Biochemical effects,hypolipidemic and anti-inflammatory activities of Artemisia vulgaris extract in hypercholesterolemic rats

The purpose of the present study was to investigate hypolipidemic and anti-inflammatory effects of Artemisia vulgaris extract in hypercholesterolemic rats. Hypercholesterolemia was induced by feeding of rats with high fat diet containing 3% cholesterol in olein oil, for 8 weeks. Feeding of rats with high fat diet for 8 weeks, leading to a significant increase in serum triglycerides, total cholesterol, low density lipoprotein cholesterol, malondialdehyde and nitric oxide, tumor necrosis factor-α levels and a significant decrease in serum high density lipoprotein cholesterol level, liver hydroxymethylglutaryl-CoA reductase activity and paraoxonase-1 activities as compared to the normal control group. Treatment of high fat diet rats with Artemisia vulgaris extract for 4 weeks at a dose of 100 mg/kg per day, resulted in normalized serum lipid profile, a significant increase in paraoxonase-1 activity and decrease in serum malondialdehyde, nitric oxide and tumor necrosis factor-α level as compared to high fat diet-treated animals. Also the extract caused a significant decrease in hydroxymethylglutaryl-CoA reductase activity as compared with both high fat diet-treated animals and control ones. In conclusion, Artemisia vulgaris extract has hypolipidemic, anti-inflammatory, antioxidant properties; it may serve as a source for the prevention of atherosclerosis and cardiovascular diseases.     

Improving Access to Noninstitutional Long‐Term Care for American Indian Veterans

Home‐based primary care (HBPC) is an effective model of noninstitutional long‐term care developed in the Department of Veterans Affairs (VA) to provide ongoing care to homebound persons. Significant rural populations of American Indians have limited access to services designed for frail older adults. Fourteen Veterans Affairs Medical Centers (VAMCs) initiated efforts to expand access to HBPC in concert with local tribes and Indian Health Service (IHS) facilities. This study characterizes the resulting emerging models of HBPC and co‐management. Using an observational design, key respondent telephone interviews (n = 37) were conducted with stakeholders representing the 14 VAMCs to describe these HBPC programs, and HBPC models were evaluated in relation to VAMC organizational culture as revealed on the annual VA All Employee Survey. Twelve VAMCs independently developed HBPC expansion programs for American Indian veterans, and six different program models were implemented. Two models were unique to collaborations between VAMCs and tribes; in these collaborations, the tribes retained primary care responsibilities. VAMC used the other four models for delivery of care in remote rural areas to all veteran populations, American Indians and non‐Indians alike. Strategies to improve access by reducing geographic barriers occur in all models. Comparing mean VAMC organizational culture ratings, as defined in the Competing Values Framework, revealed significant group differences for one of these six models. Findings from this study illustrate the flexibility of the HBPC program and opportunities for co‐management and expansion of healthcare access for American Indians and non‐Indians, particularly in rural areas.     

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis

Transient receptor potential canonical (TRPC) Ca²⁺-permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II- and 1-oleoyl-2-acetyl-sn-glycerol–induced Ca²⁺ entry in these cells, which was detected by fura-2 Ca²⁺ imaging. TRPC3 blockade or Ca²⁺ removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signal-regulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca²⁺ entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca²⁺-mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease.     

Anesthesia and the developing brain: a way forward for clinical research

It is now well established that many general anesthetics have a variety of effects on the developing brain in animal models. In contrast, human cohort studies show mixed evidence for any association between neurobehavioural outcome and anesthesia exposure in early childhood. In spite of large volumes of research, it remains very unclear if the animal studies have any clinical relevance; or indeed how, or if, clinical practice needs to be altered. Answering these questions is of great importance given the huge numbers of young children exposed to general anesthetics. A recent meeting in Genoa brought together researchers and clinicians to map a path forward for future clinical studies. This paper describes these discussions and conclusions. It was agreed that there is a need for large, detailed, prospective, observational studies, and for carefully designed trials. It may be impossible to design or conduct a single study to completely exclude the possibility that anesthetics can, under certain circumstances, produce long‐term neurobehavioural changes in humans; however , observational studies will improve our understanding of which children are at greatest risk, and may also suggest potential underlying etiologies, and clinical trials will provide the strongest evidence to test the effectiveness of different strategies or anesthetic regimens with respect to better neurobehavioral outcome.     

Traumatic female urethral avulsion

Traumatic female urethral avulsion in the absence of a pelvic fracture is an exceedingly rare entity, with no consensus on its management. Here, we present a 35-year-old pregnant woman with severe anterior vaginal wall laceration and complete urethral avulsion secondary to straddle injury. Management consisted of primary urethral and vaginal repair.Complete circumferential rupture of the female urethra is extremely rare, and represents a challenging management situation.1 As the entire posterior length of the urethra is closely adherent to the anterior wall of the vagina; it is subsequently prone to simultaneous injury. Most reported cases were associated with pelvic bone fractures, but there is no current consensus on management.2 The diagnosis should be considered in cases of deep vaginal lacerations, with an inability to void with unsuccessful catheterization.3 Our objective in presenting this particular case is to highlight that early recognition and strict adherence to the principles of reconstructive surgery are necessary to maximize the results and prevent subsequent risks of morbidity.     

Inflammatory bowel disease in rats： Bacterial and chemical interaction

AIM：To develop a novel model of colitis in rats, using a combination of iodoacetamide and enteropathogenic E. coli（EPEC）, and to elucidate the pathophysiologic processes implicated in the development of ulcerative colitis （UC）.
METHODS： Hale Sprague-Dawley rats （/7 = 158） were inoculated intrarectally on a weekly basis with 4 different combinations： （a） 1% methylcellulose （HC）, （b） 100 μL of 6% iodoacetamide （IA） in 1% HC, （c） 200 p.L containing 4×10^8 colony factor units （CFU） of EPEC, and （d） combined treatment of （IA） followed by bacteria （13） after 2 d. Thirty days post treatment, each of the four groups was divided into two subgroups; the inoculation was stopped for one subgroup and the other subgroup continued with biweekly inoculation until the end of the experiment. Colitis was evaluated by the clinical course of the disease, the macroscopic and microscopic alterations, activity of myeloperoxidase （HPO）, and by TNF-α gene expression. RESULTS： Findings indicative of UC were seen in the combined treatment （IA ＋ B） as well as the IA continued treatment groups： the animals showed slow rate of increase in body weight, diarrhea, bloody stools, high colonic ulcer score, as well as histological alterations characteristic of UC, with an extensive inflammatory reaction. During the course of the experiment, the MPO activity was consistently elevated and the TNF-α gene expression was upregulated compared to the control animals.
CONCLUSION： The experimental ulcerative colitis model used in the present study resembles, to a great extent, the human disease. It is reproducible with characteristics indicative of chronicity.     

A Pantetheinase-Resistant Pantothenamide with Potent,On-Target,and Selective Antiplasmodial Activity

Pantothenamides inhibit blood-stage Plasmodium falciparum with potencies (50% inhibitory concentration [IC₅₀], ∼20 nM) similar to that of chloroquine. They target processes dependent on pantothenate, a precursor of the essential metabolic cofactor coenzyme A. However, their antiplasmodial activity is reduced due to degradation by serum pantetheinase. Minor modification of the pantothenamide structure led to the identification of α-methyl-N-phenethyl-pantothenamide, a pantothenamide resistant to degradation, with excellent antiplasmodial activity (IC₅₀, 52 ± 6 nM), target specificity, and low toxicity.     

The Association of Diurnal Blood Glucose Variability With Subclinical Cardiac Disease in Patients With Type 2 Diabetes Mellitus

BackgroundThe relationship between glycemic control and the risk of cardiac disease in patients with Type 2 Diabetes Mellitus (T2DM) is controversial. 1,5-Anhydroglucitol (1,5-AG) is a biomarker of Glucose Variability (GV) and has been associated with clinical cardiovascular disease. However, its association with Subclinical Cardiac Disease (SCD) is unknown.Aim of the workStudy the association between GV and SCD.Subjects and methodsA cross-sectional study was conducted on 46 asymptomatic patients with T2DM as T2DM individuals group. Another 46 non-diabetic age and sex matched subjects were included as the healthy group. 1,5-AG was measured for all subjects. M-mode echocardiography in parasternal long axis view was used to measure Left Ventricular (LV) end diastolic dimension, LV end systolic dimension, ejection fraction, interventricular septum, LV posterior wall thickness, LV fractional shortening, left atrial dimension and aortic root dimension. Global Longitudinal Strain (GLS) was assessed by speckled tracking echocardiography.ResultsThere were no significant differences between both groups as regarding age, sex, BMI, AST, ALT, and serum creatinine. 1,5-AG was lower in T2DM individuals group. As regarding the echo parameters no significant difference found between both groups regarding left ventricular, left atrial and aortic root dimensions. T2DM individuals group showed a statistically significant higher mitral valve area, apical 2 chambers, apical 4 chambers, apical longitudinal axis and GLS. No correlation found between HbA1c and any echo parameters while 1,5-AG showed a significantly negative correlation with apical 2 chambers, apical 4 chambers, apical longitudinal axis and GLS. ROC curve analysis detected 1,5-AG less than 7.51 ng/ml as the best cut off value with sensitivity of 85.7%, specificity 75% to diagnose patients with T2DM and SCD.Conclusion1,5-AG might be used as an additional surrogate marker to identify patients with T2DM and SCD.     

The effects of di(2‐ethylhexyl)phthalate on rat liver in relation to selenium status

This study was performed to determine the hepatotoxicity of di(2‐ethylhexyl)phthalate (DEHP) in relation to selenium status. In 3‐week‐old Sprague‐Dawley rats, selenium deficiency was induced by a ≤0.05 selenium mg/kg. A selenium supplementation group was given 1 mg selenium/kg diet for 5 weeks. Di(2‐ethylhexyl)phthalate‐treated groups received 1000 mg/kg dose by gavage during the last 10 days of the experiment. Histopathology, peroxisome proliferation, catalase (CAT) immunoreactivity and activity and apoptosis were assessed. Activities of antioxidant selenoenzymes [glutathione peroxidase 1 (GPx1), glutathione peroxidase 4 (GPx4), thioredoxin reductase (TrxR1)], superoxide dismutase (SOD), and glutathione S‐transferase (GST); aminotransferase, total glutathione (tGSH), and lipid peroxidation (LP) levels were measured. Di(2‐ethylhexyl)phthalate caused cellular disorganization while necrosis and inflammatory cell infiltration were observed in Se‐deficient DEHP group (DEHP/SeD). Catalase activity and immunoreactivity were increased in all DEHP‐treated groups. Glutathione peroxidase 1 and GPx4 activities decreased significantly in DEHP and DEHP/SeD groups, while GST activities decreased in all DEHP‐exposed groups. Thioredoxin reductase activity increased in DEHP and DEHP/SeS, while total SOD activities increased in all DEHP‐treated groups. Lipid peroxidation levels increased significantly in SeD (26%), DEHP (38%) and DEHP/SeD (71%) groups. Selenium supplementation partially ameliorated DEHP‐induced hepatotoxicity; while in DEHP/SeD group, drastic changes in hepatic histopathology and oxidative stress parameters were observed.