The GATA1s isoform is normally down-regulated during terminal haematopoietic differentiation and over-expression leads to failure to repress MYB, CCND2 and SKI during erythroid differentiation of K562 cells

Background: Although GATA1 is one of the most extensively studied haematopoietic transcription factors little is currently known about the physiological functions of its naturally occurring isoforms GATA1s and GATA1FL in humans—particularly whether the isoforms have distinct roles in different lineages and whether they have non-redundant roles in haematopoietic differentiation. As well as being of general interest to understanding of haematopoiesis, GATA1 isoform biology is important for children with Down syndrome associated acute megakaryoblastic leukaemia (DS-AMKL) where GATA1FL mutations are an essential driver for disease pathogenesis. <p/>Methods: Human primary cells and cell lines were analyzed using GATA1 isoform specific PCR. K562 cells expressing GATA1s or GATA1FL transgenes were used to model the effects of the two isoforms on in vitro haematopoietic differentiation. <p/>Results: We found no evidence for lineage specific use of GATA1 isoforms; however GATA1s transcripts, but not GATA1FL transcripts, are down-regulated during in vitro induction of terminal megakaryocytic and erythroid differentiation in the cell line K562. In addition, transgenic K562-GATA1s and K562-GATA1FL cells have distinct gene expression profiles both in steady state and during terminal erythroid differentiation, with GATA1s expression characterised by lack of repression of MYB, CCND2 and SKI. <p/>Conclusions: These findings support the theory that the GATA1s isoform plays a role in the maintenance of proliferative multipotent megakaryocyte-erythroid precursor cells and must be down-regulated prior to terminal differentiation. In addition our data suggest that SKI may be a potential therapeutic target for the treatment of children with DS-AMKL

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Expression and function of G-protein-coupled receptorsin the male reproductive tract

This review focuses on the expression and function of muscarinic acetylcholine receptors (mAChRs), α1-adrenoceptors and relaxin receptors in the male reproductive tract. The localization and differential expression of mAChR and α1-adrenoceptor subtypes in specific compartments of the efferent ductules, epididymis, vas deferens, seminal vesicle and prostate of various species indicate a role for these receptors in the modulation of luminal fluid composition and smooth muscle contraction, including effects on male fertility. Furthermore, the activation of mAChRs induces transactivation of the epidermal growth factor receptor (EGFR) and the Sertoli cell proliferation. The relaxin receptors are present in the testis, RXFP1 in elongated spermatids and Sertoli cells from rat, and RXFP2 in Leydig and germ cells from rat and human, suggesting a role for these receptors in the spermatogenic process. The localization of both receptors in the apical portion of epithelial cells and smooth muscle layers of the vas deferens suggests an involvement of these receptors in the contraction and regulation of secretion.Esta revisão enfatiza a expressão e a função dos receptores muscarínicos, adrenoceptores α1 e receptores para relaxina no sistema reprodutor masculino. A expressão dos receptores muscarínicos e adrenoceptores α1 em compartimentos específicos de dúctulos eferentes, epidídimo, ductos deferentes, vesícula seminal e próstata de várias espécies indica o envolvimento destes receptores na modulação da composição do fluido luminal e na contração do músculo liso, incluindo efeitos na fertilidade masculina. Além disso, a ativação dos receptores muscarínicos leva à transativação do receptor para o fator crescimento epidermal e proliferação das células de Sertoli. Os receptores para relaxina estão presentes no testículo, RXFP1 nas espermátides alongadas e células de Sertoli de rato e RXFP2 nas células de Leydig e germinativas de ratos e humano, sugerindo o envolvimento destes receptores no processo espermatogênico. A localização de ambos os receptores na porção apical das células epiteliais e no músculo liso dos ductos deferentes de rato sugere um papel na contração e na regulação da secreção.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de FarmacologiaUNIFESP, EPM, Depto. de FarmacologiaSciEL

Statistical validation of the criteria for symptom remission in schizophrenia: Preliminary findings

<p>Abstract</p> <p>Background</p> <p>Published methods for assessing remission in schizophrenia are variable and none have been definitively validated or standardized. Andreasen et al (2005) suggest systematic operational criteria using eight PANSS items for which patients must score ≤ 3 (mild) for at least six months.</p> <p>Methods</p> <p>Using data from a one year, multi-site clinical trial (n = 675) remission criteria were compared to total PANSS scores and other endpoints and demonstrate excellent agreement with overall clinical status.</p> <p>Results</p> <p>Compared to total PANSS score of 60 points and other criteria, at time points > 6 months (8 and 12 months) the specificity of the remission criteria was 85%, i.e. of the patients who had a total score >60, 85% were classified as "not in remission." Sensitivity was also very high; 75% of patients with scores of <60 were classified as "in remission."Patients who dropped out of the trial were more likely not to be in remission prior to dropping out.</p> <p>Conclusion</p> <p>These findings indicate that the remission criteria are both sensitive and specific indicators of clinical status. Additional analyses are required to determine if remission status predicts other outcomes, such as employment, independent living, and prognosis.</p

Presence of Avian Influenza Viruses in Waterfowl and Wetlands during Summer 2010 in California: Are Resident Birds a Potential Reservoir?

Although wild waterfowl are the main reservoir for low pathogenic avian influenza viruses (LPAIv), the environment plays a critical role for the circulation and persistence of AIv. LPAIv may persist for extended periods in cold environments, suggesting that waterfowl breeding areas in the northern hemisphere may be an important reservoir for AIv in contrast to the warmer southern wintering areas. We evaluated whether southern wetlands, with relatively small populations (thousands) of resident waterfowl, maintain AIv in the summer, prior to the arrival of millions of migratory birds. We collected water and fecal samples at ten wetlands in two regions (Yolo Bypass and Sacramento Valley) of the California Central Valley during three bi-weekly intervals beginning in late July, 2010. We detected AIv in 29/367 fecal samples (7.9%) and 12/597 water samples (2.0%) by matrix real time Reverse Transcription Polymerase Chain Reaction (rRT-PCR). We isolated two H3N8, two H2N3, and one H4N8 among rRT-PCR positive fecal samples but no live virus from water samples. Detection of AIv RNA in fecal samples was higher from wetlands in the Sacramento Valley (11.9%) than in the Yolo Bypass (0.0%), but no difference was found for water samples (2.7 vs. 1.7%, respectively). Our study showed that low densities of hosts and unfavorable environmental conditions did not prevent LPAIv circulation during summer in California wetlands. Our findings justify further investigations to understand AIv dynamics in resident waterfowl populations, compare AIv subtypes between migratory and resident waterfowl, and assess the importance of local AIv as a source of infection for migratory birds

Antipsychotic withdrawal symptoms: Phenomenology and pathophysiology

The authors review the literature discribing non-dyskinetic antipsychotic withdrawal phenomena. Withdrawal of these agents can cause nausea, emesis, anorexia, diarrhea, rhinorrhea, diaphoresis, myalgia, paresthesia, anxiety, agitation, restlessness, and insomnia. Psychotic relapse is often presaged by increased anxiety, agitation, restlessness and insomnia, but the temporal relationship of these prodromal symptoms to reduction in the dosage or discontinuation of neuroleptics distinguishes them from the effects of abrupt withdrawal.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65190/1/j.1600-0447.1988.tb05116.x.pd

The correlation between reading and mathematics ability at age twelve has a substantial genetic component

Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children's ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child's cognitive abilities at age twelve

A genome-wide association study for late-onset Alzheimer's disease using DNA pooling

Background: Late-onset Alzheimer's disease (LOAD) is an age related neurodegenerative disease with a high prevalence that places major demands on healthcare resources in societies with increasingly aged populations. The only extensively replicable genetic risk factor for LOAD is the apolipoprotein E gene. In order to identify additional genetic risk loci we have conducted a genome-wide association (GWA) study in a large LOAD case – control sample, reducing costs through the use of DNA pooling. Methods: DNA samples were collected from 1,082 individuals with LOAD and 1,239 control subjects. Age at onset ranged from 60 to 95 and Controls were matched for age (mean = 76.53 years, SD = 33), gender and ethnicity. Equimolar amounts of each DNA sample were added to either a case or control pool. The pools were genotyped using Illumina HumanHap300 and Illumina Sentrix HumanHap240S arrays testing 561,494 SNPs. 114 of our best hit SNPs from the pooling data were identified and then individually genotyped in the case – control sample used to construct the pools. Results: Highly significant association with LOAD was observed at the APOE locus confirming the validity of the pooled genotyping approach. For 109 SNPs outside the APOE locus, we obtained uncorrected p-values ≤ 0.05 for 74 after individual genotyping. To further test these associations, we added control data from 1400 subjects from the 1958 Birth Cohort with the evidence for association increasing to 3.4 × 10-6 for our strongest finding, rs727153. rs727153 lies 13 kb from the start of transcription of lecithin retinol acyltransferase (phosphatidylcholine – retinol O-acyltransferase, LRAT). Five of seven tag SNPs chosen to cover LRAT showed significant association with LOAD with a SNP in intron 2 of LRAT, showing greatest evidence of association (rs201825, p-value = 6.1 × 10-7). Conclusion: We have validated the pooling method for GWA studies by both identifying the APOE locus and by observing a strong enrichment for significantly associated SNPs. We provide evidence for LRAT as a novel candidate gene for LOAD. LRAT plays a prominent role in the Vitamin A cascade, a system that has been previously implicated in LOAD

A hierarchical and modular approach to the discovery of robust associations in genome-wide association studies from pooled DNA samples

[Background] One of the challenges of the analysis of pooling-based genome wide association studies is to identify authentic associations among potentially thousands of false positive associations. [Results] We present a hierarchical and modular approach to the analysis of genome wide genotype data that incorporates quality control, linkage disequilibrium, physical distance and gene ontology to identify authentic associations among those found by statistical association tests. The method is developed for the allelic association analysis of pooled DNA samples, but it can be easily generalized to the analysis of individually genotyped samples. We evaluate the approach using data sets from diverse genome wide association studies including fetal hemoglobin levels in sickle cell anemia and a sample of centenarians and show that the approach is highly reproducible and allows for discovery at different levels of synthesis. [Conclusion] Results from the integration of Bayesian tests and other machine learning techniques with linkage disequilibrium data suggest that we do not need to use too stringent thresholds to reduce the number of false positive associations. This method yields increased power even with relatively small samples. In fact, our evaluation shows that the method can reach almost 70% sensitivity with samples of only 100 subjects.Supported by NHLBI grants R21 HL080463 (PS); R01 HL68970 (MHS); K-24, AG025727 (TP); K23 AG026754 (D.T.)