Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality.

AIMS The purpose of this study was to identify novel genetic variants influencing circulating asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels and to evaluate whether they have a prognostic value on cardiovascular mortality. METHODS AND RESULTS We conducted a genome-wide association study on the methylarginine traits and investigated the predictive value of the new discovered variants on mortality. Our meta-analyses replicated the previously known locus for ADMA levels in DDAH1 (rs997251; P = 1.4 × 10(-40)), identified two non-synomyous polymorphisms for SDMA levels in AGXT2 (rs37369; P = 1.4 × 10(-40) and rs16899974; P = 1.5 × 10(-38)) and one in SLC25A45 (rs34400381; P = 2.5 × 10(-10)). We also fine-mapped the AGXT2 locus for further independent association signals. The two non-synonymous AGXT2 variants independently associated with SDMA levels were also significantly related with short-term heart rate variability (HRV) indices in young adults. The major allele (C) of the novel non-synonymous rs16899974 (V498L) variant associated with decreased SDMA levels and an increase in the ratio between the low- and high-frequency spectral components of HRV (P = 0.00047). Furthermore, the SDMA decreasing allele (G) of the non-synomyous SLC25A45 (R285C) variant was associated with a lower resting mean heart rate during the HRV measurements (P = 0.0046), but not with the HRV indices. None of the studied genome-wide significant variants had any major effect on cardiovascular or total mortality in patients referred for coronary angiography. CONCLUSIONS AGXT2 has an important role in SDMA metabolism in humans. AGXT2 may additionally have an unanticipated role in the autonomic nervous system regulation of cardiac function.

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

REV7 counteracts DNA double-strand break resection and affects PARP inhibition

Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases. In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.

Dose-response resistance to HIV-1/MuLV pseudotype virus ex vivo in a hairpin ribozyme transgenic mouse model

We have investigated the efficacy of a hairpin ribozyme targeting the 5′ leader sequence of HIV-1 RNA in a transgenic model system. Primary spleen cells derived from transgenic or control mice were infected with HIV-1/MuLV pseudotype virus. A significantly reduced susceptibility to infection in ribozyme-expressing transgenic spleen cells (P = 0.01) was shown. Variation of transgene-expression levels between littermates revealed a dose response between ribozyme expression and viral resistance, with an estimated cut off value below 0.2 copies of hairpin ribozyme per cell. These findings open up possibilities for studies on ribozyme efficacy and anti-HIV-1 gene therapy.

Activation of Androgen Receptor Function by a Novel Nuclear Protein Kinase

Androgen receptor (AR) belongs to the nuclear receptor superfamily and mediates the biological actions of male sex steroids. In this work, we have characterized a novel 130-kDa Ser/Thr protein kinase ANPK that interacts with the zinc finger region of AR in vivo and in vitro. The catalytic kinase domain of ANPK shares considerable sequence similarity with the minibrain gene product, a protein kinase suggested to contribute to learning defects associated with Down syndrome. However, the rest of ANPK sequence, including the AR-interacting interface, exhibits no apparent homology with other proteins. ANPK is a nuclear protein that is widely expressed in mammalian tissues. Its overexpression enhances AR-dependent transcription in various cell lines. In addition to the zinc finger region, ligand-binding domain and activation function AF1 of AR are needed, as the activity of AR mutants devoid of these domains was not influenced by ANPK. The receptor protein does not appear to be a substrate for ANPK in vitro, and overexpression of ANPK does not increase the extent of AR phosphorylation in vivo. In view of this, it is likely that ANPK-mediated activation of AR function is exerted through modification of AR-associated proteins, such as coregulatory factors, and/or through stabilization of the receptor protein against degradation.

Inherited susceptibility to uterine leiomyomas and renal cell cancer

Herein we report the clinical, histopathological, and molecular features of a cancer syndrome with predisposition to uterine leiomyomas and papillary renal cell carcinoma. The studied kindred included 11 family members with uterine leiomyomas and two with uterine leiomyosarcoma. Seven individuals had a history of cutaneous nodules, two of which were confirmed to be cutaneous leiomyomatosis. The four kidney cancer cases occurred in young (33- to 48-year-old) females and displayed a unique natural history. All these kidney cancers displayed a distinct papillary histology and presented as unilateral solitary lesions that had metastasized at the time of diagnosis. Genetic-marker analysis mapped the predisposition gene to chromosome 1q. Losses of the normal chromosome 1q were observed in tumors that had occurred in the kindred, including a uterine leiomyoma. Moreover, the observed histological features were used as a tool to diagnose a second kindred displaying the phenotype. We have shown that predisposition to uterine leiomyomas and papillary renal cell cancer can be inherited dominantly through the hereditary leiomyomatosis and renal cell cancer (HLRCC) gene. The HLRCC gene maps to chromosome 1q and is likely to be a tumor suppressor. Clinical, histopathological, and molecular tools are now available for accurate detection and diagnosis of this cancer syndrome.

Globalisation, markets and healthcare policy:redrawing the patient as consumer

Although the last two decades have seen the healthcare systems of most developed countries face pressure for major reform, the impact of this reform on the relationship between empowerment, consumerism and citizen’s rights has received limited research attention. Globalisation, Markets and Healthcare Policy sets out to redress this imbalance. This book explores the extent to which globalisation and commercialisation relate to current and emerging health policies. It also looks at the implications for citizens, patients and social rights, as well as how policy making interacts with the interests of global and European trade and economic policies. Topics discussed include: •How the impact of globalisation on health systems is apparent in the influence of international actors and European policies. •How the impact of globalisation is mediated by national priorities and policies and is therefore reflected in diverse influences. •How commercialisation of health is presented as benefiting citizens and patients but has the potential to undermine the aims and values inherent in health systems. •How the role of citizens' interests, social rights, patient’s rights and priorities of patient and public involvement need to be separated from commercialisation, choice and consumerism in health care. Essential reading for policy makers and students of public policy, politics, law and health services, Globalisation, Markets and Healthcare Policy will also appeal to those interested in patient involvement international healthcare, international relations, trans-national organisations and the EU.

Kuudes- ja yhdeksäsluokkalaiset sanomalehtitekstin ymmärtäjinä

Tämän pro gradu -tutkielman tarkoituksena oli kartoittaa kuudes- ja yhdeksäsluokkalaisten luetun ymmärtämisen taitoja. Tutkimuksen tavoitteena oli selvittää, minkälaiset lukemisen ymmärtämisen taidot oppilailla on alakoulun ja yläkoulun lopussa. Luetun ymmärtämisen testin avulla pyrittiin selvittämään, kehittyykö luetun ymmärtämisen taito yläkoulun aikana ja onko taidossa eroja sukupuolten välillä. Tutkielman teoriaosassa käsitellään lukutaitoa ja sen merkitystä yleisellä tasolla sekä kerrotaan luetun ymmärtämisen taitojen testaamisesta. Tutkimuksessa käytettiin kvantitatiivista lähestymistapaa ja tutkimustyyppinä oli survey-tutkimus. Otosjoukko rajattiin käyttämällä harkinnanvaraista otantaa. Tutkimuksen kohteena oli 109 oppilasta neljästä eri länsisuomalaisesta koulusta. Heistä 64 oli kuudesluokkalaisia ja 45 oli yhdeksäsluokkalaisia. Poikia testiin osallistuneista oppilaista oli 57 ja tyttöjä oli 52. Oppilaat lukivat sanomalehtiartikkelin ja vastasivat kymmeneen artikkelin sisältöä koskevaan kysymykseen sekä selittivät kymmenen artikkelissa alleviivatun sanan merkityksen. Tähän tutkimukseen osallistuneilla oppilailla oli keskimäärin hyvä lukutaito. Alakoululaiset olivat kuitenkin heikompia lukijoita kuin yläkoululaiset. Verrattaessa tyttöjen ja poikien lukutaidon tasoa tytöillä oli korkeampi taso. Huomion arvoista tuloksissa oli että välttävän lukutaidon tasolle testissä yltäneet oppilaat olivat kaikki poikia ja erinomaisen lukutaidon tason saavuttaneista oppilaista prosentuaalinen enemmistö oli poikia. Tulos näyttää, että tyttöjen taitotaso on huomattavasti tasaisempi ja poikien taidot edustavat asteikon ääripäitä. Positiivista on, että poikien luetun ymmärtämisen taso oli parempi yläkoulussa kuin alakoulussa. Tutkimuksen perusteella näyttää siltä, että lukutaidon taso kehittyy yhä yläkoulun aikana. Tätä kehityssuuntaa pitäisi tukea kaikella mahdollisella tavalla. Poikia tulisi rohkaista jo pienestä pitäen lukuharrastuksen pariin, jotta asenne lukemista kohtaan säilyisi positiivisena myös alakoulun jälkeen.

Percepción de los trabajadores acerca de la seguridad en el trabajo en una empresa del sector de gas natural en Casanare

Introducción: La percepción puede ser considerada principalmente como un grupo de procesos internos en las personas que genera en los observadores una representación mental del entorno. Percibir es adelantarse al suceso, a lo que puede llegar a suceder, determinando lo que puede ser un peligro a nuestra seguridad y salud. Objetivo: El presente estudio tiene como objetivo determinar la percepción de los trabajadores acerca de la seguridad en el trabajo en áreas de procesos automatizados y mecánicas en una empresa del sector de gas natural en el departamento de Casanare, Colombia 2016. Metodología: Se llevó a cabo un estudio de corte transversal en 50 trabajadores de una empresa del sector de gas natural en Casanare. Se uttilizó el Cuestionario nórdico NOSACQ-50-Spanish, instrumento validado para evaluar la percepción acerca de la seguridad y salud en el lugar de trabajo. Se incluyeron variables sociodemográficas, laborales y las relacionadas con la percepción de la seguridad en el lugar del trabajo. Para el análsiis estadistico se calcularon medidas de tendencia central y de dispersión. El estudio de la percepción de seguridad tuvo como puntos de corte: < 2,5 mala percepción y > 2,5 buena percepción. Se emplearon pruebas de asociación X2 o test exacto de Fisher (valores esperados <5) y medidas de asociación OR con sus intervalos de confianza del 95% y se usaron modelos de regresión lineal. Resultados: El total de trabajadores fue de 50 personas, el 76% correspondió al sexo masculino y la mayor distribución se presentó en áreas mecánicas con 52% frente al 48% que se encontró en áreas automatizadas. Se halló asociación estadísticamente significativa entre las variables sociodemográficas área/sexo (Pr = 0,016), indicando que a los trabajadores de sexo femenino se les ubican en el área mecánica mientras que los de sexo masculino, laboran en todas las áreas sin darle relevancia al género. También se encontró asociación con las variables área/año de nacimiento (Pr =0.022), indicando que en el área automatizada se dejan profesionales con promedio de edad de 32 años, por el tipo de requisitos en competencias que exigen para ejecutar las labores. Para las demás variables ocupacionales que evaluaron la percepción de seguridad frente al trabajo, no se encontró asociación significativa. Conclusión: Los resultados permiten realizar acciones en pro de mejorar la percepción de los trabajadores dentro de la organización. Se podrán desarrollar programas de seguridad y salud en el trabajo, que respondan de manera efectiva a los peligros laborales detectados.