Familial adrenal hypoplasia syndromes

The adrenal cortex secretes steroid hormones, including glucocorticoids and mineralocorticoids. Glucocorticoids control body homeostasis, stress, and immune responses, while mineralocorticoids regulate the water and electrolyte balance. A spectrum of genetic defects can disrupt the normal adrenal development, causing adrenal hypoplasia and various forms of adrenal insufficiency, which usually present in infancy or childhood with or without mineralocorticoid deficiency and with or without gonadal dysfunction. The genetic causes of adrenal hypoplasia can be broadly categorized into adrenal hypoplasia due to adrenocorticotropic hormone resistance syndromes (i.e., familial glucocorticoid deficiency and triple A syndrome) and adrenal hypoplasia due to primary defects in the development of the adrenal glands (i.e., X-linked adrenal hypoplasia congenita and primary adrenal hypoplasia caused by steroidogenic factor 1 mutations).

Activation du système du complément dans les syndromes coronariens aigus

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Simplified Predictive Instrument to Rule Out Acute Coronary Syndromes in a High-Risk Population.

BACKGROUND: It is unclear whether diagnostic protocols based on cardiac markers to identify low-risk chest pain patients suitable for early release from the emergency department can be applied to patients older than 65 years or with traditional cardiac risk factors. METHODS AND RESULTS: In a single-center retrospective study of 231 consecutive patients with high-risk factor burden in which a first cardiac troponin (cTn) level was measured in the emergency department and a second cTn sample was drawn 4 to 14 hours later, we compared the performance of a modified 2-Hour Accelerated Diagnostic Protocol to Assess Patients with Chest Pain Using Contemporary Troponins as the Only Biomarker (ADAPT) rule to a new risk classification scheme that identifies patients as low risk if they have no known coronary artery disease, a nonischemic electrocardiogram, and 2 cTn levels below the assay's limit of detection. Demographic and outcome data were abstracted through chart review. The median age of our population was 64 years, and 75% had Thrombosis In Myocardial Infarction risk score ≥2. Using our risk classification rule, 53 (23%) patients were low risk with a negative predictive value for 30-day cardiac events of 98%. Applying a modified ADAPT rule to our cohort, 18 (8%) patients were identified as low risk with a negative predictive value of 100%. In a sensitivity analysis, the negative predictive value of our risk algorithm did not change when we relied only on undetectable baseline cTn and eliminated the second cTn assessment. CONCLUSIONS: If confirmed in prospective studies, this less-restrictive risk classification strategy could be used to safely identify chest pain patients with more traditional cardiac risk factors for early emergency department release.

The role of inflammatory mediators in the overactive and bladder pain syndromes

The Overactive Bladder (OAB) and Bladder Pain Syndrome (BPS) are debilitating disorders for which the pathophysiological mechanisms are poorly understood. Injury or dysfunction of the protective urothelial barrier layer, specifically the proteoglycan composition and number, has been proposed as the primary pathological characteristic of BPS. For OAB, the myogenic theory with dysfunction of the muscarinic receptors is the most reiterated hypothesis. For both over activity of the inflammatory response has been posited to play a major role in these diseases. We hypothesise that BPS and OAB are peripheral sensory disorders, with an increase in inflammatory mediators, such as cytokines and chemokines, which are capable of activating, either directly or indirectly, sensory nerve activity causing the disease. The aim of the PhD is to identify potential new therapeutic targets for the treatment of BPS and OAB. We used medium throughput quantitative gene expression analysis of 96 inflammation associated mediators to measure gene expression levels in BPS and OAB bladder biopsies and compared them to control samples. Then we created a novel animal model of disease by specific proteoglycan deglycosylation of the bladder mucosal barrier, using the bacterial enzymes Chondroitinase ABC and Heparanase III. These enzymes specifically remove the glycosaminoglycan side chains from the urothelial proteoglycan molecules. We tested role of the identified mediators in this animal model. In addition, in order to determine on which patients peripheral treatment strategies may work, we assessed the effect of local anaesthetics on patients with bladder pain. Gene expression analysis did not reveal a difference in inflammatory genes in the OAB versus control biopsies. However, several genes were upregulated in BPS versus control samples, from which two genes, FGF7 and CLL21 were correlated with patient clinical phenotypes for ICS/PI symptom and problem indices respectively. In order to determine which patients are likely to respond to treatment, we sought to characterise the bladder pain in BPS patients. Using urodynamics and local anaesthetics, we differentiated patients with peripherally mediated pain and patients with central sensitisation of their pain. Finally to determine the role of these mediators in bladder pain, we created an animal model of disease, which specifically replicates the human pathology: namely disruption in the barrier proteoglycan molecules. CCL21 led to an increase in painrelated behaviour, while FGF7 attenuated this behaviour, as measured by cystometry, spinal c-fos expression and mechanical withdrawal threshold examination. In conclusion, we have identified CCL21 and FGF7 as potential targets for the treatment of BPS. Manipulation of these ligands or their receptors may prove to be valuable previously unexploited targets for the treatment of BPS.

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings.

This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette's syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader-Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

Activation du système du complément dans les syndromes coronariens aigus

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Cryptic splicing events in the iron transporter ABCB7 and other key target genes in SF3B1-mutant myelodysplastic syndromes

The splicing factor SF3B1 is the most frequently mutated gene in myelodysplastic syndromes (MDS), and is strongly associated with the presence of ring sideroblasts (RS). We have performed a systematic analysis of cryptic splicing abnormalities from RNA sequencing data on hematopoietic stem cells (HSCs) of SF3B1-mutant MDS cases with RS. Aberrant splicing events in many downstream target genes were identified and cryptic 3' splice site usage was a frequent event in SF3B1-mutant MDS. The iron transporter ABCB7 is a well-recognized candidate gene showing marked downregulation in MDS with RS. Our analysis unveiled aberrant ABCB7 splicing, due to usage of an alternative 3' splice site in MDS patient samples, giving rise to a premature termination codon in the ABCB7 mRNA. Treatment of cultured SF3B1-mutant MDS erythroblasts and a CRISPR/Cas9-generated SF3B1-mutant cell line with the nonsense-mediated decay (NMD) inhibitor cycloheximide showed that the aberrantly spliced ABCB7 transcript is targeted by NMD. We describe cryptic splicing events in the HSCs of SF3B1-mutant MDS, and our data support a model in which NMD-induced downregulation of the iron exporter ABCB7 mRNA transcript resulting from aberrant splicing caused by mutant SF3B1 underlies the increased mitochondrial iron accumulation found in MDS patients with RS.Leukemia advance online publication, 17 June 2016; doi:10.1038/leu.2016.149.

External Validation of the ProACS Score for Risk Stratification of Patients with Acute Coronary Syndromes

INTRODUCTION: The ProACS risk score is an early and simple risk stratification score developed for all-cause in-hospital mortality in acute coronary syndromes (ACS) from a Portuguese nationwide ACS registry. Our center only recently participated in the registry and was not included in the cohort used for developing the score. Our objective was to perform an external validation of this risk score for short- and long-term follow-up. METHODS: Consecutive patients admitted to our center with ACS were included. Demographic and admission characteristics, as well as treatment and outcome data were collected. The ProACS risk score variables are age (≥72 years), systolic blood pressure (≤116 mmHg), Killip class (2/3 or 4) and ST-segment elevation. We calculated ProACS, Global Registry of Acute Coronary Events (GRACE) and Canada Acute Coronary Syndrome risk score (C-ACS) risk scores for each patient. RESULTS: A total of 3170 patients were included, with a mean age of 64±13 years, 62% with ST-segment elevation myocardial infarction. All-cause in-hospital mortality was 5.7% and 10.3% at one-year follow-up. The ProACS risk score showed good discriminative ability for all considered outcomes (area under the receiver operating characteristic curve >0.75) and a good fit, similar to C-ACS, but lower than the GRACE risk score and slightly lower than in the original development cohort. The ProACS risk score provided good differentiation between patients at low, intermediate and high mortality risk in both short- and long-term follow-up (p<0.001 for all comparisons). CONCLUSIONS: The ProACS score is valid in external cohorts for risk stratification for ACS. It can be applied very early, at the first medical contact, but should subsequently be complemented by the GRACE risk score.

Multiple endocrine neoplasia, the old and the new: a mini review

Multiple endocrine neoplasia syndromes have since been classified as types 1 and 2, each with specific phenotypic patterns. MEN1 is usually associated with pituitary, parathyroid and paraneoplastic neuroendocrine tumours. The hallmark of MEN2 is a very high lifetime risk of developing medullary thyroid carcinoma (MTC) more than 95% in untreated patients. Three clinical subtypesdMEN2A, MEN2B, and familial MTC (FMTC) have been defined based on the risk of pheochromocytoma, hyperparathyroidism, and the presence or absence of characteristic physical features). MEN2 occurs as a result of germline activating missense mutations of the RET (REarranged during Transfection) proto-oncogene. MEN2-associated mutations are almost always located in exons 10, 11, or 13 through 16. Strong genotype-phenotype correlations exist with respect to clinical subtype, age at onset, and aggressiveness of MTC in MEN2. These are used to determine the age at which prophylactic thyroidectomy should occur and whether screening for pheochromocytoma or hyperparathyroidism is necessary. Specific RET mutations can also impact management in patients presenting with apparently sporadic MTC. Therefore, genetic testing should be performed before surgical intervention in all patients diagnosed with MTC. Recently, Pellegata et al. have reported that germline mutations in CDKN1B can predispose to the development of multiple endocrine tumours in both rats and humans and this new MEN syndrome is named MENX and MEN4, respectively. CDKN1B. A recent report showed that in sporadic MTC, CDKN1B V109G polymorphism correlates with a more favorable disease progression than the wild-type allele and might be considered a new promising prognostic marker. New insights on MEN syndrome pathogenesis and related inherited endocrine disorders are of particular interest for an adequate surgical and therapeutic approach.

Estimating glomerular filtration rate in acute coronary syndromes: Different equations, different mortality risk prediction

AIMS: Renal dysfunction is a powerful predictor of adverse outcomes in patients hospitalized for acute coronary syndrome. Three new glomerular filtration rate (GFR) estimating equations recently emerged, based on serum creatinine (CKD-EPIcreat), serum cystatin C (CKD-EPIcyst) or a combination of both (CKD-EPIcreat/cyst), and they are currently recommended to confirm the presence of renal dysfunction. Our aim was to analyse the predictive value of these new estimated GFR (eGFR) equations regarding mid-term mortality in patients with acute coronary syndrome, and compare them with the traditional Modification of Diet in Renal Disease (MDRD-4) formula. METHODS AND RESULTS: 801 patients admitted for acute coronary syndrome (age 67.3±13.3 years, 68.5% male) and followed for 23.6±9.8 months were included. For each equation, patient risk stratification was performed based on eGFR values: high-risk group (eGFR<60ml/min per 1.73m2) and low-risk group (eGFR⩾60ml/min per 1.73m2). The predictive performances of these equations were compared using area under each receiver operating characteristic curves (AUCs). Overall risk stratification improvement was assessed by the net reclassification improvement index. The incidence of the primary endpoint was 18.1%. The CKD-EPIcyst equation had the highest overall discriminate performance regarding mid-term mortality (AUC 0.782±0.20) and outperformed all other equations (ρ<0.001 in all comparisons). When compared with the MDRD-4 formula, the CKD-EPIcyst equation accurately reclassified a significant percentage of patients into more appropriate risk categories (net reclassification improvement index of 11.9% (p=0.003)). The CKD-EPIcyst equation added prognostic power to the Global Registry of Acute Coronary Events (GRACE) score in the prediction of mid-term mortality. CONCLUSION: The CKD-EPIcyst equation provides a novel and improved method for assessing the mid-term mortality risk in patients admitted for acute coronary syndrome, outperforming the most widely used formula (MDRD-4), and improving the predictive value of the GRACE score. These results reinforce the added value of cystatin C as a risk marker in these patients.

Prognosis following acute coronary syndromes according to prior coronary artery bypass grafting: Meta-analysis

PURPOSE: Conduct a meta-analysis to study the prognostic influence of a previous coronary artery bypass grafting (CABG) in patients admitted for an acute coronary syndrome (ACS). METHODS: A systematic review of the literature was performed using electronic reference databases through January 2013 (MEDLINE, Cochrane Library, Web of Knowledge, Google Scholar and references cited in other studies). Studies in which ACS outcomes with a previous history of CABG were compared with ACS outcomes with no history of previous CABG were considered for inclusion. The main endpoints of interest were mortality and non-fatal acute myocardial infarction. Data was aggregated at three follow-up times using random-effects meta-analysis models. RESULTS: Twenty-four studies were included which provided 387,181 patients for analysis. Previous CABG ACS patients were older, more diabetic and had a more frequent history of a previous myocardial infarction. Pooled in-hospital mortality was higher for the previous CABG ACS patients (OR 1.22 [1.04-1.44], p<0.01, I(2) 88%). The pooled adjusted OR showed no significant differences for the two groups (adjusted OR 1.13 [0.93-1.37], p=0.22, I(2) 92%). Previous CABG ACS patient had a higher pooled 30-day mortality (OR 1.28 [1.05-1.55], p=0.02, I(2) 74%); a higher non-adjusted (OR 1.61 [1.38-1.88], p<0.01, I(2) 70%) and adjusted (adjusted OR 1.37 [1.15-1.65], p<0.01, I(2) 0%) long-term mortality. Both the in-hospital and the long-term re-infarction rates were higher for the previous CABG ACS patients. CONCLUSIONS: According to our data, ACS patients with previous CABG history had a higher risk for short- and long-term adverse events.

Paraneoplastic Polymyalgia Rheumatica as Manifestation of a Pancreatic Neuroendocrine Tumour

Autoimmune diseases may present as paraneoplastic syndrome. This is especially recognized in the case of polymyositis/dermatomyositis, but is less common in polymyalgia rheumatica. The authors describe the case of a 73-year-old man who presented with pain and stiffness of the scapular and pelvic girdles associated with asthenia lasting for a few weeks. The presence of therapeutic resistance and other atypical features directed the investigation towards the search of an occult malignancy. Patient evaluation revealed a pancreatic neuroendocrine tumour. After surgical treatment of the underlying neoplasia, the patient recovered fully with resolution of the rheumatic disease.

Étude S.AGES : recueil et suivi de nouveaux cas de syndromes d’apnées obstructives au cours du sommeil (SAOS), chez des sujets âgés de plus de 70 ans, diagnostiqués dans les structures de pneumologie et de gériatrie

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More Than Just a Case of Polymyalgia Rheumatica

Malignant neoplasms are associated with a wide range of paraneoplastic rheumatological syndromes. These can be defined as remote effects of cancer, which are not caused by the tumor and its metastasis. The authors describe the case of an 82-year-old man, who presented with a one-month history of pain, stiffness, and functional limitation of the scapular and pelvic girdles. Blood tests showed raised levels of inflammatory markers. He was diagnosed with Polymyalgia Rheumatica, but the lack of response to corticosteroids led to the suspicion of an alternative diagnosis, like, for example, an occult neoplasm. Although patient evaluation was initially normal, five months later he developed macroscopic haematuria and was diagnosed with bladder and prostate carcinomas. After surgical treatment, the patient fully recovered from his rheumatological syndrome.