Micro-macro analysis of complex networks.
Complex systems have attracted considerable interest because of their wide range of applications, and are often studied via a "classic" approach: study a specific system, find a complex network behind it, and analyze the corresponding properties. This simple methodology has produced a great deal of interesting results, but relies on an often implicit underlying assumption: the level of detail on which the system is observed. However, in many situations, physical or abstract, the level of detail can be one out of many, and might also depend on intrinsic limitations in viewing the data with a different level of abstraction or precision. So, a fundamental question arises: do properties of a network depend on its level of observability, or are they invariant? If there is a dependence, then an apparently correct network modeling could in fact just be a bad approximation of the true behavior of a complex system. In order to answer this question, we propose a novel micro-macro analysis of complex systems that quantitatively describes how the structure of complex networks varies as a function of the detail level. To this extent, we have developed a new telescopic algorithm that abstracts from the local properties of a system and reconstructs the original structure according to a fuzziness level. This way we can study what happens when passing from a fine level of detail ("micro") to a different scale level ("macro"), and analyze the corresponding behavior in this transition, obtaining a deeper spectrum analysis. The obtained results show that many important properties are not universally invariant with respect to the level of detail, but instead strongly depend on the specific level on which a network is observed. Therefore, caution should be taken in every situation where a complex network is considered, if its context allows for different levels of observability.


Generalization of learned preferences covaries with behavioral flexibility in red junglefowl chicks.
The relationship between animal cognition and consistent among-individual behavioral differences (i.e., behavioral types, animal personality, or coping styles), has recently received increased research attention. Focus has mainly been on linking different behavioral types to performance in learning tasks. It has been suggested that behavioral differences could influence also how individuals use previously learnt information to generalize about new stimuli with similar properties. Nonetheless, this has rarely been empirically tested. Here, we therefore explore the possibility that individual variation in generalization is related to variation in behavioral types in red junglefowl chicks (Gallus gallus). We show that more behaviorally flexible chicks have a stronger preference for a novel stimulus that is intermediate between 2 learnt positive stimuli compared to more inflexible chicks. Thus, more flexible and inflexible chicks differ in how they generalize. Further, behavioral flexibility correlates with fearfulness, suggesting a coping style, supporting that variation in generalization is related to variation in behavioral types. How individuals generalize affects decision making and responses to novel situations or objects, and can thus have a broad influence on the life of an individual. Our results add to the growing body of evidence linking cognition to consistent behavioral differences.


Interaction of monoclonal antibodies directed against bromodeoxyuridine with pyrimidine bases, nucleosides, and DNA.
Although antibodies directed against bromodeoxyuridine (BrdU) are being used in both clinical and basic research laboratories as tools to study and monitor DNA synthesis, little is known about the epitopes with which they react. Four monoclonal antibodies directed against BrdU were produced and were characterized to learn more about the epitopes on BrdU which are important for antibody recognition, to identify compounds other than BrdU which react with the antibodies and which might interfere with immunologic assays for BrdU, and to characterize the reaction of these antibodies with BrdU-containing DNA. By radioimmunoassays, the antibodies generally reacted well with 5-iododeoxyuridine, 5-fluorodeoxyuridine, and 5-nitrouracil. However, none of the antibodies reacted well with uridine--indicating that a substituent on uridine C5 was essential for antibody reactivity--or with 5-bromo- or iodo-cytosine, indicating that the region around pyrimidine C4 is important for antibody recognition. Although the antibodies reacted with 5-halogen-substituted uracil bases, the antibodies reacted much better with the corresponding halogenated nucleosides, indicating that the sugar moiety was important for recognition. The presence of a triphosphate group on C'5 of BrdU (i.e., BrdUTP) did not detectably alter antibody recognition. Three of the antibodies reacted only with purified DNA containing BrdU, whereas one antibody, which exhibited a weak interaction with thymidine, also reacted with BrdU-free DNA. S1 nuclease treatment of purified DNA suggested that all four monoclonal antibodies reacted exclusively with single-stranded regions of BrdU-containing DNA. Comparison of detecting DNA synthesis by [3H]TdR incorporation followed by autoradiography with that by BrdU incorporation followed by indirect immunofluorescence indicated that the latter technique was both an accurate and a sensitive measure of DNA synthesis.


[Histogenesis of stomach cancer].
A conclusion on histogenetic unity of various structural variants of carcinoma of the stomach is drawn from the analysis of the data from literature and the own observations referring to light and electron microscopy and histochemistry of precancer alterations of the gastric mucosa and carcinoma of the stomach as well as the clinical pattern and prognosis of carcinoma of the stomach depending on the morphological structure of the tumour. All the variety of morphological and functional properties of tumours depends on the level and direction of differentiation of carcinoma cells.


Genetic variation in 5-hydroxytryptamine transporter expression causes adaptive changes in 5-HT₄ receptor levels.
Genetic variation in 5-HT transporter (5-HTT) expression is a key risk factor for psychiatric disorder and has been linked to changes in the expression of certain 5-HT receptor subtypes. This study investigated the effect of variation in 5-HTT expression on 5-HT₄ receptor levels in both 5-HTT knockout (KO) and overexpressing (OE) mice using autoradiography with the selective 5-HT₄ receptor radioligand, [³H]SB207145. Compared to wild-type (5-HTT⁺/⁺) controls, homozygous 5-HTT KO mice (5-HTT⁻/⁻) had reduced 5-HT₄ receptor binding site density in all brain regions examined (35-65% of 5-HTT⁺/⁺). In contrast, the density of 5-HT₄ receptor binding sites was not significantly different between heterozygous 5-HTT KO mice (5-HTT⁻/⁺) and 5-HTT⁺/⁺ mice. The 5-HT synthesis inhibitor p-chlorophenylalanine (250 mg/kg twice daily for 3 d) abolished the difference in 5-HT₄ binding between 5-HTT⁻/⁻ and 5-HTT⁺/⁺ mice in all brain regions. Compared to wild-type (WT) littermate controls, 5-HTT OE mice had increased 5-HT₄ binding density across all brain regions, except amygdala (118-164% of WT) and this difference between genotypes was reduced by the 5-HTT inhibitor, fluoxetine (20 mg/kg twice daily, 3 d). Together, these findings suggest that variation in 5-HTT expression causes adaptive changes in 5-HT₄ receptor levels which are directly linked to alterations in 5-HT availability.


Intensity Modulated Exoskeleton Gait Training Post Stroke.
Stroke is a leading cause of long-term disability. While major advances have been made in early intervention for the treatment of patients post stroke, the majority of survivors have residual mobility challenges. Recovery of motor function is dependent on the interrelationship between dosing, intensity, and task specific practice applied during rehabilitation. Robotic exoskeleton (RE) based gait training utilizes progressive repetitive task-oriented movements to promote functional recovery. The purpose of this investigation was to demonstrate the utilization of intensity modulated exoskeleton gait training on functional outcomes and walking speed post stoke. Preliminary data is presented for individuals diagnosed with stroke who received RE gait training. The intensity modulated RE gait training was delivered by a physical therapist and participants trained at 75-85% of calculated max heart rates at each session, over 10 weeks (30 sessions). After 10 weeks of training participants increased walking speed (10 meter walk test) and functional measures (timed up and go, berg balance assessment, dynamic gait index and functional ambulation category). These preliminary results demonstrate the utilization of intensity modulated gait training for improved functional ambulation and motor recovery using a robotic exoskeleton overground gait training post stroke.Clinical Relevance- Preliminary data provides initial evidence for intensity modulated exoskeleton gait training as a therapeutic intervention post stroke. More research is needed to demonstrate the potential relationships between intensity based gait training, exoskeletons and improved functional ambulation in post stroke rehabilitation.


SERS spectroscopy as a tool for the study of thiopurine drug pharmacokinetics in a model of human B leukemia cells.
Thiopurine drugs are immunomodulatory antimetabolites relevant for pediatric patients characterized by dose-dependent adverse effects such as myelosuppression and hepatotoxicity, often related to inter-individual differences, involving the activity of important enzymes at the basis of their biotransformation, such as thiopurine S-methyltransferase (TPMT). Surface Enhanced Raman Scattering (SERS) spectroscopy is emerging as a bioanalytical tool and represents a valid alternative in terms of affordable costs, shorter analysis time and easier sample preparation in comparison to the most employed methods for pharmacokinetic analysis of drugs. The aim of this study is to investigate mercaptopurine and thioguanine pharmacokinetics by SERS in cell lysates of a B-lymphoblastoid cell line (NALM-6), that did (TPMT*1) or did not (MOCK) overexpress the wild-type form of TPMT as an in vitro cellular lymphocyte model to discriminate between cells with different levels of TPMT activity on the base of the amount of thioguanosine nucleotides (TGN) metabolites formed. SERS analysis of the cell lysates was carried out using SERS substrates constituted by Ag nanoparticles deposited on paper and parallel samples were used for quantification of thiopurine nucleotides with liquid chromatography-tandem mass spectrometry (LC-MS/MS). A direct SERS detection method has been set up that could be a tool to study thiopurine drug pharmacokinetics in in vitro cellular models to qualitatively discriminate between cells that do and do not overexpress the TPMT enzyme, as an alternative to other more laborious techniques. Results underlined decreased levels of TGN and increased levels of methylated metabolites when TPMT was overexpressed, both after mercaptopurine and thioguanine treatments. A strong positive correlation (Spearman's rank correlation coefficient rho = 0.96) exists between absolute quantification of TGMP (pmol/1 x 106 cells), obtained by LC-MS/MS, and SERS signal (intensity of TGN at 915 cm-1). In future studies, we aim to apply this method to investigate TPMT activity in pediatric patients' leukocytes.


Surgery for aortic valve endocarditis: treatment options for aortic abscess.
Patients with infective endocarditis show a large diversity of anatomical presentations, which has been a complicating factor for the surgical treatment of this condition, especially in those who develop abscesses in the aortic ring or intracardiac fistulae. For this reason, surgeons have been developing tactical options to repair it. There is consensus around the fact that the removal of infected tissue promotes radical cleaning, and that the outcome of the treatment has been improved by the manufacture of biological glues which facilitate the closure of abscesses and by the creation of new valve replacements. To demonstrate yet one more treatment option for aortic abscess for selected cases: a valved conduit placed in infra-coronary position. We employed the technique in three patients: in two of them we employed a valved conduit with a mechanical prosthesis and in one of them a valved conduit with a biological prosthesis. Two patients needed associated procedures such as replacement of mitral valve in one of them and tricuspid valvoplasty in the other. All cases involved reoperation of prostheses in aortic position. The progression during surgery and in the early postoperative period was satisfactory and the three patients were discharged from the Intensive Care Unit and were sent to hospital rooms. One of the patients progressed to death during hospital stay due to severe comorbidities which were present in the preoperative period, and which related to esophageal varices and hepatic involvement. The other two progressed well in the late postoperative period. We believe that this option is yet one more alternative for the treatment of abscesses with great involvement of aortic ring structures and mitro-aortic continuity.


[Residual histoplasmosis of the lung and bronchopulmonary lymph nodes in autopsies carried out in Uberaba, MG].
Lungs and broncho-pulmonary lymph nodes were studied from 127 sequential adult autopsies done in Uberaba, MG, Brazil through the years 1992 and 1993. Calcified lung nodules and/or calcified lymph nodes were found in 39 (30.7%) cases. For 27 (69.2%) out of those 39 autopsies, fungi morphologically compatible with Histoplasma capsulatum were found within those calcified structures. Fite-Faraco stain for acid-fast bacilli was negative for all cases. It is concluded that the majority of calcified pulmonary nodes and calcified regional lymph nodes found at autopsies in Uberaba are related to infection with H. capsulatum. These findings raise the possibility for this fungal disease to be endemic in Uberaba. Such information might be relevant to the diagnosis of this systemic mycosis.


Organization of the visual cortex: comparative anatomical and behavioral studies.
In all mammals there are two parallel visual pathways ascending to the cortex: the geniculostriate system and the tectopulvinar system. However, there is a difference among mammals in the locus and extent of the cortical target of the tectopulvinar path. In several diverse species such as squirrel and tree shrew the cortical target of the tectopulvinar system lies adjacent to area 17 and extends into the temporal lobe; but areas 18 and 19 do not receive fibers from the tectorecipient zone of the pulvinar in Galago and presumably in all primates. This anatomical difference may account for the drastic sensory effect of removing area 17 in primates, and the failure to find marked sensory changes in tree shrews or squirrels deprived of the geniculostriate system.


[Frail nephropathic patients: maximum conservative therapy or dialysis? Results from a retrospective observational study].
Background and objectives: Chronic dialysis in frail nephropathic patients can worsen the symptom load and their functional autonomy, increasing the risk of early mortality. It is key to evaluate if dialysis treatment represents a real advantage for these patients; Maximum Conservative Therapy (MCT) associated with palliative care, could improve their residual quality of life, avoiding dialysis. The aim of this work is to describe the application and the relative terms of MCT in a complete series of cases followed in our Nephrological Clinic. Study design and setting: This is a retrospective observational study on a cohort of 48 frail nephropathic patients in MCT and 58 on dialysis, in the period between January 2013 and December 2019. The place of death, Incidence Rate (IR) and Incidence Rate Ratio (IRR) related to survival and hospitalization rates were studied. Results: The average duration of MCT was 9.7 months vs 13.5 months of dialysis treatment. One-year probability of survival of dialysis patient was 0.52 [CI 0.38-0.64] vs 0.48 [CI 0.33-0.62] in MCT patients; however, dialysis patients had higher rates of hospitalization (IR 2.780 vs 1.269 in MCT patients), IRR 2.19 [CI 1.66-2.89], according to literature [13]. 67% of dialysis patients died in hospital versus 35% of MCT patients. 34% of MCT patients are still alive at the time of data analysis (January 31, 2020); no dialysis patients are still alive on the same date. Conclusions: The use of dialysis has shown a marginal, even though significant, effect on the average survival of frail nephropathic patients; however, they present a higher hospitalization rate, with consequent impact on the quality of life. The choice of the treatment (MCT vs dialysis) should not be merely based on the presence of comorbidities, but rather on the type of comorbidity found, which represents each time an element in favor of MCT or dialysis.


Interventions for treating intrahepatic cholestasis in people with sickle cell disease.
Sickle cell disease is the most common hemoglobinopathy occurring worldwide and sickle cell intrahepatic cholestasis is a complication long recognized in this population. Cholestatic liver diseases are characterized by impaired formation or excretion (or both) of bile from the liver. There is a need to assess the clinical benefits and harms of the interventions used to treat intrahepatic cholestasis in people with sickle cell disease. This is an update of a previously published Cochrane Review. To assess the benefits and harms of the interventions for treating intrahepatic cholestasis in people with sickle cell disease. We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also searched the LILACS database (1982 to 23 May 2017), the WHO International Clinical Trials Registry Platform Search Portal (23 May 2017) and ClinicalTrials.gov.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 12 April 2017. We searched for published or unpublished randomised controlled trials. Each author intended to independently extract data and assess the risk of bias of the trials by standard Cochrane methodologies; however, no trials were included in the review. There were no randomised controlled trials identified. This updated Cochrane Review did not identify any randomised controlled trials assessing interventions for treating intrahepatic cholestasis in people with sickle cell disease. Randomised controlled trials are needed to establish the optimum treatment for this condition.


Strengthening the service experiences of women impacted by gambling-related intimate partner violence.
While problem gambling does not directly cause intimate partner violence (IPV), it exacerbates that violence significantly. Women experiencing both gambling harm and IPV often find themselves in challenging situations; furthermore, stigma and shame frequently act as barriers to seeking help from health and social service agencies. Despite the links between problem gambling and IPV, little is known about women's experiences of using support services for both IPV and gambling related issues. This paper explores positive experiences of help-seeking for gambling-related IPV in Australia by adopting a strengths-based research approach. Qualitative, unstructured interviews were conducted for a larger study exploring the nature of the relationship between problem gambling and IPV. To gain new insights into the service experiences of women impacted by gambling related IPV, interviews with 48 women with lived experience of IPV relating to a male partner's gambling, and 24 women with lived experience of IPV relating to their own gambling were reanalysed using thematic analysis. Three themes emerged from the data signifying or demonstrating strength-based responses: 'Commitment to Integrated and Collaborative Responses'; 'Therapeutic Support'; and 'Instrumental Support'. The themes highlight the importance of recognising the intersectionality of gambling related IPV and supporting the person 'at the centre of the service'. Tangible and instrumental supports, such as emergency accommodation and financial assistance, were also central to the recovery process. Effective service responses are dependent on understanding how problem gambling and IPV intersect. Importantly, service providers must recognise and address the many facets of each woman's situation and the shame associated with resolving interdependent and complex issues. Responding to the needs of women impacted by gambling related IPV requires both individual-level awareness and organisational support; recommendations to strengthen service provision are provided.


Coherence of Light Passing Through a Nematic Liquid Crystal Under a dc Electric Field.
A study of spatial coherence properties of light passing through a nematic liquid-crystal (MBBA) cell is given as a function of the external dc electric field applied to the cell and of initial molecular orientation and light polarization. Two different interferometric dispositions have been used. The molecular motion induced by the electric field is also studied.


Femtosecond Electronic and Hydrogen Structural Dynamics in Ammonia Imaged with Ultrafast Electron Diffraction.
Directly imaging structural dynamics involving hydrogen atoms by ultrafast diffraction methods is complicated by their low scattering cross sections. Here we demonstrate that megaelectronvolt ultrafast electron diffraction is sufficiently sensitive to follow hydrogen dynamics in isolated molecules. In a study of the photodissociation of gas phase ammonia, we simultaneously observe signatures of the nuclear and corresponding electronic structure changes resulting from the dissociation dynamics in the time-dependent diffraction. Both assignments are confirmed by ab initio simulations of the photochemical dynamics and the resulting diffraction observable. While the temporal resolution of the experiment is insufficient to resolve the dissociation in time, our results represent an important step towards the observation of proton dynamics in real space and time.


Cost-Utility Analysis of Oxybutynin vs. OnabotulinumtoxinA (Botox) in the Treatment of Overactive Bladder Syndrome.
Background: The UK National Health Service (NHS) propose the use of oxybutynin prior to onabotulinumtoxinA (Botox) in the management of overactive bladder syndrome (OAB). Oxybutynin is costly and associated with poor adherence, which may not occur with Botox. We conducted a cost-utility analysis (CUA) to compare the medications. Methods: we compared the two treatments in quality-adjusted life years (QALYS), through the NHS's perspective. Costs were obtained from UK-based sources and were discounted. Total costs were determined by adding the treatment cost and management cost for complications on each branch. A 12-month time frame was used to model the data into a decision tree. Results: Our results found that using Botox first-line had greater cost utility than oxybutynin. The health net benefit calculation showed an increase in 0.22 QALYs when Botox was used first-line. Botox also had greater cost-effectiveness, with the exception of pediatric patients with an ICER of £42,272.14, which is above the NICE threshold of £30,000. Conclusion: Botox was found to be more cost-effective than antimuscarinics in the management of OAB in adults, however less cost-effective in younger patients. This predicates the need for further research to ascertain the age at which Botox becomes cost-effective in the management of OAB.


Recessive DES cardio/myopathy without myofibrillar aggregates: intronic splice variant silences one allele leaving only missense L190P-desmin.
We establish autosomal recessive DES variants p.(Leu190Pro) and a deep intronic splice variant causing inclusion of a frameshift-inducing artificial exon/intronic fragment, as the likely cause of myopathy with cardiac involvement in female siblings. Both sisters presented in their twenties with slowly progressive limb girdle weakness, severe systolic dysfunction, and progressive, severe respiratory weakness. Desmin is an intermediate filament protein typically associated with autosomal dominant myofibrillar myopathy with cardiac involvement. However a few rare cases of autosomal recessive desminopathy are reported. In this family, a paternal missense p.(Leu190Pro) variant was viewed unlikely to be causative of autosomal dominant desminopathy, as the father and brothers carrying this variant were clinically unaffected. Clinical fit with a DES-related myopathy encouraged closer scrutiny of all DES variants, identifying a maternal deep intronic variant within intron-7, predicted to create a cryptic splice site, which segregated with disease. RNA sequencing and studies of muscle cDNA confirmed the deep intronic variant caused aberrant splicing of an artificial exon/intronic fragment into maternal DES mRNA transcripts, encoding a premature termination codon, and potently activating nonsense-mediate decay (92% paternal DES transcripts, 8% maternal). Western blot showed 60-75% reduction in desmin levels, likely comprised only of missense p.(Leu190Pro) desmin. Biopsy showed fibre size variation with increased central nuclei. Electron microscopy showed extensive myofibrillar disarray, duplication of the basal lamina, but no inclusions or aggregates. This study expands the phenotypic spectrum of recessive DES cardio/myopathy, and emphasizes the continuing importance of muscle biopsy for functional genomics pursuit of 'tricky' variants in neuromuscular conditions.


Maternal diet-induced obesity during pregnancy alters lipid supply to mouse E18.5 fetuses and changes the cardiac tissue lipidome in a sex-dependent manner.
Maternal obesity during pregnancy has immediate and long-term detrimental effects on the offspring heart. In this study, we characterized the cardiac and circulatory lipid profiles in late gestation E18.5 fetuses of diet-induced obese pregnant mice and established the changes in lipid abundance and fetal cardiac transcriptomics. We used untargeted and targeted lipidomics and transcriptomics to define changes in the serum and cardiac lipid composition and fatty acid metabolism in male and female fetuses. From these analyses we observed: (1) maternal obesity affects the maternal and fetal serum lipidome distinctly; (2) female fetal heart lipidomes are more sensitive to maternal obesity than males; (3) changes in lipid supply might contribute to early expression of lipolytic genes in mouse hearts exposed to maternal obesity. These results highlight the existence of sexually dimorphic responses of the fetal heart to the same in utero obesogenic environment and identify lipids species that might mediate programming of cardiovascular health.


Precipitation effects on nematode diversity and carbon footprint across grasslands.
Free-living nematodes are one of the most diverse metazoan taxa in terrestrial ecosystems and are critical to the global soil carbon (C) cycling through their role in organic matter decomposition. They are highly dependent on water availability for movement, feeding, and reproduction. Projected changes in precipitation across temporal and spatial scales will affect free-living nematodes and their contribution to C cycling with unforeseen consequences. We experimentally reduced and increased growing season precipitation for 2 years in 120 field plots at arid, semiarid, and mesic grasslands and assessed precipitation controls on nematode genus diversity, community structure, and C footprint. Increasing annual precipitation reduced nematode diversity and evenness over time at all sites, but the mechanism behind these temporal responses differed for dry and moist grasslands. In arid and semiarid sites, there was a loss of drought-adapted rare taxa with increasing precipitation, whereas in mesic conditions increases in the population of predaceous taxa with increasing precipitation may have caused the observed reductions in dominant colonizer taxa and yielded the negative precipitation-diversity relationship. The effects of temporal changes in precipitation on all aspects of the nematode C footprint (respiration, production, and biomass C) were all dependent on the site (significant spatial × temporal precipitation interaction) and consistent with diversity responses at mesic, but not at arid and semiarid, grasslands. These results suggest that free-living nematode biodiversity and their C footprint will respond to climate change-driven shifts in water availability and that more frequent extreme wet years may accelerate decomposition and C turnover in semiarid and arid grasslands.


Child mortality inequalities and socioeconomic determinants of health in Iran, 2016-2018.
Measuring health inequalities is essential to inform policy making and for monitoring implementation to reduce avoidable and unfair differences in health status. We conducted a geospatial analysis of child mortality in Iran using death records from the Ministry of Health and Medical Education from 2016 to 2018 stratified by sex, age, province, and district, and household expenditure and income survey data from the Statistical Center of Iran collected in 2017. We applied multilevel mixed-effect models and detected significant inequality in child mortality and the impact of socioeconomic factors, especially household income. We advocate for using mortality rate for young children (< 5 years old) as an indicator for assessing the impact of interventions to reduce inequalities among various socioeconomic groups. We also recommend to design and implement comprehensive and longitudinal data collection systems for accurate, regular, and specific monitoring of health inequalities.


Arterial plasma histamine levels at rest, and during and after exercise in patients with asthma: effects of terbutaline aerosol.
Eight asthmatic patients and two normal subjects performed two identical exercise tests 140 minutes apart (first test preceded by inhalation of saline and the second by terbutaline sulphate). A ninth asthmatic patient exercised twice after placebo 40 minutes apart. Arterial plasma levels of histamine and cyclic AMP, expiratory flow rates and volumes were measured at rest and during and after exercise. After the first test the mean +/- SEM fall in PEFR was 45.2 +/- 2.6%. In five asthmatics there was an increase in plasma histamine (mean +/- SEM 14.8 +/- 3.3 pmol ml-1) coinciding with exercise-induced asthma (EIA). Histamine levels returned to pre-exercise values within 30 minutes. After terbutaline these five patients had histamine levels greater than those observed before, during, or after the first test. This effect may have been the result of changes in pulmonary microcirculation. After the second test the levels decreased indicating no further release of histamine in response to exercise. No EIA occurred in these patients after terbutaline. The other patients and the two normal subjects had little or no change in histamine throughout the study. The one patient in whom exercise was repeated after placebo demonstrated less histamine release and less EIA after the second test.


Consequences of altered oncogene expression in rodent cells.
By using linkage to transcriptional enhancers to increase gene expression, it was shown that the introduction of the mutant Ha-ras gene from bladder carcinoma cells into primary cultures of Chinese and Syrian hamster cells, and Wistar rat cells, was sufficient to trigger malignant conversion. The normal Ha-ras gene when linked to enhancers did not trigger malignant conversion but gave rise to cell clones with extended growth capacity. We measured the levels of transforming growth factors (TGFs) released from cells containing the ras genes, and the availability of the receptor for epidermal growth factor (EGF) to which alpha-TGF also binds. The level of ras gene expression seemed to correlate with the level of TGF secreted, a reduction in available EGF receptors and the morphology of the transformed cells. However, when an immortalized cell line (rat 208F cells) was used as a recipient for the oncogene vectors a different result was obtained. TGF release was triggered to varying degrees by almost all of the ras and myc oncogene constructions tested, regardless of the level of gene expression. Enhanced expression of the two oncogenes led to increased anchorage-independence. Significantly, both normal ras and normal myc, when linked to transcriptional enhancers, caused the recipient cells to become tumorigeneic without inducing any marked morphological alterations in culture. Enhanced and constitutive expression of the mutant Ha-ras gene resulted in the recipient cells becoming tumorigeneic and the cells displayed a transformed phenotype in culture. The transfected fibroblasts with a markedly transformed phenotype displayed a relative paucity of EGF receptors which correlated with release of alpha-TGF, suggesting a down-regulation of EGF receptors on transformation. While enhanced expression of the normal Ha-ras gene did result in a decrease in EGF receptors on these transfectants, in contrast, the transfectants with enhanced expression of the c-myc and v-myc oncogenes did not display any significant changes in available EGF receptors although the cells were tumorigenic when tested in the nude mouse. These results are discussed in relation to a hypothesis implicating a role for oncogenes at various stages in the multi-stage process of carcinogenesis.


Human corneal endothelial cell expansion for corneal endothelium transplantation: an overview.
The monolayer of cells forming the human corneal endothelium is critical to the maintenance of corneal transparency and is not known to regenerate in vivo. Thus, dysfunction of these cells constitutes the most often cited reasons for the 150,000 or so corneal transplants performed yearly. Although current corneal transplantation is more than 90% successful at 1 year, longer term results are not as encouraging with approximately 70% success at 5 years. Nonimmunologic graft failure and allograft endothelial rejection are the main problems. Furthermore, the global shortage of donor corneas greatly restricts several corneal transplantations performed. With advances in understanding corneal endothelial cell biology, it is now possible to cultivate human corneal endothelial cells (HCECs) in vitro, thus providing new opportunities to develop novel tissue-engineered human corneal endothelium. This review will provide an overview of (a) the characteristics of human corneal endothelium; (b) past and present HCECs isolation and culture protocols; (c) various potential carriers for the generation of tissue-engineered corneal endothelium, together with some of the functional studies reported in various animal models; and (d) the current rapid advancements in surgical techniques for keratoplasty. A successful combination of tissue-engineered human corneal endothelium coupled with innovative and groundbreaking surgical procedures will bridge basic research involving cultured HCECs, bringing it from bench to bedside.


The perceived risks of e-cigarettes to others and during pregnancy.
Public Health England has concluded that e-cigarettes are much safer than cigarettes for the user and for secondhand exposures, but it has not reached a definitive conclusion regarding pregnancy risks. How people perceive the risks to others is less well understood. This study uses an online UK sample of 1041 adults to examine perceived e-cigarette risks to others and during pregnancy. The survey examines relative risk beliefs of e-cigarettes compared to cigarettes and the percentage reduction in harm provided by e-cigarettes. A majority of the sample believes that secondhand exposure to e-cigarette vapors poses less risk than secondhand smoke from cigarettes, but almost two-fifths of the sample equate the secondhand risks from e-cigarettes to those from cigarettes. There is somewhat greater perception of e-cigarette risks during pregnancy compared to beliefs regarding secondhand risks of vaping. About two-fifths of the population believe that e-cigarettes are less risky than cigarettes during pregnancy. Respondents believe that e-cigarettes reduce the harm to others by 39% and the harm to babies by 36%. There is a general sense that e-cigarettes pose less risk than cigarettes, but there is a need for further risk communication regarding comparative e-cigarette risks.


Independent effects of age-related changes in waist circumference and BMI z scores in predicting cardiovascular disease risk factors in a prospective cohort of adolescent females.
Cross-sectional data indicate that central adiposity is associated with cardiovascular disease risk, independent of total adiposity. The use of longitudinal data to investigate the relation between changes in fat distribution and the emergence of risk factors is limited. We tested the hypothesis that age-related change in waist circumference (to reflect central adiposity) during adolescence is a significant predictor of longitudinal change in cardiovascular disease risk, after adjustment for change in body mass index (BMI) z score (to reflect total adiposity) in a cohort of postmenarcheal adolescent females. We also tested whether race modified this relation. We analyzed publicly available data from the National Heart, Lung, and Blood Institute Growth and Health Study. Longitudinal regression models were fitted to investigate the independent effects of changes in waist circumference on cardiovascular disease risk factors. Steeper age-related increases in waist circumference over time were associated with a greater increase in LDL-cholesterol concentrations, systolic blood pressure, diastolic blood pressure, and homeostasis model assessment of insulin resistance, after adjustment for BMI z score, in white but not in black females. Change in waist circumference was not a statistically significant predictor of age-related changes in HDL-cholesterol, triglyceride, insulin, and glucose concentrations, after adjustment for changes in BMI z score, in either white or black females. Our research suggests that monitoring waist circumference in addition to BMI z score has the potential to identify adolescents at risk of the emergence of cardiovascular disease risk factors, at least in white females. The data also suggest that race may modify the relation between fat distribution pattern and cardiovascular disease risk factors.


[Results of operative treatment of osteochondrosis dissecans of the knee joint in juveniles].
This paper reports about the check-up of 33 juvenile and 28 adult patients who were operated on because of osteochondrosis dissecans of the knee. The average period of observation was 4.7 years. According to the aspects of age and the stage of the disease the results were compared to each other. The age of the patient at the moment of operation has doubtless the greatest influence on the prognosis. Juveniles operated in stage 2 or 3 have a particularly good prognosis. From stage 4 on it does not seem reasonable to try to preserve the dissecate. In the case of juveniles metabolic or endocrinological diseases do not appear to be of any relevance whereas mechanical factors like overstress at sports, hereditary ligament laxity or deviations of axis of whatever origin seem to be of larger import.


Can breast cancer be stopped? Modifiable risk factors of breast cancer among women with a prior benign or premalignant lesion.
Physical inactivity, high postmenopausal body mass index, alcohol consumption and use of menopausal hormone therapy are established risk factors for breast cancer. Less is known about whether these factors influence the risk of progression of benign and premalignant breast lesions to invasive breast cancer. This registry-based cohort study was based on women with a precancerous lesion who were followed for breast cancer. The cohort consisted of 11 270 women with a benign lesion, 972 women with hyperplasia with atypia and 2379 women with carcinoma in situ diagnosed and treated after participation in BreastScreen Norway, 2006-2016. Information on breast cancer risk factors was collected by a questionnaire administered with the invitation letter. Cox regression analysis was used to estimate the association between breast cancer and physical activity, body mass index, alcohol consumption, tobacco smoking and menopausal hormone therapy, adjusted for age. During follow-up, 274 women with a benign lesion, 34 women with hyperplasia with atypia and 118 women with carcinoma in situ were diagnosed with invasive breast cancer. We observed an increased risk of breast cancer associated with use of menopausal hormone therapy for women with a benign or premalignant lesion. Alcohol consumption and tobacco smoking showed suggestive increased risk of breast cancer among women with a benign lesion. We were only to a limited degree able to identify associations between modifiable risk factors of breast cancer and the disease among women with a precancerous lesion, and a larger study is needed to confirm or refute associations.


Multiple genotypes of nonpathogenic H6N2 influenza viruses isolated from chickens in California.
From February 2000 through September 2001, a limited number of H6N2 influenza viruses were isolated from chickens in California. This report describes the genetic characterization of nine of these H6N2 viruses. All of the viruses analyzed had phylogenetically similar hemagglutinin (HA) and neuraminidase molecules that suggested the viruses shared a recent common ancestor. The analysis of the HA sequence of these viruses with all available H6 viruses from different hosts and locations showed that these genes do not separate into well-defined North American and Eurasian lineages. The neuraminidase genes of the California viruses contain an 18 amino acid deletion, a possible adaptation to growth in chickens. Analysis of the remaining gene segments of the California viruses revealed that three distinct genotypes of H6N2 viruses were present.


Stress-induced enhancement of cell-mediated immunity.
We have demonstrated that acute stress induces a large-magnitude, rapid, and reversible redistribution of leukocytes from the blood to other compartments within the body. These changes in leukocyte distribution are mediated by adrenal stress hormones. Because the skin is one of the target organs of a stress-induced redistribution of leukocyes, we hypothesized that such a leukocyte redistribution could be one of the factors by which acute stress may enhance cutaneous immune function. This hypothesis was tested by examining the effects of acute stress on cutaneous delayed-type hypersensitivity (DTH). DTH reactions are antigen-specific, cell-mediated immune responses that, depending on the antigen involved, mediate beneficial (resistance to viruses, bacteria, and fungi) or harmful (allergic dermatitis, autoimmunity) aspects of immune function. DTH was induced by challenging the pinnae of previously sensitized rats with 2,4-dinitro-1-fluorobenzene (DNFB). Experiments showed that acute stress administered immediately before the introduction of an antigenic challenge significantly enhances a cutaneous DTH response. In contrast, chronic stress suppresses cutaneous DTH. These results demonstrate a bidirectional relationship between stress and immune function, such that acute stress enhances, while chronic stress suppresses, an important class of immune responses in vivo. They also suggest that stress-induced alterations in lymphocyte redeployment within the body may play an important role in mediating these bidirectional effects of stress on cell-mediated immunity.


Study on driver's active emergency response in dangerous traffic scenes based on driving simulator.
A driver's active emergency response in dangerous traffic scenes consists of two parts, including reaction behavior and physiological state. In dangerous traffic scenes, the driver's active emergency response has an important impact on human collision injury. Clarifying the driver's active emergency response is an important prerequisite for the study of human collision injury under nonstandard posture. Therefore, this study investigates the driver's active emergency response in different inevitable collision scenes using driving simulator. A driving simulator with a high-speed camera system and human physiological signal acquisition system was first built. Then, three typical vehicle dangerous collision scenes were developed, including frontal collision, side collision, and rear-end collision. Finally, twenty participants (15 males and 5 females) were recruited for a driving experiment, and their active emergency responses were recorded and analyzed. All subjects would rotate the steering wheel to the left or right in the active emergency state, and the rotation of the hand would also cause the subject's upper body to tilt in the same direction. The maximum angle for male subjects to rotate the steering wheel was 59.98°, while for the female subjects, it was 44.28°. In addition, the maximum grip force between the male subjects and the steering wheel was 280.5 N, compared to 192.5 N for female subjects. Compared to the female participants, the male participants not only have a greater rotation angle and a greater grip force on the steering wheel, but also have greater pressure on the brake pedal, and the foot moves quickly from the accelerator pedal to the brake pedal and presses the brake pedal. Drivers have different active emergency responses to different vehicle collision scenes. Quantitative statistics of driver's active emergency response will have important guiding significance for the analysis of the impact of human active emergency response on human injury characteristics in subsequent vehicle collision experiments.


Botrytis cinerea: the cause of grey mould disease.
Botrytis cinerea (teleomorph: Botryotinia fuckeliana) is an airborne plant pathogen with a necrotrophic lifestyle attacking over 200 crop hosts worldwide. Although there are fungicides for its control, many classes of fungicides have failed due to its genetic plasticity. It has become an important model for molecular study of necrotrophic fungi. Kingdom: Fungi, phylum: Ascomycota, subphylum: Pezizomycotina, class: Leotiomycetes, order: Helotiales, family: Sclerotiniaceae, genus: Botryotinia. Over 200 mainly dicotyledonous plant species, including important protein, oil, fibre and horticultural crops, are affected in temperate and subtropical regions. It can cause soft rotting of all aerial plant parts, and rotting of vegetables, fruits and flowers post-harvest to produce prolific grey conidiophores and (macro)conidia typical of the disease. B. cinerea produces a range of cell-wall-degrading enzymes, toxins and other low-molecular-weight compounds such as oxalic acid. New evidence suggests that the pathogen triggers the host to induce programmed cell death as an attack strategy. Resistance: There are few examples of robust genetic host resistance, but recent work has identified quantitative trait loci in tomato that offer new approaches for stable polygenic resistance in future. http://www.phi-base.org/query.php, http://www.broad.mit.edu/annotation/genome/botrytis_cinerea/Home.html, http://urgi.versailles.inra.fr/projects/Botrytis/, http://cogeme.ex.ac.uk.


Predicting Response to Vedolizumab in Inflammatory Bowel Disease.
Vedolizumab is known to be safe, well-tolerated, and effective. However, as personalization becomes an increasingly important aspect of IBD care and in lieu of guidelines to inform clinicians on positioning of biologics, there is a need to reliably predict response to inform patient preferences and shared decision-making. Recent data from clinical trials and real-world evidence have elucidated predictors of clinical and endoscopic response while providing the framework to establish predictive models. Current models are able to predict that those patients with less severe disease, without prior biologic exposure and who demonstrate early response to VDZ have the highest rates of durable clinical and endoscopic response and remission. When incorporating these models into clinical practice, clinicians will be able to identify those patients who are likely to respond before drug initiation as well as early non-responders and response latency after initiation of vedolizumab. In a shift toward personalization of medicine in IBD, the ability of predictive models for vedolizumab to aid pre-biologic and early management will inform both clinician and patient. Ideally this will provide both a personalized and more cost-effective approach, though further studies in cost-analysis in this framework are needed. Though current models are comprehensive of existing data, future research on microbial and translational biomarkers will be additive and necessary to provide full personalization of treatment.


Collagenase-3 (matrix metalloproteinase-13) expression is induced in oral mucosal epithelium during chronic inflammation.
Increased proliferation of mucosal epithelium during inflammation is associated with degradation of subepithelial connective tissue matrix and local invasion of the epithelial cells. Here we have studied, whether collagenase-3 (MMP-13), a collagenolytic matrix metalloproteinase with an exceptionally wide substrate specificity, is expressed in the epithelium of chronically inflamed mucosa. Examination of human gingival tissue sections from subjects with chronic adult periodontitis with in situ hybridization revealed marked expression of MMP-13 in basal cells of some epithelial rete ridges expanding into connective tissue. Immunohistochemical staining demonstrated that these cells also expressed strongly laminin-5, suggesting that they are actively migrating cells. A strong signal for MMP-13 mRNA was occasionally also noted in the suprabasal epithelial cells facing the gingival pocket, whereas no collagenase-1 (MMP-1) mRNA was detected in any areas of the epithelium. MMP-13 expression was also detected in fibroblast-like cells associated with collagen fibers of the inflamed subepithelial connective tissue. In organ culture of human oral mucosa, MMP-13 mRNA expression was observed in epithelial cells growing into connective tissue of the specimens. Regulation of MMP-13 expression was examined in cultured normal nonkeratinizing epithelial cells isolated from porcine periodontal ligament. In these cells, MMP-13 expression at the mRNA and protein level was potently enhanced (up to sixfold) by tumor necrosis factor-alpha, transforming growth factor-beta(1), and transforming growth factor-alpha and by keratinocyte growth factor in the presence of heparin. In addition, plating periodontal ligament epithelial cells on type I collagen stimulated MMP-13 expression (sevenfold) as compared with cells grown on tissue culture plastic. The results of this study show, that expression of MMP-13 is specifically induced in undifferentiated epithelial cells during chronic inflammation due to exposure to cytokines and collagen. Thus, it is likely that MMP-13 expression is instrumental in the subepithelial collagenolysis and local invasion of the activated mucosal epithelium into the connective tissue.


A comparison of excess deaths by UK country and region during the first year of the COVID-19 pandemic.
We compare the impact of the first two waves of the COVID-19 pandemic on risk of age-standardized mortality by sex, UK country, and English region. Each wave is defined as lasting 26 weeks and are consecutive beginning in 2020 week 11. The expected rate is estimated from 2015 to 2019 mean and the projected mortality trend from the same period are used to estimate excess mortality. By both measures, excess mortality was highest and lowest in regions of England, London and the South-West, respectively. Excess mortality was consistently higher for males than females.


Ficolin-2 inhibits hepatitis C virus infection, whereas apolipoprotein E3 mediates viral immune escape.
Human ficolin-2 (L-ficolin/p35) is a lectin-complement pathway activator that is present in normal human plasma and is associated with infectious diseases; however, little is known regarding the roles and mechanisms of ficolin-2 during chronic hepatitis C virus (HCV) infection. In this study, we found that ficolin-2 inhibits the entry of HCV at an early stage of viral infection, regardless of the viral genotype. Ficolin-2 neutralized and inhibited the initial attachment and infection of HCV by binding to the HCV envelope surface glycoproteins E1 and E2, blocking HCV attachment to low-density lipoprotein receptor (LDLR) and scavenger receptor B1, and weakly interfering with CD81 receptor attachment. However, no interference with claudin-1 and occludin receptor attachment was observed. The C-terminal fibrinogen domain (201-313 aa) of ficolin-2 was identified as the critical binding region for the HCV-E1-E2 N-glycans, playing a critical role in the anti-HCV activity. More importantly, we found that apolipoprotein E (ApoE)3, which is enriched in the low-density fractions of HCV RNA-containing particles, promotes HCV infection and inhibits ficolin-2-mediated antiviral activity. ApoE3, but not ApoE2 and ApoE4, blocked the interaction between ficolin-2 and HCV-E2. Our data suggest that the HCV entry inhibitor ficolin-2 is a novel and promising antiviral innate immune molecule, whereas ApoE3 blocks the effect of ficolin-2 and mediates an immune escape mechanism during chronic HCV infection. HCV may be neutralized using compounds directed against the lipoprotein moiety of the viral particle, and ApoE3 may be a new target to combat HCV infection.


DNA sequences downstream of the adenovirus type 2 fiber polyadenylation site contain transcription termination signals.
The major late transcription unit of adenovirus type 2 (Ad2) terminates in a region near the end of the linear DNA genome at map units 98.2 to 100. Specific 3' ends mapping in the transcription termination region were detected in nuclear but not cytoplasmic RNA isolated at 16 to 18 h postinfection. Using S1 nuclease protection analysis, a major nuclear RNA species with a 3' terminus at map unit 98.9 was detected. With the use of recombinant expression vectors and run-on transcription in isolated nuclei, we demonstrated that the Ad2 sequences from map units 97.1 to 100, inserted into either the 5' or 3' untranslated sequences of the chloramphenicol acetyltransferase gene (cat), terminated transcription in transfected cells. Termination occurred only when the 97.1- to 100-map-unit sequence was in the same direction of transcription as the major late transcript and was not observed with Ad2 sequences upstream of map unit 97.1.


[Obstructive sialoadenitis: update of diagnosis and therapy issues].
In head and neck district, major salivary gland diseases seem to have a considerable epidemiological and clinical impact, especially in obstructive disease. Major salivary glands, in fact, having a ductal system can develop several diseases: sialoadenitis, sialodochitis and sialoceles. Particularly, the obstructive sialoadenitis, with or without sialolithiasis, are the most frequent inflammatory disorder, especially for submandibular gland. In the clinical practice, the diagnostic approach for obstructive sialoadenitis up to now consisted of traditional Rx, ultrasonographic technique, scintigraphy technique, C.T., sialography technique with contrast or sialography M.R. Since '90 years, lithotripsy and, later, sialendoscopy have been introduced as gold standard diagnostic procedures in case of obstructive sialoadenitis and also as therapeutic tool when possible. In this way, it has been possible to offer a valid alternative in place of traditional surgical techniques, with a less invasive and more efficacious approach.


Gangliosides alter morphology and growth of astrocytes and increase the activity of choline acetyltransferase in cultures of dissociated septal cells.
Administration of gangliosides has been reported to stimulate regeneration of motoneurons and of central dopaminergic and cholinergic neurons. To shed light on the mechanism by which gangliosides mediate the effects on cholinergic neurons, we studied their actions on cultures of cells dissociated from the septal area of fetal rat brains. These cultures contain cholinergic neurons, which, in vivo, give rise to the cholinergic septo-hippocampal pathway. Gangliosides produced prominent changes in the morphological appearance of the cultures. In contrast to control cultures, which contained many process-bearing cells and a confluent layer of flat cells, there were no flat cells in cultures grown in the presence of gangliosides (0.2 to 0.8 mg/ml of medium). Using immunocytochemical visualization of the astrocytic marker glial fibrillary acid protein, it was shown that all astrocytes in cultures grown in the presence of gangliosides exhibited the morphology of process-bearing cells, whereas in control cultures astrocytes represented the majority of the flat cells. Furthermore, gangliosides attenuated astrocytic proliferation. The effects of gangliosides apparently were not mediated by cAMP, since they could be differentiated from actions of forskolin, an activator of adenylate cyclase. Astrocytic growth and morphology were affected by ganglioside mixtures of various sources and composition and also by the pure gangliosides GM1 and GD1a, whereas lipid and carbohydrate components of gangliosides were ineffective. In contrast to the prominent effects on astrocytes, gangliosides failed to significantly alter survival or fiber growth of cholinergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)


CD4+ T cells from IRF-1-deficient mice exhibit altered patterns of cytokine expression and cell subset homeostasis.
Interferon regulatory factor-1 (IRF-1) is a member of a family of transcription factors that regulate an array of genes involved in cell growth, differentiation, and death. Analysis of cytokine expression by stimulated CD4+ cells from IRF-1(-/-) and IRF-1(+/+) mice revealed that IRF-1 deficiency resulted in an elevated production of Th2-related cytokines and a compensatory decrease in the expression of naive cell- and Th1-related cytokines. The altered cytokine profiles of IRF-1(-/-) cells could be explained, in part, by a shift in the representation of subsets of CD4+ cells; IRF-1(-/-) mice exhibited a decreased percentage of naive cells (a major source of IL-2) but increased numbers of memory or effector cells (the source of Th2-related cytokines). We analyzed purified, phenotypically matched memory/effector cells from IRF-1(-/-) and IRF-1(+/+) mice and found that the increased Th2:Th1 cytokine ratio was still evident in the IRF-1(-/-) group, thus suggesting that IRF-1 is involved in the polarization of the cytokine repertoire in CD4+ cells. Our data indicate that IRF-1 plays an important role in the maintenance of CD4+ cell subset homeostasis and in the expression of cytokines by naive and memory/effector cells.


Investigation of population structure in Gulf of Mexico Seepiophila jonesi (Polychaeta, Siboglinidae) using cross-amplified microsatellite loci.
Vestimentiferan tubeworms are some of the most recognizable fauna found at deep-sea cold seeps, isolated environments where hydrocarbon rich fluids fuel biological communities. Several studies have investigated tubeworm population structure; however, much is still unknown about larval dispersal patterns at Gulf of Mexico (GoM) seeps. As such, researchers have applied microsatellite markers as a measure for documenting the transport of vestimentiferan individuals. In the present study, we investigate the utility of microsatellites to be cross-amplified within the escarpiid clade of seep vestimentiferans, by determining if loci originally developed for Escarpia spp. could be amplified in the GoM seep tubeworm, Seepiophila jonesi. Additionally, we determine if cross-amplified loci can reliably uncover the same signatures of high gene flow seen in a previous investigation of S. jonesi. Seventy-seven S. jonesi individuals were collected from eight seep sites across the upper Louisiana slope (<1,000 m) in the GoM. Forty-eight microsatellite loci that were originally developed for Escarpia laminata (18 loci) and Escarpia southwardae (30 loci) were tested to determine if they were homologous and polymorphic in S. jonesi. Loci found to be both polymorphic and of high quality were used to test for significant population structuring in S. jonesi. Microsatellite pre-screening identified 13 (27%) of the Escarpia loci were homologous and polymorphic in S. jonesi, revealing that microsatellites can be amplified within the escarpiid clade of vestimentiferans. Our findings uncovered low levels of heterozygosity and a lack of genetic differentiation amongst S. jonesi from various sites and regions, in line with previous investigations that employed species-specific polymorphic loci on S. jonesi individuals retrieved from both the same and different seep sites. The lack of genetic structure identified from these populations supports the presence of significant gene flow via larval dispersal in mixed oceanic currents. The ability to develop "universal" microsatellites reduces the costs associated with these analyses and allows researchers to track and investigate a wider array of taxa, which is particularly useful for organisms living at inaccessible locations such as the deep sea. Our study highlights that non-species specific microsatellites can be amplified across large evolutionary distances and still yield similar findings as species-specific loci. Further, these results show that S. jonesi collected from various localities in the GoM represents a single panmictic population, suggesting that dispersal of lecithotrophic larvae by deep sea currents is sufficient to homogenize populations. These data are consistent with the high levels of gene flow seen in Escarpia spp., which advocates that differences in microhabitats of seep localities lead to variation in biogeography of separate species.


Design and Optimization of a Cell-Free Atrazine Biosensor.
Recent advances in cell-free synthetic biology have spurred the development of in vitro molecular diagnostics that serve as effective alternatives to whole-cell biosensors. However, cell-free sensors for detecting manmade organic water contaminants such as pesticides are sparse, partially because few characterized natural biological sensors can directly detect such pollutants. Here, we present a platform for the cell-free detection of one critical water contaminant, atrazine, by combining a previously characterized cyanuric acid biosensor with a reconstituted atrazine-to-cyanuric acid metabolic pathway composed of several protein-enriched bacterial extracts mixed in a one pot reaction. Our cell-free sensor detects atrazine within an hour of incubation at an activation ratio superior to previously reported whole-cell atrazine sensors. We also show that the response characteristics of the atrazine sensor can be tuned by manipulating the ratios of enriched extracts in the cell-free reaction mixture. Our approach of utilizing multiple metabolic steps, encoded in protein-enriched cell-free extracts, to convert a target of interest into a molecule that can be sensed by a transcription factor is modular. Our work thus serves as an effective proof-of-concept for a scheme of "metabolic biosensing", which should enable rapid, field-deployable detection of complex organic water contaminants.


Evaluation of a new formulation of fenofibric acid, ABT-335, co-administered with statins : study design and rationale of a phase III clinical programme.
Atherogenic lipid parameters in patients with mixed dyslipidaemia have been demonstrated to increase atherosclerotic coronary heart disease (CHD) risk. Clinical studies have shown that HMG-CoA reductase inhibitor (statin) and fibric acid derivative (fibrate) combination therapy is effective at improving multiple lipid abnormalities in different patient populations at increased risk of CHD. However, inconsistencies with respect to trial designs and safety issues have limited the clinical use of this combination therapy. A comprehensive, controlled clinical trial programme was thus designed to evaluate three separate statins in combination with ABT-335, a new formulation of fenofibric acid. Three separate 22-week, phase III, double-blind, active-controlled trials will evaluate combination therapy with ABT-335 135 mg/day and either rosuvastatin (10 mg/day and 20 mg/day), atorvastatin (20 mg/day and 40 mg/day) or simvastatin (20 mg/day and 40 mg/day) in comparison to either ABT-335 or the corresponding statin monotherapy. An approximate total of 2400 patients with elevated triglycerides (TG) [> or =150 mg/dL], reduced high-density lipoprotein cholesterol (HDL-C) [<40 mg/dL for men and <50 mg/dL for women], and elevated low-density lipoprotein cholesterol (LDL-C) [> or =130 mg/dL] will be randomized to one of six intervention arms per trial (two combination therapy and four monotherapy groups). The pre-specified primary efficacy endpoint is a composite of the mean percent changes in HDL-C and TG (comparing each combination therapy with the corresponding statin monotherapy dose) and LDL-C (comparing each combination therapy with ABT-335 monotherapy). Secondary endpoints include mean percent changes in non-HDL-C, very LDL-C, total cholesterol, apolipoprotein B and high sensitivity C-reactive protein levels. At study end, patients may enroll in a 12-month open-label extension study that will evaluate the long-term efficacy and safety of combination therapy. This is the largest phase III randomized, controlled clinical programme to date evaluating the efficacy and safety of the combined use of a new formulation of fenofibric acid (ABT-335) with three commonly prescribed statins in patients with mixed dyslipidaemia.


Classifying California's stream thermal regimes for cold-water conservation.
Stream temperature science and management is rapidly shifting from single-metric driven approaches to multi-metric, thermal regime characterizations of streamscapes. Given considerable investments in recovery of cold-water fisheries (e.g., Pacific salmon and other declining native species), understanding where cold water is likely to persist, and how cold-water thermal regimes vary, is critical for conservation. California's unique position at the southern end of cold-water ecosystems in the northern hemisphere, variable geography and hydrology, and extensive flow regulation requires a systematic approach to thermal regime classification. We used publicly available, long-term (> 8 years) stream temperature data from 77 sites across California to model their thermal regimes, calculate three temperature metrics, and use the metrics to classify each regime with an agglomerative nesting algorithm. Then, we assessed the variation in each class and considered underlying physical or anthropogenic factors that could explain differences between classes. Finally, we considered how different classes might fit existing criteria for cool- or cold-water thermal regimes, and how those differences complicate efforts to manage stream temperature through regulation. Our results demonstrate that cool- and cold-water thermal regimes vary spatially across California. Several salient findings emerge from this study. Groundwater-dominated streams are a ubiquitous, but as yet, poorly explored class of thermal regimes. Further, flow regulation below dams imposes serial discontinuities, including artificial thermal regimes on downstream ecosystems. Finally, and contrary to what is often assumed, California reservoirs do not contain sufficient cold-water storage to replicate desirable, reach-scale thermal regimes. While barriers to cold-water conservation are considerable and the trajectory of cold-water species towards extinction is dire, protecting reaches that demonstrate resilience to climate warming remains worthwhile.


[Expert consensus of the French society of geriatrics and gerontology and the French society of cardiology on the management of atrial fibrillation in elderly people].
The prevalence of atrial fibrillation (AF) increase with ageing. In France AF affects between 400,000 to 660,000 people aged 75 years or more. In the elderly, AF is a major risk factor of stroke and a predictive factor for mortality. Comorbidities are frequent and worsen the prognosis of AF. They can be the cause or the consequence of AF and their management is a major therapeutic objective. Comprehensive geriatric assessment (CGA), is required to analyse both medical and psychosocial elements, and to identify co-morbidities and geriatrics syndrome as cognitive disorders, risk of falls, malnutrition, mood disorders, and lack of dependency and social isolation. The objectives of AF treatment in the elderly are to prevent AF complications, particularly stroke, and to improve quality of life. Specific precautions for treatment must be taken because of the co-morbidities and age-related changes in pharmacokinetics or pharmacodynamics. Preventing AF complications relies mainly on anticoagulant therapy. Anticoagulants are recommended in patients with AF aged ≥ 75 years after assessing the bleeding risk using Hemorr2hages or HAS-BLED scores. Novel oral anticoagulants (NOACs) are promising treatments especially due to a lower risk of intracerebral haemorrhage. However, their prescriptions should take into account renal function (creatinine clearance assessed with Cockcroft formula) and cognitive function (for adherence to treatment). Studies including very old patients with several comorbidities in 'real life' are necessary to evaluate tolerance of NOACs in this population. The management of AF also involves the treatment of underlying cardiomyopathy and heart rate control rather than rhythm control strategy as first-line therapy in the elderly.


Sleep Efficiency Modulates Associations Between Family Stress and Adolescent Depressive Symptoms and Negative Affect.
The goal of this study was to determine whether sleep moderates the associations between family-related stress and depressive symptoms and negative affect outcomes during adolescence. We combined traditional survey measures of stress and depressive symptoms with daily assessments of stress and negative affect to examine whether sleep differentially impacts the link between chronic and acute experiences of stress and affect. Participants were 316 adolescents from ethnically diverse backgrounds. Primary caregivers and adolescents reported on stressful family events during the past 12 and 3 months, respectively. Adolescents also reported on their daily experiences of family demands for 15 days and wore actigraph watches for the assessment of sleep during the first eight nights. Regression analyses revealed that more stressful family events were related to more depressive symptoms. This relation was stronger among adolescents with lower sleep efficiency. The same pattern emerged for the relation between daily family demands and negative affect aggregated across the 15 days. Daily-level analyses indicated that daily negative affect was related to daily family demands when sleep efficiency was higher than usual, but only among European American adolescents. These findings suggest that chronic experiences of lower sleep efficiency, but not sleep duration, may render adolescents more vulnerable to the negative effects of family stress on emotional adjustment. A more complex picture emerged for the role of prior night's sleep in the day-to-day variation in negative affect reactivity to family stress.


Efficacy, cost-utility and reach of an eHealth self-management application 'Oncokompas' that helps cancer survivors to obtain optimal supportive care: study protocol for a randomised controlled trial.
Cancer survivors have to deal with a wide range of physical symptoms, psychological, social and existential concerns, and lifestyle issues related to cancer and its treatment. Therefore, it is essential that they have access to optimal supportive care services. The eHealth self-management application Oncokompas was developed to support cancer survivors with where they need to turn to for advice and guidance, as well as to increase their knowledge on the availability of optimal support. A randomised controlled trial will be conducted to assess the efficacy, cost-utility and reach of Oncokompas as an eHealth self-management application compared with care as usual among cancer survivors. Adult cancer survivors diagnosed with breast, colorectal or head and neck cancer or lymphoma who are at 3 months to 5 years since curative treatment will be included. In total, 544 cancer survivors will be randomly assigned to the intervention group or a wait-list control group. The primary outcome measure is patient activation. Secondary outcome measures include self-efficacy, personal control, perceived patient-physician interaction, need for supportive care, mental adjustment to cancer and health-related quality of life. Furthermore, cost-utility outcomes will be assessed. Reach is defined as the percentage of cancer survivors who get access to Oncokompas within the context of this trial. Questionnaires will be administered at baseline, post-intervention and at 3- and 6-month follow-up. In this study, we will evaluate the efficacy and cost-utility of Oncokompas among cancer survivors, as well as the reach of Oncokompas. These are essential first steps in the translation of research into practice and contribute to sustainable adoption, implementation and maintenance of an evidence-based Oncokompas. Netherlands Trial Register identifier: NTR5774 . Registered on 8 March 2016.


[Detection of patients with respiratory tuberculosis in high-risk groups ar general polyclinic].
The paper presents the results of elucidation of numerous tuberculosis risk factors. Eight most significant criteria were selected by using the multifactorial analysis. They were used to develop an algorithm for selecting patients in risk groups at the polyclinic. Follow-ups of these groups of patients were shown to enhance the detection rate of tuberculosis, thus greatly reducing material expenditures.


Evaluation of neonatal verbal autopsy using physician review versus algorithm-based cause-of-death assignment in rural Nepal.
Verbal autopsy (VA) is used to ascertain cause-specific neonatal mortality using parental/familial recall. We sought to compare agreement between causes of death obtained from the VA by physician review vs. computer-based algorithms. Data were drawn from a cluster-randomised trial involving 4130 live-born infants and 167 neonatal deaths in the rural Sarlahi District of Nepal. We examined the agreement between causes ascertained by physician review and algorithm assignment by the kappa (kappa) statistic. We also compared responses to identical questions posed posthumously during neonatal VA interviews with those obtained during maternal interviews and clinical examinations regarding condition of newborns soon after birth. Physician reviewers assigned prematurity or acute lower respiratory infection (ALRI) as causes of 48% of neonatal deaths; 41% were assigned as uncertain. The algorithm approach assigned sepsis (52%), ALRI (31%), birth asphyxia (29%), and prematurity (24%) as the most common causes of neonatal death. Physician review and algorithm assignment of causes of death showed high kappa for prematurity (0.73), diarrhoea (0.81) and ALRI (0.68), but was low for congenital malformation (0.44), birth asphyxia (0.17) and sepsis (0.00). Sensitivity and specificity of VA interview questions varied by symptom, with positive predictive values ranging from 50% to 100%, when compared with maternal interviews and examinations of neonates soon after birth. Analysis of the VA data by physician review and computer-based algorithms yielded disparate results for some causes but not for others. We recommend an analysis technique that combines both methods, and further validation studies to improve performance of the VA for assigning causes of neonatal death.


Uterine papillary serous carcinoma: epidemiology, pathogenesis and management.
Uterine papillary serous carcinoma (UPSC) is a rare but aggressive subtype of endometrial cancer. Although it represents only 10% of all endometrial cancer cases, UPSC accounts for up to 40% of all endometrial cancer-related recurrences and subsequent deaths. The present article reviews the literature concerning the epidemiology, molecular pathogenesis and recent updates on management of UPSC. Women most often present with postmenopausal vaginal bleeding but may also be diagnosed by vaginal cytology. In women diagnosed with metastatic disease, ascites, omental implants or a pelvic mass may be present. Pelvic and extrapelvic recurrences occur frequently, with extrapelvic relapses being observed most commonly. Although few prospective trials exist, several retrospective series have demonstrated that optimal cytoreduction and adjuvant platinum/taxane-based chemotherapy with or without radiotherapy appears to improve survival. In addition, another approach to UPSC management may lie in targeted therapy. Women diagnosed with UPSC should undergo comprehensive surgical staging and an attempt at optimal cytoreduction. Platinum/taxane-based adjuvant chemotherapy should be considered in the treatment of both early and advanced-stage patients. Careful long-term surveillance is indicated as many of these women will recur. Prospective studies are needed to define the optimal treatment regimens and to study the role of targeted therapies in UPSC.


A Dry Method for Preserving Tear Protein Samples.
Tears covering the ocular surface are important biofluids containing thousands of molecules, including proteins, lipids, metabolites, nucleic acids, and electrolytes. Tears are valuable resources for biomarker research of ocular and even systemic diseases. For application in biomarker studies, tear samples should ideally be stored using a simple, lowcost, and efficient method along with the patient's medical records. For this purpose, we developed a novel Schirmer's strip-based dry method that allows for storage of tear samples in vacuum bags at room temperature. Using this method, tear protein patterns can also be preserved. Liquid chromatography-mass spectrometry/mass spectrometry analysis of proteins recovered by the dry method and traditional wet method showed no significant difference. Some tissue/organ-enriched proteins were identified in tear samples, thus tears might be a good window for monitoring changes of these tissues or organs. This dry method facilitates sample transportation and enables the storage of tear samples on a large scale, increasing the availability of samples for studying disease biomarkers in tears.


Seroprevalence of Dengue and Zika Virus in Blood Donations: A Systematic Review.
The presence of antibodies to Zika virus (ZIKV) and dengue virus (DENV) can be detected in blood donations. Donation-based surveillance provides an alternative strategy to estimate population prevalence by detecting antibodies that are circulating. To estimate population prevalence, we conducted a systematic review of literature on the seroprevalence of ZIKV and DENV antibodies in blood donations. We searched PubMed and Web of Science for studies that reported the seroprevalence of ZIKV and DENV in blood donations. The title and abstract of each study were screened by 2 reviewers simultaneously for possible inclusion, and the full text of selected studies was reviewed to ensure that they met inclusion criteria (used primary data collection, reported evidence of immunoglobulin M (IgM) or immunoglobulin G (IgG) antibodies in the blood supply, and included a representative sample of the total population). Immunoglobin test measuring levels of antibodies to IgM and IgG and number of positive cases were extracted from each study. No exclusions were made based on language or country. Our initial search identified 1890 studies after excluding duplicates, of which 76 were assessed for full text eligibility to ensure that they met our final inclusion criteria. There were 14 studies included in our review; 11 examined the seroprevalence of DENV, and 3 examined ZIKV. The highest seroprevalence by IgM was 2.82% for DENV and 0.53% for ZIKV. Our results indicate that the seroprevalence of ZIKV and DENV antibody presence in countries with active transmission is higher than reports by traditional surveillance in some countries. This finding is expected due to the large percentage of asymptomatic cases. The highest seroprevalence was observed for IgG, which can persist over long periods of time compared to IgM. Screening of blood donations may help supplement traditional surveillance measures, especially during outbreak settings.


A serological marker of the N-terminal neoepitope generated during LOXL2 maturation is elevated in patients with cancer or idiopathic pulmonary fibrosis.
Lysyl oxidase like 2 (LOXL2) is associated with poor prognosis in idiopathic pulmonary disease (IPF) and cancer. We developed an Enzyme-linked immunosorbent assay (ELISA) targeting the LOXL2 neo-epitope generated through the release of the signal peptide during LOXL2 maturation. An ELISA targeting the N-terminal site of the human LOXL2 was developed including technical optimization and validation steps. Serum LOXL2 was measured in patients with breast, colorectal, lung, ovarian, pancreatic and prostate cancer, melanoma, IPF and in healthy controls (n = 16). A technically robust and specific assay was developed. LOXL2 was detectable in serum from healthy controls and showed reactivity towards recombinant LOXL2. Compared to controls, LOXL2 levels were significantly (p < 0.001-0.05) elevated in serum from patients with breast, colerectal, lung, ovarian and pancreatic cancer (mean range: 49-84 ng/mL), but not in prostate cancer (mean: 36 ng/mL) and malignant melanoma patients (41 ng/mL). Serum LOXL2 was elevated in IPF patients compared to healthy controls (mean: 76.5 vs 46.8 ng/mL; p > 0.001). A specific ELISA towards the N-terminal neo-epitope site in LOXL2 was developed which detected significantly elevated serum levels from patients with above-mentioned cancer types or IPF compared to healthy controls.


[Development and evaluation of fertilizers cemented and coated with organic-inorganic materials].
Four kinds of organic-inorganic cementing and coating materials were prepared by a coating method using water as the solvent, and the corresponding cemented and coated fertilizers (B2, PS, F2, and F2F) were produced by disc pelletizer. The tests on the properties of these fertilizers showed that the granulation rate, compression strength, and film-forming rate were B2 > PS > F2 > F2F. Soil column leaching experiment showed that the curve of accumulated nitrogen-dissolving rate was the gentlest for B2. In 48 days, the accumulated nitrogen-dissolving rate was in the order of B2, 54.65% < PS, 56.16% < F2, 59.47%, < F2F, 63.12%. Field experiment showed that compared with the same application amount of NPK, all the test fertilizers had better effects on corn yield, among which, B2 was the best, with the corn yield and fertilizer use efficiency increased by 19.72% and 20.30%, respectively. The yield-increasing effect of other test fertilizers was in the order of PS > F2 > F2F.


Appraisal of suicidal risk among adolescents and young adults through the Rorschach test.
The aims of this study are to investigate suicidal behaviors among adolescents and young adults and to test an index composed using Rorschach test responses related to an increased risk of suicide. Using a cross-sectional design, 4 groups were studied (according to criteria of the Columbia Classification Algorithm of Suicide Assessment [Posner, Oquendo, Gould, Stanley, & Davies, 2007]): A group with suicidal ideation (n = 30), a group with parasuicidal behavior (n = 30), a group with near-lethal suicide attempts (n = 26), and a control group (n = 30). Responses to the Rorschach test yielded 6 potential indicators of suicidal behavior (scored according to Exner's Comprehensive System and the Suicidal Index for Adolescents; Silberg & Armstrong, 1992 ). Rorschach scores including at least 4 of these 6 indicators selected 69% of the people who had committed serious suicide attempts. The Rorschach Suicidal Index reached an acceptable reliability and was related to other criteria of suicide risk, such as the Beck Depression Inventory (BDI; Beck, Ward, Mendelsohn, Mock, & Erbaugh, 1961) and Linehan Reasons for Living Inventory (RFL-I; Linehan, Goodstein, Nielsen, & Chiles, 1983). Moreover, the Rorschach Suicidal Index showed incremental validity over the BDI and the RFL-I to predict suicidal behavior. A path analysis additionally showed that low social support was an important mediator between the Rorschach Suicidal Index and the number of suicide attempts committed by participants.


[A non-specific veterinarian].
John Akkermans, who became 65 on july 4th, 1991, started his veterinary career on december 1st, 1952. He contributed in many ways to veterinary science. In the Netherlands many diseases were diagnosed by him for the first time. He had the ability to arouse the interest of many for his findings by writing papers as the sole author. But by stimulating his co-workers even more papers were published of which he was co-author and not always the first one. He was obviously able to follow the developments in veterinary science and animal husbandry without any problems and to create openings when the profession was confronted by problems. He was often involved in diseases of pigs but also in furred animals and ruminants. He was not a specialist in a single species of animal or in a single professional area, but in several fields. Not a specialist, but a more specific veterinarian in the sense that he is unique.


Thermal reactivity of rapeseed (Brassica napus L.) under different gas atmospheres.
Non-isothermal thermogravimetric method was applied to rapeseed to investigate its thermal reactivity under both individual dynamic atmospheres of nitrogen, steam, carbon dioxide and dry air, and under several mixtures of these gases (nitrogen+steam), (steam+dry air), and (nitrogen+carbon dioxide+steam). In this method, the sample was heated from ambient to 1273 K with a constant heating rate of 20 K/min. The trend of the TGA curves and the derived DTG profiles were interpreted regarding the conversion yields and the reactivity of the samples. Conversion yields of biomass to gaseous products changed in the range of 75-94% on original basis, with respect to the atmosphere under which the experiment was carried out. The maximum rates of the mass losses from the sample were found between 2.6 and 4.3 mg/min. The activation energies were calculated using the method of Coats-Redfern, and varied between 21.3 and 96.0 kJ/mol.


Novel preharvest strategies involving the use of experimental chlorate preparations and nitro-based compounds to prevent colonization of food-producing animals by foodborne pathogens.
Foodborne diseases caused by enterohemorrhagic Escherichia coli, Salmonella, and Campylobacter species are of public health and economic significance. Shedding of these pathogens during production and slaughter are risks for contamination of products for human consumption. Consequently, strategies are sought to prevent or reduce the carriage of these pathogens in food animals before slaughter. Experimental products containing chlorate salts have been proven efficacious in reducing concentrations of E. coli and Salmonella Typhimurium in the gut of cattle, sheep, swine, and poultry when administered as feed or water additives. Mechanistically, chlorate selectively targets bacteria expressing respiratory nitrate reductase activity, such as most members of the family Enterobacteriaceae, as this enzyme catalyzes the reduction of chlorate to lethal chlorite. Most beneficial gut bacteria lack respiratory nitrate reductase activity, and thus the technology appears compatible with many bacteria exhibiting competitive exclusion capabilities. More recently, select nitrocompounds have been investigated as potential feed additives, and although these nitrocompounds significantly reduce pathogens on their own, evidence indicates that they may most effectively be used to complement the bactericidal activity of chlorate. A particularly attractive aspect of the nitrocompound technology is that, as potent inhibitors of ruminal methanogenesis, they may allow producers the opportunity to recoup costs associated with their use. At present, neither chlorate nor the nitrocompounds have been approved as feed additives by the US Food and Drug Administration, and consequently they are not yet available for commercial use.


Milk-derived ribonuclease 5 preparations induce myogenic differentiation in vitro and muscle growth in vivo.
Ribonuclease 5, also known as angiogenin, is a stable and abundant ribonuclease in milk whey protein, which is able to regulate several cellular functions, including capillary formation, neuron survival, and epithelial cell growth. Ribonuclease 5 is important for protein synthesis directly stimulating rRNA synthesis in the nucleolus. Here, we show that biologically active RNase5 can be purified from bovine milk. Furthermore, we show that milk-derived RNase5 directly stimulates muscle cell differentiation in vitro, inducing C2C12 cell differentiation and myogenesis. When supplemented into the diet of healthy adult mice, milk-derived RNase5 preparations promoted muscle weight gain and grip strength. Collectively, these data indicate that milk-derived RNase5 preparations exhibit a novel role in skeletal muscle cell function.


[Instrumental diagnosis of peripheral arterial occlusive disease].
The increasing frequency of peripheral occlusive arterial disease in the general population emphasizes the need of suitable methods for early detection of this disease. This overview summarizes the methods of current use of angiologic investigation. Their sensitivity and practicability are critically discussed. Mechanical and electronic oscillography are simple screening methods and allow a slight localization of arterial occlusive disease. Exercise tests increase the sensitivity of oscillographic methods. Continuous wave Doppler-ultrasound can be used for measuring peripheral arterial pressure, directional or pulsed Doppler-ultrasound are needed for the determination of flow direction and for registration of flow-pressure curves. Multichannel pulsed Doppler-ultrasound is needed for quantitative flow registration in determined arteries. Detailed high quality pictures of the arterial structures can be obtained by high resolution B-mode scanners-while information on flow properties is given by frequency-analysis of Doppler signals achieved in duplex scans or color-coded scans. Plethysmography is still the standard method for quantitative flow determination in upper and lower extremities, suitable for the evaluation of the vascular capacity of the examined member. Capillaroscopy gives a direct view in the situation of microcirculation, which is very valuable for the management of diabetic microangiopathy and collagen diseases. Thermography offers the opportunity of registration of impressive imaging of functional vascular reactions.


[Problem of orthostatic intolerance in astronauts and perspectives for its pharmacological prevention].
Double-blind placebo-controlled method was applied to study venoconstrictor agent Dihydroergotamine effects on orthostatic tolerance in 8 healthy male-volunteers after 6-hour exposure to antiorthostatic stress (-6 degrees). The drug was able to induce blood centralization and diuresis additional to those caused by the simulated microgravity per se and failed to prevent the orthostatic intolerance. In 6 subjects the studies were repeated with the occlusive cuffs used in order to prevent venous blood return from the vascular bed of the lower limbs during 0-gravity simulation. The occlusive cuffs were shown to eliminate the additional drug-induced blood centralization and diuresis. Orthostatic tolerance in this case occurred to be less affected than in the case of no countermeasure used or in the case when dihydroergotamine was used alone. Thus, it was shown that mechanical prevention of the drug-induced blood centralization from being realized in 0-gravity simulation must be considered as the requirement necessary to permit the drug to perform its beneficial effect on the orthostatic tolerance after the real or simulated weightlessness.


Subcellular Trafficking and Functional Relationship of the HSV-1 Glycoproteins N and M.
The herpes simplex virus type 1 (HSV-1) glycoprotein N (gN/UL49.5) is a type I transmembrane protein conserved throughout the herpesvirus family. gN is a resident of the endoplasmic reticulum that in the presence of gM is translocated to the trans Golgi network. gM and gN are covalently linked by a single disulphide bond formed between cysteine 46 of gN and cysteine 59 of gM. Exit of gN from the endoplasmic reticulum requires the N-terminal core of gM composed of eight transmembrane domains but is independent of the C-terminal extension of gM. Co-transport of gN and gM to the trans Golgi network also occurs upon replacement of conserved cysteines in gM and gN, suggesting that their physical interaction is mediated by covalent and non-covalent forces. Deletion of gN/UL49.5 using bacterial artificial chromosome (BAC) mutagenesis generated mutant viruses with wild-type growth behaviour, while full deletion of gM/UL10 resulted in an attenuated phenotype. Deletion of gN/UL49.5 in conjunction with various gM/UL10 mutants reduced average plaque sizes to the same extent as either single gM/UL10 mutant, indicating that gN is nonessential for the function performed by gM. We propose that gN functions in gM-dependent as well as gM-independent processes during which it is complemented by other viral factors.


Whole-Genome Multilocus Sequence Typing of Extended-Spectrum-Beta-Lactamase-Producing Enterobacteriaceae.
Molecular typing has become indispensable in the detection of nosocomial transmission of bacterial pathogens and the identification of sources and routes of transmission in outbreak settings, but current methods are labor-intensive, are difficult to standardize, or have limited resolution. Whole-genome multilocus sequence typing (wgMLST) has emerged as a whole-genome sequencing (WGS)-based gene-by-gene typing method that may overcome these limitations and has been applied successfully for several species in outbreak settings. In this study, genus-, genetic-complex-, and species-specific wgMLST schemes were developed for Citrobacter spp., the Enterobacter cloacae complex, Escherichia coli, Klebsiella oxytoca, and Klebsiella pneumoniae and used to type a national collection of 1,798 extended-spectrum-beta-lactamase-producing Enterobacteriaceae (ESBL-E) isolates obtained from patients in Dutch hospitals. Genus-, genetic-complex-, and species-specific thresholds for genetic distance that accurately distinguish between epidemiologically related and unrelated isolates were defined for Citrobacter spp., the E. cloacae complex, E. coli, and K. pneumoniae wgMLST was shown to have higher discriminatory power and typeability than in silico MLST. In conclusion, the wgMLST schemes developed in this study facilitate high-resolution WGS-based typing of the most prevalent ESBL-producing species in clinical practice and may contribute to further elucidation of the complex epidemiology of antimicrobial-resistant Enterobacteriaceae wgMLST opens up possibilities for the creation of a Web-accessible database for the global surveillance of ESBL-producing bacterial clones.


Unsupportive parenting moderates the effects of family psychosocial intervention on metabolic syndrome in African American youth.
Family relationships have been linked to obesity and related disorders in youth, but few studies have provided causal evidence of this association. This study tested the impact of a family psychosocial intervention on components of metabolic syndrome-a condition driven largely by abdominal obesity-in African American youth. In particular, the study tested whether effects were strongest among those who started at highest risk, that is, with high levels of unsupportive parenting at baseline. Randomized clinical trial of a community sample of 391 African American youth (mean age=11.2 years) conducted in 2001-2002, with follow-up metabolic syndrome assessment in 2014-2015. Participants were assigned either to receive a weekly family intervention or to a control group. The primary study outcome was the number of components of metabolic syndrome that were clinically elevated at age 25, including central adiposity, blood pressure, triglycerides, glucose and low high-density lipoproteins. Unsupportive parenting was measured by questionnaires at baseline. Significant interaction effects were found between group assignment and baseline unsupportive parenting on counts of metabolic syndrome components in youth (beta=-0.17, P=0.03). Among those who started with higher levels of unsupportive parenting at age 11, participation in the family intervention reduced the number of clinically elevated components of the metabolic syndrome at age 25 relative to the control group. No such effect was seen among those who started with good parenting. Mediation analyses suggested that changes in the psychosocial targets of the parenting intervention partially accounted for the effects amongst those high in unsupportive parenting at baseline (effect size=-0.350, s.e.=0.178). These findings suggest that efforts to improve family relationships may be able to ameliorate the detrimental effects that harsh and unsupportive parenting have on obesity-related outcomes such as metabolic syndrome in youth.