Downregulation of PHEX in multibacillary leprosy patients: observational cross-sectional study

Submitted by sandra infurna ([email protected]) on 2016-03-17T16:41:44Z No. of bitstreams: 1 pedro_silva_etal_IOC_2015.pdf: 1297760 bytes, checksum: 4981ff61f37bf82b229de5fdfa9263c9 (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-03-17T16:57:22Z (GMT) No. of bitstreams: 1 pedro_silva_etal_IOC_2015.pdf: 1297760 bytes, checksum: 4981ff61f37bf82b229de5fdfa9263c9 (MD5)Made available in DSpace on 2016-03-17T16:57:22Z (GMT). No. of bitstreams: 1 pedro_silva_etal_IOC_2015.pdf: 1297760 bytes, checksum: 4981ff61f37bf82b229de5fdfa9263c9 (MD5) Previous issue date: 2015Universidade do Estado do Rio de Janeiro (UERJ). Faculdade de Ciências Médicas. Departamento de Patologia e Laboratórios. Disciplina de Patologia Geral e Laboratório de Imunopatologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular de Parasitas e Vetores. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Universidade do Estado do Rio de Janeiro (UERJ). Faculdade de Ciências Médicas. Departamento de Radiologia. Serviço de Medicina Nuclear. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Microbiologia Celular. Rio de Janeiro, RJ, BrasilUniversidade do Estado do Rio de Janeiro (UERJ). Faculdade de Ciências Médicas. Departamento de Radiologia. Serviço de Medicina Nuclear. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Microbiologia Celular. Rio de Janeiro, RJ, Brasil / Universidade do Estado do Rio de Janeiro (UERJ). Faculdade de Ciências Médicas. Departamento de Patologia e Laboratórios. Disciplina de Patologia Geral e Laboratório de Imunopatologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil / Universidade do Estado do Rio de Janeiro (UERJ). Faculdade de Ciências Médicas. Departamento de Patologia e Laboratórios. Disciplina de Patologia Geral e Laboratório de Imunopatologia. Rio de Janeiro, RJ, Brasil.Background: Peripheral nerve injury and bone lesions, well known leprosy complications, lead to deformities and incapacities. The phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) encodes a homonymous protein (PHEX) implicated in bone metabolism. PHEX/PHEX alterations may result in bone and cartilage lesions. PHEX expression is downregulated by intracellular Mycobacterium leprae (M. leprae) in cultures of human Schwann cells and osteoblasts. M. leprae in vivo effect on PHEX/PHEX is not known. Methods: Cross-sectional observational study of 36 leprosy patients (22 lepromatous and 14 borderline-tuberculoid) and 20 healthy volunteers (HV). The following tests were performed: PHEX flow cytometric analysis on blood mononuclear cells, cytokine production in culture supernatant, 25-hydroxyvitamin D (OHvitD) serum levels and 99mTc-MDP three-phase bone scintigraphy, radiography of upper and lower extremities and blood and urine biochemistry. Results: Significantly lower PHEX expression levels were observed in lepromatous patients than in the other groups (χ2 = 16.554, p < 0.001 for lymphocytes and χ2 = 13.933, p = 0.001 for monocytes). Low levels of 25-(OHvitD) were observed in HV (median = 23.0 ng/mL) and BT patients (median = 27.5 ng/mL) and normal serum levels were found in LL patients (median = 38.6 ng/mL). Inflammatory cytokines, such as TNF, a PHEX transcription repressor, were lower after stimulation with M. leprae in peripheral blood mononuclear cells from lepromatous in comparison to BT patients and HV (χ2 = 10.820, p < 0.001). Conclusion: Downregulation of PHEX may constitute an important early component of bone loss and joint damage in leprosy. The present results suggest a direct effect produced by M. leprae on the osteoarticular system that may use this mechanism

Evaluating Rates of Recurrent Ischemic Stroke Among Young Adults With Embolic Stroke of Undetermined Source: The Young ESUS Longitudinal Cohort Study.

Importance Cryptogenic strokes constitute approximately 40% of ischemic strokes in young adults, and most meet criteria for the embolic stroke of undetermined source (ESUS). Two randomized clinical trials, NAVIGATE ESUS and RESPECT ESUS, showed a high rate of stroke recurrence in older adults with ESUS but the prognosis and prognostic factors among younger individuals with ESUS is uncertain. Objective To determine rates of and factors associated with recurrent ischemic stroke and death and new-onset atrial fibrillation (AF) among young adults. Design, Setting, and Participants This multicenter longitudinal cohort study with enrollment from October 2017 to October 2019 and a mean follow-up period of 12 months ending in October 2020 included 41 stroke research centers in 13 countries. Consecutive patients 50 years and younger with a diagnosis of ESUS were included. Of 576 screened, 535 participants were enrolled after 1 withdrew consent, 41 were found to be ineligible, and 2 were excluded for other reasons. The final follow-up visit was completed by 520 patients. Main Outcomes and Measures Recurrent ischemic stroke and/or death, recurrent ischemic stroke, and prevalence of patent foramen ovale (PFO). Results The mean (SD) age of participants was 40.4 (7.3) years, and 297 (56%) participants were male. The most frequent vascular risk factors were tobacco use (240 patients [45%]), hypertension (118 patients [22%]), and dyslipidemia (109 patients [20%]). PFO was detected in 177 participants (50%) who had transthoracic echocardiograms with bubble studies. Following initial ESUS, 468 participants (88%) were receiving antiplatelet therapy, and 52 (10%) received anticoagulation. The recurrent ischemic stroke and death rate was 2.19 per 100 patient-years, and the ischemic stroke recurrence rate was 1.9 per 100 patient-years. Of the recurrent strokes, 9 (64%) were ESUS, 2 (14%) were cardioembolic, and 3 (21%) were of other determined cause. AF was detected in 15 participants (2.8%; 95% CI, 1.6-4.6). In multivariate analysis, the following were associated with recurrent ischemic stroke: history of stroke or transient ischemic attack (hazard ratio, 5.3; 95% CI, 1.8-15), presence of diabetes (hazard ratio, 4.4; 95% CI, 1.5-13), and history of coronary artery disease (hazard ratio, 10; 95% CI, 4.8-22). Conclusions and Relevance In this large cohort of young adult patients with ESUS, there was a relatively low rate of subsequent ischemic stroke and a low frequency of new-onset AF. Most recurrent strokes also met the criteria for ESUS, suggesting the need for future studies to improve our understanding of the underlying stroke mechanism in this population