The ERCC2 Gln/Gln polymorphism at codon 751 is not associated with leukaemic transformation in primary myelofibrosis

This study prospectively compared the effect of secondary prophylaxis to episodic treatment on target joint (TJ) range of motion (ROM), number of joint haemorrhages and new TJ development in patients with moderate or severe haemophilia. Two‐hundred and eighty‐six males, 17% in prophylaxis, 83% in episodic treatment group, participating in the Centers for Disease Control and Prevention's Universal Data Collection project, fulfilled inclusion criteria: age >2 years at enrolment, free of TJs at enrolment, developed at least one TJ after enrolment, and received either prophylaxis or episodic treatment continuously for two follow‐up visits after TJ development. The outcomes of interest – percentage change in TJ ROM, number of joint haemorrhages and new TJ development, were modelled using multivariate linear, Poisson and logistic regression techniques respectively. Individuals who received secondary prophylaxis in comparison to episodic treatment were younger at TJ development (P < 0·01); there was no difference in the decrease in TJ ROM between the two groups (P = 0·9). Factors significantly associated with a higher rate of haemarthroses included episodic treatment, severe haemophilia, age >5 years at TJ development, obesity and inhibitor negative status. Secondary prophylaxis significantly decreased haemarthroses but was not associated with a significant improvement in TJ ROM or with new TJ development.     

Association of Hypoglycemic Treatment Regimens With Cardiovascular Outcomes in Overweight and Obese Subjects With Type 2 Diabetes: A substudy of the SCOUT trial

OBJECTIVE

To assess the association of hypoglycemic treatment regimens with cardiovascular adverse events and mortality in a large population of type 2 diabetic patients at increased cardiovascular risk.

RESEARCH DESIGN AND METHODS

This analysis included 8,192 overweight patients with type 2 diabetes from the Sibutramine Cardiovascular Outcomes (SCOUT) trial randomized to lifestyle intervention with or without sibutramine for up to 6 years. Patients were grouped according to hypoglycemic treatment at baseline. The primary end point was the time from randomization to the first occurrence of a primary outcome event (POE), nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death. Multivariable Cox proportional hazards regression models were used to assess the impact of antiglycemic treatment on POE and all-cause mortality.

RESULTS

Treatments for type 2 diabetes were as follows: diet alone (n = 1,394 subjects), metformin monotherapy (n = 1,631), insulin monotherapy (n = 1,116), sulfonylurea monotherapy (n = 1,083), metformin plus sulfonylurea (n = 1,565), and metformin plus insulin (n = 1,000); 905 subjects experienced a POE and 708 died. Metformin monotherapy was associated with lower risk of POE than insulin (hazard ratio [HR], 0.74; 95% CI, 0.57–0.95; P = 0.02). Diet alone also was associated with lower risk of POE (HR, 0.65; 95% CI, 0.48–0.87; P = 0.004). Metformin monotherapy also was associated with lower mortality (HR, 0.73; 95% CI, 0.54–0.99; P < 0.05), whereas no other monotherapies or combination therapies were significantly associated with POE or all-cause mortality compared with insulin as monotherapy.

CONCLUSIONS

In obese patients with type 2 diabetes and high risk of cardiovascular disease, monotherapy with metformin or diet-only treatment was associated with lower risk of cardiovascular events than treatment with insulin.The prevalence of type 2 diabetes and obesity/overweight are increasing at a disturbing rate in the western world as well as in developing countries (1,2). Both diabetes and obesity have a profound effect on the risk of cardiovascular disease (CVD) (3).Although CVD-related mortality among patients with type 2 diabetes has been decreasing over the past few decades, these patients remain at significantly (twofold to threefold) higher risk for CVD-related mortality relative to comparable groups without diabetes (4). The influence of differing hypoglycemic treatment regimens on CVD has been of increasing clinical concern (5,6). To date, only a few randomized studies have addressed the impact of different hypoglycemic treatment regimens on the outcome of cardiovascular events and cardiovascular death (7). Mostly, clinical trials examining the efficacy of various antidiabetes drugs have focused on intermediate clinical outcomes such as changes in levels of HbA_1c, serum lipids, and blood pressure (8). Several studies suggest that improved glycemic control in type 2 diabetes reduces microvascular risk (7,9). However it remains unclear whether there is a specific effect of different hypoglycemic agents on “hard” clinical outcomes from macrovascular disease and all-cause mortality. Because macrovascular disease is the leading cause of morbidity and mortality in type 2 diabetes (10), it is important to explore whether any association exists between conventional approaches to hypoglycemic therapy and cardiovascular events in patients with type 2 diabetes.Therefore, we have examined data from the Sibutramine Cardiovascular Outcomes (SCOUT) trial (see list of participating investigators in the Supplementary Data) conducted in >10,000 overweight and obese subjects to explore possible links between hypoglycemic treatment regimens and cardiovascular events. SCOUT demonstrated that long-term treatment with sibutramine had a slightly increased risk of nonfatal myocardial infarction (hazard ratio [HR], 1.28; 95% CI, 1.04–1.57; P = 0.02) and nonfatal stroke (HR, 1.36; 95% CI, 1.04–1.77; P = 0.03), but not of cardiovascular death or death from any cause, among subjects at high cardiovascular risk. It has not been established, however, whether the type of therapy for diabetes affected the outcome.     

Fathers Raising Children with Autism Spectrum Disorder: Stories of Marital Stability as Key to Parenting Success

Using media reports of high divorce rates among couples of children with ASD as a point of departure, our purpose in this paper is to examine how married fathers of children with ASD understand their marriages relative to the demands of ASD and in the context of media reports of elevated divorce rates among parents raising children with ASD. We begin with a review of select literature pertaining to the impact of ASD on marriages and we include a brief account of popular media portrayals of the influence of having a child with a developmental disability, and ASD in particular, on marriages. We then describe our qualitative examination of narrative interview data from 26 married fathers raising children with ASD aged 2–13 beginning with our theoretical anchoring in social comparison to focus our attention on how fathers compare themselves with media accounts of elevated divorce rates among parents of children and also with other hypothetical family configurations. Our findings are evidence of fathers’ strong and strengthened commitments to marriages and we illustrate a re-purposing of inflated portrayals of divorce rates to shore up fathers’ sense of their own effectiveness as husbands and fathers.     

The repair of experimentally produced defects in rabbit articular cartilage by autologous chondrocyte transplantation

Using the knee joints of New Zealand White rabbits, a baseline study was made to determine the intrinsic capability of cartilage for healing defects that do not fracture the subchondral plate. A second experiment examined the effect of autologous chondrocytes grown in vitro on the healing rate of these defects. To determine whether any of the reconstituted cartilage resulted from the chondrocyte graft, a third experiment was conducted involving grafts with chondrocytes that had been labeled prior to grafting with a nuclear tracer. Results were evaluated using both qualitative and quantitative light microscopy. Macroscopic results from grafted specimens displayed a marked decrease in synovitis and other degenerative changes. In defects that had received transplants, a significant amount of cartilage was reconstituted (82%) compared to ungrafted controls (18%). Autoradiography on reconstituted cartilage showed that there were labeled cells incorporated into the repair matrix.     

The gene for Darier's disease maps to chromosome 12q23-q24.1

Darler's disease is a rare autosomal dominant skin disorderin which there is abnormal adhesion between keratlnocytes. Itappears to be associated with an Increased prevalence of neuropsychiatrlcdisorders including mental retardation and epilepsy. In additionwe have previously reported a family in which major affectivedisorder cosegregates with Darier's disease. In the presentstudy we have localized the gene for Darier's disease to chromosome12q23–q24.1 by linkage analysis in five British pedigrees.We obtained a maximum two point lod score of 4.29 with markerD12S84 at zero recombination fraction. All five families showedevidence of linkage between the disease gene and markers Inthis region. Subsequent identification of the Darier's diseasegene will provide Insights into normal mechanisms of cell adhesionand may be of importance in the genetic Investigation of neuropsychiatricdisorders as well as elucidating the pathogenesls of Darier'sdisease itself.