D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia.

BACKGROUND: D-serine, a selective full agonist at the glycine site of N-methyl-D-aspartate glutamate receptor, might presently be the compound of choice for counteracting the hypothesized dysfunction of this receptor class in schizophrenia. Studies performed with Taiwanese patients indicate that D-serine significantly improves schizophrenia symptoms when used as adjuvant to conventional neuroleptics but not to clozapine. We assessed the efficacy and safety of D-serine adjuvant treatment for Occidental schizophrenia patients treated with newer atypical antipsychotics. METHODS: Thirty-nine risperidone- or olanzapine-treated schizophrenia patients participated in a double-blind, placebo-controlled, 6-week crossover trial with 30 mg/kg/day D-serine added to their antipsychotic medication. Measures of clinical efficacy and side effects were determined biweekly throughout the study. Clinical laboratory parameters and amino acid serum levels were monitored. RESULTS: D-serine administration induced increased serine serum levels (p < .001) and resulted in significant (p < .001) improvements in negative, positive, cognitive, and depression symptoms, as measured by the Positive and Negative Syndrome Scale. For approximately one third of the sample, D-serine treatment resulted in significant (>20%) reductions in Brief Psychiatric Rating Scale total scores. D-serine was well tolerated, and no detrimental changes in clinical laboratory parameters were noted. CONCLUSIONS: These findings 1) indicate that risperidone and olanzapine efficacy might be augmented with D-serine adjuvant treatment; 2) confirm D-serine efficacy against main schizophrenia symptom domains; and 3) warrant the assessment of D-serine antipsychotic monotherapy for this illness.     

Evaluation of recombinant human interferon alpha-2b structure and stability by in-gel tryptic digestion, H/D exchange and mass spectrometry

Stability and structure of recombinant interferon alpha-2b (rHuINF alpha-2b) was studied by mass spectrometry (MALDI-TOF and Q-TOF MS), chromatography (LC-UV-FLD-DAD, LC-MS) and CD spectroscopy. Besides analysis of the substance according to Ph. Eur. methods, two additional mass spectrometric methods were developed. The aim of both methods was to estimate structure-stability relationship connected to methionine oxidation or protein degradation. Preservation or degradation of protein structure was confirmed by H/D exchange in four separate experiments. Kinetics of deuterium incorporation into macromolecule was monitored over 2670 min. Isoforms of rHuINF alpha-2b were separated by 2D gel electrophoresis. In-gel digestion with trypsin and mass spectrometric analysis, performed on four separated isoforms at the mass corresponding to the mass of rHuINF alpha-2b with oxidized methionines, confirmed oxidation of all methionines to a different extent. Another four isoforms observed in 2D gel are most likely dimers of the same macromolecules with scrambled disulphide bridges. Oxidation and dimerisation are consequences of protein interaction with oxidizing reagents in polyacrilamide gel.     

Myocardial preconditioning against ischemia-induced apoptosis and necrosis in man

BACKGROUND: Ischemic preconditioning (IPC) protects against apoptosis and necrosis but the contribution of the two forms of cell death and whether the beneficial effects are mediated by similar or different signal transduction pathways remains unclear. Here we have investigated the effect of IPC on the type of cell death in the human heart and whether the inhibition of apoptosis and necrosis by IPC requires the opening of mitoK(ATP) channels and the activation of PKC and p38MAPK. MATERIALS AND METHODS AND RESULTS: Free-hand tissue sections (n = 6/group) obtained from the right atrium of patients at the time of coronary bypass surgery were subjected to 90-min simulated ischemia followed by 120-min reoxygenation (SI/R) with or without IPC (5 min SI/5 min R) prior to SI/R. IPC reduced apoptosis from 30.0 +/- 3.8 to 11.0 +/- 1.5% (P < 0.05) by TUNEL technique and necrosis from 11.6 +/- 2.4 to 4.2 +/- 1.7% (P < 0.05) by propidium iodide staining. When inhibitors of mitoKATP channels (1 mm 5-hydroxydecanoate), PKC (10 microm chelerythrine), and p38MAPK (10 microm SB203580) were added for 10 min before SI, the protection against necrosis was abolished. However, whereas 5-hydroxydecanoate and chelerythrine also abolished the protection of IPC against apoptosis, SB203580 did not. The activation of mitoKATP channels (100 microm diazoxide), PKC (1 microm PMA), and p38MAPK (1 nm anisomycin) were a mirror image of the findings with blockers. CONCLUSIONS: IPC protects the human myocardium against both apoptosis and necrosis. The anti-necrotic effect is mediated by the opening of mitoKATP channels and activation of PKC and p38MAPK; however, the anti-apoptotic effect requires opening of the mitoKATP channels and PKC activation but is p38MAPK-independent.     

Transfusion utilization during adnexal or peritoneal cancer surgery: effects on symptomatic venous thromboembolism and survival

OBJECTIVE: To determine whether perioperative packed red blood cell (PRBC) and fresh frozen plasma (FFP) transfusions during ovarian, tubal, or peritoneal cancer surgery increase the risk of symptomatic postoperative venous thromboembolism (VTE) and adversely affect overall survival. METHODS: We conducted a retrospective review of all cases of surgical exploration for resection of stage IIIC-IV adnexal/peritoneal cancer between November 1998 and May 2002 at Memorial Sloan-Kettering Cancer Center. Patients with a history of prior or active preoperative VTE were excluded. Routine intraoperative and postoperative VTE prophylaxis including lower extremity external pneumatic compression with or without postoperative subcutaneous heparin was utilized in all cases. Symptomatic postoperative VTE was diagnosed by lower extremity Doppler or computerized tomography (excluding cases with only ovarian vein thrombosis). Clinical parameters were examined by a logistic regression analysis to identify independent prognostic predictors of postoperative symptomatic VTE, which occurred within 30 days of surgery. Survival was calculated using the Kaplan-Meier method. RESULTS: In all, 174 patients underwent exploratory surgery, and 6 (3.4%) were excluded due to active or prior history of VTE. Of the remaining 168 patients, 71 (42%) received at least one perioperative transfusion of PRBC or FFP. Postoperative VTE was documented in 5 of 46 (11%) patients who received a postoperative transfusion compared to 3 of 122 (2.5%) patients who did not (P = 0.04; odds ratio, 4.8); moreover, VTE was noted in 3:16 (19%) patients who received postoperative FFP compared to 5:152 (3.3%) patients who did not (P = 0.01, odds ratio of 6.78). Age, stage, body mass index, length of the operation, blood loss, presence of ascites, volume of ascites, residual disease status, preoperative hemoglobin level and coagulation profile were not associated with increased risk for VTE. When survival results were stratified by transfusion utilization and controlling for optimal debulking status, perioperative transfusions had no apparent effect on overall survival. CONCLUSION: In women with stage IIIC-V disease, postoperative blood product transfusions particularly FFP were associated with increased risk of DVT and PE, but transfusions had no impact on overall survival.     

Licht- und elektronenmikroskopische Untersuchungen zur Feinstruktur und Enzymhistochemie der Wurzelzellen im Sulcus externus

Summary By semithin sections (0.5 ) the structure of the whole region behind the external sulcus was examined. The root cells show treelike ramifications with vacuollike channels inside the bigger branches. These vacuollike channels form a bigger channel which presumably runs into the endolymph. The structure of the single cell and of the cell formation supports the assumption of secretory activity of the root cells.     

Delayed preconditioning of the human myocardium: signal transduction and clinical implications

OBJECTIVE: Ischemic preconditioning confers cardioprotection in early and delayed phases. We investigated the delayed window of pharmacological and ischemic preconditioning in human myocardium, and the involvement of mitoKATP, PKC and p38MAPK. METHODS: These studies were carried out using human right atrial tissue in a cell necrosis model. The tissue was obtained from patients undergoing coronary artery surgery. RESULTS: The second window triggered by ischemia, phenylephrine or adenosine resulted in similar cardioprotection between 24 and 72 h following the intervention. Atrial tissue taken from patients with a single episode of angina between 24 and 72 h prior to surgery were already protected and preconditioning with ischemia, phenylephrine or adenosine did not add to the protection. The trigger of preconditioning with mitoKATP channel opener diazoxide, PKC activator PMA and p38MAPK activator anisomycin produced similar delayed protection to that of ischemia or phenylephrine. Cardioprotection was lost when mitoKATP channels were blocked by 5HD, PKC by chelerythrine and p38MAPK by SB203580 24 h after the trigger of preconditioning. CONCLUSIONS: Ischemic and pharmacological preconditioning induce similar delayed cardioprotection of the human heart. This second window of protection that is seen between 24 and 72 h occurs in vitro and in vivo and requires opening of mitoKATP channels and activation of PKC and p38MAPK.