Neurofibromatosis type 1: Modeling CNS dysfunction

Neurofibromatosis type 1 (NF1) is the most common monogenic disorder in which individuals manifest central nervous system (CNS) abnormalities. Affected individuals develop glial neoplasms (optic gliomas, malignant astrocytomas) and neuronal dysfunction (learning disabilities, attention deficits). Nf1 genetically-engineered mouse models have revealed the molecular and cellular underpinnings of gliomagenesis, attention deficit, and learning problems with relevance to basic neurobiology. Using NF1 as a model system, these studies have revealed critical roles for the NF1 gene in non-neoplastic cells in the tumor microenvironment, the importance of brain region heterogeneity, novel mechanisms of glial growth regulation, the neurochemical bases for attention deficit and learning abnormalities, and new insights into neural stem cell function. Here we review recent studies, presented at a symposium at the 2012 Society for Neuroscience annual meeting, that highlight unexpected cell biology insights into RAS and cyclic AMP pathway effects on neural progenitor signaling, neuronal function, and oligodendrocyte lineage differentiation

Efecto de la aplicación de plasma seminal, GnRH y ablación folicular sobre la dinámica folicular en llamas (Lama glama)

The study aimed to evaluate the effect of applying seminal plasma, a GnRH analogue and follicular ablation on the follicular dynamic in llamas. The study was carried out in Puno, Peru, using 24 llamas selected under the criterion of presenting a preovulatory follicle >7 mm, determined by transrectal ultrasound. The animals were randomly distributed into four groups: T1, 1 ml PBS IM; T2, 2 ml seminal plasma IM; T3, 1 ml GnRH IM; T4, follicular ablation. The animals were evaluated, by transrectal ultrasound, every 2 h between 20 and 36 h post-treatment to determine ovulation; subsequently daily until day 9 and then every 2 days until day 15 post-stimulation to determine the interval to the emergence of a new follicular wave, the appearance of the new dominant follicle and the diameter of the corpus luteum on day 8 of treatment. No significant difference (p<0.05) was found between treatments in the variables under study. It is possible that there are other factors that could affect the interval to the emergence of a new follicular wave.El presente estudio tuvo como objetivo evaluar el efecto de la aplicación de plasma seminal, un análogo de GnRH y la ablación folicular sobre la dinámica folicular en llamas. El estudio se realizó en Puno, Perú, utilizando 24 llamas seleccionadas bajo el criterio de presentar un folículo preovulatorio >7 mm, determinado mediante ecografía transrectal. Las llamas fueron distribuidas aleatoriamente en cuatro grupos: T1, 1 ml PBS IM; T2, 2 ml plasma seminal IM; T3, 1 ml GnRH IM; T4, ablación folicular. Los animales fueron evaluados, mediante ecografía transrectal, cada 2 h entre las 20 hasta las 36 h post-tratamiento para determinar la ovulación; posteriormente en forma diaria hasta el día 9 y luego cada 2 días hasta el día 15 pos-estímulo para determinar el intervalo a la emergencia de una nueva onda folicular, la aparición del nuevo folículo dominante y el diámetro del cuerpo lúteo al día 8 del tratamiento. No se encontró diferencia significativa (p<0.05) entre tratamientos en las variables en estudio. Es posible que existan otros factores que podrían afectar el intervalo a la emergencia de una nueva onda folicular

Prediction of Children\u27s Early Academic Adjustment from Their Temperament: The Moderating Role of Peer Temperament

The goal of the study was to examine whether target children’s temperamental negative emotional expressivity (NEE) and effortful control in the fall of kindergarten predicted academic adjustment in the spring and whether a classmate’s NEE and effortful control moderated these relations. Target children’s NEE and effortful control were measured in the fall via multiple methods, academic adjustment was measured via reading and math standardized tests in the spring, and observations of engagement in the classroom were conducted throughout the year. In the fall, teachers nominated a peer with whom each target child spent the most time and rated that peer’s temperament. Target children with high effortful control had high reading and math achievement (ps = .04 and \u3c .001, respectively), and children with low NEE increased in engagement during the year (p \u3c .001). Peers’ temperament did not have a direct relation to target children’s academic adjustment. Peers’ NEE, however, moderated the relation between target children’s effortful control, as well as NEE, and changes in engagement (ps = .03 and .05, respectively). Further, peers’ effortful control moderated the relations between target children’s NEE and reading and changes in engagement (ps = .02 and .04, respectively). In each case, target children’s temperament predicted the outcome in expected directions more strongly when peers had low NEE or high effortful control. Results are discussed in terms of how children’s temperamental qualities relate to academic adjustment, and how the relation between NEE and changes in engagement, in particular, depends on peers’ temperament

Solid malignancies among etanercept‐treated patients with granulomatosis with polyangiitis (Wegener's): Long‐term followup of a multicenter longitudinal cohort

Objective An association between therapeutic inhibition of tumor necrosis factor (TNF) and solid malignancies was observed during the Wegener's Granulomatosis Etanercept Trial (WGET), which included 180 patients with granulomatosis with polyangiitis (Wegener's) (GPA). The present study was conducted to determine the malignancy risk beyond the time of exposure to study therapy. Methods The occurrence and type of solid malignancies were ascertained using a standardized data form. Data collected included vital status, histologic findings, and therapeutic interventions. The Surveillance, Epidemiology, and End‐Results database was used to estimate a standardized incidence rate (SIR) for solid malignancies. Results Post‐trial followup data were available for 153 patients (85% of the original cohort), with a median followup time of 43 months. Fifty percent of these patients had received etanercept. There were no differences in demographic characteristics between the etanercept and placebo groups. Thirteen new solid malignancies were detected, 8 in the etanercept group and 5 in the placebo group. Compared to the general population, the risk of solid malignancies in the etanercept group was increased (SIR 3.92 [95% confidence interval 1.69–7.72]), but was not different from the risk in the placebo group compared to the general population (SIR 2.89 [95% confidence interval 0.94–6.73]). All solid malignancies occurred in patients who had been exposed to cyclophosphamide. The overall duration of disease and a history of malignancy before trial enrollment were associated with the development of malignancy during post‐trial followup. Conclusion The incidence of solid malignancy remained increased during long‐term followup of the WGET cohort. However, this could not be attributed solely to etanercept exposure during the trial. Anti‐TNF therapy with etanercept appears to further increase the risk of malignancy observed in patients with GPA treated with cytotoxic agents and should be avoided in these patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87143/1/30394_ftp.pd

Treatment outcomes of new tuberculosis patients hospitalized in Kampala, Uganda: a prospective cohort study.

BACKGROUND: In most resource limited settings, new tuberculosis (TB) patients are usually treated as outpatients. We sought to investigate the reasons for hospitalisation and the predictors of poor treatment outcomes and mortality in a cohort of hospitalized new TB patients in Kampala, Uganda. METHODS AND FINDINGS: Ninety-six new TB patients hospitalised between 2003 and 2006 were enrolled and followed for two years. Thirty two were HIV-uninfected and 64 were HIV-infected. Among the HIV-uninfected, the commonest reasons for hospitalization were low Karnofsky score (47%) and need for diagnostic evaluation (25%). HIV-infected patients were commonly hospitalized due to low Karnofsky score (72%), concurrent illness (16%) and diagnostic evaluation (14%). Eleven HIV uninfected patients died (mortality rate 19.7 per 100 person-years) while 41 deaths occurred among the HIV-infected patients (mortality rate 46.9 per 100 person years). In all patients an unsuccessful treatment outcome (treatment failure, death during the treatment period or an unknown outcome) was associated with duration of TB symptoms, with the odds of an unsuccessful outcome decreasing with increasing duration. Among HIV-infected patients, an unsuccessful treatment outcome was also associated with male sex (P = 0.004) and age (P = 0.034). Low Karnofsky score (aHR = 8.93, 95% CI 1.88 - 42.40, P = 0.001) was the only factor significantly associated with mortality among the HIV-uninfected. Mortality among the HIV-infected was associated with the composite variable of CD4 and ART use, with patients with baseline CD4 below 200 cells/µL who were not on ART at a greater risk of death than those who were on ART, and low Karnofsky score (aHR = 2.02, 95% CI 1.02 - 4.01, P = 0.045). CONCLUSION: Poor health status is a common cause of hospitalisation for new TB patients. Mortality in this study was very high and associated with advanced HIV Disease and no use of ART

Tissue-Based Mapping of the Fathead Minnow (Pimephales promelas) Transcriptome and Proteome

Omics approaches are broadly used to explore endocrine and toxicity-related pathways and functions. Nevertheless, there is still a significant gap in knowledge in terms of understanding the endocrine system and its numerous connections and intricate feedback loops, especially in non-model organisms. The fathead minnow (Pimephales promelas) is a widely used small fish model for aquatic toxicology and regulatory testing, particularly in North America. A draft genome has been published, but the amount of available genomic or transcriptomic information is still far behind that of other more broadly studied species, such as the zebrafish. Here, we used a proteogenomics approach to survey the tissue-specific proteome and transcriptome profiles in adult male fathead minnow. To do so, we generated a draft transcriptome using short and long sequencing reads from liver, testis, brain, heart, gill, head kidney, trunk kidney, and gastrointestinal tract. We identified 30,378 different putative transcripts overall, with the assembled contigs ranging in size from 264 to over 9,720 nts. Over 17,000 transcripts were >1,000 nts, suggesting a robust transcriptome that can be used to interpret RNA sequencing data in the future. We also performed RNA sequencing and proteomics analysis on four tissues, including the telencephalon, hypothalamus, liver, and gastrointestinal tract of male fish. Transcripts ranged from 0 to 600,000 copies per gene and a large portion were expressed in a tissue-specific manner. Specifically, the telencephalon and hypothalamus shared the most expressed genes, while the gastrointestinal tract and the liver were quite distinct. Using protein profiling techniques, we identified a total of 4,045 proteins in the four tissues investigated, and their tissue-specific expression pattern correlated with the transcripts at the pathway level. Similarly to the findings with the transcriptomic data, the hypothalamus and telencephalon had the highest degree of similarity in the proteins detected. The main purpose of this analysis was to generate tissue-specific omics data in order to support future aquatic ecotoxicogenomic and endocrine-related studies as well as to improve our understanding of the fathead minnow as an ecological model

WHO/ILO work-related burden of disease and injury: Protocol for systematic reviews of occupational exposure to solar ultraviolet radiation and of the effect of occupational exposure to solar ultraviolet radiation on melanoma and non-melanoma skin cancer

Background: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing a joint methodology for estimating the national and global work-related burden of disease and injury (WHO/ILO joint methodology), with contributions from a large network of experts. In this paper, we present the protocol for two systematic reviews of parameters for estimating the number of deaths and disability-adjusted life years from melanoma and non-melanoma skin cancer (or keratinocyte carcinoma) from occupational exposure to solar ultraviolet radiation, to inform the development of the WHO/ILO joint methodology. Objectives: We aim to systematically review studies on occupational exposure to solar ultraviolet radiation (Systematic Review 1) and systematically review and meta-analyse estimates of the effect of occupational exposure to solar ultraviolet radiation on melanoma and non-melanoma skin cancer (Systematic Review 2), applying the Navigation Guide systematic review methodology as an organizing framework and conducting both systematic reviews in tandem and in a harmonized way. Data sources: Separately for Systematic Reviews 1 and 2, we will search electronic academic databases for potentially relevant records from published and unpublished studies, including Ovid Medline, PubMed, EMBASE, and Web of Science. We will also search electronic grey literature databases, Internet search engines and organizational websites; hand-search reference list of previous systematic reviews and included study records and consult additional experts. Study eligibility and criteria: We will include working-age ( 6515 years) workers in the formal and informal economy in any WHO and/or ILO Member State, but exclude children (<15 years) and unpaid domestic workers. For Systematic Review 1, we will include quantitative studies on the prevalence of relevant levels of occupational exposure to solar ultraviolet radiation (i.e. <0.33 SED/d and 650.33 SED/d) and of the total working time spent outdoors, stratified by country, sex, age and industrial sector or occupation, in the years 1960 to 2018. For Systematic Review 2, we will include randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies with an estimate of the effect of any occupational exposure to solar ultraviolet radiation (i.e., 650.33 SED/d) on the prevalence of, incidence of or mortality due to melanoma and non-melanoma skin cancer, compared with the theoretical minimum risk exposure level (i.e. <0.33 SED/d). Study appraisal and synthesis methods: At least two review authors will independently screen titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. At least two review authors will assess the risk of bias and the quality of evidence, using the most suited tools currently available. For Systematic Review 2, if feasible, we will combine relative risks using meta-analysis. We will report results using the guidelines for accurate and transparent health estimates reporting (GATHER) for Systematic Review 1 and the preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA) for Systematic Review 2. PROSPERO registration number: CRD42018094817