Energy and calcium stores are preserved in girls and young women with CF, independent of disease severity: An explanation for the 'gender gap'?

Bioenergetics differ between males and females of many species. Human females apportion a substantial proportion of energy resources towards gynoid fat storage, to support the energetic burden of reproduction. Similarly, axial calcium accrual is favoured in females compared with males. Nutritional status is a prognostic indicator in cystic fibrosis (CF), but girls and young women are at greater risk of death despite equivalent nutritional status to males. The aim of this study was to compare fat (energy) and calcium stores (bone density) in males and females with CF over a spectrum of disease severity. Methods: Fat as % body weight (fat%) and lumbar spine (LS) and total body (TB) bone mineral density (BMD) were measured using dual absorption X-ray photometry in 127(59M) control and 101(54M) CF subjects, aged 9–25 years. An equation for predicted age at death had been determined using survival data and history of pulmonary function for the whole clinic, based on a trivariate normal model using maximum likelihood methods (1). For the CF group, a disease severity index (predicted age at death) was calculated from the derived equations according to each subjects history of pulmonary function, current age, and gender. Disease severity was classified according to percentile of predicted age at death (‘mild’ ≥75th, ‘moderate’ 25th–75th, ‘severe’ ≤25th percentile). Wt for age z-score was calculated. Serum testosterone and oestrogen were measured in males and females respectively. Fat% and LSBMD were compared between the groups using ANOVA. Results: There was an interaction between disease severity and gender: increasing disease severity was associated with greater deficits in TB (p=0.01), LSBMD (p

Arrhythmias and mortality after myocardial infarction in diabetic patients - Relationship to diabetes treatment

OBJECTIVE- To assess the relationship between clinical course after acute myocardial infarction (AMI) and diabetes treatment. RESEARCH DESIGN AND METHODS- Retrospective analysis of data from all patients aged 25-64 years admitted to hospitals in Perth, Australia, between 1985 and 1993 with AMI diagnosed according to the International Classification of Diseases (9th revision) criteria was conducted. Short- (28-day) and long-term survival and complications in diabetic and nondiabetic patients were compared. For diabetic patients, 28-day survival, dysrhythmias, heart block, and pulmonary edema were treated as outcomes, and factors related to each were assessed using multiple logistic regression. Diabetes treatment was added to the model to assess its significance. Long-term survival was compared by means of a Cox proportional hazards model. RESULTS- Of 5,715 patients, 745 (12.9%) were diabetic. Mortality at 28 days was 12.0 and 28.1% for nondiabetic and diabetic patients, respectively (P < 0.001); there were no significant drug effects in the diabetic group. Ventricular fibrillation in diabetic patients taking glibenclamide (11.8%) was similar to that of nondiabetic patients (11.0%) but was lower than that for those patients taking either gliclazide (18.0%; 0.1 > P > 0.05) or insulin (22.8%; P < 0.05). There were no other treatment-related differences in acute complications. Long-term survival in diabetic patients was reduced in those taking digitalis and/or diuretics but type of diabetes treatment at discharge had no significant association with outcome. CONCLUSlONS- These results do not suggest that ischemic heart disease should influence the choice of diabetes treatment regimen in general or of sulfonylurea drug in particular.

Reaching those most in need: a review of diabetes self-management interventions in disadvantaged populations

There has been increased recognition of the importance of developing diabetes self-management education (DSME) interventions that are effective with under-served and minority populations. Despite several recent studies in this area, there is to our knowledge no systematic review or synthesis of what has been learned from this research. An electronic literature search identified five formative evaluations and ten controlled DSME intervention trials focused on under-served (low-income, minority or aged) populations. The RE-AIM (Reach, Efficacy, Adoption, Implementation, Maintenance) evaluation framework was used to evaluate the controlled studies on the dimensions of reach, efficacy, adoption, implementation, and maintenance. Fifty percent of the studies identified reported on the percentage of patients who participated, and the percentages were highly variable. The methodological quality of the articles was generally good and the short-term results were encouraging, especially on behavioral outcomes. Data on adoption (representativeness of settings and clinicians who participate) and implementation were almost never reported. Studies of modalities in addition to group meetings are needed to increase the reach of DSME with under-served populations. The promising formative evaluation work that has been conducted needs to be extended for more systematic study of the process of intervention implementation and adaptation with special populations. Studies that explicitly address the community context and that address multiple issues related to public health impact of DSME interventions are recommended to enhance long-term results. Copyright (C) 2002 John Wiley Sons, Ltd.

Identification of novel "pathologs" (human disease-related gene candidates) from the RIKEN full-length mouse cDNA data set

The majority of common diseases such as cancer, allergy, diabetes, or heart disease are characterized by complex genetic traits, in which genetic and environmental components contribute to disease susceptibility. Our knowledge of the genetic factors underlying most of such diseases is limited. A major goal in the post-genomic era is to identify and characterize disease susceptibility genes and to use this knowledge for disease treatment and prevention. More than 500 genes are conserved across the invertebrate and vertebrate genomes. Because of gene conservation, various organisms including yeast, fruitfly, zebrafish, rat, and mouse have been used as genetic models.

Quality of diabetes care and coronary heart disease absolute risk in patients with type 2 diabetes mellitus in Australian general practice

Objective: To examine the quality of diabetes care and prevention of cardiovascular disease (CVD) in Australian general practice patients with type 2 diabetes and to investigate its relationship with coronary heart disease absolute risk (CHDAR). Methods: A total of 3286 patient records were extracted from registers of patients with type 2 diabetes held by 16 divisions of general practice (250 practices) across Australia for the year 2002. CHDAR was estimated using the United Kingdom Prospective Diabetes Study algorithm with higher CHDAR set at a 10 year risk of >15%. Multivariate multilevel logistic regression investigated the association between CHDAR and diabetes care. Results: 47.9% of diabetic patient records had glycosylated haemoglobin (HbA1c) >7%, 87.6% had total cholesterol >= 4.0 mmol/l, and 73.8% had blood pressure (BP) >= 130/85 mm Hg. 57.6% of patients were at a higher CHDAR, 76.8% of whom were not on lipid modifying medication and 66.2% were not on antihypertensive medication. After adjusting for clustering at the general practice level and age, lipid modifying medication was negatively related to CHDAR (odds ratio (OR) 0.84) and total cholesterol. Antihypertensive medication was positively related to systolic BP but negatively related to CHDAR (OR 0.88). Referral to ophthalmologists/optometrists and attendance at other health professionals were not related to CHDAR. Conclusions: At the time of the study the diabetes and CVD preventive care in Australian general practice was suboptimal, even after a number of national initiatives. The Australian Pharmaceutical Benefits Scheme (PBS) guidelines need to be modified to improve CVD preventive care in patients with type 2 diabetes.

Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats

1 Fibrosis leads to chronic impairment of cardiac and renal function and thus reversal of existing fibrosis may improve function and survival. This project has determined whether pirfenidone, a new antifibrotic compound, and spironolactone, an aldosterone antagonist, reverse both deposition of the major extracellular matrix proteins, collagen and fibronectin, and functional changes in the streptozotocin(STZ)-diabetic rat. 2 Streptozotocin (65 mg kg(-1) i.v.)-treated rats given pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone; approximately-200 mg kg(-1) day(-1) as 0.2-2g l(-1) drinking water) or spironolactone (50 mg kg(-1) day(-1) s.c.) for 4 weeks starting 4 weeks after STZ showed no attenuation of the increased blood glucose concentrations and increased food and water intakes which characterize diabetes in this model. 3 STZ-treatment increased perivascular and interstitial collagen deposition in the left ventricle and kidney, and surrounding the aorta. Cardiac, renal and plasma fibronectin concentrations increased in STZ-diabetic rats. Passive diastolic stiffness increased in isolated hearts from STZ-diabetic rats. Both pirfenidone and spironolactone treatment attenuated these increases without normalizing the decreased + dP/dt(max) of STZ-diabetic hearts. 4 Left ventricular papillary muscles from STZ-treated rats showed decreased maximal positive inotropic responses to noradrenaline, EMD 57033 (calcium sensitizer) and calcium chloride; this was not reversed by pirfenidone or spironolactone treatment. STZ-treatment transiently decreased GFR and urine flow rates in isolated perfused kidneys; pirfenidone but not spironolactone prevented the return to control values. 5 Thus, short-term pirfenidone and spironolactone treatment reversed cardiac and renal fibrosis and attenuated the increased diastolic stiffness without normalizing cardiac contractility or renal function in STZ-diabetic rats.

Cationic drug pharmacokinetics in diseased livers determined by fibrosis index, hepatic protein content, microsomal activity, and nature of drug

The disposition kinetics of six cationic drugs in perfused diseased and normal rat livers were determined by multiple indicator dilution and related to the drug physicochemical properties and liver histopathology. A carbon tetrachloride (CCl4)induced acute hepatocellular injury model had a higher fibrosis index (FI), determined by computer-assisted image analysis, than did an alcohol-induced chronic hepatocellular injury model. The alcohol-treated group had the highest hepatic alpha(1)- acid glycoprotein, microsomal protein (MP), and cytochrome P450 (P450) concentrations. Various pharmacokinetic parameters could be related to the octanol-water partition coefficient (log P-app) of the drug as a surrogate for plasma membrane partition coefficient and affinity for MP or P450, the dependence being lower in the CCl4-treated group and higher in the alcohol-treated group relative to controls. Stepwise regression analysis showed that hepatic extraction ratio, permeability-surface area product, tissue-binding constant, intrinsic clearance, partition ratio of influx (k(in)) and efflux rate constant (k(out)), and k(in)/k(out) were related to physicochemical properties of drug (log P-app or pK(a)) and liver histopathology (FI, MP, or P450). In addition, hepatocyte organelle ion trapping of cationic drugs was evident in all groups. It is concluded that fibrosis-inducing hepatic disease effects on cationic drug disposition in the liver may be predicted from drug properties and liver histopathology.

Body mass index-related human adipocyte agouti expression is sex-specific but not depot-specific

Objective: To determine if human adipocyte agouti signal protein (ASIP) mRNA expression is associated with obesity and is gender and/or depot specific. Research Methods and Procedures: Subjects included 8 men (64 +/- 3 years) and 14 women (56 +/- 15 years) undergoing elective abdominal surgery. ASIP mRNA levels in isolated omental and subcutaneous abdominal adipocytes were measured by quantitative reverse transcription polymerase chain reaction. Results: No significant depot difference was observed between genders; ASIP mRNA levels of omental and subcutaneous abdominal adipocytes were pooled for this analysis. BMI and ASIP gene expression were negatively correlated in men (p = -0.70; p < 0.05), whereas a positive relationship was observed in women (p = 0.48; p < 0.05). No significant difference was observed in age, body weight, body mass index (BMI), and waist circumference between groups. Hip circumference was significantly higher in women than in men (p < 0.05). Also, no significant difference in ASIP mRNA expression was observed between men and women, regardless of the fat depot. Discussion: These results show that men and women of similar age and BMI present similar ASIP mRNA levels in omental and subcutaneous abdominal adipocytes. However, a sexual dimorphism exists in the relationship between ASIP expression and BMI. If ASIP is involved in appetite regulation or energy homeostasis in humans, this observation may contribute to the recognized differences in these parameters between men and women.

In overweight patients with chronic hepatitis C, circulating insulin is associated with hepatic fibrosis: implications for therapy

Background/Aims: Host factors such as increased body mass index (BMI) and genotype-specific viral factors contribute to the development of steatosis in patients with chronic hepatitis C (HCV). We hypothesized that host metabolic factors associated with increased BMI may play a role in disease progression. Methods: Fasting serum was collected from 160 patients with chronic HCV at the time of liver biopsy and 45 age, gender and BMI matched controls, and assessed for levels of insulin, c-peptide and leptin. Results: Patients with viral genotype 3 had more severe steatosis (P = 0.0001) and developed stages 1 and 2 fibrosis at a younger age (P < 0.05) than patients with genotype 1. For both genotypes, overweight patients had significantly more steatosis and increased insulin and leptin levels. In contrast to lean patients, there was a statistically significant increase in circulating insulin levels with increasing fibrosis in overweight patients with chronic HCV (P = 0.03). Following multivariate analysis, insulin was independently associated with fibrosis (P = 0.046) but not inflammation (P = 0.83). There was no association between serum leptin levels and stage of fibrosis. Conclusions: Increasing circulating insulin levels may be a factor responsible for the association between BMI and fibrosis in patients with HCV, irrespective of viral genotype. (C) 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.