The influence of uric acid treatments on liver glutathione system prevent oxidative damages in experimental autoimmune encephalomyelitis mice

Recently we reported that antioxidant system in brain and spinal cord in experimental autoimmune encephalomyelitis (EAE) mice is mainly affected at early stages of the disease [M. Zargari, A. Allameh, M.H. Sanati, T. Tiraihi, S.H. Lavasani, O. Emadyan, Relationship between the clinical scoring and demyelination in central nervous system with total antioxidant capacity of plasma during experimental autoimmune encephalomyelitis development in mice, Neurosci. Lett. 412 (2007), 24–28]. The aim of the present study was to investigate the role of uric acid (UA) on antioxidant system in liver and plasma of EAE mice. EAE was induced in C57/BL6 mice (n = 60), followed by i.p. administration of UA (10 mg/kg BW) in 30 mice at three distinct clinical stages (A: prior to onset, B: after onset, C: after development of EAE). Livers were removed and processed for measurement of lipid peroxidation products, reduced glutathione (GSH), and glutathione S-transferase (GST) and total antioxidant capacity of plasma (FRAP). The results showed that lipid peroxidation products in liver of EAE mice was increased significantly (∼85%) as compared to normal. UA administration to EAE mice caused a significant suppression of liver lipid peroxidation products (∼45%) at early stages (A and B). There was an inverse relationship between lipid peroxidation and cellular GSH in liver. GSH was significantly depleted in mice liver during the EAE progression, but it was recovered (∼29%) when UA was injected before the onset of the disease (groups A and B). Plasma total antioxidant capacity was significantly decreased during the development of EAE, however it was subsided in mice treated with UA as compared to the corresponding controls (21%) in groups A and B. Elevated liver GST as a result of EAE induction was reversed in mice treated with UA particularly in groups A and B. These results indicate that hepatic glutathione system, particularly GST plays a major role in modulation of oxidative damages to central nervous system (CNS) during EAE induction. The positive response of antioxidant system to UA administration in EAE mice was corroborated with improvement of clinical manifestation of the animals.     

A randomized,triple‐blind,placebo‐controlled clinical trial,evaluating the sesamin supplement effects on proteolytic enzymes,inflammatory markers,and clinical indices in women with rheumatoid arthritis

Inflammation is one of the main characteristics of rheumatoid arthritis. Based on the antiinflammatory properties of sesame, this study was conducted to evaluate the sesamin supplement effects on serum levels of some proteolytic enzymes, inflammatory biomarkers, and clinical indices in women with rheumatoid arthritis. In this randomized, triple‐blind, placebo‐controlled clinical trial, 44 patients were randomly divided in intervention and control groups. Patients received 200‐mg/day sesamin supplement or placebo in the intervention and control group for 6 weeks. Serum levels of proteolytic enzymes (hyaluronidase, aggrecanase, and matrix metalloproteinases‐3) and inflammatory biomarkers (hs‐CRP, IL‐1β, IL‐6, TNF‐α, and cyclooxygenase‐2) were measured with enzyme‐linked immunosorbent assay method at the beginning and end of the study. After intervention, serum levels of hyaluronidase and matrix metalloproteinases‐3 decreased significantly in sesamin group. Also, serum levels of hs‐CRP, TNF‐α, and cyclooxygenase‐2 in intervention group were significantly decreased in intervention group compared with placebo group. Sesamin supplementation also caused a significant reduction in the number of tender joints and severity of pain in these patients. According to the results, it seems that the sesamin by reducing inflammatory mediators can relieve clinical symptoms and pathological changes that caused by inflammatory impairment in patients with rheumatoid arthritis.     

Cardiac Outcomes Through Digital Evaluation (CODE) STEMI project: prehospital digitally-assisted reperfusion strategies

Background

Guidelines for reperfusion in ST-elevation myocardial infarction (STEMI) were recently adopted by the Canadian Cardiovascular Society. We have developed a blended model of prehospital thrombolytic (PHL) therapy or primary percutaneous coronary intervention (PPCI) activation, in order to achieve guideline times.

Methods

In our urban centre of 658,700 people, emergency medical services (EMS) were trained to perform and screen electrocardiograms (ECGs) for suspected STEMI. Suspected ECGs were transmitted to a physician's hand-held device. If the physician confirmed the diagnosis they coordinated initiation of either PHL or PPCI. In cases where physicians found the prehospital ECG negative for STEMI (PHENST), patients were transported to the closest emergency room.

Results

From July 21, 2008 to July 21, 2010, the Cardiac Outcomes Through Digital Evaluation (CODE) STEMI project received 380 transmitted calls. There were 226 confirmed STEMI by the on-call physician, 158 (70%) received PPCI, 48 (21%) received PHL, and 20 (9%) had angiography but no revascularization. The PPCI, median time from first medical contact to reperfusion was 76 minutes (interquartile range [IQR], 64-93). For PHL, median time from first medical contact to needle was 32 minutes (IQR, 29-39). The overall mortality rate for the STEMI patients was 8% (PHL = 4 [8.3%], PPCI = 8 [5%], medical therapy = 7 [35%]). There were 154 PHENST patients, 44% later diagnosed with acute coronary syndrome. The mortality rate for PHENST was 14%.

Conclusions

Through a model of EMS prehospital ECG interpretation, digital transmission, direct communication with a physician, and rapid coordinated service, we demonstrate that benchmark reperfusion times in STEMI can be achieved.     

Lipopolysaccharides,but not Angiotensin ll,lnduces Direct Pro‐lnflammatory Effects in Cultured Mouse Arteries and Human Endothelial and Vascular Smooth Muscle Cells

Angiotensin II (Ang II) might induce pro‐inflammatory effects directly in the vascular wall independently of its haemodynamic effects. The aim of our study was to investigate the putative direct pro‐inflammatory and vasomotor effects of Ang II and compare to those of lipopolysaccharides (LPS) in mouse isolated mesenteric resistance‐sized arteries (MRA) supported by experiments in cultured human primary endothelial and vascular smooth muscle cells. Results showed that 24‐hr organ culture of mouse MRA with 10 nM Ang II had, unlike 100 ng/mL LPS, no effects on IL‐6 or MCP‐1 secretion, VCAM1 mRNA expression or endothelial function, while Ang II significantly decreased maximal vasomotor responses to phenylephrine. In support, 24‐hr organ culture of mouse MRA significantly suppressed Agtr1a mRNA and augmented Tlr4 mRNA along with attenuated vasomotor responses to Ang II. Moreover, contrary to LPS and TNF‐α, Ang II and [Sar1]‐Ang II had no concentration‐ or time‐dependent effects on IL‐6 and MCP‐1 secretion in human umbilical vein endothelial cells (HUVEC) and human aortic smooth muscle cells (HASMC). AGTR1 or AGTR2 mRNA expression was undetectable in HUVEC, whereas HASMC expressed only AGTR1 mRNA. In summary, contrary to previous studies and the observed effects of LPS, we could not demonstrate direct vascular pro‐inflammatory effects of Ang II ex vivo or in vitro. As indicated by our results, down‐regulation or desensitization of AT₁R during culture may explain our findings.     

ED breast cases and other breast emergencies

Patients with pathologic processes of the breast commonly present in the Emergency Department (ED). Familiarity with the imaging and management of the most common entities is essential for the radiologist. Additionally, it is important to understand the limitations of ED imaging and management in the acute setting and to recognize when referrals to a specialty breast center are necessary. The goal of this article is to review the clinical presentations, pathophysiology, imaging, and management of emergency breast cases and common breast pathology seen in the ED.     

Improved dynamic connection detection power in estimated dynamic functional connectivity considering multivariate dependencies between brain regions

To estimate dynamic functional connectivity (dFC), the conventional method of sliding window correlation (SWC) suffers from poor performance of dynamic connection detection. This stems from the equal weighting of observations, suboptimal time scale, nonsparse output, and the fact that it is bivariate. To overcome these limitations, we exploited the kernel‐reweighted logistic regression (KELLER) algorithm, a method that is common in genetic studies, to estimate dFC in resting state functional magnetic resonance imaging (rs‐fMRI) data. KELLER can estimate dFC through estimating both spatial and temporal patterns of functional connectivity between brain regions. This paper compares the performance of the proposed KELLER method with current methods (SWC and tapered‐SWC (T‐SWC) with different window lengths) based on both simulated and real rs‐fMRI data. Estimated dFC networks were assessed for detecting dynamically connected brain region pairs with hypothesis testing. Simulation results revealed that KELLER can detect dynamic connections with a statistical power of 87.35% compared with 70.17% and 58.54% associated with T‐SWC (p‐value = .001) and SWC (p‐value <.001), respectively. Results of these different methods applied on real rs‐fMRI data were investigated for two aspects: calculating the similarity between identified mean dynamic pattern and identifying dynamic pattern in default mode network (DMN). In 68% of subjects, the results of T‐SWC with window length of 100 s, among different window lengths, demonstrated the highest similarity to those of KELLER. With regards to DMN, KELLER estimated previously reported dynamic connection pairs between dorsal and ventral DMN while SWC‐based method was unable to detect these dynamic connections.     

Preclinical and pharmacotoxicology evaluation of α-l-guluronic acid (G2013) as a non-steroidal anti-inflammatory drug with immunomodulatory property

Context: Therapeutic effects of α-l-guluronic acid with the greatest tolerability and efficacy (G2013) have been shown in experimental model of multiple sclerosis and other in vitro and in vivo examinations regarding α-l-guluronic acid; there are no toxicological researches on its safety although the pharmacological impacts have been recorded.

Objective: This study was designed to determine the acute and sub chronic toxicity of α-l-guluronic acid in healthy male and female BALB/c mice.

Materials and methods: For the acute toxicity study, the animals orally received five different single doses of α-l-guluronic acid and were kept under observation for 14?d. In the sub-chronic study, 24 male and female BALB/c mice were divided into four groups and treated daily with test substance preparation at dose levels of 0, 50, 250, and 1250?mg/kg body weight for at least 90 consecutive days. The mortality, body weight changes, clinical signs, hematological and biochemical parameters, gross findings, histopathological, and organs weight determinants were monitored during this study.

Results: The results of acute toxicity indicated that the LD50 of α-l-guluronic acid is 4.8?g/kg. We found no mortality or abnormality in clinical signs, body weight, relative organs weight, or necropsy in any of the animals in the subchronic study. Additionally, the results showed no significant difference in hematological, biochemical, and histopathological parameters in rats.

Conclusions: Our results suggest that α-l-guluronic acid has high safety when administered orally in animals.     

Structural and Functional Insights into Foamy Viral Integrase

Successful integration of retroviral DNA into the host chromosome is an essential step for viral replication. The process is mediated by virally encoded integrase (IN) and orchestrated by 3''-end processing and the strand transfer reaction. In vitro reaction conditions, such as substrate specificity, cofactor usage, and cellular binding partners for such reactions by the three distinct domains of prototype foamy viral integrase (PFV-IN) have been described well in several reports. Recent studies on the three‑dimensional structure of the interacting complexes between PFV-IN and DNA, cofactors, binding partners, or inhibitors have explored the mechanistic details of such interactions and shown its utilization as an important target to develop anti-retroviral drugs. The presence of a potent, non-transferable nuclear localization signal in the PFV C-terminal domain extends its use as a model for investigating cellular trafficking of large molecular complexes through the nuclear pore complex and also to identify novel cellular targets for such trafficking. This review focuses on recent advancements in the structural analysis and in vitro functional aspects of PFV-IN.