Neuroendocrine Consequences of Binge Alcohol Exposure During Peri-Puberty on Functioning of the Hypothalamo-Pituitary-Adrenal (HPA) Axis

Binge alcohol (EtOH) exposure in adolescence is a fundamental health concern. In 2005, over 20% of teenagers between ages 15 and 17 reported binge drinking behavior within a one month period preceding the survey (Dept. of Health and Human Services: Substance Abuse and Mental Health Services Administration). Binge drinking is defined as consuming enough alcohol within a 2.0 h period to bring blood alcohol concentration above 0.08%. In the adolescent population, this type of alcohol exposure tends to be repeated. In adults, alcohol abuse has been correlated with increased incidence of mood disorders and these disorders are characterized by dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, a three tiered biological system that mediates physiological stress response. Corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) localized in the paraventricular nucleus (PVN) of the hypothalamus are the major neuropeptides involved in modulating HPA axis responses to stress. Corticosterone (CORT) in rodents, and cortisol in humans, is a major glucocorticoid hormone released into the circulation upon activation of the HPA axis. Puberty is a period during which extensive maturation occurs, yet our knowledge of the nurobiological consequences of binge EtOH exposure during this time period is severely limited. I sought to investigate the neuroendocrine consequences of EtOH exposure during pubertal maturation and tested the hypothesis that EtOH exposure during puberty has long lasting detrimental consequences for a proper maturation of the HPA axis. My data revealed that repeated binge-pattern EtOH exposure resulted in a sex specific dysregulation of the HPA axis in pubertal rats. This was marked by an increase in the expression of CRH and AVP mRNA in the male, but not female, PVN. Notably, in both sexes, both single and repeated binge EtOH exposures resulted in increased circulating CORT levels and habituation effects. These results suggested that repeated binge-like EtOH exposure differentially dysregulated the HPA axis in males compared to females (Przybycien-Szymanska et al., AJP Endocrin. and Metabol., 2010). My data further showed that the sex steroid hormone, 17β-estradiol, is required for the maintenance of steady state levels of CRH and AVP mRNA in the PVN of pubertal female rats and for the habituation effects observed in CORT responses after repeated binge-pattern EtOH exposure. Most striking, these results showed that in males, binge-pattern EtOH exposure during puberty resulted in the dysregulation of adult HPA axis. This was evidenced by 1) increased adult basal levels of CRH mRNA in the PVN and lower basal circulating CORT levels, 2) differential patterns of CRH and AVP mRNA expression in the PVN after subsequent EtOH exposures in adulthood, 3) enhanced circulating CORT increase after single or repeated binge-like exposures in adulthood, 4) lack of habituation in CORT response after adult repeated binge pattern EtOH exposure (Przybycien-Szymanska et al., PLoS One, 2011). In addition, I investigated the molecular mechanisms involved in the observed EtOH-induced increase in the CRH mRNA in the PVN. Increased gene expression correlates closely with increased gene promoter activity; therefore I tested whether EtOH affects CRH promoter activity and whether glucocorticoid negative feedback at the promoter was dysregulated by EtOH. My data showed that EtOH exerts a biphasic effects on the activity of the CRH promoter and these effects are blocked by glucocorticoid receptor (GR) antagonist and deletion of glucocorticoid response element site (a binding site for GR) on CRH promoter. These results indicated that EtOH dysregulates functioning of the HPA axis by interfering with normal negative glucocorticoid feedback mechanism exerted on CRH promoter. Moreover, I showed that 17β-estradiol prevented the EtOH-induced increase in CRH promoter activity supporting a role of this hormone in the sexually dimorphic changes of CRH mRNA in the PVN after EtOH exposure. In conclusion, my data showed that binge-pattern EtOH exposure during puberty has long lasting effects on the HPA axis. These effects are manifested by alterations in PVN expression of neuropeptides involved in modulating stress responses and glucocorticoid hormone signaling. These effects are caused by EtOH-induced dysregulation of glucocorticoid negative feedback normally exerted at the level of the gene promoter in the PVN and may lead to increased risk for mood disorders in adulthood

MicroRNA expression patterns in canine mammary cancer show significant differences between metastatic and non-metastatic tumours

Background MicroRNAs may act as oncogenes or tumour suppressor genes, which make these small molecules potential diagnostic/prognostic factors and targets for anticancer therapies. Several common oncogenic microRNAs have been found for canine mammary cancer and human breast cancer. On account of this, large- scale profiling of microRNA expression in canine mammary cancer seems to be important for both dogs and humans. Methods Expression profiles of 317 microRNAs in 146 canine mammary tumours of different histological type, malignancy grade and clinical history (presence/absence of metastases) and in 25 control samples were evaluated. The profiling was performed using microarrays. Significance Analysis of Microarrays test was applied in the analysis of microarray data (both unsupervised and supervised data analyses were performed). Validation of the obtained results was performed using real- time qPCR. Subsequently, predicted targets for the microRNAs were searched for in miRBase. Results Results of the unsupervised analysis indicate that the primary factor separating the samples is the metastasis status. Predicted targets for microRNAs differentially expressed in the metastatic vs. non- metastatic group are mostly engaged in cell cycle regulation, cell differentiation and DNA-damage repair. On the other hand, the supervised analysis reveals clusters of differentially expressed microRNAs unique for the tumour type, malignancy grade and metastasis factor. Conclusions The most significant difference in microRNA expression was observed between the metastatic and non-metastatic group, which suggests a more important role of microRNAs in the metastasis process than in the malignant transformation. Moreover, the differentially expressed microRNAs constitute potential metastasis markers. However, validation of cfa-miR-144, cfa-miR-32 and cfa- miR-374a levels in blood samples did not follow changes observed in the non- metastatic and metastatic tumours

Anemia in Patients With Resistance to Thyroid Hormone α: A Role for Thyroid Hormone Receptor α in Human Erythropoiesis

Context: Patients with resistance to thyroid hormone (TH) α (RTHα) are characterized by growth retardation, macrocephaly, constipation, and abnormal thyroid function tests. In addition, almost all RTHα patients have mild anemia, the pathogenesis of which is unknown. Animal studies suggest an important role for TH and TH receptor (TR)α in erythropoiesis.Objective: To investigate whether a defect in TRα affects the maturation of red blood cells in RTHα patients.Design, Setting, and Patients: Cultures of primary human erythroid progenitor cells (HEPs), from peripheral blood of RTHα patients (n = 11) harboring different inactivating mutations in TRα (P398R, F397fs406X, C392X, R384H, A382fs388X, A263V, A263S), were compared with healthy controls (n = 11). During differentiation, erythroid cells become smaller, accumulate hemoglobin, and express different cell surface markers. We assessed cell number and cell size, and used cell staining and fluorescence-activated cell sorter analysis to monitor maturation at different time points.Results: After ∼14 days of ex vivo expansion, both control and patient-derived progenitors differentiated spontaneously. However, RTHα-derived cells differentiated more slowly. During spontaneous differentiation, RTHα-derived HEPs were larger, more positive for c-Kit (a proliferation marker), and less positive for glycophorin A (a differentiation marker). The degree of abnormal spontaneous maturation of RTHα-derived progenitors did not correlate with severity of underlying TRα defect. Both control and RTHα-derived progenitors responded similarly when differentiation was induced. T3 exposure accelerated differentiation of both control- and RTHα patient-derived HEPs.Conclusions: Inactivating mutations in human TRα affect the balance between proliferation and differentiation of progenitor cells d

We Do Not Like It: A Likert-Type Scale Survey on the Attitudes of a Young Population towards the Transhumanistic Theory of Education

Transhumanists assume that future education may be purely based on technological stimulation. The question is: Do potential clients of education “like” such vision? In order to check this, we asked over one thousand two hundred young Poles to evaluate their identification with the transhumanistic theory of education. The results are quite surprising: its show that they disagree with the assumptions of this theory, while they rather agree with the postulates of more traditional (and no technology-based) concepts of education

Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis:Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors

Objective: To investigate the efficacy and safety of ixekizumab in patients with active radiographic axial spondyloarthritis (SpA) and prior inadequate response to or intolerance of 1 or 2 tumor necrosis factor inhibitors (TNFi). Methods: In this phase III randomized, double-blind, placebo-controlled trial, adult patients with an inadequate response to or intolerance of 1 or 2 TNFi and an established diagnosis of axial SpA (according to the Assessment of SpondyloArthritis international Society [ASAS] criteria for radiographic axial SpA, with radiographic sacroiliitis defined according to the modified New York criteria and ≥1 feature of SpA) were recruited and randomized 1:1:1 to receive placebo or 80-mg subcutaneous ixekizumab every 2 weeks (IXEQ2W) or 4 weeks (IXEQ4W), with an 80-mg or 160-mg starting dose. The primary end point was 40% improvement in disease activity according to the ASAS criteria (ASAS40) at week 16. Secondary outcomes and safety were also assessed. Results: A total of 316 patients were randomized to receive placebo (n = 104), IXEQ2W (n = 98), or IXEQ4W (n = 114). At week 16, significantly higher proportions of IXEQ2W patients (n = 30 [30.6%]; P = 0.003) or IXEQ4W patients (n = 29 [25.4%]; P = 0.017) had achieved an ASAS40 response versus the placebo group (n = 13 [12.5%]), with statistically significant differences reported as early as week 1 with ixekizumab treatment. Statistically significant improvements in disease activity, function, quality of life, and spinal magnetic resonance imaging–evident inflammation were observed after 16 weeks of ixekizumab treatment versus placebo. Treatment-emergent adverse events (AEs) with ixekizumab treatment were more frequent than with placebo. Serious AEs were similar across treatment arms. One death was reported (IXEQ2W group). Conclusion: Ixekizumab treatment for 16 weeks in patients with active radiographic axial SpA and previous inadequate response to or intolerance of 1 or 2 TNFi yields rapid and significant improvements in the signs and symptoms of radiographic axial SpA versus placebo

Anemia in Patients With Resistance to Thyroid Hormone α: A Role for Thyroid Hormone Receptor α in Human Erythropoiesis

Context: Patients with resistance to thyroid hormone (TH) α (RTHα) are characterized by growth retardation, macrocephaly, constipation, and abnormal thyroid function tests. In addition, almost all RTHα patients have mild anemia, the pathogenesis of which is unknown. Animal studies suggest an important role for TH and TH receptor (TR)α in erythropoiesis. Objective: To investigate whether a defect in TRα affects the maturation of red blood cells in RTHα patients. Design, Setting, and Patients: Cultures of primary human erythroid progenitor cells (HEPs), from peripheral blood of RTHα patients (n = 11) harboring different inactivating mutations in TRα (P398R, F397fs406X, C392X, R384H, A382fs388X, A263V, A263S), were compared with healthy controls (n = 11). During differentiation, erythroid cells become smaller, accumulate hemoglobin, and express different cell surface markers. We assessed cell number and cell size, and used cell staining and fluorescence-activated cell sorter analysis to monitor maturation at different time points. Results: After ∼14 days of ex vivo expansion, both control and patient-derived progenitors differentiated spontaneously. However, RTHα-derived cells differentiated more slowly. During spontaneous differentiation, RTHα-derived HEPs were larger, more positive for c-Kit (a proliferation marker), and less positive for glycophorin A (a differentiation marker). The degree of abnormal spontaneous maturation of RTHα-derived progenitors did not correlate with severity of underlying TRα defect. Both control and RTHα-derived progenitors responded similarly when differentiation was induced. T3 exposure accelerated differentiation of both control- and RTHα patient-derived HEPs. Conclusions: Inactivating mutations in human TRα affect the balance between proliferation and differentiation of progenitor cells during erythropoiesis, which may contribute to the mild anemia seen in most RTHα patients.A.L.M.v.G., M.E.M., and R.P.P. are supported by ZonMWTOP Grant 91212044 and an Erasmus MC Medical Research Advisory Committee (MRACE) grant. A.L.M.v.G. and R.P.P. are also supported by a European Thyroid Association (ETA) research grant. K. Chatterjee is supported by Wellcome Trust Investigator Award 095564/Z/11/Z. K. Chatterjee and C.M. are supported by the National Institute for Health Research Cambridge Biomedical Research Centre

Technical Design Report for the: PANDA Micro Vertex Detector

This document illustrates the technical layout and the expected performance of the Micro Vertex Detector (MVD) of the PANDA experiment. The MVD will detect charged particles as close as possible to the interaction zone. Design criteria and the optimisation process as well as the technical solutions chosen are discussed and the results of this process are subjected to extensive Monte Carlo physics studies. The route towards realisation of the detector is outlined.Comment: 189 pages, 225 figures, 41 table

Silica-supported chlorometallate(III) ionic liquids as recyclable catalysts for Diels–Alder reaction under solventless conditions

The first catalytic application of supported chlorometallate(iii) ionic liquids as recyclable heterogeneous catalysts for a Diels–Alder reaction under solventless conditions.</p

Tyrosinemia type III in an asymptomatic girl

Tyrosinemia type 3 (HT3) is a rare inborn error of tyrosine metabolism caused by mutations in the HPD gene encoding 4-hydroxyphenyl-pyruvate dioxygenase, which is transmitted in an autosomal recessive trait. The disorder is characterized by tyrosine accumulation in body fluids and massive excretion of tyrosine derivatives into urine (www.orpha.net). Since it is the least frequent form of tyrosinemia, only few cases with the variable but rather mild clinical features have been described so far. We report an 11 year old girl presenting with no clinical symptoms and with normal mental development who has been diagnosed with HT3 through metabolic screening on the basis of elevated serum level of tyrosine ranging from 425 to 535 μmol/L (normal values: 29–86 μmol/L), and elevated urinary excretion of p-hydroxyphenyl derivatives confirmed genetically with the homozygous c.479A>G (p.Tyr160Cys) missense change in the HPD gene. The girl has been only presenting with recurrent proteinuria of unknown etiology. A phenylalanine- and tyrosine-restricted diet has never been administered. Presented case may suggest that high tyrosine concentration itself does not participate directly in neuronal damage described in patients with tyrosinemia type 3

Mediastinal lymphangioma in an adult with a tracheal bronchus

Introduction. Lymphangiomas, also known as cystic hygromas or cystic lymphangiomas, are cystic abnormalities of the lymph vessels and they are rare benign tumors. Tracheal bronchus (Bronchus suis or “pig bronchus”) is a very rare congenital anomaly. The aim of this work is to present а very rare case of а lymphangioma with tracheal bronchus. Case outline. The article presents the rare case of a 35-year-old otherwise healthy man, who was admitted to our thoracic surgery department with a mediastinal tumor. On performing bronchoscopy a tracheal bronchus was found. A thoracic CT scan revealed a well-circumscribed mass in the superior and anterior mediastinum measuring 37 x 39 x 59 mm. First a Carlens mediastinoscopy, and then a right parasternal Chamberlain mediastinotomy were performed. The final pathological diagnosis of lymphangioma was made. In this case, surgery was not performed because the patient was asymptomatic and the tumor did not grow larger during follow-up. Conclusion. The lymphangioma of the mediastinum in an adult is a rare and benign condition with a good prognosis, but it should be considered in a differential diagnosis of mediastinal tumors. We recommend only a minimally invasive diagnostic approach (parasternal mediastinotomy) when the patient is asymptomatic