Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1 disease

Objective To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Methods Multimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing?based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ?2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia. Results Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ?1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ?9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C?like progression (SARA points 2.5?5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression. Conclusions RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials. Classification of Evidence This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.FUNDING: Study Funding This work was supported via the European Union’s Horizon 2020 research and innovation program by the BMBF under the frame of the E-Rare-3 network PREPARE (01GM1607; to M. Synofzik,M.A., H.P., B.P.v.d.W.), by the DFG under the frame of EJP-RD network PROSPAX (No. 441409627; M. Synofzik, B.P.v.d.W., A.N.B.), and grant 779257 “Solve-RD” (toM. Synofzik, B.P.v.d.W.). B.P.v.d.W. receives additional research support from ZonMW, Hersenstichting, Gossweiler Foundation, uniQure, and Radboud University Medical Centre. T.B.H. was supported by the DFG (No 418081722). A.T. receives funding from the University of T¨ubingen, medical faculty, for the Clinician Scientist Program grant 439-0-0. A.C. thanks Medical Research Council, MR/T001712/1) and Fondazione CARIPLO (2019-1836) for grant support. L.S., T.K., B.P.v.d.W., and M. Synofzik are members of the European Reference Network for Rare Neurological Diseases, project 739510. A.N.B. is supported by the Suna and Inan Kirac Foundation and Koç University School of Medicine

Evaluation of the ICT Tuberculosis test for the routine diagnosis of tuberculosis

BACKGROUND: Rapid and accurate diagnosis of tuberculosis (TB) is crucial to facilitate early treatment of infectious cases and thus to reduce its spread. To improve the diagnosis of TB, more rapid diagnostic techniques such as antibody detection methods including enzyme-linked immunosorbent assay (ELISA)-based serological tests and immunochromatographic methods were developed. This study was designed to evaluate the validity of an immunochromatographic assay, ICT Tuberculosis test for the serologic diagnosis of TB in Antalya, Turkey. METHODS: Sera from 72 patients with active pulmonary (53 smear-positive and 19 smear-negative cases) and eight extrapulmonary (6 smear-positive and 2 smear-negative cases) TB, and 54 controls from different outpatient clinics with similar demographic characteristics as patients were tested by ICT Tuberculosis test. RESULTS: The sensitivity, specificity, and negative predictive value of the ICT Tuberculosis test for pulmonary TB were 33.3%, 100%, and 52.9%, respectively. Smear-positive pulmonary TB patients showed a higher positivity rate for antibodies than smear-negative patients, but the difference was not statistically significant. Of the eight patients with extrapulmonary TB, antibody was detected in four patients. CONCLUSION: Our results suggest that ICT Tuberculosis test can be used to aid TB diagnosis in smear-positive patients until the culture results are available

Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease

Behcet's disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behcet's disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behcet's disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 x 10(-8)). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 x 10(-18), odds ratio = 1.45, 95% CI 1.34-1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 x 10(-9), OR = 1.28, 95% CI 1.18-1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production

Using global team science to identify genetic parkinson's disease worldwide.

No abstract available

Investigation of the Wetting Properties of Ternary Lead-Free Solder Alloys on Copper Substrate

In the present study, wetting behaviors of Sn-9Zn-xAl ternary lead-free solder alloys produced by the addition of Al in various amounts binary Sn-9Zn eutectic lead-free solder alloy (wt%) were investigated. Contact angles of alloys were measured by using of the sessile drop method. Microstructures, inter-metallic phases, and melting temperatures of alloys were characterized by optic microscope and scanning electron microscope and energy dispersive X-ray spectroscopy, X-ray diffraction, and differential scanning calorimeter, and effects of the amount of Al on microstructure were investigated. As a result, the studies show that Al-rich areas were found on microstructure of Sn-9Zn-xAl alloys. The lowest melting temperature for Sn-9Zn-0.5Al and Sn-9Zn-0.7Al alloys was determined as 200.9°C. It was determined that wetting capability of Sn-9Zn-xAl alloys failed because of oxidation