The influence of participation in target-shooting sport for children with inattentive, hyperactive and impulsive symptoms - A controlled study of best practice.
Practising target-shooting sport requires focused attention and motoric steadiness. A previous non-controlled pilot study suggests that children with impairing symptoms of attention-deficit/hyperactivity disorder (ADHD) benefit from participating in target-shooting sport in local shooting associations, as rated by parents and teachers. This study aims at examining if, and to which extent, target-shooting sport reduces parent- and teacher-reported severity of inattentiveness, hyperactivity, and impulsivity in children with attention difficulties, and if, and to which extend, target-shooting sport improves the children's wellbeing and quality of life. A mixed method approach is applied. A non-blinded, waiting list controlled study is combined with a case study, consisting of interviews and observations. The intervention consists of children practising target-shooting sport, by attending a local shooting association, once a week for six months, during regular school hours. Data from questionnaires (ADHD-RS, SDQ, Kidscreen-27), as well as a computerized continued performance test (Qb test), measure the children's activity and attention. The study includes 50 children in an intervention group and 50 children in a waiting list control group. The Qb test collects data from at least 20 children from the intervention group and at least 20 children from the waiting list control group. Data from the questionnaires and Qb-test is collected at baseline, and six months post intervention. In addition, a case study is carried out, consisting of interviews of at least five children from the intervention group, their parents, teachers and shooting instructors. Observations are carried out, when children are in school and while they are attending the local shooting association. The case study adds to an in-depth understanding of children's participation in target-shooting sports. At present, little is known about the effects and influence of practising target-shooting sport for children experiencing difficulties with inattentiveness, hyperactivity and impulsivity. This study is expected to contribute to an understanding of the influence of participating in target-shooting sports on inattentive, hyperactive and impulsive symptoms, and the effects on the children's psychological wellbeing and quality of life. Current Controlled Trials NCT02898532 . Retrospectively registered 14 September 2016.


Quantification of the concentration of Aβ42 propagons during the lag phase by an amyloid chain reaction assay.
The aggregation of the amyloid beta peptide, Aβ42, implicated in Alzheimer's disease, is characterized by a lag phase followed by a rapid growth phase. Conventional methods to study this reaction are not sensitive to events taking place early in the lag phase promoting the assumption that only monomeric or oligomeric species are present at early stages and that the lag time is defined by the primary nucleation rate only. Here we exploit the high sensitivity of chemical chain reactions to the reagent composition to develop an assay which improves by 2 orders of magnitude the detection limit of conventional bulk techniques and allows the concentration of fibrillar Aβ42 propagons to be detected and quantified even during the lag time. The method relies on the chain reaction multiplication of a small number of initial fibrils by secondary nucleation on the fibril surface in the presence of monomeric peptides, allowing the quantification of the number of initial propagons by comparing the multiplication reaction kinetics with controlled seeding data. The quantitative results of the chain reaction assay are confirmed by qualitative transmission electron microscopy analysis. The results demonstrate the nonlinearity of the aggregation process which involves both primary and secondary nucleation events even at the early stages of the reaction during the lag-phase.


[Changes in thermoregulation, sleep and the thyroid hormone concentration of the blood in the "critical" period of the entry into hibernation of the suslik Citellus parryi].
During the first entering into hibernation in the ground squirrels there are periodic cessations of the process, especially during the transition to moderate and deep torpidity ("critical" periods) which significantly increase energy expenditure in animals during the phase of entering. During this period, high amplitude near-the-hour fluctuations are observed in total duration of wakefulness and sleep, contractile muscle activity, oxygen consumption, heart rate, brain temperature, and thyroid hormone concentration in the blood; at the end of this period, as well as during the exiting from it the duration of deep slow wave sleep significantly increases, paradoxical sleep is not identified. The data obtained confirm a hypothesis of "kindling" homeostasis as neuro-hormonal mechanism of the increase in thermal range of the activity of functional systems of the organism during the entering into torpidity in homoiothermic animals.


Antitumor Activity of Lurbinectedin, a Selective Inhibitor of Oncogene Transcription, in Patients with Relapsed Ewing Sarcoma: Results of a Basket Phase II Study.
Lurbinectedin suppresses the oncogenic transcription factor EWS-FLI1 through relocalization to the nucleolus, and delays tumor growth in mice bearing Ewing sarcoma xenografts. On the basis of this rationale, lurbinectedin was evaluated in patients with relapsed Ewing sarcoma. This open-label, single-arm, Basket phase II trial included a cohort of 28 treated adult patients with confirmed Ewing sarcoma, measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1, Eastern Cooperative Oncology Group performance status ≤2, adequate organ function, no central nervous system metastasis, and pretreated with ≤2 chemotherapy lines for metastatic/recurrent disease. Patients received lurbinectedin 3.2 mg/m2 as a 1-hour infusion every 3 weeks. Primary endpoint was overall response rate (ORR) as per RECIST v.1.1. Secondary endpoints included time-to-event parameters and safety profile. ORR was 14.3% [95% confidence interval (CI), 4.0%-32.7%], with median duration of response of 4.2 months (95% CI, 2.9-5.5 months). Median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months), clinical benefit rate was 39.3%, and disease control rate was 57.1%. With 39% censoring, median overall survival was 12.0 months (95% CI, 8.5-18.5 months). Most common grade 3/4 adverse events were neutropenia (57%), anemia, thrombocytopenia, and treatment-related febrile neutropenia (14% each). No deaths or discontinuations were due to toxicity. Lurbinectedin was active in the treatment of relapsed Ewing sarcoma and had a manageable safety profile. Lurbinectedin could represent a valuable addition to therapies for Ewing sarcoma, and is currently being evaluated in combination with irinotecan in advanced Ewing sarcoma in a phase Ib/II trial.


Childhood cumulative risk and later allostatic load: mediating role of substance use.
The present study investigated the long-term impact of exposure to poverty-related stressors during childhood on allostatic load, an index of physiological dysregulation, and the potential mediating role of substance use. Participants (n = 162) were rural children from New York State, followed for 8 years (between the ages 9 and 17). Poverty- related stress was computed using the cumulative risk approach, assessing stressors across 9 domains, including environmental, psychosocial, and demographic factors. Allostatic load captured a range of physiological responses, including cardiovascular, hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, and metabolic activity. Smoking and alcohol/drug use were tested as mediators of the hypothesized childhood risk-adolescent allostatic load relationship. Cumulative risk exposure at age 9 predicted increases in allostatic load 8 years later. Smoking, but not alcohol and drug use, was a significant mediator of the prospective, longitudinal relationship between childhood cumulative risk and adolescent allostatic load. The present paper contributes to the understanding of the role of early life stress in health across the life span and of the mechanisms by which adverse childhood environments impact health as children emerge into early adulthood. This knowledge will have implications for early intervention efforts.


Alcohol and drug use in rural colonias and adjacent urban areas of the Texas border.
Little is known about substance use and treatment utilization in rural communities of the United States/Mexico border. To compare substance use and need and desire for treatment in rural colonias and urban areas of the border. Interviews were conducted in 2002-2003 with a random sample of adults living in the lower Rio Grande Valley of Texas, adjacent to the Mexican border. The present analysis compares responses from 400 residents of rural colonias to those of 395 residents of cities and towns in the same geographic region. While the prevalence of drug use and drug-related problems was similar in both areas, binge drinking and alcohol dependence were higher in rural colonias than in urban areas and remained so after taking demographic and neighborhood variables into account. An increase in illicit drug use and substance-related problems in rural but not urban areas was seen when comparing results from this study with those of a previous survey conducted in 1996. The percentage of adults in potential need of treatment and the percentage motivated to seek it were similar in both urban and rural areas. However, colonia residents were more likely than their urban counterparts to be recent immigrants and to have lower incomes and educational attainment, factors that can increase the barriers they face in getting needed services. Rural areas are "catching up" with urban areas in problematic substance use. Given the potential barriers to accessing treatment services in rural areas, efforts should be focused on reaching those residents.


Novel Molecular Consortia of Cannabidiol with Nonsteroidal Anti-Inflammatory Drugs Inhibit Emerging Coronaviruses' Entry.
The COVID-19 pandemic provoked a global health crisis and highlighted the need for new therapeutic strategies. In this study, we explore the potential of the molecular consortia of cannabidiol (CBD) and non-steroidal anti-inflammatory drugs (NSAIDs) as novel antiviral dual-target agents against SARS-CoV-2/COVID-19. CBD is a natural compound with a wide range of therapeutic activities, including antiviral and anti-inflammatory properties, while NSAIDs are commonly used to mitigate the symptoms of viral infections. Chemical modifications of CBD with NSAIDs were performed to obtain dual-target agents with enhanced activity against SARS-CoV-2. The synthesised compounds were characterised using spectroscopic techniques. The biological activity of three molecular consortia (CBD-ibuprofen, CBD-ketoprofen, and CBD-naproxen) was evaluated in cell lines transduced with vesicular stomatitis virus-based pseudotypes bearing the SARS-CoV-1 or SARS-CoV-2 spike proteins or infected with influenza virus A/Puerto Rico/8/34. The results showed that some CBD-NSAID molecular consortia have superior antiviral activity against SARS-CoV-1 and SARS-CoV-2, but not against the influenza A virus. This may suggest a potential therapeutic role for these compounds in the treatment of emerging coronavirus infections. Further studies are needed to investigate the efficacy of these compounds in vivo, and their potential use in clinical settings. Our findings provide a promising new approach to combatting current and future viral emergencies.


Regulation of monocyte subset systemic levels by distinct chemokine receptors controls post-ischaemic neovascularization.
Monocyte systemic levels are known to be a major determinant of ischaemic tissue revascularization, but the mechanisms mediating mobilization of different monocyte subsets-Ly6C(hi) and Ly6C(lo)-to the blood and their respective role in post-ischaemic neovascularization are not clearly understood. Here, we hypothesized that distinct chemokine/chemokine receptor pathways, namely CCL2/CCR2, CX3CL1/CX3CR1, and CCL5/CCR5, differentially control monocyte subset systemic levels, and might thus impact post-ischaemic vessel growth. In a model of murine hindlimb ischaemia, both Ly6C(hi) and Ly6C(lo) monocyte circulating levels were increased after femoral artery ligation. CCL2/CCR2 activation enhanced blood Ly6C(hi) and Ly6C(lo) monocyte counts, although the opposite effect was seen in mice with CCL2 or CCR2 deficiency. CX3CL1/CX3CR1 strongly impacted Ly6C(lo) monocyte levels, whereas CCL5/CCR5 had no role. Only CCL2/CCR2 signalling influenced neovascularization, which was increased in mice overexpressing CCL2, whereas it markedly decreased in CCL2-/- mice. Moreover, adoptive transfer of Ly6C(hi)-but not Ly6C(lo)-monocytes enhanced vessel growth and blood flow recovery. Altogether, our data demonstrate that regulation of proangiogenic Ly6C(hi) monocytes systemic levels by CCL2/CCR2 controls post-ischaemic vessel growth, whereas Ly6C(lo) monocytes have no major role in this setting.


Neural systems language: a formal modeling language for the systematic description, unambiguous communication, and automated digital curation of neural connectivity.
Systematic description and the unambiguous communication of findings and models remain among the unresolved fundamental challenges in systems neuroscience. No common descriptive frameworks exist to describe systematically the connective architecture of the nervous system, even at the grossest level of observation. Furthermore, the accelerating volume of novel data generated on neural connectivity outpaces the rate at which this data is curated into neuroinformatics databases to synthesize digitally systems-level insights from disjointed reports and observations. To help address these challenges, we propose the Neural Systems Language (NSyL). NSyL is a modeling language to be used by investigators to encode and communicate systematically reports of neural connectivity from neuroanatomy and brain imaging. NSyL engenders systematic description and communication of connectivity irrespective of the animal taxon described, experimental or observational technique implemented, or nomenclature referenced. As a language, NSyL is internally consistent, concise, and comprehensible to both humans and computers. NSyL is a promising development for systematizing the representation of neural architecture, effectively managing the increasing volume of data on neural connectivity and streamlining systems neuroscience research. Here we present similar precedent systems, how NSyL extends existing frameworks, and the reasoning behind NSyL's development. We explore NSyL's potential for balancing robustness and consistency in representation by encoding previously reported assertions of connectivity from the literature as examples. Finally, we propose and discuss the implications of a framework for how NSyL will be digitally implemented in the future to streamline curation of experimental results and bridge the gaps among anatomists, imagers, and neuroinformatics databases.


Effects of oral propranolol for circumscribed choroidal hemangioma.
We aimed to evaluate the effects of oral propranolol for circumscribed choroidal hemangioma. In this prospective, longitudinal interventional study, we administered oral propranolol at a dosage of 1.5 mg/kg/day to five patients with circumscribed choroidal hemangioma. We then evaluated visual acuity, binocular indirect ophthalmoscopy, optical coherence tomography, optical coherence tomography angiography, fluorescein and indocyanine green angiography, and ocular ultrasonography at regular intervals and compared changes from the baseline assessments. No clinical or diagnostic changes were observed in the sizes of the circumscribed choroidal hemangiomas during treatment. Complications due to the hemangioma were reduced in the first four months of treatment, followed by maintenance, before worsening in the subsequent three months. The study showed that oral propranolol at a dose of 1.5 mg/kg/day did not offer effective monotherapy in the treatment of circumscribed choroidal hemangioma.


Capturing wild animal welfare: a physiological perspective.
Affective states, such as emotions, are presumably widespread across the animal kingdom because of the adaptive advantages they are supposed to confer. However, the study of the affective states of animals has thus far been largely restricted to enhancing the welfare of animals managed by humans in non-natural contexts. Given the diversity of wild animals and the variable conditions they can experience, extending studies on animal affective states to the natural conditions that most animals experience will allow us to broaden and deepen our general understanding of animal welfare. Yet, this same diversity makes examining animal welfare in the wild highly challenging. There is therefore a need for unifying theoretical frameworks and methodological approaches that can guide researchers keen to engage in this promising research area. The aim of this article is to help advance this important research area by highlighting the central relationship between physiology and animal welfare and rectify its apparent oversight, as revealed by the current scientific literature on wild animals. Moreover, this article emphasises the advantages of including physiological markers to assess animal welfare in the wild (e.g. objectivity, comparability, condition range, temporality), as well as their concomitant limitations (e.g. only access to peripheral physiological markers with complex relationships with affective states). Best-practice recommendations (e.g. replication and multifactorial approaches) are also provided to allow physiological markers to be used most effectively and appropriately when assessing the welfare of animals in their natural habitat. This review seeks to provide the foundation for a new and distinct research area with a vast theoretical and applied potential: wild animal welfare physiology.


Association between serum total cholesterol and HIV infection in a high-risk cohort of young men.
Low serum total cholesterol (TC) is associated with a variety of nonatherosclerotic diseases, but the association of TC with infectious disease has been little studied. In this study, we examined the relationship between serum TC and HIV infection in members of a large health maintenance organization in Northern California. The cohort consisted of 2446 unmarried young men 15 to 49 years of age at high risk of HIV infection, defined as self-reported history of sexually transmitted disease or liver disease. Baseline measurements were taken between 1979 and 1985, and subjects were passively followed for HIV infection until the end of 1993 (average length of follow-up, 7.7 years). From a multivariate-adjusted Cox regression, the rate ratio (RR) of HIV infection was 1.66 (95% CI = 1.07, 2.56) for men with serum TC levels <160 mg/dl compared with those with TC levels between 160 and 199 mg/dl. Similar excess risk of AIDS and AIDS-related death was observed. These findings suggest that low serum TC levels should be considered a marker of increased risk of HIV infection in men already at heightened risk of HIV infection.


A common copy-number variant within SIRPB1 correlates with human Out-of-Africa migration after genetic drift correction.
Previous reports have proposed that personality may have played a role on human Out-Of-Africa migration, pinpointing some genetic variants that were positively selected in the migrating populations. In this work, we discuss the role of a common copy-number variant within the SIRPB1 gene, recently associated with impulsive behavior, in the human Out-Of-Africa migration. With the analysis of the variant distribution across forty-two different populations, we found that the SIRPB1 haplotype containing duplicated allele significantly correlated with human migratory distance, being one of the few examples of positively selected loci found across the human world colonization. Circular Chromosome Conformation Capture (4C-seq) experiments from the SIRPB1 promoter revealed important 3D modifications in the locus depending on the presence or absence of the duplication variant. In addition, a 3' enhancer showed neural activity in transgenic models, suggesting that the presence of the CNV may compromise the expression of SIRPB1 in the central nervous system, paving the way to construct a molecular explanation of the SIRPB1 variants role in human migration.


[Preliminary plant inventory of the palm-swamps in the Caribbean of Costa Rica and Nicaragua].
In the Caribbean slope of Isthmian Central America, plant associations dominated by the palms Raphia taedigera and Manicaria saccifera develop in poorly drained or waterlogged soils. These associations are known locally as yolillales or palm-swamps, although there are differences in the forest structure and plant diversity associated with both palm species. In this paper, we report the results of a preliminary inventory of tree species found in eight palm-swamps at five locations in southeastern Nicaragua and northeastern Costa Rica. Our data reveal low tree diversity in these swamps with only 60 species accounted in them. This figure is equivalent to close to 8% of the plant species known for this region. In general, R. taedigera dominates flooded areas with extensive hydroperiods and lower floristic diversity, while M. saccifera is often found in flooded forests with more structure and diversity.


Osteopontin, Macrophage Migration Inhibitory Factor and Anti-Interleukin-8 Autoantibodies Complement CA125 for Detection of Early Stage Ovarian Cancer.
Early detection of ovarian cancer promises to reduce mortality. While serum CA125 can detect more than 60% of patients with early stage (I-II) disease, greater sensitivity might be observed with a panel of biomarkers. Ten protein antigens and 12 autoantibody biomarkers were measured in sera from 76 patients with early stage (I-II), 44 patients with late stage (III-IV) ovarian cancer and 200 healthy participants in the normal risk ovarian cancer screening study. A four-biomarker panel (CA125, osteopontin (OPN), macrophage inhibitory factor (MIF), and anti-IL-8 autoantibodies) detected 82% of early stage cancers compared to 65% with CA125 alone. In early stage subjects the area under the receiver operating characteristic curve (AUC) for the panel (0.985) was significantly greater (p < 0.001) than the AUC for CA125 alone (0.885). Assaying an independent validation set of sera from 71 early stage ovarian cancer patients, 45 late stage patients and 131 healthy women, AUC in early stage disease was improved from 0.947 with CA125 alone to 0.974 with the four-biomarker panel (p = 0.015). Consequently, OPN, MIF and IL-8 autoantibodies can be used in combination with CA125 to distinguish ovarian cancer patients from healthy controls with high sensitivity. Osteopontin appears to be a robust biomarker that deserves further evaluation in combination with CA125.


An integrated framework to improve the concept of resource specialisation.
Resource specialisation, although a fundamental component of ecological theory, is employed in disparate ways. Most definitions derive from simple counts of resource species. We build on recent advances in ecophylogenetics and null model analysis to propose a concept of specialisation that comprises affinities among resources as well as their co-occurrence with consumers. In the distance-based specialisation index (DSI), specialisation is measured as relatedness (phylogenetic or otherwise) of resources, scaled by the null expectation of random use of locally available resources. Thus, specialists use significantly clustered sets of resources, whereas generalists use over-dispersed resources. Intermediate species are classed as indiscriminate consumers. The effectiveness of this approach was assessed with differentially restricted null models, applied to a data set of 168 herbivorous insect species and their hosts. Incorporation of plant relatedness and relative abundance greatly improved specialisation measures compared to taxon counts or simpler null models, which overestimate the fraction of specialists, a problem compounded by insufficient sampling effort. This framework disambiguates the concept of specialisation with an explicit measure applicable to any mode of affinity among resource classes, and is also linked to ecological and evolutionary processes. This will enable a more rigorous deployment of ecological specialisation in empirical and theoretical studies.


Lightweight Structural Materials in Open Access: Latest Trends.
The aeronautical and automotive industries have, as an essential objective, the energy efficiency optimization of aircraft and cars, while maintaining stringent functional requirements. One working line focuses on the use of lightweight structural materials to replace conventional materials. For this reason, it is considered enlightening to carry out an analysis of the literature published over the last 20 years through Open Access literature. For this purpose, a systematic methodology is applied to minimize the possible risks of bias in literature selection and analysis. Web of Science is used as a search engine. The final selection comprises the 30 articles with the highest average numbers of citations per year published from 2015 to 2020 and the 7 articles published from the period of 2000-2014. Overall, the selection is composed of 37 Open Access articles with 2482 total citations and an average of 67.1 citations per article/year published, and includes Q1 (62%) and Q2 (8%) articles and proceeding papers (30%). The study seeks to inform about the current trends in materials and processes in lightweight structural materials for aeronautical and automotive applications with a sustainable perspective. All the information collected is summarized in tables to facilitate searches and interpretation by interested researchers.


Dental Material Choices for Pulp Therapy in Paediatric Dentistry.
The purpose of this study was to assess the restorative choices for pulpal therapy by members of the Australian and New Zealand Society of Paediatric Dentistry (ANZSPD). Members of the ANZSPD were sent an online survey asking about the procedures that they performed and their choice of dental materials. The respondents were 31 general dentists (GD) and 55 specialist paediatric dentists (PD). Materials used for indirect pulp capping included calcium hydroxide [Ca(OH)2] cement (CHC), glass ionomer cement or resin-modified glass ionomer cement (GIC/RMGIC), Ca(OH)2 paste (CHP) and mineral trioxide aggregate (MTA). Materials for direct pulp capping included MTA, CHP and CHC. Materials and techniques used for pulpotomy included MTA, ferric sulphate, formocresol and diathermy, CHP and CHC. GD and PD were similar in their choice of materials. However, there was no preferred product for pulp therapy. Most GD learnt how to use MTA from CPD lectures, while some PD learnt how to use MTA from their postgraduate training as well as CPD lectures. Many GD and PD did not have hands-on training from their education on how to use MTA (GD: 80%, PD: 43%). Most would like to attend hands-on MTA courses (GD: 86%, PD: 65%). There was no clear preferred product for the various types of pulp therapy in paediatric dentistry. Education appears to be the major barrier to the use of MTA rather than the cost of MTA.


The Current State of Subjective Training Load Monitoring: Follow-Up and Future Directions.
This article addresses several key issues that have been raised related to subjective training load (TL) monitoring. These key issues include how TL is calculated if subjective TL can be used to model sports performance and where subjective TL monitoring fits into an overall decision-making framework for practitioners. Regarding how TL is calculated, there is conjecture over the most appropriate (1) acute and chronic period lengths, (2) smoothing methods for TL data and (3) change in TL measures (e.g., training stress balance (TSB), differential load, acute-to-chronic workload ratio). Variable selection procedures with measures of model-fit, like the Akaike Information Criterion, are suggested as a potential answer to these calculation issues with examples provided using datasets from two different groups of elite athletes prior to and during competition at the 2016 Olympic Games. Regarding using subjective TL to model sports performance, further examples using linear mixed models and the previously mentioned datasets are provided to illustrate possible practical interpretations of model results for coaches (e.g., ensuring TSB increases during a taper for improved performance). An overall decision-making framework for determining training interventions is also provided with context given to where subjective TL measures may fit within this framework and the determination if subjective measures are needed with TL monitoring for different sporting situations. Lastly, relevant practical recommendations (e.g., using validated scales and training coaches and athletes in their use) are provided to ensure subjective TL monitoring is used as effectively as possible along with recommendations for future research.


Chenopodium ambrosioides L. extract prevents bone loss.
To evaluate the effect of the Chenopodium ambrosioides L (mastruz) extract for preventing bone loss and bone metabolism in ovariectomized rats. Twelve rats were subjected to bilateral ovariectomy for inducing osteoporosis. After surgery, they were divided into two groups: Ovariectomy-control group (G1, n=6), receiving 0.5 ml distilled water by gavage for 30 days, and Ovariectomy plus mastruz group (G2, n=6), receiving 0.5 ml of the hydroalcoholic extract of mastruz at 10% concentration (50mg) daily, for the same period. Then, the blood of the animals was collected for further biochemical analysis (liver function) and tibia and liver were removed for histological and histomorphometric analyses. The cortical bone was significantly larger in the G2 than G1, whereas G1 presented the highest amount of adipocytes in the bone marrow (p<0.05). The blood levels of aspartate aminotransferase, triglycerides and cholesterol were significantly higher, whereas globulin and lactate dehydrogenase were smaller in G2 than G1. The hydroalcoholic extract of mastruz has effects on bone metabolism by changing blood proteins and enzymes and preventing both bone loss and the substitution of bone marrow cells by.


Protamine use in transcarotid artery revascularization is associated with lower risk of bleeding complications without higher risk of thromboembolic events.
Recent studies have found that transcarotid artery revascularization (TCAR) is associated with lower risk of stroke or death compared with transfemoral carotid artery stenting but higher risk of bleeding complications, presumably associated with the need for an incision. Heparin anticoagulation is universally used during TCAR, so protamine use may reduce bleeding complications. However, the safety and effectiveness of protamine use in TCAR are unknown. We therefore evaluated the impact of protamine use on perioperative outcomes after TCAR in the Vascular Quality Initiative TCAR Surveillance Project. We performed a retrospective review of patients undergoing TCAR in the Vascular Quality Initiative TCAR Surveillance Project from September 2016 to April 2019. We assessed in-hospital outcomes using propensity score-matched cohorts of patients who did and did not receive protamine. The primary efficacy end point was access site bleeding complications, and the primary safety end point was in-hospital stroke or death. Secondary end points included the individual end points of stroke, death, transient ischemic attack, myocardial infarction, congestive heart failure exacerbation, and hemodynamic instability. Of the 5144 patients undergoing TCAR, all patients received heparin and 4072 (79%) patients received protamine. We identified 944 matched pairs of patients who did and did not receive protamine. Protamine use was associated with a significantly lower risk of bleeding complications (2.8% vs 8.3%; relative risk [RR], 0.33; 95% confidence interval [CI], 0.21-0.52; P < .001), including bleeding that resulted in interventional treatment (1.0% vs 3.6%; RR, 0.26; 95% CI, 0.13-0.54; P < .001) and in blood transfusion (1.2% vs 3.9%; RR, 0.30; 95% CI, 0.15-0.58; P <.001). There were no statistically significant differences in in-hospital stroke or death for patients who received protamine and those who did not (1.6% vs 2.2%; RR, 0.71; 95% CI, 0.37-1.39; P = .32); however, there was a trend toward lower risk of stroke for patients who received protamine (1.1% vs 2.0%; RR, 0.53; 95% CI, 0.24-1.13; P = .09). There were also no statistically significant differences in the rates of transient ischemic attack (0.4% vs 1.1%; RR, 0.40; 95% CI, 0.13-1.28; P = .11), myocardial infarction (0.4% vs 0.8%; RR, 0.50; 95% CI, 0.15-1.66; P = .25), heart failure exacerbation (0.4% vs 0.3%; RR, 1.33; 95% CI, 0.30-5.96; P = .71), or postoperative hypotensive hemodynamic instability (16% vs 15%; RR, 1.06; 95% CI, 0.83-1.35; P = .50) with protamine use. Protamine can be safely used in TCAR to reduce the risk of perioperative bleeding complications without increasing the risk of thrombotic events.


Resveratrol supplementation reduces ACE2 expression in human adipose tissue.
Angiotensin converting enzyme-2 (ACE2) is the cell-surface receptor enabling cellular entry of SARS-CoV-2. ACE2 is highly expressed in adipose tissue (AT), rendering AT a potential SARS-CoV-2 reservoir contributing to massive viral spread in COVID-19 patients with obesity. Although rodent and cell studies suggest that the polyphenol resveratrol alters ACE2, human studies are lacking. Here, we investigated the effects of 30-days resveratrol supplementation on RAS components in AT and skeletal muscle in men with obesity in a placebo-controlled cross-over study. Resveratrol markedly decreased ACE2 (~40%) and leptin (~30%), but did neither alter angiotensinogen, ACE and AT1R expression in AT nor skeletal muscle RAS components. These findings demonstrate that resveratrol supplementation reduces ACE2 in AT, which might dampen SARS-CoV-2 spread in COVID-19.


Reticence in disclosure of HIV infection and reasons for bereavement: impact on perinatally infected adolescents' mental health and understanding of HIV treatment and prevention in Johannesburg, South Africa.
Survival rates of perinatally infected HIV-positive adolescents (PIA) are increasing in sub-Saharan Africa. There is a gap in understanding how disclosure and bereavement have an impact on PIA beliefs and understanding of their HIV infection and its management. In-depth interviews were conducted with 25 purposively selected adolescents aged 13-19 years from 5 public health clinics in Johannesburg, South Africa. Data were analysed using NVivo 10 using a thematic approach. PIA experience incomplete disclosure both of their HIV status and reasons for their bereavements, which limits their understanding of how they became infected, vertical transmission and prevention options like prevention of mother-to-child transmission (PMTCT). Most participants were orphaned and were experiencing complicated grieving (i.e., engaged in unresolved tasks of grieving) which had a negative impact on their mental health, and ability to accept their HIV status and adhere to treatment. PIA need improved communication regarding vertical transmission and how they became HIV-positive, as well as reasons for death of their loved ones to properly understand their HIV status and engage effectively in management. Honest communication about how relatives died and truthful engagement in the process of disclosure of HIV status is necessary to reduce stigma and complicated grieving, and improve mental health in this population.


Long-term use of pitolisant to treat patients with narcolepsy: Harmony III Study.
To asses the long-term safety and efficacy of pitolisant, an histamine H3-receptor antagonist, on narcolepsy. This open-label, single-arm, pragmatic study, recruited adult patients with narcolepsy and Epworth Sleepiness Scale (ESS) score ≥12. After a titration period, patients were treated for up to 1 year with oral pitolisant once-a-day at up to 40 mg. Concomitant stimulants and anti-cataplectic agents were allowed. The primary endpoint was safety; secondary endpoints included ESS, cataplexy, and other diary parameters. Patients (n = 102, 75 with cataplexy) received pitolisant, for the first time in 73 of them. Sixty-eight patients (51 with cataplexy) completed the 12-month treatment. Common treatment-emergent adverse events were headache (11.8% of patients), insomnia (8.8%), weight gain (7.8%), anxiety (6.9%), depressive symptoms (4.9%), and nausea (4.9%). Seven patients had a serious adverse effect, unrelated to pitolisant except for a possibly related miscarriage. One-third of patients stopped pitolisant, mostly (19.6%) for insufficient benefit. ESS score decreased by 4.6 ± 0.6. Two-thirds of patients completing the treatment were responders (ESS ≤ 10 or ESS decrease ≥ 3), and one third had normalized ESS (≤10). Complete and partial cataplexy, hallucinations, sleep paralysis, and sleep attacks were reduced by 76%, 65%, 54%, 63%, and 27%, respectively. Pitolisant as monotherapy (43% of patients) was better tolerated and more efficacious on ESS than on add-on, but efficacy was maintained in this last case. Long-term safety and efficacy of pitolisant on daytime sleepiness, cataplexy, hallucinations, and sleep paralysis is confirmed.


Regulation of neutral cholesterol esterase and acyl-CoA : cholesterol acyltransferase in the rat adrenal gland.
The activities of neutral cholesterol esterase and acyl-CoA : cholesterol acyltransferase in rat adrenal gland were measured at various time intervals over 24 h. The activity of cholesterol esterase displayed diurnal rhythm, with a major peak at the onset of darkness coinciding with the peak in the diurnal rhythm of plasma corticosterone concentration. The activity of acyl-CoA : cholesterol acyltransferase also exhibited a characteristic diurnal rhythm, with the minimum activity occurring 3 h after the onset of darkness. The profile of the rhythm exhibited by the activity of the esterifying enzyme was similar to the mirror image of the pattern of diurnal rhythm in the activity of 3-hydroxy-3-methylglutaryl-CoA reductase. Microsomal non-esterified cholesterol showed a gradual decline with a significant decrease in concentration at the onset of darkness, thus suggesting that diurnal removal of cholesterol in the environment of the esterifying enzyme and hydroxymethylglutaryl-CoA reductase leads to such diurnal decrease or increase in the activities of these two enzymes. Acute administration of corticotropin led to a 3-fold increase in the activity of cholesterol esterase, a 50% decrease in the activity of acyl-CoA : cholesterol acyltransferase and a 2-fold increase in the activity of hydroxymethylglutaryl-CoA reductase. Corticotropin administration also resulted in a significant decrease in microsomal non-esterified cholesterol and increase in plasma corticosterone concentration. These observations suggest that corticotropin plays an important part in generating the diurnal rhythm in the activities of the three enzymes.


COVID-19 lockdown measures reveal human impact on water transparency in the Venice Lagoon.
The lagoon of Venice has always been affected by the regional geomorphological evolution, anthropogenic stressors and global changes. Different morphological settings and variable biogeophysical conditions characterize this continuously evolving system that rapidly responds to the anthropic impacts. When the lockdown measures were enforced in Italy to control the spread of the SARS-CoV-2 infection on March 10th 2020, the ordinary urban water traffic around Venice, one of the major pressures in the lagoon, came to a halt. This provided a unique opportunity to analyse the environmental effects of restrictions to mobility on water transparency. Pseudo true-colour composites Sentinel-2 satellite imagery proved useful for qualitative visual interpretation, showing the reduction of the vessel traffic and their wakes from the periods before and during the SARS-CoV-2 outbreak. A quantitative analysis of suspended matter patterns, based on satellite-derived turbidity, in the absence of traffic perturbations, allowed to focus on natural processes and the residual stress from human activities that continued throughout the lockdown. We conclude that the high water transparency can be considered as a transient condition determined by a combination of natural seasonal factors and the effects of COVID-19 restrictions.


Determining If Sex Bias Exists in Human Surgical Clinical Research.
Sex is a variable that is poorly controlled for in clinical research. To determine if sex bias exists in human surgical clinical research, to determine if data are reported and analyzed using sex as an independent variable, and to identify specialties in which the greatest and least sex biases exist. For this bibliometric analysis, data were abstracted from 1303 original peer-reviewed articles published from January 1, 2011, through December 31, 2012, in 5 surgery journals. Study type, location, number and sex of participants, degree of sex matching of included participants, and inclusion of sex-based reporting, statistical analysis, and discussion of data. Of 2347 articles reviewed, 1668 (71.1%) included human participants. After excluding 365 articles, 1303 remained: 17 (1.3%) included males only, 41 (3.1%) included females only, 1020 (78.3%) included males and females, and 225 (17.3%) did not document the sex of the participants. Although female participants represent more than 50% (n = 57 688 606) of the total number (115 377 213) included, considerable variability existed with the number of male (46 111 818), female (58 805 665), and unspecified (10 459 730) participants included among the journals, between US domestic and international studies, and between single vs multicenter studies. For articles included in the study, 38.1% (497 of 1303) reported these data by sex, 33.2% (432 of 1303) analyzed these data by sex, and 22.9% (299 of 1303) included a discussion of sex-based results. Sex matching of the included participants in the research overall was poor, with 45.2% (589 of 1303) of the studies matching the inclusion of both sexes by 50%. During analysis of the different surgical specialties, a wide variation in sex-based inclusion, matching, and data reporting existed, with colorectal surgery having the best matching of male and female participants and cardiac surgery having the worst. Sex bias exists in human surgical clinical research. Few studies included men and women equally, less than one-third performed data analysis by sex, and there was wide variation in inclusion and matching of the sexes among the specialties and the journals reviewed. Because clinical research is the foundation for evidence-based medicine, it is imperative that this disparity be addressed so that therapies benefit both sexes.


Effect of energy level and feeding frequency on site of digestion and postruminal nutrient flows in steers.
Four cannulated (rumen, proximal duodenum, terminal ileum) Simmental steers were fed ground corn and corn silage (low forage) or alfalfa hay and corn silage (high forage) diets twice or 12 times daily to examine effects of energy level and feeding frequency on nutrient digestion. Site of organic matter digestion was shifted from the rumen to the small intestine, and total tract organic matter digestion was increased when steers were fed the low forage diet. Although intakes and flows at all sites within the tract of NDF and ADF were greater when the high forage diet was fed, digestion of these components (percentage total tract digestion) within respective sites was unaffected by energy level. Nonbacterial N flows at the duodenum increased when steers were fed the low forage diet and when fed 12 times daily. Total amino acid flows at the duodenum tended to be increased when steers were fed the low forage diet. Results suggest that dietary energy level can impact on site of nutrient digestion and supply of nutrients at different sites within the digestive tract. However, feeding frequency had minimal effect on site or extent of nutrient digestion. The lack of interaction between energy level and feeding frequency in this experiment may be related to the level of DM intake and nature of the diets fed.


Cellular activation through the ligation of intercellular adhesion molecule-1.
In addition to its role in mediating leukocyte adherence to and migration across the endothelium, intercellular adhesion molecule (ICAM)-1 on the surface of interstitial cells has been implicated as a principal adhesion molecule controlling leukocyte infiltration at inflammatory sites. The present study demonstrates that leukocyte binding to fibroblasts isolated from both the human renal cortex and lung and to endothelial cells induced the de novo synthesis of ICAM-1 mRNA and protein through the ICAM-1-dependent activation of the cultured cells. This was mimicked by specifically cross-linking the ICAM-1 receptor with anti-ICAM-1 antibodies. Following cross-linking there was a two- to threefold increase in the steady state levels of ICAM-1 mRNA isolated from the cells. The expression of this mRNA peaked at 1-3 hours and was dose-dependent on the concentration of secondary cross-linking antibody. Peak protein expression was between 18 and 48 hours after cross-linking. Additional data demonstrated a similar increase in the expression of VCAM-1 following ICAM-1 cross-linking. In contrast, there was no reponse as a result of incubation with an isotype-matched control antibody. Both the binding of leukocytes and the cross-linking of ICAM-1 triggered a rise in cytosolic free calcium as the result, in part, of a calcium influx from the extracellular medium. Using BAPTA-AM to chelate intracellular calcium ions indicated that this increase in cytosolic free calcium was directly involved in the initiation of adhesion molecule upregulation. The present study demonstrates that both endothelial cells and fibroblasts can be stimulated by the direct cell surface interaction of ICAM-1 with its ligands on inflammatory cells. One phenotypic change resulting from this interaction is the upregulated synthesis and expression of more cellular adhesion molecules. This may have profound implications for the control and persistence of a leukocyte infiltrate and the progression of inflammatory disease.


[Isolation and quantitative analysis of ATP, synthesized by preparations of enriched plasma membrane portions from various tissues in the presence of insulin and somatotropin].
A transiently existent ATP, synthesized by the preparation enriched with plasmatic membranes of particles from rat skeletal muscles in presence of insulin 4 micrograms/ml and somatotropin 10-22 micrograms/ml within 1 min after addition of the hormones at 30 degrees, was isolated by means of chromatography on Dowex 1X8. The ATP was synthesized in a medium containing Tris-HCl buffer, pH 7.5, ADP, Mg2+ and P1 during NADH-dependent oxidation in presence of cytochrome c and oxygen; amount of the ATP was 0.1-0.3 nmole/mg/min. This form of ATP was isolated from particles enriched with plasmatic membranes and from plasmatic membranes of rat adipocytes, lymphocytes and liver tissue as well as of human erythrocytes within 1 min after addition of insulin into the mixture. The highest insulin-stimulated ATP-producing activity was found in plasmatic membranes of rat adipocytes--7.45 nmole/mg/min. Radiolabelled ATP, in presence of insulin transiently synthesized from ADP and 32P, was isolated from the preparation of human erythrocyte plasmatic membranes. Conditions of insulin-stimulated formation of the transient ATP in the preparation of human erythrocyte plasmatic membranes were studied.


Potential for a normal fetal stomach to simulate the sonographic "double bubble" sign.
The ultrasonographic appearance of the normal fetal stomach may simulate duodenal atresia when the incisura angularis is prominent. Such an erroneous diagnosis can be avoided by noting the absence of polyhydramnios and by assessing the fetal stomach in planes which traverse its long axis with real-time scanning units.


Left thoracoabdominal esophagectomy: results from a single specialist center.
The left thoracoabdominal approach to esophagectomy is not widely performed, despite offering excellent exposure to tumors of the esophagogastric junction. Criticisms of the approach have focused on historically high rates of mortality, complications, and positive resection margins. Our aim was to determine whether left thoracoabdominal esophagectomy could combine a radical oncological resection with acceptably low mortality and morbidity. A retrospective cohort study of all left thoracoabdominal esophagectomies was performed at a single specialist center over an 11-year period. Primary outcomes were in-hospital mortality, complications, resection margin involvement, and lymph node yield; secondary outcomes were 1-year and 5-year survival. Two hundred eleven esophagectomies were performed. In-hospital mortality was 5.7% (12/211). One hundred one subjects (47.9%) had an uncomplicated recovery; 110 subjects (52.1%) developed at least one complication. There were 15 clinically significant anastomotic leaks (7.1%). Twenty-four subjects (11.4%) required emergency reoperation, the most common indication being anastomotic leakage. Complete tumor excision (R0 resection) was achieved in 151 of 211 cases (71.6%); median lymph node yield was 24. One-year and 5-year survival rates were 70% (147/211) and 21% (24/116), respectively. Left thoracoabdominal esophagectomy can combine a radical oncological resection with acceptably low mortality and morbidity.


An experimental universal swine influenza a virus (IAV) vaccine candidate based on the M2 ectodomain (M2e) peptide does not provide protection against H1N1 IAV challenge in pigs.
Swine flu is a common disease problem in North American pig populations and swine influenza A viruses (IAV) are extremely diverse and the lack of cross protection between heterologous strains is impacting vaccine efficacy in the field. The objective of this study was to design and test a novel swine flu vaccine targeting the M2 ectodomain (M2e) of IAV, a highly conserved region within the IAV proteome. In brief, an M2e peptide was designed to match the predominant swine IAV M2 sequence based on global analysis of sequences from pigs and humans. The resulting sequence was used to synthesize the M2e peptide coupled to a carrier protein. The final vaccine concentration was 200 µg per dose, and a commercial, microemulsion-based aqueous adjuvant was added. Nine 3-week-old IAV negative piglets were randomly assigned to three groups and rooms including non-vaccinated pigs (NEG-CONTROLs) and vaccinated pigs using the intramuscular (M2e-IM) or the intranasal route (M2e-IN). Vaccinations were done at weaning and again at 2 weeks later. An in-house enzyme-linked immunosorbent assay (ELISA) was developed and validated to study the M2e IgG antibody response and demonstrated M2e-IM pigs had a higher systemic antibody response compared to M2e-IN pigs. Subsequently, an IAV challenge study was conducted. The results indicated that M2e-IM vaccinated pigs were not protected from H1N1 (US pandemic clade, global clade 1A.3.3.2) challenge despite having a strong humoral anti-M2e immune response. In conclusion, while the experimental IAV vaccine was able to induce anti-M2e antibodies, when challenged with H1N1, the vaccinated pigs were not protected, perhaps indicating that reactivity to the M2e antigen alone is not sufficient to reduce clinical signs, lesions or shedding associated with experimental IAV challenge.


Hydrocarbons of Biological Origin in Sediments about Two Billion Years Old.
Normal paraffins in the C(16) to C(32) range and the saturated isoprenoid hydrocarbons, pristane and phytane, have been found in chert from the Gunflint iron formation (1.9 x 10(9) years old) of the north shore of Lake Superior. The distribution of n-alkanes shows two maxima, one at about C(18) to C(19) and the other at about C(22) with a minimum occurring at C(20) to C(21). No predominance of odd- to even-carbon-number alkanes is observed within the C(16) to C(32) range. The results agree with micropaleontological observations made on the Gunflint chert and provide a chemical characterization of Precambrian life existing about two eons ago.


Apoptosis of T cells mediated by Ca2+-induced release of the transcription factor MEF2.
T cell receptor (TCR)-induced apoptosis of thymocytes is mediated by calcium-dependent expression of the steroid receptors Nur77 and Nor1. Nur77 expression is controlled by the transcription factor myocyte enhancer factor 2 (MEF2), but how MEF2 is activated by calcium signaling is still obscure. Cabin1, a calcineurin inhibitor, was found to regulate MEF2. MEF2 was normally sequestered by Cabin1 in a transcriptionally inactive state. TCR engagement led to an increase in intracellular calcium concentration and the dissociation of MEF2 from Cabin1, as a result of competitive binding of activated calmodulin to Cabin1. The interplay between Cabin1, MEF2, and calmodulin defines a distinct signaling pathway from the TCR to the Nur77 promoter during T cell apoptosis.


Associations between self-reported physical activity and screen time with cardiometabolic risk factors in adolescents: Findings from the 1993 Pelotas (Brazil) Birth Cohort Study.
The overall aim of this study was to examine the association of physical activity (PA) and screen time (ST) on indicators of cardio-metabolic risk during adolescence, by examining the combined association of PA and ST at ages 11, 15 and 18 on cardio-metabolic risk factors at 18 years. Data from the 1993 Pelotas (Brazil) Birth Cohort Study (N = 3613) were analysed in 2017. Self-reported PA and ST data were collected at 11, 15 and 18 years. Cardio-metabolic risk factors (fat mass index, waist circumference, triglycerides, blood glucose, non-HDL cholesterol and resting diastolic blood pressure) were examined at age 18. Multivariate linear regression was used to examine the associations between four mutually exclusive PA/ST groups: 1) active (≥1 h/day PA) and low ST (<5 h/day ST); 2) active (≥1 h/day PA) and high ST (≥5 h/day ST); 3) inactive (<1 h/day PA) and low ST (<5 h/day ST); 4) inactive (<1 h/day PA) and high ST (≥5 h/day ST) at each age, and outcomes at age 18. There were no significant associations between PA/ST at ages 11 and 15 with outcomes at 18 years. In the cross-sectional analyses, adolescents in the most active group had significantly better levels of all the outcomes, regardless of ST. Inactive participants with high ST had the highest levels of glucose and non-HDL-C. For diastolic blood pressure, values were higher among inactive participants. Overall, higher levels of physical activity appeared to be more important than low levels of ST for cardio-metabolic health in adolescents.


Deepening the divide: Does globalization increase the polarization between winners and losers of globalization?
Does globalization increase polarization in attitudes toward international trade, immigration, and international organizations? Research from a variety of fields and disciplines assumes this relationship, but empirical studies are few. In this study, I examine whether globalization increases the attitudinal divide between education groups, with education being one of the main characteristics of social stratification distinguishing winners from losers of globalization. I use data from three waves of the National Identity Module of the International Social Survey Programme (ISSP) from 1995 to 2013 covering 29 countries (n = 79,101) to analyze between- and within-country interactions between the level of globalization and education in explaining attitudes toward globalization. The results show that while the attitudinal divide between educational groups is larger in countries with higher levels of globalization (between effect), polarization decreases as the level of globalization increases within countries (within effect), as persons with lower and medium levels of education become more positive toward globalization under increasing levels of globalization. The results are consistent across a wide range of robustness checks, including controlling for occupational class as a further distinction between winners and losers of globalization. The findings suggest that the expectations about a widening attitudinal divide between winners and losers of globalization should be treated with more caution.


Histopathological analysis of rat mesentery as a method for evaluating neutrophil migration: differential effects of dexamethasone and pertussis toxin.
In the present study, histopathological analysis of rat mesentery was used to quantify the effect of two anti-inflammatory agents, dexamethasone (Dex) and pertussis toxin (Ptx), on leukocyte migration. The intravenous injection of Dex (1 mg/kg) and Ptx (1,200 ng) 1 h prior to the intraperitoneal injection of the inflammatory stimuli lipopolysaccharide (LPS) or formyl-methionyl-leucyl-phenylalanine (fMLP) significantly reduced the neutrophil diapedesis (LPS: Ptx = 0.86 +/- 0.19 and Dex = 0.35 +/- 0.13 vs saline (S) = 2.85 +/- 0.59; fMLP: Ptx = 0.43 +/- 0.09 and Dex 0.01 +/- 0.01 vs S = 1.08 +/- 0.15 neutrophil diapedesis/field) and infiltration (LPS: Ptx = 6.29 +/- 1.4 and Dex = 3.06 +/- 0.76 vs S = 15.94 +/- 3.97; fMLP: Ptx = 3.85 +/- 0.56 and Dex = 0.40 +/- 0.16 vs S = 7.15 +/- 1.17 neutrophils/field) induced by the two agonists in the rat mesentery. The inhibitory effect of Dex and Ptx was clearly visible in the fields nearest the venule (up to 200 microns), demonstrating that these anti-inflammatory agents act preferentially in the transmigration of neutrophils from the vascular lumen into the interstitial space, but not in cell movement in response to a haptotactic gradient. The mesentery of rats pretreated with Dex showed a decreased number of neutrophils within the venules (LPS: Dex = 1.50 +/- 0.38 vs S = 4.20 +/- 1.01; fMLP: Dex = 0.25 +/- 0.11 vs S = 2.20 +/- 0.34 neutrophils in the lumen/field), suggesting that this inhibitor may be acting at a step that precedes neutrophil arrival in the inflamed tissue. In contrast to that observed with Dex treatment, the number of neutrophils found in mesenteric venules was significantly elevated in animals pretreated with Ptx (LPS: Ptx = 9.85 +/- 2.25 vs S = 4.20 +/- 1.01; fMLP: Ptx = 4.66 +/- 1.24 vs S = 2.20 +/- 0.34 neutrophils in the lumen/field). This discrepancy shows that Ptx and Dex act via different mechanisms and suggests that Ptx prevents locomotion of neutrophils from the vascular lumen to the interstitial space. In conclusion, the method described here is useful for quantifying the inflammatory and anti-inflammatory effect of different substances. The advantage of this histopathological approach is that it provides additional information about the steps involved in leucocyte migration.


The prognostic meaning of the full spectrum of aVR ST-segment changes in acute myocardial infarction.
ST-elevation in lead aVR is known to be associated with a worse prognosis in patients with acute ST elevation myocardial infarction (MI) but the significance of ST depression in lead aVR has been unclear. Infarction of the inferior apex of the left ventricle may not be appreciated on the standard 12-lead electrocardiogram (ECG) except by observing ST depression in lead aVR which is reciprocal to lead V(7). We therefore determined the prognostic value of the full spectrum of aVR ST changes in patients presenting with acute ST elevation MI. Lead aVR ST level was measured on randomization and 60 min ECGs in 15 315 patients with normal conduction from the HERO-2 trial. The outcome measure was 30-day mortality. aVR ST elevation ≥1 mm was associated with higher 30-day mortality for both inferior (22.5% for ≥1.5 mm and 13.2% for 1 mm) and anterior (23.5% for ≥1.5 mm and 11.5% for 1 mm) infarction. In contrast, deeper aVR ST depression (0, 0.5, 1, and ≥1.5 mm) was associated with higher mortality for anterior infarction (9.8, 13.2, 12.8, and 16.8%, respectively, trend P-value <0.0001) but not for inferior infarction. The resolution of aVR ST depression and ST elevation 60 min after fibrinolysis was associated with lower mortality. There is a U-shaped relationship between 30-day mortality and aVR ST level in patients presenting with anterior but not inferior ST elevation MI.


Acute inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel by thyroid hormones involves multiple mechanisms.
The chemical structures of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) resemble those of small-molecules that inhibit the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. We therefore tested the acute effects of T3, T4 and reverse T3 (rT3) on recombinant wild-type human CFTR using the patch-clamp technique. When added directly to the intracellular solution bathing excised membrane patches, T3, T4, and rT3 (all tested at 50 μM) inhibited CFTR in several ways: they strongly reduced CFTR open probability by impeding channel opening; they moderately decreased single-channel current amplitude, and they promoted transitions to subconductance states. To investigate the mechanism of CFTR inhibition, we studied T3. T3 (50 μM) had multiple effects on CFTR gating kinetics, suggestive of both allosteric inhibition and open-channel blockade. Channel inhibition by T3 was weakly voltage dependent and stronger than the allosteric inhibitor genistein, but weaker than the open-channel blocker glibenclamide. Raising the intracellular ATP concentration abrogated T3 inhibition of CFTR gating, but not the reduction in single-channel current amplitude nor the transitions to subconductance states. The decrease in single-channel current amplitude was relieved by membrane depolarization, but not the transitions to subconductance states. We conclude that T3 has complex effects on CFTR consistent with both allosteric inhibition and open-channel blockade. Our results suggest that there are multiple allosteric mechanisms of CFTR inhibition, including interference with ATP-dependent channel gating and obstruction of conformational changes that gate the CFTR pore. CFTR inhibition by thyroid hormones has implications for the development of innovative small-molecule CFTR inhibitors.


Incidence of injury in kickboxing participation.
Cardio kickboxing classes have become a popular form of exercise to enhance fitness. This study surveyed kickboxing participants and instructors to ascertain the severity, type, and incidence of injuries sustained while performing cardio kickboxing exercise. The respondents consisted of 77.4% instructors and 29.3% participants with a mean age of 32.29 years (+/-8.98 years). Injury from kickboxing exercise was reported by 29.3% of the respondents, 31% of the instructors, and 15.5% of the participants. The most common site of injury for instructors was the back, followed by the knee, hip, and shoulder. The most common site of injury for participants was the back, knee, and ankle. Strains were the most common type of injury reported, followed by sprains and tendinitis. More than half of the injuries reported were new injuries (64%), with almost 59% of the total injuries reported causing a disruption of the normal exercise routine or an alteration of normal daily activities. Instructors who reported using music speeds greater than 140 beats per minute had a higher incidence of injury, compared with instructors who used music between 125 and 139 beats per minute. The wrist and elbow had the highest percentage of new injuries reported. This study suggests that kickboxing exercise can be a safe form of exercise for fitness purposes. Keeping music speeds below 140 beats per minute and limiting the number of kickboxing sessions per week may help to reduce injury rates.


Discovery and validation of plasma biomarkers for major depressive disorder classification based on liquid chromatography-mass spectrometry.
Major depressive disorder (MDD) is a debilitating mental disease with a pronounced impact on the quality of life of many people; however, it is still difficult to diagnose MDD accurately. In this study, a nontargeted metabolomics approach based on ultra-high-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to find the differential metabolites in plasma samples from patients with MDD and healthy controls. Furthermore, a validation analysis focusing on the differential metabolites was performed in another batch of samples using a targeted approach based on the dynamic multiple reactions monitoring method. Levels of acyl carnitines, ether lipids, and tryptophan pronouncedly decreased, whereas LPCs, LPEs, and PEs markedly increased in MDD subjects as compared with the healthy controls. Disturbed pathways, mainly located in acyl carnitine metabolism, lipid metabolism, and tryptophan metabolism, were clearly brought to light in MDD subjects. The binary logistic regression result showed that carnitine C10:1, PE-O 36:5, LPE 18:1 sn-2, and tryptophan can be used as a combinational biomarker to distinguish not only moderate but also severe MDD from healthy control with good sensitivity and specificity. Our findings, on one hand, provide critical insight into the pathological mechanism of MDD and, on the other hand, supply a combinational biomarker to aid the diagnosis of MDD in clinical usage.


High prevalence of cardiovascular risk factors in Peruvian adolescents living in a peri-urban shantytown: a cross-sectional study.
Adults of the peri-urban Peruvian shantytown of Lomas de Zapallal have a high prevalence of risk factors for developing cardiovascular disease (CVD)-likely due to behavioral choices established during childhood and adolescence. To guide the development of community-based risk reduction programs, we assessed the prevalence of risk factors for developing CVD among adolescents. We collected cross sectional data from adolescents of Peruvian peri-urban shantytown to evaluate four domains of CVD risk factors: (1) clinical (blood pressure, fasting blood glucose, and blood lipids), (2) anthropometric (height, weight, and waist circumference), (3) behavioral (physical activity, diet, and substance abuse), and (4) psychosocial (mental health and violence). We enrolled 275 adolescents (56.4% female, mean age 14 years). Prevalence of overweight or obese status was 27.8%. High blood pressure was more common in males (37.4%) than females (20.5%) (p = 0.002). Total cholesterol was elevated (>170 mg/dL) in nearly half (45.5%) of the adolescents, and 71% had impaired fasting blood glucose (>100 mg/dL). Females were less likely to exercise daily (95.4%) than males (84.2%) (p = 0.002) but reported higher rates of depression (66.4%), anhedonia (67.6%), and self-harm behavior (37.9%) (all p < 0.01). Adolescents living in the peri-urban population of Puente Piedra had high prevalence of risk factors for future development of CVD; preventative efforts focused on improving nutrition, increasing physical inactivity, and addressing mental health conditions could reduce such risk factors.


Synergistically Enhanced Mucoadhesive and Penetrable Polypeptide Nanogel for Efficient Drug Delivery to Orthotopic Bladder Cancer.
Intravesical chemotherapy has been recommended after the gold standard of transurethral resection of the bladder tumor to prevent bladder cancer (BC) from local recurrence in the clinic. However, due to rapid urine excretion and barrier protection of the bladder wall, the clinical performances of chemotherapeutic drugs are severely compromised. In the present work, a smart positively charged disulfide-crosslinked nanogel of oligoarginine-poly(ethylene glycol)-poly(L-phenylalanine-co-L-cystine) (R9-PEG-P(LP-co-LC)) was prepared to prolong the retention period and enhance the penetration capability of chemotherapeutic agent toward the bladder wall. PEG significantly improved the aqueous dispersibility of the 10-hydroxycamptothecin (HCPT)-loaded R9-PEG-P(LP-co-LC) (i.e., R9NG/HCPT) and enhanced the mucoadhesive capability by the nonspecific interaction between PEG chain and the bladder mucosa accompanied with the electrostatic interaction between the cationic R9 and negatively charged bladder mucosa. Besides, R9, as a cell-penetrating peptide, efficiently penetrated through the cell membrane and delivered carried cargo. The disulfide bond endowed the selective release behavior of HCPT triggered by the intracellular reductive microenvironment. As an advanced chemotherapeutic nanoformulation, the smart R9NG/HCPT demonstrated superior cytotoxicity against human BC 5637 cells in vitro and remarkably enhanced tumor suppression activity toward orthotopic BC models of mouse and rat in vivo, indicating its great potential in the clinical intravesical BC chemotherapy.


Intensive (pasture) beef cattle operations: the perspective of New Zealand.
Beef production in New Zealand has characteristics typical of a temperate climate and pasture-based animal husbandry. The specific pathogens which may contaminate fresh beef and which are empirically considered to be of public health importance are similar to those in other countries with temperate climates, i.e. Salmonella, Campylobacter, Escherichia coli O157:H7, Listeria monocytogenes and Toxoplasma gondii. With the exception of T. gondii, it is likely that almost all transmission of these hazards through consumption of beef results from unseen microbial cross-contamination from gastrointestinal sources during slaughter, dressing and further processing. Gaining comprehensive information on carcass contamination levels is an essential first step in establishing food safety objectives for a particular beef production system, and in designing risk-based hazard analysis and critical control point (HACCP) plans. It is likely that the lower mean and maximum numbers of indicator micro-organisms on New Zealand carcasses (when compared with other countries) are in part due to the pre-slaughter cleanliness status of cattle reared under temperate, pasture conditions. Similarly, the failure to detect specific pathogens of gastrointestinal origin in a comprehensive baseline survey most probably reflects the limited pathway for faecal contamination during slaughter and dressing under processing conditions in New Zealand. The New Zealand example provides strong evidence for the need to design HACCP plans according to the specific national (or regional) situation. Reducing all pathways for faecal contamination of products to the maximum extent practicable will be the most important factor in achieving desired food safety objectives for fresh beef. Variable densities of microbial pathogens in gastrointestinal contents are also likely to have a significant effect on subsequent contamination levels of beef carcasses: however, effective controls for limiting the presence of most pathogens of concern in the live animal have yet to be identified.


[Hemipteran diversity (Cicadellidae and Clastopteridae) in three coffee production zones affected by Xylella fastidiosa (Wells et al.) in Costa Rica].
A survey was conducted during 2002, 2003 and 2004 to determine the leafhopper species composition, abundance, richness, diversity, evenness, occurrence and flight activity among three coffee production zones of Costa Rica. Yellow sticky traps were used to qualify and quantify the number of aerial leafhoppers during the sampling period. A total of 82,500 individuals, belonging to 139 species within nine leafhopper subfamilies, were trapped. San Isidro de León Cortés site presented the highest diversity from the three surveyed sites. Twenty five species were frequently trapped at least in one of the studied zones, and only Coelidiana sp.1, Osbornellus sp.1, Scaphytopius sp.1 and Empoasca sp. were trapped throughout the sampling period. The flight activity of the taxa that contain the main vectors of Xylella fastidiosa Wells et al. showed differences among the sampling zones.


Remyelinating effect driven by transferrin-loaded extracellular vesicles.
Extracellular vesicles (EVs) are involved in diverse cellular functions, playing a significant role in cell-to-cell communication in both physiological conditions and pathological scenarios. Therefore, EVs represent a promising therapeutic strategy. Oligodendrocytes (OLs) are myelinating glial cells developed from oligodendrocyte progenitor cells (OPCs) and damaged in chronic demyelinating diseases such as multiple sclerosis (MS). Glycoprotein transferrin (Tf) plays a critical role in iron homeostasis and has pro-differentiating effects on OLs in vivo and in vitro. In the current work, we evaluated the use of EVs as transporters of Tf to the central nervous system (CNS) through the intranasal (IN) route. For the in vitro mechanistic studies, we used rat plasma EVs. Our results show that EVTf enter OPCs through clathrin-caveolae and cholesterol-rich lipid raft endocytic pathways, releasing the cargo and exerting a pro-maturation effect on OPCs. These effects were also observed in vivo using the animal model of demyelination induced by cuprizone (CPZ). In this model, IN administered Tf-loaded EVs isolated from mouse plasma reached the brain parenchyma, internalizing into OPCs, promoting their differentiation, and accelerating remyelination. Furthermore, in vivo experiments demonstrated that EVs protected the Tf cargo and significantly reduced the amount of Tf required to induce remyelination as compared to soluble Tf. Collectively, these findings unveil EVs as functional nanocarriers of Tf to induce remyelination.


Sorption of micropollutants on selected constructed wetland support matrices.
Micropollutants (MPs) are organic chemicals that are present in the environment at low concentrations (ng/L-μg/L), for example pharmaceuticals. A constructed wetland (CW) is a promising post-treatment technique to remove MPs from wastewater effluent. Selecting a suitable material for support matrix is important when designing such a CW. Nine materials were studied as potential support matrices: Light Expanded Clay Aggregates (LECA), compost, bark, granulated activated carbon (GAC), biochar, granulated cork, lava rock, sand and gravel. Batch experiments were conducted to study MP removal by nine materials in phosphate buffer with 5 or 50 μg/L MPs, or wastewater effluent with 50 μg/L of MPs. GAC and biochar removed almost all MPs in both phosphate buffer and wastewater effluent, followed by bark, compost, granulated cork. Sand, gravel, LECA and lava rock removed less than 30% of most MPs in both matrixes. Based on set criteria (e.g. removal efficiency), biochar, bark, compost, LECA and sand were selected, and used in combinations in column studies to test their overall performance. A combination of bark and biochar performed the best on MP removal, as 4 MPs were highly (70%-100%) removed, 4 MPs were moderately (30%-70%) removed while only 3 MPs were hardly removed. The main flow regime of this combination was both plug flow and dispersive flow. Moreover, we hypothesized to apply bark and biochar in a CW. Based on the assumptions and calculations, some benefits are expected, such as increasing MP removal and extending operation time.


Ischaemic Haemorrhagic Stroke in a Child with New Onset Type 1 Diabetes Mellitus.
Cerebral oedema is the most common neurological complication of diabetic ketoacidosis (DKA). However, ischaemic and haemorrhagic brain injury has been reported infrequently. A 10-year old girl who was previously well presented with severe DKA. She was tachycardic with poor peripheral perfusion but normotensive. However, two fast boluses totalling 40 ml/kg normal saline were given. She was transferred to another hospital where she was intubated due to drowsiness. Rehydration fluid (maintenance and 48-hour correction for 7.5% dehydration) was started followed by insulin infusion. She was extubated within 24 hours of admission. Her ketosis resolved soon after and subcutaneous insulin was started. However, about 48 hours after admission, her Glasgow Coma Scale score dropped to 11/15 (E4M5V2) with expressive aphasia and upper motor neuron signs. One dose of mannitol was given. Her symptoms improved gradually and at 26-month follow-up she had a near-complete recovery with only minimal left lower limb weakness. Serial magnetic resonance imaging brain scans showed vascular ischaemic injury at the frontal-parietal watershed regions with haemorrhagic transformation. This case reiterates the importance of monitoring the neurological status of patient's with DKA closely for possible neurological complications including an ischaemic and haemorrhagic stroke.


Theileria: intracellular protozoan parasites of wild and domestic ruminants transmitted by ixodid ticks.
Theileria are economically important, intra-cellular protozoa, transmitted by ixodid ticks, which infect wild and domestic ruminants. In the mammalian host, parasites infect leukocytes and erythrocytes. In the arthropod vector they develop in gut epithelial cells and salivary glands. All four intra-cellular stages of Theileria survive free in the cytoplasm. The schizont stages of certain Theileria species induce a unique, cancer-like, phenotype in infected host leukocytes. Theileria undergoes an obligate sexual cycle, involving fusion of gametes in the tick gut, to produce a transiently diploid zygote. The existence of sexual recombination in T. parva has been confirmed in the laboratory, and is presumed to contribute to the extensive polymorphism observed in field isolates. Key parameters in T. parva population dynamics are the relative importance of asymptomatic carrier cattle and animals undergoing severe disease, in transmission of the parasite to ticks, and the extent of transmission by nymphs as compared to adult ticks. Tick populations differ in vector competence for specific T. parva stocks. Recombinant forms of T. parva and T. annulata sporozoite surface antigens induce protection against parasite challenge in cattle. In future, vaccines might be improved by inclusion of tick peptides in multivalent vaccines.


Restoring consciousness with vagus nerve stimulation.
Patients lying in a vegetative state present severe impairments of consciousness [1] caused by lesions in the cortex, the brainstem, the thalamus and the white matter [2]. There is agreement that this condition may involve disconnections in long-range cortico-cortical and thalamo-cortical pathways [3]. Hence, in the vegetative state cortical activity is 'deafferented' from subcortical modulation and/or principally disrupted between fronto-parietal regions. Some patients in a vegetative state recover while others persistently remain in such a state. The neural signature of spontaneous recovery is linked to increased thalamo-cortical activity and improved fronto-parietal functional connectivity [3]. The likelihood of consciousness recovery depends on the extent of brain damage and patients' etiology, but after one year of unresponsive behavior, chances become low [1]. There is thus a need to explore novel ways of repairing lost consciousness. Here we report beneficial effects of vagus nerve stimulation on consciousness level of a single patient in a vegetative state, including improved behavioral responsiveness and enhanced brain connectivity patterns.


Acidic sphingomyelinase (ASM) is necessary for fas-induced GD3 ganglioside accumulation and efficient apoptosis of lymphoid cells.
Ceramides deriving from sphingomyelin hydrolysis are important mediators of apoptotic signals originating from Fas (APO-1/CD95). However, definitive evidence for the role played by individual sphingomyelinases is still lacking. We have analyzed lymphoblastoid cell lines derived from patients affected by Niemann Pick disease (NPD), an autosomal recessive disorder caused by loss-of-function mutations within the acidic sphingomyelinase (ASM) gene. NPD lymphoblasts, which display normal neutral sphingomyelinase activity, fail to activate ASM in response to Fas cross-linking, unlike normal lymphoblasts. NPD lymphoblasts also fail to accumulate GD3 ganglioside, a downstream mediator of ceramide-induced cell death (De Maria, R., L. Lenti, F. Malisan, F. D'Agostino, B. Tomassini, A. Zeuner, M.R. Rippo, R. Testi. 1997. Science. 277:1652-1655), and display a substantially inefficient apoptosis after Fas cross-linking. Inefficient apoptosis is due to lack of ASM activity, because proximal signaling from Fas in NPD lymphoblasts is not impaired and apoptosis can be efficiently triggered by passing the ASM defect with exogenous ceramides. Moreover, mannose receptor-mediated transfer of ASM into NPD lymphoblasts rescues their ability to transiently activate ASM, accumulate GD3, and rapidly undergo apoptosis after Fas cross-linking. These results provide definitive genetic evidence for the role of ASM in the progression of apoptotic signals originating from Fas.


Maternal exposure to magnetic fields from high-voltage power lines and the risk of birth defects.
The issue of adverse human health effects due to exposure to electromagnetic fields is still unclear, and congenital anomalies are among the outcomes that have been inconsistently associated with such exposure. We conducted a population-based, case-control study to examine the risk of congenital anomalies associated with maternal exposure to magnetic fields (MF) from high-voltage power lines during pregnancy in a community in northern Italy. We identified 228 cases of congenital malformations diagnosed in live births, stillbirths, and induced abortions among women living in the municipality of Reggio Emilia during the period 1998-2006, and a reference group of healthy newborns was matched for year of birth, maternal age, and hospital of birth. We identified maternal residence during early pregnancy and used Geographic Information System to determine whether the residences were within geocoded corridors with MF ≥0.1 μT near high-voltage power lines, then calculated the relative risk (RR) of congenital anomalies associated with maternal exposure. One case and 5 control mothers were classified as exposed, and the RR associated with MF ≥0.1 μT was 0.2 (95% CI: 0.0-2.0) after adjusting for maternal education. While small or moderate effects may have gone undetected due to low statistical power, the results of this study overall do not provide support for major effects of a teratogenic risk due to exposure to MF during early pregnancy.


Do follicular fluid advanced glycation end products levels affect the ovarian response in unexplained infertility?
To compare the advanced glycation end products (AGEs) levels in follicular fluid according to the different ovarian responses of women who underwent controlled ovarian stimulation due to unexplained infertility and to examine the relationship between these levels and pregnancy outcomes. Sixty-three women who underwent fresh IVF/ICSI cycles with GNRH antagonist protocol were divided into 3 groups according to the number of retrieved oocytes as suboptimal (4-9 oocytes), optimal (10-15 oocytes) and high (>15 oocytes) responders. AGEs levels in follicular fluid were measured by ELISA method. AGEs levels were 6.81 ± 2.20 µg/ml, 5.30 ± 2.01 and 6.44 ± 1.43 µg/ml in suboptimal, optimal and high response group, respectively. AGEs level was significantly higher in suboptimal response group than in optimal response group. The cutoff level of 6.19 µg/ml had a sensitivity of 59.3% and a specificity of 66.7% in distinguishing the suboptimal response group from the optimal response group. However, there were no statistically significant difference between AGEs levels and clinical pregnancy and live birth rates. Increased AGEs level in follicular fluid may be associated with decreased ovarian response during controlled ovarian stimulation in unexplained infertility case, however, it does not provide information about pregnancy outcomes.


[Defect coverage in the surgical therapy of advanced skin tumors].
In the operative treatment of skin cancer large excisions are often necessary. The malignant melanoma must be excised primary with the 3--5 cm safety margin depending on the localisation. Therefore a primary wound closure is not possible, and the wound must be closed in a second step with skin grafts or regional flaps. Temporary grafting of the large excision-wound with a synthetic skin substitute (Epigard) is useful to observe recurrences and to bring the wound in a good condition for grafting. In the years 1979/1980 74 malignant melanomas and 157 basal cell carcinomas and squamous cell carcinomas were treated in this manner.


Defining the Ideal Time Interval Between Planned Induction Therapy and Surgery for Stage IIIA Non-Small Cell Lung Cancer.
Induction therapy leads to significant improvement in survival for selected patients with stage IIIA non-small cell lung cancer. The ideal time interval between induction therapy and surgery remains unknown. Clinical stage IIIA non-small cell lung cancer patients receiving induction therapy and surgery were identified in the National Cancer Database. Delayed surgery was defined as greater than or equal to 3 months after starting induction therapy. A logistic regression model identified variables associated with delayed surgery. Cox proportional hazards modeling and Kaplan-Meier analysis were performed to evaluate variables independently associated with overall survival. From 2006 to 2010, 1,529 of 2,380 (64.2%) received delayed surgery. Delayed surgery patients were older (61.2 ± 10.0 years versus 60.3 ± 9.2; p = 0.03), more likely to be non-white (12.4% versus 9.7%; p = 0.046), and less likely to have private insurance (50% versus 58.2%; p = 0.002). Delayed surgery patients were also more likely to have a sublobar resection (6.3% versus 2.9%). On multivariate analysis, age greater than 68 years (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.1 to 1.7) was associated with delayed surgery, whereas white race (OR, 0.75; 95% CI, 0.57 to 0.99) and private insurance status (OR, 0.82; 95% CI, 0.68 to 0.99) were associated with early surgery. Delayed surgery was associated with higher risk of long-term mortality (hazard ratio, 1.25; 95% CI, 1.07 to 1.47). Delayed surgery after induction therapy for stage IIIA lung cancer is associated with shorter survival, and is influenced by both social and physiologic factors. Prospective work is needed to further characterize the relationship between patient comorbidities and functional status with receipt of timely surgery.


Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: A systematic review and network meta-analysis.
We performed a Bayesian network meta-analysis combining direct and indirect treatment comparisons to assess the comparative effectiveness of pharmacological agents for the treatment of nonalcoholic steatohepatitis (NASH). Through systematic literature review, we identified nine randomized, controlled trials (RCTs) including 964 patients with biopsy-proven NASH, comparing vitamin E, thiazolidinediones (TZDs), pentoxifylline, or obeticholic acid to one another or placebo. The primary outcome was improvement in fibrosis stage; secondary outcomes were improvement in ballooning degeneration, lobular inflammation, and steatosis. We reported relative risks (RRs) and 95% confidence intervals (CIs) from direct meta-analysis and 95% credible intervals (CrIs) from Bayesian network meta-analysis, and used Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to appraise quality of evidence. Moderate-quality evidence supports the use of pentoxifylline (RR, 0.26; 95% CrI: 0.05-1.00) and obeticholic acid (RR, 0.81; 95% CI: 0.70-0.95) over placebo in improving fibrosis. High-quality evidence supports the effect of vitamin E, TZDs, and obeticholic acid over placebo in improving ballooning degeneration. All four interventions seemed to have at least moderate-quality evidence over placebo to improve steatosis. Moderate-quality evidence supports that TZDs, pentoxifylline, and obeticholic acid decrease lobular inflammation. All the head-to-head comparisons were supported by very-low-quality evidence except for superiority of TZDs over vitamin E on improving steatosis and lobular inflammation, which had moderate-quality evidence. Based on direct and network meta-analysis, pentoxifylline and obeticholic acid improve fibrosis, and vitamin E, TZDs, and obeticholic acid improve ballooning degeneration in patients with NASH. Future comparative trials of combination therapies targeting distinct histological features are warranted.


Overexpression of Truncated Human DISC1 Induces Appearance of Hindbrain Oligodendroglia in the Forebrain During Development.
Genetic, neuroimaging, and gene expression studies suggest a role for oligodendrocyte (OLG) dysfunction in schizophrenia (SZ). Disrupted-in-schizophrenia 1 (DISC1) is a risk gene for major psychiatric disorders, including SZ. Overexpression of mutant truncated (hDISC1), but not full-length sequence of human DISC1 in forebrain influenced OLG differentiation and proliferation of glial progenitors in the developing cerebral cortex concurrently with reduction of OLG progenitor markers in the hindbrain. We examined gene and protein expression of the molecular determinants of hindbrain OLG development and their interactions with DISC1 in mutant hDISC1 mice. We found ectopic upregulation of hindbrain glial progenitor markers (early growth response 2 [Egr2] and NK2 homeobox 2 [Nkx2-2]) in the forebrain of hDISC1 (E15) embryos. DISC1 and Nkx2-2 were coexpressed and interacted in progenitor cells. Overexpression of truncated hDISC1 impaired interactions between DISC1 and Nkx2-2, which was associated with increased differentiation of OLG and upregulation of hindbrain mature OLG markers (laminin alpha-1 [LAMA1] and myelin protein zero [MPZ]) suggesting a suppressive function of endogenous DISC1 in OLG specialization of hindbrain glial progenitors during embryogenesis. Consistent with findings in hDISC1 mice, several hindbrain OLG markers (PRX, LAMA1, and MPZ) were significantly upregulated in the superior temporal cortex of persons with SZ. These findings show a significant effect of truncated hDISC1 on glial identity cells along the rostrocaudal axis and their OLG specification. Appearance of hindbrain OLG lineage cells and their premature differentiation may affect cerebrocortical organization and contribute to the pathophysiology of SZ.


A review of resistance training-induced changes in skeletal muscle protein synthesis and their contribution to hypertrophy.
Muscle protein synthesis (MPS) is stimulated by resistance exercise (RE) and is further stimulated by protein ingestion. The summation of periods of RE-induced increases in MPS can induce hypertrophy chronically. As such, studying the response of MPS with resistance training (RT) is informative, as adaptations in this process can modulate muscle mass gain. Previous studies have shown that the amplitude and duration of increases in MPS after an acute bout of RE are modulated by an individual's training status. Nevertheless, it has been shown that the initial responses of MPS to RE and nutrition are not correlated with subsequent hypertrophy. Thus, early acute responses of MPS in the hours after RE, in an untrained state, do not capture how MPS can affect RE-induced muscle hypertrophy. The purpose of this review is provide an in-depth understanding of the dynamic process of muscle hypertrophy throughout RT by examining all of the available data on MPS after RE and in different phases of an RT programme. Analysis of the time course and the overall response of MPS is critical to determine the potential protein accretion after an RE bout. Exercise-induced increases in MPS are shorter lived and peak earlier in the trained state than in the untrained state, resulting in a smaller overall muscle protein synthetic response in the trained state. Thus, RT induces a dampening of the MPS response, potentially limiting protein accretion, but when this occurs remains unknown.


Transcription factor activator protein-2 is required for continued luteinizing hormone-releasing hormone expression in the forebrain of developing mice.
LHRH is the neuropeptide responsible for reproductive function. Prenatally, LHRH expression begins when neurons are in the olfactory pit and continues as these cells migrate into the brain. Thus, LHRH neurons maintain neuropeptide expression through very distinct environments. The regulatory interactions that control onset and continued expression of the LHRH phenotype are unknown. To begin to address this question primary LHRH neurons were removed from nasal explants at different ages. A complementary DNA (cDNA) subtraction screen was performed comparing a 3.5-days in vitro LHRH neuron [approximately embryonic day 15 (E15) in vivo] to two 10.5-days in vitro LHRH neurons (approximately postnatal day 1 in vivo). The transcription factor activator protein-2 (AP-2alpha) was differentially expressed and was present in the developmentally younger LHRH neuron. In vivo analysis revealed that LHRH neurons expressed AP-2 as they migrated across the cribriform plate and into the forebrain beginning on E13.5, but that coexpression of LHRH and AP-2 was no longer detected in postnatal day 1 animals. This suggested a regulatory role for AP-2 in LHRH neurons. Analysis of animals lacking AP-2alpha revealed a dramatic decrease in forebrain LHRH neurons between E13.5 and E14.5, correlating with normal onset of AP-2 expression in LHRH neurons as they entered the central nervous system. Nasal cells robustly expressing LHRH were still present on E 14.5. The continued presence of forebrain LHRH cells is proposed based on a second marker, galanin, and lack of increased apoptotic/necrotic cells in this region. A decrease in LHRH messenger RNA in forebrain neurons indicates regulation of LHRH occurred at the transcriptional or posttranscriptional level in mutant animals. These results indicate a developmentally restricted involvement of the transcription factor AP-2 in LHRH expression once the LHRH neurons have migrated into the forebrain, but before establishment of an adult-like distribution.


Non-invasive determination of transcatheter pressure gradient in stenotic aortic valves: an analytical model.
Aortic stenosis (AS), in which the opening of the aortic valve is narrowed, is the most common valvular heart disease. Cardiac catheterization is considered the reference standard for definitive evaluation of AS severity, based on instantaneous systolic value of transvalvular pressure gradient (TPG). However, using invasive cardiac catheterization might carry high risks knowing that undergoing multiple cardiac catheterizations for follow-up in patients with AS is common. The objective of this study was to suggest an analytical description of the AS that estimates TPG without a need for high risk invasive data collection. For this purpose, Navier-Stokes equation coupled with the elastic-deformation equation was solved analytically. The estimated TPG resulted from the suggested analytical description was validated against published in vivo and in vitro measurement data. Very good concordances were found between TPG obtained from the analytical formulation and in vivo (maximum root mean square error: 3.8 mmHg) and in vitro (maximum root mean square error: 9.4 mmHg). The analytical description can be integrated to non-invasive imaging modalities to estimate AS severity as an alternative to cardiac catheterization to help preventing its risks in patients with AS.


Antiviral activities of 5-ethynyl-1-beta-D-ribofuranosylimidazole-4- carboxamide and related compounds.
A series of novel compounds, 5-alkynyl-1-beta-D-ribofuranosylimidazole-4- carboxamides, have been identified as broad-spectrum antiviral agents. 5-Ethynyl-1-beta-D-ribofuranosylimidazole-4- carboxamide (EICAR), the most potent congener of the group, showed antiviral potency about 10- to 100-fold greater than that of ribavirin. Similar in spectrum to ribavirin, EICAR was particularly active (50% inhibitory concentration, 0.2 to 4 micrograms/ml) against poxviruses (vaccinia virus), togaviruses (Sindbis and Semliki forest viruses), arenaviruses (Junin and Tacaribe viruses), reoviruses (reovirus type 1), orthomyxoviruses (influenza A and B viruses), and paramyxoviruses (parainfluenza virus type 3, measles virus, subacute sclerosing panencephalitis virus, and respiratory syncytial virus). EICAR was also cytostatic for rapidly growing cells (50% inhibitory concentration, 0.2 to 0.9 microgram/ml). EICAR inhibited vaccinia virus tail lesion formation at doses that were not toxic to the host. EICAR is a candidate antiviral drug for the treatment of pox-, toga-, arena-, reo-, orthomyxo, and paramyxovirus infections.


Cobb's collar: a rare cause of urinary retention.
Cobb's collar is a membranous stricture of the bulbar urethra, often misdiagnosed, potentially leading to acute urinary retention, upper urinary tract dilations, enuresis, infectious diseases, poor streaming and haematuria. A 14-year-old boy with a history of previous hospitalisations came to our attention. A Cobb's collar was diagnosed and successfully managed with a videoendoscopic one-step approach. Although extremely uncommon, paediatric urologists must be aware of this congenital anomaly. A correct and timely diagnosis and endoscopic management may affect positively the clinical onset of these patients avoiding major urethral surgery and preserving renal and bladder function.