Aortic sclerosis--a marker of coronary atherosclerosis

Aortic valve sclerosis is defined as calcification and thickening of a trileaflet aortic valve in the absence of obstruction of ventricular outflow. Its frequency increases with age, making it a major geriatric problem. Of adults aged > 65 years, 21-29% exhibit aortic valve sclerosis. Incidence of aortic sclerosis increases with age, male gender, smoking, hypertension, high lipoprotein (Lp) (a), high low-density lipoprotein (LDL), and diabetes mellitus. Aortic valves affected by aortic sclerosis contain a higher amount of oxidized LDL cholesterol and show increased expression of metalloproteinases. Clinically, it can be suspected in the presence of soft ejection systolic murmur at the aortic area, normal split of the second heart sound, and normal volume carotid pulse, but it can be best detected by echocardiography. Aortic sclerosis may be accompanied by mitral annulus calcification up to 50% of cases. It is associated with an increase of approximately 50% in the risk of death from cardiovascular causes and the risk of myocardial infarction. The mechanism by which aortic sclerosis contributes to or is associated with increased cardiovascular risk is not known. Aortic sclerosis is associated with systemic endothelial dysfunction, and a small percentage of cases may progress to aortic stenosis. Lowering of LDL cholesterol by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to decrease progression of aortic valve calcification. Aortic sclerosis is not a mere benign finding. Once diagnosis of aortic sclerosis has been made, it should be considered a potential marker of coexisting coronary disease. Aggressive management of modifiable risk factors, especially LDL cholesterol lowering, may slow progression of the disease.     

Repair of a giant omphalocele by a modified technique

 Large omphaloceles that contain centrally herniated liver pose challenges to surgical closure, the most significant being the space limitation of the abdominal cavity. In addition, the “pedicled” nature of the liver on the inferior vena cava creates a predisposition to acute hepatic vascular outflow obstruction as the liver is reduced into the abdominal cavity. In such cases, the alternatives include conservative treatment or staged silo reduction. The worst complication of silastic silo (SS) placement is tension and infection of the fascia with disruption of the suture line. Once infection or premature disruption occurs, closure of the defect is difficult or impossible. This case report details a different management technique for a newborn with a giant omphalocele and presents an interesting variation of the usual SS technique that may be helpful in the management of some cases, especially in an emergency. The thick silk sutures applied in the present case absorbed the tension and the silastic sheet prevented the risks of infection and adhesions. Accepted: 28 July 1999     

Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity

We assessed the preclinical characteristics of a novel, stringently screened selective estrogen receptor modulator, bazedoxifene acetate, including its ability to bind to and activate estrogen receptors and promote increased bone mineral density and bone strength in rats, and the effects impacting the uterine endometrium, breast cancer cell proliferation, and central nervous system-associated vasomotor responses in an animal model. Bazedoxifene bound to estrogen receptor-alpha with an IC50 of 26 nm, an affinity similar to that of raloxifene. Bazedoxifene did not stimulate proliferation of MCF-7 cells but did inhibit 17beta-estradiol-induced proliferation with an IC50 of 0.19 nm. In an immature rat uterine model, bazedoxifene (0.5 and 5.0 mg/kg) was associated with less increase in uterine wet weight than either ethinyl estradiol (10 microg/kg) or raloxifene (0.5 and 5.0 mg/kg). Histological analysis revealed that coadministration of bazedoxifene also appeared to reduce raloxifene-stimulated endometrial luminal epithelial cell and myometrial cell hypertrophy. In ovariectomized rats, bazedoxifene was associated with significant increases in bone mineral density at 6 wk, compared with control, and better compressive strength of bone samples from the L4 vertebrae, compared with samples from ovariectomized animals. In the morphine-addicted rat model of vasomotor activity, bone-sparing doses of bazedoxifene alone were not associated with 17beta-estradiol inhibition of increased vasomotor activity. Bazedoxifene acetate represents a promising new treatment for osteoporosis, with a potential for less uterine and vasomotor effects than selective estrogen receptor modulators currently used in clinical practice. Controlled clinical trial data will be needed to confirm these effects.     

Protective effect of vineatrol against kainic acid induced seizures, oxidative stress and on the expression of heat shock proteins in rats.

The aim of the present study was to evaluate the effect of an antioxidant vineatrol against kainic acid-induced seizures, markers of oxidative stress and expression of heat shock protein in brain. In rats, kainic acid (10 mg/kg i.p.) induced long lasting seizures, associated behavioral symptoms and brain damage and significantly increased level of brain malondialdehyde (MDA) (283 +/- 42 nmol/g wet tissue) as compared to control (173.3 +/- 10.2 nmol/g wet tissue). Pretreatment (5 min) of vineatrol (10, 20 and 40 mg/kg i.p.) could not inhibit the convulsions though the latency was significantly increased with 20 and 40 mg/kg. However when the drug was administrated 5 min prior and repeated at 30 and 90 min after kainic acid there was significant reduction in incidence of convulsions. The brain MDA levels were also found to be significantly attenuated, however the glutathione levels were not different in control, kainic acid and vineatrol treated animals. Expression of heat shock protein (HSP) 72 was observed in the kainic acid per se group indicating neurotoxicity as compared to the control group and was reduced by vineatrol. The study suggests the potential use of vineatrol in status epilepticus.     

Synthesis of 3-methylflavones and their antioxidant and antibacterial activities

An attempt was made to synthesise newer 3-methylflavones with various substitution on the ring A and B of 2-phenylchromen-4-one. They were evaluated for antioxidant activity and antibacterial activity against the Gram-positive and Gram-negative bacteria. Five test compounds exhibited DPPH radical scavenging activity with IC₅₀ below 100?μg/ml, and the same test compounds exhibited 50–100% growth inhibition in Gram-positive bacteria against standard Amoxicillin.     

Efficacy of Terminalia arjuna in chronic stable angina: a double-blind,placebo-controlled,crossover study comparing Terminalia arjuna with isosorbide mononitrate

BACKGROUND: Terminalia arjuna, an Indian medicinal plant, has been reported to have beneficial effects in patients with ischemic heart disease in a number of small, open studies. The need for a double-blind, randomized, placebo-controlled study with adequate sample size has long been felt. The bark extract (IPC-53) contains acids (arjunic acid, terminic acid), glycosides (arjunetin arjunosides I-IV), strong antioxidants (flavones, tannins, oligomeric proanthocyanidins), minerals. etc. and exhibits antifailure and anti-ischemic properties. METHODS AND RESULTS: Fifty-eight males with chronic stable angina (NYHA class II-III) with evidence of provocable ischemia on treadmill exercise test received Terminalia arjuna (500 mg 8 hourly), isosorbide mononitrate (40 mg/daily) or a matching placebo for one week each, separated by a wash-out period of at least three days in a randomized, double-blind, crossover design. They underwent clinical, biochemical and treadmill exercise evaluation at the end of each therapy which were compared during the three therapy periods. Terminalia arjuna therapy was associated with significant decrease in the frequency of angina and need for isosorbide dinitrate (5.69+/-6.91 mg/week v. 18.22+/-9.29 mg/week during placebo therapy, p<0.005). The treadmill exercise test parameters improved significantly during therapy with Terminalia arjuna compared to those with placebo. The total duration of exercise increased (6.14+/-2.51 min v. 4.76+/-2.38 min, p<0.005), maximal ST depression during the longest equivalent stages of submaximal exercise decreased (1.41+/-0.55 mm v. 2.21+/-0.56 mm, p<0.005), time to recovery decreased (6.49+/-2.37 min v. 9.27+/-3.39 min, p<0.005) and higher double products were achieved (25.75+/-4.81x10(3) v. 23.11+/-4.83x10(3), p<0.005) during Terminalia arjuna therapy. Similar improvements in clinical and treadmill exercise test parameters were observed with isosorbide mononitrate compared to placebo therapy. No significant differences were observed in clinical or treadmill exercise test parameters when Terminalia arjuna and isosorbide mononitrate therapies were compared. No significant untoward effects were reported during Terminalia arjuna therapy. CONCLUSIONS: Terminalia arjuna bark extract, 500 mg 8 hourly, given to patients with stable angina with provocable ischemia on treadmill exercise, led to improvement in clinical and treadmill exercise parameters as compared to placebo therapy. These benefits were similar to those observed with isosorbide mononitrate (40 mg/day) therapy and the extract was well tolerated. Limitations of this study include applicability of the results to only men with chronic stable angina but not necessarily to women, as they were not studied.     

Probiotic bacteria as modulators of cellular senescence: emerging concepts and opportunities

ABSTRACT

Probiotic bacteria are increasingly gaining importance in human nutrition owing to their multifaceted health beneficial effects. Studies have also shown that probiotic supplementation is useful in mitigating age-associated oxi-inflammatory stress, immunosenescence, and gut dysbiosis thereby promoting health and longevity. However, our current understanding of the process of aging suggests a strong interrelationship between the accumulation of senescent cells and the development of aging phenotype, including the predisposition to age-related disorders. The present review studies the documented pro-longevity effects of probiotics and highlights how these beneficial attributes of probiotics could be related to the mitigation of cellular senescence. We present a perspective that to fully understand and comprehend the anti-aging characteristics of probiotic bacteria; it is imperative that probiotics or their synbiotic amalgamation with plant polyphenols, be studied under the purview of cellular senescence, that may ultimately help devise probiotic-based anti-senescence strategies.     

Eltrombopag therapy in newly diagnosed steroid non-responsive ITP patients

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterised by isolated thrombocytopenia (peripheral blood platelet count <100 × 10⁹/L) in the absence of other causes or disorders that may be associated with thrombocytopenia. The upfront treatment in newly diagnosed ITP patients is steroids; however, about one-third patients do not respond, and require other treatment, including IVIg, anti-D, or splenectomy. Previous studies have shown decreased platelet production in some ITP patients, aside from the evidence of enhanced platelet destruction. Thrombopoietin receptor agonists (TPO-RA), such as eltrombopag have been shown to provide good response in steroid non-responsive chronic ITP patients. We have studied response to eltrombopag in 25 newly diagnosed steroid non-responsive ITP patients; 80 % patients showed response at the end of 1 month, and 76 % sustained response at the end of 3 months. The platelet count rose from a mean value of 17.5 ± 3.6–152.5 ± 107.9 × 10⁹/L at the end of 1 month. Our results suggest a possible role of eltrombopag in newly diagnosed steroid non-responsive ITP patients. However, our study is limited in that it is a single-centre study, with a small sample size, and lacks a long-term safety profile. Our findings highlight the potential value of a larger prospective study on the upfront use of TPO-RA in patients of ITP.     

Searching for new targets for treatment of pediatric epilepsy

The highest incidence of seizures in humans occurs during the first year of life. The high susceptibility to seizures in neonates and infants is paralleled by animal studies showing a high propensity to seizures during early life. The immature brain is highly susceptible to seizures because of an imbalance of excitation and inhibition. While the primary outcome determinant of early-life seizures is etiology, there is evidence that seizures which are frequent or prolonged can result in long-term adverse consequences, and there is a consensus that recurrent early-life seizures should be treated. Unfortunately, seizures in many neonates and children remain refractory to therapy. There is therefore a pressing need for new seizure drugs as well as antiepileptic targets in children. In this review, we focus on mechanisms of early-life seizures, such as hypoxia–ischemia, and novel molecular targets, including the hyperpolarization-activated cyclic nucleotide-gated channels. This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.