Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human alpha-synuclein in transgenic mouse brain.

Alpha-synuclein (SNCA) gene has been implicated in the development of rare forms of familial Parkinson disease (PD). Recently, it was shown that an increase in SNCA copy numbers leads to elevated levels of wild-type SNCA-mRNA and protein and is sufficient to cause early-onset, familial PD. A critical question concerning the molecular pathogenesis of PD is what contributory role, if any, is played by the SNCA gene in sporadic PD. The expansion of SNCA-Rep1, an upstream, polymorphic microsatellite of the SNCA gene, is associated with elevated risk for sporadic PD. However, whether SNCA-Rep1 is the causal variant and the underlying mechanism with which its effect is mediated by remained elusive. We report here the effects of three distinct SNCA-Rep1 variants in the brains of 72 mice transgenic for the entire human SNCA locus. Human SNCA-mRNA and protein levels were increased 1.7- and 1.25-fold, respectively, in homozygotes for the expanded, PD risk-conferring allele compared with homozygotes for the shorter, protective allele. When adjusting for the total SNCA-protein concentration (endogenous mouse and transgenic human) expressed in each brain, the expanded risk allele contributed 2.6-fold more to the SNCA steady-state than the shorter allele. Furthermore, targeted deletion of Rep1 resulted in the lowest human SNCA-mRNA and protein concentrations in murine brain. In contrast, the Rep1 effect was not observed in blood lysates from the same mice. These results demonstrate that Rep1 regulates human SNCA expression by enhancing its transcription in the adult nervous system and suggest that homozygosity for the expanded Rep1 allele may mimic locus multiplication, thereby elevating PD risk

Genetic testing for Inherited Arrhythmia Syndromes and Cardiomyopathies: results of the European Heart Rhythm Association Survey.

Indications and clinical impact of genetic testing for cardiac diseases have increased significantly over the past years. The aim of this physician-based EHRA survey was to assess current clinical practice and access to genetic testing for cardiac diseases across ESC countries and to evaluate adherence to the 2022 EHRA/HRS/APHRS/LAHRS Expert Consensus Statement on genetic testing. An online questionnaire composed of 28 questions was submitted to the EHRA Research Network and European Reference Network GUARD-Heart healthcare partners and promoted via dedicated social media channels. There were 357 respondents from 69 countries, 40% working in a hospital setting with a cardiac genetic service and/or a dedicated clinic focusing on inherited cardiac diseases and 27% with an onsite genetic laboratory. No genetic testing or low annual rate (<10/y) was declared by 39% of respondents. The majority of respondents (78%) declared issues or limitations to genetic testing access in their clinical practice. The main reasons for not providing or limited access to genetic testing were no availability of dedicated unit or genetic laboratory (35%) or reimbursement issues (25%). The most frequently reported indication for genetic testing was diagnostic purpose (55%). Most respondents (92%) declared offering genetic testing preceded by genetic counselling and 42% regular multidisciplinary evaluations for patients with cardiac genetic diseases. The perceived value of genetic testing in the diagnostic, prognostic, and therapeutic assessment was variable (67%, 39%, and 29%, respectively) and primarily based on the specific inherited disease. The majority of respondents recommended cascade genetic testing for the first-degree family members in case of pathogenic/likely pathogenic (P/LP) variant in the proband. This survey highlights a significant heterogeneity of genetic testing access and provision and issues attributable to the availability of dedicated unit/genetic laboratory and reimbursement. However, adequate adherence to indications in the current recommendations for genetic testing in patients with cardiac diseases was observed

The European TeleCheck-AF project on remote app-based management of atrial fibrillation during the COVID-19 pandemic: Centre and patient experiences

Aims: TeleCheck-AF is a multicentre international project initiated to maintain care delivery for patients with atrial fibrillation (AF) during COVID-19 through teleconsultations supported by an on-demand photoplethysmography-based heart rate and rhythm monitoring app (FibriCheck® ). We describe the characteristics, inclusion rates and experiences from participating centres according the TeleCheck-AF infrastructure as well as characteristics and experiences from recruited patients.Methods: Three surveys exploring centre characteristics (n=25), centre experiences (n=23) and patient experiences (n=826) were completed. Self-reported patient characteristics were obtained from the app.Results: Most centres were academic (64%) and specialized public cardiology/district hospitals (36%). Majority of centres had AF outpatient clinics (64%) and only 36% had AF ablation clinics. The time required to start patient inclusion and total number of included patients in the project was comparable for centres experienced (56%) or inexperienced in mHealth use. Within 28 weeks, 1930 AF patients were recruited, mainly for remote AF control (31% of patients) and AF ablation follow-up (42%). Average inclusion rate was highest during the lockdown restrictions and reached a steady state at a lower level after easing the restrictions (188 vs 52 weekly recruited patients). Majority (>80%) of the centres reported no problems during the implementation of the TeleCheck-AF approach. Recruited patients (median age 64 [55-71], 62% male) agreed that the FibriCheck® app was easy to use (94%).Conclusions: Despite different health care settings and mHealth experiences, the TeleCheck-AF approach could be set up within an extremely short time and easily used in different European centres during COVID-19

Applications of trusted review to information security

The review process is an important part of many everyday activities. We introduce the concept of trusted review for electronic data. The review process is performed using an insertable security device called a Trusted Reviewer. The Trusted Reviewer can be designed to satisfy high assurance evaluation requirements. We show how the Trusted Reviewer can offer increased security in messaging, certification authorities, funds transfer, witnessing, and information downgrade

Pt-KL zeolite catalysts of different preparation: Part I. Catalyst characterization

0.8% Pt on KL zeolite was prepared by reduction with H2 and NaBH4. Transmission electron microscopy and X-ray diffraction were used for characterization of morphology of the metal particles; acidity of the zeolite framework was measured with IR spectra of adsorbed pyridine. Reduction by NaBHP4 produced rather large, needle-like Pt crystallites on the outer surface of zeolite grains which contained very little acidity. Subsequent hydrogen treatment brought about their severe sintering; at the same time, small crystallites appeared. A bimodal distribution was seen when the catalyst was reduced with hydrogen; this sample exhibited appreciable acidity. X-ray diffraction data showed the presence of Pt particles above noise level in the case of borohydride-reduced catalyst only, in agreement with EM data