Loss of calpain 3 dysregulates store-operated calcium entry and its exercise response in mice.

Limb-Girdle Muscular Dystrophy 2A (LGMD2A) is caused by mutations in the CAPN3 gene encoding Calpain 3, a skeletal-muscle specific, Ca2+-dependent protease. Localization of Calpain 3 within the triad suggests it contributes to Ca2+ homeostasis. Through live-cell Ca2+ measurements, muscle mechanics, immunofluorescence, and electron microscopy (EM) in Capn3 deficient (C3KO) and wildtype (WT) mice, we determined if loss of Calpain 3 altered Store-Operated Calcium Entry (SOCE) activity. Direct Ca2+ influx measurements revealed loss of Capn3 elicits elevated resting SOCE and increased resting cytosolic Ca2+, supported by high incidence of calcium entry units (CEUs) observed by EM. C3KO and WT mice were subjected to a single bout of treadmill running to elicit SOCE. Within 1HR post-treadmill running, C3KO mice exhibited diminished force production in extensor digitorum longus muscles and a greater decay of Ca2+ transients in flexor digitorum brevis muscle fibers during repetitive stimulation. Striking evidence for impaired exercise-induced SOCE activation in C3KO mice included poor colocalization of key SOCE proteins, stromal-interacting molecule 1 (STIM1) and ORAI1, combined with disappearance of CEUs in C3KO muscles. These results demonstrate that Calpain 3 is a key regulator of SOCE in skeletal muscle and identify SOCE dysregulation as a contributing factor to LGMD2A pathology.

Recurrent acute otitis media: a survey of current management in England.

OBJECTIVE: Recurrent acute otitis media is common in children. The preferred treatment measures for recurrent acute otitis media have a mixed evidence base. This study sought to assess baseline practice across ENT departments in England. METHODS: A national telephone survey of healthcare staff was conducted. Every ENT centre in England was contacted. A telephone script was used to ask about antibiotic and grommet use and duration in recurrent acute otitis media cases. RESULTS: Ninety-six centres (74 per cent) provided complete information. Recurrent acute otitis media treatment across England by ENT departments varied. The antibiotic first- and second-line prophylaxis offered varies, with trimethoprim used in 33 centres and 29 centres not offering any antibiotics. The timing or choice about when to use grommets also varies, but 87 centres (91 per cent) offer grommet surgery at one stage. CONCLUSION: The treatments received by children in England for recurrent acute otitis media vary by centre; collaborative research in this area is advised.

Evidence into action: a policy brief exemplar supporting attainment of nursing now.

AIM: To provide a framework for the production of policy briefs, and offer a practical example of how evidence can be turned into a succinct document to inform policy and bring about change targeted at delivering universal health coverage. INTRODUCTION: Policymakers are too busy, or do not have the necessary expertise, to read and comprehend complex scientific papers. As a result, policy briefs that capture and present the essential points are needed if evidence-informed policy is to be developed and implemented. METHOD: A two-page example of how evidence from meta-analytical and systematic reviews can be presented to identify options and recommendations to address a major global disease burden. RESULTS: The example uses a simple, seven-section template for developing a policy brief. The essential characteristics of each section are provided. The briefing, targeted at the global level, provides information on the major challenges associated with the treatment of individuals with diabetes. DISCUSSION AND CONCLUSIONS: This paper demonstrates how to use existing research evidence to address the pursuit of UHC relevant to a wide range of geographies, settings or disadvantaged groups. IMPLICATIONS FOR POLICY: Gaps in universal health coverage and major disease burdens such as diabetes can be pursued through entities such as country-based Nursing Now groups. In addition, ongoing opportunities exist through the International Council of Nurses annual International Nurses Day and WHO's regular regional meetings to inform and influence policy discussions at national and subnational levels. By focusing on a small number of global topics each year, measurable changes in addressing the burden of disease can be achieved while simultaneously keeping the nursing profession's contribution centre stage.

Evidence-based policy: nursing now and the importance of research synthesis.

AIM: This study explores how scholarship relating to meta-analytical studies and systematic and integrative reviews can inform nursing's contribution to universal health coverage. INTRODUCTION: As nursing globally embraces the 200th anniversary of the birth of Florence Nightingale, the Nursing Now social movement has called for the profession to improve universal health coverage through increasing nursing's policy voice. METHODS: In determining how the Nursing Now social movement could pursue the aim of this study, researchers undertook a comparative bibliometric analysis of scholarship relating to the systematic curation of evidence. This study uses a mixed-method analysis of the bibliometric data available through extracting and synthesizing information from one of the commercially produced indexing and citation databases. RESULTS: Generally, medicine has contributed far more synthesized contributions than nursing, except in the case of integrative reviews. Co-occurrence analysis of nursing literature through examination of key terms yielded a complex visualization of 11 specific clusters of scholarship (Care of the Older Person, Nurse Education, Emergency and Critical Care, Occupational Health and Safety, Rural Services, Anxiety and Depression, Measurement, Newborn and Post-natal Health, Cardiovascular Disease, Preventative Health and Cancer Care). DISCUSSION AND CONCLUSIONS: Bibliometric analysis of curated evidence demonstrates that there is ample nursing-relevant material to inform evidence-based policy change directed towards the attainment of universal health coverage and several of the Sustainable Development Goals. IMPLICATIONS FOR POLICY: Nursing literature is available to support policy change directed towards the pursuit of universal health coverage and sustainable development goals. Leveraging existing networks of research collaboration to increase research capacity through communities of scholarship or by twinning experienced and neophyte contributors is possible. Further work is needed to equip nurses with the competencies to navigate the policy environment and develop and deliver impactful policy messaging.

Decreased medial entorhinal cortical thickness in olanzapine exposed female rats is not ameliorated by exercise.

Aerobic exercise has been associated with hippocampal plasticity, both in healthy adults and in psychosis patients, but its impact on cortical regions remains unclear. The entorhinal cortex serves as a critical gateway for the hippocampus, and recent studies suggest that this region may also be impacted following an exercise regime. In order to investigate the effects of antipsychotic medications and exercise on the entorhinal cortex, female rats were chronically administered either olanzapine or vehicle and were either sedentary or had access to a running wheel for 9 weeks. Olanzapine-treated rats had decreased medial entorhinal cortical thickness compared to vehicle-treated rats. A statistically significant interaction was observed for layer II of the entorhinal cortex, with exercising rats having significantly greater thickness compared to sedentary rats in the vehicle group, but not the olanzapine group. Greater total entorhinal and lateral entorhinal cortical thickness was associated with greater average activity. In exercising rats, decreasing glucose intolerance was associated with larger total entorhinal and layer II cortical thickness. Lower fasting insulin levels were associated with greater total entorhinal, lateral entorhinal, and layer II cortical thickness. The relationship between increased activity and greater entorhinal cortical thickness was mediated by reduced fasting insulin, indicating that regulation of metabolic risk factors may contribute to impact of aerobic exercise on the entorhinal cortex. Aerobic exercise may be helpful in counteracting metabolic side effects of antipsychotic medications and managing these side effects may be key to promoting entorhinal cortical plasticity in patients treated with second-generation antipsychotic drugs.

A content analysis of oral health messages in Australian mass media.

BACKGROUND: Social analysis regarding oral health and oral health promotion are almost non-existent in the Australian context. The usefulness of such exploration lies in framing and informing research methodologies and health promotion initiatives, and can improve our understanding of oral health behaviours and their social contexts. METHODS: We conducted a systematic content analysis of a random sample of popular Australian magazines, newspapers and television shows from May to September 2012. Our sample included the top three best-selling magazines, six weekly newspapers, one from each available Australian state, and the four highest ranked Australian prime time television shows and their associated commercials. RESULTS: Data comprised 72 hours of prime time television and 14,628 pages of hardcopy media. Seventy-one oral health related media 'incidents' were counted during a five-month period. Only 1.5% of incidents referenced fluoride and only two made dietary references. Women were represented almost six times more than men and the majority of oral health related incidents conveyed no social context (63%). CONCLUSIONS: Oral health messages conveyed in Australian media fail to provide a social context for preventive or health-promoting behaviours. In light of increased levels of oral disease and retention of natural teeth, more community based oral health promotion and support for oral health literacy would be prudent in the Australian context.

Exercise prevents downregulation of hippocampal presynaptic proteins following olanzapine-elicited metabolic dysregulation in rats: Distinct roles of inhibitory and excitatory terminals.

Schizophrenia patients treated with olanzapine, or other second-generation antipsychotics, frequently develop metabolic side-effects, such as glucose intolerance and increased adiposity. We previously observed that modeling these adverse effects in rodents also resulted in hippocampal shrinkage. Here, we investigated the impact of olanzapine treatment, and the beneficial influence of routine exercise, on the neurosecretion machinery of the hippocampus. Immunodensities and interactions of three soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin-1, synaptosome-associated protein of 25kDa (SNAP-25) and vesicle-associated membrane protein (VAMP)), synaptotagmin and complexins-1/2 were quantified in the hippocampus of sedentary and exercising rats exposed over 9weeks to vehicle (n=28) or olanzapine (10mg/kg/day, n=28). In addition, brain sections from subgroups of sedentary animals (n=8) were co-immunolabeled with antibodies against vesicular GABA (VGAT) and glutamate (VGLUT1) transporters, along with syntaxin-1, and examined by confocal microscopy to detect selective olanzapine effects within inhibitory or excitatory terminals. Following olanzapine treatment, sedentary, but not exercising rats showed downregulated (33-50%) hippocampal densities of SNARE proteins and synaptotagmin, without altering complexin levels. Strikingly, these effects had no consequences on the amount of SNARE protein-protein interactions. Lower immunodensity of presynaptic proteins was associated with reduced CA1 volume and glucose intolerance. Syntaxin-1 depletion appeared more prominent in VGAT-positive terminals within the dentate gyrus, and in non-VGAT/VGLUT1-overlapping areas of CA3. The present findings suggest that chronic exposure to olanzapine may alter hippocampal connectivity, especially in inhibitory terminals within the dentate gyrus, and along the mossy fibers of CA3. Together with previous studies, we propose that exercise-based therapies might be beneficial for patients being treated with olanzapine.

Effects of chronic exercise and treatment with the antipsychotic drug olanzapine on hippocampal volume in adult female rats.

Numerous studies have reported that the hippocampus in schizophrenia patients is reduced in volume compared to the normal population. Antipsychotic medications have had mixed benefits in maintaining hippocampal volume or reversing volume loss. Recent evidence indicates that routine aerobic exercise represents a promising intervention for reversing hippocampal loss and cognitive deficits. In the present study, we measured the effects of chronic treatment with olanzapine and daily exercise on the hippocampal volumes of rats. Adult female rats were treated during the week with either olanzapine (10mg/kg) or vehicle for 9 consecutive weeks. Subgroups of animals were provided access to exercise running wheels for 1 or 3h per day during the same period, or were sedentary. Metabolic indices, including glucose tolerance, were measured on a weekly basis. At the conclusion of the study, brains were perfused and hippocampal sections were Nissl stained. Total hippocampal volume was measured using the Cavalieri estimator. Treatment with olanzapine caused a significant decrease in hippocampal volume in sedentary rats. However, exercise was able to reverse most of this volume loss. The hippocampal sub-regions of the dentate gyrus and CA1 were most strongly affected by olanzapine and exercise. Of interest, there was a strong and highly significant negative correlation between glucose intolerance and hippocampal volume, whereby greater glucose intolerance was associated with a smaller hippocampal volume. These findings indicate that exercise may have beneficial effects on the hippocampus when antipsychotic medication can contribute to changes in volume.

Glucocorticoids increase protein carbonylation and mitochondrial dysfunction.

Many major psychiatric illnesses have been associated with excessive and prolonged release of glucocorticoid stress hormones potentially leading to deleterious neuronal effects. Recent studies have suggested that oxidative stress is associated with psychiatric illnesses. Oxidative stress is an overproduction of reactive oxygen species (ROS) that overwhelms the cellular antioxidant capacity. The mitochondria are responsible for most oxygen consumption and are a major source of ROS production. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase also contributes significantly to ROS production. This study aims to elucidate the effects of glucocorticoids on oxidative damage to protein, mitochondrial function, NADPH oxidase activity, and antioxidant capacity. Rat pheochromocytoma PC12 cells were treated with corticosterone at concentrations of 0.031, 0.063, and 0.125 mmol/l for 24 h. Protein carbonylation, activities of mitochondrial complex I and III, activity of NADPH oxidase, total antioxidant capacity, and activities of superoxide dismutase (SOD) and catalase (CAT) were analyzed. We found that chronic treatment with corticosterone increased the amount of protein carbonylation in PC12 cells. Complex I activity was decreased with corticosterone treatment, while no change was seen in complex III activity or NADPH oxidase activity. Total antioxidant capacity was increased at the lowest dosage level tested. Although corticosterone treatment had no effect on CAT activity, corticosterone at the highest dosage significantly decreased SOD activity. These results suggest that excessive glucocorticoid activity can increase oxidative damage to protein, possibly by inhibiting activities of mitochondrial complex I and antioxidant enzyme SOD.

Characterization of the count rate performance of modern gamma cameras.

PURPOSE: Evaluation of count rate performance (CRP) is an integral component of gamma camera quality assurance and system deadtime (τ) may be utilized for image correction in quantitative studies. This work characterizes the CRP of three modern gamma cameras and estimates τ using two established methods (decay and dual source) under a variety of experimental conditions. METHODS: For the decay method, uncollimated detectors were exposed to a Tc-99m source of relatively high activity and count rates were sampled regularly over 48 h. Input count rate at each time point was based on the lowest observed count rate data point. The input count rate was plotted against the observed count rate and fit via least-squares to the paralyzable detector model (PDM) to estimate τ (rates method). A novel expression for observed counts as a function of measurement time interval was derived, taking into account the PDM and the presence of background but making no assumption regarding input count rate. The observed counts were fit via least-squares to this novel expression to estimate τ (counts method). Correlation and Bland-Altman analyses were performed to assess agreement in estimates of τ between the rates and counts methods. The dependence of τ on energy window definition and incident energy spectrum were characterized. The dual source method was also used to estimate τ and its agreement with estimates from the decay method under identical conditions was also investigated. The dependences of τ on the total activity and the ratio of source activities were characterized. RESULTS: The observed CRP curves for each gamma camera agreed with the PDM at low count rates but deviated substantially from it at high count rates. The estimates of τ determined from the paralyzable portion of the CPR curve using the rates method and the counts method were found to be highly correlated (r = 0.999) but with a small (~6%) difference. No statistically significant difference was observed between the estimates of τ using the decay or dual source methods under identical experimental conditions (p = 0.13). Estimates of τ increased as a power-law function with decreasing ratio of counts in the photopeak to the total counts. Also, estimates of τ increased linearly as spectral effective energy decreased. No significant difference was observed between the dependences of τ on energy window definition or incident spectrum between the decay and dual source methods. Estimates of τ using the dual source method varied as a quadratic on the ratio of the single source to combined source activities and linearly with total activity. CONCLUSIONS: The CRP curves for three modern gamma camera models have been characterized, demonstrating unexpected behavior that necessitates the determination of both τ and maximum count rate to fully characterize the CRP curve. τ was estimated under a variety of experimental conditions, based on which guidelines for the performance of CRP testing in a clinical setting have been proposed.

Decreased mRNA expression of uncoupling protein 2, a mitochondrial proton transporter, in post-mortem prefrontal cortex from patients with bipolar disorder and schizophrenia.

Although the neurobiological basis of bipolar disorder (BD) remains unknown, mitochondrial dysfunction, oxidative stress and oxidative cell damage have been identified in this disease. Uncoupling proteins (UCP) are proton carriers located in the inner membrane of the mitochondria involved in controlling the production of mitochondrial reactive oxygen species (ROS). Therefore, in this study we wished to investigate the involvement of UCP in BD. We analyzed the RNA and protein levels of UCP2 in the dorsolateral prefrontal cortex (DLPFC) of subjects with BD and schizophrenia (SCZ) and assessed the potential relationship between the antioxidant superoxide dismutase (SOD1 and SOD2) and UCP2 in the same region. Our results showed a downregulation of UCP2 mRNA levels in the DLPFC of subjects with BD and SCZ. There were no differences in UCP2 protein, SOD1 and SOD2 levels between patients and controls. Although more studies are necessary, our results suggest that UCP2 is not been used as a compensatory mechanism to oppose the higher levels of oxidative stress found in BD and SCZ.

The effect of antipyretic medications on mortality in critically ill patients with infection: a systematic review and meta-analysis.

BACKGROUND: Antipyretic medications are widely used in critically ill patients with infection despite evidence supporting a protective, adaptive role of fever. OBJECTIVE: To assess the mortality risk of antipyretic medications among critically ill patients with infection. METHODS: A systematic search of MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and PubMed was undertaken to identify randomised controlled trials (RCTs) of antipyretic use among critically ill patients with suspected or confirmed infection that reported mortality. A quantitative meta-analysis of the risk of death was carried out with calculation of the pooled risk of death and standard evaluation of heterogeneity. RESULTS: Six RCTs investigating the use of paracetamol (1) and non-steroidal anti-inflammatory medications (5) met the inclusion criteria for meta-analysis. The trials were heterogeneous in terms of study populations and interventions, were not primarily designed to evaluate antipyretic effect on mortality risk, and significant confounding was present from the use of other concomitant antipyretic strategies. The pooled estimates of odds ratios for mortality with antipyretic treatment were 0.96 (95% CI, 0.68-1.34) and 1.08 (95% CI, 0.60-1.96) for fixed effects and random effects, respectively, and the I-squared value was 34.9 (95% CI, 0.0-73.9). CONCLUSION: The studies included in this review were insufficient to allow a robust estimate of the effect of pharmacological antipyresis on mortality in critically ill patients with suspected infection. Further RCTs are required to resolve this important area of clinical uncertainty.

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder.

There is evidence for both similarity and distinction in the presentation and molecular characterization of schizophrenia and bipolar disorder. In this study, we characterized protein abnormalities in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder using two-dimensional gel electrophoresis. Tissue samples were obtained from 35 individuals with schizophrenia, 35 with bipolar disorder and 35 controls. Eleven protein spots in schizophrenia and 48 in bipolar disorder were found to be differentially expressed (P<0.01) in comparison to controls, with 7 additional spots found to be altered in both diseases. Using mass spectrometry, 15 schizophrenia-associated proteins and 51 bipolar disorder-associated proteins were identified. The functional groups most affected included synaptic proteins (7 of the 15) in schizophrenia and metabolic or mitochondrial-associated proteins (25 of the 51) in bipolar disorder. Six of seven synaptic-associated proteins abnormally expressed in bipolar disorder were isoforms of the septin family, while two septin protein spots were also significantly differentially expressed in schizophrenia. This finding represented the largest number of abnormalities from one protein family. All septin protein spots were upregulated in disease in comparison to controls. This study provides further characterization of the synaptic pathology present in schizophrenia and of the metabolic dysfunction observed in bipolar disorder. In addition, our study has provided strong evidence implicating the septin protein family of proteins in psychiatric disorders for the first time.

Humidified nasal continuous positive airway pressure in obstructive sleep apnoea.

Heated humidification of nasal continuous positive airway pressure (nCPAP) reduces upper airway symptoms and improves initial use in obstructive sleep apnoea syndrome (OSAS). The present study aimed to assess the effect of heated humidification of nCPAP on upper airway symptoms and initial use in obstructive sleep apnoea. This study was of a randomised, crossover design. Subjects with polysomnographically confirmed OSAS were randomised to 3 weeks nCPAP treatment with heated humidification (nCPAP-humid) or placebo humidification (nCPAP pl-humid). Objective and subjective nCPAP use, upper airway symptoms, and treatment satisfaction were compared. Thirty seven of 42 patients completed the protocol. nCPAP-humid reduced the frequency of adverse upper airway symptoms. nCPAP use over 3 weeks was greater with nCPAP-humid compared with nCPAP pl-humid. No difference was found between the treatment arms in terms of subjective treatment satisfaction or alertness. Heated humidification of nasal continuous positive airway pressure reduces upper airway symptoms and is associated with a small increase in initial use but not subjective sleepiness or treatment satisfaction. The results support the use of heated humidification as a strategy to reduce side-effects related to continuous positive airway pressure but not routine initial use.

Density and distribution of white matter neurons in schizophrenia, bipolar disorder and major depressive disorder: no evidence for abnormalities of neuronal migration.

The neurodevelopmental hypothesis of schizophrenia suggests that this disorder may result from a disruption of normal brain development. While widely cited, neuropathological evidence for this is far from conclusive. Alterations in the density and position of white matter neurons have been previously described in the frontal and temporal lobes and have led to suggestions that abnormal neuronal migration may play a role in the aetiology of schizophrenia. However, these findings have not been replicated. Furthermore, developmental abnormalities may not be specific to schizophrenia. The aim of this study was to examine the density and spatial pattern distribution of white matter neurons in psychiatric and control subjects using sophisticated computerised image analysis techniques. White matter neurons immunoreactive for microtubule associated protein-2 were quantified in the frontal lobe in schizophrenia, bipolar disorder, major depressive disorder and matched controls (each group n = 15). Analysis showed that the density and spatial distribution of white matter neurons did not differ significantly between the control and psychiatric groups. This study cannot replicate the earlier findings of white matter abnormalities in schizophrenia and finds no evidence for abnormal brain development in any of the disorders studied.

Understanding the neurotransmitter pathology of schizophrenia: selective deficits of subtypes of cortical GABAergic neurons.

Research aimed at understanding the neurotransmitter pathology of schizophrenia has been underway for half a century, with much emphasis on the dopamine system. Although this approach has advanced our understanding of treatment mechanisms, identification of primary dopaminergic abnormalities in the disease has been elusive. The increasing emphasis on a neuronal pathology of schizophrenia has led to the identification of abnormalities in GABAergic and glutamatergic systems; and we have identified selective deficits in GABAergic interneurons containing the calcium binding proteins parvalbumin and calbindin. Here we report further evidence for a loss of parvalbumin-immunoreactive neurons in both dorsolateral prefrontal and medial temporal cortex, indicating that these deficits are consistent with a subtle neurodevelopmental pathogenesis and hypothesizing that they may contribute to a further degenerative process in schizophrenia.

A current review of olanzapine's safety in the geriatric patient: from pre-clinical pharmacology to clinical data.

OBJECTIVE: Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapine's mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available. METHOD: Preclinical and clinical studies of OLZ are reviewed, with emphasis on its possible effects on the cholinergic system and the histamine H(1) receptor. Weight change and related metabolic considerations, cardiac and cardiovascular safety, and motor function during treatment with OLZ are also reviewed. RESULTS AND CONCLUSION: In vitro receptor characterization methods, when done using physiologically relevant conditions allow accurate prediction of the relatively low rate of anticholinergic-like adverse events, extrapyramidal symptoms, and cardiovascular adverse events during treatment with OLZ. Currently available clinical data suggest olanzapine is predictably safe in treating adult patients of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some types of neurodegenerative disorders.

Neurochemical correlates of cortical GABAergic deficits in schizophrenia: selective losses of calcium binding protein immunoreactivity.

Deficits in a variety of different neurochemical species are consistent with a loss of cortical gamma-aminobutyric acid (GABA)ergic interneurons in schizophrenia. As well as neurochemical markers that indicate all neurons using GABA as a transmitter, and which include GABA uptake sites and glutamate decarboxylase, deficits of certain neuropeptides and calcium binding proteins coexisting with GABA have been reported. These abnormalities are indicative of losses specific to certain subtypes of GABAergic neurons. The calcium binding proteins in particular demonstrate selective deficits; we find losses of parvalbumin- and calbindin-, but not calretinin-immunoreactive cells in the prefrontal cortex in schizophrenia. These selective reductions in the density of parvalbumin- and calbindin-containing neurons could reflect functional loss of expression in intact cells or alternatively a deficit in the density of certain GABAergic neuronal subtypes. The latter interpretation is consistent with a neurodevelopmental pathogenesis involving neuronal damage at a time prior to the expression of these protective calcium-binding proteins. In this review we discuss the evidence for altered GABAergic transmission in schizophrenia.

GABAergic neuronal subtypes in the human frontal cortex--development and deficits in schizophrenia.

Recent studies have provided evidence for a deficit of GABA-containing interneurons in the frontal cortex in schizophrenia. That this deficit might be brought about during early foetal or neonatal life is a hypothesis consistent with the substantial indications for a neurodevelopmental aetiology of the disease. GABAergic neurons can be defined by the presence of one of three types of calcium binding proteins, which are thought to have neuroprotective properties. We have undertaken an investigation into the postnatal ontology of these neuronal subtypes and find that calretinin expression is relatively constant and present from before birth, calbindin expression is also present early but redistributes in the cortex over the first months of life, while parvalbumin-immunoreactivity is not observed until between 3 and 6 months of age. Investigation of frontal cortical tissue taken post mortem from a series of schizophrenic patients and matched control subjects revealed that parvalbumin-, but not calretinin-immunoreactive cells are significantly diminished in schizophrenia. These observations support the hypothesis that GABAergic deficits in schizophrenia may stem from toxic events occurring during cortical development which selectively target immature neurons before protection by parvalbumin is conferred.

Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia.

Cytoarchitectural abnormalities have been reported in the cortex in schizophrenia. These suggest a developmental origin for this disorder. The Wnt signalling pathway is involved in the regulation of brain development; disruption of this pathway may lead to abnormal cortical development. In this study levels of three components of the Wnt signalling pathway; glycogen synthase kinase-3beta(GSK-3beta), beta-catenin and dishevelled-2 (Dvl-2) were determined in the prefrontal cortex of ten schizophrenic and ten control individuals using immunoblotting. GSK-3beta levels were significantly reduced in the schizophrenic group, while levels of beta-catenin and Dvl-2 did not differ between groups. This provides further evidence for an abnormality of the Wnt signalling pathway in schizophrenia.