Imbalance between Angiotensin II - Angiotensin (1-7) system is associated with vascular endothelial dysfunction and inflammation in type 2 diabetes with newly diagnosed hypertension

AimDiabetes is associated with Renin-angiotensin-aldosterone-system (RAAS) activation. Protective role of Angiotensin (1-7) has been recently identified. The study aims to identify associations between imbalance in RAAS components with vascular endothelial dysfunction and inflammation in diabetics with newly diagnosed hypertension.MethodsBrachial Flow-mediated-dilation (FMD), Carotid Intima-media-thickness (CIMT), pulse-wave-velocity (PWV), Serum E-selectin, Vascular-Cell-Adhesion-Molecule-1 (VCAM-1), high-sensitivity C-Reactive Protein (hsCRP), Interleukin-10 (IL-10), Renin, AngiotensinII, Angiotensin-Converting-Enzyme 2 (ACE2) and Angiotensin1-7 were measured in 60 diabetic patients with newly diagnosed hypertension. Patients with AngiotensinII/Angiotensin1-7 ratio <1 were classified as Favourable-Axis (FA) group (n = 22) and those with ratio >1 were classified as Unfavourable-Axis (UA) group (n = 38).ResultshsCRP was higher [9.52 (4.64–16.19) vs 3.62 (1.77–13.09) (mg/l), p = 0.04], IL-10 was lower [2.26 (1.34–12.05) vs 10.98 (4.44–17.78) (pg/ml),p = 0.006], %FMD was lower [(5.51 ± 2.97) vs (7.66 ± 3.38) (%), p = 0.01] and CIMT was higher in UA compared to FA group [0.7 (0.55–0.79) vs 0.51 (0.49–0.65) (mm), p = 0.001]. Renin correlated positively with pressure, PWV, E-selectin and VCAM-1, opposing associations were obtained for Angiotensin1-7 and ACE2.ConclusionImbalance between AngiotensinII – Angiotensin1-7 is associated with increased inflammation and vascular dysfunction in diabetics and can contribute to development of hypertension in these patients.     

Stability of RNA virus attenuation approaches

The greatest risk from live-attenuated vaccines is reversion to virulence. Particular concerns arise for RNA viruses, which exhibit high mutation frequencies. We examined the stability of 3 attenuation strategies for the alphavirus, Venezuelan equine encephalitis virus (VEEV): a traditional, point mutation-dependent attenuation approach exemplified by TC-83; a rationally designed, targeted-mutation approach represented by V3526; and a chimeric vaccine, SIN/TC/ZPC. Our findings suggest that the chimeric strain combines the initial attenuation of TC-83 with the greater phenotypic stability of V3526, highlighting the importance of the both initial attenuation and stability for live-attenuated vaccines.     

Effect of methomyl on hepatic mixed function oxidases in rats

Objective:

To study the effect of the methomyl on mixed function oxidase system in rats.

Materials and Methods:

The effect of the methomyl on mixed function oxidase was studied using different dosages, durations and sex. Microsomes were isolated using the calcium precipitation method. The levels of cytochrome P₄₅₀ , and cytochrome b₅ were determined using extinction coefficient of 91 and 85 mM^-1 respectively. The activities of drug metabolizing enzymes, hemoglobin content, liver function enzymes, and serum cholinesterase activity were assayed by using standard methods.

Results:

Intraperitoneal administration of methomyl (4 mg/kg body weight) showed significant decrease in the level of cytochrome P₄₅₀ , and the activities of aminopyrine N-demethylase and aniline hydroxylase on the third day of the treatment. Methomyl (4 mg/kg) treatment of old male rat and adult female rat also showed a decrease in the level of cytochrome P₄₅₀ , and aminopyrine N-demethylase activity. The serum samples from methomyl treated rats (male and female), when analyzed for alanine aminotransferase (SGPT) and aspartate aminotransferase (SGOT) as markers of the liver toxicity, showed significant increase in the activity. The activities of SGPT and SGOT were significantly higher in the treated rats (2 and 4 mg/kg) than in the control group. A significant decrease in the level of hemoglobin and serum cholinesterase activity was observed, when there was an increase in the dose level. A significant increase was observed in alkaline phosphatase activity at all dose levels.

Conclusion:

Methomyl influences mixed function oxidase and creates abnormality of liver functions in the rats. This effect depends on the dose and duration of methomyl.     

Modulation of tumor induction and progression of oncogenic K-ras-positive tumors in the presence of TGF- b1 haploinsufficiency

Oncogenic K-ras is one of the most common genetic alterations in human lung adenocarcinomas. In addition, inactivation of clusters of tumor suppressor genes is required to bring about classical characteristics of cancer including angiogenesis as a prelude to invasion and metastasis. Transforming growth factor-beta (TGF-beta) 1 is a tumor suppressor gene that is implicated in lung cancer progression. Although in vitro studies have shown that TGF-beta1 and Ras pathways cooperate during tumorigenesis, the biology of interaction of TGF-beta1 and Ras has not been studied in in vivo tumorigenesis. We hypothesized that inactivation of TGF-beta1 in addition to oncogeneic activation of K-ras would lead to early initiation and faster progression to lung adenocarcinoma and invasion and metastasis. Heterozygous (HT) TGF-beta1 mice were mated with latent activatable (LA) mutated K-ras mice to generate TGF-beta1(+/+), K-ras LA (wild-type (WT)/LA) and TGF-beta1(+/-), K-ras LA (HT/LA) mice. Both HT/LA and WT/LA mice developed spontaneous lung tumors, but HT/LA mice progressed to adenocarcinomas significantly earlier compared with WT/LA mice. In addition, WT/LA adenocarcinomas had significantly higher angiogenic activity compared with HT/LA adenocarcinomas. Thus, while oncogenic K-ras mutation and insensitivity to the growth regulatory effects of TGF-beta1 is essential for initiation and progression of mouse lung tumors to adenocarcinoma, a full gene dosage of TGF-beta1 is required for tumor-induced angiogenesis and invasive potential. This study identifies a number of genes not previously associated with lung cancer that are involved in tumor induction and progression. In addition, we provide evidence that progression to invasive angiogenic lesions requires TGF-beta1 responsiveness in addition to Ras mutation.     

NEUROCYSTICERCOSIS IN CHILDREN PRESENTING WITH AFEBRILE SEIZURE: CLINICAL PROFILE,IMAGING AND SERODIAGNOSIS

Neurocysticercosis (NCC) is one of the major causes of childhood seizuresin developing countries including India and Latin America. In this study neurologicalpediatric cases presenting with afebrile seizures were screened for anti-Cysticercusantibodies (IgG) in their sera in order to estimate the possible burden ofcysticercal etiology. The study included a total of 61 pediatric afebrile seizuresubjects (aged one to 15 years old); there was a male predominance. All the sera weretested using a pre-evaluated commercially procured IgG-ELISA kit (UB-MagiwellCysticercosis Kit ^™). Anti-Cysticercus antibody in serum was positive in 23 of 61 (37.7%)cases. The majority of cases with a positive ELISA test presented with generalizedseizure (52.17%), followed by complex partial seizure (26.08%), and simple partialseizure (21.73%). Headaches were the major complaint (73.91%). Other presentationswere vomiting (47.82%), pallor (34.78%), altered sensorium (26.08%), and muscleweakness (13.04%). There was one hemiparesis case diagnosed to be NCC. In this studyone child without any significant findings on imaging was also found to be positiveby serology. There was a statistically significant association found between thecases with multiple lesions on the brain and the ELISA-positivity (p= 0.017). Overall positivity of the ELISA showed a potential cysticercal etiology.Hence, neurocysticercosis should be suspected in every child presenting with afebrileseizure especially with a radio-imaging supportive diagnosis in tropical developingcountries or areas endemic for taeniasis/cysticercosis.