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

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Rôle de la signalisation des récepteurs minéralocorticoïde et rétinoïque dans la physiologie du cortex surrénalien et le développement de l’hyperaldostéronisme primaire

Primary aldosteronism is the major cause of secondary arterial hypertension. Recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 have been identified in aldosterone producing adenoma (APA). Although the role of these mutations in regulating aldosterone biosynthesis has been clearly established, the mechanisms involved in proliferation and APA formation still remain to be elucidated. The main aim of my PhD project was to identify the role of the retinoic acid receptor alpha (RARα) and the mineralocorticoid receptor (MR) in the development of APA. We identified RARα signaling as a central molecular network involved in nodule formation in adrenals from patients with APA. Inactivation of Rarα in mice led to major structural and functional disorganization of the adrenal cortex in both sexes, with modifications of the vessel architecture and extracellular matrix and reduced expression of steroidogenic genes. These abnormalities were due to increased proliferation, decreased Vegfa expression and modifications in extracellular matrix components. Rarα inactivation reduces non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Adrenal cortex disorganization persisted with aging, while molecular abnormalities affecting Wnt signaling and Vegfa and steroidogenic gene expression regressed. Our study suggests that Rarα contributes to normal adrenal cortex development, by modulating Wnt and Vegfa signaling. My PhD project also focused on the exploration of the adrenal phenotype of mice with an MR deletion specifically in the zona glomerulosa of the adrenal cortex. This model was generated using a mouse line created in the laboratory during my PhD, where the Cre recombinase is expressed under the control of the Cyp11b2 promoter. Cyp11b2+/Cre::mrflx/flx female mice exhibit adrenal cortex disorganization, characterized by loss of radial structure in certain areas of the zona fasciculata. We also observed ectopic expression of aldosterone synthase in the cortico-medullary junction and in some cases ectopic expression of 11β-hydroxylase in the zona glomerulosa. The identification of the molecular mechanisms involved in this phenotype is currently ongoing as more mice are being included in the study. Finally, during my PhD I have also contributed to the identification of the role of the chloride channel ClC-2 in primary aldosteronism. Results obtained during my PhD have allowed a better understanding of the mechanisms underlying APA development, and open new perspectives for the identification of therapeutic targets in primary aldosteronism.L’hyperaldostéronisme primaire est la cause majeure d’hypertension artérielle secondaire. Des mutations somatiques récurrentes dans les gènes KCNJ5, CACNA1D, ATP1A1 et ATP2B3 ont été identifiées dans les adénomes produisant de l’aldostérone (APA). Bien que le rôle de ces mutations dans la régulation de la biosynthèse de l’aldostérone soit bien établi, les mécanismes impliqués dans la prolifération et la formation des APA restent à démontrer. L’objectif principal de mon projet de thèse était d’identifier le rôle de la signalisation des récepteurs à l’acide rétinoïque alpha (RARα) et minéralocorticoïde (MR) dans le développement des APA. Nous avons identifié la signalisation RARα comme étant un élément central dans la formation des nodules dans les surrénales de patients ayant un APA. L’inactivation de Rarα chez la souris induit une désorganisation structurelle et fonctionnelle majeure dans le cortex surrénalien dans les deux sexes, avec des modifications de l’architecture vasculaire et de la matrice extracellulaire, et une réduction de l’expression des gènes de la stéroïdogenèse. Ces anomalies sont dues à une augmentation de la prolifération, une réduction de l’expression de Vegfa et de la signalisation Wnt non canonique, sans modification de la voie Wnt canonique et de la signalisation PKA. La désorganisation de la corticosurrénale persiste avec l’âge, alors que les anomalies moléculaires touchant la voie Wnt et la voie du Vegfa et la réduction de l’expression des gènes de la stéroïdogenèse régressent. Notre étude suggère que RARα contribue au développement normal du cortex surrénalien, en modulant les signalisations Wnt et Vegfa. Mes travaux de thèse m’ont également amené à explorer le phénotype surrénalien des souris ayant une délétion du gène MR spécifique de la zone glomérulée du cortex surrénalien. Ce modèle a été généré en utilisant une ligné murine créée dans mon laboratoire d’accueil, où la Cre recombinase est exprimée sous le contrôle du promoteur du gène Cyp11b2. L’étude du phénotype surrénalien de souris Cyp11b2+/Cre::mrflx/flx révèle une désorganisation du cortex surrénalien chez les souris femelles. Cette désorganisation est caractérisée par une perte de la structure radiale dans certaines régions de la zone fasciculée. De plus, nous observons une expression ectopique de l’aldostérone synthase au niveau de la jonction cortico-médullaire, de même qu’une expression ectopique de la 11β-hydroxylase au niveau de la zone glomérulée dans certains cas. L’identification des mécanismes moléculaires associés à ce phénotype sont en cours d’étude. Enfin, pendant ma thèse j’ai également contribué à l’identification du rôle du canal chlorure ClC-2 dans l’hyperaldostéronisme primaire. Les résultats obtenus au cours de mon projet de thèse ont permis une meilleure compréhension des mécanismes impliqués dans les APA et ouvrent de perspectives pour l’identification de nouvelles cibles thérapeutiques dans l’hyperaldostéronisme primaire

Rôle de la signalisation des récepteurs minéralocorticoïde et rétinoïque dans la physiologie du cortex surrénalien et le développement de l’hyperaldostéronisme primaire

L’hyperaldostéronisme primaire est la cause majeure d’hypertension artérielle secondaire. Des mutations somatiques récurrentes dans les gènes KCNJ5, CACNA1D, ATP1A1 et ATP2B3 ont été identifiées dans les adénomes produisant de l’aldostérone (APA). Bien que le rôle de ces mutations dans la régulation de la biosynthèse de l’aldostérone soit bien établi, les mécanismes impliqués dans la prolifération et la formation des APA restent à démontrer. L’objectif principal de mon projet de thèse était d’identifier le rôle de la signalisation des récepteurs à l’acide rétinoïque alpha (RARα) et minéralocorticoïde (MR) dans le développement des APA. Nous avons identifié la signalisation RARα comme étant un élément central dans la formation des nodules dans les surrénales de patients ayant un APA. L’inactivation de Rarα chez la souris induit une désorganisation structurelle et fonctionnelle majeure dans le cortex surrénalien dans les deux sexes, avec des modifications de l’architecture vasculaire et de la matrice extracellulaire, et une réduction de l’expression des gènes de la stéroïdogenèse. Ces anomalies sont dues à une augmentation de la prolifération, une réduction de l’expression de Vegfa et de la signalisation Wnt non canonique, sans modification de la voie Wnt canonique et de la signalisation PKA. La désorganisation de la corticosurrénale persiste avec l’âge, alors que les anomalies moléculaires touchant la voie Wnt et la voie du Vegfa et la réduction de l’expression des gènes de la stéroïdogenèse régressent. Notre étude suggère que RARα contribue au développement normal du cortex surrénalien, en modulant les signalisations Wnt et Vegfa. Mes travaux de thèse m’ont également amené à explorer le phénotype surrénalien des souris ayant une délétion du gène MR spécifique de la zone glomérulée du cortex surrénalien. Ce modèle a été généré en utilisant une ligné murine créée dans mon laboratoire d’accueil, où la Cre recombinase est exprimée sous le contrôle du promoteur du gène Cyp11b2. L’étude du phénotype surrénalien de souris Cyp11b2+/Cre::mrflx/flx révèle une désorganisation du cortex surrénalien chez les souris femelles. Cette désorganisation est caractérisée par une perte de la structure radiale dans certaines régions de la zone fasciculée. De plus, nous observons une expression ectopique de l’aldostérone synthase au niveau de la jonction cortico-médullaire, de même qu’une expression ectopique de la 11β-hydroxylase au niveau de la zone glomérulée dans certains cas. L’identification des mécanismes moléculaires associés à ce phénotype sont en cours d’étude. Enfin, pendant ma thèse j’ai également contribué à l’identification du rôle du canal chlorure ClC-2 dans l’hyperaldostéronisme primaire. Les résultats obtenus au cours de mon projet de thèse ont permis une meilleure compréhension des mécanismes impliqués dans les APA et ouvrent de perspectives pour l’identification de nouvelles cibles thérapeutiques dans l’hyperaldostéronisme primaire.Primary aldosteronism is the major cause of secondary arterial hypertension. Recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 have been identified in aldosterone producing adenoma (APA). Although the role of these mutations in regulating aldosterone biosynthesis has been clearly established, the mechanisms involved in proliferation and APA formation still remain to be elucidated. The main aim of my PhD project was to identify the role of the retinoic acid receptor alpha (RARα) and the mineralocorticoid receptor (MR) in the development of APA. We identified RARα signaling as a central molecular network involved in nodule formation in adrenals from patients with APA. Inactivation of Rarα in mice led to major structural and functional disorganization of the adrenal cortex in both sexes, with modifications of the vessel architecture and extracellular matrix and reduced expression of steroidogenic genes. These abnormalities were due to increased proliferation, decreased Vegfa expression and modifications in extracellular matrix components. Rarα inactivation reduces non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Adrenal cortex disorganization persisted with aging, while molecular abnormalities affecting Wnt signaling and Vegfa and steroidogenic gene expression regressed. Our study suggests that Rarα contributes to normal adrenal cortex development, by modulating Wnt and Vegfa signaling. My PhD project also focused on the exploration of the adrenal phenotype of mice with an MR deletion specifically in the zona glomerulosa of the adrenal cortex. This model was generated using a mouse line created in the laboratory during my PhD, where the Cre recombinase is expressed under the control of the Cyp11b2 promoter. Cyp11b2+/Cre::mrflx/flx female mice exhibit adrenal cortex disorganization, characterized by loss of radial structure in certain areas of the zona fasciculata. We also observed ectopic expression of aldosterone synthase in the cortico-medullary junction and in some cases ectopic expression of 11β-hydroxylase in the zona glomerulosa. The identification of the molecular mechanisms involved in this phenotype is currently ongoing as more mice are being included in the study. Finally, during my PhD I have also contributed to the identification of the role of the chloride channel ClC-2 in primary aldosteronism. Results obtained during my PhD have allowed a better understanding of the mechanisms underlying APA development, and open new perspectives for the identification of therapeutic targets in primary aldosteronism

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