The gain-of-function G389R variant of the β1-adrenoceptor does not influence blood pressure or heart rate response to β-blockade in hypertensive subjects

Original article can be found at: http://www.clinsci.org/cs/099/cs0990233.htm Copyright The Biochemical Society and the Medical Research Society [Full text of this article is not available in the UHRA]Mutation scanning of the b1-adrenoceptor gene has identified a polymorphism, G389R, that markedly affects G-protein coupling of the receptor and resulting cAMP production. We have investigated the effect of this functionally active polymorphism on clinical response to b-adrenoceptor blockade. Two cohorts of untreated hypertensive patients randomly assigned to a b1-selective b-blocker at the start of antihypertensive therapy were studied retrospectively to see if the G389R polymorphism influenced the response in terms of blood pressure and heart rate. The blood pressure and heart rate responses to treatment were assessed 4 weeks later and compared with the G389R genotype, ascertained by PCR/restriction fragment length polymorphism. The falls in blood pressure and heart rate for the first group (n = 92) by genotype were: GG, 20.1±3.5/13.9±2.7 mmHg (systolic/diastolic blood pressure), 18.4±2.2 beats/min; GR, 20.0±2.2/15.0±1.3 mmHg, 16.5±1.5 beats/min; RR, 20.8±2.3/13.4±1.1 mmHg, 16.0±1.4 beats/min. For the second group (n = 55) the corresponding falls were: GG, 17.0±4.3/11.2±3.4 mmHg, 12.0±3.5 beats/min; GR, 16.6±1.8/14.4±1.1 mmHg, 13.1±2.1 beats/min; RR, 18.0±1.6/13.0±1.4 mmHg, 14.4±1.4 beats/min. The G389R genotype also failed to have a significant effect on pretreatment blood pressure or heart rate in either group. These data suggest that, despite clear functional differences between the G389R receptor variants expressed in vitro, the polymorphism does not affect the haemodynamic response of hypertensive subjects to chronic b1-adrenoceptor blockade.Peer reviewe

Detection of mutations in KLHL3 and CUL3 in families with fhht (familial hyperkalaemic hypertension or gordon's syndrome)

10.1042/CS20130326Clinical Science12610721-726CSCI

Chromosome damage induced by DNA topoisomerase II inhibitors combined with g-radiation in vitro

Combined radiation and antineoplastic drug treatment have important applications in cancer therapy. In the present work, an evaluation was made of two known topoisomerase II inhibitors, doxorubicin (DXR) and mitoxantrone (MXN), with g-radiation. The effects of DXR or MXN on g-radiation-induced chromosome aberrations in Chinese hamster ovary (CHO) cells were analyzed. Two concentrations of each drug, 0.5 and 1.0 µg/ml DXR, and 0.02 and 0.04 µg/ml MXN, were applied in combination with two doses of g-radiation (20 and 40 cGy). A significant potentiating effect on chromosomal aberrations was observed in CHO cells exposed to 1.0 µg/ml DXR plus 40 cGy. In the other tests, the combination of g-radiation with DXR or MXN gave approximately additive effects. Reduced mitotic indices reflected higher toxicity of the drugs when combined with radiation.<br>A associação de radiação ionizante com drogas antineoplásicas tem importante aplicação na terapia do câncer. No presente trabalho, foram avaliados os efeitos de dois inibidores de topoisomerase II, doxorubicina (DXR) e mitoxantrona (MXN), sobre as aberrações cromossômicas induzidas pelas radiações-g em células do ovário de hamster chinês (CHO). Foram usadas as concentrações 0,5 e 1,0 mg/ml de DXR e 0,02 e 0,04 mg/ml de MXN, combinadas com duas doses de radiações gama (20 e 40 cGy). Um significativo efeito potenciador das aberrações cromossômicas foi observado em células CHO tratadas com 1,0 mg/ml de DXR e expostas a 40 cGy de radiação. Nos outros testes, a combinação da radiação-g com a DXR ou MXN apresentou um efeito próximo ao aditivo. A redução dos índices mitóticos refletiu a alta citotoxicidade das drogas quando combinadas às radiações-g

Thrombophilia in pregnancy: a systematic review

Growing evidence suggests that thrombophilia is associated with venous thromboembolism (VTE) and adverse pregnancy outcomes. However, methodological limitations have made it difficult to obtain a clear overview of the overall risks. We conducted a systematic review to determine the risk of VTE and adverse pregnancy outcomes associated with thrombophilia in pregnancy. The effectiveness of prophylactic interventions during pregnancy was also evaluated. Major electronic databases were searched, relevant data abstracted and study quality assessed by two independent reviewers. Odds ratios (ORs) stratified by thrombophilia type were calculated for each outcome. A total of 79 studies were included in our review. The risks for individual thrombophilic defects were determined for VTE (ORs, 0·74–34·40); early pregnancy loss (ORs, 1·40–6·25); late pregnancy loss (ORs, 1·31–20·09); pre-eclampsia (ORs, 1·37–3·49); placental abruption (ORs, 1·42–7·71) and intrauterine growth restriction (ORs, 1·24–2·92). Low-dose aspirin plus heparin was the most effective in preventing pregnancy loss in thrombophilic women (OR, 1·62). Our findings confirm that women with thrombophilia are at risk of developing VTE and complications in pregnancy. However, despite the increase in relative risk, the absolute risk of VTE and adverse outcomes remains low. There is also a lack of controlled trials of antithrombotic intervention to prevent pregnancy complications. Thus, at present, universal screening for thrombophilia in pregnancy cannot be justified clinically

Observation of events with a large rapidity gap in deep inelastic scattering at HERA

In deep inelastic, neutral current scattering of electrons and protons at &#8730; s = 296 GeV, we observe in the ZEUS detector events with a large rapidity gap in the hadronic final state. They occur in the region of small Bjorken x and are observed up to Q&lt;sup&gt;2&lt;/sup&gt; of 100 GeV&lt;sup&gt;2&lt;/sup&gt;. They account for about 5% of the events with Q&lt;sup&gt;2&lt;/sup&gt; &#8805; 10 GeV&lt;sup&gt;2&lt;/sup&gt;. Their general properties are inconsistent with the dominant mechanism of deep inelastic scattering, where color is transferred between the scattered quark and the proton remnant, and suggest that the underlying production mechanism is the diffractive dissociation of the virtual photon