The atypical antidepressant tianeptine confers neuroprotection against oxygen-glucose deprivation.

Proregenerative and neuroprotective effects of antidepressants are an important topic of inquiry in neuropsychiatric research. Oxygen-glucose deprivation (OGD) mimics key aspects of ischemic injury in vitro. Here, we studied the effects of 24-h pretreatment with serotonin (5-HT), citalopram (CIT), fluoxetine (FLU), and tianeptine (TIA) on primary mouse cortical neurons subjected to transient OGD. 5-HT (50 µM) significantly enhanced neuron viability as measured by MTT assay and reduced cell death and LDH release. CIT (10 µM) and FLU (1 µM) did not increase the effects of 5-HT and neither antidepressant conferred neuroprotection in the absence of supplemental 5-HT in serum-free cell culture medium. By contrast, pre-treatment with TIA (10 µM) resulted in robust neuroprotection, even in the absence of 5-HT. Furthermore, TIA inhibited mRNA transcription of candidate genes related to cell death and hypoxia and attenuated lipid peroxidation, a hallmark of neuronal injury. Finally, deep RNA sequencing of primary neurons subjected to OGD demonstrated that OGD induces many pathways relating to cell survival, the inflammation-immune response, synaptic dysregulation and apoptosis, and that TIA pretreatment counteracted these effects of OGD. In conclusion, this study highlights the comparative strength of the 5-HT independent neuroprotective effects of TIA and identifies the molecular pathways involved.

Altered immune environment in peritoneal endometriotic lesions: relationship to lesion appearance.

OBJECTIVE: To study the localization of and quantify different immune cell populations in red, black, and white peritoneal endometriotic lesions and compare immune cell densities between lesions and the surrounding tissue. DESIGN: Cross-sectional study. SETTING: Teaching hospital, university research laboratory. PATIENT(S): Participants undergoing laparoscopic excision of endometriosis were recruited from gynecological operating theaters at Royal Prince Alfred Hospital, Sydney (n = 28). INTERVENTION(S): Immunohistochemical staining for and quantification of dendritic cells (mature and immature), T cells (effector, cytotoxic, and regulatory), B cells, and macrophages in endometriotic peritoneal lesions and the surrounding tissue. MAIN OUTCOME MEASURE(S): Immune cell densities and aggregates were quantified. RESULT(S): Red and black lesions are significantly more likely to be surrounded by immune cell aggregates than white lesions (P=.036). In the tissue surrounding the peritoneal endometriotic lesions, there was a consistent pattern of greater and more variable density of immune cell populations for red lesions than black or white lesions and a range of significant positive correlations between densities of different immune populations (all P≤.004; not observed within the lesion stroma). CONCLUSION(S): There is a greater presence of immune cells in the tissue surrounding earlier/red and black lesions than older scarred white lesions, particularly in the form of immune cell aggregates, indicating an immunologic response in close proximity to the adjacent lesion. The relationship between densities of immune populations in the tissue surrounding the lesions suggests complementary recruitment and local interactions between cells. Categorizing immune cell populations in proximity to peritoneal endometriotic lesions may improve the understanding of lesion persistence and transition to older white appearances. Early (red) peritoneal endometriotic lesions are surrounded by a greater density of immune cells, including immune aggregates, than later (black or white) lesions. These immune cells may support lesion persistence.

Deletion of muscarinic acetylcholine receptor 3 in microglia impacts brain ischemic injury.

Microglia are the immune cells of the brain and become activated during any type of brain injury. In the middle cerebral artery occlusion (MCAo) model, a mouse model for ischemic stroke, we have previously shown that microglia and invaded monocytes upregulate the expression of the muscarinic acetylcholine receptor 3 (M3R) in the ischemic lesion. Here we tested whether this upregulation has an impact on the pathogenesis of MCAo. We depleted the m3R receptor in microglia, but not in circulating monocytes by giving tamoxifen to CX3CR1-CreERT+/+M3Rflox/flox (M3RKOmi) animals 3 weeks prior to MCAo. We found that M3RKOmi male mice had bigger lesions, more pronounced motor deficits after one week and cognitive deficits after about one month compared to control males. The density of Iba1+ cells was lower in the lesions of M3RKO male mice in the early, but not in the late disease phase. In females, these differences were not significant. By giving tamoxifen 1 week prior to MCAo, we depleted m3R in microglia and in circulating monocytes (M3RKOmi/mo). Male M3RKOmi/mo did not differ in lesion size, but had a lower survival rate, showed motor deficits and a reduced accumulation of Iba1+ positive cells into the lesion site. In conclusion, our data suggest that the upregulation of m3R in microglia and monocytes in stroke has a beneficial effect on the clinical outcome in male mice.

Endothelial Cell-Specific Transcriptome Reveals Signature of Chronic Stress Related to Worse Outcome After Mild Transient Brain Ischemia in Mice.

Vascular mechanisms underlying the adverse effects that depression and stress-related mental disorders have on stroke outcome are only partially understood. Identifying the transcriptomic signature of chronic stress in endothelium harvested from the ischemic brain is an important step towards elucidating the biological processes involved. Here, we subjected male 129S6/SvEv mice to a 28-day model of chronic stress. The ischemic lesion was quantified after 30 min filamentous middle cerebral artery occlusion (MCAo) and 48 h reperfusion by T2-weighted MRI. RNA sequencing was used to profile transcriptomic changes in cerebrovascular endothelial cells (ECs) from the infarct. Mice subjected to the stress procedure displayed reduced weight gain, increased adrenal gland weight, and increased hypothalamic FKBP5 mRNA and protein expression. Chronic stress conferred increased lesion volume upon MCAo. Stress-exposed mice showed a higher number of differentially expressed genes between ECs isolated from the ipsilateral and contralateral hemisphere than control mice. The genes in question are enriched for roles in biological processes closely linked to endothelial proliferation and neoangiogenesis. MicroRNA-34a was associated with nine of the top 10 biological process Gene Ontology terms selectively enriched in ECs from stressed mice. Moreover, expression of mature miR-34a-5p and miR-34a-3p in ischemic brain tissue was positively related to infarct size and negatively related to sirtuin 1 (Sirt1) mRNA transcription. In conclusion, this study represents the first EC-specific transcriptomic analysis of chronic stress in brain ischemia. The stress signature uncovered relates to worse stroke outcome and is directly relevant to endothelial mechanisms in the pathogenesis of stroke.

Determination of Factors Affecting Physical Activity Status of University Students on a Health Sciences Campus.

Upon graduation, students studying in departments related to health will work in the health sector and will guide and enlighten people with their knowledge and behavior. The purpose of this study was to determine the factors affecting the physical activity (PA) conditions of university students on a health sciences campus. A cross-sectional study was carried out on 706 students in a Turkish university. The data was obtained from a survey prepared by the researchers. The 26-question survey aimed to discover the students' socio-demographic characteristics and their awareness and practices concerning PA. We found that 30% of the students engage in some type of PA during their university education. A relationship was observed concerning their current PA and their family inactivity levels, as well as between inactivity before entering the university and inactivity during their education. The presence of a chronic disease in family members does not affect student PA. A majority of the students believe PA is beneficial (98.7%), 93.9% believe it relieves stress, and 94.5% believe it helps control body weight. Although students of medicine and related disciplines are aware of the importance of proper diet and adequate levels of PA in health, they did not implement theory into practice. Thus, it is questionable how young health professionals will promote the positive effects and necessity of regular physical activity if they do not apply these activities to their own lifestyle.

[The frequency of embolic risk factors and adequacy of anti-embolic treatment in patients with atrial fibrillation: a single tertiary center experience]. / Atriyal fibrilasyon hastalarinda emboli risk faktörleri sikligi ve emboli önleyici tedavilerin uygunlugunun arastirilmasi: Tek üçüncül bir merkez deneyimi.

OBJECTIVE: Though atrial fibrillation (AF) is the most common sustained arrhythmia permanently; there is not enough data about the prevalence, frequency of risk factors, and adequacy of anticoagulant therapy. We aimed to investigate the prevalence of AF, the frequency of risk factors, adequacy of anticoagulant therapy in patients who were admitted to our outpatient tertiary cardiology clinic according to current guidelines. METHODS: Patients, admitted to our Cardiology outpatient clinic between January - June 2010 and had a history of AF were included to the study retrospectively. Patients' demographic findings, clinical AF classification, CHA2DS2VASC scores, treatments the measured INR values in last 12 months retrospectively and the success of anticoagulant therapy were evaluated. RESULTS: Overall, 432 (9.1%) of 4721 patients had AF. Among them 253 (58.5%) patients were female, mean age was 70.4 years. Permanent AF was the most common type. The most common risk factor was hypertension (71.9%). CHA2DS2VASC score was ≥ 2 in 377 patients (87.2%) and 254 (67.3%) of those patients had absolutely indicated for anticoagulation therapy, were taking warfarin. Sixteen of 37 patients with one risk factor, and 10 of 18 patients without risk factors were also receiving warfarin. Although warfarin was indicated in 123 patients, 36 patients had contraindications, 13 patients refused anticoagulation, and warfarin was stopped in 5 patients because of noncompliance with treatment. 15.9% of patients were not on warfarin although anticoagulation was indicated and no contraindication. 83.5% patients INR levels were between therapeutic ranges. CONCLUSION: Anticoagulation is applied successfully among an important part of AF patients in our tertiary center, but in a substantial group of patients the guidelines are still not implemented. New, cost-effective, safe, accessible treatments are needed for warfarin contraindicated patients.