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Background: Few studies in low-income settings analyse linear growth trajectories from foetal life to pre-adolescence. The aim of this study is to describe linear growth and stunting from birth to 10 years in rural Bangladesh and to analyse whether maternal and environmental determinants at conception are associated with linear growth throughout childhood and stunting at 10 years., Methods and Findings: Pregnant women participating in the MINIMat trial were identified in early pregnancy and a birth cohort (n = 1054) was followed with 19 growth measurements from birth to 10 years. Analyses of baseline predictors and mean height-for-age Z-scores (HAZ) over time were modelled using GLMM. Logistic regression analysis was used to investigate the associations between baseline predictors and stunting (HAZ<-2) at 10 years. HAZ decreased to 2 years, followed by an increase up to 10 years, while the average height-for-age difference in cm (HAD) to the WHO reference median continued to increase up to 10 years. Prevalence of stunting was highest at 2 years (50%) decreasing to 29% at 10 years. Maternal height, maternal educational level and season of conception were all independent predictors of HAZ from birth to pre-adolescence (p<0.001) and stunting at 10 years. The highest probability to be stunted at 10 years was for children born by short mothers (<147.5 cm) (ORadj 2.93, 95% CI: 2.06-4.20), mothers with no education (ORadj 1.74, 95% CI 1.17-2.81) or those conceived in the pre-monsoon season (ORadj 1.94, 95% CI 1.37-2.77)., Conclusions: Height growth trajectories and prevalence of stunting in pre-adolescence showed strong intergenerational associations, social differentials, and environmental influence from foetal life. Targeting women before and during pregnancy is needed for the prevention of impaired child growth.

Background: Proteases play a major role in inflammatory diseases of the gastrointestinal tract. Activatable probes are a major technological advance, enabling sensitive detection of active proteases in tissue samples. Our aim was to synthesize an activatable probe for cathepsin S and validate its use in a mouse model of colitis., Methods: We designed and synthesized a new fluorescent activatable probe, NB200, for the detection of active cathepsin S. Colitis was induced in C57BL/6 mice by the administration of 3% dextran sulfate sodium (DSS). Homogenized mouse colons, with or without the addition of the specific cathepsin S inhibitor MV026031, were incubated with NB200 in a fluorescent plate reader., Key Results: NB200 selectively detected purified cathepsin S and not other common inflammatory proteases. Homogenates of colon from mice with DSS colitis induced a significant fluorescent increase when compared to control animals (control vs DSS: p < 0.05 at 200 min and p < 0.01 at 220-240 min), indicating cathepsin S activation. The cathepsin S inhibitor abolished this increase in fluorescence (DSS vs DSS + MV026031: p < 0.05 at 140 min, p < 0.01 at 180 min, p < 0.001 at 200-240 min), which confirms cathepsin S activation. Cathepsin S activity correlated with the disease activity index (Spearman r = 0.77, p = 0.017)., Conclusions & Inferences: Our investigation has demonstrated the utility of activatable probes for detecting protease activity in intestinal inflammation. Panels of such probes may allow 'signature' protease profiles to be established for a range of inflammatory diseases and disorders., (© 2015 John Wiley & Sons Ltd.)

Objectives: The purpose of this cross-sectional study was to determine the prevalence of hoarseness in children attending the first or second grade of primary school and to explore possible background factors for hoarseness in children., Methods: The participants were 217 children, aged 6-10 years, from 10 different schools. Questionnaires were filled in by the parents and the teachers of the children and voice samples were recorded. The voice samples from the children were perceptually evaluated by eight trained listeners and intra- and inter-rater reliability was calculated. Additionally, the parents and teachers were in the questionnaires asked to rate the children's voices. Connections between background factors and voice quality were explored., Results: Both the intra- and inter-rater reliability for the trained listeners were relatively high and significant. The prevalence of hoarseness for the whole group was 12.0% as judged by the trained listeners. For girls, the prevalence of hoarseness was 7.8% and for boys 15.8%. A lower teacher rating of degree of maturity correlated significantly with the voice quality. Additionally, there was a significant negative correlation between the amount of talking at home and voice quality. For girls, heavy voice use as an infant correlated significantly with voice quality. For boys, being the youngest sibling correlated significantly with voice quality., Conclusions: The results from the present study indicate that more attention should be paid to hoarseness in children and that background factors should be further explored., (Copyright © 2015 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

The aims of this naturalistic non-interventional study were to quantify the level of stigma and discrimination in persons with schizophrenia and to test for potential associations between different types of stigma and adherence to antipsychotics. Antipsychotic medication use was electronically monitored with a Medication Event Monitoring System (MEMS®) for 12 months in 111 outpatients with schizophrenia and schizophrenia-like psychosis (DSM-IV). Stigma was assessed at endpoint using the Discrimination and Stigma Scale (DISC). Single DISC items that were most frequently reported included social relationships in making/keeping friends (71%) and in the neighborhood (69%). About half of the patients experienced discrimination by their families, in intimate relationships, regarding employment and by mental health staff. Most patients (88%) wanted to conceal their mental health problems from others; 70% stated that anticipated discrimination resulted in avoidance of close personal relationships. Non-adherence (MEMS® adherence≤0.80) was observed in 30 (27.3%). When DISC subscale scores (SD) were entered in separate regression models, neither experienced nor anticipated stigma was associated with adherence. Our data do not support an association between stigma and non-adherence. Further studies in other settings are needed as experiences of stigma and levels of adherence and their potential associations might vary by a healthcare system or cultural and sociodemographic contexts.

Objective: To investigate the association between the Positive and Negative Syndrome Scale (PANSS) cognitive factors and cognition assessed by neuropsychological tests., Method: Ninety patients with a psychotic illness, the majority having a schizophrenia diagnosis, were assessed with PANSS ratings and tested by a comprehensive computerized neuropsychological test battery, EuCog., Results: Test performance was in the normal range for some of the cognitive indices, but substantially reduced for others, compared with norms, particularly speed-based indices. PANSS ratings were non-specifically associated with cognitive indices representing performance (speed and accuracy) and problem solving strategies (executive functions). There was no discriminant validity for the cognitive factor. A regression analysis suggested that the PANSS cognitive factors reflected verbal IQ but no other cognitive domain like memory, attention or speed., Conclusion: Cognitive test performance is associated with psychopathology as assessed by PANSS items but in a non-specific way. The PANSS cognitive subscale seems to reflect over-learned verbal skills rather than the cognitive domains, which are known to be specifically affected in schizophrenia and relevant for the prognosis. Consequently, PANSS ratings cannot replace the information inherent in neuropsychological test data. The extensive speed problem of patients with schizophrenia should be studied in more detail using test batteries that focus on that problem.

Serine proteases such as trypsin and mast cell tryptase cleave protease-activated receptor-2 (PAR2) at R(36)↓S(37) and reveal a tethered ligand that excites nociceptors, causing neurogenic inflammation and pain. Whether proteases that cleave PAR2 at distinct sites are biased agonists that also induce inflammation and pain is unexplored. Cathepsin S (Cat-S) is a lysosomal cysteine protease of antigen-presenting cells that is secreted during inflammation and which retains activity at extracellular pH. We observed that Cat-S cleaved PAR2 at E(56)↓T(57), which removed the canonical tethered ligand and prevented trypsin activation. In HEK and KNRK cell lines and in nociceptive neurons of mouse dorsal root ganglia, Cat-S and a decapeptide mimicking the Cat-S-revealed tethered ligand-stimulated PAR2 coupling to Gαs and formation of cAMP. In contrast to trypsin, Cat-S did not mobilize intracellular Ca(2+), activate ERK1/2, recruit β-arrestins, or induce PAR2 endocytosis. Cat-S caused PAR2-dependent activation of transient receptor potential vanilloid 4 (TRPV4) in Xenopus laevis oocytes, HEK cells and nociceptive neurons, and stimulated neuronal hyperexcitability by adenylyl cyclase and protein kinase A-dependent mechanisms. Intraplantar injection of Cat-S caused inflammation and hyperalgesia in mice that was attenuated by PAR2 or TRPV4 deletion and adenylyl cyclase inhibition. Cat-S and PAR2 antagonists suppressed formalin-induced inflammation and pain, which implicates endogenous Cat-S and PAR2 in inflammatory pain. Our results identify Cat-S as a biased agonist of PAR2 that causes PAR2- and TRPV4-dependent inflammation and pain. They expand the role of PAR2 as a mediator of protease-driven inflammatory pain., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

The primary aim was to compare objective and subjective measures of adherence in a naturalistic cohort of schizophrenia outpatients over 12 months between October 2008 and June 2011. Antipsychotic medication adherence was monitored in 117 outpatients diagnosed with schizophrenia or schizophrenia-like psychosis according to DSM-IV criteria in a naturalistic prospective study. Adherence was determined by the Medication Event Monitoring System (MEMS®), pill count, plasma levels and patient, staff, psychiatrist and close informant ratings. The plasma level adherence measure reflects adherence to medication and to lab visits. Relationships between MEMS® adherence and other measures were expressed as a concordance index and kappa (K). Non-adherence (MEMS® ≤0.80) was observed in 27% of the patients. MEMS® adherence was highly correlated with pill count (concordance= 89% and K=0.72, p<0.001). Concordance and K were lower for all other adherence measures and very low for the relationship between MEMS® adherence and plasma levels (concordance=56% and K=0.05, p=0.217). Adherence measures were also entered into a principal component analysis that yielded three components. MEMS® recordings, pill count and informant ratings had their highest loadings in the first component, plasma levels alone in the second and patient, psychiatrist and staff ratings in the third. The strong agreement between MEMS® and pill count suggests that structured pill count might be a useful tool to follow adherence in clinical practice. The large discrepancy between MEMS® and the adherence measure based on plasma levels needs further study in clinical settings., (© 2013 Published by Elsevier B.V. and ECNP.)

The aim was to investigate clinical predictors of adherence to antipsychotics. Medication use was electronically monitored with a Medication Event Monitoring System (MEMS(®)) for 12 months in 112 outpatients with schizophrenia and schizophrenia-like psychosis according to DSM-IV. Symptom burden, insight, psychosocial function (PSP) and side effects were rated at baseline. A comprehensive neuropsychological test battery was administered and a global composite score was calculated. The Drug Attitude Inventory (DAI-10) was filled in. A slightly modified DAI-10 version for informants was distributed as a postal questionnaire. Non-adherence (MEMS(®) adherence ≤0.80) was observed in 27%. In univariate regression models low scores on DAI-10 and DAI-10 informant, higher positive symptom burden, poor function, psychiatric side effects and lack of insight predicted non-adherence. No association was observed with global cognitive function. In multivariate regression models, low patient-rated DAI-10 and PSP scores emerged as predictors of non-adherence. A ROC analysis showed that DAI-10 had a moderate ability to correctly identify non-adherent patients (AUC=0.73, p<0.001). At the most "optimal" cut-off of 4, one-third of the adherent would falsely be identified as non-adherent. A somewhat larger AUC (0.78, p<0.001) was observed when the ROC procedure was applied to the final regression model including DAI-10 and PSP. For the subgroup with informant data, the AUC for the DAI-10 informant version was 0.68 (p=0.021). Non-adherence cannot be properly predicted in the clinical setting on the basis of these instruments alone. The DAI-10 informant questionnaire needs further testing., (© 2013 Elsevier B.V. and ECNP. All rights reserved.)

Objectives/hypothesis: Stress reaction provokes changes in the body involving cardiovascular alterations, autonomic reactions, neuroendocrine and immunologic as well as psychoneuroimmunologic changes. Both the primary and secondary effect of stress reaction may be of consequence for vocal function. The purpose of this questionnaire study was to determine the effect of stress symptoms on the occurrence of vocal symptoms. The study also aimed at investigating whether a possible effect was different for men and women., Methods: A total number of 1728 participants completed a questionnaire concerning speech, language, and voice. Six vocal symptoms and four possible stress symptoms were included in the questionnaire., Results: There was a significant association between stress symptoms and the occurrence of vocal symptoms. The occurrence of muscle tension or a lump in the throat was significant regarding all the four possible stress symptoms. There were also significant results concerning gender difference. All vocal symptoms and two of four stress symptoms were more common among women., Conclusions: Physical changes caused by the stress reaction may result in vocal symptoms as those presented in the study. Both vocal symptoms and stress symptoms were more common among women. Stress should preferably be acknowledged as a risk factor containing and possibly entailing a number of physiological, psychological, and behavioral symptoms affecting the voice negatively., (Copyright © 2013 The Voice Foundation. Published by Mosby, Inc. All rights reserved.)

Objective: To investigate gender differences in psychiatric comorbidity patients diagnosed with attention-deficit hyperactivity disorder (ADHD) as adults., Methods: Interviews about current ADHD symptoms and psychiatric comorbidity on axis I and II (Structured Clinical Interview for DSM-IV axis I and axis II) were conducted in a clinical cohort of 168 patients (78 women, 90 men). Independent information on childhood and current symptoms was collected from parents, partners and patient files., Results: The lifetime prevalence of psychiatric comorbidity on axis I reached 92%, and current comorbidity, including autism spectrum disorders and Tourette's syndrome, was 47%. Women had a higher lifetime prevalence of mood and eating disorders compared with men, where substance-use disorders were more frequent. Ten per cent of patients fulfilled diagnostic criteria for a personality disorder. When excluding the general diagnostic criteria, 46% of the patients endorsed the specific criteria for at least one personality disorder. Gender differences were identified with predominance of histrionic personality traits in women and conduct disorder in men., Conclusion: Patients diagnosed with ADHD as adults display an extremely high lifetime axis I comorbidity with a gender-specific pattern similar to the general population. No gender differences were identified with regard to personality disorders; however, an increased prevalence of deviant personality traits was confirmed. This study stresses the importance of evaluating comorbidity among patients diagnosed with ADHD as adults to secure optimal treatment.

A set of low molecular weight compounds containing a hydroxyethylamine (HEA) core structure with different prime side alkyl substituted 4,5,6,7-tetrahydrobenzazoles and one 4,5,6,7-tetrahydropyridinoazole was synthesized. Striking differences were observed on potencies in the BACE-1 enzymatic and cellular assays depending on the nature of the heteroatoms in the bicyclic ring, from the low active compound 4 to inhibitor 6, displaying BACE-1 IC(50) values of 44 nM (enzyme assay) and 65 nM (cell-based assay)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The role played by genetic factors in influencing the clinical course of multiple sclerosis (MS) is not yet well established., Objective: We aimed to identify genetic variants associated with progressive MS (PrMS)., Methods: We conducted a genome-wide association study (GWAS) in 197 patients with PrMS and 234 controls of Italian origin. We tested the top 20 single nucleotide polymorphisms (SNPs) with suggestive evidence of association (p-value<10(-4)) in two independent sets of primary progressive MS cases and controls., Results: We identified a risk-associated SNP in the HLA region in linkage disequilibrium (LD) with DRB1*1501 and DQB*0602 loci, with genome-wide significance (rs3129934(T), p (combined)=6.7×10(-16), OR=2.34, 95% CI=1.90-2.87), and a novel locus on chromosome 7q35 with suggestive evidence of association (rs996343(G), p (combined)=2.4×10(-5), OR=0.70, 95% CI=0.59-0.83) which maps within a human endogenous retroviral (HERV) element. The new locus did not have a 'cis' effect on RNA expression in lymphoblastic cell lines, but pathway analyses of 'trans' effects point to an expression regulation of genes involved in neurodegeneration, including glutamate metabolism (p<0.01) and axonal guidance signalling (p<0.02)., Conclusions: We have confirmed the established association with the HLA region and, despite the low statistical power of the study, we found suggestive evidence for association with a novel locus on chromosome 7, with a putative regulatory role.

Background: Quantification of the visceromotor response induced by colorectal distension (CRD) in rodents is commonly used for preclinical studies of visceral pain. The model is well established but does not fully assess the central response to stimulation. The aim of this study was to establish a novel model assessing cerebral evoked potentials (CEPs) in response to CRD in awake rats., Methods: Epidural recording electrodes were chronically implanted in the skull of female Sprague-Dawley rats. Colorectal distension-induced CEPs were recorded using either rapid balloon distensions (100 ms, 20-80 mmHg) or electric stimulation (1 ms, 1-4 mA) using stimulation probes placed in the distal colon., Key Results: Colorectal distension-induced CEPs were separated in three partly temporally overlapping components consisting of five prominent peaks. Peak latencies at 80 mmHg were (P1, N1) 23 ± 1 and 55 ± 4 ms, (N2, P2a, P2b) 91 ± 3, 143 ± 5 and 174 ± 3 ms, and (P3) 297 ± 3 ms. Amplitudes and latencies were, except for the early component, intensity dependent. Intrarectal administration of lidocaine significantly reduced the amplitude of N2 (by 42 ± 6%, P < 0.001) and P2 (by 34 ± 6%, P < 0.001). Electrically induced CEPs were intensity dependent and had similar topography and latencies as the mechanical evoked potentials (P1: 26 ± 2 ms; N1: 61 ± 1 ms; P2: 84 ± 6 ms; N2: 154 ± 6 ms; P3: 326 ± 10 ms), but there were large variations in amplitudes in between repeated electrical stimulations., Conclusions & Inferences: Colorectal distension-induced CEPs can be recorded reliably in awake rats and may serve as a surrogate marker of colonic sensation and be a useful parameter in studies of visceral sensitivity., (© 2012 Blackwell Publishing Ltd.)

Drug attitude inventory (DAI-30) is considered to be the best predictor of poor adherence in first-episode schizophrenia. We compared the short version (DAI-10) with DAI-30 in long-term schizophrenia, documented if DAI was associated with poor insight, PANSS and GAF and constructed DAI-10 percentiles. DAI-30 and DAI-10 were homogenous (r = 0.82 and 0.72, respectively) with good test-retest reliability (0.79). The correlation between the DAI versions was high (0.94). Percentile scores of DAI-10 were computed. DAI is an easy-to-use self-report instrument seemingly assessing a unique clinical dimension relevant to non-adherence. DAI-10 might be preferred for its simplicity and good psychometric properties., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

Proteolytic processing of the amiloride-sensitive epithelial sodium channel (ENaC) by serine proteases is known to be important for channel activation. Inappropriate ENaC activation by proteases may contribute to the pathophysiology of cystic fibrosis and could be involved in sodium retention and the pathogenesis of arterial hypertension in the context of renal disease. We hypothesized that in addition to serine proteases, cathepsin proteases may activate ENaC. Cathepsin proteases belong to the group of cysteine proteases and play a pathophysiological role in inflammatory diseases. Under pathophysiological conditions, cathepsin-S (Cat-S) may reach ENaC in the apical membrane of epithelial cells. The aim of this study was to investigate the effect of purified Cat-S on human ENaC heterologously expressed in Xenopus laevis oocytes and on ENaC-mediated sodium transport in cultured M-1 mouse renal collecting duct cells. We demonstrated that Cat-S activates amiloride-sensitive whole-cell currents in ENaC-expressing oocytes. The stimulatory effect of Cat-S was preserved at pH 5. ENaC stimulation by Cat-S was associated with the appearance of a γENaC cleavage fragment at the plasma membrane indicating proteolytic channel activation. Mutating two valine residues (V182 and V193) in the critical region of γENaC prevented proteolytic activation of ENaC by Cat-S. Pre-incubation of the oocytes with the Cat-S inhibitor morpholinurea-leucine-homophenylalanine-vinylsulfone-phenyl (LHVS) prevented the stimulatory effect of Cat-S on ENaC. In contrast, LHVS had no effect on ENaC activation by the prototypical serine proteases trypsin and chymotrypsin. Cat-S also stimulated ENaC in differentiated renal epithelial cells. These findings demonstrate that the cysteine protease Cat-S can activate ENaC which may be relevant under pathophysiological conditions.

Echinococcus multilocularis is a parasite that can cause alveolar echinococcosis disease. After the first positive finding of E. multilocularis in Sweden in 2011, a consulting group with representatives from relevant authorities was summoned. In this group, all relevant information was shared, strategies for information dissemination and any actions to be taken due to the finding of E. multilocularis were discussed and decided. The present paper describes the actions taken during 2011 and the results thereof, including surveillance in animals, risk assessment for humans to become infected and recommendations given to the public. Further discussion about whether the parasite was introduced, and if so, how, as well as possible future development of the infection in animals and humans in Sweden and future actions are included.

Oxidative stress is suggested as a potential mechanism in impaired foetal growth, smaller birth size and thus subsequently adult chronic diseases. We have investigated associations between oxidative stress in pregnancy and birth anthropometry (weight, height, head and chest circumferences). In the MINIMat-trial (Maternal and Infant Nutrition Interventions, Matlab) in rural Bangladesh, free 8-iso-prostaglandin F(2α) (lipid peroxidation) was analysed in pregnancy week 14 and 30 and 8-Hydroxy-2 -Deoxyguanosine (DNA oxidation) in week 19. We found that higher levels of lipid peroxidation in early pregnancy were associated with larger infant size (birth length and chest circumference). In late pregnancy, no clear pattern of associations was found. Increasing level of DNA oxidation was associated with lower birth length in girls but no other associations were found. In conclusion, a higher level of lipid peroxidation in early (but not late) pregnancy was associated with a favourable larger birth size suggesting that timing of lipid peroxidation is of importance.

Background: Symptom control by drug treatment is the most important task in routine clinical care of patients with schizophrenia. Structured assessment methods are needed in this task but not used much. The US-developed Positive and Negative Syndrome Scale (PANSS) is a standard tool for symptom assessment. The Psychosis Evaluation tool for Common use by Caregivers (PECC) was constructed in Europe some years ago, with the intent to overcome some of the PANSS drawbacks., Aims and Methods: To validate PECC on three longitudinal cohorts of schizophrenic patients representative of Swedish outpatients (n = 225, six assessments over 5 years), international forensic patients (n = 186) and matched non-forensic controls (n = 116), five assessments over 2 years for both., Results: The factor structure of PECC appears to be highly robust. Norm values (in percentiles) were calculated on the materials. Such data provides for analyses of symptom profiles and improvement over time measured in absolute numbers. Forensic patients appear to have a much lower symptom load (except for cognitive symptoms) than the other groups. Forensic controls had much shorter inpatient times than any other group and never caught up with respect to symptom control, even after 2 years. These differences suggest that the scale is clinically valid., Conclusion: PECC has a more robust factor structure than PANSS and is simpler to use. Percentile norms have been constructed for outpatients with schizophrenia in general and forensic psychiatry. Percentile scores are accessed readily by the net. PECC is available in many languages. Its separate self-harm item may improve assessments of suicide risk among patients with schizophrenia.

Objective: To investigate a series of consecutive suicides at a psychosis clinic by using a psychological autopsy technique., Method: The clinic serves an adult population of 225,000 individuals, of whom 0.5% have regular contact with the clinic. During a 7½-year period, 23 men and nine women committed suicide, which corresponds to an odds ratio of 14., Results: Most patients were schizophrenic, and 24 were outpatients. Suicide methods were violent in all but two cases. Nineteen had a history of at least one suicide attempt, and 24 were known to have had suicidal ideation. More than half had no social contacts over the last year except with psychiatric staff. The median time between the last contact with the psychiatric services and the suicide was 4 days. No warning signs were noted. At the time of death, 3 of the 24 who were prescribed antipsychotics, and none of the 10 who were prescribed antidepressants had plasma levels of the corresponding drug., Conclusion: Findings of special interest are the lack of forewarnings and the poor drug compliance. Patients appear to have played "business as usual" with the care-givers, and did it well. Is it a sign of health and despair, or illness?

Aliskiren is a selective renin inhibitor recently approved for use in hypertension. Efficacy duration appears longer than what would be expected based on its circulating half-life. The aim was therefore to characterize the kinetics of the interaction between aliskiren and renin. The interaction was evaluated in three assays and compared with two other renin inhibitors including remikiren. First, the inhibition of recombinant human renin was assessed by monitoring the cleavage of fluorescent substrate. Second, human plasma renin activity (PRA) was monitored by measuring generated angiotensin I over 1 h in the presence or absence of inhibitor. Finally, the affinity, association and dissociation rate constants were determined by using a surface plasmon resonance (SPR) biosensor assay. Aliskiren and remikiren were found to be equipotent inhibitors of recombinant renin activity (K(i) ≤ 0.04 nM) while compound 1 displayed a K (i) value of 1 nM. PRA was efficiently inhibited by both aliskiren and remikiren with IC₅₀ values of 0.2-0.3 nM. Remikiren and aliskiren also displayed long-lasting interactions with immobilized renin having k (off) values of 0.18 and 0.11 × 10⁻³ s⁻¹ respectively. These dissociation rate constants corresponded to residence times of 1.5 and 2.5 h, respectively, while compound 1 had a residence time lasting only 3 min. It is therefore concluded that the long-lasting interaction between aliskiren and human renin may contribute to the 24 h anti-hypertensive effect seen in clinical trials and possibly also to target-mediated drug disposition.

Purpose: The purpose of this semicontrolled prospective study was to report on the outcomes of 10 Swedish-speaking children treated with the Lidcombe Program and how the parents viewed the treatment., Method: Ten children at an age from 2:9 to 5:8 (years:months) referred to two clinics for communication disorders were consecutively included in the study. The children had been stuttering for 0:9 to 3:3 with a mean stuttering frequency of 10.1% syllables stuttered (%SS; 0.8-33.9) before treatment. Parents and teachers filled out questionnaires concerning the children's speech and the parents also answered questions on their views on the program., Results: Eight children completed the program and were reassessed upon completion of the program, about 2 years after progressing to stage 2. There was a significant decrease in mean %SS before and after treatment (7.6 vs. 0.1%, respectively) with a large Cohen effect size (d = 2.9). Parents and teachers found that the treatment had a positive effect on the children's stuttering and all parents would recommend the Lidcombe Program to other families., Conclusion: The results of this preliminary study suggest that the Lidcombe Program can be an effective treatment for Swedish-speaking preschool children who stutter., (Copyright © 2012 S. Karger AG, Basel.)

Background: Atypical antipsychotics have similar clinical efficacy in the treatment of schizophrenia; variability in their tolerability represents the discerning factor in treatment choices. Sertindole has a relatively good tolerability profile that favours long-term patient adherence and, therefore, is associated with lower rates of relapse and rehospitalization., Aim: A model was developed to compare the cost-effectiveness of a 5-year treatment strategy starting with sertindole versus olanzapine, risperidone, aripiprazole or the typical antipsychotic agent, haloperidol., Methods: The model was based on published trials and local clinical practice, and considered costs from the perspective of the Swedish National Health Insurance Board., Results: All atypical agents were clinically superior and more cost-effective than haloperidol with a cost per quality-adjusted life year gained of approximately 490,000 Swedish kroner. Sertindole was associated with the lowest direct and indirect medical costs, driven by its tolerability profile., Conclusions: Sertindole represents a useful alternative to the current treatment options available in Sweden., Clinical Implications: The relatively good tolerability profile of sertindole translates into lower costs of schizophrenia management, primarily driven by substantially lower direct and indirect costs. Sertindole appears to be a clinically and cost-effective alternative in the management of patients with schizophrenia in Sweden.

Background: Accumulation of amyloid β-peptide (Aβ) in the plaques is one of the major pathological features in Alzheimer's disease (AD). Sequential cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE-1) and γ-secretase results in the formation of Aβ peptides. Preventing Aβ formation is believed to attenuate AD progression and BACE-1 and γ-secretase are thus attractive targets for AD drug development., Methods: Combining BACE-1 and γ-secretase inhibition on Aβ secretion from human neuroblastoma SH-SY5Y cells was evaluated in this study. Secreted Aβ40 and Aβ42 levels were measured from SH-SY5Y cells stably transfected with APPwt or APPswe genes. A selective BACE inhibitor and the γ-secretase inhibitor LY450139 (semagacestat) were used to inhibit respective secretase., Results: LY450139 increased Aβ40 and Aβ42 secretion from SH-SY5Y APPwt cells at low concentrations (by 60% at 3 nM) followed by subsequent inhibition at higher concentrations (IC(50) 90 nM). Washout studies showed that the Aβ increase evoked by 3 nM LY450139 was not due to enhanced cleavage following substrate accumulation but rather to activation of Aβ formation. By contrast, LY450139 inhibited Aβ formation from SH-SY5Y APPswe in a monophasic manner (IC(50) 18 nM). The BACE inhibitor per se inhibited Aβ secretion from both SH-SY5Y APPwt and SH-SY5Y APPswe cells with IC(50)s ranging between 7 - 18 nM and also prevented the increased Aβ secretion evoked by 3 nM LY450139. Combining the BACE inhibitor with higher inhibitory concentrations of LY450139 failed to demonstrate any clear additive or synergistic effects., Conclusion: BACE-1 inhibition attenuates the Aβ increase evoked by LY450139 while not providing any obvious synergistic effects on LY450139-mediated inhibition.

Objectives: There is a need for an observation scale for assessment and monitoring of acutely psychotic patients. Milestones based on such ratings should be defined, similar to the PANSS-based Remission criteria. FAST-O is such an instrument (11 items and a CGI rating)., Methods: Reliability, validity and factor structure were analyzed in four separate studies--most importantly in one study of 33 chronic forensic in-patients rated concurrently by three independent raters, and another study of 91 Psychiatric Intensive Care Units patients and 20 newly admitted forensic patients, rated twice, each time by two independent raters., Results: The factor structure was simple, two factors and an orphan item (Depression). Reliability was adequate on item (>0.75) as well as scale (>0.85) level. There was no bias related to the rater's professional background. The instrument was sensitive to change. Percentile-based algorithms allow characterization of patients and groups. Tentative treatment milestones are defined; a clinical state "half-way" between the acute state and remission., Conclusions: FAST-O is a reliable, valid and easy to implement observation scale for patients with a psychotic illness, which can be used without bias by all staff.

A surface plasmon resonance (SPR) biosensor-based assay for membrane-embedded full-length BACE1 (β-site amyloid precursor protein cleaving enzyme 1), a drug target for Alzheimer's disease, has been developed. It allows the analysis of interactions with the protein in its natural lipid membrane environment. The enzyme was captured via an antibody recognizing a C-terminal His6 tag, after which a lipid membrane was reconstituted on the chip using a brain lipid extract. The interaction between the enzyme and several inhibitors confirmed that the surface was functional. It had slightly different interaction characteristics as compared with a reference surface with immobilized ectodomain BACE1 but had the same inhibitor characteristic pH effect. The possibility of studying interactions with BACE1 under more physiological conditions than assays using truncated enzyme or conditions dictated by high enzyme activity is expected to increase our understanding of the role of BACE1 in Alzheimer's disease and contribute to the discovery of clinically efficient BACE1 inhibitors. The strategy exploited in the current study can be adapted to other membrane-bound drug targets by selecting suitable capture antibodies and lipid mixtures for membrane reconstitution., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: We previously showed that activation of GABA(B) receptors by intravenous baclofen reduces pseudo-affective responses to colorectal distension in rats. Here we evaluate the potential clinical significance of these observations., Material and Methods: Clinically relevant colorectal distension protocols were used to assess the effects of oral baclofen on visceromotor and autonomic cardiovascular responses in conscious rats. Plasma levels of baclofen were monitored to provide clinical relevance to the doses used. Conscious female Sprague-Dawley rats were subjected to repeated noxious colorectal distension (12 × 80 mmHg), ascending-phasic colorectal distension (10-80 mmHg, 10 mmHg increments) or ramp colorectal distension (10 min ramp at 8 mmHg/min). Visceromotor and cardiovascular responses (mean arterial blood pressure and heart rate) were monitored. Pain-related response thresholds were assessed using ascending-phasic and ramp colorectal distension., Results: Baclofen (1-10 μmol/kg, p.o.) reduced the visceromotor response to colorectal distension, reaching a 40% maximal inhibition (p < 0.05). The highest dose (10 μmol/kg, p.o.) also inhibited pain-related cardiovascular responses in telemetrized rats (50-55% reduction in colorectal distension-evoked hypertensive and tachycardic responses; p < 0.05). Similar thresholds for pain-related visceromotor responses were determined during ramp or ascending-phasic colorectal distension (34.1 ± 1.9 and 31.7 ± 3.2 mmHg, respectively). Baclofen (10 μmol/kg, p.o.) increased thresholds to 71.1 ± 3.7 and 77.5 ± 1.8 mmHg during ramp and ascending-phasic colorectal distension, respectively (p < 0.001). Plasma levels of baclofen were 3.3 ± 0.2 μmol/l at 90 min post-dosing, corresponding to the end of the colorectal distension procedure., Conclusions: Oral baclofen, at plasma levels similar to those reported safe and within a therapeutic range in humans, produced significant visceral anti-nociceptive effects in rats.

Objective: Patients treated with antipsychotic drugs often receive concomitant psychotropic compounds. Few studies address this issue from a lifetime perspective. Here, an analysis is presented of the prescription pattern of such concomitant medication from the first contact with psychiatry until the last written note in the case history documents, in patients with a diagnosis of psychotic illness., Methods: A retrospective descriptive analysis of all case history data of 66 patients diagnosed with schizophrenia or schizophrenia-like psychotic disorders., Results: Benzodiazepines and benzodiazepine-related anxiolytic drugs had been prescribed to 95% of the patients, other anxiolytics, sedatives or hypnotic drugs to 61%, anti-parkinsonism drugs to 86%, and antidepressants to 56% of the patients. However, lifetime doses were small and most of the time patients had no concomitant medication. The prescribed lifetime dose of anti-parkinsonism drugs was associated with that of prescribed first-generation but not second-generation antipsychotics., Conclusions: Most psychosis patients are sometimes treated with concomitant drugs but mainly over short periods. Lifetime concomitant add-on medication at the individual patient level is variable and complex but not extensive., (Copyright © 2011 John Wiley & Sons, Ltd.)

Only a minority of patients treated with antipsychotics in clinical studies continue their treatments throughout a longer study period. Few studies address this issue from a lifetime perspective. In this naturalistic study, we aimed at analysing the prescription pattern of antipsychotic drugs among a sample of Swedish patients with a diagnosis of psychotic illness, from the first contact with psychiatry (typically between 1973 and 1997) until the last written note in the case history documents. A retrospective descriptive analysis was performed of all case history data of 66 patients diagnosed with schizophrenia or related psychotic disorders. Patients with schizophrenia were prescribed antipsychotic medication more than 90% of the time. Each patient generally had been prescribed several (up to 16) different antipsychotic drugs and a quarter of the patients had been prescribed two or more antipsychotics for a third of their prescription time. Patients with psychosis were exposed to a cumulatively growing number of antipsychotics. Various factors, including clinician and patient expectations, and specific strengths and limitations of available antipsychotics may account for frequent medication changes over time., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: To describe the prevalence of anemia and micronutrient deficiencies as well as their determinants in early pregnancy., Design: Baseline data from a population-based randomized intervention trial., Setting: The study was conducted in Matlab, a sub-district in rural Bangladesh from 1 January to 31 December 2002., Population: Pregnant women (n= 740) were enrolled in approximately week 14 in pregnancy., Methods: Data were collected using questionnaires, physical examinations and laboratory analyses of blood samples for concentrations of hemoglobin, ferritin, zinc, folate and vitamin B-12., Main Outcome Measures: Covariates associated with anemia and micronutrient deficiencies in bivariate analyses were evaluated in multivariate logistic regression models adjusting for potential confounders., Results: Anemia was present in 28% of the women, 55% were zinc deficient, 46% were vitamin B-12 deficient and 18% were folate deficient. Anemia was not associated with iron deficiency but rather with vitamin B-12 deficiency. Infestation with Ascaris was highly prevalent (67%) and associated with both folate and vitamin B-12 deficiency. Anemia and micronutrient deficiencies all varied significantly with season., Conclusions: The high prevalences of zinc and vitamin B-12 deficiencies in early pregnancy are a concern, as it could lead to adverse pregnancy outcomes and increased health risks for both mother and child. The prevalence of iron deficiency was low, but as this was during early pregnancy, the women might develop iron deficiency and consequently iron deficiency anemia as the pregnancy progresses., (© 2010 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2010 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: Proghrelin, produced by the ghrelin (A-like) cells of the gastric mucosa, gives rise to cleavage products, including desacyl ghrelin, acyl ghrelin and obestatin. The products are thought to be secreted concomitantly. In an earlier study we found acyl ghrelin and obestatin, but not desacyl ghrelin, to suppress the release of hormones from isolated islets of mouse and rat pancreas., Results: Using isolated mouse pancreatic islets to study the suppression of the spontaneous secretion of pancreatic polypeptide (PP) by acyl ghrelin and obestatin, we determined the EC(50) values for the two peptides. For acyl ghrelin it was 2 x 10(-13)M (ranging from 1.7 to 2.8 x 10(-13)M), for obestatin it was 10(-13)M (ranging from 0.3 to 1.1 x 10(-13)M). The Hill coefficient (i.e. the midpoint slope) for the acyl ghrelin dose-response curve was 0.30 (ranging from 0.21 to 0.35); the corresponding value for obestatin was 0.35 (ranging from 0.21 to 0.35). The PP-releasing effect of acyl ghrelin, but not that of obestatin, was counteracted by desacyl ghrelin. The acyl ghrelin dose-response curve was shifted to the right in a parallel manner by increasing concentrations of desacyl ghrelin. A Schild plot was constructed with a slope of 0.78, giving an apparent pA(2) value of 14., Conclusions: The results favour the view that acyl ghrelin and obestatin suppress spontaneous PP secretion at physiologically relevant concentrations and that they act on separate receptors. However, we conclude also that desacyl ghrelin acts as a competitive, surmountable (and quite potent) inhibitor of acyl ghrelin. In view of the allegedly high circulating concentrations of desacyl ghrelin it is to be expected that the effect of acyl ghrelin - but not that of obestatin - will be impaired, in fact probably severely blunted by desacyl ghrelin, thereby compromising the functional significance of circulating acyl ghrelin. In addition, we suggest that isolated pancreatic islets are well suited for studies of receptors to acyl ghrelin and obestatin, and that suppression of PP secretion represents a convenient way to measure the effect of both these peptides., (Copyright 2010 Elsevier B.V. All rights reserved.)

BACE-1 is one of the aspartic proteases involved in the cleavage of beta amyloid peptide, an initial step in the formation of amyloid plaques whose toxicity induces neuron death in Alzheimer's disease patients. One of the central issues in the search of novel BACE-1 inhibitors is the optimum pH for the binding of inhibitors to the enzyme. It is known that the enzyme has optimal catalytic activity at acidic pH, while cell active inhibitors may bind optimally at higher pH. In this work we determine the effect of the pH on the affinities of a set of inhibitors, with a variety of chemical motifs, for the ectodomain region of BACE-1 by a surface plasmon resonance (SPR) biosensor based assay. In order to understand the molecular interactions that underlie the diverse optimum pH for the binding of the various inhibitors as observed experimentally, we have calculated the titration curves for a set of BACE-1 ligand complexes. The results indicate that the pK(a) values of the titratable residues of the protein depend on the nature of the ligand involved, in disagreement with previous work. The enzyme-inhibitor structures with the resulting protonation states at pH values 4.5 and 7.4 served as the starting point for the prediction of the pH-dependent binding ranking. Our calculations reproduced the entire affinity ranking observed upon pH increase and most of the binding trends among inhibitors, especially at low pH. Finally, our cell-based assays indicate a possible correlation between high inhibitor affinity at both acidic and neutral pH values, with optimal cell response, a result that may open new venues for the search of potent BACE-1 inhibitors that are active at the cellular level.

Background: Solutions for Wellness (SfW) is an educational 3-month program concerning nutrition and exercise for persons with psychiatric disorders on psychotropic medication, who have weight problems. This observational study assessed the impact of SfW on subjective well-being, weight and waist circumference (WC)., Methods: Data was collected at 49 psychiatric clinics. Where the SfW program was offered patients could enter the intervention group; where not, the control group. Subjective well-being was measured by the Subjective Well-being under Neuroleptics scale (SWN), at baseline, at the end of SfW participation, and at a follow-up 6 months after baseline. Demographic, disease and treatment data was also collected., Results: 314 patients enrolled in the SfW group, 59 in the control group. 54% of the patients had schizophrenia, 67% received atypical antipsychotics, 56% were female. They averaged 41 +/- 12.06 years and had a BMI of 31.4 +/- 6.35. There were significant differences at baseline between groups for weight, SWN total score and other factors. Stepwise logistic models controlling for baseline covariates yielded an adjusted non-significant association between SfW program participation and response in subjective well-being (SWN increase). However, statistically significant associations were found between program participation and weight-response (weight loss or gain < 1 kg) OR = 2; 95% CI [1.1; 3.7] and between program participation and WC-response (WC decrease or increase < 2 cm) OR = 5; 95% CI [2.4; 10.3]), at 3 months after baseline., Conclusions: SfW program participation was associated with maintaining or decreasing weight and WC but not with improved subjective well-being as measured with the SWN scale.

Objective: Assertive community treatment programmes are increasingly common worldwide but without much knowledge of their long-term effect. We investigated whether the implementation of such a programme would improve symptomatic and functional outcome 5 years later., Methods: Naturalistic cohort study between 1995 and 2000 of all first-episode psychosis patients (n = 144) in Uppsala County, Sweden. We compared a 3-year period before (non-mACT) and after the introduction of a modified assertive community treatment (mACT) programme in 1998. Five-year outcome was assessed for symptoms and functioning and the two co-primary outcome measures were positive and negative symptoms. Regression models were adjusted for a propensity score based on multiple baseline variables and use of antipsychotics at 5-year follow-up., Results: Contrary to our hypothesis, patients in the mACT group, compared to those in the non-mACT group, had a borderline significant increased risk of having a poor 5-year outcome regarding positive psychotic symptoms [adjusted odds ratio (OR) 3.21, 95% confidence interval (CI) 0.97-10.63]. There was no difference at the 5-year follow-up between the mACT and non-mACT group regarding negative symptoms (adjusted OR 1.65, 95% CI 0.48-5.66), or any of the secondary outcome measures: global assessment of functioning, hazardous alcohol use, use of illicit drugs, working or being in education, independent living, subjective satisfaction with life or suicide. Results were similar in subgroup analyses., Conclusions: The implementation of a modified assertive community treatment was not followed by subsequent improvements of 5-year outcome on a group level for patients with first-episode psychosis.

Objective: To compare the prevalence of symptoms consistent with attention deficit hyperactivity disorder (ADHD) and related problems in adults in the general population, out-patient psychiatry (where females are in majority), and female convicts., Method: A questionnaire based on the DSM-IV criteria of ADHD, reported childhood symptoms, reading and spelling problems, difficulties and suffering, and general assessment of functioning (GAF) was distributed to samples of the general population, open care psychiatry, and female prison inmates. Completed questionnaires were received from 517/1000, 349/400, and 50/65 of the three samples, respectively., Results: Symptoms consistent with ADHD were more than three times higher in out-patient psychiatry than in the general population (6.6% versus 2.1%), with a male-to-female ratio of 1.6-1.7. The severity of symptoms and frequencies of associated disabilities were similar in men and women. ADHD symptoms and related problems occurred in 50% of the female prisoners, which is similar to male prisoners according to the literature., Conclusion: The high prevalence of symptoms and disabilities of ADHD in women should lead to awareness of the disorder in both sexes and be addressed in terms of diagnostic work-up, treatment, and rehabilitation.

Transient receptor potential vanilloid 1 (TRPV1) channels have been implicated in pain mechanisms and, particularly, in the development of hyperalgesia. We used selective TRPV1 antagonists (NGV-1, SB-750364 and JYL 1421) to assess the role of TRPV1 channels in repetitive noxious colorectal distension (CRD)-induced visceral pain responses in rats. Isobaric CRD (80 mmHg) induced a viscerosomatic response, indicative of visceral pain associated to the distension procedure. Repetition (12 consecutive distensions) of the CRD resulted in an increase in the response over time (119+/-23% increase at distension 12, P<0.05 vs response during the 1st distension) indicative of acute mechanical sensitization. NGV-1 (0.1, 0.3, 1 or 3 micromol/kg, i.v.) prevented in a dose-related manner the development of sensitization, without inducing hypoalgesic responses. SB-750364 (30 micromol/kg, i.v.) had a transitory effect, partially reducing the sensitization response, while JYL 1421 (4.7 micromol/kg, i.v.) was without effect. In the same conditions, the cannabinoid receptor 1 (CB(1)) agonist, WIN55,212-2 (0.1 micromol/kg) reduced pain responses leading to a hypoalgesic state. At 3 micromol/kg, NGV-1, did not affect the pressure-volume relationship during CRD, indicating that TRPV1 channels do not modulate colonic compliance. These observations suggest that TRPV1 channels are involved in the development of acute mechanical colonic hyperalgesia during repetitive noxious CRD in rats. Antagonism of TRPV1 channels might result in antihyperalgesic effects without hypoalgesic activity and might be beneficial in the treatment of visceral pain disorders, such as irritable bowel syndrome. These observations warrant the clinical assessment of TRPV1 antagonists for the treatment of visceral pain.

5-Hydroxytryptamine 1A (5-HT(1A)) receptors have been suggested as a target for the treatment of irritable bowel syndrome (IBS). A recent clinical trial investigating the efficacy of the selective 5-HT(1A) antagonist AZD7371 [3(R)-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (R,R)-tartrate monohydrate] showed no symptomatic improvement in IBS patients. We characterized the mechanisms mediating potential analgesic effects of AZD7371 in a model of colorectal distension (CRD)-induced visceral pain in rats to understand its mechanism of action and the lack of clinical efficacy. Visceromotor and cardiovascular responses (telemetry) were assessed in conscious rats during noxious CRD (80 mm Hg). Effects of AZD7371 (3-300 nmol/kg i.v.; 1-30 micromol/kg p.o.) and a reference 5-HT(1A) antagonist, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide maleate salt; 3-300 nmol/kg i.v.), were assessed. Effects of intracerebroventricular AZD7371 were also evaluated. Intravenous AZD7371 or WAY-100635 and oral AZD7371 dose-dependently inhibited visceromotor responses to CRD (ED(50), 203, 231, and 14 micromol/kg, respectively). In telemetrized rats, oral AZD7371 inhibited visceromotor responses to CRD without affecting the concomitant hypertensive and tachycardic responses. Intracerebroventricular AZD7371 did not affect visceromotor responses, whereas it inhibited micturition. None of the doses tested induced visible gross side effects. AZD7371, likely acting at a spinal site, inhibited the visceromotor but not the cardiovascular responses to visceral pain in the CRD model in rats. Although agents effective on multiple pain-related readouts in the CRD model (e.g., pregabalin or clonidine) alleviate IBS symptoms, AZD7371, which is effective on only one pain-related pseudoaffective readout, does not. Data from preclinical CRD models of visceral pain need to be interpreted cautiously as it relates to their clinical translational value.

Tachykinin NK receptors (NKRs) differ to a large degree among species with respect to their affinities for small molecule antagonists. The aims of the present study were to clone NKRs from gerbil (NK2R and NK3R) and dog (NK1R, NK2R and NK3R) in which the sequence was previously unknown and to investigate the potency of several NKR antagonists at all known human, dog, gerbil and rat NKRs. The NKR protein coding sequences were cloned and expressed in CHO cells. The inhibitory concentrations of selective and non-selective NKR antagonists were determined by inhibition of agonist-induced mobilization of intracellular Ca2+. Receptor homology models were constructed based on the rhodopsin crystal structure to investigate and identify the antagonist binding sites and interaction points in the transmembrane (TM) regions of the NKRs. Data collected using the cloned dog NK1R confirmed that the dog NK1R displays similar pharmacology as the human and the gerbil NK1R, but differs greatly from the mouse and the rat NK1R. Despite species-related amino acid (AA) differences located close to the antagonist binding pocket of the NK2R, they did not affect the potency of the antagonists ZD6021 and saredutant. Two AA differences located close to the antagonist binding site of NK3R likely influence the NK3R antagonist potency, explaining the 3-10-fold decrease in potency observed for the rat NK3R. For the first time, detailed pharmacological experiments in vitro with cloned NKRs demonstrate that not only human, but also dog and gerbil NKR displays similar antagonist pharmacology while rat diverges significantly with respect to NK1R and NK3R.

Objective: To investigate the recently defined Positive and Negative Syndrome Scale for Schizophrenia remission criteria in a naturalistic setting of psychotic patients; to identify causal factors that change remission status; and to validate the criteria against global indices of illness, cognitive functions, and social outcome., Methods: This was a longitudinal naturalistic study of 162 patients, diagnosed with schizophrenia or schizophrenia-related psychotic disorders (mean illness duration, 11 years) and treated with risperidone at study entry. Symptoms, drug treatment, cognitive function, and social outcome were measured at baseline and annually for 5 years. Remission was constructed retrospectively with only indirect data on stability over time., Results: At study entry, 40% of the patients with schizophrenia were in symptomatic remission, stabilizing between 55% and 60% after a few years. The need for hospitalization became less frequent over time; initially 31%, dropping to 7% by years 4 and 5. Many patients went in and out of remission. Remission was strongly associated with global indices of illness, with intact insight and with social outcome (except work/studies) but not with cognition or medication., Conclusions: In spite of certain weaknesses of the study, we may conclude that current definition of remission is primarily a symptomatic measure, covering a subset of symptoms, some of which are not schizophrenia-specific. Although the definition may be clinically relevant, we must be aware of the risk that the connotation of the word could induce too much focus on symptom control.

Activation of cannabinoid receptors (CB(1), CB(2) and GPR(55)) produces analgesic effects in several experimental pain models, including visceral pain arising from the gastrointestinal tract. We assessed the role of CB(1), CB(2), and GPR(55) receptors and the endogenous cannabinoid system on basal pain responses and acute mechanical hyperalgesia during colorectal distension (CRD) in rodents. The effects of cannabinoid receptor agonists and antagonists on pain-related responses to CRD were assessed in rats and in wild-type and CB(1) receptor knock-out mice. The dual CB(1/2) agonist, WIN55,212-2, and the peripherally acting CB(1)-selective agonist, SAB-378, inhibited pain-related responses to repetitive noxious CRD (80 mmHg) in a dose-related manner in rats. The analgesic effects of WIN55,212-2 and SAB-378 were blocked by the selective CB(1) antagonist SR141716, but were not affected by the selective CB(2) antagonist SR144528. SR141716, per se, increased the responses to repetitive noxious CRD, indicative of hyperalgesia, and induced pain-related responses during non-noxious CRD (20 mmHg), indicative of allodynia. The cannabinoid receptor agonists anandamide, virodhamine and O-1602 had no effect. At analgesic doses, WIN55,212-2 did not affect colonic compliance. In accordance to the rat data, WIN55,212-2 produced analgesia, whereas SR141716 induced hyperalgesia, during noxious CRD (55 mmHg) in wild-type but not in CB(1)-knock-out mice. These data indicate that peripheral CB(1) receptors mediate the analgesic effects of cannabinoids on visceral pain from the gastrointestinal tract. The allodynic and hyperalgesic responses induced by SR141716 suggest the existence of an endogenous cannabinoid tone and the activation of CB(1) receptors during noxious CRD.

Activation of GABA(B) receptors by the selective agonist baclofen produces anti-nociceptive effects in animal models of somatic pain. The aim of the present study was to evaluate the effect of baclofen and the GABA(B) receptor positive allosteric modulator CGP7930 on pseudo-affective responses to colorectal distension in rats. Female Sprague-Dawley rats were subjected to repeated, noxious colorectal distension (CRD) (12 distensions at 80 mmHg, for 30 s with 5 min intervals). The visceromotor response (VMR) and cardiovascular responses (mean arterial blood pressure (ABP) and heart rate (HR)) to CRD were monitored in conscious, telemetrized animals. Baclofen (0.3-3 micromol/kg, i.v.) reduced the VMR to CRD dose-dependently, reaching a 61% maximal inhibition (p < 0.001). The highest doses of baclofen attenuated CRD-evoked increases in ABP by 17% (p > 0.05) and reduced the change in HR by 48% (p < 0.01). CGP7930 (3-30 micromol/kg, i.v.) reduced the VMR to CRD in a dose-dependent fashion with a maximal inhibition of 31% (p < 0.05). The highest dose of CGP7930 also attenuated the increase in ABP by 18% (p > 0.05) and inhibited the increase in HR by 24% (p < 0.05) associated with CRD. Neither baclofen nor CGP7930 affected colorectal compliance. The results suggest that activation of GABA(B) receptors produces anti-nociceptive effects in a rat model of mechanically induced visceral pain. While CGP7930 was less efficacious than baclofen overall, positive allosteric modulation of GABA(B) receptors may represent a valid approach in the treatment of visceral pain conditions, with the possibility of an improved safety profile compared to full agonism.

Although operational criteria for remission in schizophrenia have recently been proposed, the association of this definition with broader functional outcome has not yet been established in first-episode patients. The severity criteria for remission consist of a score of mild or less on eight core symptoms of schizophrenia. We applied the severity criteria for remission to a sample of patients with first-episode schizophrenia (n=76) in order to explore the association with functional outcome five years after first presentation to mental healthcare. We evaluated whether other factors than those included in the remission definition predicted good function in logistic regression models. The discriminatory capacities for remission and other factors for good function were tested using C-statistics. The proportions of remitters and non-remitters having good function were 73% and 17%, respectively. Furthermore, remitters had a higher level of subjective satisfaction with life. In comparison with non-remission, symptomatic remission was strongly associated with good function: odds ratio 13.2, 95% confidence interval, 4.3 to 40.3. A duration of untreated psychosis of three months or less as compared with a longer duration was associated with having good function at a five-year follow-up independently of remission status. The discriminatory capacity for symptomatic remission between having good function vs. not was acceptable (C-statistic=0.78), which was significantly improved to an excellent discriminatory capacity by adding duration of untreated psychosis less than three months (C-statistic=0.83, p=0.04). In conclusion, core symptoms of schizophrenia have an important limiting effect on functioning and subjective life satisfaction in the early course of the illness.

The objective of the study was to validate a self-administrated symptom rating scale for use in patients with schizophrenia spectrum disorders by item analysis, exploration of factor structure, and analyses of reliability and validity. Data on 151 patients, initially treated by risperidone, obtained within the framework of a naturalistic Phase IV longitudinal study, were analysed by comparing patient and clinician ratings of symptoms, side-effects and global indices of illness. The Symptom Self-rating Scale for Schizophrenia (4S) is psychometrically adequate (item analysis, internal consistency, factor structure). Side-effect ratings were reliable. Symptom ratings displayed consistent associations with clinicians' ratings of corresponding symptom dimensions, suggesting construct validity. Patients had most difficulties assessing negative symptom items. Patients were well able to assess their own symptoms and drug side-effects. The factor structure of symptom ratings differs between patients and clinicians as well as how they construe global indices of illness. Clinicians focus on psychotic, patients on affective symptoms. Use of symptom self-ratings is one way to improve communication and thereby strengthen the therapeutic alliance and increase treatment adherence.

Objective: To estimate the prevalence of physical health problems in patients with schizophrenia, and to appraise the impact on mortality rates and quality of life (QoL) in such patients., Method: A selective review of clinical articles relating to physical health such as cardiovascular disease, metabolic syndrome and QoL. In addition, current guidelines and recommendations for the monitoring of physical health in schizophrenia were reviewed., Results: Cardiovascular events contribute most strongly to the excess mortality observed in schizophrenia. Other factors that contribute significantly include obesity, metabolic aberrations, smoking, alcohol, lack of exercise and poor diet - all of which might be targets for health promoting activities., Conclusion: Physical health problems in patients with schizophrenia are common, and contribute to the excess mortality rate, as well as decreasing QoL. Many adverse physical factors are malleable in such patients, and physical benefit may be gained by following practical guidelines for their monitoring and improvement.

Background and Purpose: Pregabalin, which binds to the alpha2-delta subunit of voltage-gated calcium channels, increased the threshold for pain during colorectal distension (CRD) in irritable bowel syndrome (IBS) patients. We tested the effects of oral pregabalin on the visceral pain-related viscerosomatic and autonomic cardiovascular responses to CRD and colonic compliance in rats., Experimental Approach: The activity of the abdominal musculature (viscerosomatic response), monitored by electromyography and intracolonic manometry, and changes in blood pressure and heart rate, monitored by telemetry, were assessed simultaneously in conscious rats during CRD., Key Results: Pregabalin (10-200 micromol kg(-1), p.o.) inhibited dose dependently the viscerosomatic response to phasic, noxious CRD (12 distensions at 80 mm Hg). At 200 mumol kg(-1), pregabalin also reduced the increase in blood pressure and heart rate associated with noxious CRD. Moreover, pregabalin (200 micromol kg(-1), p.o.) reduced the visceromotor response to ascending phasic CRD (10-80 mm Hg) and significantly increased the threshold pressure for response. During phasic CRD (2-20 mm Hg), pregabalin (200 micromol kg(-1), p.o.) increased intracolonic volume, resulting in a shift to the left of the pressure-volume relationship curve, indicative of an increase of compliance., Conclusions and Implications: Pregabalin reduced the viscerosomatic and autonomic responses associated with CRD-induced visceral pain and increased colonic compliance in rats. These observations confirm the analgesic activity of pregabalin on visceral pain and support the translational value of the CRD model to humans. Ligands for the alpha2-delta subunit might represent interesting compounds for the treatment of visceral pain disorders, such as IBS.

Recent studies have detailed a remarkable degree of genetic and linguistic diversity in Northern Island Melanesia. Here we utilize that diversity to examine two models of genetic and linguistic coevolution. The first model predicts that genetic and linguistic correspondences formed following population splits and isolation at the time of early range expansions into the region. The second is analogous to the genetic model of isolation by distance, and it predicts that genetic and linguistic correspondences formed through continuing genetic and linguistic exchange between neighboring populations. We tested the predictions of the two models by comparing observed and simulated patterns of genetic variation, genetic and linguistic trees, and matrices of genetic, linguistic, and geographic distances. The data consist of 751 autosomal microsatellites and 108 structural linguistic features collected from 33 Northern Island Melanesian populations. The results of the tests indicate that linguistic and genetic exchange have erased any evidence of a splitting and isolation process that might have occurred early in the settlement history of the region. The correlation patterns are also inconsistent with the predictions of the isolation by distance coevolutionary process in the larger Northern Island Melanesian region, but there is strong evidence for the process in the rugged interior of the largest island in the region (New Britain). There we found some of the strongest recorded correlations between genetic, linguistic, and geographic distances. We also found that, throughout the region, linguistic features have generally been less likely to diffuse across population boundaries than genes. The results from our study, based on exceptionally fine-grained data, show that local genetic and linguistic exchange are likely to obscure evidence of the early history of a region, and that language barriers do not particularly hinder genetic exchange. In contrast, global patterns may emphasize more ancient demographic events, including population splits associated with the early colonization of major world regions., Competing Interests: The authors have declared that no competing interests exist.

It has been shown that the behavioural responses to chemically evoked visceral nociception are increased in transgenic mice lacking the kappa-opioid receptor (KOR). The aim of the present study was to evaluate the contribution of KOR in mechanically evoked visceral pain by performing colorectal distension (CRD) and monitoring the subsequent visceromotor response (VMR) in control mice (KOR(+/+)) and in mice lacking KOR (KOR(-/-)). Pseudo-affective visceral pain responses were evoked in conscious mice using increasing (10-80 mmHg) and repeated (12 x 55 mmHg) phasic CRD paradigms. The resulting VMR was determined by monitoring the electromyographic activity of the abdominal muscle. The increasing and repeated CRD paradigms, respectively, evoked similar responses in both KOR(+/+) and KOR(-/-) mice. The selective KOR-agonists U-69593 (5 and 25 mg kg(-1), s.c.) and asimadoline (25 mg kg(-1), s.c.) significantly decreased the VMR in KOR(+/+) mice, while having no effect in KOR(-/-) mice. In contrast, the selective mu-opioid receptor agonist fentanyl significantly reduced the VMR in both types of mice and appeared more efficacious in KOR(-/-) mice. The opioid receptor antagonist naloxone (0.3-30 mg kg(-1) s.c.) did not affect the response to CRD in C57BL/6 mice at any dose tested. In conclusion, the data confirm that the KOR agonists used in this study inhibit the VMR to CRD in mice by acting via KOR receptors. In addition, the data suggest that the endogenous opioid system is not likely to modulate the VMR to mechanically evoked visceral pain in mice.

The alpha(2)-adrenoceptor agonist, clonidine, modulates colorectal sensorimotor functions in humans and, given intrathecally, has analgesic effects in the colorectal distension (CRD) model in rats. We tested the effects of systemic clonidine on the visceral pain-related viscerosomatic and autonomic cardiovascular responses to CRD and colonic compliance in rats using clinically relevant CRD protocols. The activity of the abdominal musculature (viscerosomatic response), monitored by electromyography and intracolonic manometry, and changes in arterial blood pressure and heart rate, monitored by telemetry, were assessed simultaneously in conscious rats during CRD. Pressure-volume relationships during CRD served as a measure of colonic compliance. Clonidine (50-200 nmol/kg, p.o.) dose-dependently inhibited the viscerosomatic response to phasic, noxious CRD (12 distension at 80 mm Hg). At 200 nmol/kg clonidine also attenuated the increase in blood pressure (70+/-7% inhibition, P<0.05) and heart rate (67+/-16% inhibition, P<0.05) associated to noxious CRD. Similar effects were observed after i.v. administration. Likewise, clonidine (200 nmol/kg, p.o.) reduced the response to ascending phasic CRD (10-80 mm Hg) and significantly increased the threshold pressure for pain-related responses. Clonidine (50 or 150 nmol/kg, i.p.) did not affect the pressure-volume relationship during phasic CRD (2-20 mm Hg). These results show that systemic clonidine, at doses devoid of visible side effects, has analgesic effects in the CRD model of visceral pain in rats without affecting colonic compliance. These observations confirm the analgesic activity of systemic clonidine on visceral pain, support the translational value of the rat CRD model to humans and show that manometry is more sensitive than electromyography detecting pain-related responses.

Tachykinin NK(2) receptor antagonists are potentially beneficial in treating various disorders including irritable bowel syndrome, urinary incontinence, depression and anxiety. The current study evaluates the frequency of single nucleotide polymorphisms (SNPs) in the human NK(2) receptor gene (TACR2). In addition, the potency of the endogenous peptide agonist neurokinin A (NKA), and the small molecule antagonists saredutant (NK(2)-selective) and ZD6021 (pan-NK antagonist) at the various NK(2) receptor protein variants were determined. The TACR2 gene was sequenced from 37 individuals. Two amino acid changing SNPs encoding the NK(2) receptor variants Ile23Thr and Arg375His were found. The frequency of the four possible protein variants differed between populations. Site-directed mutagenesis was performed introducing either SNP or both SNPs into the TACR2 gene and the constructs were transfected into CHO cells. NKA-evoked increases in intracellular Ca(2+) were monitored by FLIPR. The potency of saredutant and ZD6021 was evaluated by their ability to inhibit NKA-induced increases in intracellular Ca(2+). NKA evoked increases in intracellular Ca(2+) with a potency ranging between 1 and 5nM in CHO cells expressing the different constructs. Saredutant and ZD6021 blocked NKA-evoked increases in intracellular Ca(2+) with pK(b) values ranging between 8.8-9.3 and 7.9-8.7, respectively. The current study demonstrates that polymorphisms leading to the Ile23Thr and Arg375His amino acid exchanges are highly prevalent in the human TACR2 gene. These polymorphisms however do not appear to affect the potency of the endogenous agonist NKA or the small molecule antagonists saredutant and ZD6021 with respect to intracellular Ca(2+) signalling.