Linkage analysis of candidate regions for coeliac disease genes

A strong HLA association is seen in coeliac disease [specifically to the DQ(alpha1*0501,beta1*0201 heterodimer], but this cannot entirely account for the increased risk seen in relatives of affected cases. One or more genes at HLA-unlinked loci also predispose to coeliac disease and are probably stronger determinants of disease susceptibility than HLA. A recent study has proposed a number of candidate regions on chromosomes 6p23 (distinct from HLA), 6p12, 3q27, 5q33.3, 7q31.3, 11p11, 15q26, 19p13.3, 19q13.1, 19q13.4 and 22cen for the location of a non-HLA linked susceptibility gene. We have examined these regions in 28 coeliac disease families by linkage analysis. There was excess sharing of chromosome 6p markers, but no support for a predisposition locus telomeric to HLA. No significant evidence in favour of linkage to coeliac disease was obtained for chromosomes 3q27, 5q33.3, 7q31.3, 11p11, 19p13.3, 19q13.1, 19q13.4 or 22cen. There was, however, excess sharing close to D15S642. The maximum non-parametric linkage score was 1.99 (P = 0.03). Although the evidence for linkage of coeliac disease to chromosome 15q26 is not strong, the well established association between coeliac disease and insulin dependent diabetes mellitus, together with the mapping of an IDDM susceptibility locus (IDDM3) to chromosome 15q26, provide indirect support for this as a candidate locus conferring susceptibility to coeliac disease in some families.      

A guide to the evaluation of fourth cranial nerve palsies

PURPOSE To devise a cost-effective guide for the evaluation of fourth nerve palsies (FNP). METHODS A review of the pertinent English language literature was performed to devise a guide for the evaluation (including neuroimaging) of FNP. The authors report a retrospective review of imaging studies performed on 206 patients with FNP. RESULTS The literature was used to develop the imaging guide. In the retrospective chart review of 206 patients from two tertiary care centers, 28 patients (13.6%) underwent a computed tomography scan and/or a magnetic resonance scan. Of these patients, five had associated neurological symptoms (non-isolated), one was traumatic, five were congenital, four were vasculopathic, eleven were non-vasculopathic, and two were progressive. Following the recommendations of the imaging guide, the five isolated congenital FNP and the four isolated vasculopathic FNP would not have undergone neuroimaging studies. The total costs of these neuroimaging studies in these nine patients were 19,000 dollars. Four patients in the retrospective review with associated neurological deficits (non-isolated) should have undergone neuroimaging according to the guide, but did not. CONCLUSIONS Although the evaluation of FNP can be difficult, the decision to order neuroimaging can be improved by using an imaging guide. An imaging guide for the evaluation of FNP may allow more appropriate and cost-effective imaging of these patients. Isolated congenital, old traumatic, or vasculopathic FNP do not require neuroimaging studies. Patients with non-isolated FNP should have directed neuroimaging studies based upon the results of clinical examination.     

Obstetric and neonatal outcomes associated with maternal naltrexone exposure

Poor maternal and neonatal outcomes are associated with the pregnant heroin user. These include increased antepartum haemorrhage, decreased neonatal birthweight and increased neonatal mortality Medically supervised withdrawal from heroin during pregnancy has, however, been discouraged due to possible risk to the fetus and because of the high incidence of return to regular illicit heroin use by the mother. In recent years, however, a number of withdrawal procedures using anaesthesia, oral sedation, or intravenous sedation, precipitated by naloxone and/or naltrexone have been developed and carried out successfully on pregnant heroin users. We have now collated information on 18 cases (19 detoxifications) from three countries (Portugal, Australia and the United Kingdom). These case study data, although limited, indicate that detoxification of the pregnant heroin user is possible without significant risk to the neonate or mother, with many women not returning to dependent heroin use following detoxification. Naltrexone maintenance has also been used in the non-pregnant heroin user to discourage illicit heroin use. Similarly to methadone, stabilisation on naltrexone may be associated with conception and pregnancy Over the past three years, 26 women have conceived while on the Western Australia naltrexone program. Due to the unknown teratogenic effects, most have ceased naltrexone intake at approximately seven or eight weeks gestation. In a number of instances, however, naltrexone maintenance has been recommenced following return to a dependent pattern of heroin use. As a consequence, neonates have had different periods of naltrexone exposure, building from the initial seven or eight weeks. We now report on seven women who have delivered and three who are well into their third trimester. Neonatal and obstetric features were unremarkable with good Apgar scores, birthweight and head circumference observed. In the three cases still in third-term gestation, normal fetal development has been observed at recent ultrasound examinations. These case data indicate that naltrexone maintenance may have a role in the management of the pregnant heroin user.     

Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice

Arsenic is an environmental toxicant and carcinogen. Exposure to arsenic is associated with development of liver fibrosis and portal hypertension through ill defined mechanisms. We evaluated hepatic fibrogenesis after long term arsenic exposure in a murine model. BALB/c mice were exposed to arsenic by daily gavages of 6 μg/gm body weight for 1 year and were evaluated for markers of hepatic oxidative stress and fibrosis, as well as pro-inflammatory, pro-apoptotic and pro-fibrogenic factors at 9 and 12 months. Hepatic NADPH oxidase activity progressively increased in arsenic exposure with concomitant development of hepatic oxidative stress. Hepatic steatosis with occasional collection of mononuclear inflammatory cells and mild portal fibrosis were the predominant liver lesion observed after 9 months of arsenic exposure, while at 12 months, the changes included mild hepatic steatosis, inflammation, necrosis and significant fibrosis in periportal areas. The pathologic changes in the liver were associated with markers of hepatic stellate cells (HSCs) activation, matrix reorganization and fibrosis including α-smooth muscle actin, transforming growth factor-β1, PDGF-Rβ, pro-inflammatory cytokines and enhanced expression of tissue inhibitor of metalloproteinase-1 and pro(α) collagen type I. Moreover, pro-apoptotic protein Bax was dominantly expressed and Bcl-2 was down-regulated along with increased number of TUNEL positive hepatocytes in liver of arsenic exposed mice. Furthermore, HSCs activation due to increased hepatic oxidative stress observed after in vivo arsenic exposure was recapitulated in co-culture model of isolated HSCs and hepatocytes exposed to arsenic. These findings have implications not only for the understanding of the pathology of arsenic related liver fibrosis but also for the design of preventive strategies in chronic arsenicosis.     

Systemic PUVA vs. narrowband UVB in the treatment of vitiligo: a randomized controlled study

Vitiligo is an acquired depigmenting disorder having disfiguring consequences. Many treatments have been attempted with varying reports of success. A parallel‐group, assessor blinded, randomized, controlled trial was designed to compare the efficacy and adverse effects of narrowband UVB (NBUVB) with oral psoralen UVA (PUVA) therapy in the treatment of vitiligo. Patients aged 13–70 years with vitiliginous lesions involving more than 5% body surface area were eligible for the study. In total, 56 patients were randomized in a 1 : 1 ratio to oral PUVA or NBUVB phototherapy groups. Patients were assessed for the percentage of repigmentation over the depigmented areas as the primary outcome measure at each visit during the first three months and then monthly within the next three months. The incidence of adverse effects was also noted during the study period as the secondary outcome measure. The median repigmentation achieved at the end of the six‐month therapy course was 45% in the NBUVB group and 40% in the oral PUVA group. Focal vitiligo had the best response in both treatment groups. There were lesser adverse effects within the NBUVB (7.4%) than in the PUVA (57.2%) group. Two PUVA patients discontinued therapy due to severe dizziness. There was no significant difference in the mean degree of repigmentation; however, NBUVB carried a greater response rate and might be superior to oral PUVA with better tolerance and color match with the surrounding normal skin, as well as fewer side effects in the treatment of vitiligo.