Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus

BACKGROUND: Ten neurodegenerative disorders characterized by spinocerebellar ataxia (SCA) are known to be caused by trinucleotide repeat (TNR) expansions. However, in some instances the molecular diagnosis is considered indeterminate because of the overlap between normal and affected allele ranges. In addition, the mechanism that generates expanded alleles is not completely understood. OBJECTIVE: To examine the clinical and molecular characteristics of a large group of Portuguese and Brazilian families with ataxia to improve knowledge of the molecular diagnosis of SCA. PATIENTS AND METHODS: We have (1) assessed repeat sizes at all known TNR loci implicated in SCA; (2) determined frequency distributions of normal alleles and expansions; and (3) looked at genotype-phenotype correlations in 202 unrelated Portuguese and Brazilian patients with SCA. Molecular analysis of TNR expansions was performed using polymerase chain reaction amplification. RESULTS: Patients from 110 unrelated families with SCA showed TNR expansions at 1 of the loci studied. Dominantly transmitted cases had (CAG)(n) expansions at the Machado-Joseph disease gene (MJD1) (63%), at SCA2 (3%), the gene for dentatorubropallidoluysian atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)(n) expansions at the SCA8 (2%) gene, whereas (GAA)(n) expansions in the Freidreich ataxia gene (FRDA) were found in 64% of families with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the TATA-binding protein gene (TBP), with 43 CAGs, was present in a patient with ataxia and mental deterioration. Associations between frequencies of SCA2 and SCA6 and a frequency of large normal alleles were found in Portuguese and Brazilian individuals, respectively. Interestingly, no association between the frequencies of DRPLA and large normal alleles was found in the Portuguese group. CONCLUSIONS: Our results show that (1) a significant number of isolated cases of ataxia are due to TNR expansions; (2) expanded DRPLA alleles in Portuguese families may have evolved from an ancestral haplotype; and (3) small (CAG)(n) expansions at the TBP gene may cause SCA17

DNA adducts in fish following an oil spill exposure

On 12 December 1999, one third of the load of the Erika tanker, amounting to about 10,000 t crude oil flowed into sea waters close to the French Atlantic Coast. This oil contained polycyclic aromatic compounds (PAC) that are known to be genotoxic. Genotoxic effects induce DNA adducts formation, which can thus be used as pollution biomarkers. Here, we assessed the genotoxic impact of the “Erika” oil spill by DNA adducts detection in the liver of immature fishes (Solea solea) from four locations of the French Brittany coasts. Two months after the spill, a high amount of DNA adducts was found in samples from all locations, amounting to 92–290 DNA adduct per 109 nucleotides. Then total DNA adduct levels decreased to reach about 50 adducts per 109 nucleotides nine months after the spill. In vitro experiments using human cell cultures and fish liver microsomes evidence the genotoxicity of the Erika fuel. They also prove the formation of reactive species able to create DNA adducts. Furthermore, in vitro and in vivo DNA adducts fingerprints are similar, thus confirming that DNA adducts are a result of the oil spill

Knowledge of general practitioners about nasopharyngeal cancer at the Puskesmas in Yogyakarta, Indonesia

<p>Abstract</p> <p>Background</p> <p>Nasopharyngeal carcinoma (NPC) is one of the leading causes of cancer death in Indonesia. At initial diagnosis, 80% of the patients present with advanced stage disease. In Indonesia, primary medical care is generally provided by the health care centres; named Puskesmas. The lack of knowledge of various aspects of NPC of the General practitioners (GPs) working in these centers might contribute to the diagnostic delay. The aim of this study was to assess the knowledge of these GPs on different aspects of NPC including symptoms, risk factors and incidence.</p> <p>Methods</p> <p>One hundred six GPs in the Puskesmas in the Yogyakarta province were subjected to a questionnaire on different aspects of NPC based on literature and interviews with Head and Neck Surgeons.</p> <p>Results</p> <p>All GPs approached participated and in total 106 questionnaires were filled in. All participants were aware of NPC as a disease and 89% confirmed that it is a serious problem in Indonesia. However, 50% of the participants believed NPC has a low incidence in their region. The question on early symptoms gave a mean 4.2 answers of which 50% were incorrect.</p> <p>The GPs provided a total of 318 answers when asked for the risk factors of NPC, 75% of which were incorrect. Fifty seven GPs (54%) stated that they did not receive sufficient education on NPC at the university and insufficient knowledge was gained during daily practice. Ninety-two percent of the GPs were interested in additional education, preferably in form of lectures, meetings or folders.</p> <p>Conclusion</p> <p>This study revealed that GPs in the Puskesmas in Yogyakarta lack knowledge on all aspects of NPC. This is an important finding as NPC is endemic in Indonesia and the Puskesmas are the institutions which provide primary medical health care in the country. Further education of the GPs in these endemic areas could be a first step to increase the rate of early detection. Therefore, we suggest 1) to conduct a medical awareness campaign for GPs on the most important subjects concerning NPC, and 2) as soon as NPC awareness among GPs has risen, provide further education on the risk factors, the early symptoms and the incidence, education to the community. We propose to extend this study to other areas in Indonesia (i.e. Jakarta, Surabaya, Central Java), using models that have been developed in Yogyakarta.</p

Influence of mercury exposure on blood pressure, resting heart rate and heart rate variability in French Polynesians: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Populations which diet is rich in seafood are highly exposed to contaminants such as mercury, which could affect cardiovascular risk factors</p> <p>Objective</p> <p>To assess the associations between mercury and blood pressure (BP), resting heart rate (HR) and HR variability (HRV) among French Polynesians</p> <p>Methods</p> <p>Data were collected among 180 adults (≥ 18 years) and 101 teenagers (12-17 years). HRV was measured using a two-hour ambulatory electrocardiogram (Holter) and BP was measured using a standardized protocol. The association between mercury and HRV and BP parameters was studied using analysis of variance (ANOVA) and analysis of covariance (ANCOVA)</p> <p>Results</p> <p>Among teenagers, the high frequency (HF) decreased between the 2^ndand 3^rdtertile (380 vs. 204 ms², p = 0.03) and a similar pattern was observed for the square root of the mean squared differences of successive R-R intervals (rMSSD) (43 vs. 30 ms, p = 0.005) after adjusting for confounders. In addition, the ratio low/high frequency (LF/HF) increased between the 2^ndand 3^rdtertile (2.3 vs. 3.0, p = 0.04). Among adults, the standard deviation of R-R intervals (SDNN) tended to decrease between the 1^stand 2^ndtertile (84 vs. 75 ms, p = 0.069) after adjusting for confounders. Furthermore, diastolic BP tended to increase between the 2^ndand 3^rdtertile (86 vs. 91 mm Hg, p = 0.09). No significant difference was observed in resting HR or pulse pressure (PP)</p> <p>Conclusions</p> <p>Mercury was associated with decreased HRV among French Polynesian teenagers while no significant association was observed with resting HR, BP, or PP among teenagers or adults</p

Oxaliplatin-DNA adduct formation in white blood cells of cancer patients

In this study, we investigated the kinetics of oxaliplatin-DNA adduct formation in white blood cells of cancer patients in relation to efficacy as well as oxaliplatin-associated neurotoxicity. Thirty-seven patients with various solid tumours received 130 mg m−2 oxaliplatin as a 2-h infusion. Oxaliplatin-DNA adduct levels were measured in the first cycle using adsorptive stripping voltammetry. Platinum concentrations were measured in ultrafiltrate and plasma using a validated flameless atomic absorption spectrometry method. DNA adduct levels showed a characteristic time course, but were not correlated to platinum pharmacokinetics and varied considerably among individuals. In patients showing tumour response, adduct levels after 24 and 48 h were significantly higher than in nonresponders. Oxaliplatin-induced neurotoxicity was more pronounced but was not significantly different in patients with high adduct levels. The potential of oxaliplatin-DNA adduct measurements as pharmacodynamic end point should be further investigated in future trials

Adult-Young Ratio, a Major Factor Regulating Social Behaviour of Young: A Horse Study

Adults play an important role in regulating the social behaviour of young individuals. However, a few pioneer studies suggest that, more than the mere presence of adults, their proportions in social groups affect the social development of young. Here, we hypothesized that aggression rates and social cohesion were correlated to adult-young ratios. Our biological model was naturally-formed groups of Przewalski horses, Equus f. przewalskii, varying in composition.We investigated the social interactions and spatial relationships of 12 one- and two-year-old Przewalski horses belonging to five families with adult-young ratios (AYR) ranging from 0.67 to 1.33. We found striking variations of aggression rates and spatial relationships related to the adult-young ratio: the lower this ratio, the more the young were aggressive, the more young and adults segregated and the tighter the young bonded to other young.This is the first study demonstrating a correlation between adult-young ratios and aggression rates and social cohesion of young individuals in a naturalistic setting. The increase of aggression and the emergence of social segregation in groups with lower proportions of adults could reflect a related decrease of the influence of adults as regulators of the behaviour of young. This social regulation has both theoretical and practical implications for understanding the modalities of the influence of adults during ontogeny and for recommending optimal settings, as for instance, for schooling or animal group management

Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients

This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830C>G) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6β-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6β-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6β-hydroxylation determination could help to determine the optimal dose of irinotecan

Theoretical and experimental activities on opacities for a good interpretation of seismic stellar probes

Opacity calculations are basic ingredients of stellar modelling. They play a crucial role in the interpretation of acoustic modes detected by SoHO, COROT and KEPLER. In this review we present our activities on both theoretical and experimental sides. We show new calculations of opacity spectra and comparisons between eight groups who produce opacity spectra calculations in the domain where experiments are scheduled. Real differences are noticed with real astrophysical consequences when one extends helioseismology to cluster studies of different compositions. Two cases are considered presently: (1) the solar radiative zone and (2) the beta Cephei envelops. We describe how our experiments are performed and new preliminary results on nickel obtained in the campaign 2010 at LULI 2000 at Polytechnique.Comment: 6 pages, 4 figures, invited talk at SOHO2

Epigenetic Factors in Cancer Risk: Effect of Chemical Carcinogens on Global DNA Methylation Pattern in Human TK6 Cells

In the current study, we assessed the global DNA methylation changes in human lymphoblastoid (TK6) cells in vitro in response to 5 direct and 10 indirect-acting genotoxic agents. TK6 cells were exposed to the selected agents for 24 h in the presence and/or absence of S9 metabolic mix. Liquid chromatography-mass spectrometry was used for quantitative profiling of 5-methyl-2′-deoxycytidine. The effect of exposure on 5-methyl-2′-deoxycytidine between control and exposed cultures was assessed by applying the marginal model with correlated residuals on % global DNA methylation data. We reported the induction of global DNA hypomethylation in TK6 cells in response to S9 metabolic mix, under the current experimental settings. Benzene, hydroquinone, styrene, carbon tetrachloride and trichloroethylene induced global DNA hypomethylation in TK6 cells. Furthermore, we showed that dose did not have an effect on global DNA methylation in TK6 cells. In conclusion we report changes in global DNA methylation as an early event in response to agents traditionally considered as genotoxic