Acute weight gain, gender, and therapeutic response to antipsychotics in the treatment of patients with schizophrenia

BACKGROUND: Previous research indicated that women are more vulnerable than men to adverse psychological consequences of weight gain. Other research has suggested that weight gain experienced during antipsychotic therapy may also psychologically impact women more negatively. This study assessed the impact of acute treatment-emergent weight gain on clinical and functional outcomes of patients with schizophrenia by patient gender and antipsychotic treatment (olanzapine or haloperidol). METHODS: Data were drawn from the acute phase (first 6-weeks) of a double-blind randomized clinical trial of olanzapine versus haloperidol in the treatment of 1296 men and 700 women with schizophrenia-spectrum disorders. The associations between weight change and change in core schizophrenia symptoms, depressive symptoms, and functional status were examined post-hoc for men and women and for each medication group. Core schizophrenia symptoms (positive and negative) were measured with the Brief Psychiatric Rating Scale (BPRS), depressive symptoms with the BPRS Anxiety/Depression Scale and the Montgomery-Asberg Depression Rating Scale, and functional status with the mental and physical component scores on the Medical Outcome Survey-Short Form 36. Statistical analysis included methods that controlled for treatment duration. RESULTS: Weight gain during 6-week treatment with olanzapine and haloperidol was significantly associated with improvements in core schizophrenia symptoms, depressive symptoms, mental functioning, and physical functioning for men and women alike. The conditional probability of clinical response (20% reduction in core schizophrenia symptom), given a clinically significant weight gain (at least 7% of baseline weight), showed that about half of the patients who lost weight responded to treatment, whereas three-quarters of the patients who had a clinically significant weight gain responded to treatment. The positive associations between therapeutic response and weight gain were similar for the olanzapine and haloperidol treatment groups. Improved outcomes were, however, more pronounced for the olanzapine-treated patients, and more olanzapine-treated patients gained weight. CONCLUSIONS: The findings of significant relationships between treatment-emergent weight gain and improvements in clinical and functional status at 6-weeks suggest that patients who have greater treatment-emergent weight gain are more likely to benefit from treatment with olanzapine or haloperidol regardless of gender

WW Domains of the Yes-Kinase-Associated-Protein (YAP) Transcriptional Regulator Behave as Independent Units with Different Binding Preferences for PPxY Motif-Containing Ligands

YAP is a WW domain-containing effector of the Hippo tumor suppressor pathway, and the object of heightened interest as a potent oncogene and stemness factor. YAP has two major isoforms that differ in the number of WW domains they harbor. Elucidating the degree of co-operation between these WW domains is important for a full understanding of the molecular function of YAP. We present here a detailed biophysical study of the structural stability and binding properties of the two YAP WW domains aimed at investigating the relationship between both domains in terms of structural stability and partner recognition. We have carried out a calorimetric study of the structural stability of the two YAP WW domains, both isolated and in a tandem configuration, and their interaction with a set of functionally relevant ligands derived from PTCH1 and LATS kinases. We find that the two YAP WW domains behave as independent units with different binding preferences, suggesting that the presence of the second WW domain might contribute to modulate target recognition between the two YAP isoforms. Analysis of structural models and phage-display studies indicate that electrostatic interactions play a critical role in binding specificity. Together, these results are relevant to understand of YAP function and open the door to the design of highly specific ligands of interest to delineate the functional role of each WW domain in YAP signaling.This work was supported by the Spanish Ministry of Education and Science [grant BIO2009-13261-CO2], the Spanish Ministry of Economy and Competitivity [grant BIO2012-39922-CO2] including FEDER (European Funds for Regional Development) funds and the Governement of Andalusia [grant CVI-5915]. Marius Sudol was supported by PA Breast Cancer Coalition Grants (#60707 and #920093) plus the Geisinger Clinic

ATP-Binding Cassette Transporter G5 and G8 Polymorphisms and Several Environmental Factors with Serum Lipid Levels

The association of ATP-binding cassette (ABC) transporter single nucleotide polymorphisms (SNPs) and serum lipid profiles is inconsistent. The present study was undertaken to detect the association of ABCG5/G8 SNPs and several environmental factors with serum lipid levels.Genotyping of the ABCG5 (rs4131229 and rs6720173) and ABCG8 (rs3806471 and rs4148211) SNPs was performed in 719 unrelated subjects of Mulao nationality and 782 participants of Han nationality. There were no differences in the genotypic and allelic frequencies of four SNPs between the two ethnic groups besides the genotypic frequencies of rs4131229 SNP in Han. The levels of triglyceride (TG), apolipoprotein (Apo) A1, and ApoA1/ApoB ratio (rs4131229); low-density lipoprotein cholesterol (LDL-C) and ApoB (rs6720173); high-density lipoprotein cholesterol (HDL-C), ApoA1, ApoB, and ApoA1/ApoB ratio (rs3806471); and HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han were different among their genotypes (P<0.05-0.001). The levels of LDL-C (rs6720173) and ApoA1 (rs3806471) in Mulao were also different among their genotypes (P<0.05 for each). The levels of TC, TG, HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4131229); LDL-C and ApoB (rs6720173); HDL-C, ApoA1, and ApoA1/ApoB ratio (rs3806471); and TG, HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han males; and ApoA1/ApoB ratio (rs4131229); LDL-C, ApoB, and ApoA1/ApoB ratio (rs3806471); HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han females were different between the genotypes (P<0.05-0.001). The levels of LDL-C in Mulao females were also different between GG and GC/CC genotypes of rs6720173 (P<0.05). The correlation between serum lipid parameters and genotypes of four SNPs was observed in Han, especially in Han males. Serum lipid parameters were also correlated with several environmental factors.The associations of four ABCG5/G8 SNPs and serum lipid levels are different between the Mulao and Han populations, or between males and females, suggesting that there may be a racial/ethnic- and/or sex-specific association between ABCG5/G8 SNPs and some serum lipid parameters

Weight Gain and New Onset Diabetes Associated with Olanzapine and Risperidone

OBJECTIVE: To assess whether newer antipsychotic medications are associated with weight gain and development of diabetes. DESIGN: Retrospective cohort study. SETTING: Data from a comprehensive electronic medical record serving an urban public hospital and a citywide network of mental health clinics. PATIENTS/PARTICIPANTS: Three thousand one hundred fifteen patients at least 18 years old who were prescribed a single antipsychotic drug for at least 1 year. METHODS: We identified independent predictors of significant weight gain (≥7%) and new onset of diabetes mellitus in the first year of antipsychotic drug treatment, using logistic regression adjusted for demographic characteristics, obesity, preexisting psychiatric diagnoses, alcohol and drug abuse, number of primary care, psychiatric clinic, and emergency department visits, and pretreatment weight. MEASUREMENTS AND MAIN RESULTS: Twenty-five percent of patients taking older phenothiazines developed significant weight gain in the first year of treatment compared to 40% of the patients taking olanzapine (adjusted odds ratio [OR], 2.8; 95% confidence interval [CI], 1.7 to 4.6; P < .0001) and 37% of patients taking risperidone (adjusted OR, 2.3; 95% CI, 1.5 to 3.4; P < .0001). New diabetes developed in 3% of patients taking older phenothiazines was new onset diabetes compared to 8.0% of patients taking olanzapine (adjusted OR, 1.9; 95% CI, 1.1 to 3.3; P= .03) and 3.5% of patients taking risperidone (adjusted OR, 0.7; 95% CI, 0.4 to 1.4; P= .3). No association was found between significant weight gain and developing diabetes (adjusted OR, 0.7; 95% CI, 0.4 to 1.4; P= .4). CONCLUSIONS: Olanzapine and risperidone use was associated with gaining weight in the first year, but only olanzapine was associated with developing diabetes mellitus

Selection of bacterial populations in the mycosphere of Laccaria proxima:is type III secretion involved?

The bacterial communities in the Laccaria proxima mycosphere (soil from beneath fruiting bodies) and the corresponding bulk soil were compared by cultivation-dependent and cultivation-independent methods. To assess the distribution of type III secretion systems (TTSS), a PCR-based system for the broad detection of a highly conserved gene involved in TTSS, that is hrcR, was developed and used to assay the cultured bacteria from the L. proxima mycosphere and surrounding bulk soil. PCR-DGGE based on the 16S ribosomal RNA gene showed the selection of presumably mycosphere-specific bacterial groups in the mycosphere of L. proxima compared to the bulk soil in 3 sampling years. Moreover, plate counts revealed that the numbers of culturable heterotrophic bacteria were increased in the mycosphere as compared to the bulk soil. Strikingly, the percentage of randomly picked isolates that carried the hrcR gene showed a significant increase, from 2.8 in the bulk to 13.4 in the mycosphere soil. The increase could be mainly attributed to the emergence of a hrcR positive Pseudomonas fluorescens, denoted BS053, which constituted the most dominant species in the culturable mycosphere communities. This organism was, together with a hrcR-positive Burkholderia terrae BS110, exclusively found in mycosphere soil. Direct detection of hrcR genes using a cultivation-independent approach showed the selection of several hrcR gene types uniquely in the mycosphere, indicating the selection of several TTSS-harboring bacterial species. Thus, different bacteria were found to be enriched in the L. proxima mycosphere and TTSS can be involved in some of the interactions with the fungal host