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.     

Human Immune Proteome in Experimental Colonization with Staphylococcus aureus

More than 20% of adults are persistently colonized with Staphylococcus aureus. When hospitalized, these carriers have increased risks of infection with their own strains. However, a recent study demonstrated a lower incidence of bacteremia-related death among carriers than among noncarriers, raising the question whether the adaptive immune system plays a protective role. In fact, S. aureus carriers mount a highly specific neutralizing antibody response against superantigens of their colonizing strains. We now used 2-dimensional immunoblotting to investigate the profiles of antibodies from healthy individuals against S. aureus extracellular proteins. Moreover, we tested whether symptom-free experimental colonization of these individuals with an S. aureus strain of low virulence, 8325-4, is sufficient to induce an antibody response. Sera obtained before and 4 weeks after colonization were screened for immunoglobulin G (IgG) antibody binding to extracellular staphylococcal proteins. At baseline, most volunteers harbored IgG directed against conserved virulence factors, including alpha-hemolysin (Hla), beta-hemolysin (Hlb), phospholipase C (Plc), staphylococcal serine protease (SspA), and cysteine protease (SspB). However, the variability of spot patterns and intensities was striking and could be important in case of infection. Experimental nasal colonization with S. aureus 8325-4 did not elicit new antibodies or boost the humoral response. Thus, the high antibody prevalence in humans is likely not induced by short-term nasal colonization, and presumably minor infections are required to trigger anti-S. aureus antibody responses.Staphylococcus aureus is one of the most common causes of nosocomial infection, and the species is becoming increasingly resistant to antibiotics (2). Apart from being a major human pathogen, S. aureus is also a frequent colonizer of human skin and mucosa (34). The bacteria find their primary ecological niche in the human nose but are also able to colonize the throat, the intestines, and the perineal region, sometimes exclusively (1, 17). Approximately 20% of the adult population carry S. aureus in the nose persistently, and another 30% carry it intermittently, frequently only for a few days, whereas 50% are noncarriers (NC) (29, 30, 34). Nasal carriers stand an increased risk of developing severe S. aureus infections caused by their autologous strains, especially upon hospitalization or immune suppression (32, 35). This underlines the fact that host and environmental factors play a decisive role in determining the outcome of S. aureus host interactions.In a recent large prospective study, carriers acquired S. aureus bacteremia more frequently than NC but, surprisingly, had a better survival rate than NC (35). This observation raises the question whether the adaptive immune system establishes immunity to the colonizing S. aureus strain, which could be of advantage in autologous infections. In support of this hypothesis, our group recently showed that S. aureus carriers raise a strong and strain-specific antibody response against the superantigen cocktail produced by their colonizing strain (12). However, S. aureus produces a broad repertoire of virulence factors, and the antibody response against superantigens is likely only the tip of an iceberg (8). In fact, anti-S. aureus antibodies against staphylococcal toxins, immune evasion molecules, and adhesins have been detected in healthy individuals as well as in patients (6, 7, 11, 31).Virulence factor expression is strictly regulated in S. aureus. While adhesins are expressed by bacterial cells in logarithmic growth, the majority of known virulence factors, including most superantigens but also cytolytic toxins, proteases, lipases, and several immune evasion molecules, are secreted in the post-exponential-growth phase (23, 38). In contrast to intracellular and cell wall-associated proteins, secreted virulence factors can act systemically while bacteria remain localized. Consequently, these factors are the most likely stimuli of the adaptive immune system during epithelial colonization with S. aureus (28).To date, a comprehensive investigation of anti-S. aureus antibody profiles from healthy individuals and their variability is still lacking. Moreover, it remains unknown which conditions (e.g., nasal colonization, minor or major infections) are required to trigger an antibody response against S. aureus. Therefore, we experimentally colonized the nares of 16 healthy human volunteers with S. aureus (36) and compared the anti-S. aureus antibody profiles before and 28 days after colonization. Our aims were to analyze the variability of the anti-S. aureus antibody profiles and to test whether experimental nasal colonization elicits or boosts an antibody response.     

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.     

Predictors of colonization with <Emphasis Type="Italic">Staphylococcus species</Emphasis> among patients scheduled for cardiac and orthopedic interventions at tertiary care hospitals in north-eastern Germany—a prevalence screening study

As methicillin-resistant Staphylococcus aureus (MRSA) colonization and infection in humans are a global challenge. In Mecklenburg and Western Pomerania (Germany) 1,517 patients who underwent surgical interventions were systematically screened for MRSA and MSSA colonization on the day of hospital admission and discharge. Demographic data, risk factors and colonization status of the (i) nose, (ii) throat, (iii) groin, and (iv) thorax or site of surgical intervention were determined. Of the 1,433 patients who were included for further evaluation, 331 (23.1%) were colonized with MSSA, while only 17 (1.2%) were MRSA carriers on the day of hospital admission. A combination of nose, throat and groin swabs returned a detection rate of 98.3% for MSSA/MRSA. Trauma patients had lower prevalence of MRSA/MSSA (OR 0.524, 95% CI: 0.37–0.75; p?<?0.001) than patients with intended orthopedic interventions. Males showed significantly higher nasal S. aureus carrier rates than females (odds ratio (OR)?=?1.478; 95% CI: 1.14–1.92; p?=?0.003). Nasal S. aureus colonization was less frequent among male smokers as compared to non-smokers (chi²?=?16.801; phi?=?0.154; p?<?0.001). Age, gender and smoking had a significant influence on S. aureus colonization. Combining at least three different swabbing sites should be considered for standard screening procedure to determine S. aureus colonization at patients scheduled for cardiac or orthopedic interventions at tertiary care hospitals.