Mental disorders and (violent) offending

Interpersonal violence is among the most frequent preventable causes of premature mortality and morbidity. The association between psychiatric disorders and violence has received substantial attention from both the public and mental health professionals. Today, an increased risk for violence has been documented for a number of severe psychiatric disorders. This non-systematic review summarises the current state of the research and discusses clinical implications with an emphasis on risk assessment and preventive approaches

Investigation of Cytotoxic T Lymphocyte Function during Allorejection in the Anterior Chamber of the Eye

Cytotoxic T lymphocytes (CTL) are an essential part of our immune system by killing infected and malignant cells. To fully understand this process, it is necessary to study CTL function in the physiological setting of a living organism to account for their interplay with other immune cells like CD4+ T helper cells and macrophages. The anterior chamber of the eye (ACE), originally developed for diabetes research, is ideally suited for non-invasive and longitudinal in vivo imaging. We take advantage of the ACE window to observe immune responses, particularly allorejection of islets of Langerhans cells by CTLs. We follow the onset of the rejection after vascularization on islets until the end of the rejection process for about a month by repetitive two-photon microscopy. We find that CTLs show reduced migration on allogeneic islets in vivo compared to in vitro data, indicating CTL activation. Interestingly, the temporal infiltration pattern of T cells during rejection is precisely regulated, showing enrichment of CD4+ T helper cells on the islets before arrival of CD8+ CTLs. The adaptation of the ACE to immune responses enables the examination of the mechanism and regulation of CTL-mediated killing in vivo and to further investigate the killing in gene-deficient mice that resemble severe human immune diseases

Study of Effector CD8+ T Cell Interactions with Cortical Neurons in Response to Inflammation in Mouse Brain Slices and Neuronal Cultures

Cytotoxic CD8+ T cells contribute to neuronal damage in inflammatory and degenerative CNS disorders, such as multiple sclerosis (MS). The mechanism of cortical damage associated with CD8+ T cells is not well understood. We developed in vitro cell culture and ex vivo brain slice co-culture models of brain inflammation to study CD8+ T cell–neuron interactions. To induce inflammation, we applied T cell conditioned media, which contains a variety of cytokines, during CD8+ T cell polyclonal activation. Release of IFNγ and TNFα from co-cultures was verified by ELISA, confirming an inflammatory response. We also visualized the physical interactions between CD8+ T cells and cortical neurons using live-cell confocal imaging. The imaging revealed that T cells reduced their migration velocity and changed their migratory patterns under inflammatory conditions. CD8+ T cells increased their dwell time at neuronal soma and dendrites in response to added cytokines. These changes were seen in both the in vitro and ex vivo models. The results confirm that these in vitro and ex vivo models provide promising platforms for the study of the molecular details of neuron–immune cell interactions under inflammatory conditions, which allow high-resolution live microscopy and are readily amenable to experimental manipulation

The Journal of Nutrition Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions Divalent Minerals Decrease Micellarization and Uptake of Carotenoids and Digestion Products into Caco-2 Cells 1-3

Abstract Carotenoids are lipophilic, dietary antioxidants with the potential to prevent chronic and age-related diseases. Prior to their availability for physiological functions, carotenoids require micellarization and intestinal uptake, both constituting marginally understood processes. Based on an in vitro digestion model coupled to Caco-2 cells, we assessed the effect of dietary abundant divalent ions on spinach-derived carotenoid micellarization and cellular uptake: calcium (Ca) and magnesium (Mg) ranging from 7.5 to 25 mmol/L in the digesta and zinc (Zn) and iron (Fe) ranging from 3.8 to 12.5 mmol/L. Both micellarization and uptake were significantly inhibited by minerals in a concentration-dependent manner, with stronger effects for Fe and Zn compared to Ca and Mg. Compared to controls (no mineral addition), fractional micellarization and uptake were decreased to the greatest extent (to 22.5 and 5.0%, respectively; P , 0.001) by 12.5 mmol/L Fe. Effects of Mg were of the least magnitude; at 25 mmol/L, only uptake was decreased significantly to 69.2% of the control value (P , 0.001). Total cellular carotenoid uptake from test meals decreased similarly compared to micellarization; however, decreased b-carotene micellarization was counterbalanced by improved fractional cellular uptakes from the micelles for all ions. Compared to controls, fractional b-carotene uptake from the micelles was greater in samples digested in the presence of Fe, Ca, and Zn, by up to 5-10 times at the highest concentrations of each ion (P , 0.001). Like for the above carotenoids, a high cellular uptake of the epoxycarotenoid conversion products neochrome (from neoxanthin) and luteoxanthin+auroxanthin (from violaxanthin) was also observed. The present results indicate that divalent ions may inhibit carotenoid micellarization and uptake. J. Nutr

A Structure-Activity Relationship Study of Bimodal BODIPY-Labeled PSMA-Targeting Bioconjugates

The aim of this study was to identify a high-affinity BODIPY peptidomimetic that targets the prostate-specific membrane antigen (PSMA) as a potential bimodal imaging probe for prostate cancer. For the structure-activity study, several BODIPY (difluoroboron dipyrromethene) derivatives with varying spacers between the BODIPY dye and the PSMA Glu-CO-Lys binding motif were prepared. Corresponding affinities were determined by competitive binding assays in PSMA-positive LNCaP cells. One compound was identified with comparable affinity (IC50=21.5±0.1 nM) to Glu-CO-Lys-Ahx-HBED-CC (PSMA-11) (IC50=18.4±0.2 nM). Radiolabeling was achieved by Lewis-acid-mediated 19F/18F exchange in moderate molar activities (∼0.7 MBq nmol−1) and high radiochemical purities (>99 %) with mean radiochemical yields of 20–30 %. Cell internalization of the 18F-labeled high-affinity conjugate was demonstrated in LNCaP cells showing gradual increasing PSMA-mediated internalization over time. By fluorescence microscopy, localization of the high-affinity BODIPY-PSMA conjugate was found in the cell membrane at early time points and also in subcellular compartments at later time points. In summary, a high-affinity BODIPY-PSMA conjugate has been identified as a suitable candidate for the development of PSMA-specific dual-imaging agents

P38α-MAPK phosphorylates Snapin and reduces Snapin-mediated BACE1 transportation in APP-transgenic mice

Amyloid β peptide (Aβ) is the major pathogenic molecule in Alzheimer's disease (AD). BACE1 enzyme is essential for the generation of Aβ. Deficiency of p38α-MAPK in neurons increases lysosomal degradation of BACE1 and decreases Aβ deposition in the brain of APP-transgenic mice. However, the mechanisms mediating effects of p38α-MAPK are largely unknown. In this study, we used APP-transgenic mice and cultured neurons and observed that deletion of p38α-MAPK specifically in neurons decreased phosphorylation of Snapin at serine, increased retrograde transportation of BACE1 in axons and reduced BACE1 at synaptic terminals, which suggests that p38α-MAPK deficiency promotes axonal transportation of BACE1 from its predominant locations, axonal terminals, to lysosomes in the cell body. In vitro kinase assay revealed that p38α-MAPK directly phosphorylates Snapin. By further performing mass spectrometry analysis and site-directed mutagenic experiments in SH-SY5Y cell lines, we identified serine residue 112 as a p38α-MAPK-phosphorylating site on Snapin. Replacement of serine 112 with alanine did abolish p38α-MAPK knockdown-induced reduction of BACE1 activity and protein level, and transportation to lysosomes in SH-SY5Y cells. Taken together, our study suggests that activation of p38α-MAPK phosphorylates Snapin and inhibits the retrograde transportation of BACE1 in axons, which might exaggerate amyloid pathology in AD brain

The comorbidity and co-medication profile of patients with progressive supranuclear palsy

BackgroundProgressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients.ObjectivesTo explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease.MethodsCross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were evaluated using AiDKlinik (R).ResultsIn total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug-drug interactions was higher in PSP patients, especially severe and moderate interactions.ConclusionsPSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Qualität forensisch psychiatrischer und psychologischer Gutachten

Zusammenfassung Die kritische Auseinandersetzung mit der Qualität psychiatrisch-psychologischer Gutachten hat eine lange Tradition. Mit der Erstellung von Mindeststandards durch interdisziplinär zusammengesetzte Arbeitsgruppen, der Abgabe von Empfehlungen, der Verbesserung der Qualifikationsmöglichkeiten für Psycholog:innen und Psychiater:innen sowie der Regulierung der Zulassung von Sachverständigen, wurde die Basis für eine bessere Gutachtenqualität gelegt. Insgesamt scheinen die Maßnahmen einen positiven Effekt zu haben, dennoch wurde auch in aktuellen Studien weiterer Verbesserungsbedarf aufgezeigt. Der vorliegende Beitrag skizziert Entwicklungspotentiale und legt dar, dass die Qualitätssicherung eine gemeinsame Aufgabe aller in die Begutachtung involvierten Disziplinen ist. Abstract The quality of court-ordered psychiatric and psychological evaluations has been the focus of substantial debate. The recent development of guidelines for writing expert reports, the improvement of forensic training opportunities for psychologists and psychiatrists and the implementation of a stricter regulation of mental health professionals admitted as experts in court have laid the groundwork for higher quality expert evaluations. Overall, the measures appear to yield a positive effect, although instances of questionable quality remain. The current review illustrates the potential for improvement and underlines the fact that all involved disciplines must act to ensure that only high-quality reports are used in court