Dynein cleavage and microtubule accumulation in okadaic acid-treated neurons

Impairment of protein phosphatase 2A (PP2A) activity is implicated in tau hyperphosphorylation and microtubule (MT) instability in Alzheimer's disease (AD). Here, we report that okadaic acid, an effective PP2A inhibitor, suppresses the levels of acetylated and detyrosinated tubulins, but enhances tyrosinated tubulins in rat primary cortical neuron cultures. Immunocytochemistry experiments reveal that MTs accumulate intensely around soma and proximal neurites, implying impairment of MT transport to distal neurites which is mediated by dynein and dynactin. Here, we reveal that they can be cleaved by calpain. Notably, shortening of process length in OA-treated neurons is alleviated when calpain cleavage activity is inhibited. Based on these results, we propose that calpain-mediated dynein cleavage in OA-treated neurons is responsible for the MT transport deficit, and consequently, neurite retraction.     

Serotonin Transporter Gene Promoter Hypomethylation as a Predictor of Antidepressant Treatment Response in Major Depression: A Replication Study

BackgroundThe serotonin transporter gene (SLC6A4; 5-HTT; SERT) is considered a prime candidate in pharmacogenetic research in major depressive disorder (MDD). Besides genetic variation, recent advances have spotlighted the involvement of epigenetic mechanisms such as DNA methylation in predicting antidepressant treatment response in “pharmaco-epigenetic” approaches. In MDD, lower SLC6A4 promoter methylation has been suggested to predict impaired response to serotonergic antidepressants. The present study sought to replicate and extend this finding in a large, independent sample of MDD patients.MethodsThe sample comprised n = 236 Caucasian patients with MDD receiving antidepressant medication in a naturalistic treatment setting. Functional DNA methylation of 9 CpG sites located in the SLC6A4 promoter region was analyzed via direct sequencing of sodium bisulfite– treated DNA extracted from blood cells. Patients were assessed over the course of a 6-week in-patient treatment using the Hamilton Depression Scale (HAM-D).ResultsResults confirm relative SLC6A4 hypomethylation to predict impaired antidepressant response both dimensionally and categorically (HAM-D reductions < 50%) and to furthermore be indicative of nonremission (HAM-D > 7). This also held true in a homogenous subgroup of patients continuously treated with selective serotonin reuptake inhibitors or serotonin/noradrenaline reuptake inhibitors (n = 110).ConclusionsImpaired response to serotonergic antidepressants via SLC6A4 hypomethylation may be conveyed by increased gene expression and consequently decreased serotonin availability, which may counteract the effects of serotonergic antidepressants. The present results could in the future inform clinical decision-making towards a more personalized treatment of MDD.     

Clinical Switching Strategies of Various Antidepressants to Vortioxetine in the PREDDICT Trial

BackgroundPartial response to antidepressant medication as well as relapse and treatment resistance are common in major depressive disorder (MDD). Therefore, for most patients with MDD, there will be a need to consider changing antidepressant medication at some stage during the course of the illness. The PREDDICT study investigates the efficacy of augmenting vortioxetine with celecoxib.MethodsWe describe the method used in the PREDDICT study to change participants, who were already taking antidepressant medication at the time of the screening visit, to vortioxetine. We used a cross-titration to change study participants to vortioxetine.ResultsOf a total of 122 study participants who were randomized to receive vortioxetine plus celecoxib or vortioxetine plus placebo at the study baseline visit, 82 were taking antidepressant medication (other than vortioxetine) prior to randomization. These medications were selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, tricyclic antidepressants, mirtazapine, or agomelatine. Eighty of these 82 participants completed the changeover to vortioxetine as well as the study baseline visit. We found side effects were generally mild during this changeover period. In addition, there was a reduction in mean total Montgomery-Åsberg Depression Rating Scale score of 2.5 (SD 6.0) from study baseline to week 2 and a further reduction in mean total Montgomery-Åsberg Depression Rating Scale of 2.5 (SD 5.9) from week 2 to week 4.ConclusionChanging other antidepressants to vortioxetine can be done safely and was generally well-tolerated. However, there are some antidepressant classes, in particular monoamine oxidase inhibitors that require a washout period, which were not represented in this study.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR); ID number 12617000527369p; http://www.anzctr.org.au/ACTRN12617000527369p.aspx     

COMMON FEMORAL ARTERY FENESTRATION IN THE TREATMENT OF THORACIC AORTIC DISSECTION

SUMMARY Although dissection of the thoracic aorta is a common aortic emergency, little has been written about fenestration procedures to revascularise femoral arteries that have been occluded by dissecting aneurysms arising from as high as the thoracic aorta.     

Postoperative cardiac surgical care: an alternative approach

Combined appropriate anaesthetic and surgical techniques have allowed increasing numbers of patients to be successfully managed in a general surgical recovery ward after cardiac surgery rather than in an intensive care unit. From 1983 to 1989, 933 of 1542 patients undergoing open heart surgery were transferred to the general surgical recovery ward in the immediate postoperative period. Of these, 718 (77%) had undergone coronary artery bypass grafts, sometimes combined with other procedures and 168 (18%) had had cardiac valve replacements with or without other procedures. The remaining 47 (5%) had had miscellaneous cardiac operations. Significant cardiac complications occurred in 29 (3%) patients. The 24 hour chest radiograph was reported as abnormal (mainly atelectasis and effusion) in 63% of patients. Most resolved spontaneously or with physiotherapy. Twenty nine (3%) patients were re-explored to achieve haemostasis. There were no deaths in the general surgical recovery ward. Thirty seven (4%) patients had to be transferred to the intensive care unit for various reasons. The remaining 896 patients were transferred to the general ward after one night (871 patients) or two nights (25 patients) in the general surgical recovery ward. The average duration of stay in hospital for these patients was 9·3 days. Because of the overall success of such management and the low rate of complications over 80% of patients are now managed in the general surgical recovery ward after open heart surgery. The resulting savings in capital expenditure of equipment, medical, nursing, and technical personnel are substantial, and there are major implications for the planning of new cardiothoracic units.     

Patterns of 8-hydroxydeoxyguanosine formation in DNA and indications of oxidative stress in rat and human pleural mesothelial cells after exposure to crocidolite asbestos

Oxidative damage is a proposed mechanism of asbestos-induced carcinogenesis, but the detection of oxidative DNA lesions in target cells of asbestos-induced mesothelioma has not been examined. In studies here, DNA was isolated from both rat pleural mesothelial (RPM) cells and a human mesothelial cell line (MET5A) after exposure in vitro to crocidolite asbestos at various concentrations. DNA was then examined for formation of 8-hydroxydeoxyguanosine (8-OHdG) at 24, 48 and 72 h using HPLC with electrochemical detection. In addition, steady- state mRNA levels of manganese-containing superoxide dismutase (MnSOD) were assessed as an indication of oxidative stress. Whereas RPM cells showed dose-dependent and significant increases in 8-OHdG formation in response to crocidolite asbestos or iron-chelated crocidolite fibers (but not after exposure to glass beads), MET5A cells showed decreases in 8-OHdG. Both cell types exhibited elevations in message levels of MnSOD. In comparison with human MET5A cells, RPM cells exhibited increased cytotoxicity and apoptosis in response to asbestos, as documented by cell viability assays and flow cytometry analysis using propidium iodide. Results in RPM cells indicate that asbestos causes oxidative damage that may result in potentially mutagenic lesions in DNA and/or apoptosis, despite compensatory increases in expression of an antioxidant enzyme.      

Autoantibodies against a kidney-liver protein associated with quinolone-induced acute interstitial nephritis or hepatitis

In the present study we report on four cases of acute interstitial nephritis (AIN) and two cases of hepatitis induced by quinolone. We show by immunoblotting analysis that all sera from these patients contained autoantibodies that recognize a 65-kDa protein expressed in normal human kidney and liver microsomes. Only 6% of sera from healthy individuals who did not ingest quinolone recognized the same protein. These findings suggest that the presence of autoantibodies could be used as a sensitive marker and that a modification of microsomal proteins by quinolone itself or by a metabolite could generate an autoimmune response.     

Night locomotor activity and quality of sleep in quetiapine-treated patients with depression

This research assesses the development of the night-activity rhythm and quality of sleep during course of treatment among patients with unipolar or bipolar depression and receiving antidepressant treatment plus quetiapine. Twenty-seven patients with major depressive episode were included into a 4-week follow-up study and compared with 27 healthy controls. Motor activity was continuously measured with an electronic wrist device (actigraphy), sleep was assessed with the Pittsburgh Sleep Quality Index, and patients were clinically assessed with the Hamilton depression score. All patients received a standard antidepressant treatment plus quetiapine. Whereas we found a rapid and maintaining improvement of subjective sleep parameters during the 4-week study, we observed a rapid improvement of some objective sleep parameters (actigraph) within the first week, but no further significant change of objective sleep parameters during the rest of the study. Another main finding of this study is that changes of subjectively and objectively assessed sleep parameters do not necessarily reflect clinical improvement of depression during the same timeline. Despite partial clinical remission, objective sleep parameters still showed significantly different patterns compared with controls. This study is the first to examine the effect of quetiapine on locomotor activity alongside with sleep in depression. As the studied patients with depression showed improvement in subjective and objective sleep parameters, quetiapine may be a promising drug for patients with depression and insomnia. Further studies need to investigate in detail the timeline of clinical remission and alterations of objective and subjective sleep parameters.