Synthesis and molecular modeling of a lisinopril-tryptophan analogue inhibitor of angiotensin I-converting enzyme

With a view to developing a more C-domain-selective angiotensin I-converting enzyme (ACE)-inhibitor, a novel analogue of lisinopril has been synthesized which incorporates a bulky P(2)(') tryptophan functionality. This inhibitor demonstrated a significantly increased specificity for the C-domain as compared with lisinopril. Molecular docking revealed hydrophobic and hydrogen-bonding interactions with residues of the C-domain S(2)(') subsite.     

Harmonised Australian Reference Intervals for Serum PINP and CTX in Adults

Bone turnover markers (BTMs) are classified as either formation or resorption markers. Their concentrations in blood or urine of adults are considered to reflect the rate of bone remodelling and may be of use in the management of patients with bone disease. Major inter-method differences exist for BTMs, and harmonisation of methods is currently being pursued at an international level. Based on published data, this article describes age- and sex-specific Australian consensus reference intervals for adults for serum procollagen type I amino-terminal propeptide (s-PINP) and serum β-isomerised carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX).     

RCPAQAP First Combined Measurement and Reference Interval Survey

Reference intervals are commonly considered to allow for between-laboratory bias. The RCPAQAP Liquid Serum Chemistry Program has collected data on laboratory measurements as well as reference intervals. This allows assessment of the between-laboratory variation in results, reference intervals and the information transmitted by the combination of these factors. For the majority of common chemistry analytes, the between-laboratory variation in reference intervals is greater than the variation in results. Additionally the reference interval variation is generally not related to bias between the results. Use of common reference intervals, either as an average of the current intervals in use, or the intervals proposed by the AACB Harmonisation Group, improved the variation seen in the information produced by different laboratories.     

Ecology of Biomphalaria (Gastropoda: Planorbidae) in Lake Albert, Western Uganda: snail distributions, infection with schistosomes and temporal associations with environmental dynamics

In Lake Albert, an ecological study was conducted, between June 2000 and May 2003, which assessed snail population dynamics, parasite infection patterns and interplay of environmental factors upon Biomphalaria. Monthly sampling surveys were conducted at 29 sites monitoring populations of Biomphalaria stanleyi and Biomphalaria sudanica. Altogether, a total of 21,715 B. stanleyi and 8452 B. sudanica were collected during the period. Both species could be found infected with Schistosoma mansoni although infection prevalence was significantly higher (p < 0.01**) in B. stanleyi (4.4%) than in B. sudanica (3.5%). Each species occupied slightly different aquatic niches with B. stanleyi preferring deeper water habitats whilst B. sudanica was found along the shoreline in shallower water. B. stanleyi was more widely distributed among the sampling locations (19 sites) than B. sudanica (10 sites). Of the four villages included in the study area, snails from sites near Piida and Bugoigo villages had the highest schistosome infection rates, presumably attributable to the closer proximity of people with intestinal schistosomiasis. After inspection of cross-correlation plots which identified most suitable time lags, snail density dynamics could be associated with seasonal variations inclusive of: air temperature, rainfall, lake level, water temperature, water conductivity and water pH. These temporal observations better reveal the relationship between snail populations and environmental factors, providing important information concerning the relative roles of B. stanleyi and B. sudanica in transmission of S. mansoni and development of integrated strategies for disease control around Lake Albert.     

Regulation of the transferrin-independent iron transport system in cultured cells

Mammalian cells accumulate iron via the binding of transferrin to high affinity surface receptors, or through a transferrin-independent pathway which involves the uptake of iron-organic anion chelates by a membrane-based transport system. Previously we determined that the transferrin-independent transport system was present on a wide variety of cultured cells (Sturrock, A., Alexander, J., Lamb, J., Craven, C. M., and Kaplan, J. (1990) J. Biol. Chem. 265, 3139-3145). In this communication we demonstrate that the transferrin-independent iron uptake system is regulated differently than the transferrin-mediated pathway. The activity of the transferrin-independent system was unaffected by changes in cellular growth rate, induction of DNA synthesis and cell division, or depletion of cellular iron. Exposure of cells to ferric or ferrous iron, however, resulted in a time-dependent increase in transport activity, due to a change in Vmax with no change in Km. Increased transport activity was seen in a variety of cultured cell types, occurred in the presence of cycloheximide, and persisted for hours after removal of iron. The ability of other transition metals to induce changes in transport, or to compete with iron for accumulation by the transferrin-independent uptake system, was critically dependent on the composition of the media in which the cells were incubated. Metals such as Cu2+ or Zn2+, but not Cd2+ or Mn2+, when dissolved in a balanced salt solution buffered with 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, induced changes in the transferrin-independent iron transport system. The same metals which induced changes in transport were ineffective in media containing amino acids, ascorbate, or N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine. The Vmax of the transferrin-independent iron transport system was also elevated by increases in intracellular Ca2+. The effect of iron on transport activity, however, did not result from an iron-induced release of intracellular Ca2+. These results suggest a novel form of regulation in which the presence of extracellular iron induces the appearance of previously cryptic transporters and thus accelerates the clearance of potentially toxic molecules.     

Attempts to manipulate specific responses to induce resistance to Schistosoma mansoni in Kenyan baboons (Papio anubis)

Attempts were made to manipulate specific responses of baboons to protect them from infection with Schistosoma mansoni. In Experiment 1, eosinophilia was induced in naive baboons with Trichinella spiralis larvae given intravenously before intraperitoneal injection of globulin fractions from S. mansoni-infected baboon sera and subsequent percutaneous exposure to S. mansoni cercariae. In Experiment 2, baboons with 8- or 32-week-old primary S. mansoni infections received T. spiralis i.v. before an S. mansoni challenge. In experiments 3 to 5 respectively, naive baboons received intramuscularly before challenge: formalin-fixed S. mansoni schistosomula, with Bordetella pertussis as an adjuvant; a preparation of S. mansoni adult worm teguments; and a preparation of IgE-immune complexes obtained from S. mansoni-infected rat sera, with Freunds Complete Adjuvant. Minor, but statistically insignificant, protection was obtained in Experiments 2 (32-week infections) and 3, but was far less than that given by intact, irradiated living vaccines. There are signs on the horizon of non-living vaccines protecting rodents against S. mansoni infection and it would be prudent, as with drugs, to test these in primates before proceeding to man. The results of our experiments, though essentially negative, should help the design of any future vaccine trials in primates.     

Natural occurrence of deoxynivalenol, 3-acetyl-deoxynivalenol, 15-acetyl-deoxynivalenol,nivalenol, 4,7-dideoxynivalenol,and zearalenone in polish wheat

Three wheat samples collected in 1987 in Central Poland and naturally infected withFusarium spp were analyzed for the presence ofFusarium spp andFusarium toxins. Heads were separated into three fractions: kernels with visibleFusarium damage, healthy looking kernels, and chaff + rachis. The samples contained deoxynivalenol (2.0 – 40.0μg/g), nivalenol (O.O1μg/g), 4,7-dideoxynivalenol (0.10 – 0.15μg/g). 15-acetyldeoxynivalenol (0.10–2.00 μg/g), 3-acetyldeoxynivalenol (O/1Oμg/g), and zearalenone (0.01–2.00μg/g). This is the first report about 15 - acetyldeoxynivalenol in European wheat and the co-occurrence of 3 - acetyldeoxynivalenol and 15-acetyldeoxynivalenol in the same sample of contaminated cereals.     

Raised titres of anti-klebsiella IgA in ankylosing spondylitis,rheumatoid arthritis,and inflammatory bowel disease

Serum titres of IgA are raised in ankylosing spondylitis and increased titres of antibodies to klebsiella have also been reported. The humoral response was investigated in ankylosing spondylitis and other inflammatory disorders. IgA antibodies to klebsiella pneumoniae K43 were measured in patients with ankylosing spondylitis, Crohn''s disease, ulcerative colitis, and rheumatoid arthritis and in controls. Significantly raised median titres of anti-klebsiella IgA, measured as optical density at 405 nm with an enzyme linked immunosorbent assay (ELISA), were seen among the patients with ankylosing spondylitis (0·7), Crohn''s disease (0·8), rheumatoid arthritis (0·6), and ulcerative colitis (0·8) compared with controls (0·4). Activity of disease in ankylosing spondylitis and titres of anti-klebsiella IgA were not correlated. In contrast, titres of anti-klebsiella IgM were significantly lower in patients with ankylosing spondylitis and ulcerative colitis.The increase in the titres of anti-klebsiella IgA may be due to increased permeability of the gut to bacterial antigens, leading to an increased IgA response in the gut mucosa and permitting the release of IgA into the circulation. As the increased antibody titres were seen in Crohn''s disease and rheumatoid arthritis as well as in ankylosing spondylitis the response may be non-specific, occurring because of possible underlying inflammatory bowel disease in these conditions.