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Determining similarities and differences in brain structure across psychiatric disorders is important to determine if psychiatric taxonomy is reflected in distinct brain structural changes. As previous neuroimaging meta-analyses have typically focused on a single disorder, precluding transdiagnostic comparisons, we aimed to quantify patterns of similarity and differences between psychiatric disorders in terms of regional brain volumes. Here we show, in network and pairwise meta-analyses of 498 studies (51,227 individuals, 17 psychiatric disorders and 17 brain regions), that psychiatric disorders show both distinct and overlapping patterns of brain volume gain and loss. A principal components analysis demonstrated that the first principal component could account for 48% of variance and corresponded to a pattern of increased basal ganglia and decreased hippocampal and amygdala volumes. This component loaded most strongly for disorders on the psychosis spectrum, and most weakly for affective disorders. Our findings illustrated that, while similar volumetric alterations are frequently shared between disorders, neuroanatomical patterns also appear related to clinically meaningful categories. (PROSPERO Registration: CRD42020221143.)

Evidence from post-mortem studies and in vivo imaging studies suggests there may be reducedIn 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 [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,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.

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 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.

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’gwas 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

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 ( HR s) 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 .

BackgroundHeart disease is the leading cause of death in schizophrenia. However, there has been little research directly examining cardiac function in schizophrenia.AimsTo investigate cardiac structure and function in individuals with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity.MethodIn 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.ResultsPatients 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.ConclusionsIndividuals 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.

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. 31 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). 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.

AimsTo conduct a meta-analysis of the effect of ketamine on psychopathology in healthy volunteers and patients with schizophrenia, and the experimental factors affecting this.BackgroundKetamine is increasingly used to treat depression and other psychiatric disorders but can induce schizophrenia-like symptoms. Despite this, the consistency and magnitude of symptoms induced by ketamine, or what factors influence the effects of ketamine on these remain unknown.MethodMEDLINE, EMBASE and PsychINFO databases were searched for within-subject placebo controlled studies reporting symptoms using the Brief Psychiatric Rating Scale (BPRS) or Positive and Negative Syndrome Scale (PANSS) in response to an acute ketamine challenge in healthy participants or people with schizophrenia. Two independent investigators extracted study-level data for a random-effects meta-analysis. Total, positive and negative BPRS and PANSS scores were extracted. Sub-group analyses were conducted examining the effect of: blinding status, ketamine preparation, infusion method and time between ketamine and placebo condition. Standardized mean change scores were used as effect sizes for individual studies. Standardized mean changes between ketamine and placebo for total, positive and negative BPRS and PANSS were calculated.ResultOf 7819 citations retrieved, 36 studies involving healthy participants were included. The overall sample included 725 healthy volunteers exposed to both the ketamine and placebo condition. Ketamine induced a significant increase in transient psychopathology in healthy participants, for total (Standardized mean change (SMC) = 1.50 (95% CI = 1.23 to 1.77), p < 0.0001), positive (SMC = 1.55 (95% CI = 1.29 to 1.81), p < 0.0001) and negative (SMC = 1.16, (95% CI = 0.96 to 1.35), p < 0.0001) symptom ratings, relative to the placebo condition. This effect was significantly greater for positive symptoms than negative symptoms (p = 0.004). Bolus followed by constant infusion increased ketamine's effect on positive symptoms relative to infusion alone (p = 0.006). Single-day study design increased ketamine's effect on total symptoms (p = 0.007), but age and gender did not moderate effects. There were insufficient studies for meta-analysis of studies in schizophrenia. Of these studies, two found a significant increase in symptoms with ketamine administration in total and positive symptoms. Only one study found an increase in negative symptom severity with ketamine.ConclusionThese findings show that acute ketamine administration induces schizophrenia-like symptomatology with large effect sizes but there is a greater increase in positive than negative symptoms, and when a bolus is used. These findings suggest bolus doses should be avoided in its therapeutic use to minimize the risk of inducing transient positive psychotic symptoms.

Background\ud \ud It has been hypothesized that dopamine function in schizophrenia exhibits heterogeneity in excess of that seen in the general population. However, this hypothesis has never been systematically tested.\ud \ud \ud Method\ud \ud We employed meta-analysis of variance to investigate inter-individual variability of striatal dopaminergic function in patients with schizophrenia and healthy controls. We included 65 studies reporting molecular imaging measures of dopamine synthesis or release capacities, D2/3 receptor (D2/3R) or transporter (DAT) availabilities, or synaptic dopamine levels, in 983 patients and 968 controls. Variability differences were quantified using variability ratio (VR) and coefficient of variation ratio.\ud \ud \ud Results\ud \ud Inter-individual variability of striatal D2/3R (VR=1.26, p0.3). Mean D2/3R (g=0.17, p=.14) and DAT (g=-0.20, p=.28) availabilities did not differ between groups.\ud \ud \ud Conclusions\ud \ud 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.

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 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.

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 g = −0.81,p g = −0.81;p g = −0.47;p g = −0.84;p g = −0.73;p = 0.053), cerebellum (g = −1.25;p g = −0.90;p p = 0.036; CVR, 1.30;p 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.

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-1β (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-β (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.

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.To investigate whether patients with first-episode schizophrenia exhibit greater variability of regional brain volumes in addition to mean volume differences.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.Case-control studies that reported regional brain volumes in patients with first-episode schizophrenia and healthy controls by using magnetic resonance imaging were selected.Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis.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.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.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.

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 Koln. 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.

Background: There is considerable interest in identifying biomarkers of antipsychotic response in schizophrenia, and brain glutamate is one key candidate.

Objectives: Abdominal pain is the most challenging symptom in chronic intestinal pseudoobstruction (CIPO) syndrome, because of its severity and the limited availability of suitable opioid formulations, especially in pediatric patients with digestive problems. Most of the children with CIPO cannot tolerate oral formulations. Case Reports: We present 4 cases of children with CIPO and severe intractable abdominal pain, and report on the use of a recently available form of opioid, transdermal buprenorphine in a dosage of 5 mcg/h. Discussion: CIPO and the unique pharmacological profile of buprenorphine are reviewed briefly

Background: It is not known whether regional brain N-acetyl aspartate (NAA) changes in the progression from prodrome to chronic schizophrenia. We used effect size meta-analysis to determine which brain regions show the most robust reductions in NAA first episode and chronic schizophrenia as measured by proton magnetic resonance spectroscopy and to determine whether these changes are present in individuals at high risk of developing schizophrenia.Methods: We identified 131 articles, of which 97 met inclusion criteria. Data were separated by stage of illness (at risk, first episode schizophrenia, chronic schizophrenia) and by brain region. For each region, mean and SD of the NAA measure was extracted.Results: Significant reductions in NAA levels were found in frontal lobe, temporal lobe, and thalamus in both patient groups (effect size > .3; p Conclusions: These data suggest that schizophrenia is associated with loss of neuronal integrity in frontal and temporal cortices and in the thalamus and suggest that these changes in the frontal and temporal lobe might occur in the transition between the at-risk phase and the first episode.

Background Psychosis is seen in a number of disorders and treated with the same drugs. However, there is considerable variability in response to treatment and clinical course. Understanding the neurobiology underlying psychosis across diagnoses and in treatment response is important to help guide the development of new treatments and biomarkers for treatment response. Elevated dopamine synthesis and release capacity and structural brain changes have been consistently associated with schizophrenia, but it remains unknown how variable these are, or how they compare across psychotic disorders. Methods Two cohorts of first episode patients, one with a diagnosis of schizophrenia (n=16) and another with a diagnosis of bipolar affective disorder (n=22) received 18F-DOPA PET and [1H]-MR spectroscopy imaging and clinical measures. All patients had experienced a psychotic episode and received clinical follow-up over 18 months to determine diagnostic stability. We then conducted a meta-analysis using a novel meta-analytic approach to quantify variability in measures to investigate structural and neurochemical heterogeneity in schizophrenia and bipolar affective disorder. The entire PubMed, EMBase and PsychInfo databases were searched from inception to identify relevant studies and the natural log of the measures of dispersion and the coefficient of variance. Results Striatal dopamine synthesis capacity (Kicer) was significantly elevated in both bipolar (effect size=1.02; p0.4). Kicer was significantly positively correlated with positive psychotic symptom severity in the transdiagnostic group of people with psychosis (r=0.52, p4000 patients and >4000 controls. Variability ratio was significantly increased in patients relative to controls in gray matter volumes in temporal lobe (VR=1.1, p=0.004) and thalamus (VR=1.16, p

Optimization of exhaust-gas emission, noise and fuel consumption of the diesel engine in the vehicle is based on stationary tuning at the test bed. Only here all relevant measured variables can be acquired precisely and all parameters can be adjusted optimally, independent from the drive train and environmental impact. Not till then the development in the vehicle can be continued, especially focusing on the optimization of driveability, dynamics, acoustics and full load next to emission performance. As the measuring equipment in the vehicle in general is not as comprehensive as at the test bed the estimation of the measure effects on the emissions, like serving the driveability, can be more complicated. The article of AVL List GmbH will present how the development of the vehicle can be improved by means of compact measuring technology and the use of model based information of the engine.

Recently, a family with idiopathic brain calcification was reported, in which one family member was diagnosed with multiple system atrophy (MSA) at autopsy. We report here a case showing similar neuropathological features in a patient with longstanding hypoparathyroidism. Our female patient had a history of hypoparathyroidism with hypocalcaemia and tetany since the age of 9 years. In her 50s she developed dementia and parkinsonism. She died of myocardial infarction aged 65 years. Neuropathology showed severe brain calcifications of the Fahr type in the basal ganglia, thalami, cerebral and cerebellar white matter and dentate nuclei. Additionally, there was prominent alpha-synucleinopathy of the multiple system atrophy type (MSA). The patient has a healthy identical twin and there is no family history of hypoparathyroidism or neurological disease. Data on alpha-synuclein accumulation in various cases of Fahr's syndrome are needed to establish the correlation between alpha-synucleinopathy and bilateral striopallidodentate calcification.

The synthesis of the T-silyl functionalized, and therefore sol-gel processable, Vaska complex [IrCl(CO){(C6H5)2PC6H4(CH2)4Si(OMe)3}2] [4(T0)] succeeded by reaction of [Ir(μ-Cl)(COE)2]2 (COE = cyclooctene; 1) with the phosphane (C6H5)2PC6H4(CH2)4Si(OMe)3 [3(T0)] in the presence of carbon monoxide. Subsequently, 4(T0) was co-polycondensed with five equivalents of (MeO)3Si(CH2)3C6H4(CH2)3Si(OMe)3 {5[Ph(1,4-C3T0)2]} to give the polysiloxane-bound complex X1. For accessibility studies of the reactive centers, X1 was reacted in the interphase systems gas/solid and liquid/solid with HCl, Cl2, CH3I (13CH3I), Cl2HCCHCl2, SO2, O2, and NCC≡CCN, in the course of which the xerogels X2−X7 were formed. With the exception of the reversible species X5 (SO2) and X6 (O2) the reactions proceeded quantitatively. The composition of the polymers and the structures of the reactive centers were elucidated by means of multinuclear solid-state NMR (13C, 29Si, 31P), IR, EDX, and EXAFS spectroscopy.

Nanostructured, mesoporous inorganic–organic hybrid xerogels were reproducibly synthesized by a sol–gel procedure. For the introduction of long alkyl chains into inorganic polymers, trifunctional n-alkyltrialkoxysilanes of the type CH3(CH2)nSi(OR)3 (n = 7, 11, 17; R = CH3, C2H5) were co-condensed with Si(OEt)4 (TEOS). The synthetic pathway involves the employment of n-hexadecylamine as template and catalyst. The xerogels obtained by the present procedure consist of uniform spherical particles with a diameter of about 1 μm. The composition of the new materials was determined by 13C and 29Si cross polarization magic angle spinning (CP/MAS) NMR spectroscopy. In addition, the degree of organization was investigated by small angle X-ray and electron diffraction. In accordance with 13C CP/MAS NMR spectroscopic measurements, the alkyl chains form a crystalline arrangement within the silica polymer. Brunauer–Emmett–Teller (BET) adsorption measurements confirm specific surface areas of up to 1400 m2/g. The material properties prove the xerogels to be suitable as stationary phases in high-performance liquid chromatography (HPLC). These novel mesoporous, nanostructured materials have been successfully employed in HPLC for the first time. Different standard reference materials (SRMs) containing polycyclic aromatic hydrocarbons have been separated with the xerogels described in the present work.

A novel T-silyl functionalized cationic (COD)(dppp)rhodium(I) complex was sol–gel processed with various amounts of the co-condensing agents MeSi(OMe) 2 (CH 2 ) 6 (OMe) 2 SiMe and MeSi(OMe) 2 (CH 2 ) 3 (C 6 H 4 )(CH 2 ) 3 (OMe) 2 SiMe to give novel stationary phases for ‘Chemistry in Interphases’. The polysiloxane matrices and the integrity of the rhodium(I) complex centers were investigated by means of multinuclear solid-state NMR ( 13 C, 29 Si, 31 P) and EXAFS spectroscopies. Dynamic NMR measurements show an increasing mobility of the matrix and the reactive centers with a higher amount of the co-condensing component. The accessibility of the anchored rhodium(I) centers was scrutinized by the metal catalyzed hydrogenation of 1-hexene. All applied xerogels show remarkable activities and selectivities. An enhancement of the activities is achieved when polar solvents are used. SEM micrographs reveal the morphology of the hybrid materials and energy dispersive X-ray spectroscopy (EDX) suggests that the distribution of the elements is in satisfying agreement with the applied composition.

A novel mono-T-silyl functionalized triphenylphosphine ligand was prepared by a simple coupling reaction of ( p -aminophenyl)diphenylphosphine and 3-triethoxysilylpropylisocyanate. The corresponding carbonylchlorobisphosphinerhodium(I) complex ClRh(CO)[PPh 2 C 6 H 4 NHCONH(CH 2 ) 3 Si(OEt) 3 ] 2 was synthesized in order to be sol–gel processed with various amounts of different D- and T-silyl bifunctionalized co-condensation agents. The polysiloxane matrices and the active rhodium centers were investigated by means of multinuclear solid state NMR ( 13 C, 29 Si, 31 P) and dynamic NMR measurements. The rhodium containing xerogels were applied in the hydroformylation of 1-hexene. These stationary phases show remarkable catalytic activities independent on the solvent. An enhancement of the activities is achieved when T-silyl bifunctionalized co-condensation agents are used to build up the carrier matrix.

Novel xerogels X1 a–d were obtained by sol-gel processing of the monomeric T-functionalized diphosphine ligand (MeO)3Si(CH2)6CH[CH2PPh2]2[1(T0)] with various amounts of the co-condensing agents MeSi(OMe)2(CH2)6(OMe)2SiMe (D0–C6–D0) and MeSi(OMe)2(CH2)3(C6H4)(CH2)3(OMe)2SiMe [Ph(1,4-C3D0)2]. 29Si CP/MAS NMR spectroscopic investigations were applied to probe the matrices and their degree of condensation. The integrity of the hydrocarbon backbone and diphosphine moiety was examined by means of solid state NMR spectroscopy (13C, 31P). To study the dynamics of the matrices and the phosphorus centers detailed measurements of relaxation time (T1ρH) and cross polarization constants (TSiH, TPH) were carried out. The accessibility of the polysiloxane-supported diphosphines was scrutinized by some typical phosphine reactions. It was found that reagents such as H2O2, MeI as well as bulky molecules like (NBD)Mo(CO)4 or (COD)PdCl2 are able to reach all phosphorus centers independent on the kind of the backbone of the matrix. SEM micrographs show the morphology of the hybrid materials and energy dispersive X-ray spectroscopy (EDX) suggest that the distribution of the elements agree with the applied composition. Zuganglichkeits- und Festkorper-NMR-Studien an Sol-Gel-prozessierten Diphosphan-Liganden Die neuartigen Xerogele X1 a–d wurden durch Sol-Gel-Prozessierung des T-funktionalisierten Diphosphanliganden (MeO)3Si(CH2)6CH[CH2PPh2]2[1(T0)] mit unterschiedlichen Mengen der Cokondensationsmittel MeSi(OMe)2(CH2)6(OMe)2SiMe (D0–C6–D0) und MeSi(OMe)2(CH2)3(C6H4)(CH2)3(OMe)2SiMe [Ph(1,4-C3D0)2] erhalten. 29Si CP/MAS NMR-spektroskopische Untersuchungen liefern einen Einblick in den Aufbau der Matrices und ihrer Kondensationsgrade. Nach 13C- und 31P-Festkorper-NMR-spektroskopischen Untersuchungen gehen das Kohlenwasserstoffgerust und insbesondere die reaktiven Phosphanzentren aus dem Sol-Gel-Prozess unzersetzt hervor. Detaillierte Relaxationzeitmessungen (T1ρH) und Messungen der Kreuzpolarisationskonstanten (TSiH, TPH) geben Aufschluss uber die Dynamik der Matrices und Phosphorzentren. Mit typischen Phosphanreaktionen wurde die Zuganglichkeit der reaktiven Zentren uberpruft. Reagenzien wie H2O2 und MeI erreichen unabhangig vom Ruckgrat der Matrix die Phosphanzentren ebenso wie die sterisch anspruchsvollen Komplexe (NBD)Mo(CO)4 und (COD)PdCl2. SEM-Aufnahmen weisen auf die Morphologie der Hybridmaterialien hin. Energiedipersive rontgenspektroskopische Messungen (EDX) belegen die Elementzusammensetzung der neuen Materialien.

Novel co-condensing agents of the type R′Si(OMe)2(CH2)3R2Si(CH2)3Si(OMe)2R′ {3[Me2Si(C3D0)2] (3a), R = Me, R′ = Me; 3[Me2Si(C3T0)2] (3b), R = Me, R′ = OMe; 4[Et2Si(C3D0)2] (4a), R = Et, R′ = Me; 4[Et2Si(C3T0)2] (4b), R = Et, R′ = OMe} were synthesised by hydrosilylation of the corresponding diallyldialkylsilanes 1, 2 with dichloro(methyl)silane and trichlorosilane, respectively, followed by treatment with trimethyl orthoformate. These precursors were sol–gel processed with or without PhSi(OMe)3 [Ph(T0)] to give the xerogels X3a–d, X4a–d. The polysiloxane matrices, the degree of condensation and the integrity of the hydrocarbon backbone were investigated by means of solid state NMR spectroscopy (13C, 29Si). To study the polymer dynamics in the dry state 29Si CP/MAS NMR measurements of relaxation times (T1ρH) and cross-polarisation parameters (TSiH) were carried out. 1H HR/MAS NMR experiments and T1ρH measurements in different solvents were undertaken to get information on the mobility of the polymers in suspension. Scanning electron microscopy (SEM) images show the morphology of the polymers and energy dispersive X-ray spectroscopy (EDX) suggests that the distribution of the elements agrees with the applied stoichiometry.

Background. Subdural hygromas after bone marrow transplantation (BMT) have been occasionally found in patients with persisting headache and vomiting. We assessed the incidence of subdural hygromas after BMT and tried to define possible risk factors associated with this complication. Methods. Fifty bone marrow graft recipients surviving more than 30 days were consecutively enrolled into a prospective study. Cranial CT scans were performed before and 30 days after BMT. Clinical data and symptoms were recorded daily during the first 30 days after BMT. In patients with subdural hygromas, a magnetic resonance imaging scan and monthly follow-up cranial computed tomography scans were performed until fluid collections had resolved completely. Results. In 9 of the 50 patients (18%) who survived 30 days after transplantation, newly acquired subdural hygromas were found. Patients with hygromas suffered significantly longer and more severely from headache and vomiting(P=0.01). Application of intrathecal methotrexate and arterial hypertension occurred significantly more often in patients with hygromas(P=0.01). In a stepwise logistic regression model, arterial hypertension and intrathecal methotrexate application were the only independent risk factors for the development of hygromas. Monthly follow-up cranial computed tomography scans showed that all hygromas resolved completely after a median of 60 days after diagnosis (range: 30-120 days). Conclusions. Subdural hygromas are a frequent complication after BMT within the first 30 days after transplantation. They are reversible and disappear within 2-3 months. The need for routine application of intrathecal methotrexate in standard risk leukemia patients should be critically addressed. Furthermore, close monitoring of blood pressure and immediate antihypertensive therapy might contribute to avoid formation of subdural hygromas.

Despite the widespread application of drug modelling in psychiatric research, the relative value of different models has never been formally compared in the same analysis. Here we compared the effects of five drugs (cannabis, psilocybin, amphetamine, ketamine and alcohol) in relation to psychiatric symptoms in a two-part subjective analysis. In the first part, mental health professionals associated statements referring to specific experiences, for example ‘I don’t bother to get out of bed’, to one or more psychiatric symptom clusters, for example depression and negative psychotic symptoms. This measured the specificity of an experience for a particular disorder. In the second part, individuals with personal experience with each of the above-listed drugs were asked how reliably each drug produced the experiences listed in part 1, both acutely and sub-acutely. Part 1 failed to find any experiences that were specific for negative or cognitive psychotic symptoms over depression. The best model of positive symptoms was psilocybin and the best models overall were the acute alcohol and amphetamine models of mania. These results challenge current assumptions about drug models and motivate further research on this understudied area.

A microangiopathic syndrome was observed in 3 of 14 (21%) patients receiving cyclosporine and methylprednisolone (CSA-MP) for graft-versus-host disease (GVHD) prophylaxis between January 1991 and June 1992 at our center. The syndrome consisted of neurological abnormalities, arterial hypertension, intravascular hemolysis with red cell fragmentation, and a drop in platelet counts after allogeneic bone marrow transplantation (BMT) for hematological malignancy, and it occurred around day 50 after BMT. Treatment with plasma exchanges against fresh-frozen plasma resulted in a decrease of serum lactate dehydrogenase and an improvement of neurological symptoms. We compared CSA-MP patients retrospectively with patients who had received cyclosporine and methotrexate (CSA-MTX) for GVHD prophylaxis (n = 70) at our institution. All patients in both groups engrafted. Day 100 survival (80% vs. 79%) and transplant-related mortality (16% vs. 14%) were identical in the two groups. CSA-MP patients had significantly more acute GVHD II-IV (57% vs. 17%, P < 0.01). Arterial hypertension (P < 0.01) and neurological symptoms (P < 0.01) were significantly more frequent in the CSA-MP group. The 11 asymptomatic CSA-MP patients had significantly higher lactate dehydrogenase levels (P < 0.01) and lower platelet counts (P < 0.01) at 40, 60, and 100 days after BMT, which suggests the presence of a subclinical form of microangiopathy. Significantly higher plasma levels of von Willebrand factor antigen in CSA-MP patients on day 50 after BMT (P < 0.05) and absence of large von Willebrand factor multimers on gel electrophoresis in 4 of 13 (31%) CSA-MP patients compared with 0 of 14 (0%) CSA-MTX patients (P < 0.01) further suggest profound endothelial damage in patients receiving CSA-MP for GVHD prophylaxis.

Many patients with schizophrenia show a limited symptomatic response to treatment with dopaminergic antipsychotics. This may reflect the additional involvement of non-dopaminergic neurochemical dysfunction in the pathophysiology of the disorder. We tested the hypothesis that brain glutamate levels would differ between patients with first-episode psychosis who were symptomatic compared with those with minimal symptoms following antipsychotic treatment. Proton magnetic resonance spectroscopy (1H-MRS) spectra were acquired at 3 Tesla in the anterior cingulate cortex and left thalamus in 15 patients with first-episode psychosis in symptomatic remission, and 17 patients with first-episode psychosis who were still symptomatic following at least one course of antipsychotic treatment. Metabolite levels were estimated in ratio to creatine (Cr) using LCModel. Levels of glutamate/Cr in the anterior cingulate cortex were significantly higher in patients who were still symptomatic than in those in remission (T(30)=3.02; P=0.005). Across the entire sample, higher levels of glutamate/Cr in the anterior cingulate cortex were associated with a greater severity of negative symptoms (r=0.42; P=0.017) and a lower level of global functioning (r=−0.47; P=0.007). These findings suggest that clinical status following antipsychotic treatment in schizophrenia is linked to glutamate dysfunction. Treatment with compounds acting on the glutamatergic system might therefore be beneficial in patients who respond poorly to dopaminergic antipsychotics.

Synchronised neural oscillations preceding speech generation are reduced in patients with schizophrenia, this deficit being implicated in symptom formation. We measured synchronisation of neural oscillations preceding vocalisation in the presence of delta-9 tetrahydrocannabinol (THC) and found they were significantly disrupted. Furthermore, the degree of disruption was related to THC-induced symptoms, suggesting THC may modulate a similar neural substrate to schizophrenia.

A grossly obese patient with bull neck required immediate intubation. Endotracheal intubation failed because visualization of the vocal cords was not possible. As an alternative, the CombitubeTM was inserted without difficulty and the patients lungs were ventilated via the Combitube until tracheotomy was performed on the following day. The patient survived and was discharged alive from the hospital 5 weeks later. The Combitube has gained worldwide interest and is now included in the Guidelines of the American Heart Association and the American Society of Anesthesiologists.

Background γ-aminobutyric acid (GABA) is an important inhibitory neurotransmitter which mainly mediates its effects on neurons via ionotropic (GABAA) and metabotropic (GABAB) receptors. GABAB receptors are widely expressed in the central and the peripheral nervous system. Although there is evidence for a key function of GABAB receptors in the modulation of pain, the relative contribution of peripherally- versus centrally-expressed GABAB receptors is unclear. Results In order to elucidate the functional relevance of GABAB receptors expressed in peripheral nociceptive neurons in pain modulation we generated and analyzed conditional mouse mutants lacking functional GABAB(1) subunit specifically in nociceptors, preserving expression in the spinal cord and brain (SNS-GABAB(1)−/− mice). Lack of the GABAB(1) subunit precludes the assembly of functional GABAB receptor. We analyzed SNS-GABAB(1)−/− mice and their control littermates in several models of acute and neuropathic pain. Electrophysiological studies on peripheral afferents revealed higher firing frequencies in SNS-GABAB(1)−/− 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 GABAB(1) expression in nociceptors. Conclusion This study addressed contribution of GABAB 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 GABAB agonist was significantly changed upon a specific deletion of GABAB receptors from peripheral nociceptive neurons in vivo. This lets us conclude that GABAB receptors in the peripheral nervous system play a less important role than those in the central nervous system in the regulation of pain.

Pain is one of the most severe and debilitating symptoms associated with several forms of cancer. Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves. Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood. Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells and tumor cells. Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) are also functionally expressed on sensory nerves. GM-CSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP release and caused sprouting of sensory nerve endings in the skin. Interruption of G-CSF and GM-CSF signaling in vivo led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain. The key significance of GM-CSF signaling in sensory neurons was revealed by an attenuation of tumor-evoked pain following a sensory nerve-specific knockdown of GM-CSF receptors. These results show that G-CSF and GM-CSF are important in tumor-nerve interactions and suggest that their receptors on primary afferent nerve fibers constitute potential therapeutic targets in cancer pain.

Many regions in the world do not have electricity, water, or access to dental facilities that allows the treatment of caries with dental handpieces and rotary burs. For restorative techniques used in these regions, an antibacterial self-adherent glass ionomer material would contribute considerably.This study aimed to test if chlorhexidine diacetate (Fluka BioChemika, Buchs, Switzerland)- or chlorhexidine digluconate (Sigma-Aldrich, Steinheim, Germany)-added ChemFil Superior glass ionomer cement (Dentsply DeTrey, Konstanz, Germany) had any long-term antibacterial effect against certain oral bacteria and to test the new formulation's physical properties.ChemFil Superior was used as a control. Chlorhexidine diacetate (powder) was added to the powder and chlorhexidine digluconate (liquid) was mixed with the powder in order to obtain 0.5, 1.25, and 2.5% concentrations of the respective groups. Setting time, compressive strength, and acid erosion were tested according to ISO 9917-1. Working time, hardness, diametral tensile strength, and biaxial flexural strength were also determined. Long-term antimicrobial activity against S. mutans, L. acidophilus, and C. albicans were tested with the agar diffusion method. Analysis of variance (ANOVA) was used for comparison (p0.05).Regarding the immediate antibacterial effect for S. mutans, all the tested groups showed inhibitions of the strain compared with the control group (p0.05), with larger zones for the higher concentration groups and all the diacetates. For L. acidophilus, all the groups were effective compared with the control, but the greatest antibacterial effect was observed with the 2.5% diacetate group. The 2.5% group of chlorhexidine diacetate showed antibacterial activity up to 90 days against S. mutans and up to 60 days against L. acidophilus. The working and setting time, acid erosion test, diametral tensile strength, and biaxial flexural strength of the tested groups were not different from the control ChemFil group. However, the 1.25 and 2.5% groups of chlorhexidine diacetate had significantly lower compressive strengths than the control group. Lower hardness values were obtained with the 0.5 and 2.5% chlorhexidine digluconate groups in comparison with the control group.The results of this in vitro investigation demonstrated that chlorhexidine diacetate or digluconate added to the ChemFil Superior glass ionomer material can exhibit long-term antibacterial effects against S. mutans and L. acidophilus without compromising the physical properties of the material.

Recently, a family with idiopathic brain calcification was reported, in which one family member was diagnosed with multiple system atrophy (MSA) at autopsy. We report here a case showing similar neuropathological features in a patient with longstanding hypoparathyroidism. Our female patient had a history of hypoparathyroidism with hypocalcaemia and tetany since the age of 9 years. In her 50s she developed dementia and parkinsonism. She died of myocardial infarction aged 65 years. Neuropathology showed severe brain calcifications of the Fahr type in the basal ganglia, thalami, cerebral and cerebellar white matter and dentate nuclei. Additionally, there was prominent alpha-synucleinopathy of the multiple system atrophy type (MSA). The patient has a healthy identical twin and there is no family history of hypoparathyroidism or neurological disease. Data on alpha-synuclein accumulation in various cases of Fahr's syndrome are needed to establish the correlation between alpha-synucleinopathy and bilateral striopallidodentate calcification.

BACKGROUND. In previous studies, alemtuzumab demonstrated considerable activity in patients with previously treated B-cell chronic lymphocytic leukemia (CLL), including fludarabine-refractory disease. In this retrospective study, the authors evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced, previously treated CLL who received treatment in the routine clinical setting. METHODS. Data were collected from 115 consecutive patients who received alemtuzumab therapy at 25 participating centers in Austria. Patients received a median of 3 prior lines of therapy (range, 1–11 prior lines of therapy), and 59% had fludarabine-refractory disease. Alemtuzumab was administered intravenously or subcutaneously with a planned schedule of 30 mg 3 times per week for up to 12 weeks. Patients received valacyclovir and trimethoprim/sulfamethoxazole for antiinfective prophylaxis. RESULTS. The overall response rate was 23%, with complete responses achieved in 5% of patients. Stable disease (SD) was achieved in 36% of patients. After a median follow-up of 17.5 months, the median overall survival (OS) was 20.2 months for all patients. A multivariate Cox regression analysis that included pretreatment baseline characteristics, response to therapy, and cumulative dose of alemtuzumab indicated that bulky lymphadenopathy, the administration of ≥3 previous therapies, and lack of response to alemtuzumab remained significant independent risk factors for inferior OS. The median OS had not been reached for responding patients. The median OS was 29.5 months for patients with SD and 10.8 months for patients with progressive disease. CONCLUSIONS. The broad use of alemtuzumab in the routine clinical practice setting is feasible and active in unselected patients with pretreated CLL, and the current results confirmed the activity and safety of this agent, as reported in previously published clinical studies. Cancer 2006. © 2006 American Cancer Society.

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.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.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.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.

Background: Extranodal marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT) is a relatively common type of lymphoma. Owing to its B cell lineage, it appears to be a potential target for treatment with the CD20 antibody rituximab. We present an analysis of our experience with rituximab for treatment of patients with advanced MALT lymphoma. Patients and Methods: A retrospective analysis of patients with histologically verified MALT lymphoma undergoing treatment with rituximab was done. After reassessment of histological samples for the presence of MALT lymphoma, patients were evaluated as regards date of diagnosis, prior therapy for MALT lymphoma, sites of involvement upon treatment with rituximab, clinical response in terms of complete remission (CR), partial response (PR), stable disease (SD) and progressive disease as well as symptomatic response, duration of response and survival. Results: A total of 9 patients with advanced MALT lymphoma undergoing therapy with single-agent rituximab were identified. All patients received treatment at a dose of 375 mg/m2 once weekly ×4. One patient each had relapsed after chemotherapy and radiation, respectively, while none of the other 7 patients had received prior cytotoxic treatment or radiation. Three patients achieved a CR, 2 patients had PR for 6 and 14 months, while the remaining patients had SD between 8 and 18+ months. One patient died of progressive disease in spite of the initiation of chemotherapy and 1 patient succumbed to a cardiovascular event while having been in ongoing PR for 11 months. The other 7 patients are currently alive with disease 10–27 months after initiation of therapy. Follow-up biopsies for histological assessment were available in 5 patients with gastric lymphoma. In 1 patient with SD, however, persistence of CD20-positive cells within lymphoepithelial lesions was noted in spite of almost complete depletion of B lymphocytes from the normal gastric mucosa, suggesting either recirculation of MALT lymphoma cells to these lesions or defining lymphoepithelial lesions as a sanctuary site from rituximab penetration. Conclusion: Rituximab had only moderate activity in terms of inducing objective responses in our unselected and heterogeneous cohort of patients with disseminated MALT lymphoma. Long-term disease stabilization, however, along with a symptomatic benefit was seen in all patients. Our data nevertheless indicate that rituximab might not optimally penetrate into the gastric mucosa in all patients.

Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs might act synergistically with mitomycin C, a randomized study using a 'pick the winner' design was undertaken to determine the effectiveness and tolerance of these two combination schedules in patients with fluoropyrimidine/leucovorin-pretreated advanced colorectal cancer.Sixty-four patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin were enrolled onto this study. They were randomly assigned to treatment with irinotecan 120 mg/m2 on days 1 + 15 plus mitomycin C 8 mg/m2 on day 1 (arm A) or oxaliplatin 85 mg/M2 on days 1 + 15 plus mitomycin C 8 mg/m2 on day 1 (arm B). In both treatment arms, courses were repeated every 4 weeks.The objective response rate in arm A is 7/33 (21.2%; 95% confidence interval, 9.0-38.9%) as compared to 5/31 in arm B (16.1%; 95% CI, 5.5-34.7%). Stable disease was noted in 48.5 vs. 45.2%, whereas the tumor progressed in 30.3 vs. 38.7%, respectively. Similar to the recorded response activities, the difference of the two combination regimens in terms of median time to progression (7.0 vs. 5.2 months) and overall survival (12.0 vs. 11.2 months) was only minor and clincally insignificant. The tolerance of treatment was acceptable in both arms, though severe adverse reactions requiring dose reductions (30 vs. 16%) and treatment delays (22 vs. 13% of courses) were more commonly noted with irinotecan/mitomycin C. The most common toxicities in arm A were neutropenia (85%; WHO grade 3/4 in 33%), thrombocytopenia (52%), diarrhea (45%), emesis (52%) and alopecia (92%). In arm B, common toxicities included neutropenia (68%; grade 3/4 in 13%), thrombocytopenia (81%), emesis (52%), and peripheral neutropathy (48%).Both mitomycin C combination regimens seem to provide an acceptable therapeutic index in patients with fluoropyrimidine/leucovorin-pretreated metastatic colorectal cancer. In view of the increasing need for a broader chemotherapeutic armentarium for second-line therapy of this common malignant disease, both regimens may be worthwhile to undergo further clinical investigation.

We studied thrombopoietic activity in hyperthyroidism by determination of reticulated platelet counts. At the time of hyperthyroidism 14/15 patients had higher reticulated platelets than after achievement of euthyroidism (P