A Major Role for Perifornical Orexin Neurons in the Control of Glucose Metabolism in Rats

OBJECTIVE-The hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats. RESEARCH DESIGN AND METHODS-We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies. RESULTS-Hypothalamic disinhibition of neuronal activity by the gamma-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone-containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes. CONCLUSIONS-Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis. Diabetes 58:1998-2005, 200

Output from VIP cells of the mammalian central clock regulates daily physiological rhythms

The suprachiasmatic nucleus (SCN) circadian clock is critical for optimising daily cycles in mammalian physiology and behaviour. The roles of the various SCN cell types in communicating timing information to downstream physiological systems remain incompletely understood, however. In particular, while vasoactive intestinal polypeptide (VIP) signalling is essential for SCN function and whole animal circadian rhythmicity, the specific contributions of VIP cell output to physiological control remains uncertain. Here we reveal a key role for SCN VIP cells in central clock output. Using multielectrode recording and optogenetic manipulations, we show that VIP neurons provide coordinated daily waves of GABAergic input to target cells across the paraventricular hypothalamus and ventral thalamus, supressing their activity during the mid to late day. Using chemogenetic manipulation, we further demonstrate specific roles for this circuitry in the daily control of heart rate and corticosterone secretion, collectively establishing SCN VIP cells as influential regulators of physiological timing

Effects of Nonresponse on the Mean Squared Error of Estimates from a Longitudinal Study

Research in this study focuses on two related aspects of unit nonresponse (nonresponse by sampled members of study populations) in the rounds of the National Longitudinal Study of Adolescent Health (Add Health) (Chantala and Tabor, 1999): (i) round-specific nonresponse bias and its component contributions, and (ii) the statistical utility of alternative approaches to adjusting sample weights for nonresponse. This work is part of four research studies funded by CDC-NCHS, at the UNC Center for Health Statistics Research. Nonrespondents in surveys can be classified according to the reason for nonresponse (Lessler and Kalsbeek, 1992): 1) Not Solicited (NS): Sample members are not solicited as perhaps their address is unknown, or they are out of the country; 2) Solicited but Unable (SUA): Sample members are contacted but decline to participate based on inability. Reasons include physical or language limitations; 3) Solicited but Unwilling (SUW): Sample members are contacted but refuse to participate for reasons such as lack of time or, apathy; and 4) Other Nonrespondents (OTH): Sample nonrespondents give a reason that does not fit in any of the previous categories. Examples are lost schedules and partial respondents Response outcome information and data to obtain 13 different measures of health risk from Add Health are used to accomplish two main tasks in this study. First, we estimate the round-specific nonresponse bias and its component contributions corresponding to the four nonresponse categories described. The sign (negative or positive) of these components and the offsetting effects of some components on the overall bias is of particular interest. Second, we compare the statistical effects of alternate sample adjustments for nonresponse on the bias and variance of study estimates. It is important to note here that we are examining the effects of nonresponse in IH1 and IH2 separately, and not the cumulative effects of nonresponse through these rounds

Nutrition and the circadian system

The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partitions incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24-h day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation, and thereby contributes to adverse metabolic consequences and chronic disease development. ‘High-fat diets’ (HFD) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day-restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFD in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases

Standards of evidence in chronobiology: critical review of a report that restoration of Bmal1 expression in the dorsomedial hypothalamus is sufficient to restore circadian food anticipatory rhythms in Bmal1-/- mice

Daily feeding schedules generate food anticipatory rhythms of behavior and physiology that exhibit canonical properties of circadian clock control. The molecular mechanisms and location of food-entrainable circadian oscillators hypothesized to control food anticipatory rhythms are unknown. In 2008, Fuller et al reported that food-entrainable circadian rhythms are absent in mice bearing a null mutation of the circadian clock gene Bmal1 and that these rhythms can be rescued by virally-mediated restoration of Bmal1 expression in the dorsomedial nucleus of the hypothalamus (DMH) but not in the suprachiasmatic nucleus (site of the master light-entrainable circadian pacemaker). These results, taken together with controversial DMH lesion results published by the same laboratory, appear to establish the DMH as the site of a Bmal1-dependent circadian mechanism necessary and sufficient for food anticipatory rhythms. However, careful examination of the manuscript reveals numerous weaknesses in the evidence as presented. These problems are grouped as follows and elaborated in detail: 1. data management issues (apparent misalignments of plotted data), 2. failure of evidence to support the major conclusions, and 3. missing data and methodological details. The Fuller et al results are therefore considered inconclusive, and fail to clarify the role of either the DMH or Bmal1 in the expression of food-entrainable circadian rhythms in rodents

More than 20 degrees posterior tilt of the femoral head in undisplaced femoral neck fractures results in a four times higher risk of treatment failure

Purpose In this study, we aimed to determine the correlation between the preoperative posterior tilt of the femoral head and treatment failure in patients with a Garden type I and II femoral neck fracture (FNF) treated with the dynamic locking blade plate (DLBP). Methods Preoperative posterior tilt was measured in a prospective documented cohort of 193 patients with a Garden type I and II FNF treated with the DLBP. The correlation between preoperative posterior tilt and failure, defined as revision surgery because of avascular necrosis, non-union, or cut-out, was analyzed. Results Patients with failed fracture treatment (5.5%) had a higher degree of posterior tilt on the initial radiograph than the patients with uneventful healed fractures: 21.4 degrees and 13.8 degrees, respectively (p = 0.03). The failure rate was 3.2% for Garden type I and II FNF with a posterior tilt = 20 degrees. A posterior tilt of >= 20 degrees was associated with an odds ratio of 4.24 (95% CI 1.09-16.83; p = 0.04). Conclusion Garden type I and II FNFs with a significant preoperative posterior tilt (>= 20 degrees) seem to behave like unstable fractures and have a four times higher risk of failure. Preoperative posterior tilt >= 20 degrees of the femoral head should be considered as a significant predictor for failure of treatment in Garden type I and II FNFs treated with the DLBP.Trauma Surger

Relativistically rotating dust

Dust configurations play an important role in astrophysics and are the simplest models for rotating bodies. The physical properties of the general--relativistic global solution for the rigidly rotating disk of dust, which has been found recently as the solution of a boundary value problem, are discussed.Comment: 18 pages, 11 figure