Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.

Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.

From brain to spinal cord: neuromodulation by direct current stimulation and its promising effects as a treatment option for restless legs syndrome.

Neuromodulation is a fast-growing field of mostly non-invasive therapies, which includes spinal cord stimulation (SCS), transcranial direct current stimulation (tDCS), vagal nerve stimulation (VNS), peripheral nerve stimulation, transcranial magnetic stimulation (TMS) and transcutaneous spinal direct current stimulation (tsDCS). This narrative review offers an overview of the therapy options, especially of tDCS and tsDCS for chronic pain and spinal cord injury. Finally, we discuss the potential of tsDCS in Restless Legs Syndrome as a promising non-invasive, alternative therapy to medication therapy.

Case report: An OSAS patient with comorbid RLS/PLMS - a closer look at the causes of PAP intolerance.

Since 2017, hypoglossal nerve stimulation has been included in the S3-guidelines on restorative sleep/sleep disorders as an alternative treatment for patients with obstructive sleep related breathing disorders who cannot tolerate conventional PAP-therapy. Under certain conditions, some of these patients have the option to have a tongue pacemaker implanted during a surgical procedure to regain a restful night's sleep. However, in some cases it does not solve the problem. In this case report, we present a patient who continued to have restless sleep despite implantation of a hypoglossus nerve stimulator. We provide a closer look at the underlying causes of PAP intolerance and emphasize the importance of a combined pneumological and neurological approach to sleep medicine in sleep-specific therapy evaluation.

Prevalence and occupational exposure to zoonotic diseases in high-risk populations in the Free State Province, South Africa.

Introduction: Zoonotic diseases are responsible for 2.5 billion human cases globally and approximately 2.7 million deaths annually. Surveillance of animal handlers and livestock for zoonotic pathogens contributes to understanding the true disease burden and risk factors within a community. This study investigated the prevalence of selected zoonoses in cattle, farm workers and occupational exposure to endemic zoonotic diseases and their associated risk factors. Methods: Sputum samples from farmworkers were screened for Mycobacterium bovis. Blood specimens from farmworkers and archived sera were tested for serological evidence of Brucella sp., hantaviruses, and Leptospira sp. Communal and commercial cattle herds were tested for bovine tuberculosis and brucellosis. Results: Mycobacterium bovis was not isolated from human samples. A total of 327 human sera were screened, and 35/327 (10.7%) were Brucella sp. IgG positive, 17/327 (5.2%) Leptospira sp. IgM positive, and 38/327 (11.6%) hantavirus IgG positive (95% CI). A higher proportion of Brucella sp. IgG-positive samples were detected among veterinarians (value of p = 0.0006). Additionally, two cattle from a commercial dairy farm were bovine tuberculosis (bTB) positive using the bTB skin test and confirmatory interferon-gamma assay. A higher percentage of confirmed brucellosis-positive animals were from communal herds (8.7%) compared to commercial herds (1.1%). Discussion: These findings highlight the brucellosis and M. bovis prevalence in commercial and communal herds, the zoonotic disease risk in commercial and subsistence farming in developing countries, and the occupational and rural exposure risk to zoonotic pathogens.

ExomeChip-based rare variant association study in restless legs syndrome.

Restless legs syndrome (RLS) is a common sleep-related movement disorder in populations of European descent and disease risk is strongly influenced by genetic factors. Common variants have been assessed extensively in several genome-wide association studies, but the contribution of rarer genetic variation has not been investigated at this scale. We therefore genotyped a case-control set of 9246 individuals for mainly rare and low frequency exonic variants using the Illumina ExomeChip. However, standard single variant and gene-level association tests were negative. This does not preclude a role of rare variants in RLS, but is likely due to the small sample size and the limited selection of rare genetic variation captured on the array. Therefore, exome or whole genome sequencing should be performed rather than increasing the sample size of ExomeChip studies in order to identify rare risk variants for RLS.

The Artificial Bowel Sphincter in the Treatment of Fecal Incontinence, Long-term Complications.

BACKGROUND: Fecal incontinence is a common and debilitating condition, of which the prevalence increases with age. Several medical and minimally invasive treatment modalities are available. However, for patients with greater sphincter defects, these treatments are often not sufficient. For these patients, the artificial bowel sphincter could be an alternative to colostomy. The artificial bowel sphincter has proven to be effective in the short term. Less is known whether the benefits sustain over time. OBJECTIVE: The aim of this study was to assess the long-term outcome of the artificial bowel sphincter in patients with refractory fecal incontinence. DESIGN: A retrospective record review was conducted in conjunction with questionnaires. SETTING: This study was conducted in a tertiary hospital setting. MAIN OUTCOME MEASURES: The primary end point was any complication. The secondary end point was fecal loss. PATIENTS: The patients included were adults experiencing severe fecal incontinence treated with artificial bowel sphincter, operated on between 1997 and 2014. RESULTS: Sixty-three patients were included in this study. After a median follow-up of 57 months (range, 1-198), the device had been explanted in 31 patients (49.2%; 95% CI, 36.5-62.0). In total, 101 reoperations were conducted, ranging from 1 to 6 reoperations per patient. The main reasons for revision were device failure and infection. At 5 years follow-up, 80% of the cohort had experienced a complication requiring surgery. Twenty-two (35%) patients had restored continence. LIMITATIONS: This study was limited by its retrospective design and subjective secondary outcome. CONCLUSION: Patients with severe end-stage fecal incontinence can benefit from artificial bowel sphincter, but this requires a large number of reoperations, and at least 20% of patients will eventually have a colostomy. Therefore, careful patient selection and the involvement of patients in decision making regarding the potential benefits and limitations of this technique are paramount. See Video Abstract at http://links.lww.com/DCR/B242. EL ESFÍNTER INTESTINAL ARTIFICIAL EN EL TRATAMIENTO DE LA INCONTINENCIA FECAL, COMPLICACIONES A LARGO PLAZO: La incontinencia fecal es una condición común y debilitante, cuya prevalencia aumenta con la edad. Se encuentran disponibles varias modalidades de tratamiento médico y mínimamente invasivo. Sin embargo, para pacientes con defectos del esfínter mayores, estos tratamientos a menudo no son suficientes. Para estos pacientes, el esfínter intestinal artificial (ABS) podría ser una alternativa a la colostomía. El esfínter intestinal artificial demostró ser efectivo a corto plazo. Se sabe menos si los beneficios se mantienen a lo largo del tiempo.El objetivo de este estudio fue evaluar el resultado a largo plazo del esfínter intestinal artificial en pacientes con incontinencia fecal refractaria.Se realizó una revisión retrospectiva de los registros junto con los cuestionarios.Realizado en un entorno de hospital de tercel nivel.El punto final primario fue cualquier complicación, el punto final secundario fue la pérdida fecal.Los pacientes incluidos fueron adultos que padecían incontinencia fecal severa tratados con esfínter intestinal artificial, operados entre 1997 y 2014.Sesenta y tres pacientes fueron incluidos en este estudio. Después de una mediana de seguimiento de 57 meses (rango 1-198), el dispositivo había sido explantado en 31 pacientes (49.2%; 95CI 36.5-62.0). En total, se realizaron 101 reoperaciones, que oscilaron de una a seis reoperaciones por paciente. Las principales razones para la revisión fueron la falla del dispositivo y la infección. A los cinco años de seguimiento, el 80% de la cohorte había experimentado una complicación que requería cirugía. 22 pacientes habían recuperado la continencia (35%).Diseño retrospectivo y resultado secundario subjetivo.Los pacientes con incontinencia fecal grave en etapa terminal pueden beneficiarse del esfínter intestinal artificial, pero esto requiere una gran cantidad de reoperaciones y al menos el 20% de los pacientes eventualmente tendrán una colostomía. Por lo tanto, la selección cuidadosa del paciente y la participación de los pacientes en la toma de decisiones con respecto a los posibles beneficios y limitaciones de esta técnica es primordial. Consulte Video Resumen en http://links.lww.com/DCR/B242.

Identification of Restless Legs Syndrome Genes by Mutational Load Analysis.

OBJECTIVE: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. METHODS: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. RESULTS: Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes. INTERPRETATION: Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193.

Effect of sedative agent selection on morbidity, mortality and length of stay in patients with increase in intracranial pressure / 世界急诊医学杂志（英文）

BACKGROUND: To identify the effects of sedative agent selection on morbidity, mortality, and length of stay in patients with suspected increase in intracranial pressure. Recent trends and developments have resulted in changes to medications that were previously utilized as pharmacological adjuncts in the sedation and intubation of patients with suspected increases in intracranial pressure. Medications that were previously considered contraindicated are now being used with increasing regularity without demonstrated safety and effectiveness. The primary objective of this study is to evaluate and compare the use of Ketamine as an induction agent for patients with increased intracranial pressure. The secondary objective was to evaluate and compare the use of Etomidate, Midazolam, and Ketamine in patients with increased intracranial pressure. METHODS: We conducted a retrospective chart review of patients transported to our facility with evidence of intracranial hypertension that were intubated before trauma center arrival. Patients were identified during a 22-month period from January 2014 to October 2015. Goals were to evaluate the impact of sedative agent selection on morbidity, mortality, and length of stay. RESULTS: During the review 148 patients were identified as meeting inclusion criteria, 52 were excluded due to incomplete data. Of those the patients primarily received; Etomidate, Ketamine, and Midazolam. Patients in the Ketamine group were found to have a lower mortality rate after injury stratification. CONCLUSION: Patients with intracranial hypertension should not be excluded from receiving Ketamine during intubation out of concern for worsening outcomes.

Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis.

BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. METHODS: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10-8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

Long-term outcome of sacral neuromodulation for chronic refractory constipation.

PURPOSE: Sacral neuromodulation has been reported as a treatment for severe idiopathic constipation. This study aimed to evaluate the long-term effects of sacral neuromodulation by following patients who participated in a prospective, open-label, multicentre study up to 5 years. METHODS: Patients were followed up at 1, 3, 6, 12, 24, 36, 48 and 60 months. Symptoms and quality of life were assessed using bowel diary, the Cleveland Clinic constipation score and the Short Form-36 quality-of-life scale. RESULTS: Sixty-two patients (7 male, median age 40 years) underwent test stimulation, and 45 proceeded to permanent implantation. Twenty-seven patients exited the study (7 withdrawn consent, 7 loss of efficacy, 6 site-specific reasons, 4 withdrew other reasons, 2 lost to follow-up, 1 prior to follow-up). Eighteen patients (29%) attended 60-month follow-up. In 10 patients who submitted bowel diary, their improvement of symptoms was sustained: the number of defecations per week (4.1 ± 3.7 vs 8.1 ± 3.4, mean ± standard deviation, p < 0.001, baseline vs 60 months) and sensation of incomplete emptying (0.8 ± 0.3 vs 0.2 ± 0.1, p = 0.002). In 14 patients (23%) with Cleveland Clinic constipation score, improvement was sustained at 60 months [17.9 ± 4.4 (baseline) to 10.4 ± 4.1, p < 0.001]. Some 103 device-related adverse events were reported in 27 (61%). CONCLUSION: Benefit from sacral neuromodulation in the long-term was observed in a small minority of patients with intractable constipation. The results should be interpreted with caution given the high dropout and complication rate during the follow-up period.

Central and peripheral nervous system excitability in restless legs syndrome.

Neurophysiological techniques have been applied in restless legs syndrome (RLS) to obtain direct and indirect measures of central and peripheral nervous system excitability, as well as to probe different neurotransmission pathways. Data converge on the hypothesis that, from a pure electrophysiological perspective, RLS should be regarded as a complex sensorimotor disorder in which cortical, subcortical, spinal cord, and peripheral nerve generators are all involved in a network disorder, resulting in an enhanced excitability and/or decreased inhibition. Although the spinal component may have dominated in neurophysiological assessment, possibly because of better accessibility compared to the brainstem or cerebral components of a hypothetical dysfunction of the diencephalic A11 area, multiple mechanisms, such as reduced central inhibition and abnormal peripheral nerve function, contribute to the pathogenesis of RLS similarly to some chronic pain conditions. Dopamine transmission dysfunction, either primary or triggered by low iron and ferritin concentrations, may also bridge the gap between RLS and chronic pain entities. Further support of disturbed central and peripheral excitability in RLS is provided by the effectiveness of nonpharmacological tools, such as repetitive transcranial magnetic stimulation and transcutaneous spinal direct current stimulation, in transiently modulating neural excitability, thereby extending the therapeutic repertoire. Understanding the complex interaction of central and peripheral neuronal circuits in generating the symptoms of RLS is mandatory for a better refinement of its therapeutic support.

Targeted resequencing and systematic in vivo functional testing identifies rare variants in MEIS1 as significant contributors to restless legs syndrome.

Restless legs syndrome (RLS) is a common neurologic condition characterized by nocturnal dysesthesias and an urge to move, affecting the legs. RLS is a complex trait, for which genome-wide association studies (GWASs) have identified common susceptibility alleles of modest (OR 1.2-1.7) risk at six genomic loci. Among these, variants in MEIS1 have emerged as the largest risk factors for RLS, suggesting that perturbations in this transcription factor might be causally related to RLS susceptibility. To establish this causality, direction of effect, and total genetic burden of MEIS1, we interrogated 188 case subjects and 182 control subjects for rare alleles not captured by previous GWASs, followed by genotyping of ∼3,000 case subjects and 3,000 control subjects, and concluded with systematic functionalization of all discovered variants using a previously established in vivo model of neurogenesis. We observed a significant excess of rare MEIS1 variants in individuals with RLS. Subsequent assessment of all nonsynonymous variants by in vivo complementation revealed an excess of loss-of-function alleles in individuals with RLS. Strikingly, these alleles compromised the function of the canonical MEIS1 splice isoform but were irrelevant to an isoform known to utilize an alternative 3' sequence. Our data link MEIS1 loss of function to the etiopathology of RLS, highlight how combined sequencing and systematic functional annotation of rare variation at GWAS loci can detect risk burden, and offer a plausible explanation for the specificity of phenotypic expressivity of loss-of-function alleles at a locus broadly necessary for neurogenesis and neurodevelopment.

Blood cis-eQTL analysis fails to identify novel association signals among sub-threshold candidates from genome-wide association studies in restless legs syndrome.

Restless legs syndrome (RLS) is a common neurologic disorder characterized by nightly dysesthesias affecting the legs primarily during periods of rest and relieved by movement. RLS is a complex genetic disease and susceptibility factors in six genomic regions have been identified by means of genome-wide association studies (GWAS). For some complex genetic traits, expression quantitative trait loci (eQTLs) are enriched among trait-associated single nucleotide polymorphisms (SNPs). With the aim of identifying new genetic susceptibility factors for RLS, we assessed the 332 best-associated SNPs from the genome-wide phase of the to date largest RLS GWAS for cis-eQTL effects in peripheral blood from individuals of European descent. In 740 individuals belonging to the KORA general population cohort, 52 cis-eQTLs with pnominal<10(-3) were identified, while in 976 individuals belonging to the SHIP-TREND general population study 53 cis-eQTLs with pnominal<10(-3) were present. 23 of these cis-eQTLs overlapped between the two cohorts. Subsequently, the twelve of the 23 cis-eQTL SNPs, which were not located at an already published RLS-associated locus, were tested for association in 2449 RLS cases and 1462 controls. The top SNP, located in the DET1 gene, was nominally significant (p<0.05) but did not withstand correction for multiple testing (p = 0.42). Although a similar approach has been used successfully with regard to other complex diseases, we were unable to identify new genetic susceptibility factor for RLS by adding this novel level of functional assessment to RLS GWAS data.

Effectiveness and tolerability of rotigotine transdermal patch for the treatment of restless legs syndrome in a routine clinical practice setting in Germany.

OBJECTIVE: We aimed to assess effectiveness and tolerability of rotigotine in patients with moderate to severe idiopathic restless legs syndrome (RLS) under daily practice conditions in Germany. METHODS: In this 3-month noninterventional study, effectiveness was assessed using RLS-6 (primary variables were symptom severity when falling asleep [item 2] and during the night [item 3]). Data were collected at baseline and at the end of treatment. Safety assessments included adverse events (AEs). RESULTS: Six hundred and eighty-four patients were treated with rotigotine and 418 (61%) completed the study. The full analysis set (FAS) comprised 564 patients (106 de novo; 458 pretreated [454 had complete rotigotine dosing data]). Mean rotigotine dose of longest duration was 2.4±1.4 mg/24 h. Rotigotine improved all RLS-6 items (mean change from baseline [item 2], -2.4±3.6; [item 3], -2.7±3.4), with the most pronounced improvement observed in daytime symptoms while at rest (item 4, -2.9±3.2). AEs were typical of dopaminergic treatment and transdermal administration. De novo patients generally started rotigotine on 1 mg/24 h (85% [90/106]) and pretreated patients on 1 (50% [227/454]) or 2 mg/24 h (40% [183/454]). Most patients who were pretreated with levodopa (57%), pramipexole (84%), or ropinirole (78%) monotherapy discontinued these medications on initiation of rotigotine. CONCLUSIONS: Rotigotine was effective and well-tolerated when used in routine clinical practice.

Medium-term outcome of sacral nerve modulation for constipation.

BACKGROUND: Sacral nerve modulation has been reported as a minimally invasive and effective treatment for constipation refractory to conservative treatment. OBJECTIVE: This study aimed to evaluate the efficacy and sustainability of sacral nerve modulation for constipation in the medium term (up to 6 years) and to investigate potential predictors of treatment success. DESIGN: We performed a retrospective review of prospectively collected data. SETTINGS: The study was performed at 2 tertiary-care centers in Europe with expertise in pelvic floor disorders and sacral nerve modulation. PATIENTS: Patients were eligible if they had had symptoms of constipation persisting for at least 1 year, if conservative treatment (dietary modification, laxatives and biofeedback therapy) had failed, and if predefined excluded conditions were not present. INTERVENTION: The first phase of the treatment process was percutaneous nerve evaluation. If this was successful, patients underwent sacral nerve modulation therapy with an implanted device (tined-lead and implantable pulse generator). MAIN OUTCOME MEASURE: Follow-up was performed at 1, 3, 6, and 12 months, and yearly thereafter. Outcome was assessed with the Wexner constipation score. RESULTS: A total of 117 patients (13 men, 104 women) with a mean age of 45.6 (SD, 13.0) years underwent percutaneous nerve evaluation. Of these, 68 patients (58%) had successful percutaneous nerve evaluation and underwent implantation of a device. The mean Wexner score was 17.0 (SD, 3.8) at baseline and 10.2 (SD 5.3) after percutaneous nerve evaluation (p < .001); the improvement was maintained throughout the follow-up period, although the number of patients continuing with sacral nerve modulation at the latest follow-up (median, 37 months; range, 4-92) was only 61 (52% of all patients who underwent percutaneous nerve evaluation). The sole predictive factor of outcome of percutaneous nerve evaluation was age: younger patients were more likely than older patients to have a successful percutaneous nerve evaluation phase. LIMITATIONS: The study was limited by a lack of consistent outcome measures. CONCLUSIONS: : Despite improvement in Wexner scores, at the latest follow-up sacral nerve modulation was only being used by slightly more than 50% of the patients who started the first phase of treatment. Further studies are needed to reassess the efficacy and sustainability of sacral nerve modulation.

Effects of transcranial direct current stimulation of the primary sensory cortex on somatosensory perception.

BACKGROUND: Transcranial direct current stimulation (tDCS) is able to modify cortical excitability and activity in humans. OBJECTIVE: The aim of the present study was to analyze the effects of tDCS of the primary sensory cortex (SI) on thermal and mechanical perception, assessed by quantitative sensory testing (QST). METHODS: The comprehensive QST protocol encompassing thermal and mechanical detection and pain thresholds as devised by the German Research Network on Neuropathic Pain (DFNS) was applied to skin areas innervated by the radial and median nerve of 12 healthy subjects, who were examined before and after each tDCS stimulation type. Anodal, cathodal, and sham tDCS was applied at a 1 mA current intensity with the active electrode placed over the left primary sensory cortex (SI) and the reference electrode above the right orbit for 15 minutes. RESULTS: After cathodal tDCS cold detection threshold (CDT) significantly increased in the contralateral (P < .01) and ipsilateral hand (P < .05) as compared to baseline condition and sham stimulation, after cathodal stimulation significantly increased warm detection threshold (WDT) was observed in the contralateral hand when compared with the baseline condition (P < .05) but not with sham stimulation. Thermal pain as well as mechanical detection and pain thresholds remained unaltered. CONCLUSIONS: Cathodal tDCS of the primary sensory cortex significantly reduced the sensitivity to Aδ-fiber-mediated cold sensation, C-fiber-mediated warm sensation was reduced only compared with baseline, whereas Aß-fiber-mediated somatosensory inputs were less affected. Our results correspond with our previous observations of primary motor cortex tDCS effects on QST parameters.

Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1.

Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10(-11), OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10(-19), OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767.

Individual voxel-based subtype prediction can differentiate progressive supranuclear palsy from idiopathic Parkinson syndrome and healthy controls.

Voxel-based morphometry (VBM) shows a differentiated pattern in patients with atypical Parkinson syndrome but so far has had little impact in individual cases. It is desirable to translate VBM findings into clinical practice and individual classification. To this end, we examined whether a support vector machine (SVM) can provide useful accuracies for the differential diagnosis. We acquired a volumetric 3D T1-weighted MRI of 21 patients with idiopathic Parkinson syndrome (IPS), 11 multiple systems atrophy (MSA-P) and 10 progressive supranuclear palsy (PSP), and 22 healthy controls. Images were segmented, normalized, and compared at group level with SPM8 in a classical VBM design. Next, a SVM analysis was performed on an individual basis with leave-one-out cross-validation. VBM showed a strong white matter loss in the mesencephalon of patients with PSP, a putaminal grey matter loss in MSA, and a cerebellar grey matter loss in patients with PSP compared with IPS. The SVM allowed for an individual classification in PSP versus IPS with up to 96.8% accuracy with 90% sensitivity and 100% specificity. In MSA versus IPS, an accuracy of 71.9% was achieved; sensitivity, however, was low with 36.4%. Patients with IPS could not be differentiated from controls. In summary, a voxel-based SVM analysis allows for a reliable classification of individual cases in PSP that can be directly clinically useful. For patients with MSA and IPS, further developments like quantitative MRI are needed.

Spectroscopic characterization of the molybdenum cofactor of the sulfane dehydrogenase SoxCD from Paracoccus pantotrophus.

The bacterial sulfane dehydrogenase SoxCD is a distantly related member of the sulfite oxidase (SO) enzyme family that is proposed to oxidize protein-bound sulfide (sulfane) of SoxY as part of a multienzyme mechanism of thiosulfate metabolism. This study characterized the molybdenum cofactor of SoxCD1, comprising the catalytic molybdopterin subunit SoxC and the truncated c-type cytochrome subunit SoxD1. Electron paramagnetic resonance spectroscopy of the Mo(V) intermediate generated by dithionite reduction revealed low- and high-pH species with g and A((95,97)Mo) matrices nearly identical to those of SO, indicating a similar pentacoordinate active site in SoxCD1. However, no sulfite-induced reduction to Mo(V) was detected, nor could a strongly coupled (1)H signal or a phosphate-inhibited species be generated. This indicates that the outer coordination sphere controls substrate binding in SoxCD, permitting access only to protein-bound sulfur via the C-terminal tail of SoxY.

Structural basis for the oxidation of protein-bound sulfur by the sulfur cycle molybdohemo-enzyme sulfane dehydrogenase SoxCD.

The sulfur cycle enzyme sulfane dehydrogenase SoxCD is an essential component of the sulfur oxidation (Sox) enzyme system of Paracoccus pantotrophus. SoxCD catalyzes a six-electron oxidation reaction within the Sox cycle. SoxCD is an α(2)ß(2) heterotetrameric complex of the molybdenum cofactor-containing SoxC protein and the diheme c-type cytochrome SoxD with the heme domains D(1) and D(2). SoxCD(1) misses the heme-2 domain D(2) and is catalytically as active as SoxCD. The crystal structure of SoxCD(1) was solved at 1.33 Å. The substrate of SoxCD is the outer (sulfane) sulfur of Cys-110-persulfide located at the C-terminal peptide swinging arm of SoxY of the SoxYZ carrier complex. The SoxCD(1) substrate funnel toward the molybdopterin is narrow and partially shielded by side-chain residues of SoxD(1). For access of the sulfane-sulfur of SoxY-Cys-110 persulfide we propose that (i) the blockage by SoxD-Arg-98 is opened via interaction with the C terminus of SoxY and (ii) the C-terminal peptide VTIGGCGG of SoxY provides interactions with the entrance path such that the cysteine-bound persulfide is optimally positioned near the molybdenum atom. The subsequent oxidation reactions of the sulfane-sulfur are initiated by the nucleophilic attack of the persulfide anion on the molybdenum atom that is, in turn, reduced. The close proximity of heme-1 to the molybdopterin allows easy acceptance of the electrons. Because SoxYZ, SoxXA, and SoxB are already structurally characterized, with SoxCD(1) the structures of all key enzymes of the Sox cycle are known with atomic resolution.