Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.
Narcolepsy, a disorder strongly associated with human leukocyte antigen (HLA)-DQA1*01:02/DQB1*06:02 (DQ0602), is characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement sleep abnormalities. It is caused by the loss of ~70,000 posterior hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (HCRT) (orexin). We identified two DQ0602-binding HCRT epitopes, HCRT56-68 and HCRT87-99, that activated a subpopulation of CD4(+) T cells in narcolepsy patients but not in DQ0602-positive healthy control subjects. Because of the established association of narcolepsy with the 2009 H1N1 influenza A strain (pH1N1), we administered a seasonal influenza vaccine (containing pH1N1) to patients with narcolepsy and found an increased frequency of circulating HCRT56-68- and HCRT87-99-reactive T cells. We also identified a hemagglutinin (HA) pHA1 epitope specific to the 2009 H1N1 strain, pHA1275-287, with homology to HCRT56-68 and HCRT87-99. In vitro stimulation of narcolepsy CD4(+) T cells with pH1N1 proteins or pHA1275-287 increased the frequency of HCRT56-68- and HCRT87-99-reactive T cells. Our data indicate the presence of CD4(+) T cells that are reactive to HCRT in narcolepsy patients and possible molecular mimicry between HCRT and a similar epitope in influenza pH1N1, pHA1275-287.
Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.
1. Reports that maternal anaemia in pregnancy is associated with a greater placental: birth weight ratio, which predisposes towards high postnatal blood pressure in the human, led us to examine the effects of maternal anaemia during pregnancy on placental size, fetal and neonatal growth, and blood pressure development in the rat. 2. Nutritional anaemia was induced in female rats prior to mating and maintained throughout pregnancy and up until weaning of the pups. Fetuses were studied at 20 days of gestation (E20). Pups were studied on postnatal days 20 (P20) and 40 (P40), having been weaned onto normal rat chow at 21 days. 3. In the anaemic group placental: fetal body weight ratios were lower compared with controls. Body weights at all ages were lower in the anaemic group than in controls, despite a greater rate of growth in the anaemic group between P20 and P40. 4. At P20 heart weights of the anaemic group were almost twice that of controls, suggesting an alteration in their cardiovascular development. However, paradoxically, the systolic blood pressure of the anaemic group was lower than that of controls. 5. By P40 the systolic blood pressure of the anaemic group (136 +/‐ 3 mmHg) had increased and was greater than that in control pups (126 +/‐ 3 mmHg). 6. In conclusion, we have shown that there is a pronounced postnatal rise in systolic blood pressure associated with maternal anaemia during pregnancy, which is not related to a greater placental: birth weight ratio. Before weaning, anaemic pups have a lower systolic blood pressure than controls and there is an important association between the rate of postnatal growth and blood pressure.
The epidemiology of severe insomnia and its effect on quality of life and healthcare consumption was assessed in a survey of the general population of five northern European countries. Applying established consumer sampling techniques, insomnia sufferers were selected from the general population using a questionnaire, conducted by face-to-face interview, and severity of insomnia was ranked (severe, mild/moderate, no sleep complaint) using a specific algorithm. Population samples were matched according to case control methodology for age, gender and geographical region. A second questionnaire gathered information on sleep problems, quality of life (SF-36 scores) and healthcare consumption. The prevalence of severe insomnia ranged from 4% to 22%, was higher in females than in males, but did not increase significantly with age. Patients with severe insomnia had been experiencing sleeping problems for a median of 2-6 years. In all countries, insomnia had a negative impact on quality of life, and the degree of impairment in quality of life was directly related to the severity of insomnia. Individuals with severe insomnia also showed a higher level of healthcare consumption. Despite this, severe insomnia did not appear to feature prominently in the doctor-patient relationship.
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