Management of bipolar disorder in the intercontinental region: an international, multicenter, non-interventional, cross-sectional study in real-life conditions

Most of the existing data on real-life management of bipolar disorder are from studies conducted in western countries (mostly United States and Europe). This multinational, observational cohort study aimed to describe the management and clinical outcomes of bipolar patients in real-life conditions across various intercontinental countries (Bangladesh, Egypt, Iran, Israel, Tunisia, and Ukraine). Data on socio-demographic and disease characteristics, current symptomatology, and pharmacological treatment were collected. Comparisons between groups were performed using standard statistical tests. Overall, 1180 patients were included. The median time from initial diagnosis was 80 months. Major depressive disorder was the most common initial diagnosis. Mood stabilizers and antipsychotics were the most common drugs being prescribed at the time of the study. Antidepressants (mainly selective serotonin uptake inhibitors [SSRIs]) were administered to 36.1% of patients. Patients with bipolar I disorder received higher number of antipsychotics and anxiolytics than those with bipolar II disorder (p < 0.001). Presence of depressive symptoms was associated with an increase in antidepressant use (p < 0.001). Bipolar disorder real-life management practice, irrespective of region, shows a delay in diagnosis and an overuse of antidepressants. Clinical decision-making appears to be based on a multidimensional approach related to current symptomatology and type of bipolar disorder

Sleep-wake sensitive mechanisms of adenosine release in the basal forebrain of rodents : an in vitro study

Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB) to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state

Immunolocalization of dually phosphorylated MAPKs in dividing root meristem cells of Vicia faba, Pisum sativum, Lupinus luteus and Lycopersicon esculentum

Key message In plants, phosphorylated MAPKs display constitutive nuclear localization; however, not all studied plant species show co-localization of activated MAPKs to mitotic microtubules. Abstract The mitogen-activated protein kinase (MAPK) signaling pathway is involved not only in the cellular response to biotic and abiotic stress but also in the regulation of cell cycle and plant development. The role of MAPKs in the formation of a mitotic spindle has been widely studied and the MAPK signaling pathway was found to be indispensable for the unperturbed course of cell division. Here we show cellular localization of activated MAPKs (dually phosphorylated at their TXY motifs) in both interphase and mitotic root meristem cells of Lupinus luteus, Pisum sativum, Vicia faba (Fabaceae) and Lycopersicon esculentum (Solanaceae). Nuclear localization of activated MAPKs has been found in all species. Colocalization of these kinases to mitotic microtubules was most evident in L. esculentum, while only about 50 % of mitotic cells in the root meristems of P. sativum and V. faba displayed activated MAPKs localized to microtubules during mitosis. Unexpectedly, no evident immunofluorescence signals at spindle microtubules and phragmoplast were noted in L. luteus. Considering immunocytochemical analyses and studies on the impact of FR180204 (an inhibitor of animal ERK1/2) on mitotic cells, we hypothesize that MAPKs may not play prominent role in the regulation of microtubule dynamics in all plant species

Refractory periods and climate forcing in cholera dynamics

Outbreaks of many infectious diseases, including cholera, malaria and dengue, vary over characteristic periods longer than 1 year(1,2). Evidence that climate variability drives these interannual cycles has been highly controversial, chiefly because it is difficult to isolate the contribution of environmental forcing while taking into account nonlinear epidemiological dynamics generated by mechanisms such as host immunity(2-4). Here we show that a critical interplay of environmental forcing, specifically climate variability, and temporary immunity explains the interannual disease cycles present in a four-decade cholera time series from Matlab, Bangladesh. We reconstruct the transmission rate, the key epidemiological parameter affected by extrinsic forcing, over time for the predominant strain ( El Tor) with a nonlinear population model that permits a contributing effect of intrinsic immunity. Transmission shows clear interannual variability with a strong correspondence to climate patterns at long periods ( over 7 years, for monsoon rains and Brahmaputra river discharge) and at shorter periods ( under 7 years, for flood extent in Bangladesh, sea surface temperatures in the Bay of Bengal and the El Nino Southern Oscillation). The importance of the interplay between extrinsic and intrinsic factors in determining disease dynamics is illustrated during refractory periods, when population susceptibility levels are low as the result of immunity and the size of cholera outbreaks only weakly reflects climate forcing.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62876/1/nature03820.pd

Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites

Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter μ, the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, μ was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery

Optimality of mutation and selection in germinal centers

The population dynamics theory of B cells in a typical germinal center could play an important role in revealing how affinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts, we present a coarse-grained model to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement. With these optimized parameters, the model is compatible with the experimental observations such as the ~100-fold affinity improvements, the number of mutations, the hypermutation rate, and the "all or none" phenomenon. Moreover, we study the reasons behind the optimal parameters. The optimal mutation rate, in agreement with the hypermutation rate in vivo, results from a tradeoff between accumulating enough beneficial mutations and avoiding too many deleterious or lethal mutations. The optimal selection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings point to the conclusion that germinal centers have been optimized by evolution to generate strong affinity antibodies effectively and rapidly. In addition, we study the enhancement of affinity improvement due to B cell migration between germinal centers. These results could enhance our understandings to the functions of germinal centers.Comment: 5 figures in main text, and 4 figures in Supplementary Informatio

Family physician and endocrinologist coordination as the basis for diabetes care in clinical practice

<p>Abstract</p> <p>Background</p> <p>To estimate the proportion of diabetic patients (DPts) with peripheral vascular disease treated at a primary health care site after an endocrinologist-based intervention, who meet ATP III and Steno targets of metabolic control, as well as to compare the outcome with the results of the patients treated by endocrinologists.</p> <p>Methods</p> <p>A controlled, prospective over 30-months period study was conducted in area 7 of Madrid. One hundred twenty six eligible diabetic patients diagnosed as having peripheral vascular disease between January 2003 and June 2004 were included in the study. After a treatment period of three months by the Diabetes team at St Carlos Hospital, 63 patients were randomly assigned to continue their follow up by diabetes team (Group A) and other 63 to be treated by the family physicians (FP) at primary care level with continuous diabetes team coordination (Group B). 57 DPts from Group A and 59 from Group B, completed the 30 months follow-up period. At baseline both groups were similar in age, weight, time from diagnosis and metabolic control. The main outcomes of this study were the proportion of patients meeting ATP III and Steno goals for HbA1c (%), Cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, blood pressure, albumine-to-creatinine excretion ratio (ACR), body mass index (BMI), waist circumference (WC), anti-aggregation treatment and smoking status.</p> <p>Results</p> <p>At the end of the follow up, no differences were found between the groups. More than 37% of diabetic patients assigned to be treated by FP achieved a HbA1c < 6.5%, more than 50% a ACR < 30 mg/g, and more than 80% reached low risk values for cholesterol, LDL cholesterol, triglycerides, diastolic blood pressure and were anti-aggregated, and 12% remained smokers. In contrast, less than 45% achieved a systolic blood pressure < 130 mm Hg, less than 12% had a BMI < 25 Kg.m-2 (versus 23% in group A; p < 0.05) and 49%/30% (men/women) had a waist circumference of low risk.</p> <p>Conclusion</p> <p>Improvements in metabolic control among diabetic patients with peripheral vascular disease treated at a primary health care setting is possible, reaching similar results to the patients treated at a specialized level. Despite such an improvement, body weight control remains more than poor in both levels, mainly at primary care level. General practitioner and endocrinologist coordination care may be important to enhance diabetes management in primary care settings.</p> <p>Trial registration</p> <p>Clinical Trial number ISRCTN75037597</p

The effects of hypertonic fluid administration on the gene expression of inflammatory mediators in circulating leucocytes in patients with septic shock: a preliminary study

Contains fulltext : 98426.pdf (publisher's version ) (Open Access)ABSTRACT: OBJECTIVE: This study was designed to investigate the effect of hypertonic fluid administration on inflammatory mediator gene expression in patients with septic shock. DESIGN AND SETTING: Prospective, randomized, controlled, double-blind clinical study in a 15-bed mixed intensive care unit in a tertiary referral teaching hospital. INTERVENTIONS: Twenty-four patients, who met standard criteria for septic shock, were randomized to receive a bolus of hypertonic fluid (HT, 250 ml 6% HES/7.2% NaCl) or isotonic fluid (IT, 500 ml 6% HES/0.9% NaCl) administered over 15 minutes. Randomization and study fluid administration was within 24 hours of ICU admission for all patients. This trial is registered with ANZCTR.org.au as ACTRN12607000259448. RESULTS: Blood samples were taken immediately before and 4, 8, 12, and 24 hours after fluid administration. Real-time reverse transcriptase polymerase chain reaction (RT rtPCR) was used to quantify mRNA expression of different inflammatory mediators in peripheral leukocytes. In the HT group, compared with the IT group, levels of gene expression of MMP9 and L-selectin were significantly suppressed (p = 0.0002 and p = 0.007, respectively), and CD11b gene expression tended to be elevated (p = NS). No differences were found in the other mediators examined. CONCLUSIONS: In septic shock patients, hypertonic fluid administration compared with isotonic fluid may modulate expression of genes that are implicated in leukocyte-endothelial interaction and capillary leakage.The study was performed at the Intensive Care Department, Waikato Hospital, and at the Molecular Genetics Laboratory, University of Waikato, Hamilton, New Zealand. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12607000259448

Understanding Actions of Others: The Electrodynamics of the Left and Right Hemispheres. A High-Density EEG Neuroimaging Study

Background: When we observe an individual performing a motor act (e.g. grasping a cup) we get two types of information on the basis of how the motor act is done and the context: what the agent is doing (i.e. grasping) and the intention underlying it (i.e. grasping for drinking). Here we examined the temporal dynamics of the brain activations that follow the observation of a motor act and underlie the observer’s capacity to understand what the agent is doing and why. Methodology/Principal Findings: Volunteers were presented with two-frame video-clips. The first frame (T0) showed an object with or without context; the second frame (T1) showed a hand interacting with the object. The volunteers were instructed to understand the intention of the observed actions while their brain activity was recorded with a high-density 128-channel EEG system. Visual event-related potentials (VEPs) were recorded time-locked with the frame showing the hand-object interaction (T1). The data were analyzed by using electrical neuroimaging, which combines a cluster analysis performed on the group-averaged VEPs with the localization of the cortical sources that give rise to different spatiotemporal states of the global electrical field. Electrical neuroimaging results revealed four major steps: 1) bilateral posterior cortical activations; 2) a strong activation of the left posterior temporal and inferior parietal cortices with almost a complete disappearance of activations in the right hemisphere; 3) a significant increase of the activations of the right temporo-parieta