S_mmmmary Nitric oxide (NO) is generated by a family of isoenzymes (NO synthases)

No statistically significant effects of CT screening on lung cancer mortality were found, but the results of post hoc high-risk subgroup analyses showed nonsignificant trends that seem to be in good agreement with the results of the National Lung Screening Trial. Clinical trial registered with www.clinicaltrials.gov (NCT00496977).

Familial hemiplegic migraine (FHM) is a rare autosomal dominantly inherited subtype of migraine with aura. The clinical characteristics of FHM have been described previously in selected materials or case studies, but population-based studies are important in order to analyse the full spectrum of the disorder. The aim of the present study was to perform a systematic search for familial cases of migraine with an aura that included motor weakness in order to generate non-selected material of as many FHM cases as possible in the Danish population of 5.2 million inhabitants, and to compare this material with already available population-based clinical descriptions of migraine with typical aura (MA). Due to the rarity of FHM, traditional population-based methods were not feasible. Therefore, the search strategy employed a computer search of the National Patient Register, screening >27 000 case records from headache clinics and private neurologists, and advertisements. A total of 147 affected FHM patients from 44 families were identified. FHM patients most often had all four 'typical' aura symptoms (visual, sensory, aphasic and motor symptoms) and all had at least two of these aura symptoms during FHM attacks. The motor, sensory and visual aura symptoms were all similar in type to the motor, sensory and visual aura symptoms in MA, but FHM had a statistically significantly longer duration of the visual and sensory aura symptoms, and these and other aura symptoms often fulfilled the criteria of the International Headache Society for prolonged aura. In addition, 69% had basilar migraine (BM) symptoms during FHM attacks. The order of the aura symptoms was usually visual, followed by sensory, aphasic, motor and, lastly, basilar-type migraine symptoms. Headache was present in 99% of FHM patients during FHM attacks, whereas the aura symptoms more often occurred without headache in MA. Headache duration was significantly longer in FHM compared with MA. Based on these data, we suggest more precise diagnostic criteria for FHM and a more clear clinical distinction between FHM and BM. Our results have significant implications for case finding in genetic studies and for clinical migraine differential diagnosis.

Migraine with aura and migraine without aura have the same pain phase, thus indicating that migraine with aura and migraine without aura share a common pathway of nociception. In recent years, increasing evidence has suggested that the messenger molecule nitric oxide (NO) is involved in pain mechanisms of migraine without aura. In order to clarify whether the same is true for migraine with aura, in the present study we examined the headache response to intravenous infusion of glyceryl trinitrate (GTN) (0.5 microg/kg/min for 20 min) in 12 sufferers of migraine with aura. The specific aim was to elucidate whether an aura and/or an attack of migraine without aura could be induced. Fourteen healthy subjects served as controls. Aura symptoms were not elicited in any subject. Headache was more severe in migraineurs than in the controls during and immediately after GTN infusion (p=0.037) as well as during the following 11 h (p = 0.008). In the controls, the GTN-induced headache gradually disappeared, whereas in migraineurs peak headache intensity occurred at a mean time of 240 min post-infusion. At this time the induced headache in 6 of 12 migraineurs fulfilled the diagnostic criteria for migraine without aura of the International Headache Society. The results therefore suggest that NO is involved in the pain mechanisms of migraine with aura. Since cortical spreading depression has been shown to liberate NO in animals, this finding may help our understanding of the coupling between cortical spreading depression and headache in migraine with aura.

The objectives of the present study were to describe the clinical characteristics of patients with severe familial non-hemiplegic migraine with aura (NHMA) and to compare these data to those from cases in previous population-based Danish studies using the same methodology. NHMA families were recruited from the Danish patient registry and from Danish neurology practices. A total of 362 NHMA patients were diagnosed according to the 1988 International Headache Society criteria using a validated semistructured physician-conducted interview. Visual aura occurred in almost every NHMA attack. In aura without headache visual aura occurred primarily in isolation. Aura without headache was most common in older, male patients. Several clinical characteristics of familial NHMA differed from migraine with aura in the general population: firstly, the age at onset was lower, secondly, the age at cessation was higher, thirdly, aura symptoms were more severe and finally, the co-occurrence of migraine without aura was higher in familial NHMA. There seems to be a correlation between more severe symptoms and familial aggregation. These results have both clinical and scientific implications.

The molecular mechanisms of migraine pain remain to be determined. Our studies of glyceryl trinitrate (GTN)-induced and histamine-induced headaches have led us to propose that nitric oxide (NO) may be the causative molecule in migraine pain. We also propose that substances capable of inducing experimental vascular headache do so with NO as the common mediator. Finally, we suggest that drugs with antimigraine activity inhibit NO and the cascade of intracellular reactions triggered by NO. We believe these observations provide new insight into the mechanisms of vascular headache. The importance of NO as a potential initiator of the migraine attack indicates new directions for the pharmacological treatment of migraine and other vascular headaches.

Patients with sporadic hemiplegic migraine had clinical symptoms identical to familial hemiplegic migraine and significantly different from migraine with typical aura. Sporadic hemiplegic migraine is a separate entity, and should be classified with familial hemiplegic migraine.

Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura and transient hemiplegia. FHM mutations are known in three genes, the CACNA1A (FHM1) gene, the ATP1A2 (FHM2) and the SCN1A (FHM3) gene and seem to have an autosomal-dominant mode of inheritance. The aim of this study was to search for FHM mutations in FHM families identified through a screen of the Danish population of 5.2 million people. FHM patients were diagnosed according to the International Classification of Headache Disorders and all FHM patients had a physical and neurological examination by a physician. A total of 147 FHM patients from 44 different families were identified; 43 FHM families participated in this study. Linkage analysis of these families shows clear linkage to the FHM locus (FHM1) on chromosome 19, supportive linkage to the FHM2 locus whereas no linkage was found to the FHM3 locus. Furthermore, we sequenced all exons and promoter regions of the CACNA1A and ATP1A2 genes and screened for the Q1489K mutation in the SCN1A gene. CACNA1A gene mutations were identified in three of the FHM families, two known FHM mutations, R583Q and T666M and one novel C1369Y mutation. Three FHM families were identified with novel mutations in the ATP1A2 gene; a family with a V138A mutation, a family with a R202Q mutation and a family with a R763C mutation. None of the Danish FHM families have the Q1489K mutation in the SCN1A gene. Our study shows that only 14% (6/42) of FHM families in the general Danish population have exonic FHM mutations in the CACNA1A or ATP1A2 gene. The families we identified with FHM mutations in the CACNA1A and ATP1A2 genes were extended, multiple affected families whereas the remaining FHM families were smaller. The existence of many small families in the Danish FHM cohort may reflect less bias in FHM family ascertainment and/or more locus heterogeneity than described previously.