Renal cysts and diabetes due to a heterozygous HNF-1beta gene deletion.

Sir, Diabetic nephropathy has become the major cause of end-stagerenal failure in Western countries. However, in the renal cystsand diabetes (RCAD) syndrome, nephropathy is an independentfeature rather than a direct consequence of the diabetes. ThisRCAD syndrome is caused by mutations of the hepatocyte nuclear     

Perceived stress,psychological well‐being and the activity of neutrophils in patients undergoing cardiopulmonary bypass surgery

This study explored relationships, before and after surgery, between perceived stress and the activity of white‐blood cells (neutrophils) in 82 patients undergoing heart surgery involving cardiopulmonary bypass surgery (CPB). On the evening before surgery and at follow‐up, 6‐weeks after discharge, patients completed self‐administered standard psychological measures. Small peripheral blood samples were taken, from which neutrophil activity was quantified using nitro‐blue tetrazolium (NBT) and luminol‐dependant chemiluminescence (phagocytic capacity). There were consistent, statistically significant associations between stress and percentageNBT cells at baseline and at follow‐up. Regression analysis showed that perceived stress was a predictor of neutrophil activity at follow‐up suggesting that higher levels of stress are associated with higher levels of activity. Results from the phagocytic capacity data support and strengthen the NBT findings; in response to stimuli the phagocytic capacity of the neutrophils is reduced at baseline (high stress) and increased at follow‐up (lower stress). Significant decreases were found on perceived stress, anxiety, depression, negative affect and health‐related stress at follow‐up. Patients' self‐efficacy was high at baseline and remained high throughout the study. Results highlighted a consistent, significant relationship between perceived stress and the ‘activity’ of neutrophils. The implications of this finding are worthy of exploration given that stress‐activated neutrophils may adversely influence health outcomes. Copyright © 2006 John Wiley & Sons, Ltd.     

How homosexual men believe they became infected with HIV: the role of risk-reduction behaviors

OBJECTIVES: A range of HIV risk reduction strategies has been described in homosexual men who practice unprotected anal intercourse (UAI), including serosorting, strategic positioning, and negotiating around an HIV-positive partner's viral load. It is uncertain how commonly these behaviors might result in HIV infection. We describe sexual behaviors and associated risk reduction strategies reported by homosexual men in their accounts of their recent seroconversion. METHODS: Homosexual men recently diagnosed with primary HIV infection between 2003 and 2006 were invited to participate in a nurse-administered survey. RESULTS: Among 158 men enrolled, 143 (91%) were able to identify the high-risk event that they believed led to their HIV seroconversion, and this involved UAI in 102 (71%). Among these 102 men, 21 (21%) reported they were certain that the source partner was HIV-negative. Ten men (10%) reported insertive UAI as the highest risk behavior. Of the 21 men who reported knowing the HIV-positive partner's viral load, 9 reported that the man had an undetectable viral load (43%). CONCLUSION: In 38% of the high-risk events involving UAI, infection occurred when the reported risk event involved serosorting, strategic positioning, or intercourse with a man whose viral load was believed to be undetectable.     

Identifying hepatic nuclear factor 1alpha mutations in children and young adults with a clinical diagnosis of type 1 diabetes

OBJECTIVE: HNF-1alpha gene mutations (MODY3) present with marked hyperglycemia in lean young adults and may, therefore, be mistaken for type 1 diabetes, with implications for individual treatment and risk of diabetes in other family members. We examined the prevalence of HNF-1alpha mutations in families with three generations of diabetes identified in a population-based study of childhood diabetes, representing a subpopulation in which misclassification was likely. RESEARCH DESIGN AND METHODS: In a study population of 1,470 families, 36 families (2.4%) with three affected generations were identified. In the 18 families in whom DNA samples were available, islet autoantibody testing, HLA class II genotyping, and HNF-1alpha sequencing were performed. RESULTS: At least one islet autoantibody was found in 13 of 14 probands, and diabetes-associated HLA class II haplotypes were found in 17 of 18. One proband, who had no islet autoantibodies and was homozygous for the protective HLA haplotype DRB1*02-DQB1*0602, had a novel HNF-1alpha heterozygous nonsense mutation (R54X). This mutation cosegregated with diabetes in the family. The proband, his brother, mother, and maternal grandmother were diagnosed with type 1 diabetes aged 14-18 years and treated with insulin (0.39-0.74 units/kg) from diagnosis. The mother has since been successfully transferred to sulfonylurea treatment. CONCLUSIONS: Family history alone is of limited value in identification of individuals with HNF-1alpha mutations, and we propose a stepwise approach that restricts sequencing of the HNF-1alpha gene to those with a family history of diabetes who also test negative for islet autoantibodies.     

No evidence for linkage at candidate type 2 diabetes susceptibility loci on chromosomes 12 and 20 in United Kingdom Caucasians

Several studies have identified evidence for linkage between type 2 diabetes and the regions on chromosomes 12 and 20 containing the maturity-onset diabetes of the young (MODY) genes, hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-4alpha. Two studies examining the HNF-1alpha region have demonstrated evidence for linkage at genome-wide levels of significance, whereas four studies examining the HNF-4alpha locus have resulted in evidence for linkage at more suggestive levels of significance. The demonstration of linkage to these regions in additional patient series will strengthen the evidence that susceptibility alleles exist at these loci. We therefore assessed the evidence for linkage to these regions using a large cohort of United Kingdom Caucasian type 2 diabetes-affected sibling pairs. A maximum total of 315 affected full sibling pairs were typed for microsatellite markers across the MODY regions and, in a subset of families, for markers spanning the whole of chromosome 20. Evidence for linkage was assessed using a multipoint, mode of inheritance-free method. Linkage analysis did not reveal any significant evidence for excess allele sharing at any of the regions studied. Loci contributing sibling recurrence risks, relative to the general population risk, of 1.75 and 1.25 could be excluded for the HNF-1alpha and HNF-4alpha regions, respectively. We have not confirmed in United Kingdom Caucasians the evidence for linkage previously reported on 12q and 20q. Our results highlight further the problems of replicating previous positive linkage results across different ethnic groups.     

A UK nationwide prospective study of treatment change in MODY: genetic subtype and clinical characteristics predict optimal glycaemic control after discontinuing insulin and metformin

Aims/hypothesis

Treatment change following a genetic diagnosis of MODY is frequently indicated, but little is known about the factors predicting future treatment success. We therefore conducted the first prospective study to determine the impact of a genetic diagnosis on individuals with GCK-, HNF1A- or HNF4A-MODY in the UK, and to identify clinical characteristics predicting treatment success (i.e. HbA_1c ≤58 mmol/mol [≤7.5%]) with the recommended treatment at 2 years.

Methods

This was an observational, prospective, non-selective study of individuals referred to the Exeter Molecular Genetic Laboratory for genetic testing from December 2010 to December 2012. Individuals from the UK with GCK- or HNF1A/HNF4A-MODY who were not on recommended treatment at the time of genetic diagnosis, and who were diagnosed below the age of 30 years and were currently aged less than 50 years, were eligible to participate.

Results

A total of 44 of 58 individuals (75.9%) changed treatment following their genetic diagnosis. Eight individuals diagnosed with GCK-MODY stopped all diabetes medication without experiencing any change in HbA_1c (49.5 mmol/mol [6.6%] both before the genetic diagnosis and at a median of 1.25 years’ follow-up without treatment, p?=?0.88). A total of 36 of 49 individuals (73.5%) diagnosed with HNF1A/HNF4A-MODY changed treatment; however, of the 21 of these individuals who were being managed with diet or sulfonylurea alone at 2 years, only 13 (36.1% of the population that changed treatment) had an HbA_1c ≤58 mmol/mol (≤7.5%). These individuals had a shorter diabetes duration (median 4.6 vs 18.1 years), lower HbA_1c (58 vs 73 mmol/mol [7.5% vs 8.8%]) and lower BMI (median 24.2 vs 26.0 kg/m²) at the time of genetic diagnosis, compared with individuals (n?=?23/36) with an HbA_1c >58 mmol/mol (>7.5%) (or <58 mmol/mol [<7.5%] on additional treatment) at the 2 year follow-up. Overall, 64% (7/11) individuals with a diabetes duration of ≤11 years and an HbA_1c of ≤69 mmol/mol (≤8.5%) at time of the genetic test achieved good glycaemic control (HbA_1c ≤58 mmol/mol [≤7.5%]) with diet or sulfonylurea alone at 2 years, compared with no participants with a diabetes duration of >11 years and an HbA_1c of >69 mmol/mol (>8.5%) at the time of genetic diagnosis.

Conclusions/interpretation

In participants with GCK-MODY, treatment cessation was universally successful, with no change in HbA_1c at follow-up. In those with HNF1A/HNF4A-MODY, a shorter diabetes duration, lower HbA_1c and lower BMI at genetic diagnosis predicted successful treatment with sulfonylurea/diet alone, supporting the need for early genetic diagnosis and treatment change. Our study suggests that, in individuals with HNF1A/HNF4A-MODY with a longer duration of diabetes (>11 years) at time of genetic test, rather than ceasing current treatment, a sulfonylurea should be added to existing therapy, particularly in those who are overweight or obese and have a high HbA_1c.

     

Suppression of emotions in essential dyspepsia and chronic duodenal ulcer. A case-control study

It remains controversial whether psychologic factors contribute to the onset or chronicity of non-ulcer dyspepsia (NUD) and duodenal ulcer. Although such patients on conventional psychologic testing have no clearly defined specific personality type, an inability to express emotion, which may result in excessive autonomic arousal, has been suggested to be important on theoretic grounds. The aim of this study was to assess whether the latter defect is associated with the subgroup of NUD patients with essential dyspepsia and with patients with chronic duodenal ulcer. Eighty-one patients with essential dyspepsia and 53 patients with duodenal ulcer studied after endoscopy were compared with 82 randomly selected dyspepsia-free community controls. All were assessed with the Courtauld emotional control scale, a valid and objective self-report measure. Control of anger, anxiety, unhappiness, and total emotional control over negative reactions were similar in all three groups. It is concluded that patients with essential dyspepsia and duodenal ulcer who present for investigation are unlikely to repress emotional reactions consciously.     

The effects of posterior cortical lesions on responses to visual threats in the Mongolian gerbil (Meriones unguiculatus).

Mongolian gerbils received aspiration lesions of either primary visual cortex (PVC), medial extrastriate visual cortex, retrosplenial cortex (RSC), or sham operations. The responses of gerbils to the presentation of an overhead visual stimulus were recorded in an open field. In all groups, presentation of the stimulus produced an increase in rearing. This suggests that the stimulus was detected by all animals. Gerbils with RSC or PVC lesions showed reduced levels of response to the stimulus. We suggest that some of the observed deficits can be explained as failures to produce responses to threat that are appropriate to the context in which the the threat was presented.