Inappropriate antidiuretic hormone secretion: long-term successful urea treatment.

Hyponatremia is the main complication of inappropriate antidiuretic hormone secretion (SIADH), sometimes fatal. Treatment strategy depends on the cause and the severity of the hyponatremia. Recent studies have shown the efficacy of urea in treating acute hyponatremia secondary to SIADH, by inducing an osmotic water drive. We describe an infant with chronic hyponatremia secondary to SIADH in which the long-term oral treatment with urea was successful and well tolerated. The aim of this paper is to highlight the potential benefits of urea treatment in case of chronic hyponatremia secondary to SIADH. CONCLUSION: Chronic oral urea treatment in children with SIADH allows an easy and safe water and sodium control and may permit a decrease in fluid restriction in this situation.

The long non-coding RNA NEAT1 is increased in IUGR placentas, leading to potential new hypotheses of IUGR origin/development.

INTRODUCTION: Intrauterine Growth Restriction (IUGR) is a multifactorial disease defined by an inability of the fetus to reach its growth potential. IUGR not only increases the risk of neonatal mortality/morbidity, but also the risk of metabolic syndrome during adulthood. Certain placental proteins have been shown to be implicated in IUGR development, such as proteins from the GH/IGF axis and angiogenesis/apoptosis processes. METHODS: Twelve patients with term IUGR pregnancy (birth weight < 10th percentile) and 12 CTRLs were included. mRNA was extracted from the fetal part of the placenta and submitted to a subtraction method (Clontech PCR-Select cDNA Subtraction). RESULTS: One candidate gene identified was the long non-coding RNA NEAT1 (nuclear paraspeckle assembly transcript 1). NEAT1 is the core component of a subnuclear structure called paraspeckle. This structure is responsible for the retention of hyperedited mRNAs in the nucleus. Overall, NEAT1 mRNA expression was 4.14 (±1.16)-fold increased in IUGR vs. CTRL placentas (P = 0.009). NEAT1 was exclusively localized in the nuclei of the villous trophoblasts and was expressed in more nuclei and with greater intensity in IUGR placentas than in CTRLs. PSPC1, one of the three main proteins of the paraspeckle, co-localized with NEAT1 in the villous trophoblasts. The expression of NEAT1_2 mRNA, the long isoform of NEAT1, was only modestly increased in IUGR vs. CTRL placentas. DISCUSSION/CONCLUSION: The increase in NEAT1 and its co-localization with PSPC1 suggests an increase in paraspeckles in IUGR villous trophoblasts. This could lead to an increased retention of important mRNAs in villous trophoblasts nuclei. Given that the villous trophoblasts are crucial for the barrier function of the placenta, this could in part explain placental dysfunction in idiopathic IUGR fetuses.

Altered thymic selection by overexpressing cellular FLICE inhibitory protein in T cells causes lupus-like syndrome in a BALB/c but not C57BL/6 strain.

The cellular FLICE inhibitory protein (c-FLIP) is an endogenous inhibitor of the caspase-8 proapoptotic signaling pathway downstream of death receptors. Recent evidence indicates that the long form of c-FLIP (c-FLIP(L)) is required for proliferation and effector T-cell development. However, the role of c-FLIP(L) in triggering autoimmunity has not been carefully analyzed. We now report that c-FLIP(L) transgenic (Tg) mice develop splenomegaly, lymphadenopathy, multiorgan infiltration, high titers of auto-antibodies, and proliferative glomerulonephritis with immune complex deposition in a strain-dependent manner. The development of autoimmunity requires CD4(+) T cells and may result from impaired thymic selection. At the molecular level, c-FLIP(L) overexpression inhibits the zeta chain-associated protein tyrosine kinase of 70 kDa (ZAP-70) activation, thus impairing the signaling pathway derived from ZAP-70 required for thymic selection. Therefore, we have identified c-FLIP(L) as a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity.

Ultra-rapid opiate detoxification using deep sedation and prior oral buprenorphine preparation: long-term results.

BACKGROUND: New methods of ultra-rapid opiate detoxification (URD) under intravenous sedation have been criticized because of limited data on safety and long-term follow-up. Premedication with buprenorphine has been advocated to improve safety by decreasing vomiting. Prior research has not explored URD in socially impaired patients. METHOD: Sixteen patients were detoxified with URD and prospectively evaluated over at least 30 months. Data of this procedure were compared with those of our previous study without buprenorphine preparation (Drug Alcohol Depend. 52(3) (1998) 243). The 16 patients were followed up by a general practitioner (GP) before and after URD. The GPs also supervised the 7-day course of buprenorphine treatment prescribed for the 16 patients prior to URD. RESULTS: During the procedure, only one episode of vomiting occurred instead of 13 out of 20 in our previous study. Post-procedure, only two patients experienced moderate withdrawal symptoms, such as persistent nausea, abdominal cramps and vomiting lasting from 24 to 48 h, in comparison with most patients in the previous study without buprenorphine. After a period of at least 30 months (36.0+/-6.38), the 16 patients were still alive and were regularly monitored by their GP. Only two of the 16 never relapsed after URD and reported total opiate abstinence. Fourteen patients relapsed; 12 of these were prescribed a licensed methadone substitution program and two were still using heroin. CONCLUSION: In this small sample, the data indicated that URD with buprenorphine preparation was safe and that it markedly decreased post-procedure morbidity. No patient died over a minimum 30-month follow-up period. Furthermore, the procedure was employed with socially impaired patients. In the long term, a few patients were still free of opiates, while the majority opted for a methadone maintenance program, showing that URD can serve as one possible step in a long-term treatment program.

Long-Term Follow-Up of Multilayer Amniotic Membrane Transplantation (MLAMT) for Non-Traumatic Corneal Perforations or Deep Ulcers with Descemetocele.

Background: To evaluate the long-term efficacy of multilayer amniotic membrane transplantation for reconstruction of epithelium and stroma in non-traumatic corneal perforations (less than 2 mm) or deep ulcers with descemetocele.Design: Retrospective, non-comparative, interventional case series.Patients and Methods: Eleven consecutive patients with non-traumatic corneal perforations or deep corneal ulcers with descemetocele refractory to conventional treatments: herpetic or zoster keratitis (n = 4), Sjögren's syndrome (n = 2), rosacea (n = 1), hydrops (n = 1), mucous membrane pemphigoid (n = 1), bacterial keratitis (n = 1) and perforation after protontherapy for melanoma (n = 1). Intervention was: multilayer amniotic membrane transplantation with cryopreserved amniotic membrane. Complication rate and clinical outcome were evaluated in this long-term follow-up.Results: Mean follow-up was 32 months (12 to 60). Integration of the multilayer amniotic membrane was obtained in 10 cases after one year. Corneal epithelium healed above the membrane in 10 cases within 3 weeks and remained stable after 32 months in 9 cases. Thickness of the stroma was increased and remained stable during the follow-up in 9 cases. In one case herpetic keratitis recurred with a corneal perforation. The clearing of the amniotic membrane was gradually obtained over a period of 11 months. Complications occurred in 15 % of the eyes during the long-term follow-up.Conclusion: Multilayer amniotic membrane transplantation is a safe and efficient technique for a long restoration of the corneal integrity after non-traumatic corneal perforations or deep corneal ulcers with descemetocele. Long-term prognosis of these eyes depends of the gravity of the initial disease.

Correlated genetic effects on reproduction define a domestication syndrome in a forest tree.

Compared to natural selection, domestication implies a dramatic change in traits linked to fitness. A number of traits conferring fitness in the wild might be detrimental under domestication, and domesticated species typically differ from their ancestors in a set of traits known as the domestication syndrome. Specifically, trade-offs between growth and reproduction are well established across the tree of life. According to allocation theory, selection for growth rate is expected to indirectly alter life-history reproductive traits, diverting resources from reproduction to growth. Here we tested this hypothesis by examining the genetic change and correlated responses of reproductive traits as a result of selection for timber yield in the tree Pinus pinaster. Phenotypic selection was carried out in a natural population, and progenies from selected trees were compared with those of control trees in a common garden experiment. According to expectations, we detected a genetic change in important life-history traits due to selection. Specifically, threshold sizes for reproduction were much higher and reproductive investment relative to size significantly lower in the selected progenies just after a single artificial selection event. Our study helps to define the domestication syndrome in exploited forest trees and shows that changes affecting developmental pathways are relevant in domestication processes of long-lived plants.

Steroid hormones interrelationships in the metabolic syndrome: an introduction to the ponderostat hypothesis

Sexual dimorphism in the metabolic syndrome. The clairvoyant early implication of sex hormones in the characterization of the metabolic syndrome (MS) was detected early, and in accordance with the well-known sex-related main patterns of fat deposition in obesity: gynoid and android. The differences point to a direct implication of androgens and estrogens in the development, properties and maintenance of obesity and, by extension, to the cumulus of diseases grouped in the MS. For a long time, the key issue of the MS, i.e. the metabolic event explaining (and justifying) most of the derangements of the MS, has been considered to be insulin resistance (...)

Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment.

BACKGROUND: Psychotropic drugs can induce substantial weight gain, particularly during the first 6 months of treatment. The authors aimed to determine the potential predictive power of an early weight gain after the introduction of weight gain-inducing psychotropic drugs on long-term weight gain. METHOD: Data were obtained from a 1-year longitudinal study ongoing since 2007 including 351 psychiatric (ICD-10) patients, with metabolic parameters monitored (baseline and/or 1, 3, 6, 9, 12 months) and with compliance ascertained. International Diabetes Federation and World Health Organization definitions were used to define metabolic syndrome and obesity, respectively. RESULTS: Prevalences of metabolic syndrome and obesity were 22% and 17%, respectively, at baseline and 32% and 24% after 1 year. Receiver operating characteristic analyses indicated that an early weight gain > 5% after a period of 1 month is the best predictor for important long-term weight gain (≥ 15% after 3 months: sensitivity, 67%; specificity, 88%; ≥ 20% after 12 months: sensitivity, 47%; specificity, 89%). This analysis identified most patients (97% for 3 months, 93% for 12 months) who had weight gain ≤ 5% after 1 month as continuing to have a moderate weight gain after 3 and 12 months. Its predictive power was confirmed by fitting a longitudinal multivariate model (difference between groups in 1 year of 6.4% weight increase as compared to baseline, P = .0001). CONCLUSION: Following prescription of weight gain-inducing psychotropic drugs, a 5% threshold for weight gain after 1 month should raise clinician concerns about weight-controlling strategies.

Long-term low-dose ketoconazole treatment in bilateral macronodular adrenal hyperplasia (BMAH)

Le traitement médicamenteux du syndrome de Cushing secondaire à une hyperplasie surrénalienne macro-nodulaire bilatérale (bilateral macronodular adrenal hyperplasia, (BMAH)) est généralement administré pour une période limitée avant de procéder à l'exérèse chirurgicale des surrénales. Les antagonistes des récepteurs surrênaïïens aberrants se sont révélés inefficaces à long terme pour empêcher la surrénalectomie. Nous reportons le cas d'une patiente avec BMAH traitée durant 10 ans par des petites doses de kétoconazole, afin de contrôler la sécrétion de Cortisol. A l'âge de 48 ans, elle a présenté des céphalées et une hypertension artérielle. Les investigations ont donné les résultats suivants: absence de signes cliniques de syndrome de Cushing ; hyperplasie nodulaire des surrénales ; valeurs normales de la creatinine, le potassium et l'aldostérone plasmatiques ; valeurs normales des métanéphrines et de l'aldostérone urinaires ; élévation du Cortisol libre et des métabolites stéroïdiens urinaires ; et suppression de l'ACTH et de l'activité de la rénine plasmatiques. Un protocole de dépistage des récepteurs surrénaliens aberrants n'a pas montré de dépendance hormonale illégitime. Le kétoconazole a permis une normalisation rapide du Cortisol et de l'ACTH avec un effet qui persiste après 10 ans de traitement, tandis que l'imagerie surrénalienne ne montre pas de changement de taille et d'aspect de celles-ci. La sécrétion stéroidienne chez les patients présentant une BMAH est moins importante que celle de surrénales normales ou de tumeurs secrétrices et peut être contrôlée avec de petites doses de kétoconazole. Ce traitement, bien toléré, constitue une alternative au traitement chirurgical.

Metabolic syndrome – early cardio-metabolic, vascular and hepatic changes

Background: Metabolic syndrome (MetS) is a combination of several cardio-metabolic risk factors including obesity, hyperglycemia, hypertension and dyslipidemia. MetS has been associated with increased levels of apolipoprotein B (apoB) and low-density lipoprotein oxidation (OxLDL) and with an increased risk of cardiovascular disease and non-alcoholic fatty liver disease. Aims: To establish the relation of apoB and OxLDL with the MetS development and to determine the status of MetS as a risk factor for adverse liver changes and for subclinical atherosclerosis. Subjects and Methods: The present thesis is part of the two large scale population-based, prospective, observational studies. Cardiovascular Risk in Young Finns study was launched in 1980 including 3,596 subjects aged 3-18 years. Thereafter follow-up studies have been conducted regularly. In the latest follow-ups that were performed in 2001 (N=2,283) and 2007 (N=2,204), non-invasive ultrasound studies were introduced to the study protocol to measure subclinical atherosclerosis i.e. carotid intima-media thickness (IMT), carotid artery distensibility (Cdist) and brachial flow-mediated dilatation (FMD). Alanine-aminotransferase (ALT) and gammaglutamyltransferase (GGT) were measured in 2007 to assess liver function. The Bogalusa Heart Study is a long-term epidemiologic study of cardiovascular risk factors launched in 1972 in a biracial community of Bogalusa, Louisiana, USA. Total of 374 youths (aged 9-18 years at baseline in 1984-88) who underwent non-invasive ultrasound studies of the carotid artery as adults, were included in the analyses of the present thesis. Results: The odds ratios (95% confidence intervals) for MetS incidence during a 6-year follow-up by quartiles of apoB were 2.0(1.0-3.8) for the second quartile, 3.1(1.7-5.7) for the third quartile and 4.2(2.3-7.6) for the fourth quartile. OxLDL was not independently associated with incident MetS. Youth (aged 9-18 years) with MetS or with high body mass index were at 2-3 times the risk of having MetS, high IMT, and type 2 diabetes 24-years later as adults. IMT increased 79±7μm (mean±SEM) in subjects with MetS and 42±2μm in subjects without the MetS (P<0.0001) during 6- years. Subjects who lost the MetS diagnosis during 6-year follow-up had reduced IMT progression compared to persistent MetS group (0.036±0.005vs.0.079±0.010 mm, P=0.001) and reduced Cdist change compared to incident MetS group (-0.12±0.05vs.-0.38±0.10 %/mmHg, P=0.03) over 6-year follow-up. MetS predicted elevated ALT (β±SEM=0.380±0.052, P<0.0001 in men and 0.160±0.052, P=0.002 in women) and GGT (β±SEM=0.240±0.058, P<0.0001 in men and 0.262±0.053, P<0.0001 in women) levels after 6-years. Conclusions: These findings suggest that apoB may give additional information on early metabolic disturbances predisposing MetS. MetS may be used to identify individuals at increased risk of developing atherosclerosis and non-alcoholic liver disease. However, recovery from the MetS may have positive effects on liver and vascular properties.

Daily blood pressure profile in Cushing's syndrome before and after surgery

No significant difference has been demonstrated in the altered circadian blood pressure pattern between the pituitary-dependent and adrenal forms of Cushing's syndrome before surgery. The effect of therapy, however, proved to be different. The mesor was normalized in the pituitary-dependent Cushing's syndrome more conspicuously for systolic than for diastolic blood pressure. In Cushing's syndrome due to adrenal adenoma, systolic and diastolic blood pressure mesors have been even significantly "overnormalized" after treatment, being 11 to 27 and 2 to 13 mmHg (95% confidence) lower than corresponding mesors in controls. There was no difference between forms in the effect of treatment on blood pressure amplitudes, which remained significantly lower than in controls. Finally, acrophase patterns were partly normalized after treatment of the pituitary-dependent form only for diastolic blood pressure, while both systolic and diastolic blood pressure acrophases were normalized in the treated adrenal form. In conclusion, complete normalization of the pattern of daily blood pressure profile has not been achieved in either form of the syndrome. This may be one of the reasons for the reduced long-term survival after surgical cure of hypercortisolism, than expected.

Corticosteroids in acute respiratory distress syndrome

Improving the course and outcome of patients with acute respiratory distress syndrome presents a challenge. By understanding the immune status of a patient, physicians can consider manipulating proinflammatory systems more rationally. In this context, corticosteroids could be a therapeutic tool in the armamentarium against acute respiratory distress syndrome. Corticosteroid therapy has been studied in three situations: prevention in high-risk patients, early treatment with high-dose, short-course therapy, and prolonged therapy in unresolving cases. There are differences between the corticosteroid trials of the past and recent trials: today, treatment starts 2-10 days after disease onset in patients that failed to improve; in the past, the corticosteroid doses employed were 5-140 times higher than those used now. Additionally, in the past treatment consisted of administering one to four doses every 6 h (methylprednisolone, 30 mg/kg) versus prolonging treatment as long as necessary in the new trials (2 mg kg-1 day-1 every 6 h). The variable response to corticosteroid treatment could be attributed to the heterogeneous biochemical and molecular mechanisms activated in response to different initial insults. Numerous factors need to be taken into account when corticosteroids are used to treat acute respiratory distress syndrome: the specificity of inhibition, the duration and degree of inhibition, and the timing of inhibition. The major continuing problem is when to administer corticosteroids and how to monitor their use. The inflammatory mechanisms are continuous and cyclic, sometimes causing deterioration or improvement of lung function. This article reviews the mechanisms of action of corticosteroids and the results of experimental and clinical studies regarding the use of corticosteroids in acute respiratory distress syndrome.

C-reactive protein in acute coronary syndrome: association with 3-year outcomes

Inflammatory markers have been associated with clinical outcome in patients with acute coronary syndrome (ACS). The present study evaluated the role of high-sensitivity C-reactive protein (CRP) measurements as a predictor of late cardiovascular outcomes after ACS. One hundred and ninety-nine ACS patients in a Coronary Care Unit from March to November 2002 were included and were reassessed clinically after ~3 years. Clinical variables and CRP levels were evaluated as predictors of major cardiovascular events (MACE, defined as the occurrence of cardiac death, ischemic stroke or myocardial infarction) and mortality. Statistical analyses included Cox multivariable analysis and survival curves (Kaplan-Meier). Of the 199 patients, 11 died within 1 month (5.5%). Of the 188 remaining patients, 22 died after a mean follow-up of 2.9 ± 0.5 years. Baseline CRP levels for patients with MACE (N = 57) were significantly higher than those of patients with no events (median = 0.67 mg/L; 25th-75th percentiles = 0.32 and 1.99 mg/L vs median = 0.45 mg/L; 25th-75th percentiles = 0.24 and 0.83 mg/L; P < 0.001). Patients with CRP levels >3 mg/L had a significantly lower survival than the other two groups (1-3 and <1 mg/L; P = 0.001, log-rank test). The odds ratio for MACE was 7.41 (2.03-27.09) for patients with CRP >3 mg/L compared with those with CRP <1 mg/L. For death by any cause, the hazard ratio was 4.58 (1.93-10.86). High CRP levels predicted worse long-term outcomes (MACE and death by any cause) in patients with ACS.

Electrophysiological analysis of the sleep onset period : a comparison between subjects with long term insomnia complaints associated with mild traumatic brain injury and matched controls /

The purpose of the current undertaking was to study the electrophysiological properties of the sleep onset period (SOP) in order to gain understanding into the persistent sleep difficulties of those who complain of insomnia following mild traumatic brain injury (MTBI). While many believe that symptoms of post concussion syndrome (PCS) following MTBI resolve within 6 to 12 months, there are a number of people who complain of persistent sleep difficulty. Two models were proposed which hypothesize alternate electrophysiological presentations of the insomnia complaints of those sustaining a MTBI: 1) Analyses of standard polysomnography (PSG) sleep parameters were conducted in order to determine if the sleep difficulties of the MTBI population were similar to that of idiopathic insomniacs (i.e. greater proportion ofREM sleep, reduced delta sleep); 2) Power spectral analysis was conducted over the SOP to determine if the sleep onset signature of those with MTBI would be similar to psychophysiological insomniacs (characterized by increased cortical arousal). Finally, exploratory analyses examined whether the sleep difficulties associated with MTBI could be explained by increases in variability of the power spectral data. Data were collected from 9 individuals who had sustained a MTBI 6 months to 5 years earlier and reported sleep difficulties that had arisen within the month subsequent to injury and persisted to the present. The control group consisted of 9 individuals who had experienced neither sleep difficulties, nor MTBI. Previous to spending 3 consecutive uninterrupted nights in the sleep lab, subjects completed questionnaires regarding sleep difficulties, adaptive functioning, and personality.

L’impact d’une diète néonatale déficiente en nutriments essentiels à la défense antioxydante sur le métabolisme énergétique à long terme

Les prématurés subissent un stress oxydant qui résulte d’une défense antioxydante faible et/ou d’une charge oxydante. Des données suggèrent qu’un stress oxydant peut affecter le métabolisme énergétique et mener au syndrome métabolique. Hypothèse: Une faible défense antioxydante tôt dans la vie est suffisante pour affecter le métabolisme énergétique à long terme. Méthodes: Quatre groupes de cobayes (n=21) ont reçu entre leurs 3e et 7e jours de vie une diète standard (C-1sem, C-14sem) ou une diète déficiente (DC-1sem, DC-14sem). À 7 jours, les groupes C-1sem et DC-1sem ont été sacrifiés, le plasma et le foie collectés. Les groupes C-14sem et DC-14sem ont reçu la diète standard jusqu’à 14sem de vie. La glycémie et les triglycérides plasmatiques ont été mesurés à 1, 3, 11, et 13-14sem. La tolérance au glucose a été évaluée à 13sem. Les antioxydants hépatiques et les protéines régulant le métabolisme énergétique ont été analysés à 1 et 14sem. Résultats: Un statut redox oxydé du glutathion était associé avec la diète déficiente et était maintenu oxydé au moins jusqu’à 14sem (p<0.01). Les faibles niveaux de triglycérides plasmatiques et de glycémies, ainsi qu’une meilleure tolérance au glucose à 14sem (p<0.05) étaient associés avec un statut redox plus oxydé. Conclusion: Le faible taux de glutathion observé chez les prématurés a été reproduit dans notre modèle. Puisque nos données suggèrent un rôle protecteur d’un redox plus oxydé et que l’environnement redox est un important régulateur métabolique influençant le développement, il faudrait faire attention avant d’initier des traitements antioxydants agressifs chez les prématurés.