Genetic variation and pesticide exposure influence blood DNA methylation signatures in females with early-stage Parkinson's disease.

Although sex, genetics, and exposures can individually influence risk for sporadic Parkinson's disease (PD), the joint contributions of these factors to the epigenetic etiology of PD have not been comprehensively assessed. Here, we profiled sex-stratified genome-wide blood DNAm patterns, SNP genotype, and pesticide exposure in agricultural workers (71 early-stage PD cases, 147 controls) and explored replication in three independent samples of varying demographics (n = 218, 222, and 872). Using a region-based approach, we found more associations of blood DNAm with PD in females (69 regions) than in males (2 regions, Δßadj| ≥0.03, padj ≤ 0.05). For 48 regions in females, models including genotype or genotype and pesticide exposure substantially improved in explaining interindividual variation in DNAm (padj ≤ 0.05), and accounting for these variables decreased the estimated effect of PD on DNAm. The results suggested that genotype, and to a lesser degree, genotype-exposure interactions contributed to variation in PD-associated DNAm. Our findings should be further explored in larger study populations and in experimental systems, preferably with precise measures of exposure.

Carryover effect of atrazine and its metabolite-from treated bovine spermatozoa to the embryo's transcriptome†.

Atrazine (ATZ) is an extensively used herbicide and ubiquitous environmental contaminant. ATZ and its metabolite, diaminochlorotriazine (DACT), cause several cellular and functional alterations in spermatozoa. We aimed to examine the effect of ATZ/DACT on spermatozoon DNA integrity, fertilization competence, embryonic development, and transcriptome profile of in vitro-produced embryos derived from fertilization with pre-exposed sperm. Bovine spermatozoa exposed to ATZ (0.1 or 1 µM) or DACT (1 or 10 µM) during in vitro capacitation were used for in vitro fertilization of untreated oocytes. Cleavage and blastocyst-formation rates were evaluated 42 h and 7 days postfertilization, respectively. The association between DNA fragmentation and apoptosis (annexin V kit) was determined. Fertilization competence of annexin-positive (AV+) and annexin-negative (AV-) spermatozoa was examined. Microarray analysis was performed for 7-day blastocysts. Intracytoplasmic sperm injection was performed with control (AV+, AV-) and DACT (AV+, AV-) spermatozoa. Cleavage rates did not differ between groups and blastocyst formation tended to be higher for AV- vs. AV+ in both control and DACT groups, suggesting that acrosome reaction, rather than DNA fragmentation, underlies the reduced cleavage. Transcriptomic analysis revealed 139 and 230 differentially expressed genes in blastocysts derived from ATZ- and DACT-exposed spermatozoa, respectively, relative to controls. Proteomic analysis shown differential expression of proteins in ATZ- or DACT-treated spermatozoa, in particular proteins related to cellular processes and biological pathways. Therefore, we assume that factors delivered by the spermatozoa, regardless of DNA fragmentation, are also involved. Overall, the current study reveals a deleterious carryover effect of ATZ/DACT from the spermatozoa to the developing embryo.

Mesoscopic engineering materials for visual detection and selective removal of copper ions from drinking and waste water sources.

The monitoring and removal of abundant heavy metals such as Cu ions are considerable global concerns because of their severe impact on the health of humans and other living organisms. To meet this global challenge, we engineered a novel mesoscopic capture protocol for the highly selective removal and visual monitoring of copper (Cu2+) ions from wide-ranging water sources. The capture hierarchy carriers featured three-dimensional, microsized MgO mesoarchitecture rectangular sheet-like mosaics that were randomly built in horizontal and vertical directions, uniformly arranged sheet faces, corners, and edges, smoothly quadrilateral surface coverage for strong Cu2+-to-ligand binding exposure, and multidiffusible pathways. The Cu2+ ion-selectively active captor surface design was engineered through the simple incorporation/encapsulation of a synthetic molecular chelation agent into hierarchical mesoporous MgO rectangular sheet platforms to produce a selective, visual mesoscopic captor (VMC). The nanoscale VMC dressing of MgO rectangular mosaic hierarchy by molecularly electron-enriched chelates with actively double core bindings of azo- and sulfonamide- groups and hydrophobic dodecyl tail showed potential to selectively trap and efficiently remove ultratrace Cu2+-ions with an extreme removal capability of ~233 mg/g from watery solutions, such as drinking water, hospital effluent, and food-processing wastewater at specific pH values. In addition to the Cu2+ ion-selective removal, the VMC design enabled the continuous visual monitoring of ultratrace Cu2+ ions (~3.35 × 10-8 M) as a consequence of strong chelate-to-Cu2+ binding events among all accumulated matrices in water sources. Our experimental recycle protocol provided evidence of reusability and recyclability of VMC (≥10 cycles). With our mesoscopic capture protocol, the VMC can be a promising candidate for the selective decontamination/removal and sensitive detection of hazardous inorganic pollutants from different water sources with indoor or outdoor applications.

Parkinson's disease polygenic risk score is not associated with impulse control disorders: A longitudinal study.

OBJECTIVE: To examine the relationship between a Parkinson's disease (PD) polygenic risk score (PRS) and impulse control disorders (ICDs) in PD. BACKGROUND: Genome wide association studies (GWAS) have brought forth a PRS associated with increased risk of PD and younger disease onset. ICDs are frequent adverse effects of dopaminergic drugs and are also more frequent in patients with younger disease onset. It is unknown whether ICDs and PD share genetic susceptibility. METHODS: We used data from a multicenter longitudinal cohort of PD patients with annual visits up to 6 years (DIG-PD). At each visit ICDs, defined as compulsive gambling, buying, eating, or sexual behavior were evaluated by movement disorders specialists. We genotyped DNAs using the Megachip assay (Illumina) and calculated a weighted PRS based on 90 SNPs associated with PD. We estimated the association between PRS and prevalence of ICDs at each visit using Poisson generalized estimating equations, adjusted for dopaminergic treatment and other known risk factors for ICDs. RESULTS: Of 403 patients, 185 developed ICDs. Patients with younger age at onset had a higher prevalence of ICDs (p < 0.001) as well as higher PRS values (p = 0.06). At baseline, there was no association between the PRS and ICDs (overall, p = 0.84). The prevalence of ICDs increased over time similarly across the quartiles of the PRS (overall, p = 0.88; DA users, p = 0.99). CONCLUSION: Despite younger disease onset being associated with both higher PRS and ICD prevalence, our findings are not in favor of common susceptibility genes for PD and ICDs.

Association of transcription factor 7-like 2 gene (TCF7L2) polymorphisms with stress-related hyperglycaemia (SRH) in intensive care and resulting outcomes: The READIAB study.

OBJECTIVE: The study aimed to evaluate the impact of the single nucleotide polymorphism (SNP) rs7903146 on the transcription factor 7-like 2 (TCF7L2) gene in stress-related hyperglycaemia (SRH), defined as blood glucose≥11mmol/L in at least two blood samples during the first 3 days in the intensive care unit (ICU), and on 28-day and 1-year mortality, and incidence of type 2 diabetes (T2D) at 6 months and 1 year in patients hospitalized in the ICU. METHODS: This prospective observational (non-interventional) multicentre READIAB study, carried out during 2012-2016 in six French ICUs, involved adult patients admitted to ICUs for at least two organ failures; patients admitted for<48h were excluded. During the 3-day ICU observational period, genetic testing, blood glucose values and insulin treatment were recorded. MAIN RESULTS: The association of rs7903146 with SRH was assessed using logistic regression models. Cox proportional hazards regression models assessed the associations between rs7903146 and mortality and between SRH and mortality, both at 28 days and 1 year. A total of 991 of the 1000 enrolled patients were included in the READIAB-G4 cohort, but 242 (24.4%) had preexisting diabetes and were excluded from the analyses. SRH occurred within the first 3 days in the ICU for one-third of the non-diabetes patients. The association between the rs7903146 polymorphism and SRH did not reach significance (P=0.078): OR(peroneTcopy): 1.24, 95% CI: 0.98-1.58. A significant association was found between rs7903146 and 28-day mortality after adjusting for severity scores (P=0.026), but was no longer significant at 1 year (P=0.61). At 28 days, mortality was increased in patients with SRH (HR: 2.09, 95% CI: 1.43-3.06; P<0.001), and remained significant at 1 year after adjusting for severity scores (HR: 1.73, 95% CI: 1.32-2.28; P<0.001). On admission, non-diabetes patients with SRH had a higher incidence of T2D at 6 months vs. those without SRH (16.0% vs. 7.6%, RR: 2.11, 95% CI: 1.07-4.20; P=0.030). At 1 year, these figures were 13.4% vs. 9.2%, RR: 1.45, 95% CI: 0.71-2.96; P=0.31). Moreover, the rs7903146 polymorphism was not significantly associated with T2D development at either 6 months (P=0.72) or 1 year (P=0.64). CONCLUSION: This study failed to demonstrate any significant association between rs7903146 and SRH. Nevertheless, the issue remains an important challenge, as SRH may be associated with increased rates of both mortality and T2D development.

Solving thermal issues in tensile-strained Ge microdisks.

We propose to use Ge-dielectric-metal stacking to allow one to address both thermal management with the metal as an efficient heat sink and tensile strain engineering with the buried dielectric as a stressor layer. This scheme is particularly useful for the development of Ge-based optical sources. We demonstrate experimentally the relevance of this approach by comparing the optical response of tensile-strained Ge microdisks with an Al heat sink or an oxide pedestal. Photoluminescence indicates a much reduced temperature rise in the microdisk (16 K with Al pedestal against 200 K with SiO2 pedestal under a 9 mW continuous wave optical pumping). An excellent agreement is found with finite element modeling of the temperature rise. This original stacking combining metal and dielectrics is promising for integrated photonics where thermal management is an issue.

Aflatoxin B1 impairs sperm quality and fertilization competence.

Aflatoxins are poisonous byproducts of the soilborne fungus Aspergillus, involved in the decomposition of plant materials. Aflatoxins can be found in various food products, such as maize, sorghum, millet, rice and wheat. AFB1 is the most toxic of these, classified as a carcinogen and mutagen for both humans and animals. AFB1 has been detected in human cord blood and placenta; however, its toxic effect on sperm is less known. The current study examines sperm responses associated with AFB1 exposure. These included acrosome integrity and function, mitochondrial polarity, DNA fragmentation, fertilization competence and early embryonic development. Spermatozoa were obtained from bull ejaculate and epididymis and capacitated in vitro for 4h with 0, 0.1, 1, 10 and 100µM AFB1. Following capacitation, acrosome reaction (AR) was induced by Ca2+ ionophore. The integrity and functionality of sperm were examined simultaneously by florescent staining. A Halosperm DNA fragmentation kit was used to evaluate DNA integrity. An in-vitro culture system was used to evaluate fertilization competence and blastocyst formation rate, using bovine oocytes. Findings indicate dose-responsive variation among compartments to AFB1 exposure. Sperm viability, expressed by integrity of the plasma membrane, was lower in sperm isolated from ejaculate or epididymis after culturing with AFB1. Exposure to AFB1 reduced the proportion of sperm from the epididymis tail undergoing acrosome reaction induced by Ca2+ ionophore. AFB1 impaired mitochondrial membrane potential (ΔYm) in sperm isolated from ejaculate and the epididymis tail. Exposing ejaculated sperm to AFB1 increased the proportion of sperm with fragmented DNA and reduced the proportion of embryos that cleaved to the 2- to 4-cell stage, 42h postfertilization, however, the proportion of embryos that developed to blastocysts, 7days postfertilization, did not differ among groups. The findings explore the harmful effects of AFB1 on sperm viability, ΔΨm and DNA integrity associated with fertility competence. We postulate that AFB1-induced fragmentation in paternal DNA might have a carryover effect on the quality of developing embryos. Further evaluation for the quality of blastocysts derived from sperm exposed to AFB1 is warranted.

Farming and incidence of motor neuron disease: French nationwide study.

BACKGROUND AND PURPOSE: The association of farming with motor neuron disease (MND) is unclear, with conflicting studies. We performed a French nationwide study of the association of farming with MND incidence, and compared findings with those for Parkinson's disease (PD), which has been shown to be more frequent in farmers. METHODS: We used the French national health insurance and hospital discharge databases to identify MND/PD incident cases. The Mutualité Sociale Agricole (MSA) guarantees health insurance for farmers and agricultural workers. We compared the incidence of MND (2010-2014) and PD (2011-2012) in MSA farmers, MSA workers and non-MSA affiliates, and estimated relative risks (RRs) and 95% confidence intervals (CIs). Probabilistic sensitivity analyses were used for external smoking adjustment. RESULTS: Analyses relied on 8931 MND (MSA, 9%) and 45 409 PD (MSA,11%) cases. There was a trend towards higher MND incidence in MSA farmers compared with non-MSA affiliates (RR,1.08; 95% CI,0.99-1.18) and MSA workers (RR, 1.13; 95% CI, 0.97-1.31) that strengthened after smoking adjustment (if associated with MND). PD incidence was higher in MSA farmers than non-MSA affiliates (RR, 1.13; 95% CI, 1.08-1.17) and MSA workers (RR, 1.10; 95% CI, 1.02-1.18); this association remained after smoking adjustment (RR, 1.09; 95% CI, 1.05-1.14). CONCLUSIONS: This French nationwide study suggested an association between farming and MND, and confirmed higher PD incidence in farmers in France, a country with high pesticide use.

Knee osteoarthritis, degenerative meniscal lesion and osteonecrosis of the knee: Can a simple gait test direct us to a better clinical diagnosis.

INTRODUCTION: The purpose of the current study was to compare the gait patterns in patients with three differing knee pathologies - knee osteoarthritis (OA), degenerative meniscal lesion (DML) and spontaneous osteonecrosis of the knee (SONK) and a group of healthy controls. HYPOTHESIS: A simple gait test will detect differences between different knee pathologies. MATERIAL AND METHODS: Forty-seven patients with bilateral knee OA, 47 patients with DML, 28 patients with SONK and 27 healthy controls were included in this analysis. Patients underwent a spatiotemporal gait assessment and were asked to complete the Western Ontario and McMaster University (WOMAC) Index and the Short-Form (SF)-36 Health Survey. ANOVA tests, followed by Bonferroni multiple comparison tests and the Chi2 tests were performed for continuous and categorical variables, respectively. RESULTS: Significant differences were found for all gait measures and clinical questionnaires between healthy controls and all knee conditions. Patients with SONK differed from patients with bilateral knee OA and DML in all gait measures and clinical questionnaires, except for WOMAC subscales. There were no significant differences between patients with bilateral knee OA and patients with DML. Symmetry was also examined and revealed asymmetry in some gait parameters in patients with SONK and DML. DISCUSSION: Based on the differences in gait parameters that were found in the current study, adding an objective functional spatiotemporal gait test may assist in the diagnostic process of knee pathologies. TYPE OF STUDY: Case Control study Level III.

Prodromal symptoms of Parkinson's disease: Implications for epidemiological studies of disease etiology.

In recent years, there has been a major shift in our understanding of the course of Parkinson's disease (PD) from a disease of the brain to a disease of long latency, characterized by the progressive emergence of multiple non-motor symptoms, including hyposmia, constipation, depression, anxiety, rapid eye movement (REM) sleep behavior disorder and excessive daytime sleepiness, as well as subtle motor signs, before the typical motor signs appear. Epidemiological studies have made major contributions by allowing better characterization of subsequent PD risk in relation to non-motor symptoms. Such findings have profound implications for the conduct of epidemiological studies examining risk and protective factors in PD, and the interpretation of their findings. Given the length of the prodromal period, reverse causation in particular is a major concern with many reported associations. One striking feature of PD etiology, compared with other diseases, is the presence of numerous inverse associations. If these associations are truly causal, they would have major implications for disease prevention and for slowing disease progression. However, whether these associations are truly causal remains to be demonstrated in future studies. Experimental studies play an important role by offering a better understanding of the underlying mechanisms. Well-designed epidemiological studies using innovative approaches will also be key in elucidating whether these intriguing associations are causal or a consequence of reverse causation.

Epidemiology of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's. PD is considered a multifactorial disorder that results, in most cases, from the combined effects of multiple risk and protective factors, including genetic and environmental ones. This review discusses some of the methodological challenges involved in assessing the descriptive, prognostic and etiological epidemiological studies of PD, and summarizes their main findings.

Characterizing the inhibitory action of zinc oxide nanoparticles on allergic-type mast cell activation.

The development of nanoparticles (NPs) for commercial products is undergoing a dramatic expansion. Many sunscreens and cosmetics now use zinc oxide (ZnO) or titania (TiO2) NPs, which are effective ultraviolet (UV) filters. Zinc oxide topical creams are also used in mild anti-inflammatory treatments. In this study we evaluated the effect of size and dispersion state of ZnO and TiO2 NPs, compared to "bulk" ZnO, on mast cell degranulation and viability. ZnO and TiO2 NPs were characterized using dynamic light scattering and disc centrifugation. Rat basophilic leukaemia (RBL-2H3) cells and primary mouse bone marrow-derived mast cells (BMMCs) were exposed to ZnO and TiO2 NPs of different sizes (25-200 nm) and surface coatings at concentrations from 1 to 200 µg/mL. The effect of NPs on immunoglobulin E (IgE)-dependent mast cell degranulation was assessed by measuring release of both ß-hexosaminidase and histamine via colorimetric and ELISA assays. The intracellular level of Zn(2+) and Ca(2+) ions were measured using zinquin ethyl ester and Fluo-4 AM fluorescence probes, respectively. Cellular viability was determined using the soluble tetrazolium-based MTS colorimetric assay. Exposure of RBL-2H3 and primary mouse BMMC to ZnO NPs markedly inhibited both histamine and ß-hexosaminidase release. This effect was both particle size and dispersion dependent. In contrast, TiO2 NPs did not inhibit the allergic response. These effects were independent of cytotoxicity, which was observed only at high concentrations of ZnO NPs, and was not observed for TiO2 NPs. The inhibitory effects of ZnO NPs on mast cells were inversely proportional to particle size and dispersion status, and thus these NPs may have greater potential than "bulk" zinc in the inhibition of allergic responses.

Excess non-psychiatric hospitalizations among employees with mental disorders: a 10-year prospective study of the GAZEL cohort.

OBJECTIVE: To examine whether non-psychiatric hospitalizations rates were higher in those with mental disorders. METHOD: In a cohort of 15,811 employees, aged 35-50 years in 1989, mental disorder status was defined from 1989 to 2000. Hospitalizations for all-causes, myocardial infarction (MI), stroke, and cancer, were recorded yearly from 2001 to 2011. Negative binomial regression models were used to estimate hospitalization rates over the follow-up. RESULTS: After controlling for baseline sociodemographic factors, health-related behaviors, self-rated health, and self-reported medical conditions, participants with a mental disorder had significantly higher rates of all-cause hospitalization [incidence rate ratio, IRR=1.20 (95%, 1.14-1.26)], as well as hospitalization due to MI [IRR=1.44 (95%, 1.12-1.85)]. For stroke, the IRR did not reach statistical significance [IRR=1.37 (95%, 0.95-1.99)] and there was no association with cancer [IRR=1.01 (95%, 0.86-1.19)]. A similar trend was observed when mental disorders groups were considered (no mental disorder, depressive disorder, mental disorders due to psychoactive substance use, other mental disorders, mixed mental disorders, and severe mental disorder). CONCLUSION: In this prospective cohort of employees with stable employment as well as universal access to healthcare, we found participants with mental disorders to have higher rates of non-psychiatric hospitalizations.

Novel classification of knee osteoarthritis severity based on spatiotemporal gait analysis.

OBJECTIVE: To describe a novel classification method for knee osteoarthritis (OA) based on spatiotemporal gait analysis. METHODS: Gait analysis was initially performed on 2911 knee OA patients. Females and males were analyzed separately because of the influence of body height on spatiotemporal parameters. The analysis included the three stages of clustering, classification and clinical validation. Clustering of gait analysis to four groups was applied using the kmeans method. Two-thirds of the patients were used to create a simplified classification tree algorithm, and the model's accuracy was validated by the remaining one-third. Clinical validation of the classification method was done by the short form 36 Health Survey (SF-36) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaires. RESULTS: The clustering algorithm divided the data into four groups according to severity of gait difficulties. The classification tree algorithm used stride length and cadence as predicting variables for classification. The correct classification accuracy was 89.5%, and 90.8% for females and males, respectively. Clinical data and number of total joint replacements correlated well with severity group assignment. For example, the percentages of total knee replacement (TKR) within 1 year after gait analysis for females were 1.4%, 2.8%, 4.1% and 8.2% for knee OA gait grades 1-4, respectively. Radiographic grading by Kellgren and Lawrence was found to be associated with the gait analysis grading system. CONCLUSIONS: Spatiotemporal gait analysis objectively classifies patients with knee OA according to disease severity. That method correlates with radiographic evaluation, the level of pain, function, number of TKR.

Role of adenosine receptors in the anti-nociceptive effects of allopurinol in mice.

BACKGROUND: Inhibition of xanthine oxidase by allopurinol increases hypoxanthine and xanthine, which are converted to purines, including the inhibitory neuromodulator adenosine. AIM: We aimed to investigate the antinociceptive effects of allopurinol in thermal and chemical pain models in mice and to evaluate its possible antinociceptive mechanism by using selective adenosine receptors A1, A2A antagonists in mice. MATERIALS AND METHODS: Sixty four adult male mice were used. Mice received an intraperitoneal injection of vehicle or allopurinol (50-200 mg/kg). Assessment of antinociceptive effects and locomotor activity were performed in three models of acute pain; a thermal model and two chemical model. RESULTS: Allopurinol presented dose-dependent antinociceptive effects in all models with no obvious motor deficits. The opioid antagonist naloxone did not reverse these effects. The selective A1 antagonist, DPCPX, and the selective A2A antagonist, ZM241385, completely prevented allopurinol-induced antinociception. CONCLUSIONS: Allopurinol-induced antinociception may be related to adenosine accumulation. Allopurinol seems to be well tolerated with no locomotor side effects at high doses and it may be useful to treat pain syndromes.

Effects of a customized biomechanical therapy on patients with medial compartment knee osteoarthritis.

OBJECTIVE: Previous studies have shown that a customized biomechanical therapy can improve symptoms of knee osteoarthritis. These studies were small and did not compare the improvements across gender, age, BMI or initial severity of knee osteoarthritis. The purpose of this study was to evaluate the effect of new biomechanical therapy on the pain, function and quality of life of patients with medial compartment knee osteoarthritis. METHODS: Six hundred and fifty-four patients with medial compartment knee osteoarthritis were examined before and after 12 weeks of a personalized biomechanical therapy (AposTherapy). Patients were evaluated using the Western Ontario and McMaster Osteoarthritis (WOMAC) Index and SF-36 Health Survey. RESULTS: After 12 weeks of treatment, the WOMAC-pain and WOMAC-function subscales were significantly lower compared to baseline (both P≤0.001). All eight categories of the SF-36 health survey significantly improved after treatment (all P≤0.001). Females and younger patients showed greater improvements with therapy. CONCLUSIONS: Twelve weeks of a customized biomechanical therapy (AposTherapy) improved symptoms of patients with medial compartment knee osteoarthritis. We recommend that this therapy will be integrated in the management of knee osteoarthritis.

Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers.

OBJECTIVE: Glucocerebrosidase (GBA) gene mutations represent a strong risk factor for Parkinson disease (PD). PD penetrance in GBA mutation carriers, which represents a key issue for genetic counseling, especially for relatives of patients with Gaucher disease (GD), is unknown. Our objective was to estimate PD penetrance in a familial study of GBA mutation carriers. METHODS: Probands with familial PD were recruited through the French Parkinson Disease Genetic Study Group. All GBA exons were sequenced in probands and their relatives. To estimate the age-specific cumulative PD risk (i.e., penetrance) in GBA mutation carriers, we used the proband's phenotype exclusion likelihood method and corrected for selection of familial cases by considering the status of one affected relative per family as unknown. RESULTS: Of 525 probands with familial PD, 24 (4.6%) were GBA mutation carriers. Of their 256 relatives, 43 (16.8%) had PD and 26 of 32 affected relatives tested for GBA mutations were mutation carriers; 213 relatives did not have PD and 31 of 71 of unaffected relatives tested for GBA mutations were mutation carriers. Under a dominant model, penetrance was estimated as 7.6%, 13.7%, 21.4%, and 29.7% at 50, 60, 70, and 80 years, respectively. There was no significant difference in penetrance at 70 years between N370S carriers, L444P carriers, and carriers of rarer mutations. CONCLUSION: The relatively high penetrance estimate in GBA carriers obtained in this study should lead to consideration of GBA as a dominant causal gene with reduced penetrance and should be taken into account for genetic counseling in relatives of patients with GD and patients with GBA-associated PD.

[Parkinson's disease: Is there a strong environmental contribution?]. / Maladie de Parkinson: une maladie à forte composante environnementale ?

Parkinson's disease (PD) is the most common cause of the parkinsonian syndromes and the most frequent neurodegenerative disease after Alzheimer's disease. Only a minority of PD cases is due to a single factor, in particular a genetic mutation. In the large majority of cases, it is considered that PD is a complex or multifactorial disease that results from the effect of multiple risk or protective factors, either genetic or environmental, and, possibly, from their interaction. Epidemiological studies, through a variety of approaches, have brought important evidence in favour of the contribution of environmental factors to the etiology of PD. In this review, we will present current evidence by focusing on specific illustrative examples.

Case-control study of writer's cramp.

Task-specific focal dystonias are thought to be due to a combination of individual vulnerability and environmental factors. There are no case-control studies of risk factors for writer's cramp. We undertook a case-control study of 104 consecutive patients and matched controls to identify risk factors for the condition. We collected detailed data on medical history and writing history as part of hobbies or occupation. Cases had a college or university degree more frequently than controls [OR = 4.6 (1.3-20.5), P = 0.01]. The risk of writer's cramp increased with the time spent writing each day (P-trend = 0.001) and was also associated with an abrupt increase in the writing time during the year before onset (OR = 5.7, 95% CI = 1.3-33.9, P = 0.02). Head trauma with loss of consciousness [OR = 3.5 (1.0-15.7), P = 0.05] and myopia [OR = 4.1 (1.7-12.0), P = 0.0009] were both associated with the condition but it was not significantly associated with peripheral trauma, left-handedness, constrained writing, writing in stressful situations or the choice of writing tool. The dose-effect relationship between writer's cramp and the time spent handwriting each day, and the additional burden of acute triggers such as an abrupt increase in the writing time in the year before onset, point to a disruptive phenomenon in predisposed subjects. Homeostatic regulation of cortical plasticity may be overwhelmed, resulting in dystonia.