Effects of donepezil adjunctive treatment to ziprasidone on cognitive deficits in schizophrenia: a double-blind, placebo-controlled study

The objective of this study was to examine the effects of adjunctive treatment with the acetylcholinesterase inhibitor, donepezil, on cognitive deficits and psychopathology in schizophrenic patients treated with the antipsychotic, ziprasidone. The design of the study was double blind, placebo controlled, and longitudinal. Patients were treated with ziprasidone for 8 weeks, thereafter randomized to 4 months of double-blind adjunctive treatment with either donepezil (dose, 5-10 mg) or placebo. The severity of psychopathology (PANSS) and the cognitive deficits were examined at baseline and after 4 months. A total of 21 schizophrenic patients were enrolled, of whom 11 patients completed the trial (donepezil, n = 7; placebo, n = 4). There were no within- or between-group differences in changes on the Positive and Negative Syndrome Scale scores or a global cognitive score. Within-group improvements (all at trend level P = 0.07) were seen in the placebo group on Trail-Making Test B, immediate verbal recall, and set-shifting errors. The donepezil group showed a significant deterioration on planning efficiency (P = 0.04). Between-group differences were found between the lack of improvement in immediate verbal recall in the donepezil group and the improvement in the placebo group (P = 0.02), and between the deterioration of planning efficiency in the donepezil group and the stability in the placebo group (trend level, P = 0.07). Linear regression analyses showed that neither baseline psychopathology scores, baseline levels of cognitive deficits, nor psychopathology changes over time accounted for these changes in cognitive scores. The study found no evidence of improved cognition after treatment with donepezil, although the conclusions that can be drawn are limited by the small sample size.     

Stability of prepulse inhibition and habituation of the startle reflex in schizophrenia: a 6-year follow-up study of initially antipsychotic-naive, first-episode schizophrenia patients

Deficits in information processing appear to be core features in the pathogenesis of schizophrenia. Prepulse inhibition (PPI) and habituation of the startle reflex are operational measures of early information processing. Impaired PPI in schizophrenia has been replicated in many studies and is regarded as an endophenotype for schizophrenia. However, reports on the stability of PPI over a longer period of time are lacking, both for patients with schizophrenia and for healthy subjects. The current study examined 25 initially drug-naive, first-episode schizophrenia patients and 23 healthy matched controls. Three PPI measures [stimulus onset asynchrony (SOA) 30, 60, 120 ms] and habituation were assessed at baseline, and again after 6 yr. Sixteen patients and 17 healthy controls completed the study, and 13 patients and 17 healthy controls were included in the final analysis. The schizophrenia patients had PPI deficits compared to controls at baseline. After 6 yr, no significant group differences were found. PPI had increased significantly in the patients and had decreased significantly in controls. In addition, patients showed significantly less habituation than controls while habituation did not change in patients or controls. The present results show that PPI in drug-naive, first-episode schizophrenia patients can improve significantly over time. As PPI increased in patients over the same period that it decreased in controls, it is likely that the increase was caused by disease-related factors such as disease process, clinical state, or medication.     

Smac mimetics and TRAIL cooperate to induce MLKL-dependent necroptosis in Burkitt's lymphoma cell lines

Burkitt''s lymphoma (BL) is a highly aggressive form of B-cell non-Hodgkin''s lymphoma. The clinical outcome in children with BL has improved over the last years but the prognosis for adults is still poor, highlighting the need for novel treatment strategies. Here, we report that the combinational treatment with the Smac mimetic BV6 and TRAIL triggers necroptosis in BL when caspases are blocked by zVAD.fmk (TBZ treatment). The sensitivity of BL cells to TBZ correlates with MLKL expression. We demonstrate that necroptotic signaling critically depends on MLKL, since siRNA-induced knockdown and CRISPR/Cas9-mediated knockout of MLKL profoundly protect BL cells from TBZ-induced necroptosis. Conversely, MLKL overexpression in cell lines expressing low levels of MLKL leads to necroptosis induction, which can be rescued by pharmacological inhibitors, highlighting the important role of MLKL for necroptosis execution. Importantly, the methylation status analysis of the MLKL promoter reveals a correlation between methylation and MLKL expression. Thus, MLKL is epigenetically regulated in BL and might serve as a prognostic marker for treatment success of necroptosis-based therapies. These findings have crucial implications for the development of new treatment options for BL.     

Metabolic wiring of murine T cell and intraepithelial lymphocyte maintenance and activation

Adaptive immunity critically depends on cell migration combined with clonal selection and rapid expansion of rare lymphocytes recognising their cognate antigen in secondary lymphoid organs. It has since become apparent that large populations of T cells are maintained in tissues, which do not migrate throughout the body and do not require clonal expansion. Murine intraepithelial lymphocytes (IELs), located in the skin and small intestines, are maintained in a state of semi‐activation, in marked contrast to the quiescent condition naive and memory lymphocytes are kept in. The poised activation state of IELs, their location in the top layers of barrier organs and close bidirectional interactions with epithelial cells suggests IELs are part of a sophisticated strategy of immune‐surveillance and compartmentalisation of immune responses. Recent murine studies have reemphasised the influence of metabolism in T‐cell activation and differentiation, with different metabolic make up of naive, effector and memory T cells. Here we highlight and discuss some of the current insights on immunometabolism of IELs, with emphasis on novel data contrasting how IELs may be maintained in a semi‐activated state and may become fully functional compared with conventional T cells.