Selective potentiation of 5-methyl-2-(1-methylcyclohexyl)-4-oxazoleacetic acid (AD-4610) on glucose-induced insulin secretion

In the perfused pancreas from normal SD rats, AD-4610 (0.01-0.1 mM) potentiated biphasic insulin secretion induced by 7.5 mM of glucose. The concentration-response curve of insulin secretion to glucose was shifted leftwards with AD-4610 (0.1 mM) without altering either the threshold concentration of glucose to induce insulin secretion or the maximal insulin response to glucose, indicating increased sensitivity of the pancreatic B-cells to glucose. On the other hand, AD-4610 was 10-fold less effective in altering insulin secretion induced by arginine and glyceraldehyde. The effect of AD-4610 on insulin secretion and glucose metabolism was compared with that of tolbutamide in vivo. AD-4610 (100 mg/kg) potentiated insulin secretion induced by an intravenous glucose load, and also accelerated glucose metabolism without altering basal insulin secretion in normal rats. On the other hand, tolbutamide (20 mg/kg) increased basal insulin secretion, but slightly decreased glucose-induced insulin secretion. In yellow KK mice with hyperglycemia, AD-4610 (10-100 mg/kg) had a dose-dependent hypoglycemic action, but tolbutamide did not. Thus, AD-4610 stimulated insulin secretion in a glucose-dependent fashion and enhanced glucose metabolism in vivo. These results suggest that AD-4610 selectively potentiates glucose-induced insulin secretion by increasing the sensitivity of pancreatic B-cells to glucose and may be useful for treating human NIDDM through a different mechanism than that of tolbutamide.     

Antibody-dependent cell-mediated cytotoxicity against cells infected with respiratory syncytial virus: characterization of in vitro and in vivo properties

An in vitro 51Cr release assay for human antibody-dependent cell-mediated cytotoxicity (ADCC) against HeLa cells infected with respiratory syncytial virus (RSV) has been characterized by using leukophoresed and adherent cell-depleted adult lymphocytes. Lymphoytes from RSV seronegative children were also competent as effector cells. Sera from children with :1) primary and recurrent natural RSV infections, or 2) live attenuated RSV vaccine infection were examined to characterize the behavior of ADCC antibody in vivo. After natural RSV infection ADCC antibody rose and fell more rapidly than neutralizing antibody. In two children undergoing primary RSV infection with attenuated vaccine, neutralizing antibody was formed in the absence of detectable ADCC antibody. The nonparallel behavior of ADCC and neutralizing antibodies suggests the heterogeneity of either the antigen involved or the mechanism of antibody production in the two antibody systems.     

A new approach to determine the stereospecificity in lipase catalysed hydrolysis using circular dichroism (CD): lipases produce optically active diglycerides from achiral triglycerides

We describe a sensitive CD method for determining the stereospecificity in lipase (E.C.3.1.1.3) catalysed hydrolysis of triacyl glycerols into diacyl glycerols. The diglycerols were converted to chiral tert-butyldimethylsilylated 1,2- or 2,3-di-O-benzoyl-sn-glycerol (5 or 5'), and their CD was measured. This approach showed for the first time that lipases produce optically active diacyl glycerides from achiral tripalmitin and tribenzoyl glyceride with a variable extent of enantioselectivity depending on the acyl groups and the enzymes.     

Isolation and characterization of calcitonin from pericardium and esophagus of eel.

Calcitonin was extracted from the pericardium and esophagus of eel in quantities sufficient to permit purification and chemical characterization. Homogeneous calcitonin could be isolated by a six-step fractionation starting from acetone powder of the organs. The fractionation procedure consisted of acid extraction, gel filtration on Sephadex G-75, chromatography on SP-Sephadex C-25, gel filtration on the Sephadex G-50, chromatography on carboxymethylcellulose, and gel filtration on Sephadex G-50. Fractionation of the hormone was monitored by assay of its biological activity and from its behaviour on thin layer chromatography and polyacrylamide gel disc electrophoresis. The hormone contained 32 amino acid residues, like calcitonins from other species of animals, but its amino acid composition was different from those of previously characterized hormones. Eel calcitonin possessed almost the same, or higher, biological activity as the salmon or chicken hormone, which show the highest specific activity among calcitonins so far isolated.     

Mouse arylamine N-acetyltransferase 2 (Nat2) expression during embryogenesis: a potential marker for the developing neuroendocrine system

Arylamine N-acetyltransferase (NAT) genes in humans and in rodents encode polymorphic drug metabolizing enzymes. Human NAT1 (and the murine equivalent mouse Nat2) is found early in embryonic development and is likely to have an endogenous role. We report the detailed expression of the murine gene (Nat2) and encoded protein in mouse embryos, using a transgenic mouse model bearing a lacZ transgene inserted into the coding region of mouse Nat2. In mouse embryos, the transgene was expressed in sensory epithelia, epithelial placodes giving rise to visceral sensory neurons, the developing pituitary gland, sympathetic chain and urogenital ridge. In Nat2^+/+ mice, the presence and activity of Nat2 protein was detected in these tissues and their adult counterparts. Altered expression of the human orthologue in breast tumours, in which there is endocrine signalling, suggests that human NAT1 should be considered as a potential biomarker for neuroendocrine tissues and tumours.     

An Invasive Fish and the Time-Lagged Spread of Its Parasite across the Hawaiian Archipelago

Efforts to limit the impact of invasive species are frustrated by the cryptogenic status of a large proportion of those species. Half a century ago, the state of Hawai''i introduced the Bluestripe Snapper, Lutjanus kasmira, to O''ahu for fisheries enhancement. Today, this species shares an intestinal nematode parasite, Spirocamallanus istiblenni, with native Hawaiian fishes, raising the possibility that the introduced fish carried a parasite that has since spread to naïve local hosts. Here, we employ a multidisciplinary approach, combining molecular, historical, and ecological data to confirm the alien status of S. istiblenni in Hawai''i. Using molecular sequence data we show that S. istiblenni from Hawai''i are genetically affiliated with source populations in French Polynesia, and not parasites at a geographically intermediate location in the Line Islands. S. istiblenni from Hawai''i are a genetic subset of the more diverse source populations, indicating a bottleneck at introduction. Ecological surveys indicate that the parasite has found suitable intermediate hosts in Hawai''i, which are required for the completion of its life cycle, and that the parasite is twice as prevalent in Hawaiian Bluestripe Snappers as in source populations. While the introduced snapper has spread across the entire 2600 km archipelago to Kure Atoll, the introduced parasite has spread only half that distance. However, the parasite faces no apparent impediments to invading the entire archipelago, with unknown implications for naïve indigenous Hawaiian fishes and the protected Papahānaumokuākea Marine National Monument.     

Neurologically normal development of a patient with severe methionine adenosyltransferase I/III deficiency after continuing dietary methionine restriction

Background

There is not much information on established standard therapy for patients with severe methionine adenosyltransferase (MAT) I/III deficiency.

Case presentation

We report a boy with MAT I/III deficiency, in whom plasma methionine and total homocysteine, and urinary homocystine were elevated. Molecular genetic studies showed him to have novel compound heterozygous mutations of the MAT1A gene: c.191T>A (p.M64K) and c.589delC (p.P197LfsX26). A low methionine milk diet was started at 31 days of age, and during continuing dietary methionine restriction plasma methionine levels have been maintained at less than 750 μmol/L. He is now 5 years old, and has had entirely normal physical growth and psychomotor development.

Conclusions

Although some severely MAT I/III deficient patients have developed neurologic abnormalities, we report here the case of a boy who has remained neurologically and otherwise normal for 5 years during methionine restriction, suggesting that perhaps such management, started in early infancy, may help prevent neurological complications.