The longitudinal interplay between negative and positive symptom trajectories in patients under antipsychotic treatment: a post hoc analysis of data from a randomized, 1-year pragmatic trial

BACKGROUND: Schizophrenia is a highly heterogeneous disorder with positive and negative symptoms being characteristic manifestations of the disease. While these two symptom domains are usually construed as distinct and orthogonal, little is known about the longitudinal pattern of negative symptoms and their linkage with the positive symptoms. This study assessed the temporal interplay between these two symptom domains and evaluated whether the improvements in these symptoms were inversely correlated or independent with each other. METHODS: This post hoc analysis used data from a multicenter, randomized, open-label, 1-year pragmatic trial of patients with schizophrenia spectrum disorder who were treated with first- and second-generation antipsychotics in the usual clinical settings. Data from all treatment groups were pooled resulting in 399 patients with complete data on both the negative and positive subscale scores from the Positive and Negative Syndrome Scale (PANSS). Individual-based growth mixture modeling combined with interplay matrix was used to identify the latent trajectory patterns in terms of both the negative and positive symptoms. Pearson correlation coefficients were calculated to examine the relationship between the changes of these two symptom domains within each combined trajectory pattern. RESULTS: We identified four distinct negative symptom trajectories and three positive symptom trajectories. The trajectory matrix formed 11 combined trajectory patterns, which evidenced that negative and positive symptom trajectories moved generally in parallel. Correlation coefficients for changes in negative and positive symptom subscale scores were positive and statistically significant (P < 0.05). Overall, the combined trajectories indicated three major distinct patterns: (1) dramatic and sustained early improvement in both negative and positive symptoms (n = 70, 18%), (2) mild and sustained improvement in negative and positive symptoms (n = 237, 59%), and (3) no improvement in either negative or positive symptoms (n = 82, 21%). CONCLUSIONS: This study of symptom trajectories over 1 year shows that changes in negative and positive symptoms were neither inversely nor independently related with each other. The positive association between these two symptom domains supports the notion that different symptom domains in schizophrenia may depend on each other through a unified upstream pathological disease process

The Shapes of Cooperatively Rearranging Regions in Glass Forming Liquids

The shapes of cooperatively rearranging regions in glassy liquids change from being compact at low temperatures to fractal or ``stringy'' as the dynamical crossover temperature from activated to collisional transport is approached from below. We present a quantitative microscopic treatment of this change of morphology within the framework of the random first order transition theory of glasses. We predict a correlation of the ratio of the dynamical crossover temperature to the laboratory glass transition temperature, and the heat capacity discontinuity at the glass transition, Delta C_p. The predicted correlation agrees with experimental results for the 21 materials compiled by Novikov and Sokolov.Comment: 9 pages, 6 figure

Mutation Accumulation May Be a Minor Force in Shaping Life History Traits

Is senescence the adaptive result of tradeoffs between younger and older ages or the nonadaptive burden of deleterious mutations that act at older ages? To shed new light on this unresolved question we combine adaptive and nonadaptive processes in a single model. Our model uses Penna's bit-strings to capture different age-specific mutational patterns. Each pattern represents a genotype and for each genotype we find the life history strategy that maximizes fitness. Genotypes compete with each other and are subject to selection and to new mutations over generations until equilibrium in gene-frequencies is reached. The mutation-selection equilibrium provides information about mutational load and the differential effects of mutations on a life history trait - the optimal age at maturity. We find that mutations accumulate only at ages with negligible impact on fitness and that mutation accumulation has very little effect on the optimal age at maturity. These results suggest that life histories are largely determined by adaptive processes. The non-adaptive process of mutation accumulation seems to be unimportant at evolutionarily relevant ages

Predictors of switching antipsychotic medications in the treatment of schizophrenia

<p>Abstract</p> <p>Background</p> <p>To identify patient characteristics and early changes in patients' clinical status that best predict subsequent switching of antipsychotic agents in the long-term treatment of schizophrenia.</p> <p>Methods</p> <p>This post-hoc analysis used data from a one-year randomized, open-label, multisite study of antipsychotics in the treatment of schizophrenia. The study protocol permitted switching of antipsychotics when clinically warranted after the first eight weeks. Baseline patient characteristics were assessed using standard psychiatric measures and reviews of medical records. The prediction model included baseline sociodemographics, comorbid psychiatric and non-psychiatric conditions, body weight, clinical and functional variables, as well as change scores on standard efficacy and tolerability measures during the first two weeks of treatment. Cox proportional hazards modeling was used to identify the best predictors of switching from the initially assigned antipsychotic medication.</p> <p>Results</p> <p>About one-third of patients (29.5%, 191/648) switched antipsychotics before the end of the one-year study. There were six variables identified as the best predictors of switching: lack of antipsychotic use in the prior year, pre-existing depression, female gender, lack of substance use disorder, worsening of akathisia (as measured by the Barnes Akathisia Scale), and worsening of symptoms of depression/anxiety (subscale score on the Positive and Negative Syndrome Scale) during the first two weeks of antipsychotic therapy.</p> <p>Conclusions</p> <p>Switching antipsychotics appears to be prevalent in the naturalistic treatment of schizophrenia and can be predicted by a small and distinct set of variables. Interestingly, worsening of anxiety and depressive symptoms and of akathisia following two weeks of treatment were among the more robust predictors of subsequent switching of antipsychotics.</p

Temperature Anomalies and Mortality Events in Marine Communities: Insights on Factors behind Differential Mortality Impacts in the NW Mediterranean

Two large-scale mass mortality events (MMEs) of unprecedented extent and severity affecting rocky benthic communities occurred during the summers of 1999 and 2003 along the coasts of the NW Mediterranean Sea. These mortality outbreaks were associated with positive thermal anomalies. In this study, we performed an analysis of inter-regional and inter-annual differences in temperature (T) conditions associated with MMEs of the red gorgonian Paramuricea clavata by analyzing high resolution T time series (hourly records for 3 to 8 years) from four regions of the NW Mediterranean with differing hydrological conditions and biological impacts. High resolution records allowed a detailed analysis using classical and new descriptors to characterize T anomalies. We were able to determine that the MMEs were triggered by two main types of positive thermal anomalies, with the first type being characterized by short periods (2 to 5 days) with high Mean T reaching more than 27°C in some regions and being associated with high intra-day and intra-period variability, while the second type of anomaly presented long duration (near one month) at warm T (24°C) with low intra-period variability. Inter-regional patterns arose; some regions displayed both types of anomalies, while others exhibited only one type. The results showed that T conditions should be considered as the main factor that explains the observed inter-regional and inter-annual differences in mortality impacts. In explaining these differences, the late timing of T anomalies, in addition to their magnitude was found to be determinant. Finally, by combining thermotolerance experimental data with the maximal T stress conditions observed in the four regions, we were able to determine the differential risk of mass mortality across regions. We conclude that expanding high resolution T series is important for the development of sound management and conservation plans to protect Mediterranean marine biodiversity in the face of climate change

Essential Role of Cyclophilin A for Hepatitis C Virus Replication and Virus Production and Possible Link to Polyprotein Cleavage Kinetics

Viruses are obligate intracellular parasites and therefore their replication completely depends on host cell factors. In case of the hepatitis C virus (HCV), a positive-strand RNA virus that in the majority of infections establishes persistence, cyclophilins are considered to play an important role in RNA replication. Subsequent to the observation that cyclosporines, known to sequester cyclophilins by direct binding, profoundly block HCV replication in cultured human hepatoma cells, conflicting results were obtained as to the particular cyclophilin (Cyp) required for viral RNA replication and the underlying possible mode of action. By using a set of cell lines with stable knock-down of CypA or CypB, we demonstrate in the present work that replication of subgenomic HCV replicons of different genotypes is reduced by CypA depletion up to 1,000-fold whereas knock-down of CypB had no effect. Inhibition of replication was rescued by over-expression of wild type CypA, but not by a mutant lacking isomerase activity. Replication of JFH1-derived full length genomes was even more sensitive to CypA depletion as compared to subgenomic replicons and virus production was completely blocked. These results argue that CypA may target an additional viral factor outside of the minimal replicase contributing to RNA amplification and assembly, presumably nonstructural protein 2. By selecting for resistance against the cyclosporine analogue DEBIO-025 that targets CypA in a dose-dependent manner, we identified two mutations (V2440A and V2440L) close to the cleavage site between nonstructural protein 5A and the RNA-dependent RNA polymerase in nonstructural protein 5B that slow down cleavage kinetics at this site and reduce CypA dependence of viral replication. Further amino acid substitutions at the same cleavage site accelerating processing increase CypA dependence. Our results thus identify an unexpected correlation between HCV polyprotein processing and CypA dependence of HCV replication

Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrogen receptor beta - regulation by selective estrogen receptor modulators and importance in breast cancer

Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen receptor (ER), now referred to as selective estrogen receptor modulators (SERMs), can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two estrogen receptor subtypes, ERα and ERβ, that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER-ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents