Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.

Hereditary sensory neuropathy type I (HSN I) is an axonal form of autosomal-dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Unrecognized, these can result in delayed wound healing and osteomyelitis, necessitating distal amputations. To elucidate the genetic basis of an HSN I subtype in a family in which mutations in the few known HSN I genes had been excluded, we employed massive parallel exon sequencing of the 14.3 Mb disease interval on chromosome 14q. We detected a missense mutation (c.1065C>A, p.Asn355Lys) in atlastin-1 (ATL1), a gene that is known to be mutated in early-onset hereditary spastic paraplegia SPG3A and that encodes the large dynamin-related GTPase atlastin-1. The mutant protein exhibited reduced GTPase activity and prominently disrupted ER network morphology when expressed in COS7 cells, strongly supporting pathogenicity. An expanded screen in 115 additional HSN I patients identified two further dominant ATL1 mutations (c.196G>C [p.Glu66Gln] and c.976 delG [p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders.

Polyurethane Composites Recycling with Styrene-Acrylonitrile and Calcium Carbonate Recovery.

The glycolysis process of flexible polyurethane foams containing styrene-acrylonitrile and calcium carbonate as fillers was explored in detail. The use of DABCO as a catalyst allowed us to reduce the catalyst concentration and the polyurethane-to-glycol mass ratio to 0.1% and 1:1, respectively. The glycolysis process allowed us to obtain a high-purity polyol (99%), which can totally replace raw polyols in the synthesis of new flexible polyurethane foams, maintaining the standard mechanical properties of the original one and modifying the ratio of isocyanates employed to correct the closed cell structure caused by the impurities present in the recovered polyol. This isocyanate mixture was also optimized, resulting in a ratio of 30 and 70% of the isocyanates TDI80 and TDI65, respectively. Additionally, the fillers incorporated in the glycolyzed foams were recovered. Both recovered fillers, styrene-acrylonitrile and calcium carbonate, were fully characterized, showing a quality very similar to that of commercial compounds. Finally, the replacement of commercial fillers by the recovered ones in the synthesis of new polyurethane foams was studied, demonstrating the feasibility of using them in the synthesis of new foams without significantly altering their properties.

Anterior shin muscles CMAP measurements: Normal limits of symmetry and intra- and interobserver reliability.

OBJECTIVE: The normal limits of symmetry for the compound muscle action potential of the shin muscles (CMAPshin) have not been determined yet. The goal of this study is to provide extensive data on the limits of symmetry and the reliability of CMAPshin. METHODS: The study was conducted in normal healthy males and females. All subjects underwent CMAPshin measurements bilaterally. The median percent differences of right/left amplitude/area, with range of these measurements, were calculated. In addition, the intra- and interobserver reliability was examined in a separate population. RESULTS: The study group consisted of 58 healthy individuals. The median percent right/left difference for amplitude and area were respectively 7.2% (range 0-23.6%) and 5.4% (range 0.7-25.6%). Right/left difference of the amplitude/area of the CMAPshin greater than 24%/26% respectively can be considered as pathological. The Pearson correlation coefficients (r) for the intra-observer reliability amplitude/area are 0.905/0.882 and for the inter-observer reliability are 0.968/0.981. CONCLUSIONS: The results confirm symmetry and good intra- and interobserver reliability in CMAPshin measurements. SIGNIFICANCE: CMAPshin can be used in practice to estimate axonal loss in case of a foot drop. Data studies examining symmetry of CMAPshin can facilitate in the clinical interpretation of these nerve conduction studies.

Reproducibility and relative validity of a semi-quantitative food frequency questionnaire designed for assessing the intake of dioxin-like contaminants.

OBJECTIVE: The aim of this study was to assess the reproducibility and relative validity of a food frequency questionnaire (FFQ) designed to estimate the intake of dioxin-like contaminants. METHOD: In total, 180 adults (50-65 years) completed the FFQ twice and 157 of them kept four times a 2-day estimated dietary record (EDR) spread over a year. RESULTS: Spearman rank correlation coefficients varied between 0.58 and 0.67 for reproducibility, versus between 0.28 and 0.46 for validity for the different food groups under study. Exact agreement within quartiles was between 34% and 39%, only between 3% and 9% was grossly misclassified. The weighed kappa statistics indicated fair agreement between the two methods (0.29 for the total diet). The correction factors used had a relevant influence on the absolute estimated intake. CONCLUSION: The FFQ presented here is a valuable tool for ranking individuals in the study population on the basis of estimated intake of dioxin-like contaminants. However, absolute intakes should be estimated without correction factors and interpreted with caution.

Probabilistic intake assessment of multiple compounds as a tool to quantify the nutritional-toxicological conflict related to seafood consumption.

Seafood represents a natural source of valuable nutrients (e.g., long chain omega-3 poly-unsaturated fatty acids (LC n-3 PUFAs), vitamin D, and iodine), but the favourable health perception is troubled by the presence of contaminants (e.g., PCBs, dioxin-like compounds, and (methyl) mercury (MeHg)). This dualism forms the basis for an important public health conflict. The objective of this study was to calculate and evaluate the simultaneous intake of multiple beneficial and harmful compounds (LC n-3 PUFAs, vitamin D, iodine, (Me)Hg, PCBs, and dioxin-like compounds) via seafood consumption in Belgium. A methodology and a software module were developed for executing probabilistic assessments of the simultaneous intake of multiple compounds leading to better insight in the problematic nature of food items involving both health benefits and risks. The simulations concerning seafood consumption in Belgium predicted that, as far as only seafood consumption is concerned, the considered populations do not reach a sufficiently high intake for the three nutrients considered (LC n-3 PUFAs, vitamin D, and iodine). Regarding the contaminants, (Me)Hg contamination of seafood on the Belgian market does not seem to be an issue of major toxicological concern. In contrast, for dioxin-like compounds the tolerable daily intake is reached by people with high seafood consumption.

Dietary exposure to dioxin-like compounds in three age groups: results from the Flemish environment and health study.

Lipophilic contaminants are present in the environment and bioaccumulate in the food chain. Therefore, their intake via animal fat of various sources was assessed for three age groups of the Flemish population, participating in a large biomonitoring program of the Flemish government. In total, 1636 adolescents (14-15 years), 1186 mothers (18-44 years), and 1586 adults (50-65 years) participated in the study and completed a semi quantitative food frequency questionnaire. Individual consumption data were combined, via a so-called simple distribution approach, with recent data on polychlorinated dibenzo-p-dioxins/furans and dioxin-like polychlorinated biphenyls, measured via the chemical-activated luciferase gene expression (CALUX) bio-assay in food items available on the Flemish market. The median (95th percentile) estimated intakes of dioxin-like contaminants were 2.24 (4.61), 2.09 (4.26), and 1.74 (3.53) pg CALUX-TEQ kg(-1) bw d(-1) for, respectively adolescents, mothers and adults. These data are in the same range as those found in other European studies. The CALUX-TEQ results of respectively 59.8%, 53.7% and 36.2% of the adolescent, mother and adult population exceed the tolerable weekly intake (TWI) of 14 pg WHO-TEQ kg(-1) bw w(-1), as derived by the Scientific Committee on Food [Scientific Committee on Food, 2001. Opinion of the Scientific Committee on Food on the Risk Assessment of Dioxins and Dioxin-like PCBs in Food, CS/CNTM/DIOXIN/20 final Brussels, Belgium]. The main contributors of dioxin-like substances are fish and seafood (25-43% of the total intake), added fats (22-25% of the total intake) and dairy products (17-20% of the total intake).

Theoretical simulation and experimental validation of inverse quasi-one-dimensional steady and unsteady glottal flow models.

In physical modeling of phonation, the pressure drop along the glottal constriction is classically assessed with the glottal geometry and the subglottal pressure as known input parameters. Application of physical modeling to study phonation abnormalities and pathologies requires input parameters related to in vivo measurable quantities commonly corresponding to the physical model output parameters. Therefore, the current research presents the inversion of some popular simplified flow models in order to estimate the subglottal pressure, the glottal constriction area, or the separation coefficient inherent to the simplified flow modeling for steady and unsteady flow conditions. The inverse models are firstly validated against direct simulations and secondly against in vitro measurements performed for different configurations of rigid vocal fold replicas mounted in a suitable experimental setup. The influence of the pressure corrections related to viscosity and flow unsteadiness on the flow modeling is quantified. The inversion of one-dimensional glottal flow models including the major viscous effects can predict the main flow quantities with respect to the in vitro measurements. However, the inverse model accuracy is strongly dependent on the pertinence of the direct flow modeling. The choice of the separation coefficient is preponderant to obtain pressure predictions relevant to the experimental data.

Low levels of Human Cytomegalovirus Infection in Glioblastoma multiforme associates with patient survival; -a case-control study.

BACKGROUND: Glioblastoma multiforme (GBM) represent the most aggressive brain tumor with a median overall survival of about 12-15 months. Over 90% of GBM tumors have recently been shown to be infected with human cytomegalovirus (HCMV). In this case-control study, we evaluated whether there was an association between the grade of HCMV infection and long-term survival (> 18 months) in GBM patients. MATERIAL AND METHODS: Brain tumor tissue sections from consecutive GBMs patients who survived more than 18 months (n = 40), and an equal number of GBM patients, matched to date of diagnosis and surgery, operated at Karolinska University Hospital in 2000-2005 were selected. HCMV infection grade was determined by estimation of the number of HCMV positive cells (scored negative or grade 1-4) in tumor tissue specimens. Using Chi-Square test and logistic regression analysis, we analyzed whether there was an association between long-term survival and HCMV low-grade infection or other clinical parameters known to be associated with prolonged survival of GBM patients; age under 50 years, radical surgery or low recursive partition analysis (RPA) subclass. RESULTS: HCMV infection was detected in tumor samples from 79 of 80 patients (99%). Among patients surviving > 18 months, HCMV infection grade 1 in the GBM tumor was predominant. A low grade HCMV infection was found in 19 patients, of these 16 survived > 18 months. Thus, 16 of 40 (40%) GBM patients who lived > 18 months had low-grade HCMV infection while only 3 of 40 (8%) GBM patients who lived < 18 months did (p .0006, Chi-Square test). Multiple logistic regression analyses yielded an odds ratio estimate of 6.604 with 95% confidence interval (1.36-32.1) (p .019) for low grade HCMV after adjustment for RPA class III and IV, radical surgery, age and gamma knife treatment. CONCLUSION: In conclusion, we found that low-grade HCMV infection was strongly associated with long-term survival in GBM patients.

The relation between the estimated dietary intake of PCDD/Fs and levels in blood in a Flemish population (50-65 years).

Dioxin-like activity was measured in the serum of 1425 Flemish men and women via the CALUX assay. The adults, aged between 50 and 65 years, participated in a large biomonitoring program, executed by the Flemish Center of Expertise for Environment and Health between 2002 and 2006. Within the context of this biomonitoring program also dietary intake of dioxin-like contaminants was assessed through a food frequency questionnaire. The relation between the estimated dietary intake and the dioxin-like activity in serum was evaluated using multivariate analyses: a logistic model was performed on the total population, while a linear regression analysis was done on the subsample with quantifiable dioxin activity levels in serum. Region, gender, age, BMI, smoking status, as well as dietary habits were entered in the model, with dioxin level as an outcome estimate. Both the logistic and linear model confirmed the contribution of dietary intake to the dioxin activity measured in serum. Also BMI and region were found to be associated with dioxin activity levels.

Fish consumption is a safe solution to increase the intake of long-chain n-3 fatty acids.

OBJECTIVES: Dietary intake of long-chain (LC) n-3 PUFA in developed countries is low compared with recommendations. Fish is naturally rich in LC n-3 PUFA, but is also a dietary source of heavy metals and organic pollutants. We investigated whether the recommendation for LC n-3 PUFA could be reached through fish consumption, without exceeding the provisional tolerable weekly intake of methylmercury (MeHg) and the tolerable weekly intake (TWI) of dioxin-like compounds. Also, the contribution of margarines enriched with LC n-3 PUFA was assessed. DESIGN: Published nutrient and contaminant data were used in a probabilistic model to calculate the simultaneous nutrient and contaminant intake for different fish consumption scenarios. RESULTS: The Belgian recommendation for EPA + DHA (0.3% of total energy intake) can be reached by consuming fatty fish a minimum of twice a week, or by varying between lean and fatty fish a minimum of three times a week. At this fish consumption level, MeHg intake is not an issue of toxicological concern. The intake of dioxin-like compounds approximates the TWI when consuming fatty fish more than twice a week, this being a potential toxicological risk because other food items also contribute to the weekly intake of dioxin-like compounds. Use of margarine enriched with LC n-3 PUFA can help to increase LC n-3 intake, on average by 159 mg/d. CONCLUSIONS: Combination of regular fish consumption (twice a week) with important contribution of fatty fish species, in combination with regular consumption of margarine enriched with EPA + DHA, can be advised to achieve the recommendation for LC n-3 intake.

Probabilistic intake assessment of polybrominated diphenyl ethers and omega-3 fatty acids through fish consumption.

Food intake is one of the principal exposure routes of polybrominated diphenyl ethers (PBDEs) in humans. This study focuses on fish consumption as a PBDE exposure route. A probabilistic intake assessment of PBDEs and healthy long chain omega-3 PUFAs (LC n-3 PUFAs) was conducted for Belgian fish consumers in order to study the balance of the intake of LC n-3 PUFAs and PBDEs. Based on the observed fish consumption level in the sample, the mean intake of brominated diphenyl ether (BDE)-28, 47, 99, 100, 153, and 154 via fish was 0.85 ng/kg body weight (bw)/day and the intake of LC n-3 PUFAs was 3.45 mg/kg bw/day, being low compared to the recommendations. Scenario analyses showed that consuming 150 g salmon twice a week is advisable to achieve the recommended LC n-3 PUFA intake with a rather low PBDE intake. When replacing 150 g salmon by herring, the PBDE intake is higher without an increase in LC n-3 PUFAs. In contrast, the combination of cod and salmon leads to a similar PBDE intake compared to twice a week salmon, but to a lower LC n-3 PUFA intake. In conclusion, the methodology presented in the paper allows balancing benefits and risks related to fish consumption.

Exposure of maintenance workers to dioxin-like contaminants during the temporary shutdown of a municipal domestic solid waste incinerator: a case series.

To evaluate workers' exposure to dioxin-like substances (such as polychlorinated dibenzo-p-dioxins, dibenzofurans, and polychlorinated biphenyls), the authors used a chemical-activated luciferase gene expression (CALUX) assay to determine serum dioxin-like activity in five workers before and after two different cleaning-up activities inside a municipal domestic solid-waste incinerator. The workers' mean serum concentration of dioxin-like substances before the first cleaning operation, shown as a weighted value of toxic equivalents (or TEQs) according to the CALUX test, was 17.2 pg CALUX TEQ/g fat (range = 12-22), which is comparable with concentrations found in similarly aged men in a Flemish environmental health pilot study. After cleaning work, the workers' mean serum concentration was 28.5 pg CALUX TEQ/g fat (range = 18-31). At the second plant stoppage, the workers' mean dioxin-like activity was 15.4 pg CALUX TEQ/g fat (range = 12-21) before and 16.4 pg CALUX TEQ/g fat (range = < 10-32, where 10 pg is the limit of determination) after the cleaning operation. These results indicate that workers may be exposed to dioxin-like substances during their performance of cleaning operations in a municipal domestic solid-waste incinerator.

Review and meta-analysis of risk estimates for prostate cancer in pesticide manufacturing workers.

PURPOSE: The purpose of the present paper is to review cohort studies that examined the occurrence of prostate cancer in pesticide manufacturing workers in order to undertake a qualitative and quantitative evaluation of the risk as well as to assess the level of epidemiological evidence for each class of chemical compounds. METHODS: Following a systematic literature search, relative risk (RR) estimates for prostate cancer were extracted from 18 studies published between 1984 and 2004. All studies were summarised and evaluated for homogeneity and publication bias. As no significant heterogeneity was detected, combined RR estimators were calculated using a fixed effect model. Meta-analyses were performed both on the whole set of data and for each chemical class separately. RESULTS: The meta-rate ratio estimate for all studies was 1.28 [95% confidence interval (CI) 1.05-1.58]. After stratification by specific chemical class, consistent increases in the risk of prostate cancer were found in all groups but statistical significance was found only for accidental or non-accidental exposure to phenoxy herbicides contaminated with dioxins and furans. There was no obvious indication of publication bias. CONCLUSION: The overall meta-analysis provides additional quantitative evidence consistent with prior reviews focusing on other groups exposed to pesticides (farmers, pesticide applicators). The results again point to occupational exposure to pesticides as a possible risk factor for prostate cancer but the question of causality remains unanswered. Epidemiological evidence did not allow identifying a specific pesticide or chemical class that would be responsible for the increased risk but the strongest evidence comes from workers exposed to phenoxy herbicides possibly in relation with dioxin and/or furan contamination.