Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity

Defects in death receptor-mediated apoptosis have been linked to cancer and autoimmune disease in humans. The in vivo role of caspase 8, a component of this pathway, has eluded analysis in postnatal tissues because of the lack of an appropriate animal model. Targeted disruption of caspase 8 is lethal in utero. We generated mice with a targeted caspase 8 mutation that is restricted to the T-cell lineage. Despite normal thymocyte development in the absence of caspase 8, we observed a marked decrease in the number of peripheral T-cells and impaired T-cell response ex vivo to activation stimuli. caspase 8 ablation protected thymocytes and activated T-cells from CD95 ligand but not anti-CD3-induced apoptosis, or apoptosis activated by agents that are known to act through the mitochondria. caspase 8 mutant mice were unable to mount an immune response to viral infection, indicating that caspase 8 deletion in T-cells leads to immunodeficiency. These findings identify an essential, cell-stage-specific role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. This is consistent with the recent identification of caspase 8 mutations in human immunodeficiency.     

Haplotype structure,LD blocks,and uneven recombination within the LRP5 gene

Patterns of linkage disequilibrium (LD) in the human genome are beginning to be characterized, with a paucity of haplotype diversity in "LD blocks," interspersed by apparent "hot spots" of recombination. Previously, we cloned and physically characterized the low-density lipoprotein-receptor-related protein 5 (LRP5) gene. Here, we have extensively analysed both LRP5 and its flanking three genes, spanning 269 kb, for single nucleotide polymorphisms (SNPs), and we present a comprehensive SNP map comprising 95 polymorphisms. Analysis revealed high levels of recombination across LRP5, including a hot-spot region from intron 1 to intron 7 of LRP5, where there are 109 recombinants/Mb (4882 meioses), in contrast to flanking regions of 14.6 recombinants/Mb. This region of high recombination could be delineated into three to four hot spots, one within a 601-bp interval. For LRP5, three haplotype blocks were identified, flanked by the hot spots. Each LD block comprised over 80% common haplotypes, concurring with a previous study of 14 genes that showed that common haplotypes account for at least 80% of all haplotypes. The identification of hot spots in between these LD blocks provides additional evidence that LD blocks are separated by areas of higher recombination.     

Marfan syndrome: Evolving organ manifestations—A 10‐year follow‐up study

The age‐dependent penetrance of organ manifestations in Marfan syndrome (MFS) is not known. The aims of this follow‐up study were to explore how clinical features change over a 10‐year period in the same Norwegian MFS cohort. In 2003–2004, we investigated 105 adults for all manifestations in the 1996 Ghent nosology. Ten years later, we performed follow‐up investigations of the survivors (n = 48) who consented. Forty‐six fulfilled the revised Ghent criteria. Median age: females 51 years, range 32–80 years; males 45 years, range 30–67 years. New aortic root dilatation was detected in patients up to 70 years. Ascending aortic pathology was diagnosed in 93 versus 72% at baseline. Sixty‐five percent had undergone aortic surgery compared to 39% at baseline. Pulmonary trunk mean diameter had increased significantly compared to baseline. From inclusion to follow‐up, two patients (three eyes) developed ectopia lentis, four developed dural ectasia, four developed scoliosis, three developed incisional or recurrent herniae, and 14 developed hindfoot deformity. No changes were found regarding protrusio acetabuli, spontaneous pneumothorax, or striae atrophicae. The study confirms that knowledge of incidence and progression of organ manifestations throughout life is important for diagnosis, treatment, and follow‐up of patients with verified or suspected MFS.     

Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma

The occuloalbinism 2 (OCA2) gene, localized at 15q11, encodes a melanosomal transmembrane protein that is involved in the most common form of human occulo-cutaneous albinism, a human genetic disorder characterized by fair pigmentation and susceptibility to skin cancer. We wondered whether allele variations at this locus could influence susceptibility to malignant melanoma (MM). In all, 10 intragenic single-nucleotide polymorphisms (SNPs) were genotyped in 113 patients with melanomas and in 105 Caucasian control subjects with no personal or family history of skin cancer. By comparing allelic distribution between cases and controls, we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). Then, a recently developed strategy, the 'combination test' enabled us to show that a combination formed by two SNPs was most strongly associated to MM, suggesting a possible interaction between intragenic SNPs. In addition, the role of OCA2 on MM risk was also detected using a logistic model taking into account the presence of variants of the melanocortin 1 receptor gene (MC1R, a key pigmentation gene) and all pigmentation characteristics as melanoma risk factors. Our data demonstrate that a second pigmentation gene, in addition to MC1R, is involved in genetic susceptibility to melanoma.     

What about N? A methodological study of sample-size reporting in focus group studies

Background  

Focus group studies are increasingly published in health related journals, but we know little about how researchers use this method, particularly how they determine the number of focus groups to conduct. The methodological literature commonly advises researchers to follow principles of data saturation, although practical advise on how to do this is lacking. Our objectives were firstly, to describe the current status of sample size in focus group studies reported in health journals. Secondly, to assess whether and how researchers explain the number of focus groups they carry out.     

The Diabetic Postoperative Mortality and Morbidity (DIPOM) trial: rationale and design of a multicenter, randomized, placebo-controlled, clinical trial of metoprolol for patients with diabetes mellitus who are undergoing major noncardiac surgery

Background

Recent trials suggest that perioperative β-blockade reduces the risk of cardiac events in patients with a risk of myocardial ischemia who are undergoing noncardiac surgery. Patients with diabetes mellitus are at a high-risk for postoperative cardiac morbidity and mortality. They may, therefore, benefit from perioperative β-blockade.

Methods

The Diabetic Postoperative Mortality and Morbidity (DIPOM) trial is an investigator-initiated and -controlled, centrally randomized, double-blind, placebo-controlled, multicenter trial. We compared the effect of metoprolol with placebo on mortality and cardiovascular morbidity rates in patients with diabetes mellitus who were β-blocker naive, ≥40 years old, and undergoing noncardiac surgery. The study drug was given during hospitalization for a maximum of 7 days beginning the evening before surgery. The primary outcome measure is the composite of all-cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure leading to hospitalization or discovered or aggravated during hospitalization. Follow-up involves re-examination of patients at 6 months and collection of mortality and morbidity data via linkage to public databases. The study was powered on the basis of an estimated 30% 1-year event rate in the placebo arm and a 33% relative risk reduction in the metoprolol arm. The median follow-up period was 18 months.

Results

Enrollment started in July 2000 and ended in June 2002. A total of 921 patients were randomized, and 54% of these patients had known cardiac disease, hypertension, or both.

Conclusion

The results of this study may have implications for reduction of perioperative and postoperative risk in patients with diabetes mellitus who are undergoing major noncardiac surgery.     

Winning Big but Feeling no Better? The Effect of Lottery Prizes on Physical and Mental Health

We use British panel data to determine the exogenous impact of income on a number of individual health outcomes: general health status, mental health, physical health problems, and health behaviours (drinking and smoking). Lottery winnings allow us to make causal statements regarding the effect of income on health, as the amount won by winners is largely exogenous. Positive income shocks have no significant effect on self‐assessed overall health, but a significant positive effect on mental health. This result seems paradoxical on two levels. First, there is a well‐known gradient in health status in cross‐sectional data, and second, general health should partly reflect mental health, so that we may expect both variables to move in the same direction. We propose a solution to the first apparent paradox by underlining the endogeneity of income. For the second, we show that lottery winnings are also associated with more smoking and social drinking. General health will reflect both mental health and the effect of these behaviours and so may not improve following a positive income shock. Copyright © 2014 John Wiley & Sons, Ltd.     

Temporal and Spatial Compartmentalization of Drug-Resistant Cytomegalovirus (CMV) in a Child with CMV Meningoencephalitis: Implications for Sampling in Molecular Diagnosis

We describe a case of antiviral-resistant cytomegalovirus meningoencephalitis occurring after hematopoietic stem cell transplantation. Antiviral-resistant cytomegalovirus was identified in blood 16 months earlier. However, wild-type cytomegalovirus was evidenced in blood when the meningoencephalitis was diagnosed. Treatment of meningoencephalitis should be adapted to all previously identified resistance mutations in any compartment.