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 treatment with insulin induces apoptosis in brown adipocytes: role of oxidative stress

Trying to define the precise role played by insulin regulating the survival of brown adipocytes, we have used rat fetal brown adipocytes maintained in primary culture. The effect of insulin on apoptosis and the mechanisms involved were assessed. Different from the known effects of insulin as a survival factor, we have found that long-term treatment (72 h) with insulin induces apoptosis in rat fetal brown adipocytes. This process is dependent on the phosphatidylinositol 3-kinase/mammalian target of rapamycin/p70 S6 kinase pathway. Short-term treatment with the conditioned medium from brown adipocytes treated with insulin for 72 h mimicked the apoptotic effect of insulin. During the process, caspase 8 activation, Bid cleavage, cytochrome c release, and activation of caspases 9 and 3 are sequentially produced. Treatment with the caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (Z-VAD), prevents activation of this apoptotic cascade. The antioxidants, ascorbic acid and superoxide dismutase, also impair this process of apoptosis. Moreover, generation of reactive oxygen species (ROS), probably through reduced nicotinamide adenine dinucleotide phosphate oxidases, and a late decrease in reduced glutathione content are produced. According to this, antioxidants prevent caspase 8 activation and Bid cleavage, suggesting that ROS production is an important event mediating this process of apoptosis. However, the participation of uncoupling protein-1, -2, and -3 regulating ROS is unclear because their levels remain unchanged upon insulin treatment for 72 h. Our data suggest that the prolonged hyperinsulinemia might cause insulin resistance through the loss of brown adipose tissue.

Long-term persistence of immunity induced by OVA-coupled gas-filled microbubble vaccination partially protects mice against infection by OVA-expressing Listeria.

Vaccination aims at generating memory immune responses able to protect individuals against pathogenic challenges over long periods of time. Subunit vaccine formulations based on safe, but poorly immunogenic, antigenic entities must be combined with adjuvant molecules to make them efficient against infections. We have previously shown that gas-filled microbubbles (MB) are potent antigen-delivery systems. This study compares the ability of various ovalbumin-associated MB (OVA-MB) formulations to induce antigen-specific memory immune responses and evaluates long-term protection toward bacterial infections. When initially testing dendritic cells reactivity to MB constituents, palmitic acid exhibited the highest degree of activation. Subcutaneous immunization of naïve wild-type mice with the OVA-MB formulation comprising the highest palmitic acid content and devoid of PEG2000 was found to trigger the more pronounced Th1-type response, as reflected by robust IFN-γ and IL-2 production. Both T cell and antibody responses persisted for at least 6 months after immunization. At that time, systemic infection with OVA-expressing Listeria monocytgenes was performed. Partial protection of vaccinated mice was demonstrated by reduction of the bacterial load in both the spleen and liver. We conclude that antigen-bound MB exhibit promising properties as a vaccine candidate ensuring prolonged maintenance of protective immunity.

Long-Term Anticoagulant Therapy of Patients with Venous Thromboembolism. What Are the Practices?

Current guidelines of antithrombotic therapy suggest early initiation of vitamin K antagonists (VKA) in non-cancer patients with venous thromboembolism (VTE), and long-term therapy with low-molecular weight heparin (LMWH) for those with cancer. We used data from RIETE (international registry of patients with VTE) to report the use of long-term anticoagulant therapy over time and to identify predictors of anticoagulant choice (regarding international guidelines) in patients with- and without cancer. Among 35,280 patients without cancer, 82% received long-term VKA (but 17% started after the first week). Among 4,378 patients with cancer, 66% received long term LMWH as monotherapy. In patients without cancer, recent bleeding (odds ratio [OR] 2.70, 95% CI 2.26-3.23), age >70 years (OR 1.15, 95% CI 1.06-1.24), immobility (OR 2.06, 95% CI 1.93-2.19), renal insufficiency (OR 2.42, 95% CI 2.15-2.71) and anemia (OR 1.75, 95% CI 1.65-1.87) predicted poor adherence to guidelines. In those with cancer, anemia (OR 1.83, 95% CI 1.64-2.06), immobility (OR 1.51, 95% CI 1.30-1.76) and metastases (OR 3.22, 95% CI 2.87-3.61) predicted long-term LMWH therapy. In conclusion, we report practices of VTE therapy in real life and found that a significant proportion of patients did not receive the recommended treatment. The perceived increased risk for bleeding has an impact on anticoagulant treatment decision.

Fondaparinux in the initial and long-term treatment of venous thromboembolism.

BACKGROUND: Even in the absence of evidence on its long-term efficacy and safety, a number of patients with venous thromboembolism (VTE) receive long-term therapy with fondaparinux alone in everyday practice. METHODS: We used the Registro Informatizado de Enfermedad Tromboembólica (RIETE) registry to compare the rate of VTE recurrences and major bleeding at 10 and 90 days in patients with and without cancer. For long-term therapy, fondaparinux was compared with vitamin K antagonists (VKA) in patients without cancer and with low-molecular-weight heparin (LMWH) in those with cancer. RESULTS: Of 47,378 patients recruited, 46,513 were initially treated with heparin, 865 with fondaparinux. Then, 263 patients (78 with cancer) were treated for at least 3 months with fondaparinux. After propensity-score matching, there were no differences between patients receiving initial therapy with heparin or fondaparinux. Among patients with cancer, there were no differences between fondaparinux and LMWH. Among patients without cancer, the long-term use of fondaparinux was associated with an increased risk of major bleeding (3.24 % vs. 0.95 %, p<0.05). CONCLUSIONS: An unexpected high rate of major bleeding was observed in non-cancer patients treated with long-term fondaparinux. Our small sample does not allow to derive relevant conclusions on the use of fondaparinux in cancer patients.

Accessing forgotten memory traces from long-term memory via visual movements

Because memory retrieval often requires overt responses, it is difficult to determine to what extend forgetting occurs as a problem in explicit accessing of long-term memory traces. In this study, we used eye-tracking measures in combination with a behavioural task that favoured high forgetting rates to investigate the existence of memory traces from long-term memory in spite of failure in accessing them consciously. In 2 experiments, participants were encouraged to encode a large set of sound-picture56 location associations. In a later test, sounds were presented and participants were instructed to visually scan, before a verbal memory report, for the correct location of the associated pictures in an empty screen. We found the reactivation of associated memories by sound cues at test biased oculomotor behaviour towards locations congruent with memory representations, even when participants failed to consciously provide a memory report of it. These findings reveal the emergence of a memory-guided behaviour that can be used to map internal representations of forgotten memories from long-term memory.

Evolution à long term du syndrom de Widal après chirurgie endoscopique endonasale

Ce travail de recherche a été effectué dans le cadre d'une formation post-graduée à l'Hôpital de La Chaux-de-Fonds, dans lequel le service ORL bénéficie d'un recrutement significatif pour les pathologies naso-sinusiennes, en particulier les polyposes. Ces pathologies sont grevées d'un handicap fonctionnel considérable, de par l'obstruction nasale, la limitation des efforts physiques et les troubles olfactifs comme principales répercussions. J'ai ainsi répertorié 303 interventions endonasales pour ablation de polypes et drainage des cavités sinusales. effectuées entre 1987 et 2006. L'étude s'est focalisée sur les 33 patients atteints d'une polypose nasale mais également d'un asthme et d'une intolérance à l'aspirine, réalisant la triade de Widal. La prévalence en Europe pour la polypose nasale est de 1 à 2 %, dont 10 à 20 % de syndromes de Widal. Cette entité est grevée d'une morbidité plus sévère en raison des mécanismes métaboliques induisant des récidives de polypes précoces, rendant la maladie plus difficile à contrôler. Ces patients ont été évalués d'une part subjectivement par une échelle visuelle analogique pour les symptômes rhinologiques et généraux, et d'autre part via une analyse objective du status endonasal de la polypose à la fin du suivi. Pour chaque patient, les troubles fonctionnels résiduels (obstruction nasale, rhinorrhée, troubles olfactifs, céphalées, éternuements, larmoiement) ainsi que le status endonasal à la fin du suivi ont été analysés pour détecter d'éventuelles associations significatives avec les caractéristiques pré-opératoires (âge, sexe, allergies, antécédants de chirurgie endonasale, données scanographiques, status endonasal). Deux groupes ont été identifiés selon la sévérité de l'atteinte fonctionnelle résiduelle. La valeur moyenne de la gêne à la fin du suivi pour l'ensemble du collectif est de 3.9/10 sur l'échelle visuelle analogique (0= absence de gêne, 10= gêne maximale). Les facteurs de mauvais pronostic qui ont été identifiés sont le sexe féminin et la présence de polyallergies, mais sans relation statistiquement significative. La seule différence statistiquement significative est le stade avancé de polypose nasale à la fin du suivi dans le groupe présentant l'atteinte fonctionnelle la plus importante (groupe 2). Malgré la combinaison des traitements chirurgicaux et médicamenteux par corticoïdes et anti-leucotriènes, la maladie de Widal est grevée d'une gêne fonctionnelle résiduelle non négligeable dans notre suivi moyen de 11,6 ans. Ceci relativise les résultats parfois trop optimistes des études avec un suivi plus court, sachant que les délais avant une deuxième intervention chirurgicale dans notre série ont été de 6,5 ans. L'évolution des traitements immuno-modulateurs topiques et systémiques combinés aux interventions chirurgicales ponctuelles renforce l'arsenal thérapeutique dans la prise en charge des patients atteints de la maladie de Widal. Cette étude pourra être élargie au collectif entier des ethmoïdectomies répertoriées (n=303) dans le service ORL et actualisées, afin de rechercher et mettre en évidence d'autres associations en comparant le groupe des polyposes simples au groupe des triades de Widal.

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.