Attenuation of insulin resistance, metabolic syndrome and hepatic oxidative stress by resveratrol in fructose-fed rats

Metabolic syndrome and oxidative stress are common complications of type 2 diabetes mellitus. The present study was designed to determine whether resveratrol, a widely used nutritional supplement, can improve insulin sensitivity, metabolic complication as well as hepatic oxidative stress in fructose-fed rats. Male Sprague Dawley rats (180-200 g) were divided into four groups with 8 animals each. Fructose-fed insulin resistant group (Dia) animals were fed 65% fructose (Research diet, USA) for a period of 8 weeks, whereas control group (Con) animals were fed 65% cornstarch (Research Diet, USA). Resveratrol, 10 mg/kg/day (Dia+Resv) or metformin 300 mg/kg/day (Dia+Met) were administered orally to the 65% fructose-fed rats for 8 weeks. At the end of the feeding schedule, Dia group had insulin resistance along with increased blood glucose, triglyceride, uric acid and nitric oxide (NO) levels. Significant (p<0.05) increase in hepatic TBARS and conjugated dienes, and significant (p<0.05) decrease in hepatic SOD and vitamin C was observed in Dia group compared to Con group. Administration of metformin or resveratrol significantly (p<0.05) normalized all the altered metabolic parameters. However, a marked insulin sensitizing action was only observed in the Dia+Resv group. Similarly, while metformin administration failed to normalize the increased TBARS levels and decreased SOD activity, resveratrol showed a more promising effect of all oxidative stress parameters measured in the present study. Attenuation of hepatic oxidative stress in fructose-fed rat liver after resveratrol administration was associated with significant (p<0.05) increase in nuclear level of NRF2 compared with other groups. The present study demonstrates that resveratrol is more effective than metformin in improving insulin sensitivity, and attenuating metabolic syndrome and hepatic oxidative stress in fructose-fed rats.     

Immunogenicity and safety study of Indirab: A Vero cell based chromatographically purified human rabies vaccine

A chromatographically purified Vero cell rabies vaccine, Indirab manufactured by Bharat Biotech International Limited, Hyderabad, India was subjected to safety and immunogenicity studies by both intramuscular and intradermal routes of administration in parallel with a reference vaccine, Verorab. A Pre-exposure study was undertaken in 239 subjects by intramuscular (IM) route (Study I), Post-exposure study in 188 patients by intramuscular route (Study II) and Simulated post-exposure study in 134 subjects by intradermal (ID) route (Study III). All subjects in these studies were administered with either the test or the reference vaccine as per WHO approved intramuscular and intradermal regimens. The blood samples were collected on days 0, 14 and 35 in case of Study 1, and days 0, 14, 28 and 90 in case of studies II and III. In all studies both vaccine groups had adequate antibody titers (>0.5 IU/mL) on all days tested post-vaccination and there was no significant difference in the titers observed (p > 0.05). Some side effects like pain, induration, itching and fever were noted in both vaccine groups in all studies. Both vaccines were well tolerated. Hence it can be concluded that Indirab is as safe and immunogenic as Verorab when administered by both intramuscular and intradermal routes.     

Impact of the RHANI Wives intervention on marital conflict and sexual coercion

Objective

To assess the effects of the RHANI (Reducing HIV among Non-Infected) Wives intervention on marital conflict and intimate partner violence (IPV) in urban India.

Methods

A 2-armed cluster-randomized controlled trial (7 intervention, 6 control clusters) of the RHANI Wives intervention was conducted with 220 women contending with a history of IPV and/or husband’s drunken behavior. Participants were surveyed at baseline and 4.5-month follow-up. Outcome measures included marital conflict (arguments with husband in past 3 months), marital IPV (physical or sexual violence from husband in past 3 months), and marital sexual coercion (husband forcing sex at last sex). Intention-to-treat logistic generalized linear mixed models were used to determine intervention impact.

Results

One-third (35.0%) of participants reported physical or sexual abuse from their husband in the past 3 months, and 58.6% reported that their husband was drunk in the past 30 days. Intention-to-treat analyses indicated time × treatment reductions in marital conflict (risk ratio [RR] 0.4; 90% confidence interval [CI], 0.1–0.9; P = 0.06) and marital sexual coercion (RR 0.2; 90% CI, 0.05–0.9; P = 0.08), but not IPV.

Conclusion

The findings suggest the potential utility of this intervention in reducing marital conflict and sexual coercion among women in urban India.ClinicalTrials.gov: NCT01592994.     

Rabies viral encephalitis with proable 25 year incubation period!

We report a case of rabies viral encephalitis in a 48-year-old male with an unusually long incubation period, historically suspected to be more than 20 years. The case was referred for histological diagnosis following alleged medical negligence to the forensic department. The histology and immunocytochemical demonstration of rabies viral antigen established the diagnosis unequivocally. The case manifested initially with hydrophobia and aggressive behavior, although he suddenly went to the bathroom and drank a small amount of water. History of dog bite 25 years back was elicited retrospectively following clinical suspicion. There was no subsequent history to suggest nonbite exposure to a rabid dog to consider recent event causing the disease, although this cannot be totally excluded.     

Association of nonalcoholic fatty liver disease with metabolic syndrome in Indian population

BackgroundNonalcoholic fatty liver disease (NAFLD), a common cause of cryptogenic cirrhosis is often associated with metabolic syndrome (MS) in the West. However, its association with MS in the Indian population is not well studied.AimsTo evaluate the association NAFLD with MS using the modified ATP-III criteria.Patients and methodsSeventy-six (62 men, mean age 40.05 ± 11.4 years, range 18–66) apparently healthy subjects with fatty liver and histological evidence of NAFLD; with (64.5%) or without raised ALT, and 100 healthy controls were included in the study. The anthropometric measurements, metabolic parameters, tests of liver function and liver histology were studied.ResultsTwenty-one percent of the patients compared to 8% controls (p < 0.01) had associated MS; according to ATP-III criteria while 42 and 12% were affected when the modified ATP-III criteria were used. About 35% of non-diabetic patients were insulin resistant with homeostatic model assessment-insulin resistance (HOMA-IR) cut-off set at 3. In patients, compared to controls, the mean BMI (25.2 vs. 22.7, p < 0.01) and waist circumferences (92.9 cm vs. 80.8 cm, p < 0.01) were higher. Seventy-nine percent of the patients and 44% of the controls were over weight. Stage 1 fibrosis was seen in 30 (39.5%), stage 2 in 10 (13.2%), stage 3 in 6 (7.9%) and stage 4 in 13 (17%) patients.ConclusionsInsulin resistance and obesity are associated in a proportion of Indian patients with NAFLD. However, the association with MS as defined by ATP-III in Indian patients is not strong compared to the West. It is likely that pathogenetic mechanisms unrelated to MS underlie development of NAFLD in a proportion of Indian patients.     

Effect of metformin against cisplatin induced acute renal injury in rats: A biochemical and histoarchitectural evaluation

Although cisplatin has been a mainstay for cancer therapy, its use is limited mainly because of nephrotoxicity. Accumulating literature suggest the antioxidant and cytoprotective effect of metformin, a first line antidiabetic drug. With this background, we investigated the effect of metformin on the cisplatin induced nephrotoxicity in rats. A single injection of cisplatin (7.5 mg/kg, i.p.) caused marked renal damage, characterized by a significant increase in blood urea nitrogen (BUN), serum creatinine (Cr) and abnormal histo-architecture of kidney. These were accompanied by significant elevation of malondialdehyde (MDA), total reactive oxygen species (tROS) and caspase-3 levels and decreased antioxidant levels. Metformin treatment significantly attenuated the increase in malondialdehyde and tROS generation and restores the decrease in both enzymatic and non-enzymatic antioxidants. However metformin treatment did not prevent the cisplatin induced renal injury as there was no significant difference of renal function parameters (BUN and Cr), kidney histopathology as well as caspase-3 activity between cisplatin per se and metformin plus cisplatin treated rats. Histopathology studies revealed that similar glomerular and tubular pathological architecture in both cisplatin per se and cisplatin plus metformin group. In conclusion, the present study demonstrated that metformin is not an adjuvant drug to treat nephrotoxicity associated with cisplatin therapy.     

Increased brain uptake of docetaxel and ketoconazole loaded folate-grafted solid lipid nanoparticles

Docetaxel is used in the treatment of many types of cancer, but its entry into the brain is restricted by p-glycoprotein (p-gp) efflux. A potential drug–drug interaction exists between docetaxel and ketoconazole because both agents are metabolized hepatically by the cytochrome P-450 system, and ketoconazole can inhibit p-gp efflux of docetaxel at blood brain barrier. Hence, these two drugs were loaded in solid lipid nanoparticles (SLNPs) and surface of these NPs were modified with folic acid for brain targeting. These NPs were characterized for particle size, zeta potential, entrapment efficiency, in vitro drug release, cytotoxicity, and cell uptake in brain endothelial cell lines. Plasma and brain pharmacokinetics have shown increased brain uptake of docetaxel with surface-modified dual drug-loaded SLNPs. Brain permeation coefficient (K_in) of folate-grafted docetaxel and ketoconazole loaded SLNPs was 44 times higher than that of Taxotere. Hence, these NPs were suitable for the delivery of lipophilic anticancer drugs to the brain.From the Clinical EditorIn this paper, successful delivery of docetaxel and ketoconazole is reported using solid lipid nanoparticles surface modified with folic acid for brain targeting, which may pave the way to optimized clinical applications of lipophilic anticancer drugs to the brain.     

Use of neutralizing murine monoclonal antibodies to rabies glycoprotein in passive immunotherapy against rabies

Passive immunization is an important parameter of post exposure rabies prophylaxis. Two types of rabies immunoglobulin (RIGs) are currently available for Passive immunization against rabies i.e., human rabies immunoglobulin (HRIG) and equine rabies immunoglobulin (ERIG). The former is very expensive and not easily available and the latter causes side effects because of which its utility is limited. In the present study we have produced murine monoclonal antibodies (Mabs) to rabies glycoprotein (G) and studied their utility in passive immunization against rabies using animal models. Their efficacy was compared to commercially available ERIG both in terms of neutralizing titer and effective protein concentration. The neutralizing titers of these Mabs ranged from 1650-75,000 IU/mL by RFFIT. They belonged to the IgG 2 a subclass. The Mabs were able to protect 70-100% of mice and guinea pigs inoculated with rabies viruses, depending on the strain of the virus. These Mabs were found to be 2,000 times more potent than commercial ERIG in terms of effective protein concentration and neutralizing titer. Further studies are required to study their utility in humans exposed to rabies.     

Comparison of saftey and immunogenicity of purified chick embryo cell rabies vaccine (PCECV) and purified vero cell rabies vaccine (PVRV) using the Thai Red Cross intradermal regimen at a dose of 0.1 ML

Intradermal (ID) vaccination with modern cell culture rabies vaccines is a means to significantly reduce the cost of post-exposure prophylaxis as compared to intramuscular vaccination. In this study we evaluated the efficacy, immunogenicity and tolerability of PCECV and PVRV administered ID in doses of 0.1 mL per site according to the 2-site Thai Red Cross (TRC) regimen. Patients with WHO category III exposure to suspect or laboratory proven rabid animals were administered either PCECV (n = 58) or PVRV (n = 52) ID at a dose of 0.1 mL per site at two sites on days 0, 3 and 7 and at one site on days 30 and 90. Serum samples were withdrawn on days 0, 14, 30, 90 and 180 and rabies virus neutralizing antibody (RVNA) titers were determined by rapid fluorescent focus inhibition test (RFFIT). Patients who were exposed to laboratory confirmed rabid animals were followed up for one year after exposure. All 110 patients developed RVNA titers above 0.5 IU/mL by day 14. Adequate titers >0.5 IU/mL were maintained up to day 180. Both vaccines induced equivalent RVNA titers at all time points and were well tolerated. Five subjects who were bitten by laboratory confirmed rabid dogs were alive and healthy one year after exposure. As demonstrated, PCECV and PVRV are both immunogenic, efficacious and well tolerated when administered in the TRC post-exposure prophylaxis regimen in ID doses of 0.1 mL as recommended by WHO guidelines. The use of PCECV in this regimen may prove more economical in developing countries like India.     

Assessing the relationship between antigenicity and immunogenicity of human rabies vaccines. Results of a meta-analysis

A meta-analysis was done to study the relationship between antigenecity and immunogenecity of human rabies vaccines. The data of ten cell culture human rabies vaccine studies conducted at a single centre during 1993-2004 were used in the study. The vaccines studied included Purified Chick Embryo Cell Vaccine (Kaketsuken, Japan and Rabipur, India), Purified Vero cell Rabies Vaccine (Verorab, France), Human Diploid Cell Vaccine (MIRV, France and Rabivax, Adsorbed and Lyophilized, India) and Rhesus Diploid Rabies Vaccine (adsorbed, USA). Interestingly, it was revealed that an higher antigenecity of rabies vaccines viz. potency of > or = 5 IU per single intramuscular dose did not result in significantly higher immunogenecity, as measured by rabies virus neutralizing antibody (RVNA) titers in the vaccinees, both on day 14 (t = 0.42, p > 0.66, GMR = 1.06, 95% CI of GMR = 0.82, 1.37) and day 90 (t = 0.80, p > 0.43, GMR = 1.15, 95% CI of GMR = 0.74, 1.14). However, as there are no reports of meta-analysis of cell culture human rabies vaccine trials, to confirm this observation the authors recommend further studies in this regard.