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BackgroundBipolar disorders (BD) are chronic, debilitating disorders. Our understanding of the pathogenesis and functional biomarkers in BD remains limited. The blood-brain barrier (BBB), a highly selective, protective physical barrier which separates the central nervous system from the peripheral circulation, has been increasingly investigated in the BD. This systematic review aimed to assess the relationship between BD and markers of BBB dysfunction.MethodsStudies were identified in PubMed and Medline databases in January 2021. Articles were limited to full-length peer-reviewed journal publications with no date restrictions. Included studies compared blood, CSF, post-mortem, genetic and imaging measures of BBB function in people with BD compared to healthy controls.Results49 studies were identified, 34 of which found an association between BD and markers of BBB dysfunction. Blood QAlb, S100B and MMP levels were found to be increased in BD participants compared to controls in 57% of the studies. In post-mortem BD studies, ICAM, neurexin, claudin-5, and chondroitin sulphate proteoglycans were increased in the anterior cingulate cortex (ACC), prefrontal grey matter, occipital cortex and cerebellum, and lateral nucleus of the entorhinal cortex respectively compared to controls. Additionally, a study of BBB leakage measured by MRI found that nearly 30% of BD participants had extensive BBB leakage compared to controls. The mood state of BD participants was also associated with markers of BBB dysfunction, with participants experiencing mania generally having increased BBB marker levels compared to participants who were depressed or in remission.ConclusionsThis review suggests an association between BD and markers of BBB dysfunction. Further research is needed to control for a number of confounding factors, and to clarify whether this association provides a pathogenic mechanism, or is an epiphenomenon of BD.

Die wichtigste Quelle von Destruktivität sieht der Autor in einem Hass, der aus traumatisch-negativen Kindheitserfahrungen stammt. Sozialpsychologisch sei die Idealisierung bedeutsam: Soziale Gruppierungen können als idealer Ort des Schutzes gegen Ohnmacht, Scham und Schuld erlebt werden; wer dieses Ideal bedroht, kann Destruktivität auf sich ziehen. In Supervision und Beratung kann Destruktivität auf der Ebene des »Falles« erscheinen, auf der Spiegelungsebene des Falles in der Supervision oder direkt zwischen Supervisand*in und Supervisor*in. In einem Fallbeispiel, der Krisenberatung einer Klinik, wird die Destruktivität auf die Angst vor Veränderung zurückgeführt. Sie zeigte sich in der Spaltung zwischen Team und Leitung und wurzelte in einer Idealisierung der Vergangenheit.

BackgroundClozapine is the only licensed pharmacotherapy for patients with treatment-resistant schizophrenia (TRS), but its use is limited due to adverse effects. Clozapine treatment has been recently associated with reductions in immunoglobulin (Ig) levels cross-sectionally, however prospective studies are required to establish longitudinal effects. This study aimed to determine whether reductions in immunoglobulin levels occur over 6 months after initiating clozapine treatment. An exploratory aim was to investigate relationships between immunoglobulin levels and symptom severity over the course of clozapine treatment.MethodsIn 56 participants with TRS, Ig A, M and G levels were measured in serum using a sandwich immunoassay. Samples for analysis were acquired prior to starting clozapine and at 6, 12 and 24 weeks after initiating clozapine treatment. Clinical symptoms were measured using the positive and negative syndrome scale for schizophrenia (PANSS).ResultsAll three classes of Ig decreased during clozapine treatment. For IgA and IgG the reduction was significant at 24 weeks (IgA: B – 32.7, 95% CI = -61.19, -4.2, p = 0.04; IgG: B – 55.94, 95% CI = -111.03, -0.844, p = 0.05). For IgM the reduction was significant at 12 and 24 weeks (12 weeks: B = -21.73, 95% CI = -37.10, -6.35, p = 0.006; 24 weeks: B = -32.54, 95% CI = -48.89, 16.18, p = 0.0001). Changes in both IgA and IgG were correlated with the percentage change in PANSS total scores over 12 weeks, such that greater reductions in IgA and IgG during clozapine treatment were associated with greater reductions in symptom severity (n = 32, IgA r = 0.59, p = 0.005; IgG r = 0.50, p = 0.02)ConclusionsThe observed reductions in immunoglobulin levels over six months of clozapine treatment add further evidence linking clozapine to secondary antibody deficiency. The associations between Ig reduction and symptom improvement may however indicate that immune mechanisms contribute to both desirable and undesirable effects of clozapine.

Im Mittelpunkt des Beitrages steht die »Psychotherapie-Richtlinie«, die die Anwendung der Psychoanalyse im Rahmen der Krankenversicherung reguliert. Der Beitrag beginnt mit einer Erorterung des Verhaltnisses von Psychoanalyse und Krankenbehandlung, um anschliesend die Entstehungsgeschichte der »Richtlinie« und ihren Kompromisscharakter darzulegen. Danach werden einzelne Bestandteile des Regelwerks diskutiert und der theoretische Hintergrund des Richtlinien-Systems beleuchtet. Im letzten Teil pladiert der Autor fur grundlegende Veranderungen.

Early immunotherapy administration improves outcomes in patients with N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis. As most patients with NMDAR-antibody encephalitis present to psychiatrists, the psychopathology of NMDAR-antibody encephalitis needs to be clearly defined to encourage accurate clinical identification and prompt treatment.For this systematic review, we searched PubMed for all studies published in English between Jan 1, 2005, and Oct 7, 2017, to identify individually reported adult patients (≥18 years) who satisfied consensus criteria for definite NMDAR-antibody encephalitis. After generating a list of 50 fine-grained, lower-level features, we extracted psychopathological data in addition to demographic and aetiological data. The lower-level features were later ordered within higher-level categories. As a means of quality control, we filtered the data according to proxy markers of psychiatric involvement in their description. Subsequently, we compared lower-level features from individual patient data with operationalised psychiatric syndromes using a constrained combination approach and principal component analysis, and did a network analysis to explore the inter-relationships between multiple lower-level features. The review protocol was prospectively registered with PROSPERO, number CRD42017068981.Of 1096 records identified in PubMed, 333 satisfied inclusion criteria and described 1100 patients in total with NMDAR-antibody encephalitis. The psychopathology of 505 (46%) patients with reported psychiatric symptoms was described in more detailed terms than only psychiatric or behavioural. 464 (91%) of the 505 patients were from papers in which patient data were reported individually. The remainder of the analyses focused exclusively on these 464 patients. Median age was 27 years (IQR 22-34), 368 (79%) of 464 patients were female and in 147 (32%), NMDAR-antibody encephalitis was associated with ovarian teratoma. The five higher-level categories into which the 464 patients most frequently grouped were behaviour (316 [68%]), psychosis (310 [67%]), mood (219 [47%]), catatonia (137 [30%]), and sleep disturbance (97 [21%]). The overall pattern of lower-level features was statistically stable across subgroups classified by age, sex, pregnancy association, presence of ovarian teratoma, prior herpes simplex virus encephalitis, and isolated psychiatric presentations (two-way ANOVA p=0·6-0·9). Constrained combination and principal component analyses found that mixtures of mood and psychosis syndromes fit each patient better than any single diagnosis alone, particularly for the patients in the psychiatric-described subgroup (mean ΔAkaike information criterion -0·04 in non-psychiatric-described subgroup vs 0·61 in psychiatric-described subgroup). The overlapping nature of the higher-level features was also enriched upon analysis of the psychiatric-described data (221 [67%] of 329 overlaps in non-psychiatric-described subgroup vs 96 [81%] of 118 overlaps in psychiatric-described subgroup, p=0·0052). Network analysis confirmed that the features were closely related and consistent between individual patients; the psychiatric-described subgroup had a markedly high and narrow range of closeness centralities (92% above 0·93 in psychiatric-described subgroup vs 51% above 0·93 in the non-psychiatric group).The distinctive aspect of NMDAR-antibody encephalitis psychopathology is complexity; core aspects of mood and psychotic disorders consistently coexist within individual patients. Alongside the predominant young female demographic, these psychopathological features could help psychiatrists identify patients who would benefit from cerebrospinal fluid testing and immunotherapies. Well-controlled prospective studies with bespoke inventories are needed to advance this clinically grounded approach.Wellcome Trust, NIHR Oxford Biomedical Research Centre, NIHR Oxford Health Biomedical Research Centre, British Medical Association Foundation for Medical Research.

BackgroundAnti-N-methyl-d-aspartate (NMDA) receptor encephalitis is an autoimmune condition caused by immunoglobulin (Ig)G antibodies directed against the NR1 subunit of the NMDA glutamate receptor. Approximately 65% of cases present with psychiatric symptoms, particularly psychosis. It remains to be established whether anti-NMDA receptor antibodies can cause a ‘purely’ psychotic illness without overt neurological symptoms.MethodWe conducted a systematic literature search to establish what proportion of patients with schizophrenia and related psychoses have antibodies directed against the NMDA receptor. Studies were included if (a) subjects had a diagnosis of schizophrenia, schizophrenia spectrum disorder or first-episode psychosis (FEP) using standard criteria, (b) serum was analysed for the presence of anti-NMDA receptor antibodies; and (c) the purpose of the study was to look for the presence of anti-NMDA receptor antibodies in patients with a primary psychiatric diagnosis without clinical signs of encephalitis.ResultsSeven studies were included, comprising 1441 patients, of whom 115 [7.98%, 95% confidence interval (CI) 6.69–9.50] were anti-NMDA receptor antibody positive. Of these, 21 (1.46%, 95% CI 0.94–2.23) patients were positive for antibodies of the IgG subclass. Prevalence rates were greater in cases than controls only for IgG antibodies; other subclasses are of less certain aetiological relevance. There was significant heterogeneity in terms of patient characteristics and the antibody assay used.ConclusionsA minority of patients with psychosis are anti-NMDA receptor antibody positive. It remains to be established whether this subset of patients differs from antibody-negative patients in terms of underlying pathology and response to antipsychotic treatment, and whether immunomodulatory treatments are effective in alleviating psychotic symptoms in this group.

Coordinated transfer of information between the brain hemispheres is essential for function and occurs via three axonal commissures in the,telencephalon: the corpus callosum (CC), hippocampal commissure (HC), and anterior commissure (AC). Commissural malformations occur in over 50 human congenital syndromes causing mild to severe cognitive impairment. Disruption of multiple commissures in some syndromes suggests that common mechanisms may underpin their development. Diffusion tensor magnetic resonance imaging revealed that forebrain commissures crossed the midline in a highly specific manner within an oblique plane of tissue, referred to as the commissural plate. This specific anatomical positioning suggests that correct patterning of the commissural plate may influence forebrain commissure formation. No analysis of the molecular specification of the commissural plate has been performed in any species; therefore, we utilized specific transcription factor markers to delineate the commissural plate and identify its various subdomains. We found that the mouse commissural plate consists of four domains and tested the hypothesis that disruption of these domains might affect commissure formation. Disruption of the dorsal domains occurred in strains with commissural defects such as Emx2 and Nfia knockout mice but commissural plate patterning was normal in other acallosal strains such as Satb2(-/-). Finally, we demonstrate an essential role for the morphogen Fgf8 in establishing the commissural plate at later developmental stages. The results demonstrate that correct patterning of the commissural plate is an important mechanism in forebrain commissure formation. J. Comp. Neurol. 518:3645-3661, 2010. (C) 2010 Wiley-Liss, Inc.

There is some evidence that basal cell carcinomas (BCCs) arising on different anatomic sites and developing to different histological subtypes differ in their pathophysiology. The expression of a number of proteins, including PTCH1, COX-2, p53, and Ki-67, is frequently altered in BCC development. This study sought to determine whether protein expression differs between BCCs at different anatomic sites and of different histological subtypes. Expression of PTCH1, COX-2, p53, and Ki-67 proteins was compared between: (i) BCCs arising on the head (n = 55) and trunk (n = 53), and (ii) nodular (n = 52) and superficial (n = 43) BCCs. The intensity of immunohistochemistry (IHC) staining (low, moderate, strong, very strong) for PTCH1 and COX-2 proteins was measured and the proportions of p53- and Ki-67-positive cells quantified. The proportion of cells expressing Ki-67 was higher in tumor tissue than in non-malignant epidermis, whereas the opposite was found for PTCH1. The IHC staining intensity for PTCH1 was substantially greater in truncal BCCs than in BCCs on the head (odds ratio [OR] 3.82, 95% confidence interval [CI] 1.63-8.96). The intensity of staining for PTCH1 was greater for superficial than for nodular BCCs (OR 3.70, 95% CI 1.53-8.97), and superficial BCCs showed a higher proportion of Ki-67-positive cells (OR 5.57, 95% CI 1.66-18.67). These differences suggest that the pathophysiology of BCC differs between lesions on the head and trunk and between nodular and superficial subtypes, perhaps indicating differences in their etiology.

Free to read We conducted a clinical trial to compare the molecular and cellular responses of human melanocytes and keratinocytes in vivo to solar-simulated ultraviolet radiation (SSUVR) in 57 Caucasian participants grouped according to MC1R genotype. We found that, on average, the density of epidermal melanocytes 14 days after exposure to 2 minimal erythemal dose (MED) SSUVR was twofold higher than baseline (unirradiated) skin. However, the change in epidermal melanocyte counts among people carrying germline MC1R variants (97% increase) was significantly less than those with wild-type MC1R (164% increase; P = 0.01). We also found that sunscreen applied to the skin before exposure to 2 MED SSUVR completely blocked the effects of DNA damage, p53 induction, and cellular proliferation in both melanocytes and keratinocytes.

We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.

The peptide transporter (PTR) family represents a group of proton-coupled secondary transporters responsible for bulk uptake of amino acids in the form of di- and tripeptides, an essential process employed across species ranging from bacteria to humans. To identify amino acids critical for peptide transport in a prokaryotic PTR member, we have screened a library of mutants of the Escherichia coli peptide transporter YdgR using a high-throughput substrate uptake assay. We have identified 35 single point mutations that result in a full or partial loss of transport activity. Additional analysis, including homology modeling based on the crystal structure of the Shewanella oneidensis peptide transporter PepT(so), identifies Glu(56) and Arg(305) as potential periplasmic gating residues. In addition to providing new insights into transport by members of the PTR family, these mutants provide valuable tools for further study of the mechanism of peptide transport.

The medial prefrontal cortex is involved in working memory and executive control. However, the collective spatiotemporal organization of the cellular network has not been possible to explain during different brain states. We show that pyramidal cells in the prelimbic cortex fire synchronized to hippocampal theta and local spindle oscillations in anesthetized rats. To identify which types of interneurons contribute to the synchronized activity, we recorded and juxtacellularly labeled parvalbumin- and calbindin-expressing (PV+/CB+) basket cells and CB-expressing, PV-negative (CB+/PV−) dendrite-targeting interneurons during both network oscillations. All CB+/PV− dendrite-targeting cells strongly decreased their firing rate during hippocampal theta oscillations. Most PV+/CB+ basket cells fired at the peak of dorsal CA1 theta cycles, similar to prefrontal pyramidal cells. We show that pyramidal cells in the ventral hippocampus also fire around the peak of dorsal CA1 theta cycles, in contrast to previously reported dorsal hippocampal pyramidal cells. Therefore, prefrontal neurons might be driven by monosynaptic connections from the ventral hippocampus during theta oscillations. During prefrontal spindle oscillations, the majority of pyramidal cells and PV+/CB+ basket cells fired preferentially at the trough and early ascending phase, but CB+/PV− dendrite-targeting cells fired uniformly at all phases. We conclude that PV+/CB+ basket cells contribute to rhythmic responses of prefrontal pyramidal cells in relation to hippocampal and thalamic inputs and CB+/PV− dendrite-targeting cells modulate the excitability of dendrites and spines regardless of these field rhythms. Distinct classes of GABAergic interneuron in the prefrontal cortex contribute differentially to the synchronization of pyramidal cells during network oscillations.