HIV Interventions to Reduce HIV/AIDS Stigma: A Systematic Review

We reviewed the literature to determine the effectiveness of HIV-related interventions in reducing HIV/AIDS stigma. Studies selected had randomized controlled trial (RCT), pretest–posttest with a non-randomized control group, or pretest–posttest one group study designs in which HIV-related interventions were being evaluated, and in which HIV/AIDS stigma was one of the outcomes being measured. A checklist was used to extract data from accepted studies, assess their internal validity, and overall quality. Data were extracted from 19 studies, and 14 of these studies demonstrated effectiveness in reducing HIV/AIDS stigma. Only 2 of these 14 effective studies were considered good studies, based on quality, the extent to which the intervention focused on reducing HIV/AIDS stigma, and the statistics reported to demonstrate effectiveness. Future studies to reduce HIV/AIDS stigma could improve by designing interventions that pay greater attention to internal validity, use validated HIV/AIDS stigma instruments, and achieve both statistical and public health significance.     

Difficulties in diagnosing pulmonary embolism in the obese patient: a literature review

Several of the signs and symptoms of pulmonary embolism, such as dyspnea, tachypnea, and tachycardia, are common in the obese population, so these patients are frequently suspected of having a pulmonary embolism. Establishing an accurate diagnosis in this situation is often difficult. We performed a review of the literature examining the difficulty of diagnosing pulmonary embolism in obese patients. Several factors compromise the ability of clinicians to accurately diagnose pulmonary embolism in obese patients. When patients weigh over 350 lbs (159 kg), thoracic imaging often cannot be performed because of the weight limitations of the scanning equipment. If equipment is available that can scan these patients, image quality is often poor. The literature that is available to guide the clinician in this difficult clinical scenario is sparse. Access to radiology equipment that can image morbidly obese patients is improving, but questions about image quality remain. Further research on both imaging and outcomes is needed.     

Melatonin Versus Placebo in Children with Autism Spectrum Conditions and Severe Sleep Problems Not Amenable to Behaviour Management Strategies: A Randomised Controlled Crossover Trial

Twenty-two children with autism spectrum disorders who had not responded to supported behaviour management strategies for severe dysomnias entered a double blind, randomised, controlled crossover trial involving 3 months of placebo versus 3 months of melatonin to a maximum dose of 10 mg. 17 children completed the study. There were no significant differences between sleep variables at baseline. Melatonin significantly improved sleep latency (by an average of 47 min) and total sleep (by an average of 52 min) compared to placebo, but not number of night wakenings. The side effect profile was low and not significantly different between the two arms.     

Dual γ rhythm generators control interlaminar synchrony in auditory cortex

Rhythmic activity in populations of cortical neurons accompanies, and may underlie, many aspects of primary sensory processing and short-term memory. Activity in the gamma band (30 Hz up to >100 Hz) is associated with such cognitive tasks and is thought to provide a substrate for temporal coupling of spatially separate regions of the brain. However, such coupling requires close matching of frequencies in co-active areas, and because the nominal gamma band is so spectrally broad, it may not constitute a single underlying process. Here we show that, for inhibition-based gamma rhythms in vitro in rat neocortical slices, mechanistically distinct local circuit generators exist in different laminae of rat primary auditory cortex. A persistent, 30-45 Hz, gap-junction-dependent gamma rhythm dominates rhythmic activity in supragranular layers 2/3, whereas a tonic depolarization-dependent, 50-80 Hz, pyramidal/interneuron gamma rhythm is expressed in granular layer 4 with strong glutamatergic excitation. As a consequence, altering the degree of excitation of the auditory cortex causes bifurcation in the gamma frequency spectrum and can effectively switch temporal control of layer 5 from supragranular to granular layers. Computational modeling predicts the pattern of interlaminar connections may help to stabilize this bifurcation. The data suggest that different strategies are used by primary auditory cortex to represent weak and strong inputs, with principal cell firing rate becoming increasingly important as excitation strength increases.     

Mania following vagus nerve stimulation: a case report and review of the literature

Vagus nerve stimulation (VNS) is an increasingly used therapy for patients with treatment-refractory epilepsy and depression. Hypomanic and manic symptoms are a rare but recognized adverse effect of VNS treatment. Here we describe a case in which VNS treatment in a patient with epilepsy and unipolar depression was associated with the rapid development of manic symptoms. The patient's manic symptoms resolved with temporary discontinuation of the VNS current, and the patient was eventually able to resume VNS treatment with good effect and without further manic symptoms. Mania is a rare but serious side effect of VNS; however, in this case and in the majority of reported cases of VNS-associated mania, symptoms resolve and VNS can be safely administered.     

Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes

OBJECTIVE

Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM.

RESEARCH DESIGN AND METHODS

Adult male Wistar rats remained nondiabetic or were injected with the β-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 μg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured.

RESULTS

Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate–phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM.

CONCLUSIONS

We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM. Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency.Recent evidence implicates leptin not only in the regulation of energy balance but also in glucose homeostasis as well. In addition to hyperphagia and obesity, insulin resistance is a prominent feature of animal models characterized by reduced leptin signaling (1), and leptin administration improves insulin sensitivity and glucose metabolism in these models (2,3) independently of its effects on energy homeostasis (4). Investigation into the role of leptin in glucose metabolism has focused largely on genetic models of impaired leptin signaling (e.g., leptin-deficient ob/ob mice), whereas other studies have used pharmacologic doses of leptin (1–6). In this study we investigated the physiologic role of leptin in glucose metabolism by determining the contribution made by leptin deficiency to the severe insulin resistance and associated metabolic and endocrine dysfunction characteristic of uncontrolled, insulin-deficient diabetes (uDM).Severe leptin deficiency is a well-documented consequence of uDM that occurs after destruction of insulin-secreting β-cells (7,8). Because insulin is required for the synthesis and storage of triglyceride in adipose tissue, weight gain cannot occur in uDM, and the associated loss of body fat is accompanied by markedly reduced plasma leptin levels. This effect, in turn, is implicated in the mechanism whereby uDM increases food intake (9), because exogenous leptin administration at doses that prevent a fall in plasma leptin levels also prevent hyperphagia in uDM (8). Another feature of uDM in humans is progressive, severe insulin resistance (10–12), an effect also observed in streptozotocin (STZ)-induced diabetes in rats (13). Although insulin deficiency clearly underlies hyperglycemia and weight loss in uDM, the contribution of markedly reduced plasma leptin levels to insulin resistance and related metabolic and endocrine derangements in this setting remains to be determined. Because plasma levels of leptin as well as of insulin are normalized by insulin treatment of STZ-induced diabetes, at least some of the beneficial effects that have been ascribed to insulin treatment could result from restoring leptin action to normal (7). Indeed, hyperleptinemia generated either by pharmacologic administration of leptin (5) or with adenoviral gene therapy (14) ameliorates hyperglycemia and associated increases of plasma glucagon levels in STZ-induced diabetes, despite persistently low insulin levels. These data raise the possibility that deficient endogenous leptin signaling may underlie at least some manifestations of uDM.Based on these considerations, we sought to determine the extent to which deficiency of endogenous leptin contributes to insulin resistance and related endocrine dysfunction in STZ-induced diabetes. To accomplish this goal, we subcutaneously infused either vehicle or leptin at a dose that prevents leptin deficiency in rats with STZ-induced uDM. We found that physiologic leptin replacement prevented the development of insulin resistance in uDM via a mechanism independent of its effects on food intake and body weight. Moreover, this leptin effect was associated with normalization of elevated plasma levels of glucagon and corticosterone, with the reversal of increased hepatic expression of the gluconeogenic genes, glucose-6-phosphatase (G6Pase), and phosphoenolpyruvate kinase (Pepck), and with improved insulin signal transduction via the insulin receptor substrate–phosphatidylinositol-3-hydroxy kinase (IRS-PI3K) pathway in the liver, but not in skeletal muscle or adipose tissue. In comparison, physiologic leptin replacement only modestly reduced hyperglycemia in STZ-induced diabetic rats and did not alter the potent upregulation of hepatic Igfbp2 mRNA levels previously reported (15). Taken together, these data suggest that reduced leptin levels contribute to the progressive, severe insulin resistance characteristic of uDM via a mechanism that appears to predominantly involve the liver.