MicroRNA regulation of islet and enteroendocrine peptides: Physiology and therapeutic implications for type 2 diabetes.

The pathogenesis of type 2 diabetes (T2D) is associated with dysregulation of glucoregulatory hormones, including both islet and enteroendocrine peptides. Microribonucleic acids (miRNAs) are short noncoding RNA sequences which post transcriptionally inhibit protein synthesis by binding to complementary messenger RNA (mRNA). Essential for normal cell activities, including proliferation and apoptosis, dysregulation of these noncoding RNA molecules have been linked to several diseases, including diabetes, where alterations in miRNA expression within pancreatic islets have been observed. This may occur as a compensatory mechanism to maintain beta-cell mass/function (e.g., downregulation of miR-7), or conversely, lead to further beta-cell demise and disease progression (e.g., upregulation of miR-187). Thus, targeting miRNAs has potential for novel diagnostic and therapeutic applications in T2D. This is reinforced by the success seen to date with miRNA-based therapeutics for other conditions currently in clinical trials. In this review, differential expression of miRNAs in human islets associated with T2D will be discussed along with further consideration of their effects on the production and secretion of islet and incretin hormones. This analysis further unravels the therapeutic potential of miRNAs and offers insights into novel strategies for T2D management.

Use of a simple liquid meal test to evaluate insulin sensitivity and beta-cell function in children.

Insulin sensitivity and ß-cell function are useful indices of metabolic disease risk but are difficult to assess in young children because of the invasive nature of commonly used methodology. A meal-based method for assessing insulin sensitivity and ß-cell function may at least partially alleviate concerns. The objectives of this study were to: (i) determine the association of insulin sensitivity assessed by liquid meal test with that determined by an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT); (ii) examine the association of insulin sensitivity derived from each test with measures of body composition, fat distribution and metabolic health (lipids, fasting insulin and glucose, and surrogate indices of insulin sensitivity); and (iii) examine the associations of indices of ß-cell function derived from each test with total and regional adiposity. Forty-seven children (7-12 years) underwent both a liquid meal test and an FSIGT. The insulin sensitivity index derived from the meal test (SI-meal) was positively associated with that from the FSIGT (SI-FSIGT; r = 0.63; P < 0.001), and inversely with all measures of insulin secretion derived from the meal test. Both SI-meal and SI-FSIGT were associated with measures of total and regional adiposity. SI-meal, but not SI-FSIGT, was associated with triglycerides and fasting insulin, after adjusting for ethnicity, gender, pubertal stage and fat mass. Basal insulin secretion measured during the meal test was positively associated with all measures of adiposity, independent of insulin sensitivity. In conclusion, a liquid meal offers a valid and sensitive means of assessing insulin sensitivity and ß-cell responsivity in young children.

African genetic admixture is associated with body composition and fat distribution in a cross-sectional study of children.

OBJECTIVE: Although differences in body composition parameters among African American (AA), Hispanic American (HA) and European American (EA) children are well documented, the factors underlying these differences are not completely understood. Environmental and genetic contributors have been evaluated as contributors to observed differences. This study evaluated the extent to which African or European ancestral genetic background influenced body composition and fat distribution in 301 peripubertal AA (n = 107), HA (n = 79) and EA (n = 115) children aged 7-12. DESIGN: Estimates of African admixture (AFADM) and European admixture (EUADM) were obtained for every subject using 142 ancestry informative DNA markers. Dual energy X-ray absorptiometry and computed tomography scanning were used to determine body composition and abdominal fat distribution, respectively. Multiple regression models were conducted to evaluate the contribution of admixture estimates to body composition and fat distribution. RESULTS: Greater AFADM was associated with lower fat mass (P = 0.0163), lower total abdominal adipose tissue (P = 0.0006), lower intra-abdominal adipose tissue (P = 0.0035), lower subcutaneous abdominal adipose tissue (P = 0.0115) and higher bone mineral content (BMC) (P = 0.0253), after adjusting for socio-economic status, sex, age, height, race/ethnicity and pubertal status. Greater EUADM was associated with lower lean mass (LM) (P = 0.0056). CONCLUSION: These results demonstrate that ancestral genetic background contributes to racial/ethnic differences in body composition above and beyond the effects of racial/ethnic classification and suggest a genetic contribution to total body fat accumulation, abdominal adiposity, LM and BMC.

Feto-placental adaptations to maternal obesity in the baboon.

Maternal obesity is present in 20-34% of pregnant women and has been associated with both intrauterine growth restriction and large-for-gestational age fetuses. While fetal and placental functions have been extensively studied in the baboon, no data are available on the effect of maternal obesity on placental structure and function in this species. We hypothesize that maternal obesity in the baboon is associated with a maternal inflammatory state and induces structural and functional changes in the placenta. The major findings of this study were: 1) decreased placental syncytiotrophoblast amplification factor, intact syncytiotrophoblast endoplasmic reticulum structure and decreased system A placental amino acid transport in obese animals; 2) fetal serum amino acid composition and mononuclear cells (PBMC) transcriptome were different in fetuses from obese compared with non-obese animals; and 3) maternal obesity in humans and baboons is similar in regard to increased placental and adipose tissue macrophage infiltration, increased CD14 expression in maternal PBMC and maternal hyperleptinemia. In summary, these data demonstrate that in obese baboons in the absence of increased fetal weight, placental and fetal phenotype are consistent with those described for large-for-gestational age human fetuses.

Effect of scalp and facial hair on air displacement plethysmography estimates of percentage of body fat.

OBJECTIVE: The objective of this study was to determine the effect of body hair (scalp and facial) on air displacement plethysmography (BOD POD) estimates of percentage of body fat. RESEARCH METHODS AND PROCEDURES: A total of 25 men (31.4 +/- 8.0 years, 83.4 +/- 12.2 kg, 181.8 +/- 6.9 cm) agreed to grow a beard for 3 weeks to participate in the study. Total body density (g/cm(3)) and percentage of body fat were evaluated by BOD POD. To observe the effect of trapped isothermal air in body hair, BOD POD measures were performed in four conditions: criterion method (the beard was shaven and a swimcap was worn), facial hair and swimcap, facial hair and no swimcap, and no facial hair and no swimcap(.) RESULTS: The presence of only a beard (facial hair and swimcap) resulted in a significant underestimation of percentage of body fat (16.2%, 1.0618 g/cm(3)) vs. the criterion method (17.1%, 1.0597 g/cm(3), p < 0.001). The effect of scalp hair (no swim cap worn) resulted in a significant underestimation in percentage of body fat relative to the criterion method, either with facial hair (facial hair and no swimcap; 14.8%, 1.0649 g/cm(3)) or without facial hair (no facial hair and no swimcap; 14.8%, 1.0650 g/cm(3), p < 0.001 for both). DISCUSSION: A significant underestimation of percentage of body fat was observed with the presence of facial hair ( approximately 1%) and scalp hair ( approximately 2.3%). This underestimation in percentage of body fat may be caused by the effect of trapped isothermal air in body hair on body-volume estimates. Thus, excess facial hair should be kept to a minimum and a swimcap should be worn at all times to ensure accurate estimates of body fat when using the BOD POD.

Defining health-related obesity in prepubertal children.

OBJECTIVE: The purpose of this study was to develop percentage of fat and waist circumference cut-points in prepubertal children with the intention of defining obesity associated with cardiovascular disease (CVD) risk. RESEARCH METHODS AND PROCEDURES: A cross-sectional analysis of 87 prepubertal children aged 4 to 11 years was used. Percentage of body fat was determined by DXA. Waist circumference was measured to the nearest millimeter. Receiver Operating Characteristic analyses of percentage of fat and waist circumference were used to develop cut-points for individuals with adverse levels of CVD risk factors. RESULTS: The risk factors selected for analyses (i.e., fasting insulin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol/high-density lipoprotein cholesterol) were significantly related to percentage of body fat and waist circumference. Likelihood ratios were used to identify percentage of fat and waist circumference cut-points associated with adverse cardiovascular risk profiles. Two cut-points, an upper cut-point of 33% body fat and a lower cut-point of 20% body fat, were derived. Waist circumference cut-points indicative of adverse and normal risk-factor profiles were 71 cm and 61 cm, respectively. DISCUSSION: The data indicate that children with > or =33% body fat and children with a waist circumference > or =71 cm were more likely to possess an adverse CVD risk-factor profile than a normal risk-factor profile. The likelihood of children with < 20% body fat or a waist circumference < 61 cm possessing an adverse CVD risk-factor profile as opposed to a normal risk-factor profile was small. The cut-points describe an adequate health-related definition of childhood obesity.

Clozapine and the treatment of schizophrenia.

Clozapine, an atypical antipsychotic medication, is the most significant pharmacological advancement in the treatment of chronic schizophrenia in years. Effective in treating the nearly 30 percent of people with schizophrenia who do not respond to conventional pharmacological and psychosocial therapies, clozapine offers new hope to many. However, high cost, a potentially lethal side effect, and a weekly mandatory monitoring system have hampered access to clozapine treatment. This article reviews a brief history of clozapine use in the United States and also the unique features of the medication. Economic, ethical, and personnel resource issues of clozapine use are summarized. The author describes her clinical experiences with the psychosocial issues faced by those who respond to clozapine treatment, case highlights, and social work interventions. Social work advocacy for increased access to clozapine, the potential contributions of social workers in the selection of patients for treatment, and the logistical management issues confronting social workers in inpatient and outpatient mental health settings are addressed.

Multidisciplinary approach to psychosis, intermittent hyponatremia, and polydipsia.

The syndrome of psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome), seen in the seriously mentally ill, can result in severe biopsychosocial impairment, including an excessive death rate if not identified early. Because of its impact on the health, functioning, and quality of life of the seriously mentally ill patient, all mental health care providers must be aware of the signs and symptoms of PIP syndrome. Physiological, psychological, behavioral, self-care, and social factors all play a role in the manifestation of the syndrome; it follows that a multidisciplinary approach is crucial to ensure early detection, monitoring, and treatment of this problem both in the hospital and in the community. This article explains how we have incorporated the strengths of various disciplinary strategies into a unified treatment model for managing PIP syndrome and its sequelae.

Explosively triggered gas-dielectric crowbar switch.

A gas-insulated gap switch with an unusually high standoff-to-trigger voltage ratio is described. Designed to standoff 500 kV when pressurized with SF(6) at 1.5 MPa (212 psi), the switch was triggered with as little as 19.3 kV across the gap by firing a shaped charge from one electrode toward the opposite electrode. Similar air-insulated and SF(6)-insulated gaps pressurized to 83 kPa (12 psi) and designed to standoff 50 and 150 kV, respectively, were triggered with 15.4 kV across the gap by firing an ordinary RP-2 detonator from one electrode toward the other.

Viruses associated with acute respiratory infections 1961-71.

Influenza-like illness, cold and sore throat was the diagnosis given in over 80% of 5177 acute respiratory illnesses in patients swabbed over a 10-year-period. A pathogenic organism was isolated twice as frequently from patients with a sore throat or an influenza-like illness as from those diagnosed as suffering from croup or laryngitis and bronchitis. A laboratory diagnosis was commoner in school children than in older or younger persons.Most of the organisms isolated were found in association with all types of acute respiratory illness but, with increasing age of the patient, one particular agent or group of agents was more likely to be of aetiological significance.