Perivascular Fat and the Microcirculation: Relevance to Insulin Resistance, Diabetes, and Cardiovascular Disease

Type 2 diabetes and its major risk factor, obesity, are a growing burden for public health. The mechanisms that connect obesity and its related disorders, such as insulin resistance, type 2 diabetes, and hypertension, are still undefined. Microvascular dysfunction may be a pathophysiologic link between insulin resistance and hypertension in obesity. Many studies have shown that adipose tissue-derived substances (adipokines) interact with (micro)vascular function and influence insulin sensitivity. In the past, research focused on adipokines from perivascular adipose tissue (PVAT). In this review, we focus on the interactions between adipokines, predominantly from PVAT, and microvascular function in relation to the development of insulin resistance, diabetes, and cardiovascular disease

Antibiotics for acute otitis media: a meta-analysis with individual patient data.

BACKGROUND: Individual trials to test effectiveness of antibiotics in children with acute otitis media have been too small for valid subgroup analyses. We aimed to identify subgroups of children who would and would not benefit more than others from treatment with antibiotics. METHODS: We did a meta-analysis of data from six randomised trials of the effects of antibiotics in children with acute otitis media. Individual patient data from 1643 children aged from 6 months to 12 years were validated and re-analysed. We defined the primary outcome as an extended course of acute otitis media, consisting of pain, fever, or both at 3-7 days. FINDINGS: Significant effect modifications were noted for otorrhoea, and for age and bilateral acute otitis media. In children younger than 2 years of age with bilateral acute otitis media, 55% of controls and 30% on antibiotics still had pain, fever, or both at 3-7 days, with a rate difference between these groups of -25% (95% CI -36% to -14%), resulting in a number-needed-to-treat (NNT) of four children. We identified no significant differences for age alone. In children with otorrhoea the rate difference and NNT, respectively, were -36% (-53% to -19%) and three, whereas in children without otorrhoea the equivalent values were -14% (-23% to -5%) and eight. INTERPRETATION: Antibiotics seem to be most beneficial in children younger than 2 years of age with bilateral acute otitis media, and in children with both acute otitis media and otorrhoea. For most other children with mild disease an observational policy seems justified

Abnormalities of glucose metabolism in spontaneously hypertensive rats

Abnormalities in glucose metabolism and insulin action are frequently detected in patients with essential hypertension. Spontaneously hypertensive rats (SHR) have been used as an experimental model to understand this pathological condition. The objective of the present study was to assess glucose metabolism and insulin action in SHR and Wistar rats under fed and fasting conditions. Peripheral glucose utilization was estimated by kinetic studies with [6-³H]-glucose and gluconeogenetic activity was measured during continuous [14C]-bicarbonate infusion. Plasma glucose levels were higher in the SHR group. Plasma insulin levels in the fed state were higher in the SHR group (99.8 ± 6.5 µM) than in the control group (70.4 ± 3.6 µM). Muscle glycogen content was reduced in SHR compared to control under the various experimental conditions. Peripheral glucose utilization was slightly lower in the SHR group in the fed state (8.72 ± 0.55 vs 9.52 ± 0.80 mg kg-1 min-1 in controls). Serum free fatty acid levels, hepatic glycogen levels, hepatic phosphoenolpyruvate carboxykinase activity and gluconeogenetic activity were similar in the two groups. The presence of hyperglycemia and hyperinsulinemia and the slightly reduced peripheral glucose utilization suggest the presence of resistance to the action of insulin in peripheral tissues of SHR. Hepatic gluconeogenesis does not seem to contribute to the metabolic alterations detected in these animals

Role of SOD3 in silica-related lung fibrosis and pulmonary vascular remodeling

Abstract Background Work-place exposure to silica dust may lead to progressive lung inflammation culminating in the development of silicosis, an irreversible condition that can be complicated by onset of pulmonary hypertension (PH). The molecular mechanisms leading to the development of PH and lung fibrosis in response to silica are not well understood. Oxidant/antioxidant imbalance in the lung may promote fibroproliferation and vascular smooth muscle proliferation, ultimately leading to the development of PH. Herein, we analyze the development of PH and lung fibrosis in mice deficient in extracellular superoxide dismutase (SOD3), an enzyme with anti-oxidant activity. Methods PH and silicosis were induced in wild-type and Sod3−/− mice through intratracheal injection of crystalline silica at dose 0.4 g/kg. Pulmonary hypertension and lung fibrosis were characterized by changes in right ventricular systolic pressure (RVSP) and collagen deposition 28 days following silica injections. Vascular remodeling was analyzed using immunohistochemistry and morphometric analysis. The expression of genes were analyzed using qRT-PCR and Western blot. Results C57BL6 mice exposed to silica showed attenuated expression of Sod3 in the lung suggesting a protective role for Sod3. Consistent with this, Sod3−/− mice developed more severe fibrotic inflammatory nodules with increased collagen deposition. Furthermore, the expression of genes involved in tissue remodeling (Timp1), fibrotic lesion formation (Fsp1) and inflammatory response (Mcp1) were significantly elevated in Sod3−/− mice compared to Sod3+/+ mice treated with silica. Infiltration of neutrophils and activated macrophages into affected lung was significantly higher in Sod3 deficient mice. In addition, silica produced more profound effects on elevation of RVSP in Sod3−/− compared to wild-type littermate. Increase in RVSP was concomitant with hypertrophy of pulmonary arteries located in silicotic nodules of both mouse strains, however, vascular remodeling in unaffected areas of lung was detected only in Sod3−/− mice. Conclusions Our data suggest that Sod3 and extracellular oxidative stress may play an important role in the development of pneumoconiosis and pulmonary vascular remodeling following exposure to environmental and occupational silica

Skeletal findings in children recently initiating glucocorticoids for the treatment of nephrotic syndrome

INTRODUCTION: Vertebral fractures are an under-recognized complication of childhood glucocorticoid-treated illnesses. Our goal was to study the relationship among glucocorticoid exposure, lumbar spine areal BMD (LS BMD) and vertebral shape in glucocorticoid-treated children with new-onset nephrotic syndrome. METHODS: Lateral thoracolumbar spine radiography and lumbar spine bone mineral density (LS BMD) were performed in 80 children with nephrotic syndrome (median age 4.4 years; 46 boys) within the first 37 days of glucocorticoid therapy. Genant semi-quantitative grading was used as the primary method for vertebral morphometry; the Algorithm-Based Qualitative (ABQ) method was used for secondary vertebral deformity analysis. RESULTS: Six of the 78 children with usable radiographs (8%; 95% confidence interval 4 to 16%) manifested a single Genant Grade 1 deformity each. All deformities were mild anterior wedging (2 at each of T6, T7 and T8). Four of the 78 children (5%; 95% confidence interval 2 to 13%) showed one ABQ sign of fracture each (loss of endplate parallelism; 2 children at T6 and 2 at T8). Two of the children with ABQ signs also had a Genant Grade 1 deformity in the same vertebral body. None of the children with a Genant or ABQ deformity reported back pain. An inverse relationship was identified between LS BMD Z-score and glucocorticoid exposure. CONCLUSIONS: Although we identified an inverse relationship between steroid exposure and LS BMD soon after glucocorticoid initiation for childhood nephrotic syndrome, there was only a low rate of vertebral deformities. The clinical significance of these findings requires further study