Nitric oxide plasma/serum levels in patients with schizophrenia: a systematic review and meta-analysis

For the last 40 years, schizophrenia has been considered to be the result primarily of a dysfunction in brain dopaminergic pathways. In this review, it is described and discussed findings concerning nitric oxide-mediated neurotransmission in schizophrenia. Studies were searched in PubMed, SciELO, and LILACS using the terms schizophrenia and nitric oxide plasma levels or nitric oxide serum levels, with no time limit. The reference lists of selected articles were also hand-searched for additional articles. From 15 potential reports, 10 were eligible to be included in the review and meta-analysis. These studies included a total of 505 patients with schizophrenia and 339 healthy volunteers. No significant difference was found between patients and healthy controls regarding total nitrite plasma/serum levels (effect size g = 0.285, 95%CI = -0.205 to 0.774, p = 0.254). However, when studies with patients under antipsychotic treatment were examined separately, there was a significant difference between patients and healthy volunteers (effect size g = 0.663, 95%CI = 0.365 to 0.961, p < 0.001), showing that patients under treatment have higher levels of plasma/serum nitric oxide than controls. These results suggest that antipsychotics increase nitric oxide plasma/serum levels and that the nitrergic pathway would be a fertile target for the development of new treatments for patients with schizophrenia.

Inserimento eterofamigliare supportato di adulti sofferenti di disturbi psichici: Valutazione degli esiti

L’Inserimento Eterofamigliare Supportato di Adulti (IESA) sofferenti di disturbi psichici consiste nell’accogliere persone in cura presso i servizi psichiatrici territoriali, nel proprio domicilio, integrandole nelle proprie relazioni famigliari. Obiettivo è migliorare la qualità di vita dell’utente e favorirne l’integrazione nella comunità. Obiettivo. Valutare gli esiti dello IESA, con un disegno di ricerca longitudinale, considerando: psicopatologia, benessere psicologico, funzionamento sociale e familiare. Metodologia. 40 soggetti: 20 pazienti e 20 ospitanti. La valutazione clinica è stata effettuata all’inizio della convivenza e al follow-up di 1, 3, 6 e 12 mesi. Strumenti utilizzati: BPRS, VGF, PWB, SQ, FAD. Analisi statistica: Modello Lineare Generale (GLM) con l’Analisi della Varianza per prove ripetute e calcolo dell’effect-size. Risultati. 15 pazienti maschi e 5 femmine, 17 italiani. 11 soddisfano i criteri diagnostici (DSM-IV-TR) per schizofrenia e disturbi psicotici, 5 per i disturbi dell’umore e 4 per i disturbi di personalità. Dopo l’inserimento 3 sono stati i ricoveri e 4 le visite psichiatriche urgenti. 8 pazienti modificano/diminuiscono la terapia e 3 la sospendono. Aumenta il benessere psicologico (PWB); diminuiscono i sintomi psicopatologici (BPRS ed SQ) e migliora il funzionamento globale (VFG). Il gruppo dei famigliari composto da 11 uomini e 9 donne, 19 di nazionalità italiana; con età media di 55 anni. 8 sono coniugati, 6 celibi/nubili, 4 divorziati e 2 vedovi. 9 hanno figli, 11 lavorano e 8 sono pensionati. Nei famigliari aumenta il benessere psicologico (PWB), migliora il funzionamento famigliare (FAD) e la valutazione del funzionamento globale (VGF) rimane costante nel tempo. Discussioni e conclusioni. Il progetto IESA sembra migliorare la psicopatologia, con una diminuzione dei comportamenti maladattativi e un aumento delle capacità relazionali dell’ospite favorendone l’integrazione. Inoltre, lo IESA sembra diminuire i costi della cronicità psichiatrica: diminuzione degli accessi al Pronto Soccorso, delle visite psichiatriche urgenti e delle giornate di ricovero.

Adding regional analgesia to general anaesthesia: increase of risk or improved outcome?

Although it is clear that regional analgesia in association with general anaesthesia substantially reduces postoperative pain, the benefits in terms of overall perioperative outcome are less evident. The aim of this nonsystematic review was to evaluate the effect on middle and long-term postoperative outcomes of adding regional perioperative analgesia to general anaesthesia. This study is based mostly on systematic reviews, large epidemiological studies and large or high-quality randomized controlled trials that were selected and evaluated by the author. The endpoints that are discussed are perioperative morbidity, cancer recurrence, chronic postoperative pain, postoperative rehabilitation and risk of neurologic damage. Epidural analgesia may have a favourable but very small effect on perioperative morbidity. The influence of other regional anaesthetic techniques on perioperative morbidity is unclear. Preliminary data suggest that regional analgesia might reduce the incidence of cancer recurrence. However, adequately powered randomized controlled trials are lacking. The sparse literature available suggests that regional analgesia may prevent the development of chronic postoperative pain. Rehabilitation in the immediate postoperative period is possibly improved, but the advantages in the long term remain unclear. Permanent neurological damage is extremely rare. In conclusion, while the risk of permanent neurologic damage remains extremely low, evidence suggests that regional analgesia may improve relevant outcomes in the long term. The effect size is mostly small or the number-needed-to-treat is high. However, considering the importance of the outcomes of interest, even minor improvement probably has substantial clinical relevance.

Genome-wide association study in German patients with attention deficit/hyperactivity disorder

The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 × 10(-7)) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values ≤ 7.57 × 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.

Cannabis use disorder and age at onset of psychosis--a study in first-episode patients

INTRODUCTION Age at onset of psychosis (AAO) may be younger in patients with cannabis use disorders (CUD) compared to those without CUD (NCUD). Previous studies included CUD co-morbid with other substance use disorders (SUD), and many did not control for confounders. METHODS Controlling for relevant confounders, differences in AAO between patients with and without CUD excluding those with any other SUD were analyzed in a large representative file audit of 625 first-episode psychosis (FEP) patients (age 14 to 29years) admitted to the Early Psychosis Prevention and Intervention Centre in Melbourne, Australia. RESULTS Three quarters of the 625 FEP patients had a CUD. Cannabis use started before psychosis onset in 87.6% of patients. AAO was not significantly different between CUD (without other SUD, n=201) and NCUD (n=157). However, AAO was younger in those with early CUD (starting age 14 or younger) compared to NCUD (F(1)=5.2; p=0.024; partial η(2)=0.026). Earlier age at onset of cannabis use predicted earlier age at onset of psychosis (β=-0.49, R(2)-change=0.25, p<0.001). CONCLUSION Only CUD starting age 14 or younger was associated with an earlier AAO at a small effect size. These findings suggest that CUD may exert an indirect effect on brain maturation resulting in earlier AAO potentially only in cannabis sensitive subjects.

Cognitive function in postmenopausal breast cancer patients one year after completing adjuvant endocrine therapy with letrozole and/or tamoxifen in the BIG 1-98 trial

Endocrine therapy for breast cancer may affect cognition. The purpose of this study was to examine whether cognitive function improves after cessation of adjuvant endocrine therapy. Change in cognitive function was assessed in 100 postmenopausal breast cancer patients in the BIG 1-98 trial, who were randomized to receive 5 years of adjuvant tamoxifen or letrozole alone or in sequence. Cognitive function was evaluated by computerized tests during the fifth year of trial treatment (Y5) and 1 year after treatment completion (Y6). Cognitive test scores were standardized according to age-specific norms and the change assessed using the Wilcoxon signed-rank test. There was significant improvement in the composite cognitive function score from Y5 to Y6 (median of change = 0.22, effect size = 0.53, P < 0.0001). This improvement was consistent in women taking either tamoxifen or letrozole at Y5 (P = 0.0006 and P = 0.0002, respectively). For postmenopausal patients who received either adjuvant letrozole or tamoxifen alone or in sequence, cognitive function improved after cessation of treatment.

The efficacy of non-directive supportive therapy for adult depression: A meta-analysis

The effects of non-directive supportive therapy (NDST) for adult depression have been examined in a considerable number of studies, but no meta-analysis of these studies has been conducted. We selected 31 studies on NDST from a comprehensive database of trials, examining psychotherapies for adult depression, and conducted meta-analyses in which NDST was compared with control groups, other psychotherapies and pharmacotherapy. We found that NDST is effective in the treatment of depression in adults (g=0.58; 95% CI: 0.45-0.72). NDST was less effective than other psychological treatments (differential effect size g=-0.20; 95% CI: -0.32 to -0.08, p<0.01), but these differences were no longer present after controlling for researcher allegiance. We estimated that extra-therapeutic factors (those processes operating in waiting-list and care-as-usual controls) were responsible for 33.3% of the overall improvement, non-specific factors (the effects of NDST compared with control groups) for 49.6%, and specific factors (the effects of NDST compared with other therapies) for 17.1%. NDST has a considerable effect on symptoms of depression. Most of the effect of therapy for adult depression is realized by non-specific factors, and our results suggest that the contribution of specific effects is limited at best.

Reporting Experiments in Homeopathic Basic Research—Description of the Checklist Development

The objective of this study was to develop a criteria catalogue serving as a guideline for authors to improve quality of reporting experiments in basic research in homeopathy. A Delphi Process was initiated including three rounds of adjusting and phrasing plus two consensus conferences. European researchers who published experimental work within the last 5 years were involved. A checklist for authors provide a catalogue with 23 criteria. The “Introduction” should focus on underlying hypotheses, the homeopathic principle investigated and state if experiments are exploratory or confirmatory. “Materials and methods” should comprise information on object of investigation, experimental setup, parameters, intervention and statistical methods. A more detailed description on the homeopathic substances, for example, manufacture, dilution method, starting point of dilution is required. A further result of the Delphi process is to raise scientists' awareness of reporting blinding, allocation, replication, quality control and system performance controls. The part “Results” should provide the exact number of treated units per setting which were included in each analysis and state missing samples and drop outs. Results presented in tables and figures are as important as appropriate measures of effect size, uncertainty and probability. “Discussion” in a report should depict more than a general interpretation of results in the context of current evidence but also limitations and an appraisal of aptitude for the chosen experimental model. Authors of homeopathic basic research publications are encouraged to apply our checklist when preparing their manuscripts. Feedback is encouraged on applicability, strength and limitations of the list to enable future revisions.

Homeopathic Preparations of Quartz, Sulfur and Copper Sulfate Assessed by UV-Spectroscopy

Homeopathic preparations are used in homeopathy and anthroposophic medicine. Although there is evidence of effectiveness in several clinical studies, including double-blinded randomized controlled trials, their nature and mode of action could not be explained with current scientific approaches yet. Several physical methods have already been applied to investigate homeopathic preparations but it is yet unclear which methods are best suited to identify characteristic physicochemical properties of homeopathic preparations. The aim of this study was to investigate homeopathic preparations with UV-spectroscopy. In a blinded, randomized, controlled experiment homeopathic preparations of copper sulfate (CuSO(4); 11c-30c), quartz (SiO(2); 10c-30c, i.e., centesimal dilution steps) and sulfur (S; 11×-30×, i.e., decimal dilution steps) and controls (one-time succussed diluent) were investigated using UV-spectroscopy and tested for contamination by inductively coupled plasma mass spectrometry (ICP-MS). The UV transmission for homeopathic preparations of CuSO(4) preparations was significantly lower than in controls. The transmission seemed to be also lower for both SiO(2) and S, but not significant. The mean effect size (95% confidence interval) was similar for the homeopathic preparations: CuSO(4) (pooled data) 0.0544% (0.0260-0.0827%), SiO(2) 0.0323% (-0.0064% to 0.0710%) and S 0.0281% (-0.0520% to 0.1082%). UV transmission values of homeopathic preparations had a significantly higher variability compared to controls. In none of the samples the concentration of any element analyzed by ICP-MS exceeded 100 ppb. Lower transmission of UV light may indicate that homeopathic preparations are less structured or more dynamic than their succussed pure solvent.

Social cognition as a mediator variable between neurocognition and functional outcome in schizophrenia: empirical review and new results by structural equation modeling

Cognitive impairments are currently regarded as important determinants of functional domains and are promising treatment goals in schizophrenia. Nevertheless, the exact nature of the interdependent relationship between neurocognition and social cognition as well as the relative contribution of each of these factors to adequate functioning remains unclear. The purpose of this article is to systematically review the findings and methodology of studies that have investigated social cognition as a mediator variable between neurocognitive performance and functional outcome in schizophrenia. Moreover, we carried out a study to evaluate this mediation hypothesis by the means of structural equation modeling in a large sample of 148 schizophrenia patients. The review comprised 15 studies. All but one study provided evidence for the mediating role of social cognition both in cross-sectional and in longitudinal designs. Other variables like motivation and social competence additionally mediated the relationship between social cognition and functional outcome. The mean effect size of the indirect effect was 0.20. However, social cognitive domains were differentially effective mediators. On average, 25% of the variance in functional outcome could be explained in the mediation model. The results of our own statistical analysis are in line with these conclusions: Social cognition mediated a significant indirect relationship between neurocognition and functional outcome. These results suggest that research should focus on differential mediation pathways. Future studies should also consider the interaction with other prognostic factors, additional mediators, and moderators in order to increase the predictive power and to target those factors relevant for optimizing therapy effects.

Bipolar disorder susceptibility region on chromosome 3q29 not confirmed in a case-control association study

We identified a bipolar disorder (BPD) susceptibility region on chromosome 3q29 in a genome-wide linkage scan (Bailer et al. 2002 (Biol Psychiatry 52: 40), NPL-score 4.09) and follow-up linkage analysis (Schosser et al. 2004 (J Psychiatr Res 38(3): 357), NPL-scores >3 with five markers). These findings were supported by further fine-mapping of this region (Schosser et al. 2007 (Eur Neuropsychopharmacol 17(6-7): 501)), finding NPL-scores >3.9 with SNPs (single nucleotide polymorphisms) spanning a region of 3.46 Mbp in BPD families. Since genetic association studies are more powerful than linkage studies for detecting susceptibility genes of small effect size, we aimed to replicate these findings in an independent case-control sample collected in London (UK) and Vienna (Austria).

Sexual selection and speciation: the comparative evidence revisited

The spectacular diversity in sexually selected traits in the animal kingdom has inspired the hypothesis that sexual selection can promote species divergence. In recent years, several studies have attempted to test this idea by correlating species richness with estimates of sexual selection across phylogenies. These studies have yielded mixed results and it remains unclear whether the comparative evidence can be taken as generally supportive. Here, we conduct a meta-analysis of the comparative evidence and find a small but significant positive overall correlation between sexual selection and speciation rate. However, we also find that effect size estimates are influenced by methodological choices. Analyses that included deeper phylogenetic nodes yielded weaker correlations, and different proxies for sexual selection showed different relationships with species richness. We discuss the biological and methodological implications of these findings. We argue that progress requires more representative sampling and justification of chosen proxies for sexual selection and speciation rate, as well as more mechanistic approaches.

Differences between RNA and DNA due to RNA editing in temporal lobe epilepsy

To investigate whether alterations in RNA editing (an enzymatic base-specific change to the RNA sequence during primary transcript formation from DNA) of neurotransmitter receptor genes and of transmembrane ion channel genes play a role in human temporal lobe epilepsy (TLE), this exploratory study analyzed 14 known cerebral editing sites in RNA extracted from the brain tissue of 41 patients who underwent surgery for mesial TLE, 23 with hippocampal sclerosis (MTLE+HS). Because intraoperatively sampled RNA cannot be obtained from healthy controls and the best feasible control is identically sampled RNA from patients with a clinically shorter history of epilepsy, the primary aim of the study was to assess the correlation between epilepsy duration and RNA editing in the homogenous group of MTLE+HS. At the functionally relevant I/V site of the voltage-gated potassium channel Kv1.1, an inverse correlation of RNA editing was found with epilepsy duration (r=-0.52, p=0.01) but not with patient age at surgery, suggesting a specific association with either the epileptic process itself or its antiepileptic medication history. No significant correlations were found between RNA editing and clinical parameters at other sites within glutamate receptor or serotonin 2C receptor gene transcripts. An "all-or-none" (≥95% or ≤5%) editing pattern at most or all sites was discovered in 2 patients. As a secondary part of the study, RNA editing was also analyzed as in the previous literature where up to now, few single editing sites were compared with differently obtained RNA from inhomogenous patient groups and autopsies, and by measuring editing changes in our mouse model. The present screening study is first to identify an editing site correlating with a clinical parameter, and to also provide an estimate of the possible effect size at other sites, which is a prerequisite for power analysis needed in planning future studies.

Osteoarthritis: rational approach to treating the individual

Osteoarthritis (OA) is the most common form of joint disease and the leading cause of pain and physical disability in older people. Risk factors for incidence and progression of osteoarthritis vary considerably according to the type of joint. Disease assessment is difficult and the relationship between the radiographic severity of joint damage and the incidence and severity of pain is only modest. Psychosocial and socio-economic factors play an important role. This chapter will discuss four main guiding principles to the management of OA: (1) to avoid overtreating people with mild symptoms; (2) to attempt to avoid doing more harm than good ('primum non nocere'); (3) to base patient management on the severity of pain, disability and distress, and not on the severity of joint damage or radiographic change; and (4) to start with advice about simple measures that patients can take to help themselves, and only progress to interventions that require supervision or specialist knowledge if simple measures fail. Effect sizes derived from meta-analyses of large randomized trials in OA are only small to moderate for most therapeutic interventions, but they are still valuable for patients and clinically relevant for physicians. Joint replacement may be the only option with a large effect size, but is only appropriate for the relatively small number of people with OA who have advanced disease and severe symptoms. The key to successful management involves patient and health professionals working together to develop optimal treatment strategies for the individual.

Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) may increase cardiovascular risk but the psychophysiological mechanisms involved are elusive. We hypothesized that proinflammatory activity is elevated in patients with PTSD as diagnosed by the Clinician Administered PTSD Scale (CAPS) interview. Plasma levels of proinflammatory C-reactive protein (CRP), interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, and of anti-inflammatory IL-4 and IL-10 were measured in 14 otherwise healthy PTSD patients and in 14 age- and gender-matched healthy non-PTSD controls. Levels of TNF-alpha (p=0.038; effect size Cohen's d=0.58) and of IL-1beta (p=0.075, d=0.68) were higher in patients than in controls. CRP (d=0.10), IL-6 (d=0.18), IL-4 (d=0.42), and IL-10 (d=0.37) were not significantly different between groups. Controlling for traditional cardiovascular risk factors, mood, and time since trauma revealed lower IL-4 in patients than in controls (p=0.029) and rendered group differences in TNF-alpha and IL-1beta insignificant. In all subjects, TNF-alpha correlated with total (frequency and intensity) PTSD symptom cluster of re-experiencing (r=0.49, p=0.008), avoidance (r=0.37, p=0.050), and hyperarousal (r=0.42, p=0.026), and with PTSD total symptom score (r=0.37, p=0.054). Controlling for time since trauma attenuated these associations. The correlation between IL-1beta and total avoidance symptoms (r=0.42, p=0.028) became insignificant when controlling for anxiety and depression. IL-4 correlated with total hyperarousal symptoms (r=-0.38, p=0.047), and after controlling for systolic blood pressure and smoking status, with PTSD total symptom score (r=-0.41, p=0.035). PTSD patients showed a low-grade systemic proinflammatory state, which, moreover, was related to PTSD symptom levels suggesting one mechanism by which PTSD could contribute to atherosclerotic disease.