Successful Reach and Adoption of a workplace health promotion RCT targeting a group of high-risk workers

Background  

Cleaners are rarely introduced to workplace health promotion programs. The study's objective was to evaluate the reach and adoption of a workplace randomized controlled trial (RCT) among cleaners in Denmark.     

Amplified Hormonal Counterregulatory Responses to Hypoglycemia in Rats After Systemic Delivery of a SUR-1–Selective K+ Channel Opener?

OBJECTIVE— In glucose-sensing neurons, ATP-sensitive K⁺ channels (K_ATP channels) are thought to translate metabolic signals into an alteration in neuronal firing rates. Because these neurons express the Kir6.2/SUR-1 isoform of the K_ATP channel, we sought to examine the therapeutic potential of the SUR-1–selective potassium channel opener (KCO), NN414, to amplify counterregulatory response to hypoglycemia.RESEARCH DESIGN AND METHODS— In vivo dose-response studies with NN414 delivered intravenously to normal Sprague-Dawley rats before the induction of controlled hypoglycemia were performed. Based on these studies, the potential for NN414 to restore counterregulatory responses in chronically cannulated nondiabetic and diabetic BB rats was explored using the in vivo hyperinsulinemic-hypoglycemic clamp technique.RESULTS— NN414 delivered systemically amplified epinephrine responses during acute hypoglycemia and showed a persisting effect to amplify the epinephrine response when given 24 h before the hypoglycemic study. Local delivery of a potassium-channel blocker to the ventromedial hypothalamus reversed the effects of systemic NN414. In addition, NN414 amplified the epinephrine response to hypoglycemia in both nondiabetic and diabetic BB rats with defective hormonal counterregulation.CONCLUSIONS— These studies demonstrate in a variety of rodent models that systemic delivery of Kir6.2/SUR-1–selective KCOs enhance the glucose counterregulatory response to insulin-induced hypoglycemia. Future studies in human subjects are now required to determine their potential as a therapy for hypoglycemia-associated autonomic failure in type 1 diabetes.The benefits of lowering average blood glucose levels in type 1 diabetes to reduce the risk of long-term microvascular complications are well established. In clinical practice, the degree to which this can be achieved is often limited by the increased risk of severe hypoglycemia that accompanies intensified glucose-lowering regimens (1,2). Individuals with type 1 diabetes are, moreover, particularly prone to develop hypoglycemia because of defects in the normal compensatory homeostatic defense response. Almost all individuals with type 1 diabetes fail to release glucagon in response to hypoglycemia, a defect that appears to relate to the progressive loss of β-cell function (3) and is thought to arise predominantly through the loss of intraislet insulin signaling (4). This leaves epinephrine as the major hormonal counterregulatory defense against low blood glucose. However, a majority of patients will also develop additional deficiencies in the epinephrine counterregulatory response (5). It has now been established in both rodent (6) and human (7) studies that antecedent exposure to hypoglycemia is a major factor involved in the genesis of this defect. Several small trials in human subjects have shown that strict avoidance of hypoglycemia can improve epinephrine (8,9) and symptomatic (10) responses during a subsequent hypoglycemic clamp study. The difficulty in achieving strict hypoglycemia avoidance in both of these trials means that this intervention has not become part of routine clinical practice. Thus, therapeutic options designed to limit the impact of hypoglycemia during intensive insulin therapy remain limited.The stimulus to epinephrine release during hypoglycemia is thought to result from activation of specialized glucose-sensing neurons within the brain (11–14) and periphery (15). Glucose-sensing neurons use glucose as a signaling molecule to alter their firing rate and are of two predominant subtypes, namely, glucose-excited neurons, whose firing rate increases, and glucose-inhibited neurons, whose firing rate decreases, as ambient glucose levels rise (16–18). Based largely on data in rodents, it is currently believed that glucose-sensing neurons react to alterations in extracellular glucose using mechanisms similar to those used by the pancreatic β-cell, with glucokinase and the ATP-sensitive K⁺ channel (K_ATP) as key steps in this process (19,20).K_ATP channels provide a link between neuronal metabolism and membrane potential in many tissues (21,22). Classical K_ATP channels comprise two subunits: a receptor (SUR-1, SUR-2A, or SUR-2B) of sulfonylureas and an inward-rectifier K⁺ channel member, Kir6.2 (22,23). Skeletal muscle and cardiac K_ATP channels comprise SUR-2A and Kir6.2, whereas the pancreatic β-cell K_ATP channel, the prototype glucose-sensing cell, comprises SUR-1 and Kir6.2 (21–24). In the pancreas, the K_ATP channel has been shown to play a key role in the mechanism by which β-cells regulate insulin release in response to changes in the glucose to which they are exposed (25,26). K_ATP channels have been demonstrated throughout the brain, including hypothalamic regions thought to be involved in glucose sensing (27–29). Examination of gene expression in glucose-sensing neurons using single-cell RT-PCR identified mRNA for SUR-1 and Kir6.2 (30). Electrophysiological studies of rat (20,31,32) and mouse brain slice preparations (33) have demonstrated that sulfonylureas can stimulate the firing of glucose-excited neurons and can alter the response of glucose-excited neurons to changes in ambient glucose levels. In animal models, transgenic Kir6.2 knockout mice show impaired glucose counterregulation (33), and we have recently shown in vivo that pharmacological closure of the K_ATP channel in the ventromedial hypothalamus (VMH; a key glucose-sensing region) via direct microinjection of glibenclamide suppressed (34), whereas K_ATP channel openers (KCOs) amplified, the counterregulatory response to hypoglycemia in both normal and recurrently hypoglycemic rats (35). In this later study, the SUR-1–selective KCO NN414, when microinjected into the VMH, a key brain glucose-sensing region (36), amplified hypoglycemic counterregulation at significantly lower concentrations than the nonselective KCO, diazoxide (35).Taken together, these data suggest that K_ATP channels allow glucose-sensing neurons to translate the metabolic signal into an alteration in neuronal firing rates and, moreover, that KCOs may offer a potential therapeutic option for individuals with type 1 diabetes. In the current study, this hypothesis is explored in a series of rodent models. Our data show that systemic administration of a SUR-1–selective KCO has a consistent effect to amplify the epinephrine response to controlled hypoglycemia in nondiabetic and diabetic rats and in those with defective counterregulation.     

Bioactive insulin-like growth factor (IGF) I and IGF-binding protein-1 in anorexia nervosa

CONTEXT: Regulation of IGF-I activity appears crucial in anorexia nervosa (AN) during adaptation to chronic starvation as well as during the regenerative processes on nutritional restoration. OBJECTIVE: The objective of this study was to examine the relationship between IGF-I bioactivity and IGF-binding capacity as expressed as formation of the binary complex of IGF-binding protein-1 (IGFBP-1) and IGF-I in patients with AN at different stages and with different subtypes of the disease. DESIGN: This was a longitudinal study. SETTING: The study took place at a clinical research center at a university hospital. STUDY PARTICIPANTS: We studied a total of 45 women with AN and 24 age-comparable healthy controls. MAIN OUTCOME MEASURES: IGF-I bioactivity was determined using an IGF-I receptor activation assay, and IGF-I/IGFBP-1 complex formation was determined by an assay that allows direct determination of the binary complex. RESULTS: IGF-I bioactivity was significantly decreased in serum from patients with AN. We found significant correlations between total, ultrafiltered free, and bioactive IGF-I. Despite increased IGFBP-1 concentrations, levels of IGF-I/IGFBP-1 binary complex were not significantly increased in AN. Oral contraceptives were associated with increased levels of IGF-I, IGFBP-1, and binary complex formation. Ghrelin levels were only significantly raised in those patients who had lost more than 5% of the body weight during the last 4 wk, whereas ghrelin levels in weight-stable as well as in weight-gaining patients did not significantly differ from the controls. CONCLUSIONS: Total IGF-I level is a suitable marker of IGF-I bioactivity in emaciated patients with AN irrespective of the clinical subtype and acute nutritional state.     

Use of phenytoin, phenobarbital, or diazepam during pregnancy and risk of congenital abnormalities: a case-time-control study

PURPOSE: Case-control studies are often used to examine putative teratogenic drug effects during organogenesis but these studies are subject to confounding by indication, recall, and participation bias. The case-time-control approach is less susceptible to these sources of bias. We studied congenital abnormalities following exposure to phenytoin, phenobarbital, and diazepam in early pregnancy, i.e., second and third month, compared to mid-pregnancy, i.e., fifth and sixth month of pregnancy. METHODS: We analyzed data from the Hungarian Case-Control Surveillance of Congenital Abnormalities (1980-1996) in a case-time-control study. RESULTS: The study included 22 843 children with congenital abnormalities (cases) and 38 151 children with no abnormalities (controls). Overall, odds ratio (OR) for congenital abnormalities after exposure to one of the three drugs in early pregnancy was 1.2 (95% confidence interval (CI): 1.0-1.4). Among children exposed to phenytoin OR for congenital abnormalities was 3.7 (95%CI: 0.3-49.6), for children exposed to phenobarbital the OR was 1.1 (95%CI 0.7-1.7), and for diazepam, OR for congenital abnormalities was 1.2 (95%CI: 1.0-1.4). CONCLUSIONS: The associations we found between the drugs examined and congenital abnormalities were either only borderline significant or not statistically significant. The case-time-control study provides an interesting way of using existing case-control data to study rare side effect of drugs taken during pregnancy.     

How patient-centred am I?: A new method to measure physicians’ patient-centredness

OBJECTIVE: To describe a new method to determine physicians' self-perceived degree of patient-centredness. A pilot study combining qualitative and quantitative methods. METHODS: Forty-one general practitioners (GPs) answered a questionnaire consisting of three open-ended questions about their view of the consultation and by choosing among 28 roles of the physician in the physician-patient relationship. Twenty of the GPs had participated in Balint groups while 21 had had no access to Balint group. Patient-centredness is central to Balint groups and consequently Balint group participants would be expected to be patient-centred. RESULTS: The answers to the two parts were divided into three groups each, patient-centred, non-patient-centred and intermediary, and analysed statistically. Significantly more Balint participants were patient-centred than the reference group. CONCLUSION: The instrument describes physicians' self-perceptions of their patient-centredness and can distinguish a group of patient-centred physicians from a group of non-patient-centred physicians. PRACTICE IMPLICATIONS: The instrument can be useful to evaluate educational programmes and detect decline in patient-centredness as early sign of burnout.     

Inhibition of placenta growth factor with TB-403: a novel antiangiogenic cancer therapy

INTRODUCTION: There is clinical evidence that therapies targeting the vascular endothelial growth factor pathway are effective in delaying cancer progression. However, tumors may be either intrinsically resistant or evolve resistance to such therapies. Hence, there is a need for new therapies targeting angiogenesis. AREAS COVERED: The data are obtained by searching in the PubMed database. The search terms used included antiangiogenic therapy, TB-403 (RO5323441), placenta growth factor (PlGF) and VEGFR-1 (Flt-1). We review preclinical data concerning the function and inhibition of PlGF and summarize data on expression of PlGF in cancer patients. Data from early-phase clinical trials of TB-403 (RO5323441), a monoclonal antibody inhibiting PlGF, are discussed. Future development strategies, therapeutic potentials and limitations of TB-403 are further evaluated. EXPERT OPINION: There are some conflicting data on the function of PlGF and the importance of its role in primary tumor growth. Data from some preclinical models of PlGF inhibition and early-phase clinical trials with TB-403 are, however, promising, although the true potential of the drug is yet to be determined. Further clinical development should be preceded by molecular studies in the context of well-designed preclinical models and/or small translational studies. Future challenges involve identifying predictive biomarkers.