Plasma total ghrelin and leptin levels in human narcolepsy and matched healthy controls:basal concentrations and response to sodium oxybate

\u3cp\u3eSTUDY OBJECTIVES: Narcolepsy is caused by a selective loss of hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with hypocretin neurons to influence energy homeostasis. Here, we evaluated whether human hypocretin deficiency, or the narcolepsy therapeutic agent sodium oxybate, alter the levels of these hormones.\u3c/p\u3e\u3cp\u3eMETHODS: Eight male, medication free, hypocretin deficient, narcolepsy with cataplexy patients, and 8 healthy controls matched for age, sex, body mass index (BMI), waisttohip ratio, and body fat percentage were assessed. Blood samples of total ghrelin and leptin were collected over 24 hours at 60 and 20-min intervals, respectively, during 2 study occasions: baseline, and during the last night of 5 consecutive nights of sodium oxybate administration (2 × 3.0 g/night).\u3c/p\u3e\u3cp\u3eRESULTS: At baseline, mean 24-h total ghrelin (936 ± 142 vs. 949 ± 175 pg/mL, p = 0.873) and leptin (115 ± 5.0 vs. 79.0 ± 32 mg/L, p = 0.18) levels were not different between hypocretin deficient narcolepsy patients and controls. Furthermore, sodium oxybate did not significantly affect the plasma concentration of either one of these hormones.\u3c/p\u3e\u3cp\u3eCONCLUSIONS: The increased BMI of narcolepsy patients is unlikely to be mediated by hypocretin deficiency-mediated alterations in total ghrelin or leptin levels. Thus, the effects of these hormones on hypocretin neurons may be mainly unidirectional. Although sodium oxybate may influence body weight, the underlying mechanism is unlikely to involve changes in total ghrelin or leptin secretion.\u3c/p\u3

HLA associations in narcolepsy type 1 persist after the 2009 H1N1 pandemic

\u3cp\u3eWe aimed to compare HLA-DQB1-associations in narcolepsy type 1 (NT1) patients with disease onset before and after the 2009 H1N1 pandemic in a large Dutch cohort. 525 NT1 patients and 1272 HLA-DQB1*06:02-positive healthy controls were included. Because of the discussion that has arisen on the existence of sporadic and post-H1N1 NT1, HLA-DQB1-associations in pre- and post-H1N1 NT1 patients were compared. The associations between HLA-DQB1 alleles and NT1 were not significantly different between pre- and post-H1N1 NT1 patients. Both HLA-DQB1-associations with pre- and -post H1N1 NT1 reported in recent smaller studies were replicated. Our findings combine the results of studies in pre- and post-H1N1 NT1 and argue against considering post-H1N1 NT1 as a different entity.\u3c/p\u3

DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe

\u3cp\u3eSTUDY OBJECTIVE: Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects.\u3c/p\u3e\u3cp\u3eDESIGN: Retrospective case-control study.\u3c/p\u3e\u3cp\u3eSETTING: A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication.\u3c/p\u3e\u3cp\u3ePATIENTS AND PARTICIPANTS: For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included.\u3c/p\u3e\u3cp\u3eMEASUREMENTS AND RESULTS: None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified.\u3c/p\u3e\u3cp\u3eCONCLUSION: An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.\u3c/p\u3

Hypocretin/Orexin Peptides Excite Rat Neuroendocrine Dopamine Neurons through Orexin 2 Receptor-Mediated Activation of a Mixed Cation Current

Hypocretin/Orexin (H/O) neurons of the lateral hypothalamus are compelling modulator candidates for the chronobiology of neuroendocrine output and, as a consequence, hormone release from the anterior pituitary. Here we investigate the effects of H/O peptides upon tuberoinfundibular dopamine (TIDA) neurons – cells which control, via inhibition, the pituitary secretion of prolactin. In whole cell recordings performed in male rat hypothalamic slices, application of H/O-A, as well as H/O-B, excited oscillating TIDA neurons, inducing a reversible depolarising switch from phasic to tonic discharge. The H/O-induced inward current underpinning this effect was post-synaptic (as it endured in the presence of tetrodotoxin), appeared to be carried by a Na(+)-dependent transient receptor potential-like channel (as it was blocked by 2-APB and was diminished by removal of extracellular Na(+)), and was a consequence of OX2R receptor activation (as it was blocked by the OX2R receptor antagonist TCS OX2 29, but not the OX1R receptor antagonist SB 334867). Application of the hormone, melatonin, failed to alter TIDA membrane potential or oscillatory activity. This first description of the electrophysiological effects of H/Os upon the TIDA network identifies cellular mechanisms that may contribute to the circadian rhythmicity of prolactin secretion