RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits

Mutations in the LRRK2 kinase are the most common cause of familial Parkinson's disease, and variants increase risk for the sporadic form of the disease. LRRK2 phosphorylates multiple RAB GTPases including RAB8A and RAB10. Phosphorylated RAB10 is recruited to centrosome-localized RILPL1, which may interfere with ciliogenesis in a disease-relevant context. Our previous studies indicate that the centrosomal accumulation of phosphorylated RAB8A causes centrosomal cohesion deficits in dividing cells, including in peripheral patient-derived cells. Here, we show that both RAB8 and RAB10 contribute to the centrosomal cohesion deficits. Pathogenic LRRK2 causes the centrosomal accumulation not only of phosho-RAB8 but also of phospho-RAB10, and the effects on centrosomal cohesion are dependent on RAB8, RAB10 and RILPL1. Conversely, the pathogenic LRRK2-mediated ciliogenesis defects correlate with the centrosomal accumulation of both phospho-RAB8 and phospho-RAB10. LRRK2-mediated centrosomal cohesion and ciliogenesis alterations are observed in patient-derived peripheral cells, as well as in primary astrocytes from mutant LRRK2 mice, and are reverted upon LRRK2 kinase inhibition. These data suggest that the LRRK2-mediated centrosomal cohesion and ciliogenesis defects are distinct cellular readouts of the same underlying phospho-RAB8/RAB10/RILPL1 nexus and highlight the possibility that either centrosomal cohesion and/or ciliogenesis alterations may serve as cellular biomarkers for LRRK2-related PD

FAHN/SPG35 : a narrow phenotypic spectrum across disease classifications

The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers

Dysautonomia in COVID-19 patients: a narrative review on clinical course, diagnostic and therapeutic strategies

IntroductionOn March 11, 2020, the World Health Organization sounded the COVID-19 pandemic alarm. While efforts in the first few months focused on reducing the mortality of infected patients, there is increasing data on the effects of long-term infection (Post-COVID-19 condition). Among the different symptoms described after acute infection, those derived from autonomic dysfunction are especially frequent and limiting. ObjectiveTo conduct a narrative review synthesizing current evidence of the signs and symptoms of dysautonomia in patients diagnosed with COVID-19, together with a compilation of available treatment guidelines. ResultsAutonomic dysfunction associated with SARS-CoV-2 infection occurs at different temporal stages. Some of the proposed pathophysiological mechanisms include direct tissue damage, immune dysregulation, hormonal disturbances, elevated cytokine levels, and persistent low-grade infection. Acute autonomic dysfunction has a direct impact on the mortality risk, given its repercussions on the respiratory, cardiovascular, and neurological systems. Iatrogenic autonomic dysfunction is a side effect caused by the drugs used and/or admission to the intensive care unit. Finally, late dysautonomia occurs in 2.5% of patients with Post-COVID-19 condition. While orthostatic hypotension and neurally-mediated syncope should be considered, postural orthostatic tachycardia syndrome (POTS) appears to be the most common autonomic phenotype among these patients. A review of diagnostic and treatment guidelines focused on each type of dysautonomic condition was done. ConclusionSymptoms deriving from autonomic dysfunction involvement are common in those affected by COVID-19. These symptoms have a great impact on the quality of life both in the short and medium to long term. A better understanding of the pathophysiological mechanisms of Post-COVID manifestations that affect the autonomic nervous system, and targeted therapeutic management could help reduce the sequelae of COVID-19, especially if we act in the earliest phases of the disease

Variability in the performance of preventive services and in the degree of control of identified health problems: A primary care study protocol

Background: Preventive activities carried out in primary care have important variability that makes necessary to know which factors have an impact in order to establish future strategies for improvement. The present study has three objectives: 1) To describe the variability in the implementation of 7 preventive services (screening for smoking status, alcohol abuse, hypertension, hypercholesterolemia, obesity, influenza and tetanus immunization) and to determine their related factors; 2) To describe the degree of control of 5 identified health problems (smoking, alcohol abuse, hypertension, hypercholesterolemia and obesity); 3) To calculate intraclass correlation coefficients. Design: Multi-centered cross-sectional study of a randomised sample of primary health care teams from 3 regions of Spain designed to analyse variability and related factors of 7 selected preventive services in years 2006 and 2007. At the end of 2008, we will perform a cross-sectional study of a cohort of patients attended in 2006 or 2007 to asses the degree of control of 5 identified health problems. All subjects older than16 years assigned to a randomised sample of 22 computerized primary health care teams and attended during the study period are included in each region providing a sample with more than 850.000 subjects. The main outcome measures will be implementation of 7 preventive services and control of 5 identified health problems. Furthermore, there will be 3 levels of data collection: 1) Patient level (age, gender, morbidity, preventive services, attendance); 2) Health-care professional level (professional characteristics, years working at the team, workload); 3) Team level (characteristics, electronic clinical record system). Data will be transferred from electronic clinical records to a central database with prior encryption and dissociation of subject, professional and team identity. Global and regional analysis will be performed including standard analysis for primary health care teams and health-care professional level. Linear and logistic regression multilevel analysis adjusted for individual and cluster variables will also be performed. Variability in the number of preventive services implemented will be calculated with Poisson multilevel models. Team and health-care professional will be considered random effects. Intraclass correlation coefficients, standard error and variance components for the different outcome measures will be calculated

Inactivation of CDK/pRb Pathway Normalizes Survival Pattern of Lymphoblasts Expressing the FTLD-Progranulin Mutation c.709-1G>A

8 figuras, 2 tablasBackground Mutations in the progranulin (PGRN) gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP), although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK) CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation. Methodology/Principal Findings We performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal. Conclusion/Significance The use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDPThis work has been supported by grants from Ministry of Education and Science (SAF2007-61701, SAF2010-15700, SAF2011-28603), Fundación Eugenio Rodríguez Pascual, and Basque Government (Saiotek program 2008–2009). NE holds a fellowship of the JAE predoctoral program of the CSICPeer reviewe

Health promotion in primary care: How should we intervene? A qualitative study involving both physicians and patients

<p>Abstract</p> <p>Background</p> <p>The effects of tobacco, physical exercise, diet, and alcohol consumption on morbidity and mortality underline the importance of health promotion and prevention (HPP) at the primary health care (PHC) level. Likewise, the deficiencies when putting such policies into practice and assessing their effectiveness are also widely recognised. The objectives of this research were: a) to gain an in-depth understanding of general practitioners' (GPs) and patients' perceptions about HPP in PHC, and b) to define the areas that could be improved in future interventions.</p> <p>Methods</p> <p>Qualitative methodology focussed on the field of health services research. Information was generated on the basis of two GP-based and two patient-based discussion groups, all of which had previously participated in two interventions concerning healthy lifestyle promotion (tobacco and physical exercise). Transcripts and field notes were analysed on the basis of a sociological discourse-analysis model. The results were validated by triangulation between researchers.</p> <p>Results</p> <p>GPs and patients' discourses about HPP in PHC were different in priorities and contents. An overall explanatory framework was designed to gain a better understanding of the meaning of GP-patient interactions related to HPP, and to show the main trends that emerged from their discourses. GPs linked their perceptions of HPP to their working conditions and experience in health services. The dimensions in this case involved the orientation of interventions, the goal of actions, and the evaluation of results. For patients, habits were mainly related to ways of life particularly influenced by close contexts. Health conceptions, their role as individuals, and the orientation of their demands were the most important dimensions in patients' sphere.</p> <p>Conclusions</p> <p>HPP activities in PHC need to be understood and assessed in the context of their interaction with the conditioning trends in health services and patients' social micro-contexts. On the basis of the explanatory framework, three development lines are proposed: the incorporation of new methodological approaches according to the complexity of HPP in PHC; the openness of habit change policies beyond the medical services; and the effective commitments in the medium to long term by the health services themselves at the policy management level.</p

Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors

BACKGROUND: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen. METHODS: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen. RESULTS: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//muL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location. CONCLUSIONS: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location

Modelling innovative interventions for optimising healthy lifestyle promotion in primary health care: "Prescribe Vida Saludable" phase I research protocol

<p>Abstract</p> <p>Background</p> <p>The adoption of a healthy lifestyle, including physical activity, a balanced diet, a moderate alcohol consumption and abstinence from smoking, are associated with large decreases in the incidence and mortality rates for the most common chronic diseases. That is why primary health care (PHC) services are trying, so far with less success than desirable, to promote healthy lifestyles among patients. The objective of this study is to design and model, under a participative collaboration framework between clinicians and researchers, interventions that are feasible and sustainable for the promotion of healthy lifestyles in PHC.</p> <p>Methods and design</p> <p>Phase I formative research and a quasi-experimental evaluation of the modelling and planning process will be undertaken in eight primary care centres (PCCs) of the Basque Health Service – OSAKIDETZA, of which four centres will be assigned for convenience to the Intervention Group (the others being Controls). Twelve structured study, discussion and consensus sessions supported by reviews of the literature and relevant documents, will be undertaken throughout 12 months. The first four sessions, including a descriptive strategic needs assessment, will lead to the prioritisation of a health promotion aim in each centre. In the remaining eight sessions, collaborative design of intervention strategies, on the basis of a planning process and pilot trials, will be carried out. The impact of the formative process on the practice of healthy lifestyle promotion, attitude towards health promotion and other factors associated with the optimisation of preventive clinical practice will be assessed, through pre- and post-programme evaluations and comparisons of the indicators measured in professionals from the centres assigned to the Intervention or Control Groups.</p> <p>Discussion</p> <p>There are four necessary factors for the outcome to be successful and result in important changes: (1) the commitment of professional and community partners who are involved; (2) their competence for change; (3) the active cooperation and participation of the interdisciplinary partners involved throughout the process of change; and (4) the availability of resources necessary to facilitate the change.</p