Psychedelics and schizophrenia: Distinct alterations to Bayesian inference.

Schizophrenia and states induced by certain psychotomimetic drugs may share some physiological and phenomenological properties, but they differ in fundamental ways: one is a crippling chronic mental disease, while the others are temporary, pharmacologically-induced states presently being explored as treatments for mental illnesses. Building towards a deeper understanding of these different alterations of normal consciousness, here we compare the changes in neural dynamics induced by LSD and ketamine (in healthy volunteers) against those associated with schizophrenia, as observed in resting-state M/EEG recordings. While both conditions exhibit increased neural signal diversity, our findings reveal that this is accompanied by an increased transfer entropy from the front to the back of the brain in schizophrenia, versus an overall reduction under the two drugs. Furthermore, we show that these effects can be reproduced via different alterations of standard Bayesian inference applied on a computational model based on the predictive processing framework. In particular, the effects observed under the drugs are modelled as a reduction of the precision of the priors, while the effects of schizophrenia correspond to an increased precision of sensory information. These findings shed new light on the similarities and differences between schizophrenia and two psychotomimetic drug states, and have potential implications for the study of consciousness and future mental health treatments.

Magnitude and heterogeneity of brain structural abnormalities in 22q11.2 deletion syndrome: a meta-analysis.

The 22q11.2 deletion syndrome (22q11.2DS) is a neurodevelopmental disorder associated with a number of volumetric brain abnormalities. The syndrome is also associated with an increased risk for neuropsychiatric disorders including schizophrenia and autism spectrum disorder. An earlier meta-analysis showed reduced grey and white matter volumes in individuals with 22q11.2DS. Since this analysis was conducted, the number of studies has increased markedly, permitting more precise estimates of effects and more regions to be examined. Although 22q11.2DS is clinically heterogeneous, it is not known to what extent this heterogeneity is mirrored in neuroanatomy. The aim of this study was thus to investigate differences in mean brain volume and structural variability within regions, between 22q11.2DS and typically developing controls. We examined studies that reported measures of brain volume using MRI in PubMed, Web of Science, Scopus and PsycINFO from inception to 1 May 2019. Data were extracted from studies in order to calculate effect sizes representing case-control difference in mean volume, and in the variability of volume (as measured using the log variability ratio (lnVR) and coefficient of variation ratio (CVR)). We found significant overall decreases in mean volume in 22q11.2DS compared with control for: total brain (g = -0.96; p < 0.001); total grey matter (g = -0.81, p < 0.001); and total white matter (g = -0.81; p < 0.001). There was also a significant overall reduction of mean volume in 22q11.2DS subjects compared with controls in frontal lobe (g = -0.47; p < 0.001), temporal lobe (g = -0.84; p < 0.001), parietal lobe (g = -0.73; p = 0.053), cerebellum (g = -1.25; p < 0.001) and hippocampus (g = -0.90; p < 0.001). Significantly increased variability in 22q11.2DS individuals compared with controls was found only for the hippocampus (VR, 1.14; p = 0.036; CVR, 1.30; p < 0.001), and lateral ventricles (VR, 1.56; p = 0.004). The results support the notion that structural abnormalities in 22q11.2DS and schizophrenia are convergent, and also to some degree with findings in autism spectrum disorder. Finally, the increased variability seen in the hippocampus in 22q11.2DS may underlie some of the heterogeneity observed in the neuropsychiatric phenotype.

Cardiac structure and function in schizophrenia: cardiac magnetic resonance imaging study.

BACKGROUND: Heart disease is the leading cause of death in schizophrenia. However, there has been little research directly examining cardiac function in schizophrenia. AIMS: To investigate cardiac structure and function in individuals with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity. METHOD: In total, 80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity and glycated haemoglobin levels. Individuals with schizophrenia ('patients') and controls were matched for age, gender, ethnicity and body surface area. RESULTS: Patients had significantly smaller indexed left ventricular (LV) end-diastolic volume (effect size d = -0.82, P = 0.001), LV end-systolic volume (d = -0.58, P = 0.02), LV stroke volume (d = -0.85, P = 0.001), right ventricular (RV) end-diastolic volume (d = -0.79, P = 0.002), RV end-systolic volume (d = -0.58, P = 0.02), and RV stroke volume (d = -0.87, P = 0.001) but unaltered ejection fractions relative to controls. LV concentricity (d = 0.73, P = 0.003) and septal thickness (d = 1.13, P < 0.001) were significantly larger in the patients. Mean concentricity in patients was above the reference range. The findings were largely unchanged after adjusting for smoking and/or exercise levels and were independent of medication dose and duration. CONCLUSIONS: Individuals with schizophrenia show evidence of concentric cardiac remodelling compared with healthy controls of a similar age, gender, ethnicity, body surface area and blood pressure, and independent of smoking and activity levels. This could be contributing to the excess cardiovascular mortality observed in schizophrenia. Future studies should investigate the contribution of antipsychotic medication to these changes.

A new predictive coding model for a more comprehensive account of delusions.

Attempts to understand psychosis-the experience of profoundly altered perceptions and beliefs-raise questions about how the brain models the world. Standard predictive coding approaches suggest that it does so by minimising mismatches between incoming sensory evidence and predictions. By adjusting predictions, we converge iteratively on a best guess of the nature of the reality. Recent arguments have shown that a modified version of this framework-hybrid predictive coding-provides a better model of how healthy agents make inferences about external reality. We suggest that this more comprehensive model gives us a richer understanding of psychosis compared with standard predictive coding accounts. In this Personal View, we briefly describe the hybrid predictive coding model and show how it offers a more comprehensive account of the phenomenology of delusions, thereby providing a potentially powerful new framework for computational psychiatric approaches to psychosis. We also make suggestions for future work that could be important in formalising this novel perspective.

A cross-sectional MR study of body fat volumes and distribution in chronic schizophrenia.

People with schizophrenia show higher risk for abdominal obesity than the general population, which could contribute to excess mortality. However, it is unclear whether this is driven by alterations in abdominal fat partitioning. Here, we test the hypothesis that individuals with schizophrenia show a higher proportion of visceral to total body fat measured using magnetic resonance imaging (MRI). We recruited 38 participants with schizophrenia and 38 healthy controls matched on age, sex, ethnicity, and body mass index. We found no significant differences in body fat distribution between groups, suggesting that increased abdominal obesity in schizophrenia is not associated with altered fat distribution.

The association between N-methyl-d-aspartate receptor availability and glutamate levels: A multi-modal PET-MR brain imaging study in first-episode psychosis and healthy controls.

BACKGROUND: Evidence from post-mortem studies and in vivo imaging studies suggests there may be reduced N-methyl-d-aspartate receptor (NMDAR) levels in the hippocampus in patients with schizophrenia. Other studies have reported increased glutamate in striatum in schizophrenia patients. It has been hypothesised that NMDAR hypofunction leads to the disinhibition of glutamatergic signalling; however, this has not been tested in vivo. METHODS: In this study, we investigated the relationship between hippocampal NMDAR and striatal glutamate using simultaneous positron emission tomography-magnetic resonance (PET-MR) imaging. We recruited 40 volunteers to this cross-sectional study; 21 patients with schizophrenia, all in their first episode of illness, and 19 healthy controls. We measured hippocampal NMDAR availability using the PET ligand [18F]GE179. This was indexed relative to whole brain as the distribution volume ratio (DVR). Striatal glutamatergic indices (glutamate and Glx) were acquired simultaneously, using combined PET-MR proton magnetic resonance spectroscopy (1H-MRS). RESULTS: A total of 33 individuals (15 healthy controls, 18 patients) were included in the analyses (mean (SD) age of controls, 27.31 (4.68) years; mean (SD) age of patients, 24.75 (4.33), 27 male and 6 female). We found an inverse relationship between hippocampal DVR and striatal glutamate levels in people with first-episode psychosis (rho = -0.74, p < 0.001) but not in healthy controls (rho = -0.22, p = 0.44). CONCLUSION: This study show that lower relative NMDAR availability in the hippocampus may drive increased striatal glutamate levels in patients with schizophrenia. Further work is required to determine whether these findings may yield new targets for drug development in schizophrenia.

The magnitude and variability of brain structural alterations in bipolar disorder: A double meta-analysis of 5534 patients and 6651 healthy controls.

BACKGROUND: Bipolar disorder is thought to be associated with structural brain alterations, but findings have been inconsistent. Our double meta-analysis investigated the variability and magnitude of differences in regional brain volumes in patients with bipolar disorder relative to healthy volunteers. METHODS: Databases were systematically searched for MRI studies reporting regional brain volumetric measures in patients with bipolar disorder and controls. The primary outcome measures were variability ratio (VR), coefficient of variability ratio (CVR) and Hedge's g. RESULTS: 118 studies comprising 5534 patients and 6651 controls were included. The variability meta-analysis showed higher variability in amygdala (VR, 1.14; P = .02; CVR, 1.25; P = .005) and hippocampal (VR, 1.16; P = .001; CVR, 1.22; P = <.001) volumes in patients relative to controls. The meta-analysis of volume differences showed higher lateral (g, -0.43; P = <.0001) and third ventricle (g, -0.22; P = .01) volumes in patients; and lower hippocampus (g, 0.41; P = .001), grey matter (g, 0.25; P = .001), white matter (g, 0.23; P = .0002) and total brain volumes (g, 0.20; P = .003) in patients relative to controls. A higher proportion of male subjects was associated with decreased mean volumes of the amygdala, hippocampus and thalamus and increased lateral ventricle volumes. LIMITATIONS: There was significant publication bias and between-study inconsistency for several brain regions. CONCLUSIONS: Bipolar disorder is associated with generalised alterations in white and grey matter brain volumes, particularly marked in the hippocampus volumes, which were smaller but showed greater variability in volumes relative to controls. This suggests that heterogeneity in neurobiological processes involving the hippocampus contribute to clinical heterogeneity in the disorder, and this may be more marked in males than females.

Could Reducing Body Fatness Reduce the Risk of Aggressive Prostate Cancer via the Insulin Signalling Pathway? A Systematic Review of the Mechanistic Pathway.

Excess body weight is thought to increase the risk of aggressive prostate cancer (PCa), although the biological mechanism is currently unclear. Body fatness is positively associated with a diminished cellular response to insulin and biomarkers of insulin signalling have been positively associated with PCa risk. We carried out a two-pronged systematic review of (a) the effect of reducing body fatness on insulin biomarker levels and (b) the effect of insulin biomarkers on PCa risk, to determine whether a reduction in body fatness could reduce PCa risk via effects on the insulin signalling pathway. We identified seven eligible randomised controlled trials of interventions designed to reduce body fatness which measured insulin biomarkers as an outcome, and six eligible prospective observational studies of insulin biomarkers and PCa risk. We found some evidence that a reduction in body fatness improved insulin sensitivity although our confidence in this evidence was low based on GRADE (Grading of Recommendations, Assessment, Development and Evaluations). We were unable to reach any conclusions on the effect of insulin sensitivity on PCa risk from the few studies included in our systematic review. A reduction in body fatness may reduce PCa risk via insulin signalling, but more high-quality evidence is needed before any conclusions can be reached regarding PCa.

Heterogeneity and efficacy of antipsychotic treatment for schizophrenia with or without treatment resistance: a meta-analysis.

Two important clinical questions are whether there is a subtype of schizophrenia which responds differently to clozapine relative to other antipsychotics, and whether greater efficacy of clozapine is dependent on the degree of treatment-resistance. The authors address this by examining both variability and magnitude of response in patients treated with clozapine and other antipsychotics for both treatment-resistant schizophrenia (TRS) and non-resistant schizophrenia. Double-blind randomised controlled trials comparing clozapine with other antipsychotics in patients with schizophrenia were identified using five databases. Standard deviations and means of change in total, positive, and negative symptoms were extracted. Variability ratio (VR) and coefficient of variation ratio (CVR) were used to quantify relative variability in symptom change. Hedges' g was used to quantify mean differences. Ten TRS studies (n = 822) and 29 non-TRS studies (n = 2566) were meta-analysed. Relative variability in change of total symptoms did not differ significantly between clozapine and other antipsychotics in TRS studies (VR = 1.84; 95%CI, 0.85-4.02). These findings were similar with CVR, and for positive and negative symptoms. Clozapine was superior to other antipsychotics in improving total symptoms in both TRS (g = 0.34; 95%CI, 0.13-0.56) and non-TRS (g = 0.20; 95%CI, 0.08-0.32) studies. Furthermore, clozapine was superior in improving positive symptoms in both study groups, but not for negative symptoms. Pooled effect sizes showed no significant difference between TRS and non-TRS studies. These findings do not support a subtype of schizophrenia which responds specifically to clozapine. Clozapine is more effective than other antipsychotics irrespective of treatment-resistance, arguing for its use more generally in schizophrenia. PROSPERO CRD42018086507.

Associations of Serum Dickkopf-1 and Sclerostin With Cardiovascular Events: Results From the Prospective Bruneck Study.

Background Dickkopf-1 and sclerostin have been implicated in atherosclerosis and vascular calcification. We aimed to quantify the association of their serum levels with incident cardiovascular disease (CVD) in the general population. Methods and Results Among 706 participants of the prospective, population-based Bruneck Study, mean±SD of serum levels were 44.5±14.7 pmol/L for dickkopf-1 and 47.1±17.5 pmol/L for sclerostin. The primary outcome was a composite CVD end point composed of ischemic or hemorrhagic stroke, transient ischemic attack, myocardial infarction, angina pectoris, peripheral vascular disease, and revascularization procedures. Over a median follow-up duration of 15.6 years, 179 CVD events occurred. For the primary CVD outcome, multivariable-adjusted hazard ratios (HRs) per SD higher level were 1.20 for dickkopf-1 (95% CI, 1.02-1.42; P=0.028) and 0.92 for sclerostin (95% CI, 0.78-1.08; P=0.286). Secondary outcome analyses revealed that the association of dickkopf-1 was primarily driven by ischemic and hemorrhagic stroke (67 events; HR, 1.37; 95% CI, 1.06-1.78; P=0.017), whereas no increase in risk was observed for transient ischemic attack (22 events; HR, 0.87; 95% CI, 0.53-1.44; P=0.593), myocardial infarction (45 events; HR, 1.10; 95% CI, 0.78-1.54; P=0.598), or for other CVD (45 events; HR, 1.25; 95% CI, 0.88-1.76; P=0.209). Conclusions In this prospective, population-based study, elevated baseline levels of dickkopf-1, but not sclerostin, were independently associated with incident cardiovascular events, which was mainly driven by stroke. Our findings support the hypothesis of a role of dickkopf-1 in the pathogenesis of CVD.

Heterogeneity of Striatal Dopamine Function in Schizophrenia: Meta-analysis of Variance.

BACKGROUND: It has been hypothesized that dopamine function in schizophrenia exhibits heterogeneity in excess of that seen in the general population. However, no previous study has systematically tested this hypothesis. METHODS: We employed meta-analysis of variance to investigate interindividual variability of striatal dopaminergic function in patients with schizophrenia and in healthy control subjects. We included 65 studies that reported molecular imaging measures of dopamine synthesis or release capacities, dopamine D2/3 receptor (D2/3R) or dopamine transporter (DAT) availabilities, or synaptic dopamine levels in 983 patients and 968 control subjects. Variability differences were quantified using variability ratio (VR) and coefficient of variation ratio. RESULTS: Interindividual variability of striatal D2/3R (VR = 1.26, p < .0001) and DAT (VR = 1.31, p = .01) availabilities and synaptic dopamine levels (VR = 1.38, p = .045) but not dopamine synthesis (VR = 1.12, p = .13) or release (VR = 1.08, p = .70) capacities were significantly greater in patients than in control subjects. Findings were robust to variability measure. Mean dopamine synthesis (g = 0.65, p = .004) and release (g = 0.66, p = .03) capacities, as well as synaptic levels (g = 0.78, p = .0006), were greater in patients overall, but mean synthesis capacity did not differ from that of control subjects in treatment-resistant patients (p > .3). Mean D2/3R (g = 0.17, p = .14) and DAT (g = -0.20, p = .28) availabilities did not differ between groups. CONCLUSIONS: Our findings demonstrate significant heterogeneity of striatal dopamine function in schizophrenia. They suggest that while elevated dopamine synthesis and release capacities may be core features of the disorder, altered D2/3R and DAT availabilities and synaptic dopamine levels may occur only in a subgroup of patients. This heterogeneity may contribute to variation in treatment response and side effects.

Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia: A Systematic Review and Meta-analysis.

Importance: Ketamine hydrochloride is increasingly used to treat depression and other psychiatric disorders but can induce schizophrenia-like or psychotomimetic symptoms. Despite this risk, the consistency and magnitude of symptoms induced by ketamine or what factors are associated with these symptoms remain unknown. Objective: To conduct a meta-analysis of the psychopathological outcomes associated with ketamine in healthy volunteers and patients with schizophrenia and the experimental factors associated with these outcomes. Data Sources: MEDLINE, Embase, and PsychINFO databases were searched for within-participant, placebo-controlled studies reporting symptoms using the Brief Psychiatric Rating Scale (BPRS) or the Positive and Negative Syndrome Scale (PANSS) in response to an acute ketamine challenge in healthy participants or patients with schizophrenia. Study Selection: Of 8464 citations retrieved, 36 studies involving healthy participants were included. Inclusion criteria were studies (1) including healthy participants; (2) reporting symptoms occurring in response to acute administration of subanesthetic doses of ketamine (racemic ketamine, s-ketamine, r-ketamine) intravenously; (3) containing a placebo condition with a within-subject, crossover design; (4) measuring total positive or negative symptoms using BPRS or PANSS; and (5) providing data allowing the estimation of the mean difference and deviation between the ketamine and placebo condition. Data Extraction and Synthesis: Two independent investigators extracted study-level data for a random-effects meta-analysis. Total, positive, and negative BPRS and PANSS scores were extracted. Subgroup analyses were conducted examining the effects of blinding status, ketamine preparation, infusion method, and time between ketamine and placebo conditions. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Main Outcomes and Measures: Standardized mean differences (SMDs) were used as effect sizes for individual studies. Standardized mean differences between ketamine and placebo conditions were calculated for total, positive, and negative BPRS and PANSS scores. Results: The overall sample included 725 healthy volunteers (mean [SD] age, 28.3 [3.6] years; 533 [73.6%] male) exposed to the ketamine and placebo conditions. Racemic ketamine or S-ketamine was associated with a statistically significant increase in transient psychopathology in healthy participants for total (SMD = 1.50 [95% CI, 1.23-1.77]; P < .001), positive (SMD = 1.55 [95% CI, 1.29-1.81]; P < .001), and negative (SMD = 1.16 [95% CI, 0.96-1.35]; P < .001) symptom ratings relative to the placebo condition. The effect size for this association was significantly greater for positive than negative symptoms of psychosis (estimate, 0.36 [95% CI, 0.12-0.61]; P = .004). There was significant inconsistency in outcomes between studies (I2 range, 77%-83%). Bolus followed by constant infusion increased ketamine's association with positive symptoms relative to infusion alone (effect size, 1.63 [95% CI, 1.36-1.90] vs 0.84 [95% CI, 0.35-1.33]; P = .006). Single-day study design increased ketamine's ability to generate total symptoms (effect size, 2.29 [95% CI, 1.69-2.89] vs 1.39 [95% CI, 1.12-1.66]; P = .007), but age and sex did not moderate outcomes. Insufficient studies were available for meta-analysis of studies in schizophrenia. Of these studies, 2 found a statistically significant increase in symptoms with ketamine administration in total and positive symptoms. Only 1 study found an increase in negative symptom severity with ketamine. Conclusions and Relevance: This study found that acute ketamine administration was associated with schizophrenia-like or psychotomimetic symptoms with large effect sizes, but there was a greater increase in positive than negative symptoms and when a bolus was used. These findings suggest that bolus doses should be avoided in the therapeutic use of ketamine to minimize the risk of inducing transient positive (psychotic) symptoms.

Conditional gene deletion reveals functional redundancy of GABAB receptors in peripheral nociceptors in vivo.

BACKGROUND: gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter which mainly mediates its effects on neurons via ionotropic (GABA(A)) and metabotropic (GABA(B)) receptors. GABA(B) receptors are widely expressed in the central and the peripheral nervous system. Although there is evidence for a key function of GABA(B) receptors in the modulation of pain, the relative contribution of peripherally- versus centrally-expressed GABA(B) receptors is unclear. RESULTS: In order to elucidate the functional relevance of GABA(B) receptors expressed in peripheral nociceptive neurons in pain modulation we generated and analyzed conditional mouse mutants lacking functional GABA(B1) subunit specifically in nociceptors, preserving expression in the spinal cord and brain (SNS-GABA(B1)-/- mice). Lack of the GABA(B1) subunit precludes the assembly of functional GABA(B) receptor. We analyzed SNS-GABA(B1)-/- mice and their control littermates in several models of acute and neuropathic pain. Electrophysiological studies on peripheral afferents revealed higher firing frequencies in SNS-GABA(B1)-/- mice compared to corresponding control littermates. However no differences were seen in basal nociceptive sensitivity between these groups. The development of neuropathic and chronic inflammatory pain was similar across the two genotypes. The duration of nocifensive responses evoked by intraplantar formalin injection was prolonged in the SNS-GABAB(1)-/- animals as compared to their control littermates. Pharmacological experiments revealed that systemic baclofen-induced inhibition of formalin-induced nociceptive behaviors was not dependent upon GABA(B1) expression in nociceptors. CONCLUSION: This study addressed contribution of GABA(B) receptors expressed on primary afferent nociceptive fibers to the modulation of pain. We observed that neither the development of acute and chronic pain nor the analgesic effects of a systematically-delivered GABA(B) agonist was significantly changed upon a specific deletion of GABA(B) receptors from peripheral nociceptive neurons in vivo. This lets us conclude that GABA(B) receptors in the peripheral nervous system play a less important role than those in the central nervous system in the regulation of pain.

A Meta-analysis of Immune Parameters, Variability, and Assessment of Modal Distribution in Psychosis and Test of the Immune Subgroup Hypothesis.

Immune parameters are elevated in psychosis, but it is unclear whether alterations are homogenous across patients or heterogeneity exists, consistent with the hypothesis that immune alterations are specific to a subgroup of patients. To address this, we examine whether antipsychotic-naïve first-episode psychosis patients exhibit greater variability in blood cytokines, C-reactive protein, and white cell counts compared with controls, and if group mean differences persist after adjusting for skewed data and potential confounds. Databases were searched for studies reporting levels of peripheral immune parameters. Means and variances were extracted and analyzed using multivariate meta-analysis of mean and variability of differences. Outcomes were (1) variability in patients relative to controls, indexed by variability ratio (VR) and coefficient of variation ratio (CVR); (2) mean differences indexed by Hedges g; (3) Modal distribution of raw immune parameter data using Hartigan's unimodality dip test. Thirty-five studies reporting on 1263 patients and 1470 controls were included. Variability of interleukin-6 (IL6) (VR = 0.19), tumor necrosis factor-α (TNFα) (VR = 0.36), interleukin-1ß (VR = 0.35), interleukin-4 (VR = 0.55), and interleukin-8 (VR = 0.28) was reduced in patients. Results persisted for IL6 and IL8 after mean-scaling. Ninety-four percent and one hundred percent of raw data were unimodally distributed in psychosis and controls, respectively. Mean levels of IL6 (g = 0.62), TNFα (g = 0.56), interferon-γ (IFNγ) (g = 0.32), transforming growth factor-ß (g = 0.53), and interleukin-17 (IL17) (g = 0.48) were elevated in psychosis. Sensitivity analyses indicated this is unlikely explained by confounders for IL6, IFNγ, and IL17. These findings show elevated cytokines in psychosis after accounting for confounds, and that the hypothesis of an immune subgroup is not supported by the variability or modal distribution.

Cardiac structure and function in patients with schizophrenia taking antipsychotic drugs: an MRI study.

Cardiovascular disease (CVD) is a major cause of excess mortality in schizophrenia. Preclinical evidence shows antipsychotics can cause myocardial fibrosis and myocardial inflammation in murine models, but it is not known if this is the case in patients. We therefore set out to determine if there is evidence of cardiac fibrosis and/or inflammation using cardiac MRI in medicated patients with schizophrenia compared with matched healthy controls. Thirty-one participants (14 patients and 17 controls) underwent cardiac MRI assessing myocardial markers of fibrosis/inflammation, indexed by native myocardial T1 time, and cardiac structure (left ventricular (LV) mass) and function (left/right ventricular end-diastolic and end-systolic volumes, stroke volumes, and ejection fractions). Participants were physically fit, and matched for age, gender, smoking, blood pressure, BMI, HbA1c, ethnicity, and physical activity. Compared with controls, native myocardial T1 was significantly longer in patients with schizophrenia (effect size, d = 0.89; p = 0.02). Patients had significantly lower LV mass, and lower left/right ventricular end-diastolic and stroke volumes (effect sizes, d = 0.86-1.08; all p-values < 0.05). There were no significant differences in left/right end-systolic volumes and ejection fractions between groups (p > 0.05). These results suggest an early diffuse fibro-inflammatory myocardial process in patients that is independent of established CVD-risk factors and could contribute to the excess cardiovascular mortality associated with schizophrenia. Future studies are required to determine if this is due to antipsychotic treatment or is intrinsic to schizophrenia.

Heterogeneity and Homogeneity of Regional Brain Structure in Schizophrenia: A Meta-analysis.

Importance: Schizophrenia is associated with alterations in mean regional brain volumes. However, it is not known whether the clinical heterogeneity seen in the disorder is reflected at the neurobiological level, for example, in differences in the interindividual variability of these brain volumes relative to control individuals. Objective: To investigate whether patients with first-episode schizophrenia exhibit greater variability of regional brain volumes in addition to mean volume differences. Data Sources: Studies that reported regional brain volumetric measures in patients and controls by using magnetic resonance imaging in the MEDLINE, EMBASE, and PsycINFO databases from inception to October 1, 2016, were examined. Study Selection: Case-control studies that reported regional brain volumes in patients with first-episode schizophrenia and healthy controls by using magnetic resonance imaging were selected. Data Extraction and Synthesis: Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis. Main Outcomes and Measures: Relative variability of regional brain volumetric measurements in patients compared with control groups as indexed by the variability ratio (VR) and coefficient of variation ratio (CVR). Hedges g was used to quantify mean differences. Results: A total of 108 studies that reported measurements from 3901 patients (1272 [32.6%] female) with first-episode schizophrenia and 4040 controls (1613 [39.9%] female) were included in the analyses. Variability of putamen (VR, 1.13; 95% CI, 1.03-1.24; P = .01), temporal lobe (VR, 1.12; 95% CI, 1.04-1.21; P = .004), thalamus (VR, 1.16; 95% CI, 1.07-1.26; P < .001), and third ventricle (VR, 1.43; 95% CI, 1.20-1.71; P < 1 × 10-5) volume was significantly greater in patients, whereas variability of anterior cingulate cortex volume was lower (VR, 0.89; 95% CI, 0.81-0.98; P = .02). These findings were robust to choice of outcome measure. There was no evidence of altered variability of caudate nucleus or frontal lobe volumes. Mean volumes of the lateral (g = 0.40; 95% CI, 0.29-0.51; P < .001) and third ventricles (g = 0.43; 95% CI, 0.26-0.59; P < .001) were greater, whereas mean volumes of the amygdala (g = -0.46; -0.65 to -0.26; P < .001), anterior cingulate cortex (g = -0.26; 95% CI, -0.43 to -0.10; P = .005), frontal lobe (g = -0.31; 95% CI, -0.44 to -0.19; P = .001), hippocampus (g = -0.66; 95% CI, -0.84 to -0.47; P < .001), temporal lobe (g = -0.22; 95% CI, -0.36 to -0.09; P = .001), and thalamus (g = -0.36; 95% CI, -0.57 to -0.15; P = .001) were lower in patients. There was no evidence of altered mean volume of caudate nucleus or putamen. Conclusions and Relevance: In addition to altered mean volume of many brain structures, schizophrenia is associated with significantly greater variability of temporal cortex, thalamus, putamen, and third ventricle volumes, consistent with biological heterogeneity in these regions, but lower variability of anterior cingulate cortex volume. This finding indicates greater homogeneity of anterior cingulate volume and, considered with the significantly lower mean volume of this region, suggests that this is a core region affected by the disorder.

Low SpO2 With Normal SaO2 During General Anesthesia: A Case Report.

A 25-year-old Caucasian man with a history of spherocytosis, splenectomy, recurrent blood transfusion, and no cardiopulmonary disease presented for an emergent laparoscopic cholecystectomy with a baseline pulse oximetric saturation (SpO2) of 88% while breathing room air. The SpO2 increased to only 89% during preoxygenation with an FIO2 1.0. Multiple arterial blood samples revealed SaO2 as high as 100% with PaO2 averaging 390 mm Hg. He was subsequently diagnosed with a dyshemoglobin, hemoglobin Köln. The simultaneous presentation of a stable patient from a cardiopulmonary perspective with normal arterial oxygen tension and saturation in the blood gas analyses despite a low SpO2 measurement outlines the importance of integrating the history of present illness and both the importance and the limitation of the pulse oximetry.

Randomized multicenter phase II trial of oxaliplatin plus irinotecan versus raltitrexed as first-line treatment in advanced colorectal cancer.

PURPOSE: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting. PATIENTS AND METHODS: Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m(2) plus irinotecan 175 mg/m(2) or raltitrexed 3 mg/m(2) given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected. RESULTS: Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P =.0025) and longer progression-free survival (median, 7.1 v 5.0 months; P =.0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P =.3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m(2), tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%). CONCLUSION: Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.

Screening for NUP98 rearrangements in hematopoietic malignancies by fluorescence in situ hybridization.

BACKGROUND AND OBJECTIVES: The aim of this study was to determine the incidence of rearrangements of NUP98 (the gene coding for nucleoporin 98kDa protein) in childhood acute myeloid leukemia (AML) and selected patients with 11p13-15 rearrangements. This aim was achieved using a fluorescence in situ hybridization (FISH) assay that allows the detection of NUP98 aberrations independently of the partner gene involved. DESIGN AND METHODS: Screening of 59 consecutive patients enrolled in the Austrian AML-BFM93 clinical trial was performed by dual-color FISH. In addition, 14 selected cases with various hematologic malignancies and 11p13-15 aberrations were analyzed. NUP98-positive cases were further investigated by fusion gene-specific FISH and reverse transcription polymerase chain reaction assays. RESULTS: Among the 59 AML patients, one NUP98-NSD1 positive case (1.7%) was detected. Among the 14 selected patients, five new NUP98 positive cases were determined. Two cases showed an inv(11)(p15q22)/NUP98-DDX10 fusion, one each displayed a t(5;11)(q35;p15)/NUP98-NSD1 and a t(11;20)(p15;q12)/NUP98-TOP1 fusion, and one case with a putative new fusion partner gene at 3p24 was identified. INTERPRETATION AND CONCLUSIONS: The observed frequency of 1.7% confirmed the low incidence of NUP98 rearrangements in childhood AML. The low occurrence of NUP98 rearrangements in selected samples with 11p13-15 alterations suggests the existence of variable chromosomal breakpoints and affected genes in this region. The identification of a new NUP98 fusion partner region confirms the evident promiscuity of NUP98. Thus, analysis of NUP98 aberrations by FISH seems to be the method of choice for determining the presence of these genetic lesions in unselected patients, and to confirm the involvement of NUP98 in cases with 11p15 aberrations.