The spectrum of mutations in this study can be used to plan appropriate screening protocols; a suggested protocol is to screen exon 4, and proceed to exons 3, 5, and 6 where indicated. GOM on skin biopsy is diagnostic but can be negative. Anterior temporal pole involvement on MRI is a useful diagnostic marker.

In patients with CVD we confirmed a relationship between the MTHFR genotype and serum homocysteine concentration and an interaction with serum folate concentration. We found no association between CVD and genotype. However, the interaction with serum folate suggests that the genotype could still be a risk factor in populations with a low folic acid intake.

Background and Purpose-The role of endothelial nitric oxide synthase (eNOS) in normal physiology suggests that it could be a potential candidate gene for stroke. Reduced eNOS activity could mediate an increased stroke risk through hypertension or independent of hypertension through abnormal vasomotor responses, promoting atherogenesis, or increased platelet adhesion and aggregation. Recently, a common polymorphism in exon 7 of the eNOS gene (894G3 T) has been reported to be a strong risk factor for coronary artery disease. We determined whether it was also a risk factor for transient ischemic attack (TIA) and ischemic stroke and for carotid atheroma. Methods-We studied 361 consecutive white patients presenting with ischemic stroke or TIA to a neurological cerebrovascular disease service and 236 normal white controls. In all patients CT and/or MR head imaging and high-resolution carotid duplex ultrasound were performed. The presence of the polymorphism (N/n) was determined by polymerase chain reaction and restriction with the enzyme BanII. Results-There was no difference in the frequency of the NN genotype between patients and controls (13.0% versus 15.3%; Pϭ0.44) or in N allele frequency (39% versus 37%; Pϭ0.57). There was no association with genotype when only patients with stroke (excluding those with TIA) or when only individuals aged Յ65 years were considered. In contrast, there was a highly significant independent association between cerebrovascular disease and hypertension (odds ratio, 2.87; 95% CI, 2.0 to 4.15; PϽ0.00001), smoking (odds ratio, 2.58; 95% CI, 1.80 to 3.70; PϽ0.00001), and diabetes (odds ratio, 2.68; 95% CI, 1.38 to 5.24; Pϭ0.004). There was no relationship between the polymorphism and any particular stroke subtype: large-vessel disease, for NN, 15 of 105 (14.3%); lacunar disease, 10 of 75 (13.3%); cardioembolic and unknown, 18 of 151 (11.9%); and tandem pathology, 4 of 30 (13.3%) (Pϭ0.68, 2 ). There was no difference in the mean degree of carotid stenosis between the 3 genotypes: NN, 31.1% (SD, 27.1); Nn, 30.1% (29.0); and nn, 31.2% (26.3) (Pϭ0.9). There was no association between the NN genotype or the N allele and hypertension. Conclusions-We failed to find a relationship between this exon 7 polymorphism and ischemic cerebrovascular disease.In particular, it was not associated with stroke and TIA secondary to large-vessel atherosclerosis or with the degree of carotid stenosis in patients with cerebrovascular disease. It is unlikely that this particular polymorphism or any closely linked polymorphism is a major risk factor in the majority of white patients with stroke. (Stroke. 1998;29:1908-1911.)

Catabolism of free heme by heme oxygenase-1 (HO-1) generates carbon monoxide, biliverdin, and free iron (Fe). These end-products are responsible for much of the biologic activity of HO-1, including anti-inflammatory, antiapoptotic, antiproliferative, and antioxidant effects. We have identified an additional cytoprotective action, the regulation of complement activation, mediated via induction of decay-accelerating factor (DAF) . IntroductionVascular endothelial cells (ECs) express constitutive and inducible cytoprotective genes, which exert cytoprotective and antiinflammatory effects, maintain vascular integrity, and assist in endothelial repair. 1 Vascular endothelial growth factor (VEGF) plays an important role in the maintenance of these pathways in the normal adult vasculature. This notion is supported by the observation that VEGF up-regulates expression of several protective genes in EC, including endothelial nitric oxide synthase (eNOS), prostacyclin, and Bcl-2, and protects EC against oxidative stress. 2 Furthermore, we have reported that VEGF induces the expression of the cytoprotective, anti-inflammatory enzyme heme oxygenase-1 (HO-1) 3 and the complement inhibitory protein decay-accelerating factor (DAF). 4 HO-1 is the inducible form of the heme oxygenase system, acting as the rate-limiting factor in the catabolism of heme into biliverdin, releasing free iron (Fe) and carbon monoxide (CO). 5 Biliverdin is subsequently converted to bilirubin by biliverdin reductase, whereas intracellular Fe induces expression of the iron-binding protein heavy-chain ferritin 6 and the opening of Fe 2ϩ -export channels. 7 The importance of HO-1 in vasculoprotection is demonstrated by the severe and persistent endothelial damage observed in human HO-1 deficiency 8 and Hmox1 Ϫ/Ϫ mice. 9 HO-1 exerts a potent protective effect against atherogenesis, 10 cardiac ischemia/reperfusion injury, 11 and both graft rejection and accelerated arteriosclerosis after transplantation. [12][13][14] The complement cascade provides an innate defense mechanism against bacterial infection, bridging innate and adaptive immunity while affording clearance of antibody immune complexes. However, by the nature of its cytolytic effects, complement has the potential to inflict injury on bystander host tissues, including vascular endothelium. C3a, C5a, and the C5b-9 membrane attack complex (MAC) exert a variety of effects, including cytokine release, induction of cellular adhesion molecules, leukocyte adhesion, and generation of a prothrombotic endothelial surface. 15,16 Hence, complement activation has been implicated in the pathogenesis of atherosclerosis and the rejection of transplanted organs.Mechanisms for the control of complement activation on the surface of human cells include membrane-bound regulatory proteins: DAF (CD55), membrane cofactor protein (MCP; CD46), and CD59. In addition, murine cells express complement receptorrelated protein-Y (Crry/p65), which combines the functions of DAF and MCP. Membrane-bound human DAF prevents the formation...

Huntington’s disease is caused by the expansion of a CAG repeat within exon 1 of the HTT gene, which is unstable, leading to further expansion, the extent of which is brain region and peripheral tissue specific. The identification of DNA repair genes as genetic modifiers of Huntington’s disease, that were known to abrogate somatic instability in Huntington’s disease mouse models, demonstrated that somatic CAG expansion is central to disease pathogenesis, and that the CAG repeat threshold for pathogenesis in specific brain cells might not be known. We have previously shown that the HTT gene is incompletely spliced generating a small transcript that encodes the highly pathogenic exon 1 HTT protein. The longer the CAG repeat, the more of this toxic fragment is generated, providing a pathogenic consequence for somatic expansion. Here, we have used the R6/2 mouse model to investigate the molecular and behavioural consequences of expressing exon 1 HTT with 90 CAGs, a mutation that causes juvenile Huntington’s disease, compared to R6/2 mice carrying ∼200 CAGs, a repeat expansion of a size rarely found in Huntington’s disease patient’s blood, but which has been detected in post mortem brains as a consequence of somatic CAG repeat expansion. We show that nuclear aggregation occurred earlier in R6/2(CAG)90 mice and that this correlated with the onset of transcriptional dysregulation in these lines. Whereas in R6/2(CAG)200 mice, cytoplasmic aggregates accumulated rapidly and closely tracked with the progression of behavioural phenotypes and with end-stage disease. We find that aggregate species formed in the R6/2(CAG)90 brains have different properties to those in the R6/2(CAG)200 mice. Within the nucleus, they retain a diffuse punctate appearance throughout the course of the disease, can be partially solubilised by detergents and have a greater seeding potential in young mice. In contrast, aggregates from R6/2(CAG)200 brains polymerise into larger structures that appear as inclusion bodies. These data emphasise that a subcellular analysis, using multiple complementary approaches, must be undertaken in order to draw any conclusions about the relationship between HTT aggregation and the onset and progression of disease phenotypes.