Genetic risk estimation by healthcare professionals

OBJECTIVES: To assess whether healthcare professionals correctly incorporate the relevance of a favourable test outcome in a close relative when determining the level of risk for individuals at risk for Huntington's disease. DESIGN AND SETTING: Survey of clinical geneticists and genetic counsellors from 12 centres of clinical genetics (United Kingdom, 6; The Netherlands, 4; Italy, 1; Australia, 1) in May-June 2002. Participants were asked to assess risk of specific individuals in 10 pedigrees, three of which required use of Bayes' theorem. PARTICIPANTS: 71 clinical geneticists and 41 other healthcare professionals involved in genetic counselling. MAIN OUTCOME MEASURES: Proportion of respondents correctly assessing risk in the three target pedigrees; proportion of respondents who were confident of their estimate. RESULTS: 50%-64% of respondents (for the three targets separately) did not include the favourable test information and inc

Thrombin generation during cardiopulmonary bypass: the possible role of retransfusion of blood aspirated from the surgical field

BACKGROUND: In spite of using heparin-coated extracorporeal circuits, cardiopulmonary bypass (CPB) is still associated with an extensive thrombin generation, which is only partially suppressed by the use of high dosages of heparin. Recent studies have focused on the origins of this thrombotic stimulus and the possible role of retransfused suctioned blood from the thoracic cavities on the activation of the extrinsic coagulation pathway. The present study was designed to find during CPB an association between retransfusion of suctioned blood from the pericardium and pleural space, containing activated factor VIIa and systemic thrombin generation. METHODS: Blood samples taken from 12 consenting patients who had elective cardiac surgery were assayed for plasma factor VIIa, prothrombin fragment 1+2 (F(1+2)), and thrombin-antithrombin (TAT) concentrations. Blood aspirated from the pericardium and pleural space was collected separately, assayed for F(1+2), TAT, and factor VIIa and retransfused to the patient after the aorta occlusion. RESULTS: After systemic heparinization and during CPB thrombin generation was minimal, as indicated by the lower than base line plasma levels of F(1+2), and TAT after correction for hemodilution. In contrast, blood aspirated from the thoracic cavities had significantly higher levels of factor VIIa, F(1+2), and TAT compared to the simultaneous samples from the blood circulation (P < 0.05). Furthermore, after retransfusion of the suctioned blood (range, 200–1600 mL) circulating levels of F(1+2), and TAT rose significantly from 1.6 to 2.9 nmol/L (P = 0.002) and from 5.1 to 37.5 μg/L (P = 0.01), respectively. The increase in both F(1+2), and TAT levels correlated significantly with the amount of retransfused suctioned blood (r = 0.68, P = 0.021 and r = 0.90, P = 0.001, respectively). However, the circulating factor VIIa levels did not correlate with TAT and F(1+2 )levels. CONCLUSIONS: These data suggest that blood aspirated from the thoracic cavities during CPB is highly thrombogenic. Retransfusion of this blood may, therefore, promote further systemic thrombin generation during CPB

Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry

Background: Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. Methods: We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Findings: Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250?4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30?4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250?4000 mg/day (OR 2·41, 95% CI 1·33?4·38; p=0·0055) and oxcarbazepine at doses of 75?4500 mg/day (2·37, 1·17?4·80; p=0·0169). Interpretation: Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. Funding: Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.Fil: Tomson, Torbjörn. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Battino, Dina. Foundation Irccs Neurological Institute "c. Besta"; ItaliaFil: Bonizzoni, Erminio. Università degli Studi di Milano; ItaliaFil: Craig, John. Belfast Health And Social Care Trust; Reino UnidoFil: Lindhout, Dick. Stichting Epilepsie Instellingen Nederland; Países BajosFil: Perucca, Emilio. Universita Degli Studi Di Pavia; ItaliaFil: Sabers, Anne. Rigshospitalet; DinamarcaFil: Thomas, Sanjeev V. Sree Chitra Tirunal Institute For Medical Sciences And Technology; IndiaFil: Vajda, Frank. University of Melbourne; AustraliaFil: Kochen, Sara Silvia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Bohorquez Morera, Natalia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentin

An insulin receptor mutant (Asp707 → Ala), involved in leprechaunism, is processed and transported to the cell surface but unable to bind insulin

We have identified a homozygous mutation near the carboxyl terminus of the insulin receptor (IR) α subunit from a leprechaun patient, changing Asp707 into Ala. Fibroblasts from this patient had no high affinity insulin binding sites. To examine the effect of the mutation on IR properties, the mutant IR was stably expressed in Chinese hamster ovary cells. Western blot analysis and metabolic labeling showed a normal processing of the mutant receptor to α and β subunits. No increase in high affinity insulin binding sites was observed on Chinese hamster ovary cells expressing the mutant receptor, and also, affinity cross-linking of 125I- labeled insulin by disuccinimidyl suberate to these cells failed to label the mutant α subunit. Biotinylation of cell surface proteins by biotin succinimidyl ester resulted in efficient biotinylation of the mutant IR α and β subunits, showing its presence on the cell surface. On solubilization of the mutant insulin receptor in Triton X. 100-containing buffers, 125I- insulin was efficiently cross-linked to the receptor a subunit by disuccinimidyl suberate. These studies demonstrate that Ala707 IR is normally processed and transported to the cell surface and that the mutation distorts the insulin binding site. Detergent restores this site. This is an example of a naturally occurring mutation in the insulin receptor that affects insulin binding without affecting receptor transport and processing. This mutation points to a major contribution of the a subunit carboxyl terminus to insulin binding

Условия формирования зон скопления метана в углепородном массиве

Розглянуті основні геологічні чинники, які впливають на формування зон скупчення метану у вуглепородному масиві. Виділені, найбільш ефективні показники для середнього катагенеза порід – опосередковані локальні структури, зони тріщинуватості порід, стрижневі ділянки пісковиків (палеопотоки). Для виділених показників виконаний розрахунок дисперсійного аналізу по альтернативній ознаці. На основі розрахунків встановлено вплив кожного фактора на формування зон скупчення метану у вуглепродному масиві.Basic geological factors, which influence on forming of zone of accumulation of methane in coalrock massif, are presented. The most effective indexes for middle katagenesis of rock are determinated - medial local structures, zone of jointing of rock, race areas of sandstones (paleocurrent). For determinated indexes calculation of dispersion on an alternative character is executed. On the basis of calculations influence of every factor on forming of zone of accumulation of methane in a coalrock massif is definited

Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4

Genes for familial hemiplegic migraine (FHM) and episodic ataxia type-2 (EA-2) have been mapped to chromosome 19p13. We characterized a brain- specific P/Q-type Ca2+ channel α1-subunit gene, CACNLIA4, covering 300 kb with 47 exons. Sequencing of all exons and their surroundings revealed polymorphic variations, including a (CA)(n)-repeat (D19S1150), a (CAG)(n)- repeat in the 3'-UTR, and different types of deleterious mutations in FHM and EA-2. In FHM, we found four different missense mutations in conserved functional domains. One mutation has occurred on two different haplotypes in unrelated FHM families. In EA-2, we found two mutations disrupting the reading frame. Thus, FHM and EA-2 can be considered as allelic channelopathies. A similar etiology may be involved in common types of migraine