A novel drug delivery system for type 1 diabetes: insulin-mimetic vanadyl-poly(gamma-glutamic acid) complex

Insulin-mimetic vanadyl-poly(gamma-glutamic acid) complex, VO-gamma-PGA, is proposed as a novel drug delivery system for treating type 1 diabetic animals. The structure of VO-gamma-PGA in solution as well as in solid state was analyzed by electronic absorption, infra-red, and electron spin resonance spectra, and proposed that the equatorial coordination mode of VO(2+) is in either carboxylate(O)-VO-(OH(2))(3) or 2 carboxylate(O(2))-VO-(OH(2))(2). In vitro insulin-mimetic activity, metallokinetic feature in the blood of healthy rats, and in vivo normoglycemic effect of the complex prepared in solution were evaluated in streptozotocin(STZ)-induced type 1 diabetic mice, and these effects were compared with those of a solution containing only VOSO(4) as a positive control. The in vitro insulin-mimetic activity of VO-gamma-PGA was examined by determining both inhibition of free fatty acid (FFA) release and glucose uptake in isolated rat adipocytes, in which the concentration of VO-gamma-PGA for 50% inhibition of FFA release was significantly lower than that of VOSO(4). Metallokinetic study suggested that the bioavailability of VO-gamma-PGA complex was much higher than that of VOSO(4). The complex showed a significant hypoglycemic activity within at least 4h after a single oral administration, the effect being sustained for at least 24h. Furthermore, VO-gamma-PGA normalized the hyperglycemia in STZ-mice within 3 days when it was given orally at doses of 5-10mgVkg(-1) body mass for 16 days. The improvement in diabetes was also supported by the results on oral glucose tolerance test, HbA(1c) levels, and blood pressure.     

Lymphocyte surface marker genes in fugu

At present, much of the fish adaptive immune system remains unknown due to the paucity of marker-specific reagents (e.g. antibodies) to identify immune cells. The genomic sequence of Takifugu rubripes (fugu) represents an important resource to facilitate the identification of lymphocyte-related genes. Here, we review the recent works on B-lymphocyte markers, the heavy (H) chains of IgM and IgD, and Ig light chain, and T-cell marker gene homologues, CD3ε, CD3γ/δ, CD4, and CD8α in a single fish species, fugu. Expressions of these B- and T-lymphocyte markers homologues in peripheral blood leukocytes and other lymphoid tissues of fugu suggest that these molecules in fish would be available as lymphocyte markers. These findings will lead us to develop reliable reagents for the identification of lymphocyte subpopulations. Fugu holds great promise as one of the model organisms for studies of development and evolution of adaptive and innate immunity in vertebrates.     

CpG oligonucleotides enhance the tumor antigen-specific immune response of an anti-idiotype antibody-based vaccine strategy in CEA transgenic mice

A murine monoclonal anti-idiotype (Id) antibody, 3H1 has been developed and characterized previously. Anti-Id 3H1 mimics a specific epitope of carcinoembryonic antigen (CEA) and can be used as a surrogate antigen for CEA. 3H1 induced anti-CEA immunity in different species of animals as well as humans and showed promise as a potential vaccine candidate in phase I/II clinical trials for colon cancer patients. One area of interest to us has been the development of new immune adjuvants that may augment the potency of 3H1 as a tumor vaccine. Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) are potent immunostimulatory agents capable of enhancing the Ag-specific Th1 response when used as immune adjuvants. In this study, we have evaluated the efficacy of 3H1 as a tumor vaccine when admixed with a select CpG ODN 1826 in transgenic mice that express human CEA. The vaccine potential of 3H1 was also assessed in the presence of another widely used adjuvant, QS-21. 3H1 coupled to keyhole limpet hemocyanin (KLH) and mixed with Freund’s adjuvant (FA) was used as a gold standard in this system. 3H1 vaccination with different adjuvants induced both humoral and cellular anti-3H1, as well as anti-CEA immunity in CEA transgenic mice. The immune sera could lyse CEA-transfected murine colon carcinoma cells, C15 effectively in an antibody-dependent cellular cytotoxicity assay. The anti-CEA antibody responses were somewhat comparable in each adjuvant-treated group of mice, whereas cellular immune responses were significantly greater when CpG was used as an adjuvant. Splenocytes obtained from 3H1–CpG-immunized mice showed an increased proliferative CD4⁺ Th1-type T-cell response when stimulated in vitro with 3H1 or CEA and secreted elevated levels of Th1 cytokines (IL-2, IFN-γ). This vaccine also induced MHC class I antigen-restricted CD8⁺ T-cell responses. In a solid tumor model, C15 tumor growth was significantly inhibited by 3H1 vaccinations. In 3H1–CpG-vaccinated mice, the duration of survival was, however, longer compared to the 3H1–QS21-vaccinated mice. These findings suggest that 3H1-CpG vaccinations can break peripheral tolerance to CEA and induce protective antitumor immunity in this murine model transgenic for human CEA.     

Herniation of gravid uterus: report of 2 cases and review of literature

Anterior abdominal wall hernias are uncommon, and herniation of a gravid uterus into these hernias is even rarer. Although reducible initially, the herniation of pregnant uterus may be complicated by incarceration and subsequent strangulation within the hernial sac, late in the course of pregnancy. There is no consensus over the management of this rare condition. Each case should be individualized. If uncomplicated, a conservative approach until term followed by delivery and herniorrhaphy is a good option. Here, 2 cases of herniation of gravid uterus into the anterior abdominal wall are described along with a brief review of literature pertaining to its presentation, complications, and management.     

Pseudo-Second-Order Kinetic Model for Biosorption of Methylene Blue onto Tamarind Fruit Shell: Comparison of Linear and Nonlinear Methods

In this study, the sorption of methylene blue, a basic dye, onto tamarind fruit shell was studied by performing batch kinetic sorption experiments. The equilibrium kinetic data were analyzed using the pseudo-second-order kinetic model. A comparison between linear least squares method and nonlinear regression method of estimating the kinetic parameters was examined. Four pseudo-second-order kinetic linear equations were discussed. The coefficient of determination (r ²), and the chi-square (χ²) test were employed as error analysis methods to determine the best-fitting equation. Kinetic parameters obtained from four kinetic linear equations using the linear method differed but they were the same when nonlinear method was used. Present investigation showed that by linear method a Type 1 expression very well represent the kinetic uptake of methylene blue onto tamarind fruit shell. Linear method was found to check only the hypothesis instead of verifying the kinetic model. Nonlinear regression method was found to be the more appropriate method to determine the rate kinetic parameters.     

Exploration of amino alcohol derivatives as novel,potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists

In pursuit of a potent and highly selective sphingosine-1-phosphate receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration.     

Metabolism and Tissue Distribution of Trace Elements in Broiler Chickens' Fed Diets Containing Deficient and Plethoric Levels of Copper,Manganese, and Zinc

Supplementation of broiler diets with copper, manganese, and zinc at levels higher than that stipulated by the National Research Council 1994 reportedly improved live weight, feed conversion, and cured leg abnormality supposedly caused by inadequate intake of Mn and Zn. The objective of the study was to ascertain the effects of plethoric supplementation of copper (Cu), manganese (Mn), and zinc (Zn) on performance and metabolic responses in broiler chickens. The study also aimed to discriminate the responses of the birds when the mineral elements were supplemented either in an inorganic or in an organic form. Cobb 400 broiler chickens (1-day old, n = 300) were assigned to three dietary treatments each containing nine replicates with ten birds for 39 days. The treatments included a control in which the diet was devoid of supplemental trace elements and treatments supplemented with an inorganic trace element premix (ITM) and supplemented with a combination of the inorganic and an organic trace element premix (OTM). The ITM contained (per kilogram) copper, 15 g; iron, 90 g; manganese, 90 g; zinc, 80 g (all as sulfated salts); iodine (as potassium iodide), 2 g; and selenium (as sodium selenite), 0.3 g. The OTM on the other hand, contained copper, 2.5 g; iron, 15 g; manganese, 15 g; zinc, 13.33 g; and chromium, 0.226 g (all as protein chelates). Plethoric supplementation of trace elements improved live weight gain and feed/gain ratio (p < 0.05). Leg abnormality developed in the 16% of the control group of birds but not in the supplemented group. Metabolizability of dry matter, organic matter, and protein was higher (p < 0.01) in the ITM and OTM groups. Excretion of Cu, Fe, and Zn decreased (p < 0.1) due to supplementation of the trace elements leading to increased apparent absorption of the said mineral elements (p < 0.01). Concentration of the concerned trace elements in serum, liver, and composite muscle samples was higher (p < 0.05) in the ITM and OTM dietary groups indicating an increased deposition of the said mineral elements due to supplementation. Although the study revealed subtle difference between the inorganic and organic mineral premixes with regards to the parameters mentioned above, it became apparent that it is possible to reduce excretion of these trace elements by a judicious escalation in the level of supplementation. The results of the present investigation further revealed that the trace mineral requirement of broiler chickens suggested by the National Research Council may not be optimum to support the maximum growth potential of the high yielding strains, and it is reasonable to consider a review of the current NRC recommendations to meet the needs of the modern birds.     

Differential antioxidative responses of indica rice cultivars to drought stress

The present study investigated the linkages between drought stress, oxidative damages and variations in antioxidants in the three rice varieties IR-29 (salt-sensitive), Pokkali (salt-tolerant) and aromatic Pusa Basmati (PB), to elucidate the antioxidative protective mechanism governing differential drought tolerance. Water deficit, induced by 20% (w/v) polyethylene glycol (PEG-6000), provoked severe damages in IR-29 and PB in the form of huge chlorophyll degradation and elevated H₂O₂, malondialdehyde and lipoxygenase (LOX, EC 1.13.11.12) levels as compared to Pokkali. The protein oxidation was more conspicuous in IR-29. Increment in antioxidants, particularly flavonoids and phenolics was several folds higher over control in Pokkali, while much lesser in IR-29 and PB. The activity of catalase (CAT, EC 1.11.1.6) and superoxide dismutase (SOD, EC 1.15.1.1) were decreased in IR-29 and PB, but unaltered in Pokkali. However, marked drought-induced increase in guaiacol peroxidase (GPX, EC 1.11.1.7) activity was noted in both IR-29 and PB. Induction in radical scavenging activity, being the maximum in IR-29, and increased reducing power ability in all the cultivars, accompanied with drought stress, were observed as a defense mechanism. The novelty of our work is that it showed the aromatic rice PB behaving more closely to IR-29 in greater susceptibility to dehydration stress, while the salt-tolerant Pokkali also showed effective drought tolerance properties.