IFIH1 (MDA5) is required for innate immune detection of intron-containing RNA expressed from the HIV-1 provirus.

Intron-containing RNA expressed from the HIV-1 provirus activates type 1 interferon in primary human blood cells, including CD4+ T cells, macrophages, and dendritic cells. To identify the innate immune receptor required for detection of intron-containing RNA expressed from the HIV-1 provirus, a loss-of-function screen was performed with short hairpin RNA-expressing lentivectors targeting twenty-one candidate genes in human monocyte-derived dendritic cells. Among the candidate genes tested, only knockdown of XPO1 (CRM1), IFIH1 (MDA5), or MAVS prevented activation of the interferon-stimulated gene ISG15. The importance of IFIH1 protein was demonstrated by rescue of the knockdown with nontargetable IFIH1 coding sequence. Inhibition of HIV-1-induced ISG15 by the IFIH1-specific Nipah virus V protein, and by IFIH1-transdominant 2-CARD domain-deletion or phosphomimetic point mutations, indicates that IFIH1 (MDA5) filament formation, dephosphorylation, and association with MAVS are all required for innate immune activation in response to HIV-1 transduction. Since both IFIH1 (MDA5) and DDX58 (RIG-I) signal via MAVS, the specificity of HIV-1 RNA detection by IFIH1 was demonstrated by the fact that DDX58 knockdown had no effect on activation. RNA-Seq showed that IFIH1 knockdown in dendritic cells globally disrupted the induction of IFN-stimulated genes by HIV-1. Finally, specific enrichment of unspliced HIV-1 RNA by IFIH1 (MDA5), over two orders of magnitude, was revealed by formaldehyde cross-linking immunoprecipitation (f-CLIP). These results demonstrate that IFIH1 is the innate immune receptor for intron-containing RNA from the HIV-1 provirus and that IFIH1 potentially contributes to chronic inflammation in people living with HIV-1, even in the presence of effective antiretroviral therapy.

IFIH1 (MDA5) is required for innate immune detection of intron-containing RNA expressed from the HIV-1 provirus.

Antiretroviral therapy (ART) suppresses HIV-1 viremia and prevents progression to AIDS. Nonetheless, chronic inflammation is a common problem for people living with HIV-1 on ART. One possible cause of inflammation is ongoing transcription from HIV-1 proviruses, whether or not the sequences are competent for replication. Previous work has shown that intron-containing RNA expressed from the HIV-1 provirus in primary human blood cells, including CD4+ T cells, macrophages, and dendritic cells, activates type 1 interferon. This activation required HIV-1 rev and was blocked by the XPO1 (CRM1)-inhibitor leptomycin. To identify the innate immune receptor required for detection of intron-containing RNA expressed from the HIV-1 provirus, a loss-of-function screen was performed with shRNA-expressing lentivectors targeting twenty-one candidate genes in human monocyte derived dendritic cells. Among the candidate genes tested, only knockdown of XPO1 (CRM1), IFIH1 (MDA5), or MAVS prevented activation of the IFN-stimulated gene ISG15. The importance of IFIH1 protein was demonstrated by rescue of the knockdown with non-targetable IFIH1 coding sequence. Inhibition of HIV-1-induced ISG15 by the IFIH1-specific Nipah virus V protein, and by IFIH1-transdominant inhibitory CARD-deletion or phosphomimetic point mutations, indicates that IFIH1 filament formation, dephosphorylation, and association with MAVS, are all required for innate immune activation in response to HIV-1 transduction. Since both IFIH1 and DDX58 (RIG-I) signal via MAVS, the specificity of HIV-1 RNA detection by IFIH1 was demonstrated by the fact that DDX58 knockdown had no effect on activation. RNA-Seq showed that IFIH1-knockdown in dendritic cells globally disrupted the induction of IFN-stimulated genes. Finally, specific enrichment of unspliced HIV-1 RNA by IFIH1 was revealed by formaldehyde crosslinking immunoprecipitation (f-CLIP). These results demonstrate that IFIH1 is required for innate immune activation by intron-containing RNA from the HIV-1 provirus, and potentially contributes to chronic inflammation in people living with HIV-1.

The HIV-1 capsid core is an opportunistic nuclear import receptor.

The movement of viruses and other large macromolecular cargo through nuclear pore complexes (NPCs) is poorly understood. The human immunodeficiency virus type 1 (HIV-1) provides an attractive model to interrogate this process. HIV-1 capsid (CA), the chief structural component of the viral core, is a critical determinant in nuclear transport of the virus. HIV-1 interactions with NPCs are dependent on CA, which makes direct contact with nucleoporins (Nups). Here we identify Nup35, Nup153, and POM121 to coordinately support HIV-1 nuclear entry. For Nup35 and POM121, this dependence was dependent cyclophilin A (CypA) interaction with CA. Mutation of CA or removal of soluble host factors changed the interaction with the NPC. Nup35 and POM121 make direct interactions with HIV-1 CA via regions containing phenylalanine glycine motifs (FG-motifs). Collectively, these findings provide additional evidence that the HIV-1 CA core functions as a macromolecular nuclear transport receptor (NTR) that exploits soluble host factors to modulate NPC requirements during nuclear invasion.

Coexisting Coronary and Carotid Artery Disease: What We Did, What Happened

ABSTRACT Introduction: There is no complete consensus on the three surgical methods and long-term consequences for coexisting coronary and carotid artery disease. We retrospectively evaluated the surgical results in this high-risk group in our clinic for a decade. Methods: Between 2005 and 2015, 196 patients were treated for combined carotid and coronary artery disease. A total of 50 patients were operated on with the staged method, 40 of which had carotid endarterectomy (CEA) priority, and 10 had coronary artery bypass grafting (CABG) priority. CABG and CEA were simultaneously performed in 82 patients; and in 64 asymptomatic patients with unilateral carotid artery lesions and stenosis over 70%, only CABG was done (64 patients). Results were evaluated by uni-/multivariate analyses for perioperative, early, and late postoperative data. Results: In the staged group, interval between the operations was 2.82±0.74 months. Perioperative and early postoperative (30 days) parameters did not differ between groups (P-value < 0.05). Postoperative follow-up time was averaged 94.9±38.3 months. Postoperative events were examined in three groups as (A) deaths (all cause), (B) cardiovascular events (non-fatal myocardial infarction, recurrent angina, congestive heart failure, palpitation), and (C) fatal neurological events (amaurosis fugax, transient ischemic attack, and stroke). When group C events were excluded, event-free actuarial survival rates were similar in all three methods (P=0.740). Actuarial survival rate was significantly different when all events were included (P=0.027). Neurological events increased markedly between months 34 and 66 (P=0.004). Conclusion: Perioperative and early postoperative event-free survival rates were similar in all three methods. By the beginning of the 34th month, the only CABG group has been negatively separated due to neurological events. In the choice of methodology, "most threatened organ priority'' was considered as clinical parameter.

Coexisting Coronary and Carotid Artery Disease: What We Did, What Happened.

INTRODUCTION: There is no complete consensus on the three surgical methods and long-term consequences for coexisting coronary and carotid artery disease. We retrospectively evaluated the surgical results in this high-risk group in our clinic for a decade. METHODS: Between 2005 and 2015, 196 patients were treated for combined carotid and coronary artery disease. A total of 50 patients were operated on with the staged method, 40 of which had carotid endarterectomy (CEA) priority, and 10 had coronary artery bypass grafting (CABG) priority. CABG and CEA were simultaneously performed in 82 patients; and in 64 asymptomatic patients with unilateral carotid artery lesions and stenosis over 70%, only CABG was done (64 patients). Results were evaluated by uni-/multivariate analyses for perioperative, early, and late postoperative data. RESULTS: In the staged group, interval between the operations was 2.82±0.74 months. Perioperative and early postoperative (30 days) parameters did not differ between groups (P-value < 0.05). Postoperative follow-up time was averaged 94.9±38.3 months. Postoperative events were examined in three groups as (A) deaths (all cause), (B) cardiovascular events (non-fatal myocardial infarction, recurrent angina, congestive heart failure, palpitation), and (C) fatal neurological events (amaurosis fugax, transient ischemic attack, and stroke). When group C events were excluded, event-free actuarial survival rates were similar in all three methods (P=0.740). Actuarial survival rate was significantly different when all events were included (P=0.027). Neurological events increased markedly between months 34 and 66 (P=0.004). CONCLUSION: Perioperative and early postoperative event-free survival rates were similar in all three methods. By the beginning of the 34th month, the only CABG group has been negatively separated due to neurological events. In the choice of methodology, "most threatened organ priority'' was considered as clinical parameter.

Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution.

3' untranslated region (3'UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the massively parallel reporter assay for 3'UTRs (MPRAu) to sensitively assay 12,173 3'UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3'UTR function, suggesting that simple sequences predominately explain 3'UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base pair resolution, including an adenylate-uridylate (AU)-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3'UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14 and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.

Influence of Different Glycoproteins and of the Virion Core on SERINC5 Antiviral Activity.

Host plasma membrane protein SERINC5 is incorporated into budding retrovirus particles where it blocks subsequent entry into susceptible target cells. Three structurally unrelated proteins encoded by diverse retroviruses, human immunodeficiency virus type 1 (HIV-1) Nef, equine infectious anemia virus (EIAV) S2, and ecotropic murine leukemia virus (MLV) GlycoGag, disrupt SERINC5 antiviral activity by redirecting SERINC5 from the site of virion assembly on the plasma membrane to an internal RAB7+ endosomal compartment. Pseudotyping retroviruses with particular glycoproteins, e.g., vesicular stomatitis virus glycoprotein (VSV G), renders the infectivity of particles resistant to inhibition by virion-associated SERINC5. To better understand viral determinants for SERINC5-sensitivity, the effect of SERINC5 was assessed using HIV-1, MLV, and Mason-Pfizer monkey virus (M-PMV) virion cores, pseudotyped with glycoproteins from Arenavirus, Coronavirus, Filovirus, Rhabdovirus, Paramyxovirus, and Orthomyxovirus genera. SERINC5 restricted virions pseudotyped with glycoproteins from several retroviruses, an orthomyxovirus, a rhabdovirus, a paramyxovirus, and an arenavirus. Infectivity of particles pseudotyped with HIV-1, amphotropic-MLV (A-MLV), or influenza A virus (IAV) glycoproteins, was decreased by SERINC5, whether the core was provided by HIV-1, MLV, or M-PMV. In contrast, particles pseudotyped with glycoproteins from M-PMV, parainfluenza virus 5 (PIV5), or rabies virus (RABV) were sensitive to SERINC5, but only with particular retroviral cores. Resistance to SERINC5 did not correlate with reduced SERINC5 incorporation into particles, route of viral entry, or absolute infectivity of the pseudotyped virions. These findings indicate that some non-retroviruses may be sensitive to SERINC5 and that, in addition to the viral glycoprotein, the retroviral core influences sensitivity to SERINC5.

AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma.

The STING and absent in melanoma 2 (AIM2) pathways are activated by the presence of cytosolic DNA, and STING agonists enhance immunotherapeutic responses. Here, we show that dendritic cell (DC) expression of AIM2 within human melanoma correlates with poor prognosis and, in contrast to STING, AIM2 exerts an immunosuppressive effect within the melanoma microenvironment. Vaccination with AIM2-deficient DCs improves the efficacy of both adoptive T cell therapy and anti-PD-1 immunotherapy for "cold tumors," which exhibit poor therapeutic responses. This effect did not depend on prolonged survival of vaccinated DCs, but on tumor-derived DNA that activates STING-dependent type I IFN secretion and subsequent production of CXCL10 to recruit CD8+ T cells. Additionally, loss of AIM2-dependent IL-1ß and IL-18 processing enhanced the treatment response further by limiting the recruitment of regulatory T cells. Finally, AIM2 siRNA-treated mouse DCs in vivo and human DCs in vitro enhanced similar anti-tumor immune responses. Thus, targeting AIM2 in tumor-infiltrating DCs is a promising new treatment strategy for melanoma.

Protective effect of cabergoline on mitochondrial oxidative stress-induced apoptosis is mediated by modulations of TRPM2 in neutrophils of patients with endometriosis.

Calcium ion (Ca2+) signaling in endometriosis (ENDO) is associated with increased neutrophil activation and oxidative stress. A Ca2+ signaling modulator and antioxidant actions of cabergoline (CBG) in some cells were recently reported. TRPM2 cation channel is activated by reactive oxygen species (ROS). Antioxidant action of CGB via inhibition of ROS may modulate the channel. We aimed to investigate the effect of CBG on TRPM2 inhibition in serum and neutrophils of patients with ENDO. The serum and neutrophil samples were grouped into healthy samples (no treatment), ENDO and ENDO + CBG treated groups (n = 10 in each). In some experiments, the neutrophils were also incubated with TRPM2 (ACA) and PARP-1 (PJ34) blockers. The values of intracellular ROS, Ca2+ concentration, mitochondrial membrane depolarization, lipid peroxidation, apoptosis, and caspase - 3, caspase - 9, PARP-1 and TRPM2 expressions were high in the neutrophils of patients with ENDO, although antioxidant levels (reduced glutathione, glutathione peroxidase, vitamin A, and vitamin E) were low in the neutrophils and serum from these patients. However, markers for apoptosis, oxidative stress, and mitochondrial dysfunction were reduced with CBG, ACA and PJ34 treatments, although the antioxidant levels were increased in the serum and neutrophils following treatment with CBG. Taken together, our current results suggest that CBG are useful antagonists against apoptosis and mitochondrial oxidative stress via inhibition of TRPM2 in neutrophils of patients with ENDO.

Surgical risk assessment for gynecological oncologic patients.

OBJECTIVE: Preoperative surgical risk assessment is important in terms of postoperative morbidity and mortality. Therefore, it is necessary to evaluate the efficacy and safety of these surgeries via an ideal risk assessment model, and reduce risks via applying some findings (for instance, perioperative beta-blockers). There are some risk assessment systems, but these have generally not been verified for patients with gynecologic cancer. The aim of this study was to assess the risk of surgery for gynecological oncologic patients and suggest an easy risk assessment model and risk reduction by applying our findings. MATERIALS AND METHODS: We retrospectively analyzed 258 gynecologic patients with cancer. Age, diagnosis, staging, performance scale, metoprolol use, heart, renal diabetes, Chronic Obstructive Pulmonary disease, diabetes, operation type and length, carcinoma antigen 125, ascites, albumin, surgical procedure, hospitalization length, and complications were recorded. RESULTS: Of the 258 patients, 173 patients (67.1%) had no complications, 43 patients (16.7%) had one and 42 patients (16.3%) had two or more complications. The most common complication was the acid-base imbalance (14%), followed by urinary tract infection (9.7%). Parameters associated with complications were performance status, ascites, operating length, metoprolol use, and upper abdominal surgery. In our proposed scoring model with a total score range 0-23, cut-off value points for both the presence and rate of complications was found as >5. CONCLUSION: In gynecological patients with cancer, the addition of metoprolol use and upper abdominal surgery within preoperative risk assessment evaluation parameters are significantly effective in predicting the rate and severity of complications. Moreover, we have suggested a simple, practical, and convenient scoring model for this evaluation.

Effect of using magnifying loupe glasses on lymphocele formation and surgical outcomes in gynecologic oncology.

OBJECTIVE: To investigate the effect of using magnifying loupes during surgery on surgical outcomes and lymphocele formation. MATERIALS AND METHODS: We prospectively enrolled 36 patients with gynecologic cancer who underwent pelvic and para-aortic lymphadenectomy. Age, body mass index, menopausal status, type of cancer, comorbid diseases, preoperative albumin and albumin replacement therapy, performance status, serum CA125, hemoglobin, platelets and white blood cells, surgical procedure, blood loss, blood transfusion, the count of removed lymph nodes, presence of metastatic lymph nodes, total amount of drainage, postoperative complications, operation length, and count of used hemoclips were recorded. Patients were randomized into two groups: group 1 operated using loupe glasses, and group 2, without loupes. RESULTS: In the loupe-negative group, total drainage volume was 6698 mL, whereas in the loupe-positive group, it was only 1049 mL (p<0.01). Postoperatively, the mean drainage duration was 10.6±5.1 days in loupe-negative group and 4.8±2.4 days in the loupe-positive group (p=0.0001). There were no differences between the two groups in terms of surgical site infections, fascial defects, and pulmonary thromboembolism (p=0.39, 0.33, 0.59, respectively). There was no significant difference in the number of harvested lymph nodes in patients who underwent surgery with or without loupes being used. The count of used hemoclips were 50.22±8.05 and 41.38±9.7 for the loupe-negative and positive groups, respectively (p<0.01). There was no lymphocele in the loupe-positive group, but we detected 5 (27.8%) lymphocele in the loupe-negative group (p=0.05). CONCLUSION: Gynecologic oncologic surgeons can add magnifying loupe glasses to their armament and benefit from this technical device; lymphocele development, total drainage volume, length of drainage time, and clip counts can be decreased by using loupe glasses in gynecologic cancer surgery.

Primate immunodeficiency virus proteins Vpx and Vpr counteract transcriptional repression of proviruses by the HUSH complex.

Host factors that silence provirus transcription in CD4+ memory T cells help HIV-1 escape eradication by the host immune system and by antiviral drugs1. These same factors, however, must be overcome for HIV-1 to propagate. Here we show that Vpx and Vpr encoded by diverse primate immunodeficiency viruses activate provirus transcription. Vpx and Vpr are adaptor proteins for the DCAF1-CUL4A/B E3 ubiquitin ligase that degrade SAMHD1 and increase reverse transcription2-4. Nonetheless, Vpx and Vpr have effects on reporter gene expression that are not explained by SAMHD1 degradation5-8. A screen for factors that mimic these effects identified the human silencing hub (HUSH) complex, FAM208A (TASOR/RAP140), MPHOSPH8 (MPP8), PPHLN1 (PERIPHILIN) and MORC29-13. Vpx associated with the HUSH complex and decreased steady-state level of these proteins in a DCAF1/CUL4A/B/proteasome-dependent manner14,15. Replication kinetics of HIV-1 and SIVMAC was accelerated to a similar extent by vpx or FAM208A knockdown. Finally, vpx increased steady-state levels of LINE-1 ORF1p, as previously described for FAM208A disruption11. These results demonstrate that the HUSH complex represses primate immunodeficiency virus transcription, and that, to counteract this restriction, viral Vpx or Vpr proteins degrade the HUSH complex.

Premenstrual syndrome and fibromyalgia: the frequency of the coexistence and their effects on quality of life.

OBJECTIVE: We aimed to investigate the association between Premenstrual syndrome (PMS) and fibromyalgia syndrome (FMS), to assess common symptoms and quality of life (QOL) of them. METHODS: Patients with PMS formed the PMS group and age-matched healthy normal controls were included in the control group. The diagnosis of the FMS and PMS were based on new American College of Rheumatology FMS criteria and DSM-IV PMS criteria. FMS-related symptoms assessed by visual analog scale and number of tender points (TePs) were analyzed. QOL, PMS severity and FMS severity were assessed with SF-36, fibromyalgia impact questionnaire (FIQ) and premenstrual assessment form (PAF), respectively. Patients with PMS were divided into two subgroups according to coexistence of FMS or not. RESULTS: The frequency of FMS in PMS and control group were 20 and 0%, respectively (p = 0.002). FMS-related symptoms, number of TePs in the PMS group were higher than those in the control group. The mean mental component summary (MCS) score of SF-36 was low in the PMS group. The mean PAF score in PMS with FMS subgroup was higher than those in without FMS subgroup. The mean physical component summary of SF-36 was low in the PMS patient with FMS. There was correlation between PAF score and FIQ score (r = 0.476, p < 0.001). CONCLUSION: FMS was common among the patients with PMS and frequently seen in the PMS patients having severe premenstrual complaints. Mental QOL was distressed in the patients with PMS but while FMS accompanied to PMS, the physical QOL was decreased.

Non-steroidal anti-inflammatory drug modulates oxidative stress and calcium ion levels in the neutrophils of patients with primary dysmenorrhea.

Primary dysmenorrhea is a common inflammatory disease with an uncertain pathogenesis, although one consistent finding is increased neutrophil activity. We aimed to investigate the effects of a non-steroidal anti-inflammatory drug (NSAID) on oxidative stress and Ca²âº levels in neutrophils from patients with primary dysmenorrhea. Blood samples were obtained for neutrophil isolation from six female patients with primary dysmenorrhea (patients) and six healthy female subjects. The NSAID (diclofenac) was taken daily by the patient group for 6 weeks before a second blood sample was taken. Neutrophils isolated after diclofenac treatment were investigated in three settings: (1) after incubation with verapamil and diltiazem (V+D), (2) after incubation with 2-aminoethoxydiphenyl borate (2-APB), and (3) with neither exposure. Neutrophil lipid peroxidation and stimulated intracellular Ca²âº levels were higher in the patients than in the controls, although their levels were reduced after six weeks of treatment with diclofenac. Ca²âº levels from neutrophils obtained after diclofenac treatment were further decreased after incubation with V+D or 2-APB, compared with those exposed to neither agent. Neutrophil glutathione peroxidase and total antioxidant status were lower in the patients than in the controls and higher post-treatment with diclofenac. Reduced glutathione levels were similar in the control, patient, and treatment groups. In conclusion, we observed the importance of Ca²âº influx into the neutrophils and oxidative stress in the pathogenesis of the patients with primary dysmenorrhea. The NSAID diclofenac appeared to provide a protective effect against oxidative stress and Ca²âº entry through modulation of neutrophil VGCC and TRP calcium channels.

Comparison of the effects of laparoscopic bipolar electrocoagulation and intracorporeal suture application to ovarian reserve in benign ovarian cysts.

PURPOSE: Aim of the present study is to determine the effects of bipolar electrocoagulation and intracorporeal suture on the ovarian reserve after ovarian cystectomy. METHODS: Sixty patients aged 18-42 years old and with a persistent adnexal mass were recruited to the study. Patients were randomized into suture hemostasis group or bipolar hemostasis group. Laparoscopic ovarian cystectomy was performed to all patients. Hemostasis was obtained by bipolar coagulation in 30 patients and by intracorporeal sutures in 30 patients. Serum levels of FSH, LH, estradiol, inhibin B and ultrasonographic measurements (antral follicle count and ovarian volume) were analyzed and recorded at day 3 of menstrual cycle, 1 and 3 months after the surgery. RESULTS: Basal FSH level measurement at the postoperative third month was significantly increased to 6.96 ± 1.86 mIU/ml (p < 0.05) in the bipolar electrocoagulation group. However, the decreased ovarian volume and antral follicle count was restored at the postoperative third month in the bipolar electrocoagulation group. Preoperative and postoperative FSH, LH, estradiol and inhibin B levels and ultrasonographic measurements were similar in the intracorporeal suture group. CONCLUSION: The unwanted effect of bipolar electrocoagulation on ovarian reserve is probably transient and causes minimal damage to ovary. FSH levels may be slightly elevated. Gentle use of bipolar electrocoagulation or intracorporeal are not found to effect ovarian reserve.

Intramedullary hydatid cyst of the cervical spine.

Hydatid disease (Echinococcosis) is a common parasitic infection caused by Echinococcus granulosus mainly in sheep-raising areas of the world. Liver, lungs and brain are the predominantly involved organs. However, 0.5-1% of the hydatid disease involves the spine and in 90% of the cases it is confined to the bone and the epidural space. Although intramedullary involvement is extremely rare, in this report, we present a 55-year-old female patient who was diagnosed with a cervical intramedullary hydatid cyst during magnetic resonance imaging of the cervical vertebrae. Accordingly, we imply that particularly in endemic areas, hydatid cyst disease should be kept in mind for the differential diagnosis of spinal mass lesions.

Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio are prolonged in patients with moderate and severe obstructive sleep apnea.

BACKGROUND: Prolongation of the peak and the end of T wave (Tp-e) has been reported to be associated with ventricular arrhythmias. Tp-e/QT ratio and Tp-e/QTc ratio are used as an index of ventricular arrhythmogenesis. An increased incidence of ventricular arrhythmias has been reported in patients with obstructive sleep apnea (OSA). The aim of this study was to assess ventricular repolarization in patients with OSA by using Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio. METHODS: We have studied 72 patients who underwent overnight polysomnography (PSG) between the years 2010-2011 at our institution. Patients with moderate and severe OSA (23 patients; mean age: 45±10), according to the apnea-hypopnea index, constituted the study group. Patients with normal PSG (23 patients; mean age: 42±11) were used as the control group. In all patients, Tp-e interval, Tp-e/QT ratio, Tp-e/QTc ratio, as well as some other electrocardiogram intervals were measured. Independent samples t-tests were used for comparison of continuous and categorical variables and correlations were calculated by Spearman rank correlation. RESULTS: Although QT and QTc intervals were not different between the groups, mean Tp-e interval (81.6±11.1 msn; 63.9±7.3 msn; respectively; P < 0.001), Tp-e/QT ratio (0.21±0.03; 0.17±0.02; respectively; P < 0.001), and Tp-e/QTc ratio (0.20±0.03; 0.16±0.02; respectively; P < 0.001) were prolonged in the study group compared to the control group. Correlation analysis showed a significant positive correlation between the presence of moderate and severe OSA and Tp-e interval (r = 0.72; P < 0.001), Tpe/QT ratio (r = 0.70; P < 0.001), and Tp-e/QTc ratio (r = 0.70; P < 0.001). CONCLUSIONS: Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio are prolonged in patients with moderate and severe OSA patients. There is a positive correlation between the presence of OSA and Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio.

Selenium-vitamin E combination modulates endometrial lipid peroxidation and antioxidant enzymes in streptozotocin-induced diabetic rat.

Diabetes mellitus is associated with diabetic impairment of uterine function, ultimately leading to reduced fertility. Its etiology may involve oxidative damage by reactive oxygen substances, and protection against this damage can be offered by antioxidant supplementation. In the present study, the effects of a vitamin E-plus-selenium (VESe) combination on lipid peroxidation (MDA) and the scavenging enzyme activity in the uterine endometrium of streptozotocin (STZ)-induced diabetic rats were investigated. Twenty-four female rats were equally divided into three groups as follows: group I (control); group II (diabetic); group III (diabetic + VESe), STZ + vitamin E (60 mg/kg over 1 day) + selenium-treated (Na2SeO3, 1 mg/kg over 1 day). After 4 weeks of receiving the VESe treatment, endometrium samples were taken from the uterus. Although the VESe treatment decreased the MDA and blood glucose levels in the STZ group, the observed values remained significantly higher than in the controls. Catalase, superoxide dismutase, and glutathione peroxidase activities and body weight gain were significantly (p < 0.01) lower in STZ groups as compared to control group, whereas their activities were (p < 0.01) increased by VESe treatment. However, there was no significant difference on body weight gain and uterine weights between control and STZ + VESe groups. In conclusion, the endometrial complications caused by oxidative stress, and the abnormal blood glucose levels in diabetic of rats, can be alleviated by strengthening the physiological antioxidative defense through the administration of vitamin E and Se.

Reduction of postoperative adhesions by trimetazidine: an experimental study in a rat model.

OBJECTIVE: Trimetazidine (TMZ) reduces intracellular acidosis and inhibits oxygen-derived free radicals and neutrophile infiltration in ischemia and hypoxia, which are the primary steps of adhesion formation. Our aim is to study the anti-adhesion potential of trimetazidine in a rat uterine horn model. METHODS: Forty non-pregnant female Wistar-Albino rats were randomly assigned, with ten in each group, to receive 2 ml saline, or 5 mg/kg intraperitoneal trimetazidine postoperatively, and control and sham. TMZ was administered to TMZ postoperative group 5 mg/kg i.p. daily for 5 days after the operation. Both uterine horns were exposed, and then a 2 cm segment of the anti-mesenteric surface of both the uterine horns were traumatized in 10 spots with unipolar electrocautery for 2 s with a power of 50 Watts. All the animals were killed by lethal dose of ether on postoperative 14th day. Intraperitoneal adhesions were scored by clinical adhesion scoring system, and histological and morphometric analysis was performed. RESULTS: Total adhesion score (TAS) of control group was 10 while the sham group was found to be 0. TAS of the placebo group that was given saline (TAS 5), and postoperative TMZ applied group (TAS 3.5) were significantly lower than the control group (p < 0.05). The severity scores of postoperative TMZ and sham groups were significantly smaller than the other groups (p < 0.05). CONCLUSION: TMZ significantly reduced the extent and severity of horn adhesions. The promising efficacy demonstrated by the intraperitoneal TMZ in this model warrants further investigation in clinical trials focused on gynecological procedures.

Myocardial ischemia in severe aortic regurgitation despite angiographically normal coronary arteries.

Patients with severe aortic regurgitation frequently present with angina pectoris. The exact pathophysiology for angina in aortic regurgitation is not clear. Left ventricular hypertrophy and myocardial blood supply-demand mismatch have been the suggested mechanisms to explain ischemia. However, no conclusive clinical study exists to define the incidence of ischemia in patients with severe aortic regurgitation and normal coronary arteries. We, therefore, investigated the frequency of myocardial ischemia in relation to left ventricular hypertrophy or dilatation in patients with severe aortic regurgitation and normal coronary arteries. We reviewed the medical records of all patients (n = 311) with aortic valve replacement due to aortic regurgitation between 2007 and 2010. We selected subjects with normal coronary arteries (n =182) for the study purpose, and we identified 35 patients who underwent myocardial perfusion scintigraphy prior to the coronary angiography (19 female and 16 male subjects; age 45.0 ± 8.9 years). Left ventricular hypertrophy and dilatation were detected in 9 (26%) and 5 (14%) patients, respectively. Myocardial perfusion scintigraphy showed evidence of ischemia in 10 (29%) patients with normal coronary arteries. The presence of ischemia did not relate to the presence of left ventricular hypertrophy and/or dilatation. As a potential mechanism, aortic regurgitation causes backflow of blood from the aorta into the left ventricle, hence disturbs coronary flow dynamics. In conclusion, myocardial ischemia is common (nearly one-third) among patients with severe aortic regurgitation even in the absence of coronary obstruction, left ventricular hypertrophy and/or dilatation.