Pan-cancer subtyping in a 2D-map shows substructures that are driven by specific combinations of molecular characteristics.
The use of genome-wide data in cancer research, for the identification of groups of patients with similar molecular characteristics, has become a standard approach for applications in therapy-response, prognosis-prediction, and drug-development. To progress in these applications, the trend is to move from single genome-wide measurements in a single cancer-type towards measuring several different molecular characteristics across multiple cancer-types. Although current approaches shed light on molecular characteristics of various cancer-types, detailed relationships between patients within cancer clusters are unclear. We propose a novel multi-omic integration approach that exploits the joint behavior of the different molecular characteristics, supports visual exploration of the data by a two-dimensional landscape, and inspection of the contribution of the different genome-wide data-types. We integrated 4,434 samples across 19 cancer-types, derived from TCGA, containing gene expression, DNA-methylation, copy-number variation and microRNA expression data. Cluster analysis revealed 18 clusters, where three clusters showed a complex collection of cancer-types, squamous-cell-carcinoma, colorectal cancers, and a novel grouping of kidney-cancers. Sixty-four samples were identified outside their tissue-of-origin cluster. Known and novel patient subgroups were detected for Acute Myeloid Leukemia's, and breast cancers. Quantification of the contributions of the different molecular types showed that substructures are driven by specific (combinations of) molecular characteristics.


[Use of ftorafur for the treatment of 3d-4th stage].
To treat ovarian cancer of stage III-IV the authors have used an antimetabolite-fluorafur. A total dosage of 17-23 g. "marked improvement" was noted in 15 patients, "insignificant improvement" - in 9, there was no improvement in one case. It was found that the level of FSH excretion was reduced twice under the influence of fluorafur, the greater decrease corresponding to a better clinical effect. The drug used in doses applied by the authors, proved to be nontoxic.


An epidemiologic study of neural tube defects in Los Angeles County II. Etiologic factors in an area with low prevalence at birth.
Epidemiologic characteristics of neural tube defect (NTD) births occurring in Los Angeles County, California, residents during the period 1966-1972 are presented. The prevalence at birth was 0.52/1000 births for anencephalus, 0.51/1000 for spina bifida, and 0.08/1000 for encephalocele, rates considered to be low for a predominantly white population. We hypothesized that environmental (nongenetic) factors are of less etiologic importance in a low-prevalence population than in areas or time periods with high prevalence. We tested that hypothesis by examining epidemiologic characteristics of NTDs in Los Angeles County and comparing them with high-prevalence populations. The data did not support a major etiologic role for environmental factors: (1) no significant differences between rates by month of birth or conception; (2) no significant association with maternal age or parity for anencephalus; for spina bifida a significant maternal age effect (P less than 0.01) and for encephalocele a parity effect (P less than 0.02); and (3) no significant relationship with father's occupational class for either anencephalus or encephalocele but a marginally significant (P less than 0.05) inverse association for spina bifida when a statistic based on ordinal relationships was used. Findings supporting the importance of genetic factors in etiology included: (1) a high percentage of males; (2) a higher twin concordance rate than in high-prevalence populations; and (3) an anencephalus rate among blacks comparable with rates for blacks in other United States populations. Our findings in conjunction with those from other areas and times of low prevalence suggest environmental factors play a relatively insignificant role in the etiology of NTDs in such populations.


An investigation of the structural, connectional, and functional subspecialization in the human amygdala.
Although the amygdala complex is a brain area critical for human behavior, knowledge of its subspecialization is primarily derived from experiments in animals. We here employed methods for large-scale data mining to perform a connectivity-derived parcellation of the human amygdala based on whole-brain coactivation patterns computed for each seed voxel. Voxels within the histologically defined human amygdala were clustered into distinct groups based on their brain-wide coactivation maps. Using this approach, connectivity-based parcellation divided the amygdala into three distinct clusters that are highly consistent with earlier microstructural distinctions. Meta-analytic connectivity modelling then revealed the derived clusters' brain-wide connectivity patterns, while meta-data profiling allowed their functional characterization. These analyses revealed that the amygdala's laterobasal nuclei group was associated with coordinating high-level sensory input, whereas its centromedial nuclei group was linked to mediating attentional, vegetative, and motor responses. The often-neglected superficial nuclei group emerged as particularly sensitive to olfactory and probably social information processing. The results of this model-free approach support the concordance of structural, connectional, and functional organization in the human amygdala and point to the importance of acknowledging the heterogeneity of this region in neuroimaging research.


X-ray diffraction from magnetically oriented solutions of macromolecular assemblies.
A simple system was developed for obtaining x-ray diffraction patterns from magnetically oriented solutions of macromolecular assemblies. A small permanent magnet was designed that produces a magnetic field of 16 kilogauss in a volume of 1 cubic millimeter and is mountable on most x-ray cameras. Many subcellular structures have sufficient diamagnetic anisotropy that they exhibit orientation in dilute solution when placed between the poles of the magnet. Diffraction from solutions oriented in this magnet can provide substantially more structural information than small-angle scattering from isotropic solutions. In favorable cases, such as dilute solutions of filamentous bacteriophages, it is possible to produce oriented fiber diffraction patterns from which intensities along layer lines can be measured to 7-angstrom resolution. The magnetically induced birefringence observed in solutions of other macromolecular assemblies suggests that this technique may have broad applicability to subcellular structures.


Next-Generation Accurate, Transferable, and Polarizable Potentials for Material Simulations.
PHAHST (potentials with high accuracy, high speed, and transferability) intermolecular potential energy functions have been developed from first principles for H2, N2, the noble gases, and a metal-organic material, HKUST-1. The potentials are designed from the outset to be transferable to heterogeneous environments including porous materials, interfaces, and material simulations. This is accomplished by theoretically justified choices for all functional forms, parameters, and mixing rules, including explicit polarization in every environment and fitting to high quality electronic structure calculations using methods that are tractable for real systems. The models have been validated in neat systems by comparison to second virial coefficients and bulk pressure-density isotherms. For inhomogeneous applications, our main target, comparisons are presented to previously published experimental studies on the metal-organic material HKUST-1 including adsorption, isosteric heats of adsorption, binding site locations, and binding site energies. A systematic prescription is provided for developing compatible potentials for additional small molecules and materials. The resulting models are recommended for use in complex heterogeneous simulations where existing potentials may be inadequate.


A machine learning approach toward automating spatial identification of LAG3+/CD3+ cells in ulcerative colitis.
Over the past decade, automation of digital image analysis has become commonplace in both research and clinical settings. Spurred by recent advances in artificial intelligence and machine learning (AI/ML), tissue sub-compartments and cellular phenotypes within those compartments can be identified with higher throughput and accuracy than ever before. Recently, immune checkpoints have emerged as potential targets for auto-immune diseases. As such, spatial identification of these proteins along with immune cell markers (e.g., CD3+/LAG3+ T-cells) is a crucial step in understanding the potential and/or efficacy of such treatments. Here, we describe a semi-automated imaging and analysis pipeline that identifies CD3+/LAG3+ cells in colorectal tissue sub-compartments. While chromogenic staining has been a clinical mainstay and the resulting brightfield images have been utilized in AI/ML approaches in the past, there are associated drawbacks in phenotyping algorithms that can be overcome by fluorescence imaging. To address these tradeoffs, we developed an analysis pipeline combining the strengths of brightfield and fluorescence images. In this assay, immunofluorescence imaging was conducted to identify phenotypes followed by coverslip removal and hematoxylin and eosin staining of the same section to inform an AI/ML tissue segmentation algorithm. This assay proved to be robust in both tissue segmentation and phenotyping, was compatible with automated workflows, and revealed presence of LAG3+ T-cells in ulcerative colitis biopsies with spatial context preserved.


A Cluster RCT to Reduce Workers' Sitting Time: Impact on Cardiometabolic Biomarkers.
To evaluate the initial and long-term impacts on cardiometabolic health indicators of the Stand Up Victoria intervention-a 12-month, multicomponent workplace-delivered intervention that successfully reduced overall sitting time, primarily by increasing standing time. Office worksites (≥1 km apart) from a single organization were cluster randomized to intervention (n = 7) or control (n = 7). Participants were 136 intervention and 95 control desk-based workers (5-39 per worksite; 68% women; mean ± SD age = 45.6 ± 9.4 yr). Outcomes, assessed at baseline (0 months), 3, and 12 months, were 14 individual biomarkers of body composition, blood pressure, glucose metabolism, lipid metabolism, and a composite overall cardiometabolic risk score. Intervention effects were assessed by linear mixed models, accounting for repeated measures and clustering, baseline values, and potential confounders. Missing data were multiply imputed. Significance was set at P < 0.05, two-tailed. No significant intervention effects were observed at 3 months. Significant effects, favoring intervention, were observed at 12 months for fasting glucose (-0.34; 95% confidence interval [CI], -0.65 to -0.03; P = 0.028 mmol·L) and the overall cardiometabolic risk score (-0.11, 95% CI, -0.29 to -0.00; P = 0.046). Other intervention effects were typically weakly in favor of the intervention group, but were nonsignificant and estimated with wide CI. In "healthy" workers (not selected as having any specific health condition), a workplace intervention showed a small benefit for improving biomarkers of cardiometabolic risk, but only with 12 months of intervention and not for all biomarkers. Long-term facilitation of movement and standing at work may be a useful approach to reducing cardiovascular disease risk in the working population. The potential benefits for workers at high risk for cardiovascular disease (e.g., with diabetes) may be even greater and merit investigation.


Light-induced photoreceptor shedding in teleost retina blocked by dibutyryl cyclic AMP.
In retinas of lower vertebrates, at least two retinal phenomena appear to be closely tied to the diurnal light-dark cycle: photoreceptor renewal and retinomotor movements. The authors have previously reported that treatments that elevate retinal cyclic AMP levels induce dark-adaptive retinomotor movements. In the present study, the authors have tested whether cyclic nucleotides might also inhibit the burst of rod outer segment shedding expected to occur shortly following light onset. Green sunfish (Lepomis cyanellus) entrained to a 12hL:12hD schedule were given intraocular injections 1 hr before the time of light onset and killed 1 hr after light onset. Epon sections of retinas were used for RPE phagosome counts and for measurements of photoreceptor and RPE retinomotor positions. It is reported that injection of the cyclic AMP analog dibutyryl cyclic AMP before light onset (1) completely blocked the light-induced burst of photoreceptor shedding seen at dawn in these fish; and (2) inhibited light-adaptive retinomotor movements in the pigment epithelium but not in photoreceptors.


Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation: insights from the RE-LY trial.
Anemia may predispose to thromboembolic events or bleeding in anticoagulated patients with atrial fibrillation (AF). To investigate whether anemia is associated with thromboembolic events and bleeding in patients with AF. We retrospectively analyzed the RE-LY trial database, which randomized 18 113 patients with AF and a risk of stroke to receive dabigatran or warfarin for a median follow-up of 2 years. Cox regression analysis was used to determine whether anemia predicted cardiovascular events and bleeding complications in these patients. Anemia was present in 12% of the population at baseline, and the presence of anemia was associated with a higher risk of thromboembolic cardiovascular events, including the composite endpoint of all-cause mortality or myocardial infarction (adjusted hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.32-1.71) and the primary RE-LY outcome of stroke or systemic embolism (adjusted HR 1.41, 95% CI 1.12-1.78). Anemia was also associated with a higher risk of major bleeding complications (adjusted HR 2.14, 95% CI 1.87-2.46) and discontinuation of anticoagulants (adjusted HR 1.40, 95% CI 1.28-1.79). The association between anemia and outcome was similar irrespective of cardiovascular comorbidities, randomized treatment allocation, or prior use of warfarin. The incidence of events was lower in patients with transient anemia than in patients in whom anemia was sustained (adjusted HR 0.66, 95% CI 0.49-0.91). Anemia is associated with an increased risk of thromboembolic events, bleeding complications and mortality in anticoagulated patients with AF. These findings suggest that patients with anemia should be monitored closely during all types of anticoagulant treatment.


Proteomic analyses of soybean root tips during germination.
Plant root systems form complex networks with the surrounding soil environment and are controlled by both internal and external factors. To better understand the function of root tips of soybean during germination, three proteomic techniques were used to analyze the protein profiles of root tip cells. Proteins were extracted from the root tips of 4-day-old soybean seedlings and analyzed using two-dimensional (2D) gel electrophoresis-based proteomics, SDS-gel based proteomics, and gel-free proteomics techniques. A total of 121, 862, and 341 proteins were identified in root tips using the 2D gel-based, SDS gel-based, and gel-free proteomic techniques, respectively. The proteins identified by 2D gel-based proteomic analysis were predominantly localized in the cytoplasm, whereas nuclear-localized proteins were most commonly identified by the SDS gel-based and gel-free proteomics techniques. Of the 862 proteins identified in the SDS gel-based proteomic analysis, 190 were protein synthesis-related proteins. Furthermore, 24 proteins identified using the 2D-gel based proteomic technique shifted between acidic and basic isoelectric points, and 2 proteins, heat shock protein 70.2 and AAA-type ATPase, displayed two different molecular weights at the same isoelectric point. Taken together, these results suggest that a number of proteins related to protein synthesis and modification are activated in the root tips of soybean seedlings during germination.


Ticagrelor monotherapy in patients with chronic kidney disease undergoing percutaneous coronary intervention: TWILIGHT-CKD.
The aim of this study was to assess the impact of chronic kidney disease (CKD) on the safety and efficacy of ticagrelor monotherapy among patients undergoing percutaneous coronary intervention (PCI). In this prespecified subanalysis of the TWILIGHT trial, we evaluated the treatment effects of ticagrelor with or without aspirin according to renal function. The trial enrolled patients undergoing drug-eluting stent implantation who fulfilled at least one clinical and one angiographic high-risk criterion. Chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, was a clinical study entry criterion. Following a 3-month period of ticagrelor plus aspirin, event-free patients were randomly assigned to aspirin or placebo on top of ticagrelor for an additional 12 months. Of the 6835 patients randomized and with available eGFR at baseline, 1111 (16.3%) had CKD. Ticagrelor plus placebo reduced the primary endpoint of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding as compared with ticagrelor plus aspirin in both patients with [4.6% vs. 9.0%; hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31-0.80] and without (4.0% vs. 6.7%; HR 0.59, 95% CI 0.47-0.75; Pinteraction = 0.508) CKD, but the absolute risk reduction was greater in the former group. Rates of death, myocardial infarction, or stroke were not significantly different between the two randomized groups irrespective of the presence (7.9% vs. 5.7%; HR 1.40, 95% CI 0.88-2.22) or absence of (3.2% vs. 3.6%; HR 0.90, 95% CI 0.68-1.20; Pinteraction = 0.111) CKD. Among CKD patients undergoing PCI, ticagrelor monotherapy reduced the risk of bleeding without a significant increase in ischaemic events as compared with ticagrelor plus aspirin.


Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice.
Heterozygous loss-of-function SCN1A mutations cause Dravet syndrome, an epileptic encephalopathy of infancy that exhibits variable clinical severity. We utilized a heterozygous Scn1a knockout (Scn1a(+/-)) mouse model of Dravet syndrome to investigate the basis for phenotype variability. These animals exhibit strain-dependent seizure severity and survival. Scn1a(+/-) mice on strain 129S6/SvEvTac (129.Scn1a(+/-)) have no overt phenotype and normal survival compared with Scn1a(+/-) mice bred to C57BL/6J (F1.Scn1a(+/-)) that have severe epilepsy and premature lethality. We tested the hypothesis that strain differences in sodium current (INa) density in hippocampal neurons contribute to these divergent phenotypes. Whole-cell voltage-clamp recording was performed on acutely-dissociated hippocampal neurons from postnatal days 21-24 (P21-24) 129.Scn1a(+/-) or F1.Scn1a(+/-) mice and wild-type littermates. INa density was lower in GABAergic interneurons from F1.Scn1a(+/-) mice compared to wild-type littermates, while on the 129 strain there was no difference in GABAergic interneuron INa density between 129.Scn1a(+/-) mice and wild-type littermate controls. By contrast, INa density was elevated in pyramidal neurons from both 129.Scn1a(+/-) and F1.Scn1a(+/-) mice, and was correlated with more frequent spontaneous action potential firing in these neurons, as well as more sustained firing in F1.Scn1a(+/-) neurons. We also observed age-dependent differences in pyramidal neuron INa density between wild-type and Scn1a(+/-) animals. We conclude that preserved INa density in GABAergic interneurons contributes to the milder phenotype of 129.Scn1a(+/-) mice. Furthermore, elevated INa density in excitatory pyramidal neurons at P21-24 correlates with age-dependent onset of lethality in F1.Scn1a(+/-) mice. Our findings illustrate differences in hippocampal neurons that may underlie strain- and age-dependent phenotype severity in a Dravet syndrome mouse model, and emphasize a contribution of pyramidal neuron excitability.


Unveiling Stability Criteria of DNA-Carbon Nanotubes Constructs by Scanning Tunneling Microscopy and Computational Modeling.
We present a combined approach that relies on computational simulations and scanning tunneling microscopy (STM) measurements to reveal morphological properties and stability criteria of carbon nanotube-DNA (CNT-DNA) constructs. Application of STM allows direct observation of very stable CNT-DNA hybrid structures with the well-defined DNA wrapping angle of 63.4° and a coiling period of 3.3 nm. Using force field simulations, we determine how the DNA-CNT binding energy depends on the sequence and binding geometry of a single strand DNA. This dependence allows us to quantitatively characterize the stability of a hybrid structure with an optimal π-stacking between DNA nucleotides and the tube surface and better interpret STM data. Our simulations clearly demonstrate the existence of a very stable DNA binding geometry for (6,5) CNT as evidenced by the presence of a well-defined minimum in the binding energy as a function of an angle between DNA strand and the nanotube chiral vector. This novel approach demonstrates the feasibility of CNT-DNA geometry studies with subnanometer resolution and paves the way towards complete characterization of the structural and electronic properties of drug-delivering systems based on DNA-CNT hybrids as a function of DNA sequence and a nanotube chirality.


Cytokine levels (IL-4, IL-6, IL-8 and TGFβ) as potential biomarkers of systemic inflammatory response in trauma patients.
Much research is now being conducted in order to understand the role of cytokines in the development of the inflammatory response following trauma. The purpose of this study was to evaluate whether serum levels of certain cytokines, measured immediately after initial injury, can be used as potential biomarkers for predicting the development and the degree of severity of the systemic inflammatory response (SIRS) in patients with moderate and severe trauma. We conducted a prospective study with 71 individuals of whom 13 (18.3 %) were healthy controls and 58 (81.7 %) were traumatized orthopaedic patients who were categorized into two groups: 31 (43.6 %) with moderate injuries and 27 (38.1 %) patients with severe orthopaedic trauma. Thirty cc of heparinized blood were drawn from each individual within a few hours after the injury. Serum levels of pro-inflammatory, regulatory and anti-inflammatory cytokines were measured in each individual participant. High levels of pro-inflammatory cytokines IL-1β,-6,-8,-12, tumour necrosis factor alpha and interferon gamma were found in all injured patients compared to healthy controls. Only IL-6 and IL-8 were significantly higher in the injured patients. Levels of the regulatory cytokines, transformed growth factor beta (TGF-β) and IL-10 were higher in the injured patients, but significant only for TGF-β. Levels of IL-4 were significantly lower in the injured groups as compared to the controls. Secretion of large amounts of pro-inflammatory cytokines and decreased level of anti-inflammatory cytokines during the acute phase of trauma may lead to the development of systemic inflammatory response syndrome (SIRS) in unstable polytraumatized patients. SIRS may result in life threatening conditions as acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF). High levels of IL-6, IL-8, TGFβ and low levels of IL-4 were found to be reliable markers for the existence of immune reactivity in trauma patients. More research is needed to study pattern of cytokine levels along the acute period of injury, after surgical interventions and during recovery.


Effects of combined enalapril and folic acid therapy on the serum uric acid levels in hypertensive patients: a multicenter, randomized, double-blind, parallel-controlled clinical trial.
Objective The efficacy of combined treatment consisting of enalapril and folic acid (FA) was compared to that of enalapril alone in reducing the serum uric acid (UA) levels in adult hypertensive patients in China. Methods Patients with mild to moderate hypertension (n=480) were randomly assigned to one of three treatment groups: (1) 10 mg enalapril (control group), (2) 10 mg enalapril plus 0.4 mg FA (low-FA group) or (3) 10 mg enalapril plus 0.8 mg FA (high-FA group) daily for eight weeks. The primary outcome was the UA ratio (week 8 UA: baseline UA). Results The final analysis included 450 patients (43.1% men, 27-75 years of age). An adjusted multivariable regression analysis revealed no significant differences in the UA ratio between the three groups after eight weeks of treatment. In the subgroup analysis stratified according to the baseline UA level, the high-FA group demonstrated a significantly greater UA-lowering response among the patients with an elevated baseline UA concentration (UA ≥310 μmol/L) [median UA ratio (25th percentile, 75th percentile): 0.94 (0.83, 1.01)], compared with that observed in the control group [0.97 (0.90, 1.00), p=0.025]. Similar results were found in the participants with baseline hyperuricemia (HUA; UA: men >420 μmol/L, women >350 μmol/L). Conclusion In this sample of adult hypertensive patients, the administration of a daily dose of 10 mg of enalapril combined with 0.8 mg of FA had a greater beneficial effect on the serum UA levels than did that of 10 mg of enalapril alone in patients with either an elevated UA concentration or HUA.


Distribution of Campylobacter jejuni Penner serotypes in broiler flocks 1998-2000 in a small Danish community with special reference to serotype 4-complex.
During the period January 1998-December 2001, all Danish broiler flocks were monitored bacteriologically for thermophilic campylobacters and isolates were stored at -80 degrees C. Six neighbouring broiler farms in a small community were selected for detailed examination of all Campylobacter jejuni isolated (n = 180) from these farms during 1998-2000 using Penner serotyping and pulsed-field gel electrophoresis (PFGE). The area and the farms were selected according to their prevalence of campylobacter so that both farms with low and high frequencies of campylobacter positive flocks were included in the study. The frequency of campylobacter positive flocks on the six farms ranged from 24.5 to 72.7%. One hundred and eighty of the isolates were C. jejuni (included in this study), 14 isolates were C. coli whereas 7 isolates belonged to other species but were not further identified. By serotyping of all C. jejuni 56 isolates (31.5%) were assigned to the 4-complex, 32 isolates (18.0%) to serotype 2, 12 isolates (6.7%) to serotype 11, and 11 isolates (6.2%) were assigned to serotype 12. In three farms, 4-complex was the most prevalent serotype, in one farm it was the second most frequently isolated serotype, while serotypes 2 and 1,44, respectively, were the most frequently isolated from the two remaining farms. This serotype distribution differed from the overall country-wide distribution where serotypes 2 and 1,44 are the most prevalent. All serotype 4-complex isolates from the six selected farms were compared by PFGE to serotype 4-complex isolates from the rest of the country. The results showed that there was a high level of diversity among isolates from the whole country, whereas isolates from the six farms were very homogeneous and only displayed one or a few different PFGE patterns on each farm. It is suggested that certain campylobacter clones persist in a confined geographical area, probably at the farm, and that the broiler houses may be repeatedly infected with a few C. jejuni clones during succeeding broiler flocks. New clones may be introduced, however, the sources and vehicles are yet unknown.


[Grief for loss of a spouse: a study with discussion groups in primary care].
To understand the grieving process after the loss of a spouse and to find the opinion of the person grieving about the best intervention under the circumstances. Qualitative, with discussion groups. Primary care. Widowers/widows between 30 and 70, who suffered their loss between 3 months and 2 years before the study. MEASUREMENTS AND MAIN RESULTS. The data were obtained from recordings and transcriptions, and the main ideas analysed. Two groups were defined: 11 widows between 49 and 68 years old and 6 widowers between 36 and 70. The majority of deaths had followed a previous terminal illness. Four phases of grief were found: 1) anticipated grief, 2) early grief, 3) intermediate grief and 4) delayed grief. There were differences between widows and widowers. An intervention could involve: pre-arranged appointments, home visits, and groups and, in general, spaces to be able to "talk". The results, in so far as they refer to the grieving process and similarities and differences of type, coincide with other authors. The participants highlighted the importance of psychological support from health workers during the last moments of the illness and the importance of this in how grieving developed. Similarly, they evaluated their own support to the dying spouse as an additional factor which helped them.


Mental health effects of the COVID-19 pandemic on children and young adults: empirical analysis of the past, present and the way forward.
The SARS-CoV-2 virus and its variants have had and are having serious implications for the mental health of the public. The critical limitations in the published literature for children, adolescents and young adults raise doubts about their clinical utility and overall generalisability. Amidst these gaps in knowledge, a twin study (Rimfeld et al) addresses several of these issues in relation to heritable individual differences and responses to environmental stressors. Besides calculating genetic correlation, the longitudinal study also compares symptoms at four different time points during the pandemic. These findings reflect a counterintuitive understanding of the role of resilience in the mental health of young adults in the UK. Unlike prior studies, this study focuses on methodological designs and underscores the applications of accurate statistical measures in observing these complex phenomena.


Surgical options to enhance intestinal function in patients with short bowel syndrome.
This review will provide the practitioner with an understanding of the spectrum of nontransplant surgical options for managing patients with short bowel syndrome (SBS). Intestinal lengthening procedures are a promising therapy to allow autonomy from parenteral nutrition. The recently described serial transverse enteroplasty is an effective procedure that is easier to perform and has similar outcomes to the more standard longitudinal lengthening procedure described by Bianchi. There are several surgical options for management of the SBS, including construction of intestinal valves or reversed intestinal segments, interposition of segments of colon, or intestinal lengthening procedures. The choice of technique is dictated by the patient's underlying pathophysiology and includes such factors as intestinal transit time, length of remnant bowel, presence of intact colon, and degree of small bowel dilation. Nontransplant surgical interventions are important adjuncts to the elimination of parenteral nutrition dependence and need for intestinal transplantation.


Fenton oxidation for soil remediation: A critical review of observations in historically contaminated soils.
Fenton-based treatments have received tremendous attention in recent decades as viable strategies for soil decontamination. Historically contaminated soils are characterized by particular contamination types, pollution composition patterns, soil constituents, and complex soil-pollutant interactions arising due to long-term pollutant aging. These major pitfalls dictate the remediation efficiency in a significantly different way in soils with a history of contamination than that in a spiked soil. It becomes, therefore, highly challenging to treat historically contaminated soils. Despite the immense amount of collected research data in these soils, to our knowledge, no comprehensive review of this topic has been published. This article is intended to provide a critical review of the applications, limitations, and implications of various Fenton-based processes exclusively in these soils. These processes are differentiated on the basis of experimental conditions, reaction chemistry, efficiency, and impacts on soil biota. These processes are critically evaluated to illustrate the promising techniques with a brief description of related challenges and their potential solutions. Moreover, coupling Fenton oxidation with other remediation techniques such as bioremediation, chemical reduction, and soil washing has also been discussed. The last part of this review describes the effects of these processes onto soil quality and native biota, and how they can be addressed. It is also highly demanding to identify the processes which are not likely to evolve in practice either due to their poor efficiency, treatment cost, or environmental impacts. Future critical research directions have been identified to promote research for the upscaling of this technique for real field application.


Antipsychotic-induced hyponatremia: case report and literature review.
We report a case of hyponatremia in a patient that occurred 3 days after initiation of treatment with aripiprazole. The patient was a 50-year-old man admitted to an inpatient psychiatric unit for exacerbation of schizophrenia. He was started on aripiprazole and developed hyponatremia that resolved when the medication was stopped. We postulate that the hyponatremia was due to an aripiprazole-induced syndrome of inappropriate secretion of antidiuretic hormone. There have been numerous case reports in the literature of hyponatremia in the literature associated with atypical antipsychotics. We caution clinicians to be aware that the potential hyponatremic-inducing effects of atypical antipsychotics can occur rapidly after initiation of the medications.


A 21-day-old boy with an annular eruption. Tinea faciei / Tinea capitis.
A healthy 21-day-old black male was referred to pediatric dermatology for evaluation of a facial and scalp eruption that had been present for less than 1 week. The child's parents had applied a topical corticosteroid cream for several days without any improvement noted. The child was otherwise well and thriving. Review of systems was negative. Family history was unremarkable for autoimmune or infectious skin diseases. On physical examination the patient was alert, active, and vigorous. He had multiple 1 to 2.5-cm erythematous annular, scaly plaques with pustules on the periphery on his upper cheeks, forehead, and anterior scalp (Figures 1-2). No alopecia was noted. Occipital and neck lymph nodes were not palpable. A potassium hydroxide skin preparation was negative for fungal elements and a fungal culture was performed. Serum laboratory testing was also performed.


Obturator-nerve palsy resulting from intrapelvic extrusion of cement during total hip replacement. Report of four cases.
Obturator neuropathy is an infrequently identified complication of total hip replacement that may cause debilitating pain. There have been isolated reports of this complication in the literature, but only one case has been published in which intrapelvic cement was the causative agent. We are describing the cases of four patients with obturator neuropathy after total hip replacement, documented by electromyography and attributed to intrapelvic extension of cement. In each patient the source of the symptoms was not initially apparent. In three of the patients the extruded cement and obturator nerve were explored surgically. One of the three patients was improved by obturator neurectomy. Of the other two patients, both treated by excision of cement, only one was improved. The fourth patient was not treated. Persistent pain in the groin and thigh, intrapelvic cement visible on plain roentgenograms, and adductor weakness after total hip replacement suggest that this complication has occurred. Electromyography can confirm the presence of obturator neuropathy. Based on this limited series, excision of the extruded cement and preservation of the nerve should be attempted only when the nerve is grossly normal and functional as determined by electrical stimulation at the time of surgical exploration; otherwise, obturator neurectomy should be considered.


Contribution of specific disulphide bonds to two epitopes of thyrotropin beta-subunit associated with receptor recognition.
In previous studies, we have shown that two epitopes of bovine thyrotropin beta-subunit that are recognised by the monoclonal antibodies designated mAb 279 and mAb 299 are also associated with the receptor-binding site of bovine thyrotropin. The present investigation has examined the role of the six disulphide bonds of bovine thyrotropin beta-subunit in the conformational stabilisation of these two epitopes, and hence assessed the relative contribution that these disulphide bonds make to the stabilisation of the receptor-binding region of the beta-subunit. The experimental procedure involved the production of several bovine thyrotropin beta-subunit-related derivatives in which an increasing number of the disulphide bonds were selectively reduced with dithiothreitol and alkylated with iodoacetic acid. Antibody-binding properties of these derivatives were then evaluated in thyrotropin beta-subunit-specific immunoassays based on the use of the well characterised mAb 279 and mAb 299, to determine the effect of disulphide bond reduction and alkylation on each epitopic specificity. In separate experiments, the residual disulphide bonds that remained intact following these selective partial reductive alkylation procedures were then fully reduced and alkylated with the fluorescent reagent 5-N-[(iodoacetamidoethyl)amino]naphthalene 1-sulphonic acid. The relative contribution of individual disulphide bonds in the stabilisation of each epitope could then be assessed after application of reverse-phase HPLC peptide mapping methods. Epitope recognition by mAb 279 was not dependent on the preservation of the so-called determinant loop Cys88-Cys95 disulphide bond nor directly involved binding interactions via the Cys2-Cys52, Cys27-Cys83, and Cys31-Cys85 disulphide bonds. However, the experimental results indicated that the mAb 279 epitope was stabilised by the Cys19-Cys105 and Cys16-Cys67 disulphide bonds, which is consistent with other data on the role of the C-terminal region of the thyrotropin beta-subunit in this epitope. In contrast, the presence of an intact Cys88-Cys95 disulphide bond was required for the stabilisation of the mAb 299 epitope, although the location of this disulphide bond is distal to the hairpin loop structure that constitutes the mAb 299 epitope. These results on the relative contribution of these disulphide bonds are also discussed in terms of their relationship to the stabilisation of the predicted region of bovine thyrotropin beta-subunit involved in receptor binding.


Identification of general fuzzy measures by genetic algorithms based on partial information.
This study develops an identification procedure for general fuzzy measures using genetic algorithms. In view of the difficulty in data collection in practice, the amount of input data is simplified through a sampling procedure concerning attribute subsets, and the corresponding detail design is adapted to the partial information acquired by the procedure. A specially designed genetic algorithm is proposed for better identification, including the development of the initialization procedure, fitness function, and three genetic operations. To show the applicability of the proposed method, this study simulates a set of experimental data that are representative of several typical classes. The experimental analysis indicates that using genetic algorithms to determine general fuzzy measures can obtain satisfactory results under the framework of partial information.


Dietary Guidance From the International Organization for the Study of Inflammatory Bowel Diseases.
Recent evidence points to a plausible role of diet and the microbiome in the pathogenesis of both Crohn's disease (CD) and Ulcerative Colitis (UC). Dietary therapies based on exclusion of table foods and replacement with nutritional formulas and/or a combination of nutritional formulas and specific table foods may induce remission in CD. In UC, specific dietary components have also been associated with flare of disease. While evidence of varying quality has identified potential harmful or beneficial dietary components, physicians and patients at the present time do not have guidance as to which foods are safe, may be protective or deleterious for these diseases. The current document has been compiled by the nutrition cluster of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) based on the best current evidence to provide expert opinion regarding specific dietary components, food groups and food additives that may be prudent to increase or decrease in the diet of patients with inflammatory bowel diseases to control and prevent relapse of inflammatory bowel diseases.


Involvement of the accessory gene regulator (agr) in expression of type 5 capsular polysaccharide by Staphylococcus aureus.
The effect of an agr mutation on expression of type 5 capsular polysaccharide (CP) by Staphylococcus aureus Newman was investigated in different complex and synthetic media. CP expression by the agr mutant was strongly reduced in certain media but slightly in others, indicating that CP synthesis is positively controlled by agr. CP expression occurred in the post-exponential growth phase in both wild-type and mutant strains, suggesting that other regulatory systems could act in conjunction with agr.


Animal models provide insight into psychosomatic factors in diabetes.
To review the literature regarding the use of animal models in research addressing psychosomatic aspects of diabetes. We examine the key findings in animal model vs. human research in the area of stress and diabetes. Previous research has suggested that stress is a potential contributor to chronic hyperglycemia in diabetes. Stress affects metabolic activity via the stimulation of a variety of hormones that can result in elevated blood glucose levels. In patients with diabetes, due to a relative or absolute lack of insulin, stress-induced increases in glucose cannot be properly metabolized. Additionally, regulation of these stress hormones may be abnormal in diabetes. Human studies on the role of stress in the onset and course of type II diabetes are few and are limited by the constraints and logistics of examining life stress in humans. However, animal research allows for tight experimental control and the manipulation of factors that may contribute to the development and/or course of diabetes, such as stress, eating behavior, the nutrient content of food, and physical activity. Disease processes can be examined at a mechanistic level in animals which is typically limited in human research. There is a large body of animal work to support the notion that stress reliably produces hyperglycemia in type II diabetes. Furthermore, there is evidence that the autonomic nervous system plays a role in the pathophysiology of this condition in both animals and humans. Examination of eating behavior and nutrient content of food in animal models of diabetes has shed light on the role of these factors in the development of diabetes, as well as obesity. Finally, genetic research using animal models of diabetes will provide new directions for research in humans to delineate the genetic contribution to the development of diabetes.


An XAFS study of Cs adsorption by the precipitation bands of Mn-Fe-based Prussian blue analogues spontaneously formed in agarose gel.
The adsorption of Cs+ ions by the precipitation bands of a Mn-Fe based Prussian blue analogue (Mn-Fe PBA) that form spontaneously in agarose gel was investigated by X-ray absorption fine structure spectroscopy coupled with scanning electron microscopy (SEM) and X-ray fluorescence (XRF) distribution analysis. Two gel samples were prepared by contacting a gel containing 0.05 M [Fe(CN)6]3- and 2.3 mass% agarose with a 0.50 M MnSO4 solution, into one of which a 0.10 M CsCl solution was introduced. The SEM images and the XRF intensity distributions reveal that Mn-Fe PBA forms cubic crystallites (approx. 3 × 3 × 3 μm in size) in the gels that trap Cs+ ions with considerably high affinity. Cs L3-edge and Mn K-edge X-ray absorption near-edge structure (XANES) spectra, which were analyzed with the aid of FEFF simulations, strongly suggest that Cs adsorption occurs at relatively large defect sites close to the sub-cube faces in the PBA. This suggestion is supported by Cs L3-edge extended X-ray absorption fine structure spectroscopy, which suggested that the first and second coordination shells around the Cs+ ions are at a Cs-O distance of 0.35 ± 0.02 nm and a Cs-N distance of 0.43 ± 0.01 nm, respectively, with coordination numbers of 1.5 ± 0.5 and 3.0 ± 0.5. The Mn K-edge XANES data also suggest that H2O molecules, which initially occupy many cubic centers in the Mn-Fe PBAs, are mostly displaced during Cs adsorption. These findings provide valuable insight toward fully understanding Cs adsorption by Mn-Fe PBA.


Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide.
Class I and class II MHC-restricted T cells specific for proteins present in myelin have been shown to be involved in autoimmunity in the central nervous system (CNS). It is not yet known whether CD1d-restricted T cells reactive to myelin-derived lipids are present in the CNS and might be targeted to influence the course of autoimmune demyelination. Using specific glycolipid-CD1d tetramers and cloned T cells we have characterized a T cell population reactive to a myelin-derived glycolipid, sulfatide, presented by CD1d. This population is distinct from the invariant Valpha14+ NK T cells, and a panel of Valpha3/Valpha8+ CD1d-restricted NK T cell hybridomas is unable to recognize sulfatide in the presence of CD1d+ antigen-presenting cells. Interestingly, during experimental autoimmune encephalomyelitis a model for human multiple sclerosis, sulfatide-reactive T cells but not invariant NK T cells are increased severalfold in CNS tissue. Moreover, treatment of mice with sulfatide prevents antigen-induced experimental autoimmune encephalomyelitis in wild-type but not in CD1d-deficient mice. Disease prevention correlates with the ability of sulfatide to suppress both interferon-gamma and interleukin-4 production by pathogenic myelin oligodendrocyte glycoprotein-reactive T cells. Since recognition of sulfatide by CD1d-restricted T cells has now been shown both in mice and humans, study of murine myelin lipid-reactive T cells may form a basis for the development of intervention strategies in human autoimmune demyelinating diseases.


Anesthesia considerations in pediatric glaucoma management.
This article reviews the potentially adverse neurodevelopmental effects of early exposure to general anesthesia and examines a changing paradigm in the management of pediatric glaucoma. Literature across multiple subspecialties has examined the potentially neurotoxic effects of general anesthesia on the developing child's brain. Associations between general anesthesia exposure early in life and attention deficit hyperactivity disorder, language processing, and cognition have been suggested but not confirmed. Several population studies support the conclusion that early anesthetic exposure may increase the risk of neurodevelopmental deficits, although this is unsupported in sibling cohorts. Newer technology such as rebound tonometry may decrease the frequency of examination under anesthesia in the long-term management of patients with pediatric glaucoma and may decrease the risk of these potentially adverse neurodevelopmental outcomes. As the potential long-term adverse neurodevelopmental effects of general anesthesia become better understood, pediatric glaucoma specialists should be cognizant of the relative lifelong risks and benefits of repeat examinations under anesthesia in young patients.


Relationships between coping, coping resources and quality of life in patients with chronic illness: a pilot study.
The original purpose of the study was to determine differences between two groups of patients with chronic illness (ESRD and CHF) regarding the following study variables: coping, sense of coherence (SOC), self-efficacy and quality of life (QOL). Following this, the aim was to explore the relationships between demographic variables (sex, age, educational level and living area) and QOL as well as between coping, SOC, self-efficacy and QOL for the combined sample of patients with ESRD and CHF. A comparative and correlative design was used with a sample of 100 patients (n = 41 ESRD, n = 59 CHF). The data were collected during 2004, using four standardized questionnaires and regression analyses were conducted. No significant differences were found between the two groups. Positive correlations were identified between SOC, general self-efficacy and QOL, whereas negative correlations emerge between emotion-focused coping, SOC, general self-efficacy and QOL. SOC, general self-efficacy and emotion-focused coping explained 40% of the variance in QOL. Those with low SOC and general self-efficacy showed negative correlations between emotion-focused coping and QOL, whereas no such correlations were shown for those with high values on SOC and general self-efficacy. The present results on coping and QOL correspond with previous research regarding how other groups with chronic illness handled their daily life. Preliminary results indicate that how individuals tackle their present situation is more important than which chronic illness they have. Women used more emotion-focused coping than men, which constitute an important finding for further research.


Haloperidol treatment downregulates DCC expression in the ventral tegmental area.
A core feature in the pathophysiology of schizophrenia is abnormal development and function of mesocorticolimbic dopamine (DA) circuitry. We have previously shown that variations in the function of the netrin-1 receptor, deleted in colorectal cancer (DCC), result in changes to the development, organization and ongoing plasticity of DA circuitry. In rodents, repeated exposure to the indirect DA-agonist, amphetamine upregulates DCC expression in the ventral tegmental area (VTA), but not in DA terminal regions. This elevation in DCC expression is associated with increased vulnerability to developing and maintaining sensitized mesolimbic DA function. Antipsychotic medications remain the best treatment option for managing the symptoms in schizophrenia. The peak effects of these medications are gradual, suggesting that a therapeutic component of antipsychotic treatment involves structural reorganization. Here we assessed whether repeated exposure to typical and atypical antipsychotics could also regulate DCC. Adult mice were orally administered haloperidol, clozapine, or risperidone via their drinking water for 4 weeks. Levels of DCC were measured by Western blot analysis of tissue punches of the VTA, medial prefrontal cortex, nucleus accumbens, and dorsal striatum. Haloperidol decreased DCC levels by approximately 50% in the VTA, but not in DA targets. Furthermore, haloperidol did not alter UNC-5 homologue levels, another family of netrin-1 receptors, confirming that its effects target DCC-mediated netrin-1 signaling specifically. The atypical antipsychotics did not alter DCC expression. These results suggest that typical antipsychotics induce selective functional reorganization in the VTA via DCC-mediated netrin-1 signaling.


PCAS--a precomputed proteome annotation database resource.
Many model proteomes or "complete" sets of proteins of given organisms are now publicly available. Much effort has been invested in computational annotation of those "draft" proteomes. Motif or domain based algorithms play a pivotal role in functional classification of proteins. Employing most available computational algorithms, mainly motif or domain recognition algorithms, we set up to develop an online proteome annotation system with integrated proteome annotation data to complement existing resources. We report here the development of PCAS (ProteinCentric Annotation System) as an online resource of pre-computed proteome annotation data. We applied most available motif or domain databases and their analysis methods, including hmmpfam search of HMMs in Pfam, SMART and TIGRFAM, RPS-PSIBLAST search of PSSMs in CDD, pfscan of PROSITE patterns and profiles, as well as PSI-BLAST search of SUPERFAMILY PSSMs. In addition, signal peptide and TM are predicted using SignalP and TMHMM respectively. We mapped SUPERFAMILY and COGs to InterPro, so the motif or domain databases are integrated through InterPro. PCAS displays table summaries of pre-computed data and a graphical presentation of motifs or domains relative to the protein. As of now, PCAS contains human IPI, mouse IPI, and rat IPI, A. thaliana, C. elegans, D. melanogaster, S. cerevisiae, and S. pombe proteome.PCAS is available at http://pak.cbi.pku.edu.cn/proteome/gca.php PCAS gives better annotation coverage for model proteomes by employing a wider collection of available algorithms. Besides presenting the most confident annotation data, PCAS also allows customized query so users can inspect statistically less significant boundary information as well. Therefore, besides providing general annotation information, PCAS could be used as a discovery platform. We plan to update PCAS twice a year. We will upgrade PCAS when new proteome annotation algorithms identified.


Distinct neural contributions to metacognition for detecting, but not discriminating visual stimuli.
Being confident in whether a stimulus is present or absent (a detection judgment) is qualitatively distinct from being confident in the identity of that stimulus (a discrimination judgment). In particular, in detection, evidence can only be available for the presence, not the absence, of a target object. This asymmetry suggests that higher-order cognitive and neural processes may be required for confidence in detection, and more specifically, in judgments about absence. In a within-subject, pre-registered and performance-matched fMRI design, we observed quadratic confidence effects in frontopolar cortex for detection but not discrimination. Furthermore, in the right temporoparietal junction, confidence effects were enhanced for judgments of target absence compared to judgments of target presence. We interpret these findings as reflecting qualitative differences between a neural basis for metacognitive evaluation of detection and discrimination, potentially in line with counterfactual or higher-order models of confidence formation in detection.


Vacuolation Activity and Intracellular Trafficking of ArtB, the Binding Subunit of an AB5 Toxin Produced by Salmonella enterica Serovar Typhi.
Various Salmonella enterica serovars, including S. enterica serovar Typhi, encode an AB5 toxin (ArtAB), the A subunit of which is an ADP-ribosyltransferase related to the S1 subunit of pertussis toxin. However, although the A subunit is able to catalyze ADP-ribosylation of host G proteins, a cytotoxic phenotype has yet to be identified for the holotoxin. Here we show that its B subunit pentamer (ArtB) binds to receptors on the surface of Vero (African green monkey kidney) cell, CHO (Chinese hamster ovary) cell, U937 (human monocyte) cell, and HBMEC (human brain microvascular endothelial cell) lines. Moreover, ArtB induced marked vacuolation in all cell lines after 4 h of incubation. Further studies in Vero cells showed that vacuolation was inhibited by bafilomycin A1 and was dependent on the clathrin-mediated uptake of ArtB. Vacuolation was also inhibited by treatment of cells with neuraminidase, indicating that sialylated glycans are functional receptors for ArtB. Confocal colocalization studies indicated that after cell binding and internalization, ArtB undergoes retrograde transport via early endosomes, the trans-Golgi network, and the Golgi apparatus, reaching the endoplasmic reticulum (ER) after approximately 2 h. The onset of vacuolation also coincided with gross cytoskeletal reorganization. At later time points, ArtB colocalized with ER-Tracker Red in the vacuolar membrane, implying that vacuolation is a consequence of ER disorganization. Thus, the isolated B subunit of this cryptic AB5 toxin has significant effects on target cells with the potential to contribute directly to pathogenesis independently of the catalytic A subunit.


Artificial neural network is highly predictive of outcome in paediatric acute liver failure.
Current prognostic models in PALF are unreliable, failing to account for complex, non-linear relationships existing between multiple prognostic factors. A computational approach using ANN should provide superior modelling to PELD-MELD scores. We assessed the prognostic accuracy of PELD-MELD scores and ANN in PALF in children presenting to the QLTS, Australia. A comprehensive registry-based data set was evaluated in 54 children (32M, 22F, median age 17 month) with PALF. PELD-MELD scores calculated at (i) meeting PALF criteria and (ii) peak. ANN was evaluated using stratified 10-fold cross-validation. Outcomes were classified as good (transplant-free survival) or poor (death or LT) and predictive accuracy compared using AUROC curves. Mean PELD-MELD scores were significantly higher in non-transplanted non-survivors (i) 37 and (ii) 46 and transplant recipients (i) 32 and (ii) 43 compared to transplant-free survivors (i) 26 and (ii) 30. Threshold PELD-MELD scores ≥27 and ≥42, at meeting PALF criteria and peak, gave AUROC 0.71 and 0.86, respectively, for poor outcome. ANN showed superior prediction for poor outcome with AUROC 0.96, sensitivity 82.6%, specificity 96%, PPV 96.2% and NPV 85.7% (cut-off 0.5). ANN is superior to PELD-MELD for predicting poor outcome in PALF.


4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone from cigarette smoke stimulates colon cancer growth via beta-adrenoceptors.
Cigarette smoking is a risk factor for colorectal cancer. It is suggested that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, mediates the carcinogenic action of cigarette smoking by promoting cancer growth. In the present study, the proliferative response of a cultured colon cancer cell line HT-29 to NNK was determined. It was found that NNK dose-dependently stimulated HT-29 cell proliferation. In this regard, the stimulatory action of NNK was abolished by atenolol and ICI 118,551, a beta1- and beta2-selective antagonist, respectively. In addition, cell growth was stimulated by the nonselective adrenergic agonist, noradrenaline, and more effectively by the beta-selective agonist, isoproterenol. The second message cyclic AMP level for beta-adrenoceptor activation was elevated by isoproterenol and NNK treatment. These agents also up-regulated cyclooxygenase-2 expression, cytosolic phospholipase A2 expression, and prostaglandin E2 release. Beta2-adrenoceptor blockade with ICI 118,551, in contrast, significantly decreased cyclooxygenase-2 expression, cytosolic phospholipase A2 expression and prostaglandin E2 release induced by NNK and isoproterenol. To conclude, it is proposed that NNK stimulates HT-29 cell proliferation through beta-adrenoceptors, preferentially beta2 receptors. Activation of the beta-adrenoceptors, and the consequent cyclic AMP elevation coupled with the downstream arachidonic acid pathway, is perhaps an important mechanistic cascade in the promotion of colon cancer growth. These findings partly elucidate the carcinogenic actions of cigarette smoke and shed new light on the novel modulatory role of beta-adrenoceptors in the development of colon cancer.


Two novel flavans from Cyperus conglomeratus.
Separation of the extract of the underground tubers of Cyperus conglomeratus Rottb. (family Cyperaceae) afforded, in addition to known compounds, two novel flavans, which were identified, by one and two dimensional NMR, MS and IR spectra, as 5-hydroxy-7,3',5'-trimethoxyflavan and 5,7-dihydroxy-3',5'-dimethoxy-6-prenylflavan.


Multiple Myeloma in a Patient With Familial Mediterranean Fever.
Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent episodes of painful inflammation in the abdomen, chest, or joints. The coexistence of multiple myeloma (MM) and FMF is an extremely rare event. Here, we report a case of FMF with concurrent MM. A 63-year-old woman was diagnosed with FMF since 15 years earlier. She was admitted with a complaint of low back pain. Regarding the presence of back pain, anemia, hypercalcemia, and kidney failure, a diagnosis of MM was suspected. A skeletal survey showed punched-out lesions in the skull. Serum protein electrophoresis demonstrated an immunoglobulin G kappa monoclonal gammopathy, and bone marrow aspiration revealed 30% involvement by abnormally appearing plasma cells, suggestive of MM. Although the association between FMF and MM may be a mere coincidence, further studies are necessary to understand their concurrent development.


Maternal vascular malperfusion in spontaneous preterm birth placentas related to clinical outcome of subsequent pregnancy.
Spontaneous preterm birth (SPTB) has several causes and its pathophysiology remains unclear. In a significant proportion of SPTB, placental histology shows signs of maternal vascular malperfusion (MVM); commonly associated with hypertensive disorders of pregnancy (HD), fetal growth restriction (FGR) and placental abruption, together referred to as clinical ischemic placental diseases (IPD). We hypothesized that women with SPTB and placental MVM are at elevated risk for IPD in a subsequent pregnancy. We included women with SPTB in our cohort and followed the subsequent ongoing pregnancy (n = 110). Histological placental characteristics in the index were reported according to new international guidelines, and related to the clinical outcome of the subsequent pregnancy. In the SPTB placentas, we observed MVM in 61.8% (n = 68). In the subsequent pregnancies in 19.1% (n = 21) at least one clinical sign of IPD was present (HD (12.7%), FGR (5.5%) or placental abruption (0.9%)). There was no significant difference in the prevalence of clinical IPD or recurrence of SPTB in the subsequent pregnancy between women with and without placental MVM in the index pregnancy, although our study was not powered to detect small differences. Women with a history of SPTB have an elevated risk of IPD in the subsequent pregnancy. MVM is present in a large proportion of SPTB placentas. The presence of placental MVM in the index pregnancy does not predict clinical IPD or recurrent SPTB in a subsequent pregnancy.


Glucose metabolism and insulin release in mouse beta HC9 cells, as model for wild-type pancreatic beta-cells.
Glucose metabolism and its relationship with glucose-induced insulin release were studied in beta HC9 and beta TC3 cells to identify and characterize key factors controlling the intermediary metabolism of glucose and glucose-induced insulin release. The beta HC9 cell line, derived from pancreatic islets with beta-cell hyperplasia, is characterized by a normal concentration-dependency curve for glucose-stimulated insulin release, whereas the beta TC3 cell line, derived from pancreatic beta-cell tumors, shows a marked leftward shift of this curve. Maximum velocity and the Michaelis-Menten constant of glucose uptake in beta HC9 and beta TC3 cells were similar, even though GLUT-2 expression in these two cell lines differed. In both cell lines, the kinetic characteristics of glucose usage, glucose oxidation, and glucose-induced oxygen consumption were similar to those of glucose phosphorylation, indicating that the kinetics of glucose metabolism from the glucose phosphorylation step in the cytosol to the mitochondrial process of oxidative phosphorylation are determined by the glucose-phosphorylating enzyme, that is, by glucokinase in beta HC9 cells and by hexokinase in beta TC3 cells. Thus beta HC9 cells provide an opportunity for the quantitative analysis of glucose metabolism, the associated generation of coupling factors, and other essential beta-cell functions involved in glucose sensing and insulin secretion.


Ultrafast Single-Particle Imaging with Intense X-Ray Pulses.
Ultrafast single-particle imaging with intense x-ray pulses from free-electron laser sources provides a new approach for visualizing structure and dynamics on the nanoscale. After a short introduction to the novel free-electron laser sources and methods, we highlight selected applications and discuss how ultrafast imaging flourishes from method development to early applications in physics and biology to opportunities for chemical sciences.


Long-term efficacy and safety of fluticasone propionate powder administered once or twice daily via inhaler to patients with moderate asthma.
To evaluate the efficacy and safety of fluticasone propionate administered as a once-daily or twice-daily regimen over a period of 1 year to patients with moderate asthma. Double-blind, randomized, parallel group, and placebo-controlled phase (12 weeks) and an open-label phase (54 weeks). Multicenter study in an outpatient setting. Patients (n = 253; age, > or = 12 years) with a mean FEV(1) of 67% predicted normal were stratified according to baseline therapy of maintenance inhaled corticosteroids vs beta(2)-agonists alone. Fluticasone propionate (250 microg bid or 500 microg qd) or placebo (bid) was administered via the Diskus multidose powder inhaler (Glaxo Wellcome; Research Triangle Park, NC) for 12 weeks. During open-label treatment, patients were re-randomized to once-daily or twice-daily fluticasone propionate. Compared to placebo, fluticasone propionate administered qd or bid significantly improved FEV(1) (p < 0.001), morning (p < 0.001) and evening peak expiratory flow (PEF; p < 0.001), asthma symptom scores (p < or = 0.001), and albuterol use (p </= 0.001), and decreased nighttime awakenings. By the end of 12 weeks, withdrawal due to lack of efficacy was significantly higher in the placebo group than in the once-daily (p = 0.001) or twice-daily (p < 0.001) groups. When comparing the two active dosing regimens, significant differences in favor of twice-daily dosing were noted in FEV(1), albuterol use, and withdrawal due to lack of efficacy. During 54 weeks of open-label treatment, FEV(1) and PEF continued to improve with both regimens, and improvements seen in the first 12 weeks were maintained in patients who switched from twice-daily to once-daily dosing. Fluticasone propionate treatment over a 54-week period was well tolerated, with few drug-related adverse events, which were primarily topical effects of inhaled corticosteroids. Fluticasone propionate powder improved lung function when administered either qd or bid over a 1-year period to patients with moderate asthma, with twice-daily dosing demonstrating significantly greater improvement in some efficacy parameters than once-daily dosing over the first 12 weeks of treatment. Fluticasone propionate treatment was not associated with significant systemic effects.


Molecular prognostic prediction for locally advanced nasopharyngeal carcinoma by support vector machine integrated approach.
Accurate prognostication of locally advanced nasopharyngeal carcinoma (NPC) will benefit patients for tailored therapy. Here, we addressed this issue by developing a mathematical algorithm based on support vector machine (SVM) through integrating the expression levels of multi-biomarkers. Ninety-seven locally advanced NPC patients in a randomized controlled trial (RCT), consisting of 48 cases serving as training set and 49 cases as testing set of SVM models, with 5-year follow-up were studied. We designed SVM models by selecting the variables from 38 tissue molecular biomarkers, which represent 6 tumorigenesis signaling pathways, and 3 EBV-related serological biomarkers. We designed 3 SVM models to refine prognosis of NPC with 5-year follow-up. The SVM1 displayed highly predictive sensitivity (sensitivity, specificity were 88.0% and 81.9%, respectively) by integrating the expression of 7 molecular biomarkers. The SVM2 model showed highly predictive specificity (sensitivity, specificity were 84.0% and 94.5%, respectively) by grouping the expression level of 12 molecular biomarkers and 3 EBV-related serological biomarkers. The SVM3 model, constructed by combination SVM1 with SVM2, displayed a high predictive capacity (sensitivity, specificity were 88.0% and 90.3%, respectively). We found that 3 SVM models had strong power in classification of prognosis. Moreover, Cox multivariate regression analysis confirmed these 3 SVM models were all the significant independent prognostic model for overall survival in testing set and overall patients. Our SVM prognostic models designed in the RCT displayed strong power in refining patient prognosis for locally advanced NPC, potentially directing future target therapy against the related signaling pathways.


[Site-specific restriction endonuclease RME211 from Rhizobium meliloti].
A new site-specific restriction endonuclease Rme211 from Rhizobium meliloti has been shown to recognize the following nucleotide sequence 5'-ATCGAT-3' in the double-stranded DNA. Thus, the enzyme is a true isoschizomer for restriction endonucleases Bsu151 and ClaI.


Scaling of bony canals for encephalic vessels in euarchontans: Implications for the role of the vertebral artery and brain metabolism.
Supplying the central nervous system with oxygen and glucose for metabolic activities is a critical function for all animals at physiologic, anatomical, and behavioral levels. A relatively proximate challenge to nourishing the brain is maintaining adequate blood flow. Euarchontans (primates, dermopterans and treeshrews) display a diversity of solutions to this challenge. Although the vertebral artery is a major encephalic vessel, previous research has questioned its importance for irrigating the cerebrum. This presents a puzzling scenario for certain strepsirrhine primates (non-cheirogaleid lemuriforms) that have reduced promontorial branches of the internal carotid artery and no apparent alternative encephalic vascular route except for the vertebral artery. Here, we present results of phylogenetic comparative analyses of data on the cross-sectional area of bony canals that transmit the vertebral artery (transverse foramina). These results show that, across primates (and within major primate subgroups), variation in the transverse foramina helps significantly to explain variation in forebrain mass even when variation in promontorial canal cross-sectional areas are also considered. Furthermore, non-cheirogaleid lemuriforms have larger transverse foramina for their endocranial volume than other euarchontans, suggesting that the vertebral arteries compensate for reduced promontorial artery size. We also find that, among internal carotid-reliant euarchontans, species that are more encephalized tend to have a promontorial canal that is larger relative to the transverse foramina. Tentatively, we consider the correlation between arterial canal diameters (as a proxy for blood flow) and brain metabolic demands. The results of this analysis imply that human investment in brain metabolism (∼27% of basal metabolic rate) may not be exceptional among euarchontans.


Anaphylactic reactions in adult patients in Southern Israel.
Southern Israel is inhabited by Jews and Bedouins. Children from these populations differ in the epidemiology of anaphylactic reactions; however, the effects of ethnicity on the epidemiology of anaphylactic reactions in adults in these populations are unknown. Retrospective review of medical records of patients with anaphylactic reactions treated in a single institution during 2008-2012. A total of 192 evaluable cases of anaphylaxis were recorded; 155 (80.7%) anaphylactic reactions occurred in Jews and 37/192 (19.3%) occurred in Bedouins. A trend towards an older mean age of occurrence of anaphylaxis was recorded in Jewish patients compared with Bedouin patients: 48.1 years versus 41.2, respectively (P = 0.053). Anaphylaxis was more common in Jewish female patients than males and more common in Bedouin male patients than females. Overall, 93/155 (60.0%) females in Jewish patients were affected compared with 14/37 (37.8%) in the Bedouin population (P = 0.015). More Jewish patients had more anaphylaxis attributed to food compared with Bedouin patients: 31/155 (20%) versus 2/37 (5.4%) (P = 0.034). The mean yearly incidence of anaphylaxis was similar in Bedouin and Jewish patients: 12.1 ± 5.3 versus 17.6 ± 15.3, respectively (P = 0.466). However, a significant trend towards a higher incidence of anaphylactic reactions was recorded throughout the study years only in Jewish patients (r = 0.906, P = 0.034). Adult Jewish patients have a significantly higher probability of having anaphylactic reactions due to food compared with Bedouin patients, with females being more affected, and the incidence of anaphylactic reaction is increasing only in the Jewish population. The epidemiology of anaphylactic reactions can differ between populations residing in the same geographical area.


The diagnostic accuracy of straight leg raise test in patients more than 60 years of age suffering lumbar disk herniation with low back pain and sciatica.
To determine the diagnostic accuracy of the SLR test in elderly patients suffering from lumbar disk herniation with sciatica and low back pain, using magnetic resonance imaging (MRI) as the gold standard. A cross-sectional study was conducted at Jinnah Postgraduate Medical Center and a total of 120 patients, above 60 years of age, with symptomatic lumbar disk herniation were enrolled. SLR test was performed and the results recorded. MRI of the lumbar spine was undertaken for confirmation of disk herniation. The sensitivity of the SLR test in patients 60 years and older is 33.3%. A decrease in the diagnostic accuracy of the SLR test with an increment in age was also noted. It was found that with an increment in age, there is a steady decline in the diagnostic accuracy of SLR Test.


Unilateral impairment of leg blood flow in chronic stroke patients.
Previous studies comparing paretic limb blood flow with the unaffected limb have been contradictory and have often omitted comparisons of peak reactive hyperemic flow. Our objective was to perform bilateral measurements of resting and reactive hyperemic blood flow in the lower legs of chronic (>6 months) stroke patients. A secondary purpose was to determine the extent to which any unilateral changes in limb blood flow were a function of decreases in lean tissue mass on the affected side. We hypothesized that the chronic hemiparesis accompanying ischemic stroke creates an altered metabolic environment in the tissues of the affected side that ultimately impairs vasomotor function. The study used a single-visit cross-sectional design. All tests were performed at the Baltimore VA Medical Center. Nineteen chronic hemiparetic stroke patients (15 male, 4 female) who had mild to moderate hemiparetic gait after ischemic stroke were recruited for observation. Bilateral measurements of resting and reactive hyperemic blood flow were made using venous occlusion strain gauge plethysmography. Paired t-tests were used for the between leg comparison. Regression analysis and analysis of covariance were utilized to determine the strength of the relationship between lower leg lean tissue mass and blood flow. Resting and reactive hyperemic blood flows were significantly reduced in the paretic compared with the non-paretic limb (32 and 35%, respectively, p < 0.001). Lean tissue mass was also significantly lower in the affected limb (p < 0.01). However, neither resting nor reactive hyperemic blood flows were significantly correlated with lower leg lean tissue mass by dual energy X-ray absorptiometry. The difference in blood flow between limbs remained after covarying for lean tissue mass. Hemiparesis causes impairments in vasomotor function under both resting and hyperemic conditions that are independent of the muscle atrophy on the affected side.


Transcriptome changes associated with elongation of bovine conceptuses II: differentially expressed transcripts in the endometrium on day 17 after insemination.
The objective was to characterize endometrial transcriptome on d 17 of gestation in dairy cows according to conceptus length. Nonlactating Holstein cows (n = 48) were euthanized 17 d after AI and the uterine horn ipsilateral to the CL was flushed with saline solution. Recovered conceptuses were classified as small (1.2 to 6.9 cm; n = 9), medium (10.5 to 16.0 cm; n = 9), or large (18.0 to 26.4 cm; n = 10). Samples of intercaruncular endometrium dissected from the caudal, intermediate, and cranial portions of the uterine horn ipsilateral to the pregnancy were pooled for analyses. Total mRNA was extracted from endometrial tissue and subjected to transcriptome analyses using the Affymetrix Gene Chip Bovine array. Data were normalized using the GCRMA method and analyzed by robust regression using the Linear Models for Microarray library within Bioconductor in R. Transcripts with P ≤ 0.05 after adjustment for false discovery rate and fold change ≥1.5 were considered differentially expressed. Functional analyses were conducted using the Ingenuity Pathway Analysis platform. Comparisons between endometria of cows carrying large vs. small (LvsS), large vs. medium (LvsM), and medium vs. small (MvsS) conceptuses yielded a total of 235, 21, and 94 differentially expressed transcripts, respectively. Top canonical pathways included the antigen presentation pathway and Th1/Th2 activation pathways, both for LvsS and MvsS. Interferon-α and -γ were identified as activated upstream regulators, primarily based on differently expressed transcripts such as IDO1, ISG20, WARS, LGALS9, IFI44, and PSMB9 (LvsS and MvsS). For LvsS, regulator analyses revealed predicted activation of FOXO1, IFN, NFACTC2, IL-12, IL-6, and IL-18, whereas it depicted inhibition of IL10RA and ZBTB1. Changes in these regulators were associated with a downstream activation of leukocytes, as well as quantity and expansion of T lymphocytes. Canonical pathways associated with the comparison LvsM included cell cycle G2/M DNA damage checkpoint regulation, cell cycle control of chromosomal replication. Moreover, tretinoin was predicted, as activated in upstream analysis for the same comparison. In conclusion, most of the differently expressed transcripts in the endometrium on d 17 of gestation were identified between cows carrying small conceptuses compared with counterparts carrying medium and large conceptuses and were involved with pathways associated with modulation of the immune response.


[Hand bones disorders in vibrational disease caused by local vibration should be considered as pathogenetic characteristic of the disease].
Opposite to the authors of the publication, that dystrophic changes in locomotory apparatus of hands and shoulders girdle could not be considered as vibration disease signs, the article authors believe that hand bone changes--tuberosity of distal finger bones, cystic transparency, local osteoporosis--could be pathogenetic signs of vibration disease, along with vascular and neurologic signs. The authors agree that periarthrosis, miofibrosis, if characterized properly through sanitary and hygienic regulations in new List of Occupational diseases, that will be put into practical medicine in the nearest future, could be considered as second occupational disease in the same patient.


Integration of multiple-whisker inputs in rat somatosensory cortex.
Rats explore their surroundings through rhythmic movement of their mystacial vibrissae. At any given moment, multiple whiskers are simultaneously moved and may contact the surface of an object. The aim of this work is to understand how simultaneous multiple-whisker deflections are processed in the somatosensory cortex. Arrays of 25 electrodes were inserted into the vibrissal representation of barrel cortex of adult rats. Multi-unit responses were recorded during (i) stimulation of single whiskers, and (ii) simultaneous stimulation of two, three or four whiskers of a whisker arc or whisker row. The whole-array response elicited by the simultaneous stimulation of multiple-whiskers (observed response) was compared to a multiple-whisker response predictor, defined as the sum of the whole-array responses to the separate stimulation of the corresponding single whiskers. The observed response to stimulation of four whiskers was nearly always less than the predicted response, indicating a sublinear summation of multiple coincident inputs. Examining the poststimulus time course of sublinearity, we found that the earliest cortical response to whisker deflection - reflecting the thalamocortical volley - was linear, whereas the successive cortical response was highly sublinear. This suggests a cortical origin of the phenomenon.


Effects of organic acids on the formation of the barrier to radial oxygen loss in roots of Hordeum marinum.
A barrier to radial O2 loss (ROL) is an adaptive trait of many wetland plants, yet the signal(s) for barrier induction remain uncertain. We assessed the effects of monocarboxylic acids produced in waterlogged soils (acetic, propionic, N-butyric and caproic acids) on barrier formation in adventitious roots of the waterlogging tolerant Hordeum marinum Huds. These acids were applied in nutrient solution either individually (at 0.4mM) or as a mixture ('cocktail') at various total concentrations (0.1, 0.4 and 2mM) at pH 6. The barrier to ROL was formed in basal zones of roots exposed to the cocktail at 0.4mM, but not at 0.1mM. Individually, only N-butyric and caproic acids invoked a 'tight' barrier in subapical positions of the roots. These organic acids accelerated deposition of suberin in the hypodermis/exodermis, but did not affect overall root porosity (% gas space). The organic acids also reduced root extension rate and tissue K+; effects were more pronounced at higher concentrations of the cocktail and as the molecular weight of the organic acid increased. Moreover, the cocktail at 2mM and caproic acid at 0.4mM alone induced development of intercellular occlusions, suggesting phytotoxin injury. In summary, even relatively low concentrations of organic acids can promote barrier formation in roots, and the potential toxicity of these compounds was demonstrated by declines in root growth and tissue K+ in the wetland species H. marinum.


Universal Access to HIV prevention, treatment and care: assessing the inclusion of human rights in international and national strategic plans.
Rhetorical acknowledgment of the value of human rights for the AIDS response continues, yet practical application of human rights principles to national efforts appears to be increasingly deficient. We assess the ways in which international and national strategic plans and other core documents take into account the commitments made by countries to uphold human rights in their efforts towards achieving Universal Access. Key documents from the Joint United Nations Programme on HIV and AIDS (UNAIDS), the World Health Organization (WHO), the World Bank, the Global Fund to Fight AIDS, TB and Malaria (GFATM) and the US President's Emergency Plan for AIDS Relief (PEPFAR) were reviewed along with 14 national HIV strategic plans chosen for their illustration of the diversity of HIV epidemic patterns, levels of income and geographical location. Whereas human rights concepts overwhelmingly appeared in both international and national strategic documents, their translation into actionable terms or monitoring frameworks was weak, unspecific or absent. Future work should analyse strategic plans, plans of operation, budgets and actual implementation so that full advantage can be taken, not only of the moral and legal value of human rights, but also their instrumental value for achieving Universal Access.


Adaptive motion processing in bilateral vestibular failure.
Patients with bilateral vestibular failure (BVF) suffer from oscillopsia during head movements. This is secondary to the loss of the vestibulo-ocular reflex which is responsible for stabilising retinal images during head movements of high frequency or velocity. Previous studies documented decreased visual motion sensitivity in such patients at low velocities. The authors now examine motion coherence tasks, which have two advantages: (1) the task is associated with the functions of the middle temporal area; and (2) it affords testing at low and high motion velocities, as relevant for patients with oscillopsia due to BVF. Nine BVF patients and nine healthy control subjects were examined with a random dot pattern with variable percentages of dots moving in the target direction. Participants were asked to indicate in which of two possible directions they perceived the coherent motion. Horizontal and vertical planes were tested at speeds from 0.156 to 40°/s. Motion coherence thresholds were lower at higher speeds in both groups (p<0.0001). BVF patients had raised motion coherence thresholds (p=0.002) across all velocities as compared with the control subject group. In a motion coherence paradigm, BVF patients show raised thresholds. This is the first demonstration of diminished visual motion processing at high velocities, supporting the view that the changes allow BVF patients to partly compensate for the oscillopsia. The findings are interpreted as an adaptive process likely to involve the middle temporal visual motion processing areas.


Location and frequency cues in auditory selective attention.
The roles of frequency and location cues in auditory selective attention were investigated in a series of experiments in which target tones were distinguished from distractors by frequency, location, or the conjunction of frequency and location features. When frequency separations in high-rate tone sequences were greater than 1 octave, participants were fastest at identifying targets defined by frequency and were sometimes faster at identifying conjunction than location targets. Frequency salience diminished as filtering demands were reduced: At long interstimulus intervals (> 2.0 s), performance was superior in location conditions. The results suggest that frequency may play a role in auditory selective attention tasks analogous to the role of spatial position in visual attention.


Long-term evaluation of the performance of four point-of-use water filters.
Despite technological advances water supply quality and poor access to safe water remain a major problem in developing countries, especially in rural areas. Point-of-use (POU) water treatment has been shown to be a viable option to produce safe drinking water quality. The aim of this study was to evaluate, under laboratory conditions over 14 months, the performance of four household filtration systems: membrane filter (MF), one-candle ceramic filter (1CCF), two-candle ceramic filter (2CCF) and pot ceramic filter (PCF). The evaluation was made using spiked water having the required concentrations of turbidity, Escherichia coli and Total Dissolved Solids (TDS). The results show that all systems have high removal efficiencies for turbidity (98-99%), and E. coli 4-5 Log Reduction Value (LRV). The poorest efficiency was for TDS (9-18%). The MF and the CCF displayed no significant difference in efficiencies for these parameters. The PCF had less significant differences for turbidity removal than the other systems. The average filtration rate for all systems decreased during the operation time. The CPF showed the major potential to be used in rural communities mainly for its low operational level and maintenance requirements as well as its local craftsmanship. It was observed that the efficiency of the systems is highly sensitive to cleaning and maintenance activities and therefore, the system sustainability will depend considerably on the training and education of the potential users.


Promising significance of the association of miR-204-5p expression with clinicopathological features of hepatocellular carcinoma.
Decreased level of miR-204-5p has been documented in various malignancies. However, the expression and clinical significance of miR-204-5p in hepatocellular carcinoma has not been investigated. The aim of this study is to examine the relationship between miR-204-5p expression and clinicopathological features in hepatocellular carcinoma (HCC) as well as to predict the relevant signaling pathways. The miR-204-5p expression level was detected in HCC and in matched paraneoplastic liver from 95 formalin-fixed paraffin-embedded tissues by the real-time reverse transcription polymerized chain reaction (qRT-PCR). The association of miR-204-5p expression with clinicopathological features as well as the prognosis of HCC was examined. Public data portals including the Gene Expression Omnibus and The Cancer Genome Atlas were used to retrieve the HCC-related data in order to perform a comprehensive meta-analysis. Meanwhile, protein-protein interaction (PPI) and enrichment analyses were performed using predicted target genes. The relative expression of miR-204-5p was remarkably reduced in HCC than that in paraneoplastic hepatic tissues. In HCC, the miR-204-5p expression was downregulated in the metastasis, vasoinvasion, and advanced stage (III and IV) subgroups compared with their counterparts. Furthermore, the meta-analysis based on qRT-PCR data demonstrated that miR-204-5p was markedly downregulated in HCC with a standardized mean difference of -5.19 (P < .001). However, no significant association was observed between miR-204-5p and survival outcomes. The potential target genes of miR-204-5p were significantly enriched in several pathways which might be associated with HCC, such as "cell proliferation" from GO terms and "pathways in cancer" from the KEGG analysis. A PPI network of miR-204-5p potential target genes identified prospective core genes potentially involved in the regulation of HCC oncogenesis and progression. Our findings suggested that miR-204-5p might act as a tumor-suppressive gene in the tumorigenesis and progression of HCC via vital signaling pathways and that miR-204-5p could be regarded as a protective factor in HCC.


[Hypogonadism and chronic obstructive pulmonary disease].
Chronic obstructive pulmonary disease (COPD) is a systemic disease that affects not only the respiratory system. Sex hormones deficiency in men can be correlated with the COPD stages and make a negative contribution during its progression. Up to date, there are no long-term trials evaluating the effects of androgens on the parameters of respiratory function in patients with COPD. Changes of testosterone levels in patients with COPD correlate with forced expiratory volume, and hypoxemia and hypercapnia levels. Glucocorticosteroids exacerbate androgen deficiency in patients with COPD, and the use of hormone replacement therapy with testosterone in these patients is justified. Androgens, in particular drug nebido, testosterone depot, can be effectively used in treatment and rehabilitation of patients with COPD.


How should "ambidexterity" be estimated?
Weak and absent hand preferences have often been associated with developmental disorders or with cognitive functioning in the typical population. The results of different studies in this area, however, are not always coherent. One likely reason for discrepancies in findings is the diversity of cut-offs used to define ambidexterity and mixed right- and mixed left-handedness. Establishing and applying a common criterion would constitute an important step on the way to producing systematically comparable results. We thus decided to try to identify criteria for classifying individuals ambidextrous, mixed right- or left-handed or strong right- or left-handed. For that purpose, we first administered a handedness questionnaire to 716 individuals and performed multiple correspondence analyses to define handedness groups. Twenty-four participants were categorized as ambidextrous (3.3%), as opposed to mixed (29.2%) and strong (56%) right-handers, and to mixed (9.1%) and strong (2.4%) left-handers. We then compared this categorization with laterality index (LI)-based categories using different cut-offs and found that it was most correlated with LI cut-offs at -90, -30, +30 and +90, successively delimiting strong left-handedness, mixed left-handedness, ambidexterity (-30 to +30), mixed right-handedness and strong right-handedness. The characteristics of ambidextrous and lateralized individuals are also compared.


Commensal bacterial modulation of the host immune response to ameliorate pain in a murine model of chronic prostatitis.
The human commensal microflora plays an essential role in modulating the immune response to control homeostasis. Staphylococcus epidermidis, a commensal bacterium most commonly associated with the skin exerts such effects locally, modulating local immune responses during inflammation and preventing superinfection by pathogens such as Staphylococcus aureus. Although the prostate is considered by many to be sterile, multiple investigations have shown that small numbers of gram-positive bacterial species such as S. epidermidis can be isolated from the expressed prostatic secretions of both healthy and diseased men. Chronic pelvic pain syndrome is a complex syndrome with symptoms including pain and lower urinary tract dysfunction. It has an unknown etiology and limited effective treatments but is associated with modulation of prostate immune responses. Chronic pelvic pain syndrome can be modeled using murine experimental prostatitis (EAP), where CD4+ve IL17A+ve T cells have been shown to play a critical role in disease orchestration and development of pelvic tactile allodynia. Here, we report that intraurethral instillation of a specific S. epidermidis strain (designated NPI [non-pain inducing]), isolated from the expressed prostatic secretion of a healthy human male, into EAP-treated mice reduced the pelvic tactile allodynia responses and increased CD4+ve IL17A+ve T-cell numbers associated with EAP. Furthermore, a cell wall constituent of NPI, lipoteichoic acid, specifically recapitulates these effects and mediates increased expression of CTLA4-like ligands PDL1 and PDL2 on prostatic CD11b+ve antigen-presenting cells. These results identify a new potential therapeutic role for commensal S. epidermidis NPI lipoteichoic acid in the treatment of prostatitis-associated pain.


Adapted Fencing for Patients With Invasive Breast Cancer: The RIPOSTE Pilot Randomized Controlled Trial.
Even if indications for mastectomy have been progressively reduced in loco-regional breast cancer (BC) treatment, the harmful effects of surgery are still numerous and can impact physical and psychological wellbeing of women. The RIPOSTE (Reconstruction, self-Image, Posture, Oncology, "Santé"-Health, Therapy, "Escrime"-Fencing) program aimed to propose adapted fencing to patients with BC. This study aims to investigate the effect and conditions of effectiveness of the RIPOSTE program. This is a prospective randomized controlled trial including 24 patients with invasive BC who have just undergone surgery. The study will be proposed to the patient and if interested, the patient will be referred to a sports physician for a medico-sportive evaluation. At the end the evaluation, if the patient meets the inclusion criteria, she will be randomly assigned to one of the 2 groups based on a 1:1 principle: Early RIPOSTE group (receive one fencing session per week for 3 months immediately after their inclusion), Delayed RIPOSTE group (receive one fencing session per week for 3 months but within the 3 months following their inclusion). Patients will be included for 6 months with 3 follow-up times (0, 3, and 6 months) by a sport physician. The primary outcome is the evolution of quality of life score. Secondary outcomes are disability score, fatigue, anxiety-depression, cost-effectiveness and process evaluation. The study protocol has been approved by a French ethics committee (CPP Sud Méditerranée IV, N°ID-RCB: 2020-A01916-33). Results will be submitted for publication, at scientific conferences and through press releases. NCT04627714.


Neonatal morbidity in term neonates is related to gestational age at birth and level of care.
The objective of this study was to assess whether the incidence of neonatal morbidity of neonates born at term and admitted to a neonatal intensive care unit (NICU) differs by gestational age and level of care. This is a 5-year retrospective cohort study of singleton term births admitted to the NICU of the VU University Medical Center with a gestational age ≥37+0 weeks. In total, 497 neonates were included in the study. The incidence of neonates born with an arterial cord blood pH<7.10, neonatal asphyxia, and meconium aspiration syndrome increased with advancing gestational age. The incidence of secondary cesarean section and operative vaginal delivery also increased with advancing gestational age. Neonatal death occurred in 29 (5.84%) of the 497 cases; 27 (93%) of 29 were due to asphyxia. Seventeen (34%) of the 50 neonates born in primary care were admitted for asphyxia. Eight (47%) of these 17 neonates died. Neonatal morbidity in term neonates is related to gestational age at birth. Since asphyxia is an important cause of both morbidity and mortality in term neonates, it is important to clearly define and include asphyxia in future perinatal audits.