Diabetic Basement Membrane Thickening Does Not Occur in Myocardial Capillaries of Transgenic Mice When Metallothionein is Overexpressed in Cardiac Myocytes

Diabetic cardiomyopathy is a clinically distinct disease characterized by impaired cardiac function as a result of reduced contractility and hypertension‐induced athero‐ or arteriosclerosis. This may be due either to generalized vascular disease, tissue‐based injury such as focal cardiomyocyte dysmorphia, or microvascular damage manifested by myocardial capillary basement membrane (CBM) thickening. Hyperglycemia‐driven increases in reactive oxygen species (ROS) have been proposed to contribute to such damage. To address this hypothesis, we utilized light (LM) and transmission electron microscopy (TEM) to demonstrate cardiomyocyte morphology and myocardial CBM thickness in the left ventricles of four mouse genotypes: FVB (background Friend virus B controls), OVE (transgenic diabetics), Mt [transgenics with targeted overexpression of the antioxidant protein metallothionein (MT) in cardiomyocytes], and OVEMt (bi‐transgenic cross of OVE and Mt) animals. Mice were prepared for morphometric analysis by vascular perfusion. Focal myocardial disorganization was identified in OVE mice but not in the remaining genotypes. Not unexpectedly, myocardial CBM thickness was increased significantly in OVE relative to FVB (P < 0.05) and Mt (P < 0.05) animals (+28% and +39.5%, respectively). Remarkably, however, OVEMt myocardial CBMs showed no increase in width; rather they were ～3% thinner than FVB controls. Although the molecular mechanisms regulating CBM width remain elusive, it seems possible that despite a significant hyperglycemic environment, MT antioxidant activity may mitigate local oxidative stress and reduce downstream excess microvascular extracellular matrix (ECM) formation. In addition, the reduction of intra‐ and perivascular ROS may protect against incipient endothelial damage and the CBM thickening that results from such injury. Anat Rec, 296:480–487, 2013. © 2013 Wiley Periodicals, Inc.     

The role of fish in food-based strategies to combat vitamin A and mineral deficiencies in developing countries

Fish is important in the diets and livelihoods of many poor people suffering from vitamin and mineral deficiencies. In this article, fish intake in rural Bangladesh and Cambodia and the vitamin A, calcium, iron, and zinc contents and nutrient bioavailability of commonly consumed species are presented. The contribution of these species to nutrient intakes as well as their potential to meet dietary recommendations are presented and discussed. Data from consumption surveys were analyzed to obtain fish intake by species. Commonly consumed species were analyzed for nutrient contents, and studies on nutrient bioavailability were conducted. In poor, rural, Bangladeshi households, mean fish intake was 13-83 g raw, whole fish per person/d. Frequency of intake of small fish was high, and small fish made up 50-80% of all fish eaten during the fish production season in rural Bangladesh and Cambodia. Many small fish are eaten whole and therefore are a rich calcium source; some are also rich in vitamin A, iron, and zinc. Even small production of the vitamin A-rich fish mola in ponds in Bangladesh can meet the annual vitamin A recommendation of 2 million children, and a traditional daily meal with the iron-rich fish trey changwa plieng can meet 45% of the daily median iron requirement of Cambodian women. Fish consumption data on the species level, nutrient analyses, awareness of the nutritional value of fish, as well as promotion of the production and accessibility of nutrient-dense species can lead to the use of fish in food-based strategies to combat nutrient deficiencies in poor people in Asia and Africa.     

Utilization of traditional,complementary and alternative medicine and mental health among patients with chronic diseases in primary health care settings in Cambodia

Background

Coping with chronic illnesses often involves major lifestyle changes that may lead to poor mental health. Furthermore, in order to treat the chronic conditions, many sufferers in Asia turn to traditional, complementary and alternative medicines (TCAM). This study explores prevalence of TCAM use and factors associated with anxiety and depressive symptoms among patients with chronic diseases in Cambodia.

Methods

In 2015, this cross-sectional study was conducted with outpatients receiving treatment and care for chronic diseases in two urban and two rural primary health centers. Every eligible patient was randomly selected at the health centers using a systematic sampling procedure. Symptoms of anxiety and depression were assessed by using the Hospital Anxiety and Depression Scale (HADS). Multivariate logistic regression models were constructed to explore factors associated with anxiety and depressive symptoms.

Results

The study participants included 1528 patients, of whom 77.2% were female, with a mean age of 46.5 years (SD = 15.3). After adjustment, patients with depressive symptoms remained significantly more likely to be in the age groups between 41 and 60 years old and to be married, separated/divorced or widowed compared to those without depressive symptoms. Regarding the use of TCAM, patients with depressive symptoms remained significantly more likely to report using an herbalist, practicing visualization and praying for own health, but less likely to report using vitamins or supplements in the past 12 months. For quality of life, patients with depressive symptoms remained significantly less likely to agree that they had enough energy for their everyday life and had enough money to meet their daily needs. Similar risk factors were also found to be significantly associated with anxiety symptoms.

Conclusions

Cambodian patients with chronic diseases who experienced symptoms of anxiety or depression were more likely to report reduced quality of life, greater chronic disease-related stigma and more TCAM use. Given the potential interaction of TCAM, mental health and other chronic conditions, a history of TCAM use and mental health should be elicited in clinical practices in primary health care settings, particularly in developing countries.

     

Diabetes as a Determinant of Mortality in Cystic Fibrosis

OBJECTIVE

Diabetes is increasingly common in cystic fibrosis, but little information describing its influence on mortality exists. Using national U.K. data, in this study we document diabetes-specific mortality rates, estimate the impact of diabetes on survival, and estimate population-attributable fractions.

RESEARCH DESIGN AND METHODS

This retrospective cohort study identified 8,029 individuals aged 0–65 years from the U.K. Cystic Fibrosis Registry (1996–2005). A total of 5,892 patients were included in analyses of mortality rates, and 4,234 were included in analyses of risk factors. We calculated age-adjusted mortality rates using Poisson regression, standardized mortality ratios using the population of England and Wales, and relative risks using proportional hazards modeling.

RESULTS

During 17,672 person-years of follow-up, 393 subjects died. The age-adjusted mortality rate was 1.8 per 100 person-years (95% CI 1.6–2.0). The age-adjusted mortality rates per 100 person-years were 2.0 (1.8–2.4) in female subjects and 1.6 (1.4–1.9) in male subjects, and 4.2 (3.4–5.1) in individuals with diabetes vs. 1.5 (1.3–1.7) in those without diabetes. Independent risk factors for death included diabetes (hazard ratio 1.31 [95% CI 1.03–1.67], female sex (1.71 [1.36–2.14]) plus poorer pulmonary function, lower BMI, Burkholderia cepacia infection, absence of Staphylococcus aureus infection, allergic bronchopulmonary aspergillosis, liver disease, prior organ transplantation, and corticosteroid use.

CONCLUSIONS

Individuals with cystic fibrosis die earlier if they have diabetes, which, if delayed or better treated, might reasonably extend survival; this hypothesis merits testing.Cystic fibrosis is the most common autosomal recessive disease leading to premature death in white populations. Because of improvements in care, both survival, with a life expectancy to the mid-30s, and, as a consequence, the prevalence of complications have increased dramatically (1–3). The influence of birth year and sex on mortality has been described in the British cystic fibrosis population (2,4), but little is documented about the association between complications and specifically diabetes and mortality.The majority of patients with cystic fibrosis die of respiratory complications. In patients with cystic fibrosis, there is a high incidence of diabetes (5), which has been shown to increase the risk of death in the U.S. (6). Yet, little information exists worldwide to document the absolute mortality rates associated with diabetes in cystic fibrosis. Using national registry data, in this study we estimate the impact of diabetes on survival in adults and children with cystic fibrosis in Britain, taking into account recognized and potential risk factors for death. We document mortality rates, estimate the risk increase associated with diabetes, and calculate the population-attributable fraction (PAF) for diabetes associated with death.     

Cardiovascular risk assessment scores for people with diabetes: a systematic review

People with type 2 diabetes have an increased risk of cardiovascular disease (CVD). Multivariate cardiovascular risk scores have been used in many countries to identify individuals who are at high risk of CVD. These risk scores include those originally developed in individuals with diabetes and those developed in a general population. This article reviews the published evidence for the performance of CVD risk scores in diabetic patients by: (1) examining the overall rationale for using risk scores; (2) systematically reviewing the literature on available scores; and (3) exploring methodological issues surrounding the development, validation and comparison of risk scores. The predictive performance of cardiovascular risk scores varies substantially between different populations. There is little evidence to suggest that risk scores developed in individuals with diabetes estimate cardiovascular risk more accurately than those developed in the general population. The inconsistency in the methods used in evaluation studies makes it difficult to compare and summarise the predictive ability of risk scores. Overall, CVD risk scores rank individuals reasonably accurately and are therefore useful in the management of diabetes with regard to targeting therapy to patients at highest risk. However, due to the uncertainty in estimation of true risk, care is needed when using scores to communicate absolute CVD risk to individuals.     

Changes in risk behaviors among Thai men who have sex with men and transgender women enrolled in the test and treat cohort

The test-and-treat approach has the potential to reduce high-risk sexual behaviors by linking high-risk individuals to health education, although this has not been proven yet. We used longitudinal data from the Test and Treat Demonstration Project among Thai men who have sex with men (MSM) and transgender women (TGW) who were not known to be HIV-positive to analyze changes in risk behaviors during the 24-month study period categorized by three groups: HIV-negative without seroconversion, seroconverters, and HIV-positive at enrollment. Five binary risk behavior outcomes – laboratory-diagnosed sexually transmitted infections (STIs); multiple sexual partners, unprotected anal intercourse, self-perceived HIV risk, and amphetamine-type stimulants use in the past month – were assessed. Among 689 participants, with a mean (SD) age of 23.1 (6.2) years, 165 participants were diagnosed with HIV: 115 at enrollment and 50 with seroconversions. HIV-positive participants at enrollment showed significant reductions in all five behavioral risk outcomes. Seroconverters demonstrated higher risks at enrollment than HIV-negative participants, and continued to practice high-risk behaviors even after seroconversion despite a significant reduction in self-perceived moderate-to-high HIV risk. Continuation of risk behaviors among seroconverters could negatively affect the ending AIDS goal, thus the integration of other effective preventive measures into HIV/STIs management programs are needed.     

Non-diabetic hyperglycaemia and cardiovascular risk: moving beyond categorisation to individual interpretation of absolute risk

Aims/hypothesis  

Non-diabetic hyperglycaemia is usually not considered at all or is viewed as a binary risk category in isolation from other factors when quantifying cardiovascular risk. We argue that hyperglycaemia should be considered as a continuous risk factor and only in the context of other vascular risk factors. To examine the potential impact of hyperglycaemia on cardiovascular disease (CVD) risk, we calculated the absolute CVD risk in groups defined by different levels of HbA_1c and other CVD risk factors.     

Renoprotection From Diabetic Complications in OVE Transgenic Mice by Endothelial Cell Specific Overexpression of Metallothionein: A TEM Stereological Analysis

We previously demonstrated that OVE transgenic diabetic mice are susceptible to chronic complications of diabetic nephropathy (DN) including substantial oxidative damage to the renal glomerular filtration barrier (GFB). Importantly, the damage was mitigated significantly by overexpression of the powerful antioxidant, metallothionein (MT) in podocytes. To test our hypothesis that GFB damage in OVE mice is the result of endothelial oxidative insult, a new JTMT transgenic mouse was designed in which MT overexpression was targeted specifically to endothelial cells. At 60 days of age, JTMT mice were crossed with age‐matched OVE diabetic mice to produce bi‐transgenic OVE‐JTMT diabetic progeny that carried the endothelial targeted JTMT transgene. Renal tissues from the OVE‐JTMT progeny were examined by unbiased TEM stereometry for possible GFB damage and other alterations from chronic complications of DN. In 150 day‐old OVE‐JTMT mice, blood glucose and HbA1c were indistinguishable from age‐matched OVE mice. However, endothelial‐specific MT overexpression in OVE‐JTMT mice mitigated several DN complications including significantly increased non‐fenestrated glomerular endothelial area, and elimination of glomerular basement membrane thickening. Significant renoprotection was also observed outside of endothelial cells, including reduced podocyte effacement, and increased podocyte and total glomerular cell densities. Moreover, when compared to OVE diabetic animals, OVE‐JTMT mice showed significant mitigation of nephromegaly, glomerular hypertrophy, increased mesangial cell numbers and increased total glomerular cell numbers. These results confirm the importance of oxidative stress to glomerular damage in DN, and show the central role of endothelial cell injury to the pathogenesis of chronic complications of diabetes. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 300:560–576, 2017. © 2016 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.     

Change in HbA1c over 3 years does not improve the prediction of cardiovascular disease over and above HbA1c measured at a single time point

Aims/hypothesis

HbA_1c is an important risk factor for cardiovascular disease (CVD), with 1% higher HbA_1c levels associated with a 10–20% increased risk of CVD. Little is known about the association between change in HbA_1c over time and cardiovascular risk in non-diabetic populations. This study examined the association between change in HbA_1c over time and cardiovascular risk in a non-diabetic British population.

Methods

We used data on HbA_1c collected at baseline and at a second health examination 3 years later among a population of 5,790 non-diabetic men and women who participated in the European Prospective Investigation of Cancer (EPIC)–Norfolk. The association between change in HbA_1c over 3 years and incident cardiovascular events over the following 8 years was examined using multivariate Cox regression. We also examined whether information on change in HbA_1c over time improved prediction of cardiovascular events over a single measure of HbA_1c by comparing the area under the receiver operating characteristic curves (aROC) and computing the net reclassification improvement.

Results

The mean change (SD) in HbA_1c over 3 years was 0.13% (0.52). During 44,596 person-years of follow-up, 529 cardiovascular events occurred (incidence 11.9 per 1,000 person-years). Each 0.5% rise in HbA_1c over 3 years was associated with a 9% increase in risk of a cardiovascular event (HR 1.09; 95% CI 1.01, 1.18) after adjustment for baseline HbA_1c and other major cardiovascular risk factors. However, change in HbA_1c was not associated with cardiovascular risk after adjustment for HbA_1c at follow-up. Multivariate models with and without information on change in HbA_1c over time showed a similar aROC of 0.78. Adding change in HbA_1c to the model with HbA_1c at follow-up did not improve risk classification.

Conclusions/interpretation

Addition of information on change in HbA_1c over 3 years did not improve the prediction of CVD over and above information on HbA_1c and other major cardiovascular risk factors from a single time point.