First mutation in the voltage-gated NaV1.1 subunit gene SCN1A with co-occurring familial hemiplegic migraine and epilepsy

Almost all mutations in the SCN1A gene, encoding the α₁ subunit of neuronal voltage-gated Na_V1.1 sodium channels, are associated with severe childhood epilepsy. Recently, two mutations were identified in patients with pure familial hemiplegic migraine (FHM). Here, we identified a novel SCN1A L263V mutation in a Portuguese family with partly co-segregating hemiplegic migraine and epilepsy. The L263V mutation segregated in five FHM patients, three of whom also had epileptic attacks, occurring independently from their hemiplegic migraine attacks. L263V is the first SCN1A mutation associated with FHM and co-occurring epilepsy in multiple mutation carriers, and is the clearest molecular link between migraine and epilepsy thus far. The results extend the clinical spectrum associated with SCN1A mutations and further strengthen the molecular evidence that FHM and epilepsy share, at least in part, similar molecular pathways.     

007 冠脉造影正常的急性心肌梗死病人卵园孔未闭的流行病学

非冠状动脉病变的急性心肌梗死(AMI)占小于1％～6％。有研究发现年轻的中风病人中卵园孔未闭(PFO)比例很高，右心系统的血栓可通过PFO导致反常的脑栓塞。同理，右心系统的血栓也可进入冠状动脉从而导致冠脉闭塞或AMI。本文对没有冠状动脉病变的AMI病人进行研究，旨在探讨其PFO比例是否高于一般人群。 研究对象选自大宗的心导管检查的病人，筛选出19例冠状动脉正常的AMI病人，其中一例因超声心动图图象质量问题而剔除，18例年龄、性别匹配者作对照组。结果，两组之间统计资料无显著差异，仅见AMI组高血压病人有增高趋势，未见房间隔瘤样形成的病例；两组各检出5例PFO，占各自样本数的28％((p值无显著性差异)。     

Is the risk of cancer increased in Asians living in the UK?

The pattern of cancer in white and Asian (Indian, Pakistani, and Bangladeshi) children living in the West Midlands Health Authority Region was investigated using age standardised incidence rates. Two sets of rates were calculated, a 10 year rate (1982-91) using survey based estimates of the ethnic population and a four year rate (1989-92) using the ethnic population counts from the 1991 census. The 10 year rates showed a significantly higher annual incidence of cancer in Asian (159.1/million/year) than in white (130.8) children. The pattern of cancers in Asian children was different, with an excess of lymphomas and germ cell tumours, and a deficit of rhabdomyosarcomas. These findings were confirmed by the four year rates. Although underestimation of the Asian population probably contributes to the apparent excess, there remains cause for concern that UK Asian children may be at higher risk of cancer. Accurate ethnic population figures and confirmatory studies are urgently required.     

Chronic bullous disease of childhood and a paecilomyces lung infection in chronic granulomatous disease

A 12 year old boy suffering from p67-phox deficient chronic granulomatous disease presented with a bullous skin disease and a lung infection with paecilomyces species. The histopathology of a bullous lesion showed subepidermal blister formation and microabcesses containing eosinophils in the dermal papillae. By direct immunofluorescence, linear staining of IgA at the dermal-epidermal junction was detected which confirmed the clinical diagnosis of chronic bullous disease of childhood (linear IgA dermatosis).     

Contribution of genetic and nutritional factors to DNA damage in heavy smokers

Prior epidemiological evidence suggests that genes controlling the metabolism of carcinogens and antioxidant/nutritional status are associated with lung cancer risk, possibly through their ability to modulate DNA damage by carcinogens. We performed a cross-sectional analysis of 159 heavy smokers from a cohort of subjects enrolled in a smoking cessation program. A total of 159 blood samples were analyzed to determine the relative contributions of genetic polymorphisms [CYP1A1 MspI and exon 7 and glutathione S-transferase M1 (GSTM1)] and plasma micronutrients to polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adduct levels. DNA damage in smokers was affected by genetic polymorphisms and nutritional status. Smokers with the CYP1A1 exon 7 valine polymorphism had significantly higher (2-fold, P < or = 0.03) levels of DNA damage than those without. In parallel models, PAH-DNA adducts were inversely associated with plasma levels of retinol (beta = -0.93, P = 0.01), beta-carotene (beta = -0.18, P = 0.09), and alpha- tocopherol (beta = -0.28, P = 0.21) in 159 subjects. The association between smoking-adjusted plasma beta-carotene levels and DNA damage was only significant in those subjects lacking the GSTM1 detoxification gene (beta = -0.30, P = 0.05, n = 75). There was a statistical interaction between beta-carotene and alpha-tocopherol; when beta- carotene was low, alpha-tocopherol had a significant protective effect (beta = -0.78, P = 0.04) on adducts, but not when beta-carotene was high (beta = -0.16, P = 0.57). Plasma alpha-tocopherol was significantly correlated with beta-carotene (r = 0.36, P = 0.0005) and less strongly with retinol (r = 0.20, P = 0.0005). These results suggest that several micronutrients may act in concert to protect against DNA damage and highlight the importance of assessing overall antioxidant status. In conclusion, a subset of smokers may be at increased risk of DNA damage and possibly lung cancer due to the combined effect of low plasma micronutrients and genetic susceptibility factors. The use of biological markers to assess efficacy of interventions and to study mechanisms of micronutrients is timely given the current debate regarding the use of chemopreventive agents in high risk populations.      

Truncal site and detoxifying enzyme polymorphisms significantly reduce time to presentation of further primary cutaneous basal cell carcinoma

Basal cell carcinoma (BCC) is the commonest cancer in Caucasians. Its incidence is rising and many patients develop multiple primary tumours at separate sites. Factors determining time between first primary tumour presentation and the next new primary lesion are unclear. We used Cox's proportional hazards model to study, in 856 Caucasians, the influence of tumour site, individual characteristics and polymorphism in glutathione S-transferase (GSTM1, GSTT1) and cytochrome P450 (CYP2D6, CYP1A1) loci on time to next primary tumour presentation. More than one tumour at first presentation (P <0.0001, hazard ratio 2.72) and GSTT1 null (P = 0.028, hazard ratio 1.74) were associated with decreased time to next primary tumour presentation. Significant two- factor interactions, corrected for number of tumours at presentation, were identified between a truncal tumour at first presentation and each of male gender, GSTM1 null and CYP2D6 EM (P <0.003, hazard ratios 3.09- 3.82). In each of these cases, all patients with the risk combination demonstrated further separate tumours within 5 years of first presentation. Thus, patients with a truncal tumour at first presentation, especially males and those presenting with more than one lesion have a significantly decreased time to presentation of further tumours and should receive more meticulous follow-up. Polymorphism in GSTM1 and CYP2D6 also influences the rate of new primary tumour accrual giving insights into the link between ultraviolet exposure and multiple tumour development.      

Role of amylase-treated, energy-dense liquid diet in the nutritional management of acute shigellosis in children: a controlled clinical trial

To evaluate if an energy-dense porridge liquefied by amylase-rich flour (ARF) from germinated wheat increased the calorie intake in children with acute shigellosis, we studied 66 children, aged 6-35 months, in a randomized, controlled clinical trial. Children were randomized to receive either an energy-dense porridge liquefied with ARF (group 1), a thick unaltered porridge (group 2) or a porridge diluted with water (group 3) to a similar viscosity as that in group 1. MeanSD calorie intakes (kJ/kg/ day) from the porridges were 280 113, 167100 and 15180 in groups 1, 2 and 3, respectively (p = 0.006, ANOVA). Total energy intakes (meanSD) from the study diet and other food sources were 469151, 377121 and 351look J/kg/day, respectively (p = 0.006, ANOVA). Intake of breast milk was similar in all groups. Using multiple regression analysis the effect of ARF-treated energy-dense porridge in increasing the calorie intake persisted after adjusting for a number of confounders, such as age of the child, isolation of Shigella dysenteriae type 1 and fever. The results of this study suggest that ARF-treated porridge increases energy intake in infants and young children during acute shigellosis. This feeding approach may be useful in preventing malnutrition following dysentery due to shigellosis. Amylase, energy-dense, energy intake, liquefied, shigellosis
D Mahalanabis, Clinical Sciences Division, International Centre for Diarrhoeal Disease Research, GPO Box 128, Dhaka 1000, Bangladesh     

Human renin binding protein: complete genomic sequence and association of an intronic T/C polymorphism with the prorenin level in males

The role of renin binding protein (RnBP) in human (patho)physiology, despite its biochemical characterization, is as yet unclear. RnBP has been shown to bind and inactivate renin, a key player of the blood pressure regulating renin-angiotensin system. This renders the RnBP gene a promising candidate gene in human hypertension. Herein, a molecular genetic approach was employed to investigate if RnBP might affect renin, prorenin and/or blood pressure levels. Sequencing of the human Xq28 chromosomal region provided the precise chromosomal location and full genomic sequence of the RnBP gene. All 11 exons, adjacent intronic splice sites and the promoter region were sequenced in 20 patients with essential hypertension of early onset and possible X- linked inheritance and in four normotensive individuals. The only variant found was a single base exchange polymorphism 61 base pairs upstream of the intron 6/exon 7 boundary (T61C). Several cardiovascular parameters, the renin, and prorenin levels and the T61C allele status were determined in 505 Caucasian individuals. Male individuals without medication who were hemizygous for the C allele were characterized by lower prorenin levels (196 +/- 15 versus 256 +/- 12 mU/l, P = 0.05) and a significantly higher renin/prorenin ratio (10.7 +/- 1.5 versus 7.7 +/- 0.3%, P = 0.002), whereas no variations in circulating renin, blood pressure, heart rate and left ventricular mass index were associated with the C allele. No significant association was observed in women. The data do not exclude a role of RnBP in essential hypertension. The complete genomic structure of the RnBP gene, including the identified repetitive sequence elements, provides an essential tool for further studies of the RnBP gene in hypertensive patients with a different genetic background.