Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma

The occuloalbinism 2 (OCA2) gene, localized at 15q11, encodes a melanosomal transmembrane protein that is involved in the most common form of human occulo-cutaneous albinism, a human genetic disorder characterized by fair pigmentation and susceptibility to skin cancer. We wondered whether allele variations at this locus could influence susceptibility to malignant melanoma (MM). In all, 10 intragenic single-nucleotide polymorphisms (SNPs) were genotyped in 113 patients with melanomas and in 105 Caucasian control subjects with no personal or family history of skin cancer. By comparing allelic distribution between cases and controls, we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). Then, a recently developed strategy, the 'combination test' enabled us to show that a combination formed by two SNPs was most strongly associated to MM, suggesting a possible interaction between intragenic SNPs. In addition, the role of OCA2 on MM risk was also detected using a logistic model taking into account the presence of variants of the melanocortin 1 receptor gene (MC1R, a key pigmentation gene) and all pigmentation characteristics as melanoma risk factors. Our data demonstrate that a second pigmentation gene, in addition to MC1R, is involved in genetic susceptibility to melanoma.     

Structures et propriétés diélectriques des poly(α-acétoxystyréne)s parasubstitués

The relations between structure and isothermal, dielectric properties of poly(α-acetoxystyrene)s substituted in para position by ? OCOCH₃ ( 1a ), ? OCOCH₂CH₃ ( 1b ), ? OCOCH₂CH₂CH₃ ( 1c ), ? OCOC₆H₅ ( 1d ), ? OCOCH₂CH₂Cl ( 1f ) and ? OCOOCH₃ ( 1g ) were studied. The dielectric constants, at 10⁵ Hz and 20 ± 2°C, were found to be: 3,79 ( 1a ), 3,36 ( 1b ), 3,18 ( 1c ), 3,51 ( 1d ), 3,36 ( 1e ), 3,65 ( 1f ) and 3,07 ( 1g ). The polymers 1a – 1g do not show any α- or β-transition. Increasing bulkiness of the para substituent gives rise to a decreasing dielectric constant due to an increase of the degree of syndiotacticity, as determined from ¹H and ¹³C NMR spectra.     

Evaluation of the prognosis of mitral valve prolapse

It is not easy to evaluate the prognosis of mitral valve prolapse. First of all, a positive diagnosis is difficult: the clinical insufficiencies are ill-compensated by sonocardiography as it is less reliable than expected; the very existence of the "mitral valve prolapse" described by Barlow is being challenged. Secondly, the most severe complications of mitral prolapse are rare, with respect to its frequency. Some complications are currently well defined. Thus, severe mitral insufficiency, leading to valve replacement, affects elderly men more than young women, although the pathological lesions correspond to the same disease. Endocarditis is rare and only occurs when there is an audible murmur. Rhythm disorders are varied, with however, frequent junction tachycardias and a marked influence of catecholamines, which may explain the clinical effectiveness of beta-blockers. Unfortunately, severe complications are not as well known. Thus, the risk of sudden death and cerebral vascular accident cannot be figured out from large statistical studies. Only studies of some so called "risk" sub-groups, should allow a better knowledge of these two complications and a more effective prevention.     

Clonally restricted insulin autoantibodies in a cohort of 2200 healthy blood donors

Summary Serum samples of 2200 blood donors were screened for anti-insulin IgG by enzyme-linked immunosorbent assay. Specificity of detected antibodies was verified by competition with an excess of insulin and observation that saturated anti-insulin IgG were no longer measurable. The upper limit of measured signal in the population was defined as the mean plus three SD. In the direct assay, 32 sera were positive. Among these, 22 (1%) contained saturable insulin antibodies (true positive) and 10 were non-saturable and considered as non-insulin-specific. The positive blood donors were requested to answer a questionnaire and according to their answers, none had ever received insulin, was a first degree relative of a Type 1 (insulin-dependent) diabetic patient or had experienced a hypoglycaemic episode. None of the 22 true positive sera detected by enzyme-immunosorbent assay bound ¹²⁵-I-insulin to any significant extent. The nine sera yielding the highest signal were further characterized with regard to heavy and light chains as well as species specificity of ligand. Anti-insulin IgG from healthy blood donors contained only one heavy (1 2/9; 3 7/9) and one light ( 8/9; 1/9) chain. Three sera were human insulin specific; two were non-species-specific; the other four bound insulin in the order human = porcine > bovine. These results indicate that low affinity clonally restricted antibodies against insulin are present in unselected blood donors with a prevalence of 1%.     

Use of polymerase chain reaction in human African trypanosomiasis stage determination and follow-up.

Stage determination of human African trypanosomiasis is based on the detection of parasites and measurements of biological changes in the cerebrospinal fluid (CSF) (concentration of white blood cells > 5 cells per mm3 and increased total protein levels). The patient is treated accordingly. Demonstration of the absence or presence of trypanosomes by the double centrifugation technique is still the only test available to clinicians for assessing treatment success. In this study, however, we evaluate the polymerase chain reaction (PCR) as a tool for assessing the disease stage of trypanosomiasis and for determining whether treatment has been successful. All 15 study patients considered to be in the advanced stage of the disease were PCR positive; however, trypanosomes were demonstrated by double centrifugation in only 11 patients. Of the five remaining patients, who were considered to be in the early stage, PCR and double centrifugation were negative. Following treatment, 13 of the 15 second-stage patients were found to be negative for the disease in at least two samples by PCR and double centrifugation. Two others were still positive by PCR immediately and one month after the treatment. Trypanosome DNA detection using PCR suggested that the two positive patients were not cured but that their possible relapse could not be identified by a search for parasites using the double centrifugation technique. Further evaluation of the PCR method is required, in particular to determine whether PCR assays could be used in studies on patients who fail to respond to melarsoprol, as observed in several foci.     

Preoperative radiotherapy of rectal cancer. The Lyons experience, 1985-1996. Prognostic study apropos of 312 patients

AIM OF STUDY: Preoperative radiotherapy is used increasingly in rectal cancer in Europe. This study is a retrospective analysis of a series of 312 patients with rectal adenocarcinoma treated by preoperative radiotherapy. MATERIAL AND METHOD: From 1985 to 1996, 312 patients were included in this study. Preoperative staging was: T2: 83, T3: 192 et T4: 21. On digital rectal examination, 25 patients were classified as N1. Endorectal sonographic staging was: uT1: 3, uT2: 77, uT3: 163, uN0: 122, uN1-2: 127. After surgery, pathological staging was: pT0: 43 (14%), pT1 24, pT2: 81, pT3: 151, pN0: 229, pN1-2: 81. Radiotherapy was delivered to the posterior pelvis with an accelerated schedule 39 Gy/13 fractions/17 days with x 18 MV. RESULTS: Median follow-up is 54 months. For pM0 patients (297 patients), the overall 5-year survival rate is 67%. Local failure rate is 9%. Since 1986, the rate of sphincter saving surgery is close to 65%. Various parameters related to the tumor were found to be significant prognostic factors on multivariate analysis in relation to 5-year overall survival rate: the T stage as judged by digital rectal examination and endorectal sonography, the N stage as evaluated on digital rectal examination but not with endorectal sonography. Pathological examination of the operative specimen retains a very strong prognostic value for pT and pN. CONCLUSION: Pathological examination of the specimen of rectal carcinoma retains a very strong prognostic value after preoperative radiation therapy. Endorectal sonography is of interest to evaluate T staging of the tumor but is not reliable for N stage.     

Nitric Oxide and -Arginine Cause an Accumulation of Utrophin at the Sarcolemma: A Possible Compensation for Dystrophin Loss in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD), a severe X-linked recessive disorder which results in progressive muscle degeneration, is due to a lack of dystrophin, a membrane cytoskeletal protein. An approach to treatment is to compensate for dystrophin loss with utrophin, another cytoskeletal protein with over 80% homology with dystrophin. Utrophin is expressed, at the neuromuscular junction, in normal and DMD muscles and there is evidence that it may perform the same cellular functions as dystrophin. So, the identification of molecules or drugs that could up-regulate utrophin is a very important goal for therapy. We show that in adult normal and mdx mice (an animal model of Duchenne myopathy) treated with -arginine, the substrate of nitric oxide synthase (NOS), a pool of utrophin localized at the membrane appeared and increased, respectively. In normal and mdx myotubes in culture, -arginine, nitric oxide (NO), or hydroxyurea increased utrophin levels and enhanced its membrane localization. This effect did not occur with -arginine, showing the involvement of NOS in this process. The NO-induced increase in utrophin was prevented by oxadiazolo-quinoxalin-1-one, an inhibitor of a soluble guanylate cyclase implicated in NO effects. These results open the way to a potential treatment for Duchenne and Becker dystrophies.     

Hexachlorophene and the central nervous system

Summary A study on hexachlorophene encephalopathy in mice and baboons is reported. By light microscopy, a severe spongiform lesion of the central nervous system (CNS) was localized in the white matter, without myelin breakdown or cellular reaction. By electron microscopy, the myelin alteration was characterized by wide intralamellar spaces or splitting developed in the intraperiod line of compact sheaths. The acute changes described were induced by administration of the drug by the digestive or cutancous routes at various dosage levels in an aqueous solution or in talcum powder. The toxic effects depended on the age of the animals, the survival times and the concentrations of hexachlorophene, i.e., 6%, 3%, and 0.5%. The findings are compared with previous reports on the neurotoxicity of hexachlorophene and other chemicals in humans and experimental animals. Hexachlorophene cannot be recommended for use in young infants because of its neurotoxicity in very low doses as demonstrated in the present report.