogenes isolates to the first-line antibiotics namely penicillin, ampicillin/amoxicillin, gentamicin, and trimethoprim-sulfamethoxazole has been increased in recent years. Altogether, the results indicated a concern for the antibiotic resistance in L. monocytogenes isolates over time. The implement of the registry and surveillance systems is required to improve the insight of L. monocytogenes antibiotic susceptibility and its treatment choices.


Seronegative patients vaccinated with cytomegalovirus gB-MF59 vaccine have evidence of neutralising antibody responses against gB early post-transplantation.
Human cytomegalovirus (HCMV) causes a ubiquitous infection which can pose a significant threat for immunocompromised individuals, such as those undergoing solid organ transplant (SOT). Arguably, the most successful vaccine studied to date is the recombinant glycoprotein-B (gB) with MF59 adjuvant which, in 3 Phase II trials, demonstrated 43-50% efficacy in preventing HCMV acquisition in seronegative healthy women or adolescents and reduction in virological parameters after SOT. However, the mechanism of vaccine protection in seronegative recipients remains undefined. We evaluated samples from the cohort of seronegative SOT patients enroled in the Phase II glycoprotein-B/MF59 vaccine trial who received organs from seropositive donors. Samples after SOT (0-90 days) were tested by real-time quantitative PCR for HCMV DNA. Anti-gB antibody levels were measured by ELISA. Neutralization was measured as a decrease in infectivity for fibroblast cell cultures revealed by expression of immediate-early antigens. Serological analyses revealed a more rapid increase in the humoral response against gB post transplant in vaccine recipients than in those randomised to receive placebo. Importantly, a number of patient sera displayed HCMV neutralising responses - neutralisation which was abrogated by pre-absorbing the sera with recombinant gB. We hypothesise that the vaccine primed the immune system of seronegative recipients which, when further challenged with virus at time of transplant, allowed the host to mount rapid immunological humoral responses even under conditions of T cell immune suppression during transplantation.


Over-the-scope-clip applications for perforated peptic ulcer.
To investigate the effectiveness of over-the-scope-clip (OTSC)-based endoscopic closure in patients with perforated peptic ulcer (PPU). One hundred six patients diagnosed with PPU were treated with either OTSC (n = 26) or conservative treatments (n = 80), respectively. The outcome assessments included technical success rate, clinical success rate, post-treatment complications after 1 month, mortality rate, time to resume oral feeding, length of hospital stay, and the administration of antibiotics. In the OTSC group, technical and clinical success was achieved in 100% of patients without any complications, including death, incomplete closure, duodenal obstruction, and gastrointestinal bleeding, with a median operation time of 10 min. All patients in the OTSC group were discharged, while the mortality rate in the control group was 13.8%. Subsequent surgeries were required in 30% of patients in the control group. The median times to resume oral feeding were 3.5 (interquartile range [IQR] 2.0-5.25) days in the OTSC group and 7.0 (IQR 5.0-9.0) days in the control group (p < 0.001). One month post-procedure, 30% (24/80) of patients in the control group and 0 (0/26) in the OTSC group required additional operations (p < 0.001). No significant difference was found in the length of the hospital stay and the administration of antibiotics between the two groups (p > 0.05). OTSC-based endoscopic technique, with a high clinical success rate and a shorter time to resume oral feeding, was effective in achieving closure of PPU with a diameter < 15 mm.


Long-term calorie restriction has minimal impact on brain metabolite and fatty acid profiles in aged rats on a Western-style diet.
The effect of long-term calorie restriction (CR) on metabolites, fatty acid profiles and energy substrate transporter expression in the brain was assessed in aged rats. Three groups of male Sprague-Dawley rats were studied: (i) a 2 month old ad libitum-fed (2AL group), (ii) a 19 month old ad libitum-fed (19AL group), and (iii) a 19 month old group subjected to 40% CR from the age of 7.5 to 19 months (19CR group). The diet contained high sucrose and low n-3 polyunsaturated fatty acids (PUFA) so as to imitate a Western-style diet. High resolution magic angle spinning-(1)H NMR showed an effect of aging on brain cortex metabolites compared to 2AL rats, the largest differences being for myo-inositol (+251% and +181%), lactate (+203% and +188%), β-hydroxybutyrate (+176% and +618%) and choline (+148% and +120%), in 19AL and 19 CR rats, respectively. However, brain metabolites did not differ between the 19AL and 19CR groups. Cortex fatty acid profiles showed that n-3 PUFA were 35-47% lower but monounsaturated fatty acids were 40-52% higher in 19AL and 19CR rats compared to 2AL rats. Brain microvessel glucose transporter (GLUT1) was 68% higher in 19AL rats than in 2AL rats, while the monocarboxylate transporter, MCT1, was 61% lower in 19CR rats compared to 19AL rats. We conclude that on a high-sucrose, low n-3 PUFA diet, the brain of aged AL rats had higher metabolites and microvessel GLUT1 expression compared to 2AL rats. However, long-term CR in aged rats did not markedly change brain metabolite or fatty acid profile, but did reduce brain microvessel MCT1 expression.


Preimplantation genetic diagnosis of chromosome abnormalities: implications from the outcome for couples with chromosomal rearrangements.
Chromosomal rearrangements can lead to infertility or repeated spontaneous or induced abortions. The use of preimplantation genetic diagnosis (PGD) allows the selected transfer of chromosomally balanced embryos. The aim of this study was to carry out detailed analysis of the outcome of 11 PGD cycles for 8 patients carrying various chromosomal rearrangements. Patients underwent routine in vitro fertilisation with biopsy of embryos on day 3. Specific fluorescent in situ hybridisation protocols were developed for each couple. Embryo transfer was possible in all 11 cycles. The outcome was four pregnancies, leading to three live births and one biochemical pregnancy. Post-zygotic mosaicism was detected in 75% of untransferred embryos, the majority of which were chaotic. Detailed follow-up and analysis provided evidence for the co-existence of chromosomally balanced and abnormal cells in six embryos. The mechanisms involved included chromosome breakage and loss of material. Biopsy and analysis of two blastomeres, where possible, reduced the risk of misdiagnosis in cases of balanced/aneuploid mosaics. The three live births achieved for the eight couples treated in this series, despite the poor history in almost all cases, is further proof that a policy of biopsying two cells from embryos consisting of six or more cells and a single cell from four- or five-cell embryos is compatible with a positive outcome.


A tripeptide protease inhibitor attenuates conditioned avoidance behavior.
In a single 10-s training trial, hatchling chicks were conditioned to suppress their spontaneous peck response to a small spherical target by coating it with an aversive liquid. A 24-h test trial employing a dry target demonstrated a robust memory for the training manifested in passive avoidance behavior. Leupeptin, a low-molecular-weight antiprotease, injected i.c.v. 1 h or 15 min prior to training attenuated the long-term avoidance response but not the initial training-induced peck suppression. Leupeptin had no effect on memory if given posttraining. A dose response experiment revealed that a 100- or 200-micrograms dose of leupeptin reliably impaired conditioned avoidance, whereas a 25 or 50-micrograms dose was ineffective. A dipeptide leupeptin analog (L-leucyl-L-arginine) possessed one-half the potency of the tripeptide in the memory task, and a different protease inhibitor (aprotinin) failed to effect the conditioned avoidance behavior. The mechanisms by which leupeptin may exert its influence in this behavioral paradigm and others are discussed.


Consensus building in metastatic spine disease.
Arana E, Kovacs FM, Royuela A, Asenjo B, Pérez-Ramírez Ú, Zamora J, the Spanish Back Pain Research Network Task Force for the Improvement of Inter-Disciplinary Management of Spinal Metastasis. Spine Instability Neoplastic Score: agreement across different medical and surgical specialties. Spine J 2016;16:591-9 (in this issue).


Rhodamine 123 as a probe of in vitro toxicity in MDCK cells.
The effect of mercuric chloride on Madin-Darby Canine Kidney (MDCK) cells grown in culture was assayed by the mitochondrial-specific fluorescent probe, rhodamine 123. Treatment of cells with mercuric chloride resulted in a dissipation of rhodamine fluorescence from the mitochondria into the cytoplasm, followed by a release into the medium bathing the cells. Toxicity was assayed either by determining the proportion of cells with delocalized rhodamine fluorescence, or by measuring the rhodamine released from or retained in the cells. Quantifying the release or retention of rhodamine 123 is semi-automated and represents a highly sensitive method of using a vital fluorescent dye for in vitro toxicity analysis.


[Microiontophoretic study of the effect of acetylcholine and noradrenaline on the monosynaptic reflex activity of the spinal cord].
In anesthetized and spinal cats the influence of microionophoretic local injections of acetylcholine and noradrenaline into different layers of grey substance of lumbar segments of the spinal cord were studied with aid of monosynaptic EPSPs of motoneurons. Injections of ACH and NA in the surface layers of the grey substance of dorsal horn induced depression of monosynaptic reactions. In the area of 6--7 layers ACH induced a weak depression, while NA significantly increased the reflex responses. In the given arrangement of motoneurons NA depressed and ACH facilitated extensor and flexor monosynaptic reactions of motoneurons.


Small data global regularity for half-wave maps in n = 4 dimensions.
We prove that the half-wave maps problem on R 4 + 1 with target S 2 is globally well-posed for smooth initial data which are small in the critical l 1 based Besov space. This is a formal analogue of the result proved by Tataru for wave maps.


Transient hyperprolactinemia during cycle stimulation: influence on the endocrine response and fertilization rate of human oocytes and effects of bromocriptine treatment.
The effect of transient hyperprolactinemia and its treatment during cycle stimulation on the endocrine response and fertilization rate of human oocytes was studied. Fifty stimulated cycles were included in the study and divided into three groups: group I consisted of 18 cycles with serum prolactin (PRL) levels less than or equal to 25 ng/ml; group II contained 15 cycles, where patients developed PRL levels greater than 25 ng/ml; group III consisted of 17 cycles, where patients, who already developed hyperprolactinemia in a previous cycle, were treated by 3.75 mg bromocriptine daily. The serum estradiol (E2), progesterone (P) and PRL levels 1, 2, and 3 days before and at oocyte retrieval were evaluated. The E2 decrease at oocyte retrieval was significantly steeper in groups I and III. Follicular luteinization was more effective in groups I and III. The fertilization rate in groups I and III was significantly higher than in group II. High serum PRL levels seem to interfere in follicular and oocyte development. The treatment of transient hyperprolactinemia improved the patients' endocrine response and the fertilization rate of oocytes.


Hormone replacement therapy in hypothyroidism and nerve conduction study.
To evaluate the electrodiagnostic evidence of peripheral nerve dysfunction in patients with hypothyroidism before and after hormone replacement treatment. Forty patients aged above 18 years diagnosed with hypothyroidism were included in our study. Patients with FT4 levels below 11.6 pmol/l and TSH levels above 4.2 IU/ml were accepted as hypothyroidic. Electrodiagnostic evaluation was performed at the onset of the study and after 3 months. Electrodiagnostic evaluation included motor and sensory nerve conduction studies, and F wave. The differences between pre- and post-treatment FT4, FT3 and TSH values were found to be statistically significant. At the onset, electrophysiological evaluation revealed carpal tunnel syndrome in 15 patients and polyneuropathy in seven patients; whereas 18 patients were found normal in these respects. After treatment, the electrodiagnostic evaluation revealed that 35 patients were normal, while only two patients had carpal tunnel syndrome and three patients had polyneuropathy. The differences between before and after treatment values of median motor distal latency and amplitude, median sensorial nerve conduction velocity, tibial motor nerve conduction velocity and sural sensory nerve conduction velocity were found to be statistically significant. The results of the control evaluation after treatment demonstrated that the findings related to entrapment neuropathy and polyneuropathy in hypothyroid patients can be reversible in a period of 3 months if appropriate hormone replacement treatment can be obtained. Especially in the treatment of entrapment neuropathy in hypothyroidism, the chance of medical treatment must be given to patients before considering surgical treatment.


Atypical crusted scabies.
Five cases of an atypical form of crusted (or Norwegian) scabies are described. Three cases occurred in patients who suffered from a malignant tumor, and two additional cases occurred in mentally retarded and physically debilitated patients. These cases should draw attention to the possibility of a scabietic infestation whenever a widespread, scaly, itchy dermatosis develops in a debilitated immunosuppressed patient.


A land surface ¹⁴C transfer model and numerical experiments on belowground ¹⁴C accumulation and its impact on vegetation ¹⁴C level.
A model simulating transport and exchange for ¹⁴C (or ¹⁴CO₂) in a land surface ecosystem was developed and the belowground ¹⁴C accumulation and its impact on vegetation ¹⁴C accumulation at a hypothetical cultivated field were studied with the model through numerical experiments. The developed model involved physical ¹⁴CO₂ transport in surface atmosphere and soil and physiological ¹⁴CO₂ exchanges in leaves, and was incorporated into a dynamical model (SOLVEG-II) that calculates transport and exchange for heat, water and CO₂. The model was tested through a simulation of an existing-experiment on an acute exposure of grape plants to ¹⁴CO₂. The calculated ¹⁴C amount in leaves agreed with the observations within a factor of 1.7. A hypothetical scenario used for the numerical experiments considered an annual ¹⁴C input into surface soil layers via ¹⁴C-enriched foliage or root litter under a continually heightened atmospheric ¹⁴CO₂ concentration. The specific activity of ¹⁴C in the surface soil layers increased with time and several decades after the start of accumulation it eventually converged to eight times the initial specific activity. At this equilibrium state, the increased belowground ¹⁴CO₂ production enhanced the atmospheric ¹⁴CO₂ level and, consequently, ¹⁴CO₂ uptake by vegetation increased to 1.1 times the control calculated without belowground ¹⁴C accumulation. The model results also demonstrated that ¹⁴C accumulated in soil can maintain an enhanced vegetation ¹⁴C level for at least several decades even after the end of accumulation.


Epstein-Barr Virus Latent Membrane Protein 1 (LMP-1) in Hodgkin's Lymphoma Patients in Turkey.
Epstein-Barr virus (EBV) has been implicated as a contributing factor in the development of Hodgkin's lymphoma. The aim of this study was to elucidate the association of Hodgkin's lymphoma with EBV in a Turkish population using immunohistochemical detection of LMP-1. We studied a total of 21 consecutive cases of Hodgkin's lymphoma from Turkey. LMP-1 protein was detected in 9 of 21 (42.8%) cases. LMP-1 was positive in 4 of 7 (57%) mixed cellularity and 5 of 13 (38.4%) nodular sclerosis subtype. The results of the current study suggests a strong association of Epstein-Barr virus with Hodgkin's lymphoma in Turkey and, together with those reported previously showed that Epstein-Barr virus correlated with mixed cellular type, with a slight male predominancy while there was no correlation with age.


Conventional patellar-tendon-bearing (PTB) socket/stump interface dynamic pressure distributions recorded during the prosthetic stance phase of gait of a trans-tibial amputee.
Force sensing resistors (FSR) have been used to measure dynamic stump/socket interface pressures during the gait of a trans-tibial amputee. A total of 350 pressure sensor cells were attached to the inner wall of a patellar-tendon-bearing (PTB) socket. Data was sampled at 150 Hz during the approximate 0.8 seconds of prosthetic stance of gait. A total of 42,000 pressures were recorded during a single prosthetic stance. This paper describes the distribution of the pressure patterns monitored during the prosthetic stance phase of gait.


BCG revaccination boosts adaptive polyfunctional Th1/Th17 and innate effectors in IGRA+ and IGRA- Indian adults.
BACKGROUNDBacille Calmette-Guérin (BCG) vaccine is protective against Tuberculosis (TB) in children, but its efficacy wanes with age. Consequently, determining if BCG revaccination augments anti-TB immunity in young adults in TB endemic regions is vital.METHODSTwo hundred healthy adults, BCG vaccinated at birth, were tested for their IFN-γ release assay (IGRA) status. Of these, 28 IGRA+ and 30 IGRA- were BCG revaccinated, and 24 IGRA+ and 23 IGRA- subjects served as unvaccinated controls. T and innate cell responses to mycobacterial antigens were analyzed by 14-color flow cytometry over 34 weeks.RESULTSIFN-γ and/or IL-2 Ag85A- and BCG-specific CD4+ and CD8+ T cell responses were boosted by revacciantion at 4 and 34 weeks, respectively, and were > 2-fold higher in IGRA+ compared with IGRA- vaccinees. Polyfunctional Ag85A, BCG, and mycobacterium tuberculosis (Mtb) latency Ag-specific (LTAg-specific) CD4+ T cells expressing up to 8 cytokines were also significantly enhanced in both IGRA+ and IGRA- vaccinees relative to unvaccinated controls, most markedly in IGRA+ vaccinees. A focused analysis of Th17 responses revealed expansion of Ag85A-, BCG-, and LTAg-specific total IL-17A+,IL-17F+,IL-22+, and IL-10+ CD4+ T cell effectors in both IGRA+ and IGRA- subjects. Also, innate IFN-γ+ NK/γδ/NKT cell responses were higher in both IGRA+ and IGRA- vaccinees compared with controls. This is the first evidence to our knowledge that BCG revaccination significantly boosts antimycobacterial Th1/Th17 responses in IGRA+ and IGRA- subjects.CONCLUSIONThese data show that BCG revaccination is immunogenic in IGRA- and IGRA+ subjects, implying that Mtb preinfection in IGRA+ subjects does not impact immunogenicity. This has implications for public health and vaccine development strategies.FUNDINGThis work was funded principally by DBT-NIH (BT/MB/Indo-US/HIPC/2013).


Caerulein, a cholecystokinin-related peptide, depresses somatic function via the vagal afferent system.
Intravenous doses of 0.5-8 micrograms/kg (0.3-4.9 nmol/kg) of caerulein, a cholecystokinin-related peptide, depressed the crossed extensor reflex response of chloralose-anesthetized rats in a dose-dependent manner. Intraventricularly administered caerulein was effective only at high doses (1-2 micrograms/animal, i.e., 0.6-1.2 nmol/animal). Cervical vagotomy completely abolished the inhibitory effect of peripherally injected caerulein. Electrical stimulation of vagal afferent nerves could simulate the caerulein effect to some extent. These results suggest that the primary site of action of peripherally administered caerulein is located in the gastrointestinal tract and thus the generated afferent vagal impulses mediate the reflex depression via the nucleus tractus solitarius and other as yet unclarified brain stem structures.


Impaired cough suppression in chronic refractory cough.
Functional brain imaging in individuals with chronic cough demonstrates reduced activation in cortical regions associated with voluntary cough suppression. Little is known about the ability of patients with chronic cough to suppress cough. This study aimed to compare the ability to voluntarily suppress cough during inhaled capsaicin challenge in participants with chronic refractory cough with that in healthy controls. In addition, this study aimed to assess the repeatability of capsaicin challenge test with voluntary cough suppression.Participants with chronic refractory cough and healthy controls underwent inhaled capsaicin challenge tests while attempting to suppress their cough responses. After 5 days, either a conventional capsaicin challenge test with no cough suppression attempt, or a repeat test with an attempt at cough suppression was performed. Threshold capsaicin concentrations required to elicit one, two and five coughs were calculated by interpolation. Objective 24-h cough frequency was measured in individuals with chronic refractory cough.Healthy controls were able to suppress capsaicin-evoked cough while participants with chronic refractory cough were not. Geometric mean±sd capsaicin dose thresholds for five coughs with (CS5) and without (C5) suppression attempts were 254.40±3.78 versus 45.89±3.95 µmol·L-1, respectively, in healthy controls (p=0.033) and 3.34±5.04 versus 3.86±5.13 µmol·L-1, respectively, in participants with chronic refractory cough (p=0.922). Capsaicin dose thresholds for triggering five coughs with self-attempted cough suppression were significantly lower in participants with chronic refractory cough than in healthy controls; geometric mean±sd 4.94±4.43 versus 261.10±4.34 µmol·L-1, respectively; mean difference (95% CI) 5.72 (4.54-6.91) doubling doses (p<0.001). Repeatability of cough suppression test in both patients and healthy controls was high; intraclass correlation coefficients of log(CS5) values 0.81 and 0.87, respectively. CS5 was associated with objective cough frequency (ρ=-0.514, p=0.029).Participants with chronic refractory cough were less able to voluntarily suppress capsaicin-evoked cough compared to healthy controls. This may have important implications for the pathophysiology and treatment of chronic cough.


Acid hydrolase activity in red and white skeletal muscle of mice during a two-week period following exhausting exercise.
The activities of beta-glucuronidase, beta-N-acetylglucosaminidase, arylsulphatase, ribonuclease, p-nitrophenylphosphatase, and malate dehydrogenase together with protein content were assayed from representative mixed (m. rectus femoris), predominantly red (proximal heads of m. vastus lateralis, m.v. medius and m. v. intermedius), and predominantly white (distal head of m. vastus lateralis) muscle homogenates of mice during a two-week period following one single exposure to exhausting intermittent running on a treadmill. The activities of cathepsin D and beta-glycerophosphatase were assayed from mixed muscle only. In all three muscle types, particularly in red muscle, the activities of beta-glucuronidase, beta-N-acetylglucosaminidase, arylsulphatase, and ribonuclease progressively increased between one to five days after the exercise; thereafter the activities began to decrease, being near the conrol values 15 days after the exercise. In mixed muscle, cathepsin D activity increased. No corresponding changes were observed in the activities of acid phosphatases. The time course of the activity changes closely resembled that earlier found to be caused by ischaemia in rabbit muscles. It is tentatively concluded that the two treatments, exhaustive exercise and temporary ischaemia, cause similar cell injuries, and that the lysosomal system involved seems to function similarly in the post-stress recovery of the fibres from these injuries.


Liquid-liquid transition and critical point in sulfur.
The liquid-liquid transition (LLT), in which a single-component liquid transforms into another one via a first-order phase transition, is an intriguing phenomenon that has changed our perception of the liquid state. LLTs have been predicted from computer simulations of water1,2, silicon3, carbon dioxide4, carbon5, hydrogen6 and nitrogen7. Experimental evidence has been found mostly in supercooled (that is, metastable) liquids such as Y2O3-Al2O3 mixtures8, water9 and other molecular liquids10-12. However, the LLT in supercooled liquids often occurs simultaneously with crystallization, making it difficult to separate the two phenomena13. A liquid-liquid critical point (LLCP), similar to the gas-liquid critical point, has been predicted at the end of the LLT line that separates the low- and high-density liquids in some cases, but has not yet been experimentally observed for any materials. This putative LLCP has been invoked to explain the thermodynamic anomalies of water1. Here we report combined in situ density, X-ray diffraction and Raman scattering measurements that provide direct evidence for a first-order LLT and an LLCP in sulfur. The transformation manifests itself as a sharp density jump between the low- and high-density liquids and by distinct features in the pair distribution function. We observe a non-monotonic variation of the density jump with increasing temperature: it first increases and then decreases when moving away from the critical point. This behaviour is linked to the competing effects of density and entropy in driving the transition. The existence of a first-order LLT and a critical point in sulfur could provide insight into the anomalous behaviour of important liquids such as water.


Associations of SGLT2 genetic polymorphisms with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors lowers blood pressure (BP) and exert a salutary effect on the salt sensitivity of BP. This study aimed to examine the associations of SGLT2 genetic variants with salt sensitivity, longitudinal BP changes and the risk of incident hypertension in Baoji Salt-Sensitive Study. A total of 514 participants were recruited when the cohort was established in 2004, and 333 participants received a dietary intervention that consisted of a 3-day usual diet followed sequentially by a 7-day low-salt diet and a 7-day high-salt diet. The cohort was then followed up for 14 years to evaluate the longitudinal BP changes and development of hypertension. We found that SGLT2 SNP rs3813007 was significantly associated with the systolic BP (SBP) responses to the low-salt diet. Over the 14 years of follow-up, SNPs rs3116149 and rs3813008 were significantly associated with the longitudinal SBP changes, and SNPs rs3116149, rs3813008, rs3813007 in SGLT2 were significantly associated with incidence of hypertension. Furthermore, gene-based analyses revealed that SGLT2 was significantly associated with hypertension incidence. Our study suggests that SGLT2 genetic polymorphisms may be involved in salt sensitivity and development of hypertension.


Sensory gamma entrainment: Impact on amyloid protein and therapeutic mechanism.
The deposition of amyloid β peptide (Aβ) is one of the main pathological features of AD. The much-talked sensory gamma entrainment may be a new treatment for Aβ load. Here we reviewed the generation and clearance pathways of Aβ, aberrant gamma oscillation in AD, and the therapeutic effect of sensory gamma entrainment on AD. In addition, we discuss these results based on stimulus parameters and possible potential mechanisms. This provides the support for sensory gamma entrainment targeting Aβ to improve AD.


FCC to BCC transformation-induced plasticity based on thermodynamic phase stability in novel V10Cr10Fe45CoxNi35-x medium-entropy alloys.
We introduce a novel transformation-induced plasticity mechanism, i.e., a martensitic transformation from fcc phase to bcc phase, in medium-entropy alloys (MEAs). A VCrFeCoNi MEA system is designed by thermodynamic calculations in consideration of phase stability between bcc and fcc phases. The resultantly formed bcc martensite favorably contributes to the transformation-induced plasticity, thereby leading to a significant enhancement in both strength and ductility as well as strain hardening. We reveal the microstructural evolutions according to the Co-Ni balance and their contributions to a mechanical response. The Co-Ni balance plays a leading role in phase stability and consequently tunes the cryogenic-temperature strength-ductility balance. The main difference from recently-reported metastable high-entropy dual-phase alloys is the formation of bcc martensite as a daughter phase, which shows significant effects on strain hardening. The hcp phase in the present MEA mostly acts as a nucleation site for the bcc martensite. Our findings demonstrate that the fcc to bcc transformation can be an attractive route to a new MEA design strategy for improving cryogenic strength-ductility.


Chemical Reactions Impede Thermal Transport Across Metal/β-Ga2O3 Interfaces.
The impact of chemical reactions on the thermal boundary conductance (TBC) of Au/metal contact/β-Ga2O3 layered samples as a function of contact thickness is investigated using high-throughput thermoreflectance measurements. A maximum in TBC of 530 ± 40 (260 ± 25) MW/m2 K is discovered for a Cr (Ti) contact at a thickness of 2.5 (5) nm. There is no local maximum for a Ni contact, for which the TBC saturates at 410 ± 35 MW/m2 K for thicknesses greater than 3 nm. Relative to the Au/β-Ga2O3 interface, which has a TBC of 45 ± 7 MW/m2 K, these nanoscale contacts enhance TBC by factors of 6 to 12. The TBC maximum only exists for metals capable of forming oxides that are enthalpically favorable compared to β-Ga2O3. The formation of Cr2O3, via oxygen removal from the β-Ga2O3 substrate, is confirmed by TEM analysis. The reaction-formed oxide layer reduces the potential TBC and leads to the maximum, which is followed by a plateau at a lower value, as its thickness saturates due to passivation. Many advanced materials are prone to similar chemical reactions, impacting contact engineering and thermal management for a variety of applications.


Enhanced intestinal absorption of cyclosporine in rats through the reduction of emulsion droplet size.
The intestinal absorption of cyclosporine was measured in situ in rats using an olive oil emulsion prepared by either stirring or homogenization. The surface area of the homogenized dosage form was twice that of the stirred dosage form. The apparent permeability of cyclosporine from the homogenized emulsion was about twice that of the emulsion prepared by stirring. The examination of absorption in different intestinal segment lengths suggested the presence of an "absorption window." The absorption of cyclosporine appeared to be concentration independent and, therefore, non-carrier mediated. The dependence of absorption upon the intestinal perfusion rate suggested that the stagnant aqueous layer is the rate-limiting barrier in cyclosporine absorption. These results indicate that the bioavailability of cyclosporine administered in an emulsion can possibly be increased by enhancing its rate of absorption through the reduction of droplet size.


Enhanced Thermoelectric Performance of Cu₂SnSe₃-Based Composites Incorporated with Nano-Fullerene.
In this study, nano-sized fullerene C60 powder was sufficiently mixed with Cu₂SnSe₃ powder by ball milling method, and the C60/Cu₂SnSe₃ composites were prepared by spark plasma sintering technology. The fullerene C60 distributed uniformly in the form of clusters, and the average cluster size was less than 1 μm. With increasing C60 content, the electrical conductivity of C60/Cu₂SnSe₃ composites decreased, while the Seebeck coefficient was enhanced. The thermal conductivity of composites decreased significantly, which resulted from the phonon scattering by the C60 clusters located on the grain boundaries of the Cu₂SnSe₃ matrix. The highest figure of merit ZT of 0.38 was achieved at 700 K for 0.8% C60/Cu₂SnSe₃ composite.


Induction immunosuppressive therapy in renal transplantation: does basiliximab make the difference?
The optimal prophylactic induction immunosuppressive therapy to prevent renal transplant rejection remains controversial. Recently, basiliximab efficiency has been reported in several studies. We sought to evaluate the efficiency of induction immunosuppressive therapy with basiliximab in renal transplantation in our unit based upon the acute rejection rate, patient and graft survivals, first hospital admission length, and incidence of infectious or malignant complications during 4 years of follow-up. We retrospectively evaluated the outcome of two groups of renal transplant recipients treated with triple immunosuppressive therapy (cyclosporine, mycophenolate mofetil, and prednisolone) without (group 1, 149 patients) or with (group 2, 104 patients) induction immunosuppression with basiliximab. The two groups did not differ in demographic characteristics, number of hypersensitized patients, cold ischemia time, or donor age. The group receiving basiliximab displayed a significantly lower acute rejection rate (7.6% vs 24%, P = .001) and shorter first hospital admission (14.4 +/- 8 vs 19.5 +/- 11 days). There was no difference in graft or patient survival, death due to sepsis, or incidence of posttransplant malignancies. Although there was no difference in graft or patient survival, immunosuppressive induction therapy with basiliximab yielded a significant reduction in the acute rejection rate.


Predicting protein secondary structure and solvent accessibility with an improved multiple linear regression method.
We have improved the multiple linear regression (MLR) algorithm for protein secondary structure prediction by combining it with the evolutionary information provided by multiple sequence alignment of PSI-BLAST. On the CB513 dataset, the three states average overall per-residue accuracy, Q(3), reached 76.4%, while segment overlap accuracy, SOV99, reached 73.2%, using a rigorous jackknife procedure and the strictest reduction of eight states DSSP definition to three states. This represents an improvement of approximately 5% on overall per-residue accuracy compared with previous work. The relative solvent accessibility prediction also benefited from this combination of methods. The system achieved 77.7% average jackknifed accuracy for two states prediction based on a 25% relative solvent accessibility mode, with a Mathews' correlation coefficient of 0.548. The improved MLR secondary structure and relative solvent accessibility prediction server is available at http://spg.biosci.tsinghua.edu.cn/.


Profiling of miRNAs in porcine Sertoli cells.
Sertoli cells (SCs) create a specialized environment to support and dictate spermatogenesis. MicroRNAs (miRNAs), a kind of ~ 22 nt small noncoding RNAs, have been reported to be highly abundant in mouse SCs and play critical roles in spermatogenesis. However, the miRNAs of porcine SCs remain largely unknown. We isolated porcine SCs and conducted small RNA sequencing. By comparing miRNAs in germ cells, we systematically analyzed the miRNA expression pattern of porcine SCs. We screened the highly enriched SC miRNAs and predicted their functions by Gene Ontology analysis. The dual luciferase assay was used to elucidate the regulation of tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) by ssc-miR-149. The analysis showed that 18 miRNAs were highly expressed in SCs and 15 miRNAs were highly expressed in germ cells. These miRNAs were predicted to mediate SC and germ cell functions. In addition, ssc-miR-149 played critical roles in SCs by targeting TRAF3. Our findings provide novel insights into the miRNA expression pattern and their regulatory roles of porcine SCs.


The use of augmentation rhinoplasty techniques for the correction of the non-caucasian nose.
To refine, enlarge, and enhance the mestizo nose, it is necessary to augment the structural support. The authors report on a series of more than 3000 patients over the last 20 years, exploring the possibilities of autogenous graft for augmentation of the nose. Their series showed minimal resorption of the bone grafts, no loss of volume of the cartilage grafts, and satisfactory long-term results.


A 1H NMR study of cobalt(II) arsanilazocarboxypeptidase A.
Cobalt(II) arsanilazotyrosine-248 carboxypeptidase A has been characterized through 1H NMR spectroscopy. The ability of the azoenzyme to form binary and ternary complexes with L- and D-phenylalanine and azide has been investigated. Comparison with the 1H NMR results obtained on unmodified cobalt(II) carboxypeptidase provides direct information on the specific effect of the presence of the azo group on the reactivity of the system. Marked differences in the interaction with D-phenylalanine have been observed, and structural inferences are drawn.


Metabolism of 19 nortestosterone-14C associated with oestradiol in mice and calves.
Metabolic study of 14C-19 Nortestosterone has been carried out in mice by macroscopic autoradiography and in calves by liquid scintillation counting. From the results, it is obvious that radioactivity is quickly eliminated mainly in urine and faeces. Ten weeks after administration, residual levels are very low.


A prospective study of the clinical value and accuracy of grey scale ultrasound in detecting gallstones.
The accuracy and possible clinical value of grey scale ultrasonography in the detection of gallstones has been prospectively studied in 100 unselected patients presenting with recurrent biliary colic, acute cholecystitis or acute pancreatitis. Adequate visualization of the gallbladder was obtained in 79 cases, with 3 false positive and no false negative reports. Oral cholecystography remains the initial investigation of choice in patients presenting with recurrent biliary colic, but grey scale ultrasound has been shown in this study to be a reliable means of detecting gallstones in the 'acute' situation, when conventional contrast radiology is of limited value.


Non linear behavior of vocal fold vibration in an experimental model of asymmetric larynx: role of coupling between the two folds.
One of the main factors involved in the laryngeal dynamic's non-linearity is the coupling between the two vocal folds. Evaluation of the different coupling elements requires various investigations. The present work evaluate the non-linearity effects in clinical situations such as unilateral laryngeal paralysis using Lyapunov's coefficients. It also demonstrate the coupling effects on excised larynx made experimentally asymmetrical, using a specially designed device to measure vibrations from each vocal fold (opto-reflectometer).


Alleviation mechanisms of metal(loid) stress in plants by silicon: a review.
Silicon (Si), although not considered as an essential element for plants in general, can ameliorate the phytotoxicity induced by excess metal(loid)s whether non-essential (e.g. Cd, Pb, Cr, Al, As, and Sb) or essential (e.g. Cu, Ni, and Zn). The Si-enhanced resistance allowing plants to cope with this type of abiotic stress has been developed at multiple levels in plants. Restriction of root uptake and immobilization of metal(loid)s in the rhizosphere by Si is probably one of the first defence mechanism. Further, retention of elements in the root apoplasm might enhance the resistance and vigour of plants. At the cellular level, the formation of insoluble complexes between Si and metal(loid)s and their storage within cell walls help plants to decrease available element concentration and restrict symplasmic uptake. Moreover, Si influences the oxidative status of plants by modifying the activity of various antioxidants, improves membrane stability, and acts on gene expression, although its exact role in these processes is still not well understood. This review focuses on all currently known plant-based mechanisms related to Si supply and involved in amelioration of stress caused by excess metal(loid)s.


Social and family characteristics of Hispanics with epilepsy.
The purpose of this study is to determine how acculturation, social support, family emotional involvement, perceived family criticism and stigma are associated with epilepsy self-efficacy and depression. A principal components analysis (PCA) was used to describe the salience of these characteristics within a sample of Hispanics with epilepsy. A total of 50 Hispanic adults of Mexican descent identified in our Epilepsy Clinic participated in this study. The PCA identified four distinct types, two were relatively culture-free, and two were distinctly culturally oriented. The first non-culture affiliated type described a well-adjusted group of individuals that tended to be males with moderate self-efficacy, who received social support, and who were unlikely to have depression or feel stigmatized. The second non-culture affiliated type described a dimension in which family emotional involvement tended to co-occur with perceived criticism. The Anglo-oriented group had a family environment that did not appear to criticize the individual with epilepsy and had good self-efficacy. The Mexican-oriented group had high self-efficacy and was unlikely to have depression. Results suggest that acculturation variables must be taken into consideration among ethnic groups because social, psychological and acculturation variables interact in complex ways. Additionally, it is clear that a diagnosis of epilepsy does not automatically lead to poor quality of life, stigma, or depression.


Transcriptionally Active Androgen Receptor Splice Variants Promote Hepatocellular Carcinoma Progression.
Owing to the marked sexual dimorphism of hepatocellular carcinoma (HCC), sex hormone receptor signaling has been implicated in numerous aspects of liver cancer pathogenesis. We sought to reconcile the clear contribution of androgen receptor (AR) activity that has been established in preclinical models of HCC with the clinical failure of AR antagonists in patients with advanced HCC by evaluating potential resistance mechanisms to AR-targeted therapy. The AR locus was interrogated for resistance-causing genomic modifications using publicly available primary HCC datasets (1,019 samples). Analysis of HCC tumor and cell line RNA-seq data revealed enriched expression of constitutively active, treatment-refractory AR splice variants (AR-SV). HCC cell lines expressed C-terminal-truncated AR-SV; 28 primary HCC samples abundantly expressed AR-SV. Low molecular weight AR species were nuclear localized and constitutively active. Furthermore, AR/AR-SV signaling promoted AR-mediated HCC cell progression and conferred resistance to AR antagonists. Ligand-dependent and -independent AR signaling mediated HCC epithelial-to-mesenchymal transition by regulating the transcription factor SLUG. These data suggest that AR-SV expression in HCC drives HCC progression and resistance to traditional AR antagonists. Novel therapeutic approaches that successfully target AR-SVs may be therapeutically beneficial for HCC. SIGNIFICANCE: Treatment-refractory, constitutively active androgen receptor splice variants promote hepatocellular carcinoma progression by regulating the epithelial-to-mesenchymal transition pathway.


Kaempferol-zinc(II) complex synthesis and evaluation of bone formation using zebrafish model.
Flavonoids are known for their wide range of bioactive properties including beneficial effect on bone formation. Their intense metal ion chelating capacity endorsed their nomination as a new biomaterial for biomedical applications. The present study examined the functional role of Kaemferal-Zinc(II) (Kaem-Zn) complex in bone formation, in vitro and in vivo. The cyto-compatibility assay confirmed that upto 25 μM of Kaem and Kaem-Zn complex was non-toxic. In fact, it facilitates ALP activity and accumulation of calcium in osteoblast; it was confirmed by Alizarin red and von Kossa staining. In addition to this, osteoblast markers, Runx2, type 1 col., ALP mRNAs expression, and osteocalcin and osteonectin secretory proteins level were also induced by the Kaem-Zn complex. Furthermore, bone forming ability of Kaem and Kaem-Zn was assessed by zebrafish model. The optimal concentration of Kaem and Kaem-Zn was determined by the viability assay of Zebrafish larvae. Osteoblasts distribution in scale, vertebrae and caudal fin ossification was studied by alizarin red staining accompanied by confocal imaging were carried out in adult zebrafish exposed to Kaem and Kaem-Zn complex. To sum up, our findings showed that Kaem promotes bone growth, and Kaem-Zn complex has further strengthened it. Kaem-Zn complex could be an effectively explored and used use in bone tissue engineering.


Antiviral silencing in animals.
RNA silencing or RNA interference (RNAi) refers to the small RNA-guided gene silencing mechanism conserved in a wide range of eukaryotic organisms from plants to mammals. As part of this special issue on the biology, mechanisms and applications of RNAi, here we review the recent advances on defining a role of RNAi in the responses of invertebrate and vertebrate animals to virus infection. Approximately 40 miRNAs and 10 RNAi suppressors encoded by diverse mammalian viruses have been identified. Assays used for the identification of viral suppressors and possible biological functions of both viral miRNAs and suppressors are discussed. We propose that herpes viral miRNAs may act as specificity factors to initiate heterochromatin assembly of the latent viral DNA genome in the nucleus.


Selection and Evaluation of Probiotic and Functional Characteristics of Autochthonous Lactic Acid Bacteria Isolated from Fermented Wheat Flour Dough Babroo.
The present study aimed to isolate and identify the potential probiotic lactic acid bacteria (LAB) from traditionally fermented wheat flour dough known as "babroo." A total of 26 lactic isolates were obtained from 50 different samples collected from different locations of the Himalayan province (Himachal Pradesh). To ascertain non-pathogenic nature, the isolates were screened by hemolytic activity leading to 20 non-hemolytic strains which were subjected to tolerance to simulated gastrointestinal conditions. Seven different strains were selected based on their tolerance to gastrointestinal conditions. All the selected seven isolates were found to be susceptible to ampicillin and resistant to gentamicin. The phylogenetic analysis revealed three different strains of Lactobacillus fermentum, two strains of Lactobacillus plantarum, and two of Pediococcus acidilactici. The isolates exhibit different degrees of cell surface hydrophobicity (20.0-42.0%), cellular autoaggregation (5.0-41.0%), and adhesion to mucin (35.0-78.0%). The different lactic strains also possessed higher antioxidant properties (87.6-92.9%) determined in terms of free radical scavenging activity, bile salt hydrolase activity, cholesterol lowering activity (49.0-75.0%), and exopolysaccharide production. The principal component analysis (PCA) on probiotic attributes indicated that L. plantarum K90, L. fermentum K75, and L. fermentum K78 can be used as potential probiotic candidates.


Segmented hippocampal volume in children and adolescents with posttraumatic stress disorder.
Although many studies of adults with posttraumatic stress disorder (PTSD) have reported smaller hippocampal volume compared with control subjects, comparable studies of children and adolescents have failed to replicate these findings or have noted opposite trends suggesting a larger hippocampus. We therefore performed a secondary analysis combining data from prior studies to examine the hypothesis that hippocampus would be larger in pediatric subjects with PTSD compared with non-maltreated control subjects. We also hypothesized that differences in PTSD subjects would be observed between boys and girls. Sixty-one subjects (31 boys, 30 girls) with maltreatment-related PTSD and 122 control subjects matched on age and gender underwent magnetic resonance imaging. As hypothesized, we observed a significantly larger hippocampus controlling for cerebral volume in PTSD subjects compared with control subjects. Segmented hippocampal white-matter volume was greater in PTSD subjects but not gray-matter volume. Hippocampal volume was positively related to age of trauma onset and level of psychopathology, particularly externalizing behavior. No interactions with group were observed for age or gender. Future longitudinal studies with trauma control subjects and neuropsychological measures are indicated to further elucidate the relationship between hippocampus and behavioral abnormalities in young PTSD subjects.


HSP100, a 100-kDa heat shock protein, is a Ca2+-calmodulin-regulated actin-binding protein.
The 100-kDa heat shock protein, HSP100, was purified from mouse lymphoma cells. Amino acid sequences of three peptide fragments which were obtained from the purified protein by lysylendopeptidase digestion were completely or nearly identical with those of a mouse endoplasmic reticulum protein, ERp99, of a hamster glucose-regulated protein, GRP94, and of a chicken heat shock protein, HSP108, all of which have been known to have strong homology with the 90-kDa heat shock protein, HSP90. HSP100 bound to actin filaments and an apparent Kd for the binding was determined to be 8 x 10(-7) M in 2 mM MgCl2 + 100 mM KCl. Calmodulin inhibited the binding in a Ca2+-dependent manner. Equilibrium gel filtration demonstrated that HSP100 has an ability to bind to calmodulin only in the presence of Ca2+. Moreover, HSP100 competed with HSP90 for binding to actin filaments. These results together with our previous findings that HSP90 and HSP100 have similar physicochemical properties (Koyasu, S., Nishida, E., Kadowaki, T., Matsuzaki, F., Iida, K., Harada, F., Kasuga, M., Sakai, H., and Yahara, I. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 8054-8058) and HSP90 is a calmodulin-regulated actin-binding protein (Nishida, E., Koyasu, S., Sakai, H., and Yahara, I. (1986) J. Biol. Chem. 261, 16033-16036), strongly suggest that HSP100 is structurally and functionally related to HSP90.


Baricitinib improves pulmonary fibrosis in mice with rheumatoid arthritis-associated interstitial lung disease by inhibiting the Jak2/Stat3 signaling pathway.
The study explored improvements in pulmonary inflammation and fibrosis in a bovine type II collagen-induced rheumatoid arthritis-associated interstitial lung disease mouse model after treatment with baricitinib and the possible mechanism of action. A rheumatoid arthritis-associated interstitial lung disease mouse model was established, siRNA Jak2 and lentiviral vectors were transfected with human embryonic lung fibroblast cells. And the levels of relevant proteins in mouse lung tissue and human embryonic lung fibroblasts were detected by Western blotting. The levels of JAK2, p-JAK2, p-STAT3, p-SMAD3, SMA, TGFβR2, FN and COL4 were increased in the lung tissues of model mice (P < 0.5) and decreased after baricitinib intervention (P < 0.05). The expression levels of p-STAT3, p-SMAD3, SMA, TGFβR2, FN and COL4 were reduced after siRNA downregulation of the JAK2 gene (P < 0.01) and increased after lentiviral overexpression of the JAK2 gene (P < 0.01). Baricitinib alleviated fibrosis in the lung tissue of rheumatoid arthritis-associated interstitial lung disease mice, and the mechanism of action may involve the downregulation of Smad3 expression via inhibition of the Jak2/Stat3 signaling pathway, with consequent inhibition of the profibrotic effect of transforming growth factor-β1.


Release property study on the novel divalproex sodium enteric-coated capsules.
In the present study, a novel divalproex sodium (DS) enteric-coated capsule was prepared, and high performance liquid chromatography (HPLC) assay method for DS was developed. Their uniformity, release curve and release characteristics in different solvents were examined. The release studies were performed using marketed sample as a reference and data were analyzed in terms of cumulative release amounts as a function of time. It was demonstrated by the results that assay developed was specific, rapid and reliable, which can be used to determine DS in vitro accurately, and our developed samples were similar to reference preparation in in vitro release characteristics. The release characteristics of different batches of samples were quite similar to each other, and the total release percents of DS from enteric-coated capsule were within 0-10% in HCl, and reached close to 100% in phosphate buffer. Similarity factors (f 2) of three batches between two preparations were all higher than 50. The developed enteric-coated capsule may be a promising alternative dosage form for treatment of related diseases.


Acute vision loss: a fuzzy presentation of sarcoidosis.
Acute vision loss is a devastating problem for patients and a challenging diagnostic dilemma for Emergency Physicians. This chief complaint is one in which we must be adept at quickly evaluating and initiating either care or referral. This case reviews the approach to acute vision loss and shows the importance of expanding the differential in atypical and complex presentations. A 31-year-old, previously healthy, white woman presented to the Emergency Department (ED) with 1 day of painless right eye vision loss. Ocular ultrasound and slit-lamp examination were unremarkable. Fundoscopic examination revealed retinal hemorrhages and papillitis. Her chest X-ray study was significant for bilateral hilar adenopathy, and subsequent lymph node biopsy confirmed the diagnosis of sarcoidosis. Although sarcoidosis is more common in African Americans, it must be considered in all patients in the appropriate clinical context. Sarcoidosis is an important diagnosis to include on the differential of many chief complaints that present to the ED, including acute vision loss and dyspnea.


Recent advances in preimplantation genetic diagnosis and screening.
Preimplantation genetic diagnosis/screening (PGD/PGS) aims to help couples lower the risks of transmitting genetic defects to their offspring, implantation failure, and/or miscarriage during in vitro fertilization (IVF) cycles. However, it is still being debated with regard to the practicality and diagnostic accuracy of PGD/PGS due to the concern of invasive biopsy and the potential mosaicism of embryos. Recently, several non-invasive and high-throughput assays have been developed to help overcome the challenges encountered in the conventional invasive biopsy and low-throughput analysis in PGD/PGS. In this mini-review, we will summarize the recent progresses of these new methods for PGD/PGS and discuss their potential applications in IVF clinics.


Weight of communities: a multilevel analysis of body mass index in 32,814 neighborhoods in 57 low- to middle-income countries (LMICs).
The extent to which body mass index (BMI) varies between small areas or neighborhoods in low- to middle-income countries (LMICs) remains unknown. Further, whether such variation is reflective of characteristics of individuals living in these neighborhoods is also not clear. We estimated the extent to which there is variation in BMI is attributable to neighborhoods in 57 LMICs. The data were from non-pregnant women of reproductive age (20-49 y) participating in Demographic and Health Surveys conducted in 57 countries between 1994 and 2008. Body mass index (BMI, weight [in kg] divided by height squared [in m(2)]) was used to assess weight status. Height and weight were measured objectively by trained field investigators. Age, household wealth, education were included as individual covariates and place of residence (urban or rural) as a neighborhood-level covariate. We conducted a multilevel analysis of 451,321 women (aged 20-49 y) from 32,814 neighborhoods and 57 countries. We used linear and multinomial models to partition the variation in BMI (in kg/m(2)), underweight (BMI <18.5 kg/m(2)) and overweight (BMI ≥25.0 kg/m(2)) at the level of neighborhoods and countries. We also explored the heterogeneity in neighborhood variation by socioeconomic status (SES). Of the total variation in BMI 17.6% was attributable to countries (Standard Deviation [SD] 2.0, 95% credible interval [CI] 1.7, 2.4) and 10.6% (SD 1.56, 95% CI 1.54, 1.58) was attributable to neighborhoods in age-adjusted models. Adjusting for individual- and neighborhood-level covariates reduced the SD attributable to countries and neighborhoods to 1.9, and 1.17, respectively. Between-country variation was 13.4% (SD 0.75, 95% CI 0.62-0.90) for underweight and 18.9% (SD 0.92, 95% CI 0.76-1.10) for overweight, and between-neighborhood variation was 7.7% (SD 0.57, 95% CI 0.55-0.58) for underweight and 7.1% (SD 0.56, 95% CI 0.55-0.58) for overweight in the fully-adjusted multinomial model. In country-specific models, the neighborhood variation in BMI ranged from 0.4 SD in Central African Republic to 2.7 SD in Sierra Leone in fully-adjusted models. Our results demonstrate a considerable range in neighborhood variation in BMI. In countries with greater neighborhood variation it is possible that BMI is being influenced by local conditions more than others with lesser neighborhood variation.


Rebamipide reduces delay in gastric ulcer healing in cyclooxygenase-2-deficient mice.
Rebamipide is an antiulcer drug capable of various actions including the induction of cyclooxygenase-2 (COX-2). In this study, we investigated the effect of rebamipide on gastric ulcer healing in COX-2-deficient mice. Wild-type (N=34) and COX-2-deficient mice (N=28) with gastric ulcers were administered 30 mg/kg of rebamipide or the vehicle. Ulcerous tissues were subjected to measurements of ulcer size, immunohistochemical staining of CD31 (an endothelial cell marker), and mRNA levels. COX-2 deficiency delayed ulcer healing and inhibited angiogenesis and bFGF mRNA expression in the granulation tissue. In wild-type mice, rebamipide accelerated ulcer healing and increased COX-2 mRNA expression. In COX-2-deficient mice, rebamipide prevented delayed ulcer healing and reversed the inhibition in angiogenesis and bFGF mRNA expression. The effect of rebamipide on the enhancement of ulcer healing, angiogenesis, and induction of bFGF expression was more prominent in wild-type mice than in COX-2-deficient mice. In conclusion, rebamipide may accelerate gastric ulcer healing through both COX-2-dependent and COX-2-independent mechanisms.


Effects of interleukin-8 and Helicobacter pylori on histamine release from isolated canine gastric mucosal mast cells.
In recent studies, the involvement of mast cells in the pathogenesis of Helicobacter pylori infection was suggested. In the present study, using isolated canine gastric mucosal mast cells, we undertook to elucidate the effects of interleukin-8 (IL-8) and H. pylori on histamine release from these cells. Enriched canine gastric mucosal mast cells (50% target cells) were incubated in Hanks medium with IL-8, or water extract or sonicate of H. pylori for 15 min at 37 degrees C. The content of histamine in the supernatants and the cell pellets after centrifugation was assayed with a histamine radioimmunoassay (RIA) kit. IL-8 (50 ng/ml) and concanavalin A (20 microg/ml) significantly increased histamine release from enriched gastric mucosal mast cells. Dose-dependent stimulation of histamine release by IL-8 (5-50 ng/ml) was also seen. Water extract and sonicate of H. pylori (10(8) bacteria) increased histamine release from mast cells. A concentration-dependent stimulation of histamine release by water extract or sonicate was also seen. The maximal response of histamine release was seen at the highest concentration of the water extract or sonicate. The results indicated that IL-8 and H. pylori had stimulatory effects on histamine release from canine gastric mucosal mast cells. The results imply that IL-8 and soluble factors of H. pylori may accelerate inflammation of the gastric mucosa via histamine release from mast cells.


Periaqueductal grey projection to the ventrobasal complex in the cat: an horseradish peroxidase study.
Horseradish peroxidase (HRP) was injected within the thalamic ventrobasal complex of 14 cats. The aim was to ascertain whether the periaqueductal grey matter (PAG) sends fibres to this complex. Retrogradely labelled cells were found within the PAG following HRP delivery either in the nucleus ventralis posterolateralis (VPL) or ventralis posteromedialis (VPM). PAG-VPL projection is only ipsilateral and arises mainly from lateral PAG, PAG-VPM projection is bilateral and originates from latero-ventral regions of the central grey. The hypothesis that PAG might control the activity of ventrobasal nociceptive neurones is proposed.


Trends in oral anticoagulant use in patients with atrial fibrillation in Belgium from 2013 to 2019: A nationwide cohort study.
Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly preferred over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management. However, differences in oral anticoagulant (OAC) prescribing according to patient's age, sex and physician's specialty may be present. Therefore, incident and prevalent use of OACs, NOACs and VKAs, stratified by age, sex and prescriber, and factors associated with the choice of OAC were investigated. Using two Belgian nationwide healthcare databases, AF patients ≥45 years old with ≥1 OAC prescription claim between 2013 and 2019 were identified. OAC use was investigated per half-year. Factors influencing NOAC vs. VKA initiation were identified by multivariable logistic regression. Among 448 661 included OAC-treated AF patients, 297 818 were newly treated. Incident OAC use ranged from 45-49 to 42-44 users/10 000 persons between 2013 and 2019, whereas prevalent OAC use increased from 337 to 435 users/10 000 persons. Incident and prevalent NOAC use exceeded VKA use since 2013 and 2015, respectively, and NOACs represented 92% of incident and 81% of prevalent OAC users in 2019. Apixaban was the most frequently used NOAC since 2016. NOACs were significantly more prescribed by cardiologists and to older patients, whereas VKAs were more initiated in patients with cardiovascular, renal and hepatic comorbidities. Prevalent OAC use increased less in women than men (25.3% vs. 33.0% between 2013 and 2019) and female subjects had 5% significantly lower odds of NOAC vs. VKA initiation than men. Since 2013, prevalent anticoagulant use increased almost one third in Belgium, while incident use was stable. Potential (N)OAC underuse in women requires further exploration.