Loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1) cause a novel,X-linked syndrome of central hypothyroidism and testicular enlargement

BackgroundCongenital central hypothyroidism occurs either as isolated thyroid-stimulating hormone (TSH) deficiency or in conjunction with other pituitary hormone deficits. Undetected central hypothyroidism is associated with developmental delay in children and adverse cardiometabolic sequelae in adults. Hitherto, mutations in the thyrotropin-releasing hormone receptor gene (TRHR) or the TSHb subunit gene (TSHB) are the only known causes of isolated TSH deficiency.MethodsUsing whole exome and candidate gene sequencing, we have studied 11 unrelated families with males exhibiting isolated TSH deficiency, testicular enlargement, and variably low serum prolactin levels.FindingsWe have identified eight distinct mutations and two whole gene deletions disrupting the X-linked immunoglobulin superfamily member 1 gene (IGSF1) in affected males. IGSF1 encodes a pituitary-enriched plasma membrane glycoprotein; disease-associated mutations block trafficking of IGSF1 from the endoplasmic reticulum to the membrane, consistent with loss-of-protein function. Adult male IGSF1 null mice exhibit central hypothyroidism with decreased pituitary TSH content and circulating T3 levels; TSH secretion in response to TRH is blunted and pituitary TRHR mRNA levels are decreased, suggesting that impaired TRH signalling may provide the basis for hypothyroidism.InterpretationOur observations delineate a novel X-linked syndrome in which loss-of-function mutations in IGSF1 cause central hypothyroidism, testicular enlargement, and variable prolactin deficiency, and identify a previously unsuspected role for IGSF1 in hypothalamic-pituitary control of thyroid and testicular function. Variable biochemical penetrance in these families highlights the importance of genetic ascertainment in this syndrome, so that asymptomatic affected individuals can benefit from early initiation of thyroxine treatment.FundingWellcome Trust and National Institute for Health Research Biomedical Research Centre.     

Development and validation of nail psoriasis quality of life scale (NPQ10)

Background The chronic and treatment‐resistant nature of nail psoriasis affects patients’ lives not only physically but also psychologically. Although there are scoring systems available for disease severity, there is as yet no scale to evaluate the impact of this condition upon the patients’ quality of life. Objectives This study aims to develop and validate a quality of life scale specifically for nail psoriasis. Methods A questionnaire was developed during a study conducted in France between 2004 and 2005. With the cooperation of l’Association Pour la Lutte Contre le Psoriasis, the questionnaire was sent to a random sample of 4000 of its 17 000 members. Results The response rate was 33%. Of the 1309 questionnaires returned, 795 showed the presence of nail psoriasis and these were eligible. The scale score is obtained by adding together the responses to the 10 questionnaire items and the result is expressed as a percentage. The value of the score obtained is proportional to the functional difficulty experienced. The determination of Cronbach's α coefficient and a Principal Component Factor Analysis show, respectively, very good internal consistency and the unidimensional nature of the scale. Test–retest results on 15 patients showed good reproducibility. Results were validated with reference to the Dermatology Life Quality Index. In this study, the NPQ10 score is significantly influenced by gender (women have a higher score) and by the duration of psoriasis (recent onset implies greater functional difficulty). Finally, the score is much higher when the nail psoriasis affects both the hands and the feet. Conclusion This study confirms a change in the quality of life of patients who have nail psoriasis. The NPQ10 scale, specific to this condition, is simple to use and has the attributes needed in a quality of life scale. The scale must now be tested in longitudinal studies (such as clinical trials) to confirm its ability to measure a change in status.     

Proprotein Convertase Inhibition Results in Decreased Skin Cell Proliferation,Tumorigenesis, and Metastasis

PACE4 is a proprotein convertase (PC) responsible for cleaving and activating proteins that contribute to enhance tumor progression. PACE4 overexpression significantly increased the susceptibility to carcinogenesis, leading to enhanced tumor cell proliferation and premature degradation of the basement membrane. In the present study, we sought to evaluate a novel approach to retard skin tumor progression based on the inhibition of PACE4. We used decanoyl-RVKR-chloromethylketone (CMK), a small-molecule PC inhibitor, for in vitro and in vivo experiments. We found that CMK-dependent blockage of PACE4 activity in skin squamous cell carcinoma cell lines resulted in impaired insulin-like growth factor 1 receptor maturation, diminished its intrinsic tyrosine kinase activity, and decreased tumor cell proliferation. Two-stage skin chemical carcinogenesis experiments, together with topical applications of CMK, demonstrated that this PC inhibitor markedly reduced tumor incidence, tumor multiplicity, and metastasis, pointing to a significant delay in tumor progression in wild-type and PACE4 transgenic mice. These results identify PACE4, together with other PCs, as suitable targets to slow down or block tumor progression, suggesting that PC inhibition is a potential approach for therapy for solid tumors.     

Direct-to-Consumer基因检测是福是祸? 如何应对消费者驱动的基因组时代?

<正>快速发展的基因组技术可以一次检测基因组的数百万个基因变异位点,据此,我们估计每个个体发生肿瘤、糖尿病、心血管病或其他常见疾病的可能风险。这些技术进步集中体现在两方面:消费者驱动型     

No association between nickel allergy and reporting cosmetic dermatitis from mascara or eye shadow: a cross‐sectional general population study

Background In theory, all pigmented make‐up products may contain metal allergens including nickel. Eyelid dermatitis has previously been observed among nickel allergic dermatitis patients following exposure to nickel containing mascara and eye shadow. However, an association between nickel eyelid dermatitis and nickel in make‐up products remains controversial. Objective This cross‐sectional patch test study investigated whether the frequency of self‐reported cosmetic dermatitis from mascara or eye shadow use was higher among nickel allergic Danish women than women without nickel allergy. Methods In 2006, a total of 1843 18–69 year old women completed a postal questionnaire including questions on cosmetic dermatitis and were patch tested with nickel sulphate. Data were analysed by logistic regression analyses and associations were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Results The prevalence of nickel allergy was similar among women who reported cosmetic dermatitis from eye shadow or mascara and among women who did not report such symptoms. Cosmetic dermatitis was positively associated with self‐reported atopic dermatitis and age. Conclusion Overall, no association between having nickel allergy and reporting cosmetic dermatitis from mascara or eye shadow use was found in the general population. This does not exclude a causal relationship in selected cases.     

Schistosoma mansoni excretory circulating cathodic antigen shares Lewis- x epitopes with a human granulocyte surface antigen and evokes host antibodies mediating complement-dependent lysis of granulocytes

Parasitic worms of the genus Schistosoma excrete relatively large amounts of immunogenic glycoproteins (circulating cathodic antigen [CCA]) that contain polysaccharide side chains with the trisaccharide Lewis-x (L(ex)) as a repeating unit. These carbohydrates evoke high titers of specific IgM antibodies that cross-react with the repeating L(ex) units on the surface of granulocytes. Consequently this might lead, in the presence of complement, to lysis of the granulocytes. In the present study, this hypothesis was investigated using anti-CCA mouse monoclonal antibodies (MoAbs) and polyclonal antibodies purified from sera of infected humans. By flow cytometry, it was demonstrated that the mouse MoAbs directed against CCA strongly recognized the granulocytes. It could also be shown that these MoAbs, as well as anti- CCA IgM antibodies purified from infected human sera, caused lysis of granulocytes in a complement-dependent cytotoxicity assay. Sera from healthy controls or from patients with other helminth infections resulted in negligible granulocytotoxicity. These in vitro observed phenomena may explain the mild to moderate neutropenia that occurs in schistosomiasis patients.     

Current concepts and issues in the management of regurgitation of infants: a reappraisal

Regurgitation in infants is a common problem. Recent issues, such as the increased risk of sudden infant death in the prone sleeping position, the finding of persisting occult gastro-oesophageal reflux with feed thickeners, and the increasing awareness of the cost-benefit ratio of medications may challenge the currently recommended management approach. A round table was organized to elaborate on the impact of (i) the pro supine sleeping campaigns in relation to sudden infant death and (ii) advancement in medical treatment on therapeutic strategies in regurgitating infants. The participants were opinion leaders from Europe and North America (Belgium, Canada, France, UK, Italy, Switzerland and The Netherlands). The importance of parental reassurance is stressed. As a consequence of the supine sleeping campaigns aiming to decrease the incidence of sudden infant death syndrome, the "prone elevated sleeping position" is no longer advised as a first-line therapeutic approach, although it is still recommended in "complicated reflux". It is emphasized that milk thickeners are an adequate therapeutic tool for regurgitation, but not in reflux disease. According to the literature, the efficacy of (alginate-) antacids, although very popular in some countries, is questionable. These recommendations will be of interest to first-line paediatricians, since about 40% of their patients, according to the literature, present because of regurgitation.     

The mental and physical health of miners following the 1992 national pit closure programme: a cross sectional survey using General Health Questionnaire GHQ-12 and Short Form SF-36

Background: In the twelve months following the announcement of the UK pit closure programme in October 1992, 22 500 miners were made redundant. In 1994 we undertook a cross-sectional survey to determine whether the mental and physical health of men who had been employed in the Nottinghamshire mining industry differed from that of the general population.Methods: A postal questionnaire was designed incorporating the General Health Questionnaire (GHQ-12), and six domains from SF-36. Questionnaires were sent to 1064 miners and ex-miners and 2097 other men in Nottinghamshire. Non-responders were sent two reminders.Results: The final response rate was 51%. The percentage of responders with GHQ-12 scores of three or more (suggesting psychological disorder) was 46% for those still employed in the mining industry, 52% for unemployed former miners and 22% for working non-miners (odds ratios: 3.0 [95% C.I. 2.2–4.1] for current miners and 3.9 [95% C.I. 2.6–5.7] for unemployed miners compared with working non-miners). The miners and ex-miners also had lower scores (suggesting greater morbidity) for each of the SF-36 domains tested. When stratifying for age in respondents of social classes IIIM-V the scores of current miners were significantly lower than those of working non-miners (P < 0.01).Conclusions: This study suggests that when surveyed in 1994, men who had been employed in three Nottinghamshire collieries in 1992 were psychologically and physically disadvantaged compared with working non-miners. Whether these findings are a result of pit closures is uncertain. However, significant potential health needs have been demonstrated.