Cluster headache genome-wide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor.

OBJECTIVE: Aggregating data for the first genome-wide association study meta-analysis of cluster headache, to identify genetic risk variants and gain biological insights. METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from ten European and one East Asian cohorts. We first performed an inverse-variance genome-wide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by five complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis and Mendelian randomization were part of the downstream analyses. RESULTS: The estimated SNP-based heritability of cluster headache was 14.5%. We identified nine independent signals in seven genome-wide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, ADHD, depression and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. INTERPRETATION: This first genome-wide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. This article is protected by copyright. All rights reserved

I trattamenti farmacologici nelle disintossicazioni

La detossificazione ha lo scopo di far superare con poca sofferenza e in modo sicuro la sintomatologia astinenziale che compare in seguito alla sospensione dell\u2019uso cronico di oppiacei. Il metodo classico, piu\u2019 utilizzato per effettuarla consiste nell\u2019impiego del metadone in dosi scalari. Altre modalit\ue0 di intervento prevedono l\u2019impiego della clonidina, da sola oppure associata a naloxone o naltrexone (detossificazione rapida) e della buprenorfina. Recentemente sono state sperimentate procedure \u201cultra-rapide\u201d che vengono eseguite in condizione di sedazione profonda o anestesia. La sicurezza e l\u2019efficacia a lungo termine di tali metodiche non e\u2019 stata ancora definita

Cannabinoid CB1 receptor blockade enhances the protective effect of melanocortins in hemorrhagic shock in the rat

Activation of peripheral cannabinoid CB1 receptors contributes to hemorrhagic hypotension, and endocannabinoids produced by macrophages and platelets may be mediators of this effect. A number of studies have provided evidence that functional links exist in the mechanisms of action of cannabinoids and opioid peptides; and opioids too play an important role in the pathophysiology of hemorrhagic hypotension and shock. On the other hand, melanocortin peptides, which are the main endogenous functional antagonists of opioid peptides, have an antishock effect in animals and humans. Thus, we investigated whether an interaction exists between endocannabinoids and the endogenous opioid/antiopioid system also in a condition of hemorrhagic shock and, particularly, whether the blockade of cannabinoid CB1 receptors potentiates the antishock effect of melanocortins, Urethane-anesthetized rats were stepwise bled until mean arterial pressure decreased to, and stabilized at, 21-23 mm Hg. In this model of hemorrhagic shock, which caused the death of all control rats within 30 min after vehicle (tween 80, 5% in saline) injection, the intravenous (i.v.) bolus injection of the cannabinoid CB1 receptor antagonist N-pip -eridino-5-[4-chlorophenyl]-1-[2,4 dichlorophenyl]-4-methyl-3-pyrazolecarboxaniide (SR141716A) increased mean arterial pressure, pulse pressure, respiratory rate and survival rate in a dose-related manner (0.1-3 mg/kg), an almost complete recovery of mean arterial pressure, pulse pressure and respiratory rate, and 100% survival at the end of the observation period (2 h), occurring with the dose of 3 mg/kg. The melanocortin ACTH-(1-24) (adrenocorticotropin) also produced in a dose-related manner (0.02-0.16 mg/kg i.v.) a restoration of cardiovascular and respiratory functions, and increased survival rate, an almost complete recovery and 100% survival at the end of the observation period (2 h) occurring with the dose of 0.16 mg/kg. When a subactive dose of SR141716A (0.2 mg/kg; 30% survival) was associated with a subactive dose of ACTH-(1-24) (0.02 mg/kg; 12% survival), a complete reversal of the shock condition was obtained with 100% survival at the end of the 2-h observation period. The present results show that the concurrent inhibition of both endogenous opioid and cannabinoid systems produces a reversal of hemorrhagic shock more effective than that produced by the inhibition of either of them. These data suggest that functional interactions between endocannabinoids and opioid/antiopioid are at work also in the pathophysiology of hemorrhagic shock. (C) 2002 Elsevier Science B.V. All rights reserved

High blood levels of nitric oxide in rats subjected to prolonged respiratory arrest and their modulation during adrenocorticotropin-induced resuscitation

Anaesthetized rats, endotracheally intubated and mechanically ventilated with room air, were subjected to a 5-min period of asphyxia by turning off the ventilator. The ventilator was then turned back on and, simultaneously, the animals were treated with either the adrenocorticotropin fragment 1-24 [ACTH-(1-24), 160 mu g/kg in a volume of 1 ml/kg i.v.] or an equivalent volume of saline. Nitric oxide (NO)-haemoglobin formation was detected ex vivo in arterial blood by electron spin resonance spectrometry; arterial blood pressure, electrocardiogram (ECG) and electroencephalogram (EEG) were monitored for a 60-min observation period, or until prior death. During asphyxia, there was massive formation of NO (red cell concentrations 40-80 mu M), associated with a dramatic fall in mean arterial pressure and pulse pressure, marked bradycardia and ECG signs of ischaemic damage, as well as an isoelectric EEG. Treatment with ACTH-(1-24) produced a prompt (within 15 min) and long-lasting drop in NO blood levels, associated with an almost immediate (within 1 min) restoration of cardiovascular function and with a more gradual recovery of EEG, which became normal after 30-40 min; all parameters remained stable throughout the 60-min observation period. In saline-treated rats, on the other hand, there was a further increase in NO blood levels, as detected 3 min after treatment, and all died within 5-8 min. Moreover, pretreatment and treatment with S-methylisothiourea sulphate (SMT, 3 mg/kg i.v.), a relatively specific inhibitor of inducible NO synthase, inhibited NO formation, but did not affect the mortality rate (100% within 5-8 min). The present results provide the first evidence that prolonged asphyxia is associated with high blood concentrations of NO, and that the life-saving effect of melanocortin peptides in severe hypoxic conditions is associated with a complete normalization of NO blood levels. However, the lack of SMT protection in this experimental model seems to rule out the possibility that the ACTH-(1-24)-induced resuscitation is due to an effect on NO overproduction

Serum concentrations of vitamin B12 and folate in chronic daily headache.

Lower serum vitamin B12 and folate levels were detected in chronic headache patients without anemia. Since these vitamins are important for monoamine metabolsim their deficiency could complicate the headache

Efficacia di rizatriptan in relazione alla presenza di allodinia cutanea in pazienti affetti da emicrania senz’aura. Risultati preliminari.

Introduzione - L’allodinia cutanea (AC) è caratterizzata dalla percezione di dolore o fastidio provocata da una stimolazione non dolorosa della cute. Burstein per primo [1] ha messo in evidenza la frequente occorrenza di AC durante gli attacchi di emicrania e ne ha correlato la presenza all’inefficacia dei triptani. Gli studi di Burstein sono stati tuttavia condotti su casistiche limitate, mentre clinical trials successivi non hanno confermato la presenza di una correlazione negativa tra efficacia dei triptani e AC. Scopo del presente studio è quello di accertare, in un setting naturalistico (che prevede l’assunzione di un triptano - rizatriptan 10 mg -, a qualsiasi timing e con qualunque severità del dolore durante attacchi di emicrania senz’aura), se la presenza di AC è correlata all’efficacia dei triptani. Metodi – Verranno inclusi nello studio 120 pazienti affetti da emicrania senz’aura (EsA). Vengono qui presentati i risultati preliminari riferiti ai primi 47 pazienti arruolati. Durante la prima visita sono stati consegnati ai pazienti due diari della cefalea per il trattamento di altrettanti attacchi di EsA ed è stato loro raccomandato di assumere rizatriptan wafer 10 mg, nel momento che ritenessero più opportuno. Oltre a variabili concernenti le caratteristiche della cefalea, il timing dell’assunzione di rizatriptan e gli esiti della somministrazione del farmaco a 2 e a 24 ore, il diario conteneva anche un questionario con 8 items sull’AC [2]. L’outcome principale era rappresentato dalla percentuale di pazienti liberi da dolore a 2 ore dall’assunzione del farmaco nei gruppi con (AC+) e senza (AC-) AC. Risultati – Sono entrati nello studio 47 pazienti (F 87%, età media 37,3 anni). L’assunzione di rizatriptan è avvenuta in media 88 minuti dopo l’esordio dell’attacco; l’intensità del dolore era lieve nel 13% dei pazienti e moderata-severa nell’87%. A 2 ore dall’assunzione del farmaco era libero da dolore il 26,5% dei pazienti AC+ vs il 69,2% dei pazienti AC- (p = 0,02); libertà sostenuta dal dolore era presente nel 14,7% dei pazienti AC+ e nel 61,5% dei pazienti AC- (p = 0,003). I pazienti con dolore lieve erano pain-free a 2 ore nel 83,3% dei casi e a 24 ore nel 66,7% dei casi contro il 31,7% (p = 0,02) e il 22,0% (p = 0,04) rispettivamente dei pazienti con dolore moderato-grave. Conclusioni – L’efficacia di rizatriptan sembra inferiore nei pazienti con AC. Rimane da accertare se si tratti di un effetto primitivamente dovuto all’AC oppure secondario alla severità del dolore. Bibliografia [1] Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000;47:614–624 [2] Ashkenazi A, Silberstein S, Jakubowski M, Burstein R. Improved identification of allodynic migraine patients using a questionnaire. Cephalalgia 2007;27:325-32