FMD empty capsids combined with the Immunostant Particle Adjuvant -ISPA or ISA206 induce protective immunity against foot and mouth disease virus.

Foot and Mouth Disease Virus (FMDV) causes economy losses and is controlled by vaccination in many countries. Vaccine formulations based on empty capsids or Virus-Like Particles (VLPs) have the advantage of avoiding the biological hazard of using infectious FMDV, albeit are poorly immunogenic. Recently, we have described that ISPA a new Immune Stimulating Complex adjuvant, is useful to improve the response against FMD of vaccines that use inactivated virus. Now, the adjuvant effects of ISPA and ISA 206 (water/oil/water) on a VLPs-based FMD vaccine were evaluated. VLPs (strain A/Argentina/2001) were obtained in mammalian cell cultures and their elicitation of an immune response against FMDV with and without ISPA or ISA 206 was evaluated in mice as a first approach. Notably, VLPs-ISPA and VLPs-ISA 206 vaccines induced protection against viral challenge in 100 % of mice, while protection induced by VLPs alone was of 40 %. Total and neutralizing FMDV antibodies were higher in the VLPs-ISPA and VLPs-ISA 206 groups compared to the VLPs group. VLPs-ISPA induced significantly higher (p < 0.001) IgG1, IgG2a, IgG2b and IgG3 titers than the VLPs vaccine. Moreover, in comparison with non-adjuvanted VLPs, VLPs-ISPA and VLPs-ISA 206 elicited an increased virus-specific T response, including higher IFNγ+/CD8 + lymphocyte production in mice. When these vaccines were tested in calves, antibody titers reached an Expected Percentage of Protection (EPP) above 90 % in the case of the VLPs-ISPA and VLPs-ISA 206 vaccines, while, in the VLPs group, EPP reached 25 %. IFNγ levels secreted by mononuclear cells of VLP-ISPA-vaccinated cattle were significantly higher than in the VLPs group. Overall, the results demonstrate that VLPs-ISPA or VLPs-ISA 206 are promising formulations for the development of a novel FMD vaccine.

Severe hypoglycemia in users of sulfonylurea antidiabetic agents and antihyperlipidemics.

Drug-drug interactions causing severe hypoglycemia due to antidiabetic drugs is a major clinical and public health problem. We assessed whether sulfonylurea use with a statin or fibrate was associated with severe hypoglycemia. We conducted cohort studies of users of glyburide, glipizide, and glimepiride plus a statin or fibrate within a Medicaid population. The outcome was a validated, diagnosis-based algorithm for severe hypoglycemia. Among 592,872 persons newly exposed to a sulfonylurea+antihyperlipidemic, the incidence of severe hypoglycemia was 5.8/100 person-years. Adjusted hazard ratios (HRs) for sulfonylurea+statins were consistent with no association. Most overall HRs for sulfonylurea+fibrate were elevated, with sulfonylurea-specific adjusted HRs as large as 1.50 (95% confidence interval (CI): 1.24-1.81) for glyburide+gemfibrozil, 1.37 (95% CI: 1.11-1.69) for glipizide+gemfibrozil, and 1.63 (95% CI: 1.29-2.06) for glimepiride+fenofibrate. Concomitant therapy with a sulfonylurea and fibrate is associated with an often delayed increased rate of severe hypoglycemia.

The effects of a low-carbohydrate versus low-fat diet on adipocytokines in severely obese adults: three-year follow-up of a randomized trial.

BACKGROUND: Adipocytokines are associated with insulin resistance and cardiovascular disease and can be modified with weight loss. While we previously demonstrated weight loss and a reduction in leptin in obese adults who followed a low-carbohydrate diet for 6 months, the long-term effects of this diet on adipocytokines are unknown. METHODS: 132 obese adults with a body mass index of > or = 35 kg/m2 were randomized to receive one year of dietary counseling to follow either a low-carbohydrate diet < 30 g/day (LC) or a caloric-restricted diet (reduced by 500 calories/day with < 30% of calories from fat) (LF). Weight, leptin, adiponectin, TNF-alpha, CRP, and insulin were measured at 0, 6, and 36 months (24 months post-counseling). Follow-up data at was collected for 53 participants who returned at 36 months. RESULTS: Mean weight change from baseline was not different between the groups at 36 months. Between 6 and 36 months weight was unchanged for LF, while LC appeared to regain weight [+ 4.84 +/- 35.6 kg (+ 3.0%)]. This difference, however, was not significant (p = 0.08). Leptin was unchanged in LF at both 6 and 36 months. In LC leptin decreased by 8.49 +/- 6.4 ng/mL or 22.7% at 6 months (p < 0.001) and increased by 10.68 +/- 25.2 ng/mL or 41.9% between 6 and 36 months (p = 0.02). There were no differences in insulin, adiponectin, TNF-alpha, or CRP between the groups. CONCLUSIONS: Favorable changes in leptin that accompany weight loss are not sustained in individuals who followed a low-carbohydrate diet for one year. A low-carbohydrate diet had no significant effect on insulin, adiponectin, TNF-alpha, or CRP compared to a low-fat diet at 36 months.

Smooth muscle cell hypertrophy and hyperplasia in the partially obstructed gut of the rat: a quantitative evaluation.

Partial surgical stenosis of the gut induces smooth muscle cell hypertrophy and hyperplasia in the loops upstream from the obstruction in a few days. In the present study we report a quantitative evaluation of these phenomena in the circular smooth muscle layer of the small intestine of the rat 7 days after a subtotal stenosis. In the loops upstream from the obstruction, lumen diameter and muscle wall thickness were found to be increased in comparison with downstream tracts. Morphometrical analysis showed that cross-sectional profile areas of smooth muscle cells, within the circular layer of upstream loops, significantly increased in size. Moreover, smooth muscle underwent a marked cell hyperplasia; in fact, estimates of the number of smooth muscle cell nuclear profiles turned out to be from 2.0 to 3.8 times greater in upstream loops than in downstream loops. The relation between the degree of lumen dilatation and the degree of the increase of the circular muscle layer thickness and of hypertrophic and hyperplastic response is discussed.

Vitamin A preserves the cytotoxic activity of adriamycin while counteracting its peroxidative effects in human leukemic cells in vitro.

Previous results from our laboratory gave evidence that safe doses of vitamin A were very effective in protecting rats from adriamycin-induced oxidative stress and lethal cardiotoxicity (Tesoriere, L. et al. (1994) J. Pharmacol. Experim. Ther. 269, 430-436). This was an incentive also to evaluate whether or not vitamin A affected the antitumor activity of adriamycin. K562 human erythroleukemia cells were exposed to adriamycin or to adriamycin plus vitamin A. Presence of 2.5 to 15 microM all-trans retinol in the cell culture did not impair the cytotoxicity of adriamycin. Rather, an enhanced cell death was observed when cell colony was exposed to both compounds. Additional assays showed that all-trans retinol counteracted the lipoperoxide formation, assayed as malondialdehyde, induced in cell cultures by the redox cycling activity of adriamycin. These data strongly encourage a new therapeuthical approach with safe doses of vitamin A as an adjuvant in cancer chemotherapy.