Search

Diabetes is associated with decreased epoxyeicosatrienoic acids (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase (sEH) inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of VEGF-A signaling pathway attenuates diabetes-induced glomerular injury. We also aimed to delineate the crosstalk between cytochrome P450 2C (CYP2C)-derived EETs and VEGF-A. Streptozotocin (STZ)-induced type 1 diabetic (T1D) rats were treated with 25 mg/L of AUDA in drinking water for 6 weeks. In parallel experiments, T1D rats were treated with either SU5416 or humanized monoclonal anti-VEGF-A neutralizing antibody for 8 weeks. Following treatment, the rats were euthanized, and kidney cortices were isolated for further analysis. Treatment with AUDA attenuated the diabetes-induced decline in kidney function. Furthermore, treatment with AUDA decreased diabetes-associated oxidative stress and NADPH oxidase activity. Interestingly, the downregulation of CYP2C11-derived EET formation is found to be correlated with the activation of VEGF-A signaling pathway. In fact, inhibiting VEGF-A using anti-VEGF or SU5416 markedly attenuated diabetes-induced glomerular injury through the inhibition of Nox4-induced ROS production. These findings were replicated in vitro in rat and human podocytes cultured in a diabetic milieu. Taken together, our results indicate that hyperglycemia-induced glomerular injury is mediated by the downregulation of CYP2C11-derived EET formation, followed by the activation of the VEGF-A signaling and upregulation of Nox4. To our knowledge, this is the first study to highlight VEGF-A as a mechanistic link between CYP2C11-derived EET production and Nox4.

It is common to encounter anatomical variations and some pathological processes during wet anatomy dissection lab, however, a ruptured abdominal aortic aneurysm (AAA) is a rare encounter - the first in the senior author's experience. This article reports the incidental finding of a ruptured abdominal aortic aneurysm during cadaveric dissection of first year medical students. Case report: We illustrate the essential anatomical parameters that surgeons take into consideration in planning endovascular repair of a AAA, according to the American Association for Vascular Surgery guidelines. We also highlight the educational benefits of post mortem dissection in understanding medical conditions, engaging medical students and stimulating learning curiosity; along with its role as a feedback mechanism on previously accepted diagnosis. Implications: We hope this article serves as a reminder that even in the era of modern medicine, autopsy can still offer still has a valuable role as a driver for healthcare training and improvement., Journal of Academic Development and Education

ObjectiveWe recently demonstrated that EBV DNA is correlated with proinflammatory responses in mice and in rheumatoid arthritis (RA) patients; hence, we utilized an RA mouse model to examine whether EBV DNA enhances the risk and severity of arthritis and to assess its immunomodulatory effects.MethodsC57BL/6J mice were treated with collagen (arthritis-inducing agent), EBV DNA 6 days before collagen, EBV DNA 15 days after collagen, Staphylococcus epidermidis DNA 6 days before collagen, EBV DNA alone, or water. Mice were then monitored for clinical signs and affected joints/footpads were histologically analysed. The relative concentration of IgG anti- chicken collagen antibodies and serum cytokine levels of IL-17A and IFNϒ were determined by ELISA. The number of cells co-expressing IL-17A and IFNϒ in joint histological sections was determined by immunofluorescence.ResultsThe incidence of arthritis was significantly higher in mice that received EBV DNA prior to collagen compared to mice that only received collagen. Similarly, increased clinical scores, histological scores and paw thicknesses with a decreased gripping strength were observed in groups treated with EBV DNA and collagen. The relative concentration of IgG anti-chicken collagen antibodies was significantly increased in the group that received EBV DNA 6 days prior to collagen in comparison to the collagen receiving group. On the other hand, the highest number of cells co-expressing IFNϒ and IL-17A was observed in joints from mice that received both collagen and EBV DNA.ConclusionEBV DNA increases the incidence and severity of arthritis in a RA mouse model. Targeting mediators triggered by viral DNA may hence be a potential therapeutic avenue.

Acute kidney injury in patients undergoing cardiovascular surgery is a complex problem with associated increased risks for dialysis, short- and long-term mortality, and progression to end-stage renal disease. Interventions to prevent and treat renal complications in this cohort have seldom been uniformly satisfactory due to the differences in strategies for intervention, drug doses and duration of treatment, baseline renal functions, and population studied. Nonetheless, significant advances have been made and include recognition of the effect of preexisting organ dysfunction on renal outcomes, reassessment of existing therapeutic interventions, and exploration of the feasibility of newer agents to prevent and treat acute kidney injury in cardiovascular surgery patients. This article briefly reviews several of these issues with an emphasis on recent clinical trials in this cohort.

This study was designed to explore factors involved in the regulation of Na-K pumps in erythrocytes and blood pressure in anephric Sprague-Dawley female rats. Twenty-four hours following bilateral nephrectomy, the rats were given a 1-h infusion of 1 ml of either 0.9% or 5.4% saline, or 5% or 30% glucose. At the completion of the infusion, tail blood pressure was determined and blood was drawn for the measurement of the ouabain-furosemide-sensitive sodium efflux rate constant in erythrocytes. Infusion of 5.4% saline or 30% glucose caused a significant reduction in the erythrocyte sodium efflux rate constant, more pronounced with the former, and an elevation in blood pressure. Nephrectomy or infusion of 0.9% saline or 5% glucose had no effect on either parameter. These findings suggest that in anephric rats (1) extracellular fluid hyperosmolality rather than extracellular fluid volume expansion inhibits the Na-K pump in all cells; (2) a Na-K pump inhibitor is involved in the genesis of hypertension.

Management of acute stroke varies greatly within and between different countries. This study assesses the current practices of physicians in Lebanon routinely involved in ischemic stroke (IS) management. We conducted a prospective observational study of patients hospitalized at 8 different Lebanese hospitals in the period August 1, 2015 to July 31, 2016, with a diagnosis of acute stroke. Baseline characteristics and data on diagnostic studies, as well as treatments received during hospitalization and at discharge, were collected and analyzed. Two hundred and three strokes/transient ischemic attacks (TIAs) were recorded but only 173 patients (85%) with ischemic events were included in the study. The patients' mean age was 69.8±12.7 years. All underwent brain imaging (CT scan and/or MRI) on admission. All ISs were managed by a neurologist, and patient management included consultation of a cardiologist. Hypertension was the most prevalent risk factor (78.6%), followed by a current cigarette smoking habit (50.3%), diabetes mellitus (42.8%), hypercholesterolemia (39.9%), previous stroke or TIA (17.3%), and atrial fibrillation (14.7%). Only four patients (accounting for 2.5% of the ISs) received thrombolytic therapy. More than 89% of the patients were discharged on at least one anti-hypertensive drug, 89.2% on statins and 37.6% on antidiabetic medications. More than 55% of patients were dependent at discharge, as shown by a modified Rankin Scale (mRS) score of 0-2, whereas 33% were independent (mRS score of 3-5). There are many challenges facing stroke care in Lebanon, and there is potential for improvement in this setting. Reperfusion therapy is still largely underused and remains a major challenge in achieving guideline-based reperfusion goals.

The heat shock protein 60 (Hsp60) is a chaperonin belonging to the chaperoning (chaperone) system that typically contributes to protein homeostasis inside mitochondria, but also plays various non-canonical roles unrelated to protein quality control beyond the organelle. Chaperonopathies are disorders in which chaperones play an etiologic-pathogenic role and contribute to the onset/progression of disease. Hsp60 chaperonopathies by mistake are diseases in which the chaperonin is apparently normal (as far as it can be determined with current methodologies) but it actively contributes to pathology, for example in certain types of cancer, and autoimmune and chronic inflammatory disorders. In certain cancers, Hsp60 is associated with the onset of malignancy and metastasization, although the mechanisms are poorly understood. In this chapter, we summarize findings on Hsp60 quantitative changes and distribution alterations in cells and tissues accompanying tumor initiation and progression. We also discuss the potential of HSP60-based anticancer therapies that are currently being investigated.Methods Journals and data bases were surveyed, and pertinent works were chosen for discussion. Results The data have stimulated experimental and clinical studies aiming at establishing the usefulness of Hsp60 as biomarker for diagnosis, and for assessing prognosis and response to treatment. Likewise, investigations are ongoing on the possible use of Hsp60 as a therapeutic agent or target. The reported results indicate that in neoplasms, Hsp60 migrates outside its canonical location, the mitochondrion, augments in the cytoplasm and plasma-cell membrane, and exits the cell via lipid rafts-exosomes. Exosomal Hsp60 occurs in extracellular fluids such as blood, through which it reaches target cells near and far, normal or cancerous. With these target cells, exosomes carrying Hsp60 and other molecules interact and, thereby, modify their functions. Thus, detection of exosomal Hsp60 in body fluids appears as a promising variety of liquid biopsy applicable to monitoring cancers already diagnosed and to screen for malignancies before they are clinically manifest. We also discuss Hsp60-based vaccines as a novel means of eliminating cancer cells with cytotoxic T lymphocytes (CTL). Tumor-derived Hsp60 associated with a tumorderived antigen activates CD8+ T cells and induces an antitumor immune response. It is highly probable that soon there will be implementation of clinical trials, involving the use of Hsp60 alone or in various combinations and complexes to prevent cancer progression and treat patients. Conclusions Hsp60 is actively involved in tumor development and progression. Its presence in extracellular fluids renders it a potential non-invasive biomarker. Also, considering the antitumor activities of Hsp60 observed in some types of cancer one can foresee a bright future for Hsp60-based therapies.