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Murphy SB. The national impact of clinical cooperative group trials for pediatric cancer. Med Pediatr Oncol 1995; 24: 279–80. Bleyer WA, Tejeda H Murphy SB, et al. National cancer clinical trials: children have equal access; adolescents do not. J Adolesc Health 1997; 21: 366–73. Masera G, Baez F, Biondi A, et al. North-South twinning in paediatric haematology-oncology. Lancet 1998; 352: 1923–26.
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Ribeiro RC, Marina N, Crist WM. St Jude Children’s Research Hospital’s International Outreach Program. Leukemia 1996; 10: 570–74. Masera G, Eden T, Schrappe M, et al. Statement by members of the Ponte di Legno Group on the right of children to have full access to essential treatment for acute lymphoblastic leukemia. Pediatr Blood Cancer 2004; 43: 103–04.
A functional autoantibody in human narcolepsy? See Research Letters page 2122
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Autoimmune mechanisms have been suspected in the pathogenesis of human narcolepsy for many years on the basis of the disease’s strong association with HLA DQB1*0602. In today’s Lancet, Anthony Smith and colleagues report preliminary data about a functional autoantibody in human narcolepsy. The investigators used a physiological assay with live tissue, rather than routine immunological methods. If the findings are confirmed with a larger cohort of patients with narcolepsy and appropriate controls, this bioassay might represent a sensitive and specific diagnostic marker for human narcolepsy. There is compelling evidence that narcolepsy might be a neurodegenerative or autoimmune disorder resulting in selective loss of hypothalamic neurons containing the neuropeptide hypocretin (also known as orexin).1-4 The hypocretin system is widely distributed in the brain and is involved with regulation of sleeping and waking, energy balance, and neuroendocrine function. Most patients with narcolepsy with cataplexy have low or undetectable concentrations of hypocretin in cerebrospinal fluid.5,6 This finding and the strong association between narcolepsy and HLA DQB1*0602 suggests a highly selective autoimmune attack against hypocretin-containing neurons in the hypothalamus. Other findings that support the autoimmune hypothesis of narcolepsy include the association between narcolepsy and multiple sclerosis,7,8 the co-occurrence of narcolepsy and Rasmussen’s syndrome (a rare inflammatory condition),9 the frequent presence of triggering events, and the observation that treatment with immunosuppressive and anti-inflammatory agents delays onset of canine narcolepsy and reduces symptom severity.10 Gerashchenko and Shiromani11 also showed that chronic infusion of the pro-inflammatory agent lipopolysaccharide into the lateral hypothalamus in rats reduced hypocretin, suggesting that inflammation affects loss of hypocretin neurons in narcolepsy. Gordon and colleagues12,13 have developed sensitive tissue-based physiological assays to identify functional autoantibodies against muscarinic receptors and calcium channels in Sjögren’s syndrome and type 1 diabetes, respectively, that are not detectable by conventional immunoassays. Because altered cholinergic neurotransmission has been suspected in human narcolepsy, Smith and colleagues hypothesised that cholinergic autoantibodies are important in pathogenesis, and they developed
a sensitive bioassay similar to that used in their earlier work in Sjögren’s syndrome. Passive transfer of purified IgG from patients with narcolepsy to mice caused an increase in contractile responses of strips of detrusor muscle in the bladder to cholinergic stimulation compared with IgG from healthy controls. The investigators acknowledge that identifying the primary target of the narcolepsy autoantibody will require additional physiological, pharmacological, and immunological studies. Future work in this area will need to use appropriate controls, including healthy controls with and without HLA DQB1*0602 (not included in this report). This point is important because simply being positive for HLA DQB1*0602 might convey an IgG molecule with properties that alter this bioassay, either specifically or non-specifically. As noted by Smith and colleagues, it will be interesting to compare changes in autoantibody activity with the duration and severity of narcolepsy symptoms, and with concentrations of hypocretin in cerebrospinal fluid. Longitudinal evaluation of autoantibody levels from symptom onset to disease evolution might shed light on the pathogenesis of narcolepsy, and examination of the autoantibody response to immunomodulatory therapy might be informative. Patients with and without cataplexy need to be assessed. For patients and clinicians who care for those with sleep disorders, Smith and colleagues’ work offers hope for earlier and more definitive diagnosis. The diagnosis of narcolepsy is now done mostly on the basis of the history and polygraphic findings. A definitive diagnosis is sometimes challenging because of several factors. Many patients do not meet diagnostic criteria initially, resulting in the need to repeat evaluations. Patients might not develop cataplexy for years after onset of pathological sleepiness, and narcolepsy might coexist with other sleep disorders, such as obstructive sleep apnoea and circadian rhythm disorders. Although measuring the concentration of hypocretin in the cerebrospinal fluid is informative, the lumbar puncture required to make the measurement is not done routinely in the clinical setting, and patients will prefer a blood test rather than lumbar puncture. If these preliminary findings are replicated with larger numbers of narcolepsy patients and appropriately selected healthy and diseased controls, Smith and colleagues will have opened an exciting new chapter in the narcolepsy www.thelancet.com Vol 364 December 11, 2004
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story. The investigators might have identified the missing link that connects an autoimmune process to selective loss of hypocretin neurons and the development of narcolepsy. A clinically useful assay could lead to earlier diagnosis and improve the likelihood for effective use of immunomodulators, hypocretin agonists, or perhaps a preventive strategy before loss of hypocretin neurons below a critical threshold.
Merrill S Wise Departments of Pediatrics and Neurology, Baylor College of Medicine, Houston, TX 77030, USA
[email protected] I declare I have no conflict of interest. 1 2 3
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Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003; 53: 154–66. Peyron C, Charnay Y. Hypocretins/orexins and narcolepsy: from molecules to disease. Rev Neurol 2003; 159 (suppl 11): 6S35–41. Lodi R, Tonon C, Vignatelli L, et al. In vivo evidence of neuronal loss in the hypothalamus of narcoleptic patients. Neurology 2004; 63: 1513–15. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000; 27: 469–74.
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Nishino S, Ripley B, Overeem S, et al. Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 2001; 50: 381–88. Ripley B, Overeem S, Fujiki N, et al. CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 2001; 57: 2253–58. Carlander B, Dauvilliers Y, Billiard M. Immunological aspects of narcolepsy. Rev Neurol 2001; 157 (11 Pt 2): S97–100. Wang CY, Kawashima H, Takami T, et al. A case of multiple sclerosis with initial symptoms of narcolepsy. No To Hattatsu 1998; 30: 300–06. Lagrange AH, Blaivas M, Gomez-Hassan D, Malow BA. Rasmussen’s syndrome and new-onset narcolepsy, cataplexy, and epilepsy in an adult. Epilepsy Behav 2003; 4: 788–92. Boehmer LN, Wu MF, John J, Siegel JM. Treatment with immunosuppressive and anti-inflammatory agents delays onset of canine genetic narcolepsy and reduces symptom severity. Exp Neurol 2004; 188: 292–99. Gerashchenko D, Shiromani PJ. Effects of inflammation produced by chronic lipopolysaccharide administration on the survival of hypocretin neurons and sleep. Brain Res 2004; 1019: 162–69. Waterman SA, Gordon TP, Rischmueller M. Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjögren’s syndrome. Arthritis Rheum 2000; 43: 1647–54. Jackson MW, Gordon TP, Waterman SA. Disruption of intestinal motility by a calcium channel-stimulating autoantibody in type 1 diabetes. Gastroenterology 2004; 126: 819–28.
Coronary heart disease in people of south-Asian origin Important minority ethnic populations in many countries worldwide are people of south-Asian origin. A consistent finding in these migrant populations is a higher incidence and prevalence of premature coronary heart disease (CHD) than the indigent population. In the UK, mortality from CHD is 46% higher for men and 51% higher for women of south-Asian origin than in the general non-Asian population.1 It is therefore timely to see a major conference organised on the prevention, treatment, and rehabilitation of cardiovascular disease in south Asians by the South Asian Health Foundation, a non-profit organisation whose aim is to promote improvements in the quality of, and access to, health care and health promotion in south Asians.2 There has been much speculation about what causes the increased occurrence of and mortality from CHD in south Asians. South Asians are not a uniform group but include ethnic subgroups with different cultures and practices. The prevalence of recognised risk factors for CHD varies between the subgroups.3 However, even taking these differences into account, classical risk factors do not fully explain the increased risk in south Asians.4 Migration is clearly an important factor in determining the increased risk of CHD in south Asians.5 However, other migrating populations (eg, Afro-Caribbean people) do not have an increased risk of CHD compared with the indigenous population.1 Thus some other or specific factors must apply to south Asians. A popular hypothesis to explain the increased risk in immigrant populations from south Asia is that the increased risk is because of adverse gene–environment interactions. For example, lipoprotein(a) is a genetically www.thelancet.com Vol 364 December 11, 2004
determined risk factor for CHD, especially when accompanied by increased concentrations of LDL cholesterol. Some studies have shown that south Asians have higher plasma levels of lipoprotein(a), whether living in the UK or Punjab, than do white Europeans,5 presumably because they have a higher prevalence of the variants in the apolipoprotein(a) gene that increase lipoprotein(a). The capacity of a migrating population to rapidly acquire a higher concentration of LDL cholesterol because of changes in dietary patterns, lifestyle, or both shows how a genetically determined risk factor—increased lipoprotein(a)—can be made more potent by westernisation.6 A more specific version of this hypothesis is the thrifty gene hypothesis;7 this much-debated hypothesis proposes that genetic variants that were protective and enhanced survival at a time when calories were less abundant are now harmful because of increased caloric intake. Such alleles could be more common in south Asians and predispose them to central obesity, insulin resistance, and diabetes mellitus, which are important risk factors for CHD in this population. Hence one of the eagerly awaited outcomes of the intense effort to identify functional genetic variants that modify susceptibility to complex diseases is whether varying prevalence of such alleles can also explain inter-ethnic differences in risk for various conditions. In the meantime, what can we do about the growing epidemic of CHD in south Asians? Several measures are possible and appropriate. First, aggressively manage conventional risk factors in south Asians: to identify patients who are suitable for primary prevention, we must calculate 2077