A computational approach to study functional monomer-protein molecular interactions to optimize protein molecular imprinting.
Molecular imprinting has become a promising approach for synthesis of polymeric materials having binding sites with a predetermined selectivity for a given analyte, the so-called molecularly imprinted polymers (MIPs), which can be used as artificial receptors in various application fields. Realization of binding sites in a MIP involves the formation of prepolymerization complexes between a template molecule and monomers, their subsequent polymerization, and the removal of the template. It is believed that the strength of the monomer-template interactions in the prepolymerization mixture influences directly on the quality of the binding sites in a MIP and consequently on its performance. In this study, a computational approach allowing the rational selection of an appropriate monomer for building a MIP capable of selectively rebinding macromolecular analytes has been developed. Molecular docking combined with quantum chemical calculations was used for modeling and comparing molecular interactions among a model macromolecular template, immunoglobulin G (IgG), and 1 of 3 electropolymerizable functional monomers: m-phenylenediamine (mPD), dopamine, and 3,4-ethylenedioxythiophene, as well as to predict the probable arrangement of multiple monomers around the protein. It was revealed that mPD was arranged more uniformly around IgG participating in multiple H-bond interactions with its polar residues and, therefore, could be considered as more advantageous for synthesis of a MIP for IgG recognition (IgG-MIP). These theoretical predictions were verified by the experimental results and found to be in good agreement showing higher binding affinity of the mPD-based IgG-MIP toward IgG as compared with the IgG-MIPs generated from the other 2 monomers.


Optic nerve sheath diameter is associated with outcome in severe Covid-19.
Neurological symptoms are common in Covid-19 and cerebral edema has been shown post-mortem. The mechanism behind this is unclear. Elevated intracranial pressure (ICP) has not been extensively studied in Covid-19. ICP can be estimated noninvasively with measurements of the optic nerve sheath diameter (ONSD). We performed a cohort study with ONSD ultrasound measurements in severe cases of Covid-19 at an intensive care unit (ICU). We measured ONSD with ultrasound in adults with severe Covid-19 in the ICU at Karolinska University Hospital in Sweden. Patients were classified as either having normal or elevated ONSD. We compared ICU length of stay (ICU-LOS) and 90 day mortality between the groups. 54 patients were included. 11 of these (20.4%) had elevated ONSD. Patients with elevated ONSD had 12 days longer ICU-LOS (95% CI 2 to 23 p = 0.03) and a risk ratio of 2.3 for ICU-LOS ≥ 30 days. There were no significant differences in baseline data or 90 day mortality between the groups. Elevated ONSD is common in severe Covid-19 and is associated with adverse outcome. This may be caused by elevated ICP. This is a clinically important finding that needs to be considered when deciding upon various treatment strategies.


2018 Infectious Diseases Society of America Clinical Practice Guideline for the Management of Outpatient Parenteral Antimicrobial Therapy.
A panel of experts was convened by the Infectious Diseases Society of America to update the 2004 clinical practice guideline on outpatient parenteral antimicrobial therapy (OPAT) [1]. This guideline is intended to provide insight for healthcare professionals who prescribe and oversee the provision of OPAT. It considers various patient features, infusion catheter issues, monitoring questions, and antimicrobial stewardship concerns. It does not offer recommendations on the treatment of specific infections. The reader is referred to disease- or organism-specific guidelines for such support.


Catheter-Associated Urinary Tract Infections: Implementing a Protocol to Decrease Incidence in Oncology Populations .
The impact of catheter-associated urinary tract infections (CAUTIs) on immunocompromised patients with cancer requires preventive intervention from bedside nurses. . This protocol aims to prevent CAUTIs in the inpatient oncology population by implementing an evidence-based, nurse-driven protocol for discontinuing indwelling urinary catheters (IUCs). . Following a literature review of 34 articles, a nurse-driven CAUTI prevention protocol was developed and implemented on two 26-bed oncology units. Unit staff were educated on the protocol and use of the audit tool. . Although CAUTI rates remained unchanged, infections per 1,000 IUC days decreased, and adherence among oncology nurses rose 66%-90% within the first two months. The protocol encouraged preventive intervention from RNs to protect patients with cancer from CAUTIs.


Likelihood maximization approach to image registration.
A likelihood maximization approach to image registration is developed in this paper. It is assumed that the voxel values in two images in registration are probabilistically related. The principle of maximum likelihood is then exploited to find the optimal registration: the likelihood that given image f, one has image g and given image g, one has image f is optimized with respect to registration parameters. All voxel pairs in the overlapping volume or a portion of it can be used to compute the likelihood. A knowledge-based method and a self-consistent technique are proposed to obtain the probability relation. In the knowledge-based method, prior knowledge of the distribution of voxel pairs in two registered images is assumed, while such knowledge is not required in the self-consistent method. The accuracy and robustness of the likelihood maximization approach is validated by single modality registration of single photon emission computed tomographic (SPECT) images and magnetic resonance (MR) images and by multimodality registration (MR/SPECT). The results demonstrate that the performance of the likelihood maximization approach is comparable to that of the mutual information maximization technique. Finally the relationship between the likelihood approach and the entropy, conditional entropy, and mutual information approaches is discussed.


Dynamical and orientational structural crossovers in low-temperature glycerol.
Mean-square displacements of hydrogen atoms in glass-forming materials and proteins, as reported by incoherent elastic neutron scattering, show kinks in their temperature dependence. This crossover, known as the dynamical transition, connects two approximately linear regimes. It is often assigned to the dynamical freezing of subsets of molecular modes at the point of equality between their corresponding relaxation times and the instrumental observation window. The origin of the dynamical transition in glass-forming glycerol is studied here by extensive molecular dynamics simulations. We find the dynamical transition to occur for both the center-of-mass translations and the molecular rotations at the same temperature, insensitive to changes of the observation window. Both the translational and rotational dynamics of glycerol show a dynamic crossover from the structural to a secondary relaxation at the temperature of the dynamical transition. A significant and discontinuous increase in the orientational Kirkwood factor and in the dielectric constant is observed in the same range of temperatures. No indication is found of a true thermodynamic transition to an ordered low-temperature phase. We therefore suggest that all observed crossovers are dynamic in character. The increase in the dielectric constant is related to the dynamic freezing of dipolar domains on the time scale of simulations.


Synthesis of heterocyclic thiosulfonates
[formula: see text] A simple synthesis of heterocyclic thiosulfonates containing indole, indoline, benzoimidazole, and quinoxaline rings is described. The synthesis of these thiosulfonates involves the preparation of the appropriately substituted thiols followed by sulfonylation to give thiosulfonates. The corresponding thiols were prepared in a simple and efficient manner by using a thiocyanation reaction either prior to heterocycle ring formation or after heterocycle ring formation. These thiosulfonates were coupled successfully to the 5,6-dihydropyran-2-one ring to give products that showed excellent HIV protease activity.


The prp1+ gene required for pre-mRNA splicing in Schizosaccharomyces pombe encodes a protein that contains TPR motifs and is similar to Prp6p of budding yeast.
The prp (pre-mRNA processing) mutants of the fission yeast Schizosaccharomyces pombe have a defect in pre-mRNA splicing and accumulate mRNA precursors at a restrictive temperature. One of the prp mutants, prp1-4, also has a defect in poly(A)+ RNA transport. The prp1+ gene encodes a protein of 906 amino acid residues that contains 19 repeats of 34 amino acids termed tetratrico peptide repeat (TPR) motifs, which were proposed to mediate protein-protein interactions. The amino acid sequence of Prp1p shares 29.6% identity and 50.6% similarity with that of the PRP6 protein of Saccharomyces cerevisiae, which is a component of the U4/U6 snRNP required for spliceosome assembly. No functional complementation was observed between S. pombe prp1+ and S. cerevisiae PRP6. We examined synthetic lethality of prp1-4 with the other known prp mutations in S. pombe. The results suggest that Prp1p interacts either physically or functionally with Prp4p, Prp6p and Prp13p. Interestingly, the prp1+ gene was found to be identical with the zer1+ gene that functions in cell cycle control. These results suggest that Prp1p/Zer1p is either directly or indirectly involved in cell cycle progression and/or poly(A)+ RNA nuclear export, in addition to pre-mRNA splicing.


The inhibitory factors of hematopoiesis in chronic hemodialysis patients treated with recombinant human erythropoietin.
In order to clarify possible factors responsible for varying responses in uremic patients treated with recombinant human erythropoietin (rHuEPO), we determined the inhibitory effects of ten uremic sera on the erythroid progenitors (CFU-E) and erythroid bursts (BFU-E). We also measured plasma EPO titers, Fe, UIBC, ferritin, PTH-C, beta 2-microglobulin, and aluminum in all ten patients. The inhibitor of CFU-E but not BFU-E, was present in the serum of the single anemic patient whose recovery took longer after the administration of rHuEPO. He did not have such conditions as iron deficiency, excess of aluminum, or chronic inflammation. The remaining patients, who had no CFU-E or BFU-E inhibitors, were good responders to rHuEPO. In none of ten patients were there inhibitors of granulocyte-macrophage progenitors (CFU-GM) or any differences in the other parameters. Although the inhibitory factor of CFU-E can be overcome with a larger dose, its prior determination may be useful to set out minimal effective dose of EPO treatment.


Interferon alpha 2b decreases hepatic micrometastasis in a murine model of ocular melanoma by activation of intrinsic hepatic natural killer cells.
To investigate in a murine model the mechanism by which micrometastatic melanoma, which spreads from the eye to the liver, is controlled by interferon (IFN)-alpha 2b. Major histocompatibility (MHC) class I antigen (H-2, all haplotypes) expression in three murine melanoma cell lines (Queens, B16LS9, B16F10) was determined by flow cytometric immunophenotyping. The cell lines were heterotopically inoculated into the posterior compartments (PCs) of C57Bl/6 mice, and the mice were given intraperitoneal (IP) injections of IFN-alpha 2b or PBS for 1 or 4 days before enucleation at 7 days after inoculation. Groups of mice were made NK deficient or depleted with subcutaneous (s.c.) injection of anti-asialo GM1. The mice were killed at 28 days or 56 days (survival experiment) after inoculation, and the number of hepatic micrometastases was histologically determined. NK cells were isolated from the spleen and liver at necropsy, and propidium iodide labeled target-specific cytolysis was determined by flow cytometry. The micrometastases were evaluated for apoptosis and proliferation with TUNEL and MIB1 immunostaining, respectively, and TUNEL-to-MIB1 ratios were determined. Hepatic NK cells were immunostained with CD49b. MHC class I antigen was expressed in the three cell lines in the order of Queens < B16LS9 < B16F10. All cell lines grew, were confined to the PC, and formed hepatic micrometastases. A decrease in micrometastases, an increase in target-specific cytolysis, and an increase in survival correlated with decreased HLA class I expression by the melanoma cells. The IFN-alpha 2b treatment resulted in a boost of intrinsic hepatic NK cells, demonstrated in NK-deficient but not NK-depleted mice. The treatment effect corresponded to increased apoptosis (TUNEL)-proliferation (MIB1) ratios in the micrometastases. Immunostaining demonstrated an increased number of intrahepatic NK cells associated with the micrometastases in treated groups. Neoadjuvant IFN-alpha 2b results in decreased hepatic micrometastasis and increased survival time through increased intrinsic hepatic NK cell-mediated tumor apoptosis in a murine model of metastatic ocular melanoma.


[Calcium kinetics in the progression of heart failure].
The heart has the basic function of pumping blood continuously to the whole body, alternating periods of systole, when it ejects blood, with periods of diastole, when it fills. These mechanical phenomena are strictly regulated by cardiomyocyte physiology, in which calcium (Ca2+) kinetics has a critical role. In fact, Ca2+ influx during the action potential and consequent Ca2+ outflow from the sarcoplasmic reticulum (SR) are essential for myofilament activation--excitation-contraction coupling--whereas Ca2+ reuptake to the SR and extracellular space is crucial for relaxation--inactivation-relaxation coupling. However, it is known that in heart failure progression the expression of genes that code for proteins involved in the regulation of cardiomyocyte Ca2+ homeostasis is profoundly disturbed. In particular, the decreased expression of SERCA2a, the main protein implicated in Ca2+ reuptake during relaxation, is established in the failing human heart. These molecular disturbances lead to cardiomyocyte contractile failure and to systolic and diastolic dysfunction of the heart. The functional and molecular characterization of heart failure progression enables a better understanding of its pathophysiology and the definition of new therapeutic targets. Recent in-vitro and in-vivo experiments have demonstrated that SERCA2a gene transfer can reverse or impede the contractile dysfunction of heart failure progression. In this context, and given the current limitations in the treatment of this disease, evaluation of the clinical impact of these new therapeutic strategies is warranted.


Construction and Calibration of an Exposure Matrix for the Welding Trades.
This study aimed to construct, validate, and calibrate an exposure matrix that would be used to estimate personal airborne exposures to total dust, manganese, nickel, chromium, and aluminum for welders in the WHAT-ME cohort. The Workers' Health in Apprenticeship Trades: metal and electrical (WHAT-ME) study established a cohort of women and men welders to investigate pregnancy and other birth outcomes along with health issues related to welding. To construct the matrix, data were extracted and assembled from the literature and analyzed to produce exposure models. Final models derived in this first step were then compared with external data gathered under controlled conditions and later combined to form calibrated models. A systematic literature search was conducted to identify and extract all relevant data from published journal articles appearing in selected databases. Summary data were extracted that represented airborne personal exposures to total, inhalable and respirable dusts along with metal concentrations for manganese, nickel, chromium, and aluminum. Mathematical exposure models were derived and a validation of the models undertaken in the second part of this study. The most common welding combinations of welding process, base metal, and consumable (welding scenarios) for welders taking part in the WHAT-ME study were identified through detailed welding questionnaires completed by WHAT-ME participants. These were replicated under controlled conditions with a welder equipped with a personal air sampling pump to gather samples. A gravimetric analysis was performed to determine total dust exposures followed by a metals analysis using ICP-MS. Predictions were made for these welding scenarios replicated in the laboratory, using the exposure models derived in the literature and the predictions correlated against the results from the welding laboratory replications. The systematic review yielded 92 published articles from which 737 summary statistics were extracted representing 4620 personal samples of total dust, 4762 of manganese, 4679 of nickel, 3972 of chromium, and 676 of aluminum. The highest total dust exposures were for flux-core arc welding (FCAW) while the highest manganese producing base metal was mild steel. For nickel, the highest emissions were from high alloyed steel using gas metal arc welding while chromium emissions were most abundant in manual metal arc welding on stainless steel. Aluminum exposures were highest in FCAW welding and on aluminum as a base metal. The replication of 21 scenarios covered more than 90% of the scenarios in the WHAT-ME study. Sixty-one laboratory welding sessions took place with a minimum of two replications per scenario. Spearman rank correlations between predicted exposures and mean measured exposures yielded a rho of 0.93 (P < 0.001) for total dust, 0.87 (P < 0.001) for manganese, 0.54 (P < 0.024) for nickel, 0.43 (P = 0.055) for chromium, and 0.29 (P = 0.210) for aluminum. This study produced the first welding exposure matrix composed of process, base metal, and consumable. This model was able to predict exposures observed under controlled conditions and could be used by any researcher to estimate welding exposures in a wide range of occupational contexts.


Maturity onset diabetes mellitus: response to intensive dietary management.
Analysis of the first six months of intensive dietary management of 57 maturity onset diabetics showed that a large proportion of such patients could be satisfactorily controlled without the need of either oral hypoglycaemic agents or insulin. A dietitian's assessment of the patient's adherence to the prescribed diet allowed groups of good and poor dieters to be selected. Among the poor dieters the plasma insulin and triglyceride levels were significantly increased though plasma glucose levels were not significantly higher. Dietary adherence may thus be an prognostic risk factor in this group of diabetic patients.


[Formation of digestive tract microflora of neonates in dynamics].
Comparative study of the microbiota of neonates in relation to vaginal and intestinal microflora state of conditionally healthy primipara pregnant women. Bacteriological study of vaginal and intestinal microflora of 24 conditionally healthy primipara pregnant women at week 32 and 38 of pregnancy as well as bacteriological study of meconium and feces at day 5 of their neonates was performed. Despite detection of lactobacilli by delivery in all the pregnant women their quantity was significantly lower than normal. In colon microflora dysbiotic changes corresponding to grade 1 (46.7%) and 2 (53.3%) dysbacteriosis were detected. In 60.0% of cases of conditionally healthy neonates various microorganism species were isolated from meconium. At day 5 in feces of neonates at natural feeding lactobacilli (85.8%), bifidobacteria and escherichia (71.4% each), enterococci (100%) were detected. The course of dysbiotic changes in vagina and intestines of conditionally healthy pregnant women had subclinical level. Detection of microorganisms in meconium in conditionally healthy neonates could be explained by translocation mechanism.


A quasi-experimental study on the effectiveness of a standardized comprehensive sexuality education curriculum for primary school students.
Although the importance of sexuality education has been recognized, Chinese rural students have limited access to sexual and reproductive information. This study aims to evaluate the effectiveness of a standardized comprehensive sexuality education curriculum package featuring cartoon animation on sexuality-related knowledge and skills, attitudes, and practices of primary school students. This quasi-experimental study recruited 1725 students in grades 4-6 (aged 9-13) from eight primary schools sampled as school clusters in 2020 in China. Internet-based questionnaires from three intervention schools' participants were collected after trained schoolteachers had conducted six 45-min sexuality education sessions. We performed optimal full matching and treatment effects were estimated in the matched sample by outcome regression models that further adjusted the covariates. Compared with the control group, intervention group students achieved significantly higher scores by 3.35 out of 38 and 2.02 out of 34 in knowledge- and skill-based tests and attitudinal tests, respectively. For the five self-reported practices on genital care, the experimental group showed significantly better performance than the control group in genital hygiene, by 6.92%, 22.45%, and 30.66% higher rates in the overall prevalence of three proper practices of genital hygiene, with effect sizes larger for boys than girls. Our sexuality education package effectively improved primary school students' sexuality-related knowledge, skills, attitudes, and hygiene practices. Our study suggests that the standardized curriculum package could be a promising approach to improving the quality and accessibility of sexuality education in underdeveloped rural China.


Work characteristics predict psychiatric disorder: prospective results from the Whitehall II Study.
The impact of work on the risk of future psychiatric disorder has been examined in few longitudinal studies. This was examined prospectively in a large epidemiological study of civil servants. In the Whitehall II study, a longitudinal, prospective cohort study of 6895 male and 3413 female London based civil servants, work characteristics measured at baseline (phase 1: 1985-8) and first follow up (phase 2: 1989) were used to predict psychiatric disorder measured by a 30 item general health questionnaire (GHQ) at phase 2 and phase 3 follow up (phase 3: 1991-3). Work characteristics and GHQ were measured at all three phases. Low social support at work and low decision authority, high job demands and effort-reward imbalance were associated with increased risk of psychiatric disorder as assessed by the GHQ at follow up adjusting for age, employment grade, and baseline GHQ score. Social support and control at work protect mental health while high job demands and effort-reward imbalance are risk factors for future psychiatric disorder. Intervention at the level of work design, organisation, and management might have positive effects on mental health in working populations.


Unexplained orofacial pain - is an early diagnosis possible?
Aim To identify distinct characteristics of unexplained orofacial pain that could be used by dental practitioners in making an early diagnosis.Methods Subjects reporting orofacial pain in a postal questionnaire-based cross-sectional survey were invited for clinical examination. The interviewer was blinded to the questionnaire responses of the subjects. A diagnosis was made following the examination and subjects were assigned into two groups: unexplained pain and dental pain. The questionnaire responses of subjects who had consulted a healthcare professional within these two groups were then compared with particular attention to demographics, orofacial pain characteristics, consultation behaviour and relationship with other unexplained syndromes.Results Subjects who had consulted for their pain and were assigned to the unexplained orofacial pain group were significantly (p <0.05) more likely to report the following characteristics: pain descriptors (nagging, aching, tingling), pain pattern (worse with stress), site (poorly localised), duration (persistent/chronic), high disability, multiple consultations and co-morbidities (teeth grinding, reporting of other unexplained syndromes).Conclusion This study has shown that unexplained orofacial pain has distinct characteristics that differentiate it from other common dental conditions. This provides a good evidence base which can reduce uncertainty among dental practitioners, allowing them to make an early diagnosis.


Sleep deprivation can inhibit adult hippocampal neurogenesis independent of adrenal stress hormones.
Sleep deprivation (SD) can suppress cell proliferation in the hippocampal dentate gyrus of adult male rodents, suggesting that sleep may contribute to hippocampal functions by promoting neurogenesis. However, suppression of cell proliferation in rats by the platform-over-water SD method has been attributed to elevated corticosterone (Cort), a potent inhibitor of cell proliferation and nonspecific correlate of this procedure. We report here results that do not support this conclusion. Intact and adrenalectomized (ADX) male rats were subjected to a 96-h SD using multiple- and single-platform methods. New cells were identified by immunoreactivity for 5-bromo-2'-deoxyuridine (BrdU) or Ki67 and new neurons by immunoreactivity for BrdU and doublecortin. EEG recordings confirmed a 95% deprivation of rapid eye movement (REM) sleep and a 40% decrease of non-REM sleep. Cell proliferation in the dentate gyrus was suppressed by up to 50% in sleep-deprived rats relative to apparatus control or home cage control rats. This effect was also observed in ADX rats receiving continuous low-dose Cort replacement via subcutaneous minipumps but not in ADX rats receiving Cort replacement via drinking water. In these latter rats, Cort intake via water was reduced by 60% during SD; upregulation of cell proliferation by reduced Cort intake may obscure inhibitory effects of sleep loss on cell proliferation. SD had no effect on the percentage of new cells expressing a neuronal phenotype. These results demonstrate that the Cort replacement method is critical for detecting an effect of SD on cell proliferation and support a significant role for sleep in adult neurogenesis.


[Change in the rat liver microsomal monooxygenase system upon induction with phenobarbital in acute pancreatitis].
While injecting phenobarbital (PB) into the rats, on the second day of an experimental pancreatitis, cytochrome P450 2B1 and 2C6 activities were found, on the forth day of disease, as being considerably higher in comparison with data obtained in sham-operated control animals. On the tenth day of the acute pancreatitis (in three days upon having the induction canceled), activity of the cytochrome P450 isozymes was lower than that of control animals. Thus, the rats with acute pancreatitis, are characterized by an increased indycibility of liver monooxygenases. In addition, a release from induction (decrease of these activities upon having the induction canceled) proceeds faster than that in control animals.


Evaluation of a new Argovit as an antiviral agent included in feed to protect the shrimp Litopenaeus vannamei against White Spot Syndrome Virus infection.
In this study, four experimental assays were conducted to evaluate the use of a new silver nanoparticle formulation named Argovit-4, which was prepared with slight modifications to enhance its biological activity against white spot syndrome virus (WSSV) in shrimp culture. The goals of these assays were to (1) determine the protective effect of Argovit-4 against WSSV, (2) determine whether Argovit-4 supplemented in feed exhibits toxicity towards shrimp, (3) determine whether Argovit-4 as antiviral additive in feed can prevent or delay/reduce WSSV-induced shrimp mortality, and (4) determine whether Argovit-4 supplemented in feed alters the early stages of the shrimp immune response. In bioassay 1, several viral inocula calibrated at 7 SID50(shrimp infectious doses 50% endpoint) were exposed to 40, 100, 200 and 1,000 ng/SID50 of Ag+ and then intramuscularly injected into shrimp for 96 h. In bioassay 2, shrimp were fed Argovit-4 supplemented in feed at different concentrations (10, 100 and 1,000 µg per gram of feed) for 192 h. In bioassay 3, shrimp were treated with Argovit-4 supplemented in feed at different concentrations and then challenged against WSSV for 192 h. In bioassay 4, quantitative real-time RT-qPCR was performed to measure the transcriptional responses of five immune-relevant genes in haemocytes of experimental shrimp treated with Argovit-4 supplemented in feed at 0, 6, 12, 24 and 48 h. The intramuscularly injected Argovit-4 showed a dose-dependent effect (p < 0.05) on the cumulative shrimp mortality from 0-96 h post-infection. In the second bioassay, shrimp fed Argovit-4 supplemented in feed did not show signs of toxicity for the assayed doses over the 192-h experiment. The third and fourth bioassays showed that shrimp challenged with WSSV at 1,000 µg/g feed exhibited reduced mortality without altering the expression of some immune system-related genes according to the observed level of transcriptional. This study is the first show that the new Argovit-4 formulation has potential as an antiviral additive in feed against WSSV and demonstrates a practical therapeutic strategy to control WSSV and possibly other invertebrate pathogens in shrimp aquaculture.


Molecular weight and structure of water soluble (1→3), (1→4)-β-glucans affect pasting properties of oat flours.
Seven experimental oat lines with high (5.9% to 7.2%), medium (5.3% to 5.5%), and low (4.4%) β-glucan concentrations were evaluated for the effects of β-glucan molecular weight (MW) and structure on viscosities of oat-flour slurries. The MW of β-glucans was determined by size-exclusion high-performance liquid chromatography. The structural features of β-glucans were measured by using fluorophore-assisted capillary-electrophoresis after complete hydrolysis with lichenase. The oat-slurry viscosities were measured on a Rapid Visco Analyser under 4 conditions: (1) without starch (amylolysis, removal of starch by α-amylase); (2) without β-glucan (removal of β-glucan by lichenase); (3) natural action of enzymes (autolysis, in sodium buffer); and (4) inhibition of enzymes (in silver nitrate solution). Excluding one line (regression outlier), significant correlations (P < 0.05) between peak MW of β-glucan and viscosities of oat slurries were obtained under inhibition. The ratio of degree of polymerization (DP) 3/DP4 negatively correlated with viscosity under amylolysis, autolysis, and inhibition (P < 0.05). The amount of DP ≥ 5 negatively correlated with pasting final viscosity after β-glucan removal by lichenase (P < 0.05). Positive correlations (P < 0.05) between the ratio of β-(1→4)/β-(1→3) linkages and viscosities under autolysis and inhibition were found. Overall, these findings demonstrated that the peak MW, ratio of DP3/DP4, amount of DP ≥ 5, and ratio of β-(1→4)/β-(1→3) linkages of β-glucans impacted pasting properties of oat-flour slurries.


Time-Resolved Freely Dissolved Concentrations of Semivolatile and Hydrophobic Test Chemicals in In Vitro Assays-Measuring High Losses and Crossover by Headspace Solid-Phase Microextraction.
In vitro assays are normally conducted in plastic multiwell plates open to exchange with the ambient air. The concentration of test substances freely available to cells is often not known, can change over time, and is difficult to measure in the small volumes in microplates. However, even a well-characterized toxicological response is of limited value if it cannot be linked to a well-defined exposure level. The aim of this study was to develop and apply an approach for determining time-resolved freely dissolved concentrations of semivolatile and hydrophobic organic chemicals (SVHOCs) in in vitro assays: (1) free fractions were measured by a new medium dilution method and (2) time-resolved loss curves were obtained by measurements of total concentrations in 96-well plates during incubations at 37 °C. Headspace solid-phase microextraction was used as an analytical technique for 24 model chemicals spanning 6 chemical groups and 4-5 orders of magnitude in Kow and Kaw. Free fractions were >30% for chemicals with log Kow < 3.5 and then decreased with increasing log Kow. Medium concentrations declined significantly (>50%) within 24 h of incubation for all 20 chemicals having log Kow > 4 or log Kaw > -3.5 in serum-free medium. Losses of chemicals were lower for medium containing 10% fetal bovine serum, most significantly for chemicals with log Kow > 4. High crossover to neighboring wells also was observed below log Kow of 4 and log Kaw of -3.5. Sealing the well plates had limited effect on the losses but clearly reduced crossover. The high losses and crossover of most tested chemicals question the suitability of multiwell plates for in vitro testing of SVHOCs and call for (1) test systems that minimize losses, (2) methods to control in vitro exposure, (3) analytical confirmation of exposure, and (4) exposure control and confirmation being included in good in vitro reporting standards.


Surfaces and Air Contamination by Severe Acute Respiratory Syndrome Coronavirus 2 Using High-Flow Nasal Oxygenation or Assisted Mechanical Ventilation in Intensive Care Unit Rooms of Patients With Coronavirus Disease 2019.
Understanding patterns of environmental contamination by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential for infection prevention policies. We screened surfaces and air samples from single-bed intensive-care unit rooms of adult patients with coronavirus disease 2019 (COVID-19) for SARS-CoV-2 RNA and viable viruses. We evidenced viral RNA environmental contamination in 76% of 100 surfaces samples and in 30% of 40 air samples without any viable virus detection by cell culture assays. No significant differences of viral RNA levels on surfaces and in ambient air were observed between rooms of patients with assisted mechanical ventilation and those of patients with a high-flow nasal cannula system. Using an original experimental SARS-CoV-2 infection model of surfaces, we determined that infectious viruses may have been present on benches within 15 hours before the time of sampling in patient rooms. We observed that SARS-CoV-2 environmental contamination around patients with COVID-19 hospitalized in single-bed ICU rooms was extensive and that a high-flow nasal cannula system did not generate more viral aerosolization than a mechanical ventilation system in patients with COVID-19. Despite an absence of SARS-CoV-2 viable particles in study samples, our experimental model confirmed the need to apply strict environmental disinfection procedures and classic standard and droplet precautions in ICU wards.


CD146-targeted nuclear medicine imaging in cancer: state of the art.
The transmembrane glycoprotein adhesion molecule CD146 is overexpressed in a wide variety of cancers. Through molecular imaging, a specific biomarker's expression and distribution can be viewed in vivo non-invasively. Radionuclide-labeled monoclonal antibodies or relevant fragments that target CD146 may find potential applications in cancer imaging, thereby offering tremendous value in cancer diagnosis, staging, prognosis evaluation, and prediction of drug resistance. This review discusses the recent developments of CD146-targeted molecular imaging via nuclear medicine, especially in malignant melanoma, brain tumor, lung cancer, liver cancer, breast cancer, and pancreatic cancer. Many studies have proved that CD146 targeting may present a promising strategy for cancer theranostics.


Clinical studies on ferric sulphate as a pulpotomy medicament in primary teeth.
The purpose of this paper is to review three prospective and two retrospective studies that have been published on the use of ferric sulphate as a pulpotomy medicament and, also, present the results of a recently completed, 3 year comparative study in pulpotomized primary teeth using ferric sulphate and diluted formocresol. The most important finding from the reviewed studies was that ferric sulphate gives very good clinical and radiographic results with high tooth survival rates and with no statistically significant differences from that of formocresol. Internal resorption is a common radiographic finding in both ferric sulphate and formocresol treatments with no statistically significant differences between them. However, internal resorption differs in size and progression rate among teeth. There were cases reported in which the size of the internal resorption was very small and unchanged over time, and even cases where the area of the resorption was self-repaired with hard tissue. Some of the authors considered only teeth with progressing and/or extensive internal resorption as failures, while small size and unchanged with time internal resorption was not considered as failure. Based on the data of the reviewed studies it is suggested that ferric sulphate be used, rather than formocresol, for pulpotomies of primary teeth as the latter has been blamed for systemic and local side effects on the developing successors.


Sexual and reproductive health for young adults in Colombia: teleconsultation using mobile devices.
Sexual risk behaviors associated with poor information on sexuality have contributed to major public health problems in the area of sexual and reproductive health in teenagers and young adults in Colombia. To report our experience with the use of DoctorChat Mobile to provide sexual education and information among university students in Bogota, Colombia, and knowledge about the sexual risk factors detected among them. A mobile app that allows patients to ask about sexual and reproductive health issues was developed. Sexual and reproductive risk behaviors in a sample of young adults were measured before and after the use of the app through the validated survey Family Health International (FHI) Behavioral Surveillance Survey (BSS) for Use With Adults Between 15 and 49 Years. A nonprobabilistic convenience recruitment was undertaken through the study´s webpage. After completing the first survey, participants were allowed to download and use the app for a 6-month period (intervention), followed by completion of the same survey once again. For the inferential analysis, data was divided into 3 groups (dichotomous data, discrete quantitative data, and ordinal data) to compare the results of the questions between the first and the second survey. The study was carried out with a sample of university students between 18 and 29 years with access to mobile phones. Participation in the study was voluntary and anonymous. A total of 257 subjects met the selection criteria. The preintervention survey was answered by 232 subjects, and 127 of them fully answered the postintervention survey. In total, 54.3% (69/127) of the subjects completed the survey but did not use the app, leaving an effective population of 58 subjects for analysis. Of these subjects, 53% (31/58) were women and 47% (27/58) were men. The mean age was 21 years, ranging between 18 and 29 years. The differences between the answers from both surveys were not statistically significant. The main sexual risk behaviors identified in the population were homosexual intercourse, nonuse of condoms, sexual intercourse with nonregular and commercial partners, the use of psychoactive substances, and lack of knowledge on symptoms of sexually transmitted diseases and HIV transmission. Although there were no differences between the pre- and postintervention results, the study revealed different risk behaviors among the participating subjects. These findings highlight the importance of promoting high-impact educational strategies on this matter and the importance of providing teenagers and young adults with easily accessible tools with reliable health information, regardless of their socioeconomic status.


[New aspects by the therapy of ovarian cancer--What changes after the ASCO-Meeting 2001].
The standard primary therapy of advanced ovarian cancer consists of platinum derivatives in combination with paclitaxel. In a first report presented at this year's meeting of the American Society of Clinical Oncology (ASCO) docetaxel appeared to be as effective as paclitaxel in combination with carboplatin, while the toxicity profile present some advantages. The addition of a third drug to platinum-taxane-combination does not appear to improve the therapeutic index. According to the data of the ICON1- and ACTION-trial, carboplatin containing chemotherapies are associated with a significant benefit also in early ovarian cancer. Platinum-resistant disease remains a therapeutic challenge, since the available drugs display only limited activity of short duration. Some experimental data suggest evidence for a possible therapeutic role of small molecules that inhibit the epidermal growth factor receptor (OSI-774) or antisense oligonucleotides interfering with EGF-receptor signalling (ISIS 5132). Novel classes of chemotherapeutic agents, including the acylfulvenes and the epothilone-analogues warrant further study in this disease. Multimodal therapies combining cytotoxic agents with antibodies against CA 12-5 or metalloproteinase inhibitors have failed to demonstrate any survival benefit in patients with ovarian cancer. Despite significant progress in the last decade ovarian cancer remains the most lethal gynaecologic malignancy in women in most western countries. Further multicenter clinical studies are needed to better define new therapeutic options.


Single-stage breast reconstruction using Strattice™: A retrospective study.
Strattice™, a porcine acellular dermal matrix, has emerged as a product to augment implant-based breast reconstruction. It aims to resolve problems related to poor tissue coverage of the implant. Presently, evidence justifying the use of Strattice in breast reconstruction is lacking. The objective of this study is to assess the clinical outcomes of a patient cohort that underwent single-stage implant-based breast reconstruction with the additional use of Strattice. We conducted a retrospective chart review of patients who underwent single-stage breast reconstruction with the use of Strattice. All cases of breast reconstruction after oncologic or prophylactic mastectomy between 2010 and 2014 in one of eight different centres in the Netherlands were included. Patient demographics, treatment characteristics and clinical outcome data were collected. The outcomes were presented using descriptive statistics, and the associations were evaluated using Fisher's exact test. Eighty-eight patients who underwent either unilateral (60 patients) or bilateral (25 patients) (n = 110 breasts) single-stage breast reconstruction with the use of Strattice were identified. The indication for mastectomy was therapeutic in 69.1% (76) of cases and prophylactic in 30.9% (34) of cases. The reported minor complications included seroma (20.9%), skin necrosis (20.0%), wound dehiscence (11.8%), erythema/inflammation (14.5%) and infection (11.8%). In 22 breasts (22.7%), reoperation was necessary, with explantation of the implant in 11 breasts (11.8%). In this cohort, the total complication rate was very high (78%). Although most complications were minor, reoperation was performed in 22.7%, with explantation of the implant in 11.8% of breasts. We suggest that patient selection, experience of the surgeon and handling of early complications are factors playing a crucial role in the success of the operation. The use of a Strattice sheet in single-stage implant-based breast reconstruction may be a promising technique, but more evidence from prospective, randomized studies is necessary to justify its use. IV.


Expression of epidermal growth factor receptor in human gastric and colonic carcinomas.
The expression of epidermal growth factor (EGF) receptor was examined immunohistochemically in a total of 122 gastric and 61 colonic carcinomas, out of which 16 gastric and 8 colonic carcinomas were also examined by 125I-labeled EGF binding analysis and Western blotting. The values of EGF binding were 12.68 +/- 1.98 (SE; n = 16) fmol/mg protein in gastric carcinomas and 5.72 +/- 2.15 (n = 8) fmol/mg protein in nonneoplastic gastric mucosa, the difference being significant (P less than 0.01). In the colonic tissue, the binding capacities in carcinomas and nonneoplastic mucosa were 13.29 +/- 4.17 (n = 8) and 10.68 +/- 0.41 (n = 3) fmol/mg protein, respectively. Scatchard analysis of 125I-labeled EGF binding indicated a single class of receptors in gastric and colonic carcinomas with an apparent Kd value of from 111 to 277 (n = 4) and from 87.4 to 341 fM (n = 5), respectively, except for one gastric carcinoma having two classes of receptors (Kd = 15.9 and 896 fM). In Western blotting using monoclonal anti-EGF receptor antibody, various levels of EGF receptor expression were detected in 12 (85.7%) of the 14 gastric carcinomas and in 7 (87.5%) of the 8 colonic carcinomas. Immunohistochemically, EGF receptor immunoreactivity was detected in one (3.8%) of the 26 early gastric carcinomas, while it was observed in 33 (34.4%) of the 96 advanced gastric carcinomas, the incidence between the two being significantly different (P less than 0.01). In the colonic carcinomas, 47 (77.1%) of the 61 cases showed positive immunoreactivity to EGF receptor, which did not differ by histological type.


Life-course body size and perimenopausal mammographic parenchymal patterns in the MRC 1946 British birth cohort.
Dense mammographic parenchymal patterns are associated with an increased risk of breast cancer. Certain features of body size have been found to be associated with breast cancer risk, but less is known about their relation to breast density. We investigated the association of birth size, childhood growth and life-course changes in body size with Wolfe grade in 1298 perimenopausal women from a British cohort of women born in 1946. The cohort benefits from repeated measures of body size in childhood and adulthood. We obtained mammograms for 90% of women who at age 53 years reported having previously had a mammogram. We found no associations with birth weight or maximum attained height. Body mass index (BMI) at age 53 years and breast size were independently and inversely associated with Wolfe grade (P-value for trend <0.001 for both). Women who reached puberty later were at a greater odds of a higher Wolfe grade than women who had an earlier puberty (odds ratio associated with a 1 year delay in menarche 1.14, 95% CI: 1.01-1.27, adjusted for BMI and breast size at mammography). A higher BMI at any age during childhood or adult life was associated with a reduction in the odds of a higher Wolfe grade, after controlling for breast size and BMI at mammography, for example, standardised odds ratio for height at age 7 was 0.72 (95% CI: 0.64, 0.81). These findings reveal the importance of taking life-course changes in body size, and not just contemporaneous measures, into account when using mammographic density as an intermediate marker for risk of breast cancer.


Intraductal carcinoma. Analysis of presentation, pathologic findings, and outcome of disease.
A retrospective analysis of 52 patients with intraductal carcinoma or ductal carcinoma in situ (DCIS) and 30 patients with microinvasive DCIS was performed. All patients but one were treated by mastectomy. The average follow-up was 5 1/2 years. The clinical presentation of the patients having DCIS only included the presence of a mass in 33% (17/52), nipple discharge in 34% (18/52), or suspicious mammographic finding in 33% (17/52), whereas in those patients having DCIS with microinvasion, the initial presenting symptom was a mass in 63% (19/30) of the patients, nipple discharge in 13% (4/30), and mammographic finding in 23% (7/30). The presence of axillary lymph node metastasis was identified in one of the 52 patients with DCIS and six (20%) of the 30 patients with DCIS and microinvasion. Associated carcinomas in the mastectomy specimens of patients with DCIS were as follows: DCIS, 18% (9/51); lobular carcinoma in situ, 13% (7/51); Paget's disease, 8% (4/51); and invasive carcinoma, 2% (1/51). In the 30 patients with microinvasion, DCIS was found in other quadrants in 23% (7/51) of the patients; lobular carcinoma in situ, 7% (2/51); Paget's disease, 13% (4/51); and invasive carcinoma, 7% (2/51). There was one death due to cancer in the patients with DCIS only. Of the patients diagnosed as having DCIS with microinvasion, seven patients have developed metastasis and four have died of the disease.


Modulation of synaptic transmission and excitation-contraction coupling in the opener muscle of the crayfish, Astacus leptodactylus, by 5-hydroxytryptamine and octopamine.
The modulatory actions of 5-hydroxytryptamine (5-HT) and octopamine (OA) were investigated in the opener nerve-muscle preparation of the crayfish, Astacus leptodactylus. Membrane resistance and resting potential were unaltered by 5-HT and OA at concentrations up to 2.5 X 10(-5) M; but EPSP-amplitudes were increased, up to 3-fold by OA and up to 18-fold by 5-HT. The lowest effective concentration was 2.5 X 10(-9) M; a maximal effect was produced at 2.5 X 10(-6) M. The effect was reversible only after prolonged washing. The enhancement of EPSPs by 5-HT or OA is due to an increased amplitude of the synaptic current; the current duration is not altered. The facilitation ratio (ratio of amplitudes of a pair of EPSPs) is not significantly affected by 5-HT or OA despite the often enormous increase of the absolute EPSP-amplitudes. The modulatory action also affects the excitation-contraction (e-c) coupling process: the effectiveness of e-c coupling was increased 7.4-fold by 5-HT (2.5 X 10(-6) M) and 18.7-fold by OA (5 X 10(-6) M). The threshold potential of e-c coupling was not affected.


The effect of grapeseed oil on performance, rumen fermentation, antioxidant status and subcutaneous adipose fatty acid profile in lambs.
This experiment was carried out to examine the effect of grapeseed oil (GSO) on performance, rumen fermentation, antioxidant status and subcutaneous adipose fatty acid (FA) profile in lambs. Eighteen Baluchi lambs, 196 ± 14 days of age and 39.8 ± 1.7 kg body weight, were randomly assigned to three experimental diets: (i) diet without GSO (control), (ii) diet containing 2% of GSO (GSO2) and (iii) diet containing 4% of GSO (GSO4) for 42 days. Results showed that the experimental diets had no significant effect on dry matter intake and performance (p > 0.05). The supplemented diets with GSO had no effect on pH and NH3 -N of rumen fluid (p > 0.05), but GSO4 increased (p = 0.003) the concentration of propionic acid and reduced (p = 0.002) the concentration of acetate acid compared to the control. Inclusion 4% of GSO to the diet increased total antioxidant activity and decreased malondialdehyde in serum and muscle (p < 0.001). The level of blood glutathione peroxidase in diets containing GSO was higher than control diet (p = 0.02), but diets had no effect on superoxide dismutase in blood and muscle tissues (p > 0.05). The concentration of vaccenic acid, rumenic acid and linoleic acid and thus polyunsaturated fatty acid in subcutaneous fat was affected by experimental diets (p < 0.001), as control had the lowest amount of these FAs and GSO4 had the highest amount of them. Therefore, it can be concluded that the use of GSO up to 4% improves the antioxidant status and adipose fatty acid profile in lambs without effects on performance.


Posterior reversible encephalopathy syndrome: a review.
Encephalopathy due to reversible cerebral edema is an important cause of neurologic morbidity accompanying many disorders. Although controversy remains concerning the pathophysiologic trigger, the mechanism of this disorder ultimately depends on failure of the blood-brain barrier to maintain the compartmentalization of intravascular fluid. This failure of the blood-brain barrier depends primarily on the capillary hydrostatic pressure, under the influence of the systemic blood pressure, and on the integrity of the structures that make up the blood-brain barrier, most importantly the vascular endothelium, under the influence of various diseases and toxic medications. Although typical clinical contexts and presentations have been well defined, many patients have atypical features that pose a diagnostic challenge. Therefore, awareness of this clinical variability is important for prompt diagnosis. This review discusses the history and pathophysiology of posterior reversible encephalopathy syndrome and then addresses its clinical diagnosis and management.


Tuina-focused integrative chinese medical therapies for inpatients with low back pain: a systematic review and meta-analysis.
Objective. To evaluate the effectiveness of Tuina-focused integrative Chinese medical therapies (TICMT) on inpatients with low back pain (LBP). Methods. 6 English and Chinese databases were searched for randomized controlled trials (RCTs) of TICMT for in-patients with LBP. The methodological quality of the included RCTs was assessed based on PEDro scale. And the meta-analyses of TICMT for LBP on pain and functional status were conducted. Results. 20 RCTs were included. The methodological quality of the included RCTs was poor. The meta-analyses' results showed that TICMT had statistically significant effects on pain and functional status, especially Tuina plus Chinese herbal medicine (standardised mean difference, SMD: 1.17; 95% CI 0.75 to 1.60 on pain; SMD: 1.31; 95% CI 0.49 to 2.14 on functional status) and Tuina plus acupuncture (SMD: 0.94; 95% CI 0.38 to 1.50 on pain; SMD: 0.53; 95% CI 0.21 to 0.85 on functional status). But Tuina plus moxibustion or hot pack did not show significant improvements on pain. And the long-term evidence of TICMT was far from sufficient. Conclusions. The preliminary evidence from current studies suggests that TICMT might be effective complementary and alternative treatments for in-patients with LBP. However, the poor methodological quality of the included RCTs means that high-quality RCTs with long follow-up are warranted.


Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases.
Data indicate significant phenotypic and genotypic overlap, plus a common pathogenesis, between two groups of inherited disorders, autosomal dominant polycystic kidney diseases (ADPKD), a significant cause of ESRD, and autosomal dominant polycystic liver diseases (ADPLD), which result in significant PLD with minimal PKD. Eight genes have been associated with ADPKD (PKD1 and PKD2), ADPLD (PRKCSH, SEC63, LRP5, ALG8, and SEC61B), or both (GANAB). Although genetics is only infrequently used for diagnosing these diseases and prognosing the associated outcomes, its value is beginning to be appreciated, and the genomics revolution promises more reliable and less expensive molecular diagnostic tools for these diseases. We therefore propose categorization of patients with a phenotypic and genotypic descriptor that will clarify etiology, provide prognostic information, and better describe atypical cases. In genetically defined cases, the designation would include the disease and gene names, with allelic (truncating/nontruncating) information included for PKD1 Recent data have shown that biallelic disease including at least one weak ADPKD allele is a significant cause of symptomatic, very early onset ADPKD. Including a genic (and allelic) descriptor with the disease name will provide outcome clues, guide treatment, and aid prevalence estimates.


Graphene platforms for the detection of caffeine in real samples.
The analysis of food components is of high importance due to food safety and security. Here the electrochemical detection of caffeine was performed on different chemically modified graphene (CMG) surfaces carrying diverse amount of defects and oxygen functionalities. The analytical performances of graphite oxide (GPO), graphene oxide (GO), and electrochemically reduced graphene oxide (ERGO) were compared for the first time for the detection of caffeine. It was found that ERGO showed the most favourable analytical parameters, such as lower oxidation potential, sensitivity, linearity and reproducibility of the response. ERGO was then used for the analysis of real samples. Caffeine levels of soluble coffee, teas and energetic drinks were measured without the need of any sample pre-treatment. Our findings are very important to gain more insight into the applicability of different graphene materials to real samples for sense-and-act analysis.


The psychological cycle behind dental appointment attendance: a cross-sectional study of experiences, anticipations, and behavioral intentions.
This study explored a promising theoretical model to explain dental patients' experiences and planning behavior for future appointments. The model predicts that patients pass through a 'psychological cycle' when undergoing a course of dental care: past appointment experiences influence their anticipations for future dental visits, which in turn affect behavioral intentions to attend appointments. Variables representing the hypothesized model stages and other potentially relevant context variables (dental anxiety, subjective oral health ratings, general anxiety, stress) were assessed by means of a cross-sectional online survey (n = 311). Multiple regression analyses were calculated to estimate the model's fit while controlling for potentially confounding factors. Consistent with the hypothesized cycle, recollections of past appointment experiences influenced behavioral intentions to attend future appointments. This association was mediated by evaluations of prior visits and expectations for future appointments. The variables included within this model explained 42% of the variance in attendance intentions when controlling for the potential moderating effects of context variables. The findings highlight the contribution of cognitive factors, such as evaluations and expectations, to patients' attendance intentions. This knowledge could help find ways to improve treatment expectations to foster better dental service utilization.


Lunar cycles of coho salmon, Oncorhynchus kisutch. II. Scale amino acid uptake, nucleic acids, metabolic reserves and plasma thyroid hormones.
[14C]glycine uptake by scales in vitro was measured in coho salmon (Oncorhynchus kisutch Walbaum) smolts at different times during several semi-lunar cycles. There was a clear cyclical pattern of glycine uptake during the semi-lunar period. Evidence for semi-lunar cycles of liver and muscle RNA:DNA ratios, carcass water content, haematocrit, and plasma triglyceride, glucose and cholesterol levels was also found in coho salmon parrs. Plasma L-thyroxine (T4) levels exhibited a cyclical pattern during the semi-lunar cycle in parrs sampled in March when plasma T4 levels tended to be low, but no such pattern was seen in parrs sampled in January when the plasma T4 levels were relatively high (1.39-1.88 micrograms dl-1 in January compared with 0.38-0.83 micrograms dl-1 in March). There were no apparent semi-lunar cycles in liver mass:body mass ratios and plasma triiodo-L-thyronine (T3) levels. Changes in growth parameters (nucleic acid levels and glycine uptake by scales) and the content of nutrient reserves are discussed in relation to the semi-lunar patterns of growth in length, growth in mass, and food intake in this species.


Engagement of interleukin-7 receptor stimulates tyrosine phosphorylation, phosphoinositide turnover, and clonal proliferation of human T-lineage acute lymphoblastic leukemia cells.
The purposes of this study were to examine the biologic effects of the engagement of the interleukin-7 receptor (IL-7R) with recombinant human interleukin-7 (rhIL-7) in immunophenotypically distinct T-lineage acute lymphoblastic leukemia (ALL) blasts and to elucidate the biochemical nature of the IL-7R-linked transmembrane signal in rhIL-7-responsive T-lineage ALL blast populations. In the absence of costimulants, rhIL-7 stimulated the in vitro proliferation and colony formation of freshly isolated leukemic blasts from six to eight T-lineage ALL patients with a mean plating efficiency of 196 +/- 53 (background subtracted) colonies/10(5) blasts plated. Stimulation of T-lineage ALL blasts with rhIL-7 resulted in markedly enhanced tyrosine phosphorylation of six distinct phosphoproteins with molecular weights of 57, 72, 98, 123, 150, and 190 Kd, and induced a rapid increase in the production of inositol-1,4,5-trisphosphate (Ins-1,4,5-P3), which was inhibitable by the tyrosine-specific protein kinase inhibitor genistein, but not by the serine/threonine-specific protein kinase C inhibitor H7. Similarly, rhIL-7 stimulated Ins-1,4,5-P3 production in CEM-1.3 T-lineage ALL cells and this stimulation was inhibitable by the tyrosine-specific protein kinase inhibitors genistein and herbimycin A, but not by H-7. Thus, the transmembrane signal triggered by engagement of the IL-7R is intimately linked to a functional tyrosine-specific protein kinase pathway and stimulates the phosphoinositide (PI) turnover and proliferation of T-lineage ALL blasts. The presented data confirm and extend previous studies on the expression of functional IL-7R on T-lineage ALL blasts and support the hypothesis that IL-7 may play an important regulatory role in the biology of T-lineage ALL.


Identification of reliable reference genes for quantitative real-time PCR analysis of the Rhus chinensis Mill. leaf response to temperature changes.
Rhus chinensis Mill. (RCM) is the host plant of Galla chinensis, which is valued in traditional medicine. Environmental temperature directly determines the probability of gallnut formation and RCM growth. At present, there is no experiment to systematically analyse the stability of internal reference gene (RG) expression in RCM. In this experiment, leaves that did not form gallnuts were used as the control group, while leaves that formed gallnuts were used as the experimental group. First, we conducted transcriptome experiments on RCM leaves to obtain 45 103 differential genes and functional enrichment annotations between the two groups. On this basis, this experiment established a transcriptional gene change model of leaves in the process of gallnut formation after being bitten by aphids, and RCM reference candidate genes were screened from RNA sequencing (RNA-seq) data. This study is based on RCM transcriptome data and evaluates the stability of 11 potential reference genes under cold stress (4 °C) and heat stress (34 °C), using three statistical algorithms (geNorm, NormFinder, and BestKeeper). The results show that GAPDH1 + PP2A2/UBQ are stable reference genes under heat stress, while GAPDH1 + ACT are the most stable under cold stress. This study is the first to screen candidate reference genes in RCM and could help guide future molecular studies in this genus.


The effect of Pot1 binding on the repair of thymine analogs in a telomeric DNA sequence.
Telomeric DNA can form duplex regions or single-stranded loops that bind multiple proteins, preventing it from being processed as a DNA repair intermediate. The bases within these regions are susceptible to damage; however, mechanisms for the repair of telomere damage are as yet poorly understood. We have examined the effect of three thymine (T) analogs including uracil (U), 5-fluorouracil (5FU) and 5-hydroxymethyluracil (5hmU) on DNA-protein interactions and DNA repair within the GGTTAC telomeric sequence. The replacement of T with U or 5FU interferes with Pot1 (Pot1pN protein of Schizosaccharomyces pombe) binding. Surprisingly, 5hmU substitution only modestly diminishes Pot1 binding suggesting that hydrophobicity of the T-methyl group likely plays a minor role in protein binding. In the GGTTAC sequence, all three analogs can be cleaved by DNA glycosylases; however, glycosylase activity is blocked if Pot1 binds. An abasic site at the G or T positions is cleaved by the endonuclease APE1 when in a duplex but not when single-stranded. Abasic site formation thermally destabilizes the duplex that could push a damaged DNA segment into a single-stranded loop. The inability to enzymatically cleave abasic sites in single-stranded telomere regions would block completion of the base excision repair cycle potentially causing telomere attrition.


The T cell receptors of human gamma delta T cells reactive to Mycobacterium tuberculosis are encoded by specific V genes but diverse V-J junctions.
The observation that gamma delta T lymphocytes react to mycobacteria has provided an important model for investigation of these cells in the immune response to infection. One important question regarding human gamma delta T cells is the breadth of the T cell repertoire in response to specific pathogens. The present study was undertaken to characterize, in molecular terms, the mycobacterium-specific gamma delta TCR repertoire. Mononuclear cells were isolated from the peripheral blood and pleural fluid of patients with tuberculous pleuritis and stimulated with Mycobacterium tuberculosis in vitro. Cytofluorometric analysis of the expressed gamma delta TCR repertoire of M. tuberculosis expanded cells was performed using anti-V region antibodies. The majority of responding gamma delta T cells express a receptor composed of V delta 2 and V gamma 9 chains. Molecular analysis by PCR amplification confirmed use of the V delta 2 and V gamma 9 gene segments in these cells, and demonstrated predominant usage of J delta 1 and J gamma P gene segments. Analysis of nucleotide sequence at the V-J junctions revealed extensive diversity including nucleotide deletions of V, D, and J gene segments and nucleotide segment additions. The predicted amino acid sequences further indicates diversity in the V-J encoded region of the protein chains. The data indicate that M. tuberculosis-driven expansion of gamma delta T cells in vitro depends on specific pairing of the V delta 2 and V gamma 9 polypeptide chains, without apparent selection of explicit V-J junction regions.


Large Farm Animals Used for Research Purposes: A Survey on Purchase, Housing and Hygiene Management.
Farm animals (FAs) are frequently used in biomedical research. Recommendations for the purchase, housing and health monitoring of these animals (sheep, goats, cattle and pigs) are still missing, and many institutes have developed their own strategies and protocols to face the challenges associated with the use of farm animals. This may influence the comparability of research results and increase data variances, thus increasing animal use that contradicts the obligation to apply the 3Rs principle of reduction, refinement and replacement required in Directive 2010/63 EU and the German animal protection law. A survey was conducted to define the current state of the art in research institutes working with pigs, and large and small ruminants. The results of the survey clearly show that there are no uniform procedures regarding the purchase, housing and hygiene management of farm animals contrary to small laboratory animals. The facilities make purpose-bound decisions according to their own needs and individual work instructions and implement their own useful protocols to improve and maintain the health of the animals. This survey was the first step to filling the gaps and identifying the status quo and practical applied measures regarding the purchase and hygiene monitoring of FAs in order to improve animal welfare and scientific validity.


A phase I study of the WT2725 dosing emulsion in patients with advanced malignancies.
WT2725 is a Wilms' tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1+ tumors in human leukocyte antigen (HLA)-A*0201+ and/or HLA-A*0206+ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, the WT2725 dosing emulsion was administered as a monotherapy to patients with advanced malignancies known to overexpress WT1, including glioblastoma. In part 1, 44 patients were sequentially allocated to four doses: 0.3 mg (n = 5), 0.9 mg (n = 5), 3 mg (n = 6), and 9 mg (n = 28). In part 2, 18 patients were allocated to two doses: 18 mg (n = 9) and 27 mg (n = 9). No dose-limiting toxicities were observed, so the maximum tolerated dose was not reached. Median progression-free survival was 58 (95% confidence interval [CI] 56-81) days (~ 2 months) across all patients with solid tumors; median overall survival was 394 days (13.0 months) (95% CI 309-648). Overall immune-related response rate in solid tumor patients was 7.5% (95% CI 2.6-19.9); response was most prominent in the glioblastoma subgroup. Overall, 62.3% of patients were considered cytotoxic T-lymphocyte responders; the proportion increased with increasing WT2725 dosing emulsion dose. WT2725 dosing emulsion was well tolerated. Preliminary tumor response and biological marker data suggest that WT2725 dosing emulsion may exert antitumor activity in malignancies known to overexpress the WT1 protein, particularly glioblastoma, and provide a rationale for future clinical development.Trial registration: NCT01621542.


An update on management of the patient presenting with non-ST-elevation acute coronary syndromes.
Over 780,000 patients in the United States are diagnosed with an acute coronary syndrome (ACS) each year. As physicians, it is our responsibility to provide prompt workup, diagnosis and management of these patients. After identification of the patient with ACS and confirming there is not ST-segment elevation MI requiring immediate revascularization, physicians should pursue a work-up for non-ST-elevation acute coronary syndrome (NSTE-ACS). It is important to understand the latest best practice guidelines in the treatment and management of patients with NSTE-ACS who carry high rates of in-hospital mortality. Physicians must integrate the clinical history and examination, electrocardiogram and laboratory findings in order to properly diagnose an NSTE-ACS. Early treatment with guideline directed medical therapy is imperative even in the setting of an early invasive strategy with cardiac catheterization and percutaneous coronary intervention. The focus of this review is to discuss the appropriate strategies for evaluation and management of patients with NSTE-ACS based on the most recent ACC/AHA practice guidelines.


Outcomes in patients with advanced heart failure and small body size undergoing continuous-flow left ventricular assist device implantation.
Left ventricular assist devices (LVADs) have become a preferred treatment option for patients with end-stage heart failure when used as a bridge to transplant or as a destination therapy. However, the association between small body size and postoperative outcomes for continuous-flow (CF) LVAD recipients is still being studied. We sought to determine whether body surface area (BSA) is associated with patient outcomes after CF-LVAD implantation. The study cohort of our single-center, retrospective review consisted of all patients (n = 526) who underwent CF-LVAD implantation (n = 403 HeartMate II, n = 123 HeartWare) between November 2003 and March 2016 regardless of indication. Patients were stratified into 2 cohorts according to their BSA measurements: small BSA (<1.5 m2, n = 13) and non-small BSA (≥1.5 m2, n = 513). We compared the survival of the small-BSA cohort with that of the non-small-BSA cohort. Patients with a small BSA had lower survival rates at 1, 6, 12, and 24 months (76.9, 61.5, 53.8, and 38.5%, respectively) than did patients with a non-small BSA (90.4, 80.9, 74.7, and 67.6% respectively; overall, p = 0.004). Cox proportional hazard analysis showed that a small BSA was an independent predictor of postoperative mortality (hazard ratio = 0.22, 95% confidence interval = 0.05-0.97, p < 0.04). These findings highlight the adverse impact of a small BSA on outcomes after CF-LVAD implantation.


Oral Administration of Faecalibacterium prausnitzii Decreased the Incidence of Severe Diarrhea and Related Mortality Rate and Increased Weight Gain in Preweaned Dairy Heifers.
Probiotics are a promising alternative to improve food animal productivity and health. However, scientific evidence that specific microbes can be used to benefit animal health and performance is limited. The objective of this study was to evaluate the effects of administering a live culture of Faecalibacterium prausnitzii to newborn dairy calves on subsequent growth, health, and fecal microbiome. Initially, a safety trial was conducted using 30 newborn bull calves to assess potential adverse effects of the oral and rectal administration of F. prausnitzii to neonatal calves. No adverse reactions, such as increased body temperature or heart and respiratory rates, were observed after the administration of the treatments. All calves survived the experimental period, and there was no difference in fecal consistency score, attitude, appetite or dehydration between the treatment groups. The rectal route was not an efficient practice while the oral route ensures that the full dose is administered to the treated calves. Subsequently, a randomized field trial was completed in a commercial farm with preweaned calves. A total of 554 Holstein heifers were assigned to one of two treatment groups: treated calves (FPTRT) and non-treated calves (control). Treated calves received two oral doses of F. prausnitzii, one at treatment assignment (1st week) and another one week later. The FPTRT group presented significantly lower incidence of severe diarrhea (3.1%) compared with the control group (6.8%). Treated calves also had lower mortality rate associated with severe diarrhea (1.5%) compared to control calves (4.4%). Furthermore, FPTRT calves gained significantly more weight, 4.4 kg over the preweaning period, than controls calves. The relative abundance of F. prausnitzii in the fecal microbiota was significantly higher in the 3rd and 5th weeks of life of FPTRT calves than of the control calves, as revealed by sequencing of the 16S rRNA gene. Our findings showed that oral administration of F. prausnitzii improves gastrointestinal health and growth of preweaned calves, supporting its use as a potential probiotic.


Practical guidance for conducting mediation analysis with multiple mediators using inverse odds ratio weighting.
Despite the recent flourishing of mediation analysis techniques, many modern approaches are difficult to implement or applicable to only a restricted range of regression models. This report provides practical guidance for implementing a new technique utilizing inverse odds ratio weighting (IORW) to estimate natural direct and indirect effects for mediation analyses. IORW takes advantage of the odds ratio's invariance property and condenses information on the odds ratio for the relationship between the exposure (treatment) and multiple mediators, conditional on covariates, by regressing exposure on mediators and covariates. The inverse of the covariate-adjusted exposure-mediator odds ratio association is used to weight the primary analytical regression of the outcome on treatment. The treatment coefficient in such a weighted regression estimates the natural direct effect of treatment on the outcome, and indirect effects are identified by subtracting direct effects from total effects. Weighting renders treatment and mediators independent, thereby deactivating indirect pathways of the mediators. This new mediation technique accommodates multiple discrete or continuous mediators. IORW is easily implemented and is appropriate for any standard regression model, including quantile regression and survival analysis. An empirical example is given using data from the Moving to Opportunity (1994-2002) experiment, testing whether neighborhood context mediated the effects of a housing voucher program on obesity. Relevant Stata code (StataCorp LP, College Station, Texas) is provided.


Peyer's patch organogenesis is intact yet formation of B lymphocyte follicles is defective in peripheral lymphoid organs of mice deficient for tumor necrosis factor and its 55-kDa receptor.
Targeted inactivation of genes in the tumor necrosis factor (TNF)/lymphotoxin (LT) ligand and receptor system has recently revealed essential roles for these molecules in lymphoid tissue development and organization. Lymphotoxin-alphabeta (LTalphabeta)/lymphotoxin-beta receptor (LTbeta-R) signaling is critical for the organogenesis of lymph nodes and Peyer's patches and for the structural compartmentalization of the splenic white pulp into distinct B and T cell areas and marginal zones. Moreover, an essential role has been demonstrated for TNF/p55 tumor necrosis factor receptor (p55TNF-R) signaling in the formation of splenic B lymphocyte follicles, follicular dendritic cell networks, and germinal centers. In contrast to a previously described essential role for the p55TNF-R in Peyer's patch organogenesis, we show in this report that Peyer's patches are present in both TNF and p55TNF-R knockout mice, demonstrating that these molecules are not essential for the organogenesis of this lymphoid organ. Furthermore, we show that in the absence of TNF/p55TNF-R signaling, lymphocytes segregate normally into T and B cell areas and a normal content and localization of dendritic cells is observed in both lymph nodes and Peyer's patches. However, although B cells are found to home normally within Peyer's patches and in the outer cortex area of lymph nodes, organized follicular structures and follicular dendritic cell networks fail to form. These results show that in contrast to LTalphabeta signaling, TNF signaling through the p55TNF-R is not essential for lymphoid organogenesis but rather for interactions that determine the cellular and structural organization of B cell follicles in all secondary lymphoid tissues.


Trend analysis of disaster health articles in peer-reviewed publications pre- and post-9/11.
The aim of this study was to determine which journals publish medical disaster-related work, their individual focus, and publication volume pre- and post-9/11. PubMed and Google Scholar were searched using key words to identify peer-review journals (print or electronic) publishing medical and public health disaster-related manuscripts. All medical journals with an average volume of at least five disaster-related publications per year over the 11-year study period (1996-2006) were selected. Identified journals were categorized as either general or specialty medical, or disaster health dedicated. All disaster-related articles in each journal were identified and classified according to 11 subtopics. Of 16 journals meeting entry criteria, 10 were disaster dedicated. Of these, only six existed pre-9/ 11. Only six general journals (JAMA, American Journal of Public Health, The Lancet, New England Journal of Medicine, Annals of Emergency Medicine, Academic Emergency Medicine) had sufficient publications for analysis. Of the 2899 disaster articles identified, 1769 (61 percent) were from the dedicated journals. Publications increased by 320 percent in the general/subspecialty journals and 145 percent for disaster-specific journals in the 5-year period post-9/11 (2002-2006) versus the previous 5-year period (1996-2000). Among the dedicated journals, Journal of Prehospital and Disaster Medicine published the most (21 percent), followed by Disaster Prevention and Management: An International Journal (18 percent). Among the general/subspecialty journals, The Lancet published the most (33 percent), followed by JAMA (28 percent) and Annals of Emergency Medicine (18 percent). These journals published the most pre- and post-9/11. Bioterrorism (36 percent) and Preparedness (18 percent) were the most frequent topic areas for the general/subspecialty journals, while General Disasters (38 percent) and Preparedness (27 percent) were of the highest interest for the dedicated journals. The greatest increase in the proportion of publications pre- and post-9/11 was by the New England Journal of Medicine (2340 percent) and Academic Emergency Medicine (1275 percent). Individual journals appear to emphasize particular subtopic areas. Interest in publishing medical disaster-related articles has increased tremendously since 9/11 in both general/subspecialty journals as well as disaster-dedicated medical journals. Some journals focus on certain topics. Details of this study should help authors identify appropriate journals for their manuscript submissions.


Identification of distinct glycoforms of IgA1 in plasma from patients with immunoglobulin A (IgA) nephropathy and healthy individuals.
Immunoglobulin A nephropathy (IgAN) is the most common form of glomerulonephritis worldwide and is histologically characterized by the deposition of IgA1 and consequent inflammation in the glomerular mesangium. Prior studies suggested that serum IgA1 from IgAN patients contains aberrant, undergalactosylated O-glycans, for example, Tn antigen and its sialylated version, SialylTn (STn), but the mechanisms underlying aberrant O-glycosylation are not well understood. Here we have used serial lectin separation technologies, Western blot, enzymatic modifications, and mass spectrometry to explore whether there are different glycoforms of IgA1 in plasma from patients with IgAN and healthy individuals. Although total plasma IgA in IgAN patients was elevated ∼ 1.6-fold compared with that in healthy donors, IgA1 in all samples was unexpectedly separable into two distinct glycoforms: one with core 1 based O-glycans, and the other exclusively containing Tn/STn structures. Importantly, Tn antigen present on IgA1 from IgAN patients and controls was convertible into the core 1 structure in vitro by recombinant T-synthase. Our results demonstrate that undergalactosylation of O-glycans in IgA1 is not restricted to IgAN and suggest that in vivo inefficiency of T-synthase toward IgA1 in a subpopulation of B or plasma cells, as well as overall elevation of IgA, may contribute to IgAN pathogenesis.


RNA-Seq de novo assembly and differential transcriptome analysis of the nematode Ascaridia galli in relation to in vivo exposure to flubendazole.
The nematode Ascaridia galli (order Ascaridida) is an economically important intestinal parasite responsible for increased food consumption, reduced performance and elevated mortality in commercial poultry production. This roundworm is an emerging problem in several European countries on farms with laying hens, as a consequence of the recent European Union (EU) ban on conventional battery cages. As infection is associated with slow development of low levels of acquired protective immunity, parasite control relies on repeated use of dewormers (anthelmintics). Benzimidazoles (BZ) are currently the only anthelmintic registered in the EU for use in controlling A. galli and there is an obvious risk of overuse of one drug class, selecting for resistance. Thus we developed a reference transcriptome of A. galli to investigate the response in gene expression before and after exposure to the BZ drug flubendazole (FLBZ). Transcriptional variations between treated and untreated A. galli showed that transcripts annotated as mitochondrial glutamate dehydrogenase and cytochrome P450 were significantly down-regulated in treated worms, whereas transcripts homologous to heat shock proteins (HSP), catalase, phosphofructokinase, and a multidrug resistance P-glycoprotein (PGP1) were significantly up-regulated in treated worms. Investigation of candidate transcripts responsible for anthelmintic resistance in livestock nematodes led to identification of several tubulins, including six new isoforms of beta-tubulin, and several ligand-gated ionotropic receptors and ABC-transporters. We discovered several transcripts associated with drug binding and processing genes, but further characterisation using a larger set of worms exposed to BZs in functional assays is required to determine how these are involved in drug binding and metabolism.


Nuclear progestin receptor-like component in human cervical tissue.
To study progestin action in human glandular cervix, we extracted the nuclear pellet with 0.5 M KCl and immediately adsorbed a progestin-binding receptor-like component to hydroxylapatite. Binding of 2 nM [3H]R5020 at 4 degrees C for 18 h, in the presence or absence of 100-fold molar excess progesterone and other steroids, was used to measure the total extractable and adsorbed progestin-binding component. With this assay, the amounts of progestin-binding component in the nuclear-rich fraction in specimens from women in the follicular and luteal phases of the ovarian cycle were 930 +/- 143 and 995 +/- 148 fmol/g wet wt (+/- SE), respectively; total cytoplasmic progestin receptor was 2,989 +/- 812 and 1,861 +/- 188 fmol/g wet wt (+/- SE) in the follicular and luteal phases, respectively. The progestin-binding component extracted from the nuclear pellet has a sedimentation velocity coefficient in the 3.5 S region when measured in high salt on 5-20% linear sucrose density gradients that contain 10% glycerol. The progestin binding measured by the hydroxylapatite-exchange assay with [3H]R5020 and radio-insert progesterone is high affinity (Kd 2.6 X 10(-10) M) and heat labile and appears specific for progestins and progesterone target tissues.


EBM+: Advancing Evidence-Based Medicine via two level automatic identification of Populations, Interventions, Outcomes in medical literature.
Evidence-Based Medicine (EBM) has been an important practice for medical practitioners. However, as the number of medical publications increases dramatically, it is becoming extremely difficult for medical experts to review all the contents available and make an informative treatment plan for their patients. A variety of frameworks, including the PICO framework which is named after its elements (Population, Intervention, Comparison, Outcome), have been developed to enable fine-grained searches, as the first step to faster decision making. In this work, we propose a novel entity recognition system that identifies PICO entities within medical publications and achieves state-of-the-art performance in the task. This is achieved by the combination of four 2D Convolutional Neural Networks (CNNs) for character feature extraction, and a Highway Residual connection to facilitate deep Neural Network architectures. We further introduce a PICO Statement classifier, that identifies sentences that not only contain all PICO entities but also answer questions stated in PICO. To facilitate this task we also introduce a high quality dataset, manually annotated by medical practitioners. With the combination of our proposed PICO Entity Recognizer and PICO Statement classifier we aim to advance EBM and enable its faster and more accurate practice.


Collaborative practice between Ontario nurses and physicians: is it possible?
Numerous historical, psychological, social and cultural factors have caused the development and endurance of an unequal relationship pattern between the physician and the nurse. Nurses have assumed a position of lower status and dependency on physicians, and have been viewed as physicians' helpers or "handmaidens". However, with today's rapid technological changes, ethical and moral dilemmas, and cost constraints, high quality patient care cannot occur without equal contribution of both nursing and medicine. A shift from the traditional physician dominated relationship to a more balanced nurse-physician collaboration is needed. In a collaborative relationship, the physician and nurse jointly assume responsibility and accountability for patient care. This paper addresses the barriers to establishing a nurse-physician collaborative practice in Ontario and how they may be overcome.


Evidence that a West-East admixed population lived in the Tarim Basin as early as the early Bronze Age.
The Tarim Basin, located on the ancient Silk Road, played a very important role in the history of human migration and cultural communications between the West and the East. However, both the exact period at which the relevant events occurred and the origins of the people in the area remain very obscure. In this paper, we present data from the analyses of both Y chromosomal and mitochondrial DNA (mtDNA) derived from human remains excavated from the Xiaohe cemetery, the oldest archeological site with human remains discovered in the Tarim Basin thus far. Mitochondrial DNA analysis showed that the Xiaohe people carried both the East Eurasian haplogroup (C) and the West Eurasian haplogroups (H and K), whereas Y chromosomal DNA analysis revealed only the West Eurasian haplogroup R1a1a in the male individuals. Our results demonstrated that the Xiaohe people were an admixture from populations originating from both the West and the East, implying that the Tarim Basin had been occupied by an admixed population since the early Bronze Age. To our knowledge, this is the earliest genetic evidence of an admixed population settled in the Tarim Basin.


COVID-19 Vaccination Willingness in Four Asian Countries: A Comparative Study including Thailand, Indonesia, the Philippines, and Vietnam.
Globally, 67% of the population has received at least one COVID-19 vaccine dose, but coverage varies across countries. This study aimed to compare people's willingness to receive COVID-19 vaccination across Thailand, Indonesia, Philippines, and Vietnam, where vaccination intention tends to be high, to determine factors associated with willingness, and to obtain suggestions for developing strategies. We conducted a secondary data analysis of the Japan International Cooperation Agency survey "Building Resilience: COVID-19 Impact and Responses in Urban Areas-Case of Southeast Asia," including1842 unvaccinated participants from Thailand (n = 461), Indonesia (n = 246), the Philippines (n = 609), and Vietnam (n = 526). Vaccination willingness was high in all countries (69.6%), but the social and psychological factors motivating people to undergo vaccination differed among these countries. The highest vaccination willingness was in the Philippines, followed by Vietnam and Indonesia, whereas the lowest vaccination willingness was in Thailand. Vaccination willingness was affected by not only sociodemographic attributes, but also risk perception and beliefs, which, in turn, were shaped by social factors such as infection trends and vaccine policies. To achieve effective vaccination promotion programs, a system allowing the flexible modification of promotion methods in response to social conditions must be established.


Modelling conservation in the Amazon basin.
Expansion of the cattle and soy industries in the Amazon basin has increased deforestation rates and will soon push all-weather highways into the region's core. In the face of this growing pressure, a comprehensive conservation strategy for the Amazon basin should protect its watersheds, the full range of species and ecosystem diversity, and the stability of regional climates. Here we report that protected areas in the Amazon basin--the central feature of prevailing conservation approaches--are an important but insufficient component of this strategy, based on policy-sensitive simulations of future deforestation. By 2050, current trends in agricultural expansion will eliminate a total of 40% of Amazon forests, including at least two-thirds of the forest cover of six major watersheds and 12 ecoregions, releasing 32 +/- 8 Pg of carbon to the atmosphere. One-quarter of the 382 mammalian species examined will lose more than 40% of the forest within their Amazon ranges. Although an expanded and enforced network of protected areas could avoid as much as one-third of this projected forest loss, conservation on private lands is also essential. Expanding market pressures for sound land management and prevention of forest clearing on lands unsuitable for agriculture are critical ingredients of a strategy for comprehensive conservation.


Prevalence and risk indicators of depression in elderly nursing home patients: the AGED study.
Depression is a common and disabling psychiatric disorder in later life. Particular frail nursing home patients seem to be at increased risk. Nursing home-based studies on risk indicators of depression are scarce. Prevalence and risk indicators of depression were assessed in 333 nursing home patients living on somatic wards of 14 nursing homes in the North West of the Netherlands. Depressive symptoms were measured by means of the Geriatric Depression Scale (GDS). Major and minor depression were diagnosed according to the DSM-IV criteria, sub-clinical depression was defined as a GDS score >10 while not meeting the DSM-V criteria for depression. The prevalence of major depression was assessed to be 8.1% and the prevalence of minor depression was 14.1%, while a further 24% of the patients suffered from sub-clinical depression. For major depression significant risk indicators were found for pain, functional limitations, visual impairment, stroke, loneliness, lack of social support, negative life events and perceived inadequacy of care. For sub-clinical depression the same risk indicators were found, with the exception of lack of social support. Data were collected cross-sectional. The prevalence of depression in the nursing home population is very high. Whichever way defined, the prevalence rates found were three to four times higher than in the community-dwelling elderly. Age, pain, visual impairment, stroke, functional limitations, negative life events, loneliness, lack of social support and perceived inadequacy of care were found to be risk indicators for depression. Consequently, optimal physical treatment and special attention and focus on psychosocial factors must be major goals in developing care programs for this frail population.


NPY-Y1 coexpressed with NPY-Y5 receptors modulate anxiety but not mild social stress response in mice.
The Y1 and Y5 receptors for neuropeptide Y have overlapping functions in regulating anxiety. We previously demonstrated that conditional removal of the Y1 receptor in the Y5 receptor expressing neurons in juvenile Npy1r(Y5R-/-) mice leads to higher anxiety but no changes in hypothalamus-pituitary-adrenocortical axis activity, under basal conditions or after acute restraint stress. In the present study, we used the same conditional system to analyze the specific contribution of limbic neurons coexpressing Y1 and Y5 receptors on the emotional and neuroendocrine responses to social chronic stress, using different housing conditions (isolation vs. group-housing) as a model. We demonstrated that control Npy1r(2lox) male mice housed in groups show increased anxiety and hypothalamus-pituitary-adrenocortical axis activity compared with Npy1r(2lox) mice isolated for six weeks immediately after weaning. Conversely, Npy1r(Y5R-/-) conditional mutants display an anxious-like behavior but no changes in hypothalamus-pituitary-adrenocortical axis activity as compared with their control littermates, independently of housing conditions. These results suggest that group housing constitutes a mild social stress for our B6129S mouse strain and they confirm that the conditional inactivation of Y1 receptors specifically in Y5 receptor containing neurons increases stress-related anxiety without affecting endocrine stress responses.


Disease modification and biomarker development in Parkinson disease: Revision or reconstruction?
A fundamental question in advancing Parkinson disease (PD) research is whether it represents one disorder or many. Does each genetic PD inform a common pathobiology or represent a unique entity? Do the similarities between genetic and idiopathic forms of PD outweigh the differences? If aggregates of α-synuclein in Lewy bodies and Lewy neurites are present in most (α-synucleinopathies), are they also etiopathogenically significant in each (α-synuclein pathogenesis)? Does it matter that postmortem studies in PD have demonstrated that mixed protein-aggregate pathology is the rule and pure α-synucleinopathy the exception? Should we continue to pursue convergent biomarkers that are representative of the diverse whole of PD or subtype-specific, divergent biomarkers, present in some but absent in most? Have clinical trials that failed to demonstrate efficacy of putative disease-modifying interventions been true failures (shortcomings of the hypotheses, which should be rejected) or false failures (shortcomings of the trials; hypotheses should be preserved)? Each of these questions reflects a nosologic struggle between the lumper's clinicopathologic model that embraces heterogeneity of one disease and the splitter's focus on a pathobiology-specific set of diseases. Most important, even if PD is not a single disorder, can advances in biomarkers and disease modification be revised to concentrate on pathologic commonalities in large, clinically defined populations? Or should our efforts be reconstructed to focus on smaller subgroups of patients, distinguished by well-defined molecular characteristics, regardless of their phenotypic classification? Will our clinical trial constructs be revised to target larger and earlier, possibly even prodromal, cohorts? Or should our trials efforts be reconstructed to target smaller but molecularly defined presymptomatic or postsymptomatic cohorts? At the Krembil Knowledge Gaps in Parkinson's Disease Symposium, the tentative answers to these questions were discussed, informed by the failures and successes of the fields of breast cancer and cystic fibrosis.