Health-related quality of life of relapsing or remitting multiple sclerosis patients: A case-control study

Background: Patients with multiple sclerosis (MS) report lower health-related quality of life (HRQoL) than other chronic disease populations. This study aims to identify risk factors of relapsing or remitting multiple sclerosis (RRMS) and assess its impact on HRQoL in Lebanese MS patients. Patients and methods: A thre-month case-control study was performed among 75 RRMS case patients recruited from two clinics in Beirut and 225 controls from the general population. Results: Heavy cigarette smoking, moderate and heavy waterpipe smoking, vitamin D deficiency, cardiovascular disease, and psychological disorders were significantly associated with RRMS. Linear regression showed that the multiple sclerosis international quality of life global index significantly decreased with the number of relapses, the incomplete recovery between relapses, and the psychological disorder. Higher-income and physical activity had a positive effect on QoL. Conclusions: Findings of this study highlighted the risk factors of RRMS, which can be used for informed decision-making and targeted awareness campaigns. Other factors affecting the HRQoL of MS patients should be considered to improve their experience throughout and after treatment

Incidence and clinical outcomes of nosocomial infections in patients presenting with STEMI complicated by cardiogenic shock in the United States

OBJECTIVES: This study addresses the incidence, trends, and impact of nosocomial infections (NI) on the outcomes of patients admitted with ST-segment elevation myocardial infarction (STEMI) and cardiogenic shock (STEMI-CS) using the United States National Inpatient Sample (NIS) database. METHODS: We analyzed data from 105,184 STEMI-CS patients using the NIS database from the years 2005-2014. NI was defined as infections of more than or equal to three days, comprising of central line-associated bloodstream infection (CLABSI), urinary tract infection (UTI), hospital-acquired pneumonia (HAP), Clostridium difficile infection (CDI), bacteremia, and skin related infections. Outcomes of the impact of NI on STEMI-CS included in-hospital mortality, length of hospital stay (LOS) and costs. Significant associations of NI in patients admitted with STEMI-CS were also identified. RESULTS: Overall, 19.1% (20,137) of patients admitted with STEMI-CS developed NI. Trends of NI have decreased from 2005-2014. The most common NI were UTI (9.2%), followed by HAP (6.8%), CLABSI (1.5%), bacteremia (1.5%), skin related infections (1.5%), and CDI (1.3%). The strongest association of developing a NI was increasing LOS (7-9 days; OR: 1.99; 95% CI: 1.75-2.26; \u3e9 days; OR: 4.51; 95% CI: 4.04-5.04 compared to 4-6 days as reference). Increased mortality risk among patients with NI was significant, especially those with sepsis-associated NI compared to those without sepsis (OR: 2.95; 95% CI: 2.72-3.20). Patients with NI were found to be associated with significantly longer LOS and higher costs, irrespective of percutaneous mechanical circulatory support placement. CONCLUSIONS: NI were common among patients with STEMI-CS. Those who developed NI were at a greater risk of in-hospital mortality, increased LOS and costs

Retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling

International audiencePrimary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. Mutations in different genes increase aldosterone production in PA, but additional mechanisms may contribute to increased cell proliferation and aldosterone producing adenoma (APA) development. We performed transcriptome analysis in APA and identified retinoic acid receptor alpha (RARα) signaling as a central molecular network involved in nodule formation. To understand how RARα modulates adrenal structure and function, we explored the adrenal phenotype of male and female Rarα knockout mice. inactivation of Rarα in mice led to significant structural disorganization of the adrenal cortex in both sexes, with increased adrenal cortex size in female mice and increased cell proliferation in males. Abnormalities of vessel architecture and extracellular matrix were due to decreased Vegfa expression and modifications in extracellular matrix components. On the molecular level, Rarα inactivation leads to inhibition of non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Our study suggests that Rarα contributes to the maintenance of normal adrenal cortex structure and cell proliferation, by modulating Wnt signaling. Dysregulation of this interaction may contribute to abnormal cell proliferation, creating a propitious environment for the emergence of specific driver mutations in PA. Primary aldosteronism (PA) is the most common and curable form of secondary arterial hypertension, with prevalence estimations of up to 10% of cases in referred hypertensive patients, 4% of patients in primary care 1,2 and 20% of patients with resistant hypertension 3,4. Rapid diagnosis and treatment are important to prevent severe cardiovas-cular consequences of long term aldosterone exposure, which are independent of blood pressure levels and are du

Molecular genetics of Conn adenomas in the era of exome analysis

International audienceAldosterone-producing adenomas (APA) are a major cause of primary aldosteronism (PA), the most common form of secondary hypertension. Exome analysis of APA has allowed the identification of recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 in more than 50 % of sporadic cases. These gain of function mutations in ion channels and pumps lead to increased and autonomous aldosterone production. In addition, somatic CTNNB1 mutations have also been identified in APA. The CTNNB1 mutations were also identified in cortisol-producing adenomas and adrenal cancer, but their role in APA development and the mechanisms specifying the hormonal production or the malignant phenotype remain unknown. The role of the somatic mutations in the regulation of aldosterone production is well understood, while the impact of these mutations on cell proliferation remains to be established. Furthermore, the sequence of events leading to APA formation is currently the focus of many studies. There is evidence for a two-hit model where the somatic mutations are second hits occurring in a previously remodeled adrenal cortex. On the other hand, the APA-driver mutations were also identified in aldosterone-producing cell clusters (APCC) in normal adrenals, suggesting that these structures may represent precursors for APA development. As PA due to APA can be cured by surgical removal of the affected adrenal gland, the identification of the underlying genetic abnormalities by novel biomarkers could improve diagnostic and therapeutic approaches of the disease. In this context, recent data on steroid profiling in peripheral venous samples of APA patients and on new drugs capable of inhibiting mutated potassium channels provide promising preliminary data with potential for translation into clinical care

Mitochondria-targeted melatonin photorelease supports the presence of melatonin MT1 receptors in mitochondria inhibiting respiration

The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly recognized. Recently, the presence of Gi/o protein-coupled melatonin MT1 receptors in mitochondria has been revealed, in addition to the plasma membrane. Melatonin is highly cell permeant, activating plasma membrane and mitochondrial receptors equally. Here, we present MCS-1145, a melatonin derivative bearing a triphenylphosphonium cation for specific mitochondrial targeting and a photocleavable o-nitrobenzyl group releasing melatonin upon illumination. MCS-1145 displayed low affinity for MT1 and MT2 but spontaneously accumulated in mitochondria, where it was resistant to washout. Uncaged MCS-1145 and exogenous melatonin recruited β-arrestin 2 to MT1 in mitochondria and inhibited oxygen consumption in mitochondria isolated from HEK293 cells only when expressing MT1 and from mouse cerebellum of WT mice but not from MT1-knockout mice. Overall, we developed the first mitochondria-targeted photoactivatable melatonin ligand and demonstrate that melatonin inhibits mitochondrial respiration through mitochondrial MT1 receptors.We thank Drs. E. Cecon and O. Lahuna for help in image and data analysis. This work was supported by Agence Nationale de la Recherche (ANR-19-CE16-0025-01 « mitoGPCR » to R.J.) and ANR-19-CE14-JCJC to L.B. Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS). R.J. was supported by the Fondation pour la Recherche Médicale (Equipe FRM DEQ20130326503), and ANR-21-CE18-00XX « alloGLP1R » and La Ligue Contre le Cancer N/Ref: RS19/75-127. G.S.B. was supported by a doctoral fellowship from the Fondation pour la Recherche Médicale (FRM grant number ECO20170637544) obtained by R.J. This work was supported by Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación and ERDF-FEDER European Fund A way of making Europe, European Union (projects CTQ2017-89222-R and PID2020-120499RB-I00) to A.L. and by the Catalan government (2021 SGR 00508) to A.L. We thank Carolina Cera (SimChem, IQAC-CSIC, Barcelona) for support in the synthesis and analysis of compounds.Peer reviewe

Epidemiology and clinical characteristics of viral infections in hospitalized children and adolescents with cancer in Lebanon.

BackgroundViral infections in children and adolescents with malignancy are commonly encountered and have a significant impact on morbidity and mortality. Studies and epidemiological data regarding viral infections in children with cancer in developing countries are lacking. This retrospective cohort study aims to assess the burden of viral infections in children and adolescents with cancer, by assessing prevalence, risk factors, as well as morbidity and mortality of common viruses over a period of 8 years.Methods and findingsMedical records of cancer patients treated at the Children Cancer Center of Lebanon were reviewed and 155 participants under the age of 21 were identified with at least one documented viral infection during the period from July 2009 to November 2017. This subset included 136 participants with active malignancy and 19 participants with a history of cancer who underwent hematopoietic stem cell transplantation [HSCT] and were in remission; the latter group was analyzed separately. Information regarding participant characteristics, hospital course, and complications were obtained. Associations between viral infections and certain factors were assessed. In the cohort, 64% were male, 81% were Lebanese. In participants with active malignancy, 90% received chemotherapy in the 6 months preceding the viral infection episode, 11% received radiotherapy. 51% of participants were neutropenic at the time of viral detection, and 77% were lymphopenic. 17% experienced a bacterial co-infection, and 3 experienced a viral co-infection. Among 162 viral infection episodes, clinically diagnosed skin infections, mainly herpes simplex virus type 1 and varicella-zoster virus, were the most common [44% of cases]. These were followed by laboratory-proven systemic herpes infections: cytomegalovirus [14%] and Epstein-Barr virus [6%]. Respiratory viruses: influenza and respiratory syncytial virus, accounted for 9% and 4%, respectively, whereas rotavirus represented 11% and BK virus represented 3% of cases. Acute lymphocytic leukemia was the most prevalent neoplasia [57%]. Fever was the most common presenting symptom [55%] and febrile neutropenia was the reason for admission in 24% of cases. The mean length of stay was significantly longer in participants with cytomegalovirus infections and significantly lower in rotavirus infection. Admission to the ICU occurred in 9%, complications in 8%, and mortality in 5%. Participants with viral infections post-HSCT were noted to have a significantly longer length of hospital stay compared to non-HSCT participants, with no other significant differences in clinical course and outcome. The study was limited by its retrospective nature and by the late introduction and underuse of multiplex PCR panels, which may have led to underdiagnosis of viral infections.ConclusionsViral infections were prevalent in our sample of cancer patients and may have contributed to morbidity and mortality. Newly available viral diagnostics are likely to vastly increase the number and scope of detectable viral infections in this population. Prospective studies using multiplex PCR technology with systematic testing of patients will be more helpful in defining the burden of viral infections. Furthermore, efforts at antimicrobial stewardship would benefit from the identification of viral causes of infection and limit the unnecessary use of antibiotics in the pediatric cancer population

A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism

International audiencePrimary aldosteronism is the most common and curable form of secondary arterial hypertension. We performed whole-exome sequencing in patients with early-onset primary aldosteronism and identified a de novo heterozygous c.71G>A/p.Gly24Asp mutation in the CLCN2 gene, encoding the voltage-gated ClC-2 chloride channel 1 , in a patient diagnosed at 9 years of age. Patch-clamp analysis of glomerulosa cells of mouse adrenal gland slices showed hyperpolarization-activated Cl- currents that were abolished in Clcn2-/- mice. The p.Gly24Asp variant, located in a well-conserved 'inactivation domain'2,3, abolished the voltage- and time-dependent gating of ClC-2 and strongly increased Cl- conductance at resting potentials. Expression of ClC-2Asp24 in adrenocortical cells increased expression of aldosterone synthase and aldosterone production. Our data indicate that CLCN2 mutations cause primary aldosteronism. They highlight the important role of chloride in aldosterone biosynthesis and identify ClC-2 as the foremost chloride conductor of resting glomerulosa cells