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To conduct a pragmatic, randomized controlled trial to assess whether thiopurine methyltransferase (TPMT) genotyping prior to azathioprine reduces adverse drug reactions (ADRs). A total of 333 participants were randomized 1:1 to undergo genotyping prior to azathioprine or to commence treatment without genotyping. There was no difference in the primary outcome of stopping azathioprine due to an adverse reaction (ADR, p = 0.59) between the two study arms. ADRs were more common in older patients (p = 0.01). There was no increase in stopping azathioprine due to ADRs in heterozygotes compared with wild-type individuals. The single individual with TPMT variant homozygosity experienced severe neutropenia. Our work supports the strong evidence that individuals with TPMT variant homozygosity are at high risk of severe neutropenia, whereas heterozygotes are not at increased risk of ADRs at standard doses of azathioprine. Original submitted 5 January 2011; Revised submitted 18 February 2011

Although quality assurance schemes have been proven effective in preventing genetic testing errors, a recent survey of services in the EU reveals that laboratory participation in these schemes is fragmented and incomplete.

Aim: To conduct a pragmatic, randomized controlled trial to assess whether thiopurine methyltransferase (TPMT) genotyping prior to azathioprine reduces adverse drug reactions (ADRs). Methods: A total of 333 participants were randomized 1:1 to undergo TPMT genotyping prior to azathioprine or to commence treatment without genotyping. Results: There was no difference in the primary outcome of stopping azathioprine due to an adverse reaction (ADR, p = 0.59) between the two study arms. ADRs were more common in older patients (p = 0.01). There was no increase in stopping azathioprine due to ADRs in TPMT heterozygotes compared with wild-type individuals. The single individual with TPMT variant homozygosity experienced severe neutropenia. Conclusion: Our work supports the strong evidence that individuals with TPMT variant homozygosity are at high risk of severe neutropenia, whereas TPMT heterozygotes are not at increased risk of ADRs at standard doses of azathioprine. Original submitted 5 January 2011; Revised submitted 18 February 2011

Chorionic villi can be obtained by direct transcervical aspiration at 9 to 10 weeks' gestation and used for analysis of fetal DNA. However, for the method to be reliable, there must be no detectable contamination by maternal DNA. To investigate the question of contamination, we compared the DNA of chorionic villi from five fetuses with that obtained from maternal lymphocytes, using the restriction endonuclease Taq I and specific DNA probes for a pair of alleles on the X chromosome. The alleles yield fragments of different lengths when digested with Taq I (length polymorphism), which can be demonstrated by electrophoresis and hybridization with the radioactive DNA probes. If the pattern obtained with the chorionic DNA is different from that obtained with the maternal DNA, contamination is not present. In two cases the fetal DNA of the chorionic villi was shown to be uncontaminated by maternal tissue. In one of these cases the mother was heterozygous and the fetus was homozygous; in the other the mother was homozygous and the fetus was heterozygous. In three other cases no definitive conclusions could be drawn, because the genotypes of the fetus and mother were identical. We conclude that chorionic villi at 9 to 10 weeks' gestation are a source of fetal DNA that can be used for gene analysis, with no detectable contamination by maternal DNA. (N Engl J Med 1983; 308:1433–5.) In the first trimester of gestation, chorionic villi of the fetus are accessible by transcervical aspiration without anesthesia, as a source of trophoblasts for direct analysis of fetal DNA. 1 Although the method has been used for both the early diagnosis of hemoglobinopathies 2 and determination of fetal sex, 3 for its potential to be exploited, the chorionic tissue must be shown to be free of contaminating maternal tissue. Overgrowth by maternal cells is a documented risk. 4 In this article we show that chorionic villi obtained 9 to 10 weeks after the last menstrual period provide fetal DNA without detectable maternal contamination. The . . .

This chapter will examine some of the issues and trends that need to be taken into account in evolving policy and developing opportunities in genetic and genomic (testing) services in emerging economies. This is based on a case study selected from among the leading group of fastemerging economies of the developing world recognized by international intergovernmental agencies, such as the G20 and Organization for Economic Cooperation and Development (OECD). This cluster of countries includes Brazil, Russia, India, China, and South Africa (BRICS). Each economy is relatively large and is characterized by rapid and sustained growth, but typically with large disparities between rich and poor classes. Each has a different health system, but only in Russia is the state the main provider of healthcare. In each of the remaining countries, healthcare is provided by a mixture of public and commercial institutions.

Adult Polycystic Kidney Disease is an autosomal dominant condition and one of the commonest Mendelian diseases in the Caucasian population. The gene is said to be carried by about 1:1000 individuals. The principal pathological event characterising the disease is the development of multiple fluid filled renal cysts which increase in size and number and which may result in end stage renal failure. In 1985 a linkage was found between markers on chromosome 16p13.3 at the HBA locus and APKD. The locus was named PKD1. This opened the way for a genetic test for the condition as an aid to genetic counselling. This work consists of a study of 150 families ascertained through a renal clinic and followed up by a voluntary family register. This resource was used to measure the probability of detection of the APKD gene in the first degree relatives of probands with and without the aid of ultrasonographic imaging of renal cysts. In addition a study was made of the diagnostic efficiency of ultrasonography as a method of detecting gene carriers. Family studies with DNA genetic markers permitted a calculation of statistical risks for individuals from APKD families requesting genetic counselling. Over the period of this work the proportion of families and individuals informative for genetic marker studies improved as new markers were brought into diagnostic use. Use of DNA markers allowed the detection of families not transmitting APKD at 16p 13.3. Calculations were made of the probability of non PKD1 inheritance in individual families and of the rate of non PKD1 disease in the ascertained population. Finally a hypothesis was tested that linkage disequilibrium exists between close markers and the major (PKD1) locus.

London, June 21. -- How did Liebknecht and Rosa Luxemburg, the two original fire brands die the German SPartacist party, die and who was responsible for their unofficial executions in Berlin early in the year? These questions, never adequately answered, seem now to have received and official response from German government sources.

The editorial \"Use cloning to heal, not reproduce\" (Nov. 27) argued cogently for limited cloning. Gregory Pence, in his Equal Time reply (\"Cloning is just another means to start a family,\" Nov. 27), wants cloning without restriction. How about equal time for the majority opinion on this? One aspect of human cloning blatantly absent from all the debates is the fact that the requirements for cloning a human being are: an egg, a nucleus of a cell (any cell) and a womb. All these three things a woman can provide. That means we don't need a man to make a baby.

Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19–2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20–1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82–3·29) for intracranial haemorrhage and 1·23 (1·08–1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08–6·72] for intracranial haemorrhage vs 1·47 [1·19–1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36–9·05] vs 1·43 [1·07–1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69–15·81] vs 1·86 [1·23–2·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48–84] per 1000 patient-years vs 27 intracranial haemorrhages [17–41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46–108] per 1000 patient-years vs 39 intracranial haemorrhages [21–67] per 1000 patient-years). In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. British Heart Foundation and UK Stroke Association.

Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69–0·77) with a calibration slope of 0·94 (0·81–1·06) for the intracranial haemorrhage model and 0·63 (0·62–0·65) with a calibration slope of 0·97 (0·87–1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. British Heart Foundation and Stroke Association.