An 18th century understanding of migraine - Samuel Tissot (1728-1797)

During the period 1778-1780 the Swiss physician Samuel A A D Tissot (1728-1797) published his Traite des nerfs et de leur maladies, a work which continued to be available and widely influential until at least the middle of the following century. It contained a long chapter dealing with migraine, based on the earlier literature on the topic and on Tissot's own clinical experience. The work appeared at the beginning of the modern era of interest in migraine, and provided the first reasonably adequate and systematic account of the disorder to become widely available. Its descriptions of migraine phenomena have an enduring validity, though Tissot's ideas on the pathogenesis of the disorder, viz. that it usually arose from stomach disturbance, were not founded on satisfactory evidence and are long since superseded. (C) 2003 Elsevier Science Ltd. All rights reserved.

Analysis of Melanoma Onset: Assessing Familial Aggregation by Using Estimating Equations and Fitting Variance Components via Bayesian Random Effects Models

We investigate whether relative contributions of genetic and shared environmental factors are associated with an increased risk in melanoma. Data from the Queensland Familial Melanoma Project comprising 15,907 subjects arising from 1912 families were analyzed to estimate the additive genetic, common and unique environmental contributions to variation in the age at onset of melanoma. Two complementary approaches for analyzing correlated time-to-onset family data were considered: the generalized estimating equations (GEE) method in which one can estimate relationship-specific dependence simultaneously with regression coefficients that describe the average population response to changing covariates; and a subject-specific Bayesian mixed model in which heterogeneity in regression parameters is explicitly modeled and the different components of variation may be estimated directly. The proportional hazards and Weibull models were utilized, as both produce natural frameworks for estimating relative risks while adjusting for simultaneous effects of other covariates. A simple Markov Chain Monte Carlo method for covariate imputation of missing data was used and the actual implementation of the Bayesian model was based on Gibbs sampling using the free ware package BUGS. In addition, we also used a Bayesian model to investigate the relative contribution of genetic and environmental effects on the expression of naevi and freckles, which are known risk factors for melanoma.

Expression and localization of mutant p16 proteins in melanocytic lesions from familial melanoma patients

Little is known about the correlation between the loss of p16 expression and tumor progression in familial melanoma; no systematic study has been conducted on p16 expression in melanocytic tumors from patients carrying germline CDKN2A mutations. We analyzed 98 early primary lesions from familial patients, previously tested for germline CDKN2A status, by quantitative immunohistochemistry using 3 p16 antibodies. We found that p16 expression was inversely correlated with tumor progression and was significantly lower in melanomas,. including in situ lesions, than in nevi. Of other features analyzed, tumor thickness showed the most significant correlation with p16 levels. Lesions from mutation-negative patients displayed combined nuclear and cytoplasmic staining. However, some mutation-positive lesions (ie, G101W, 113insR, M53I, R24P, and 33ins24), including benign nevi, showed nuclear mislocalization, confirming previous studies suggesting that subcellular distribution indicates functional impairment of p16. (C) 2004 Elsevier Inc. All rights reserved.

Effects of LDL-immunoapheresis on plasma concentrations of vitamin E and carotenoids in patients with familial hypercholesterolemia

Recently very potent extracorporeal cholesterol-lowering treatment options have become available for patients with hypercholesterolemia. LDL immunoapheresis treatment selectively removes LDL and lipoprotein(a) from the circulation. Since LDL is the major carrier of lipophilic antioxidants in plasma, the purpose of the present study was to assess the effects of a single LDL apheresis treatment on plasma concentrations of tocopherols (alpha- and gamma-tocopherol) and carotenoids (alpha- and beta-carotene, zeaxanthin, cryptoxanthin, canthaxanthin, lycopene, and retinol). Plasma antioxidant concentrations were determined by HPLC in 7 patients with familial hypercholesterolemia before and after LDL immunoapheresis treatment. Plasma concentrations of both alpha- and gamma-tocopherol and the different carotenoids were significantly reduced by LDL apheresis. However, when standardized for cholesterol to adjust for cholesterol removal, alpha- and gamma-tocopherol, retinol, and the more polar carotenoids lutein and zeaxanthin increased in response to apheresis treatment, while the more unpolar carotenoids such as beta-carotene and lycopene did not change. These data demonstrate that a single LDL immunoapheresis treatment affects tocopherols and individual carotenoids differently. This may be explained by differences in chemical structure and preferential association with different lipoproteins. These results further imply that tocopherols, lutein, zeaxanthin, and retinol, are associated in part with lipoproteins and other carriers such as retinol-binding protein that are not removed during apheresis treatment. (C) 2004 Wiley-Liss, Inc.

Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications

Familial hyperparathyroidism is not uncommon in clinical endocrine practice. It encompasses a spectrum of disorders including multiple endocrine neoplasia types 1 (MEN1) and 2A, hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH), and familial isolated hyperparathyroidism (FIHP). Distinguishing among the five syndromes is often difficult but has profound implications for the management of patient and family. The availability of specific genetic testing for four of the syndromes has improved diagnostic accuracy and simplified family monitoring in many cases but its current cost and limited accessibility require rationalisation of its use. No gene has yet been associated exclusively with FIHP. FIHP phenotypes have been associated with mutant MEN1 and calcium-sensing receptor ( CASR) genotypes and, very recently, with mutation in the newly identified HRPT2 gene. The relative proportions of these are not yet clear. We report results of MEN1, CASR, and HRPT2 genotyping of 22 unrelated subjects with FIHP phenotypes. We found 5 (23%) with MEN1 mutations, four (18%) with CASR mutations, and none with an HRPT2 mutation. All those with mutations had multiglandular hyperparathyroidism. Of the subjects with CASR mutations, none were of the typical FHH phenotype. These findings strongly favour a recommendation for MEN1 and CASR genotyping of patients with multiglandular FIHP, irrespective of urinary calcium excretion. However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred. Also apparent is the need for further investigation to identify additional genes associated with FIHP.

Ergot of rye - the first specific for migraine

Over the past decade the various triptan derivatives have been accepted as the most effective available agents for relieving migraine attacks. Prior to that, for a period of half a century, ergotamine was the only 'specific' available for this purpose. In 1918, Stoll had isolated it from the various alkaloids present in extracts of the sclerotia of the fungus Claviceps purpurea (ergot), which grow on rye and, to a lesser extent, on other grasses. By 1925 ergotamine was beginning to be used to treat migraine attacks. However, as ergotamine was present in extracts of ergot, which had been used to treat migraine first, In Italy in 1862, and then by Edward Woakes (11868) in England, and after him by Albert Eulenburg in Germany (1883), the drug had actually come into unrecognised use for the disorder more than half a century before ergotamine itself was known to exist. Unfortunately, because of ergotamine's chemical and pharmacokinetic properties, extracts of ergot of rye were incapable of producing consistent therapeutic results, so that general acceptance that the first specific substance for migraine treatment existed had to wait until pure ergotamine was available for administration. (C) 2003 Elsevier Ltd. All rights reserved.

The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups

Migraine is a painful and debilitating disorder with a significant genetic component. Steroid hormones, in particular estrogen, have long been considered to play a role in migraine, as variations in hormone levels are associated with migraine onset in many sufferers of the disorder. Steroid hormones mediate their activity via hormone receptors, which have a wide tissue distribution. Estrogen receptors have been localized to the brain in regions considered to be involved in migraine pathogenesis. Hence it is possible that genetic variation in the estrogen receptor gene may play a role in migraine susceptibility. This study thus examined the estrogen receptor 1 (ESRalpha) gene for a potential role in migraine pathogenesis and susceptibility. A population-based cohort of 224 migraine sufferers and 224 matched controls were genotyped for the G594A polymorphism located in exon 8 of the ESR1 gene. Statistical analysis indicated a significant difference between migraineurs and non-migraineurs in both the allele frequencies (P=0.003) and genotype distributions (P=0.008) in this sample. An independent follow-up study was then undertaken using this marker in an additional population-based cohort of 260 migraine sufferers and 260 matched controls. This resulted in a significant association between the two groups with regard to allele frequencies (P=8x10(-6)) and genotype distributions (P=4x10(-5)). Our findings support the hypothesis that genetic variation in hormone receptors, in particular the ESR1 gene, may play a role in migraine.

Familial influence on offspring gambling: a cognitive mechanism for transmission of gambling behavior in families

Background. The problem-gambling literature has identified a range of individual, cognitive, behavioral and emotional factors as playing important roles in the development, maintenance and treatment of problem gambling. However, familial factors have often been neglected. The current study aims to investigate the possible influence of parental factors on offspring gambling behavior. Method. A total of 189 families (546 individuals) completed several questionnaires including the South Oaks Gambling Screen (SOGS) and the Gambling Related Cognition Scale (GRCS). The relationships were examined using Pearson product-moment correlations and structural equation modeling (SEM) analyses. Results. Results showed that generally parents' (especially fathers') gambling cognitions and gambling behaviors positively correlated with offspring gambling behaviors and cognitions. However, SEM analyses showed that although parental gambling behavior was directly related to offspring gambling behavior, parental cognitions were not related to offspring gambling behavior directly but indirectly via offspring cognitions. Conclusion. The findings show that the influence of parental gambling cognition on offspring gambling behavior is indirect and via offspring cognitions. The results suggest a possible cognitive mechanism of transmission of gambling behavior in the family from one generation to the next.

Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS)

Background Women genetically predisposed to breast cancer often develop the disease at a young age when dense breast tissue reduces the sensitivity of X-ray mammography. Our aim was, therefore, to compare contrast enhanced magnetic resonance imaging (CE MRI) with mammography for screening. Methods We did a prospective multicentre cohort study in 649 women aged 35-49 years with a strong family history of breast cancer or a high probability of a BRCA1, BRCA2, or TP53 mutation. We recruited participants from 22 centres in the UK, and offered the women annual screening with CE MRI and mammography for 2-7 years. Findings We diagnosed 35 cancers in the 649 women screened with both mammography and CE MRI (1881 screens): 19 by CE MRI only, six by mammography only, and eight by both, with two interval cases. Sensitivity was significantly higher for CE MRI (77%, 95% CI 60-90) than for mammography (40%, 24-58; p=0.01), and was 94% (81-99) when both methods were used. Specificity was 93% (92-95) for mammography, 81% (80-83) for CE MRI (p

Migraine and risk of subarachnoid haemorrhage: a population-based case-control study

Objective. Evidence exists for an association between migraine and ischaemic stroke, but there is uncertainty about whether migraine is a risk factor for subarachnoid haemorrhage (SAH). Methods. A multi-centre, population-based, case-control study using cases of first-ever SAH during 1995-98 and matched controls in four study centres in Australia and New Zealand. Self- or proxy-reported history, frequency and characteristics of headaches, classified according to 1988 International Headache Society diagnostic criteria. Results. 206 of 432 (48%) cases and 236 of 473 (50%) controls had a history of headaches. The frequency and characteristics of headaches were similar between the two groups. No association was found in logistic regression analyses for history or frequency of headaches, or migraine headaches. Conclusions. No evidence was found for an association between recurrent headaches and SAH. Such information is important for counselling patients and families about the significance of past and ongoing headaches in relation to this illness. (c) 2005 Elsevier Ltd. All rights reserved.

The pathogenesis of migraine - 17th to early 20th Century understandings

The modern understanding of the pathogenesis of migraine, based on the concept that it is a neurovascular disorder, is often thought to have emerged from the work of Harold Wolff in the period 1932-1962. However, over the preceding 300 years, from William Harvey onwards, various hypotheses of the pathogenesis of migraine had been proposed, a few bearing reasonably strong resemblances to Wolff's ideas, though based on less adequate evidence. Many of these earlier hypotheses regarded migraine either primarily as a vascular (e.g., Willis, Wepfer, Latham) or as a neural disorder (e.g., Harvey, Lieving and his 'nerve storms'). There were also variations around these two major themes and in the 19th Century a number of neurovascufar type hypotheses emerged assigning a major role in migraine pathogenesis to the autonomic nervous system. In addition, during the three centuries there were a number of other hypotheses based on different postulated pathogenic mechanisms, some quite ingenious, which had relatively brief vogues. No hypothesis has yet proved capable of explaining all the features of migraine satisfactorily. (c) 2005 Elsevier Ltd. All rights reserved.