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Biomedical subjects

R M Welch

Publications and source records attributed to R M Welch.

At least 19 recordsLinked to original sources

Cadmium absorption and retention by rats fed durum wheat (Triticum turgidum L. var. durum) grain.

A whole-body radioassay procedure was used to assess the retention and apparent absorption by rats of Cd in kernels of durum wheat (Triticum turgidum L. var. durum) harvested from plants grown hydroponically in 109Cd-labelled nutrient solution. Wholegrain wheat, containing 5 micromol Cd (570 microg)/kg dry weight labelled intrinsically with 109Cd, was incorporated into test meals fed to rats that had been maintained on diets containing marginally adequate, adequate or surplus levels of Zn (0.12 mmol (8 mg), 0.43 mmol (28 mg) or 1.55 mmol (101 mg) Zn/kg respectively), and either 0 or 50 g durum wheat/kg. Regardless of diet, all rats consumed about 99 % of the test meal offered. In rats fed diets without wheat, initial Cd absorption averaged 7.7, 4.6 and 2.4 % of the dose when the diet contained 0.12 mmol (8 mg), 0.43 mmol (28 mg) or 1.55 mmol (101 mg) Zn/kg diet respectively. In rats fed wheat-containing diets, initial Cd absorption averaged 3.8 and 2.6 % of the dose when dietary Zn concentration was 0.12 mmol (8 mg) and 0.43 mmol (28 mg)/kg diet respectively. The amount of Cd retained in the body at 15 d postprandial was <2 % of the dose in all rats, and decreased as Zn in the diet increased. Even at 15 d postprandial, 32 to 44 % of the Cd retained in the body was still in the gastrointestinal tract. The results show that: (1) the bioavailability to rats of Cd in wholegrain durum wheat was depressed when wholegrain wheat was part of the regular diet; (2) increased intake of dietary Zn lowered Cd absorption and retention; (3) retention of Cd in the body at 15 d postprandial from diets containing adequate Zn was <1.3 %.

Analysis of Variance↗

Climatic impact of tropical lowland deforestation on nearby montane cloud forests.

Tropical montane cloud forests (TMCFs) depend on predictable, frequent, and prolonged immersion in cloud. Clearing upwind lowland forest alters surface energy budgets in ways that influence dry season cloud fields and thus the TMCF environment. Landsat and Geostationary Operational Environmental Satellite imagery show that deforested areas of Costa Rica's Caribbean lowlands remain relatively cloud-free when forested regions have well-developed dry season cumulus cloud fields. Further, regional atmospheric simulations show that cloud base heights are higher over pasture than over tropical forest areas under reasonable dry season conditions. These results suggest that land use in tropical lowlands has serious impacts on ecosystems in adjacent mountains.

Altitude↗

Genetic selection for enhanced bioavailable levels of iron in bean (Phaseolus vulgaris L.) seeds.

The bioavailability of Fe from 24 select genotypes of bean (Phaseolus vulgaris L.) seeds containing a range of concentrations of Fe, myo-inositol pentaphosphate plus phytic acid (IP5+IP6), and tannins was studied using a rat model. Bean accessions, selected from field trials for their variations in Fe, phytate, and tannin seed concentrations, were grown in a greenhouse in nutrient solutions radiolabeled with (59)Fe. Mature seeds were autoclaved and lyophilized. Test meals (containing 1 g of dried bean, 0.5 g of sucrose, and 1 g of basal Fe-deficient diet) were fed to marginally Fe-depleted weanling rats over a 3-h period; rats were radioassayed in a gamma-spectrometer immediately after feeding and daily thereafter for the next 10 d. Radioiron retention data were used to calculate percent Fe absorption (i.e., Fe bioavailability) from the meals. Seed Fe concentrations ranged from 52 to 157 microg g(-)(1) dry weight. There was a tendency to also select for higher Zn concentrations in the beans when selecting for high Fe concentrations. The Fe bioavailability to rats from test meals depended on the genotype and varied from 53% to 76% of the total Fe. Bean genotypes with higher seed Fe concentrations resulted in increased amounts of bioavailable Fe to rats. There was no significant correlation between the Fe concentration in different bean genotypes and Fe bioavailability to rats attributable to variations in IP5+IP6 or tannins, even though these antinutrients varied widely (i.e., from 19.6 to 29.2 micromol of IP5+IP6 g(-)(1) and from 0.35 to 2.65 mg of tannins g(-)(1)) in the test meals. Other unknown seed factors (i.e., antinutrients or promoter substances) may be contributing factors affecting Fe bioavailability from bean seeds.

Animals↗

Uptake and retranslocation of leaf-applied cadmium (109Cd) in diploid, tetraploid and hexaploid wheats.

Uptake and retranslocation of leaf-applied radiolabeled cadmium (109Cd) was studied in three diploid (Triticum monococcum, AA), four tetraploid (Triticum turgidum, BBAA) and two hexaploid (Triticum aestivum, BBAADD) wheat genotypes grown for 9 d under controlled environmental conditions in nutrient solution. Among the tetraploid wheats, two genotypes were primitive (ssp. dicoccum) and two genotypes modern wheats (ssp. durum). Radiolabelled Cd was applied by immersing the tips (3 cm) of mature leaf into a 109Cd radiolabelled solution. There was a substantial variation in the uptake and export of 109Cd among and within wheat species. On average, diploid wheats (AA) absorbed and translocated more 109Cd than other wheats. The largest variation in 109Cd uptake was found within tetraploid wheats (BBAA). Primitive tetraploid wheats (ssp. dicoccum) had a greater uptake capacity for 109Cd than modern tetraploid wheats (ssp. durum). In all wheats studied, the amount of the 109Cd exported from the treated leaf into the roots and the remainder of the shoots was poorly related to the total absorption. For example, bread wheat cultivars were more or less similar in total absorption, but differed greatly in the amount of 109Cd retranslocated. The diploid wheat genotype 'FAL-43' absorbed the lowest amount of 109Cd, but retranslocated the greatest amount of 109Cd in roots and remainder of shoots. The results indicate the existence of substantial genotypic variation in the uptake and retranslocation of leaf-applied 109Cd. This variation is discussed in terms of potential genotypic differences in binding of Cd to cell walls and the composition of phloem sap ligands possibly affecting Cd transport into sink organs.

Biological Transport↗

Nutritional rickets without vitamin D deficiency in Bangladesh.

To understand nutritional rickets in Bangladesh better, 14 rachitic and 13 'unaffected' children were evaluated. Seventy per cent of children with active rickets had no evidence of either vitamin D deficiency or familial rickets. Rickets in Bangladesh is probably related to calcium deficiency. Abnormalities in 'unaffected' children suggest that subclinical calcium insufficiency is common.

Bangladesh↗

Physiologic processes affecting the content and distribution of phytonutrients in plants.

Plant physiologists and biochemists are unraveling the transport mechanisms and biosynthetic pathways that determine each plant's unique phytonutrient composition so that crop plants can be modified to improve their nutrition quality. However, before this goal can be achieved, more information is needed on various plant and human phytonutrient-related processes, and some new technical capabilities are required. The current status of our knowledge base and recommendations for technical improvements and research priorities will be discussed.

Humans↗

Potent hypocholesterolemic activity of novel ureido phenoxyisobutyrates correlates with their intrinsic fibrate potency and not with their ACAT inhibitory activity.

The hypocholesterolemic activity for novel ureido fibrate analogues was found to be over 100-fold greater than for any "second-generation" fibrate in cholesterol-fed rats. A comparison of 12 related analogues revealed that the optimal configuration for a urea-bridging region located between two aromatic rings consisted of a trisubstituted nitrogen, optimally substituted with a C7 alkyl chain and linked by dimethylene to a phenoxyisobutyrate moiety found in most fibrate analogues. The hypocholesterolemic potency of these compounds was found to correlate with their increased intrinsic fibrate activity as determined by the ability to induce omega-hydroxylase activity either in rat hepatocyte cultures or in vivo, and not with their 10-fold increased ACAT inhibitory potency when compared to other fibrates. The most active compound, 2-(4-(2-(N'-(2,4- difluorophenyl)-N-heptylureido)ethyl)phenoxy)-2-methylpropionic acid, referred to as (2), was found to induce omega-hydroxylase activity in hepatocytes at concentrations between 5 and 100 nM compared to 1-20 microM concentrations for bezafibrate, and lower serum VLDL+LDL cholesterol in rats at doses between 0.1 and 0.5 mg/kg per day compared to doses of 25-100 mg/kg per day for bezafibrate. Single-dose pharmacokinetic studies with 2 indicated that total drug exposure will be much lower at hypocholesterolemic doses due to the enhanced intrinsic activity, and may result in an improved safety profile for these novel trisubstituted ureido fibrate analogues in rats and humans compared to other fibrates.

Animals↗

Food systems for improved health: linking agricultural production and human nutrition.

OBJECTIVES: Link traditional agricultural production disciplines to the food sciences and the various disciplines concerned with human nutrition and health in order to find sustainable solutions to malnutrition. DESIGN: Develop a new integrated program area within a university by forging explicit linkages within a wide array of disciplines concerned with food systems and human health. SETTING: The College of Agriculture and Life Sciences, the College of Human Ecology, the Division of Nutrition, and the Cornell International Institute for Food, Agriculture, and Development at Cornell University, Ithaca, New York, USA. INTERVENTIONS: Use food-based, system approaches to meet human nutrition goals. Current focus is on the provision of micronutrients (especially iron, vitamin A and iodine) for people globally. RESULTS: A new program area 'Food Systems for Health' has been developed at Cornell University. The program fosters effective interdisciplinary research, teaching and extension activities directed towards sustainable improvements in human nutrition and health. CONCLUSIONS: The old paradigms of agriculture, human nutrition, and public health must be shifted from current linear approaches to integrated and interactive approaches if effective long-term, food-based solutions to micronutrient malnutrition are to be found.

Agriculture↗

Agronomic problems related to provitamin A carotenoid-rich plants.

OBJECTIVES: Review how agricultural systems might be changed to increase the vitamin A density of diets in developing countries to provide sustainable solutions to vitamin A deficiency globally. DESIGN: Develop agricultural systems that not only assure calorie adequacy for people, but also address vitamin A density in diets. SETTINGS: Agricultural systems could be modified in some developing nations in ways that would provide adequate dietary amounts of provitamin A carotenoids from plant food sources. SUBJECTS: Infants and children of low-income families are most at risk of developing vitamin A deficiency in developing countries. INTERVENTIONS: Cropping systems could be modified to include more vegetable and fruit crops containing higher bioavailable amounts of provitamin A carotenoids in some countries. Additionally, cultural practices could be modified through education, agricultural extension and/or social marketing to insure that the bioavailable provitamin A carotenoid levels in food crops are optimized. Staple food crops could be improved as sources of provitamin A carotenoids by traditional plant breeding and/or by genetic engineering efforts. RESULTS: Currently, many techniques are available to increase the vitamin A content of diets through sustainable food-based approaches. Agricultural approaches should be examined closely to finding sustainable food-based system solutions to vitamin A deficiency globally. CONCLUSIONS: The world community should strive to find food-based system approaches to eliminating vitamin A deficiency. Modifying agricultural systems in ways that will not only maximizing food production, but also insure nutritional adequacy of vitamin A is a desirable goal for many developing countries.

Agriculture↗

The in vitro degradation of cisatracurium, the R, cis-R'-isomer of atracurium, in human and rat plasma.

OBJECTIVE: To assess the mechanism and rate of in vitro degradation of cisatracurium in aqueous buffer and in human and rat plasma. METHODS: Cisatracurium was incubated in aqueous buffer at various pH values or in human and rat plasma maintained at pH 7.4 with HEPES buffer. Cisatracurium and the degradation products, laudanosine and the monoquaternary alcohol, were quantitated by HPLC with use of fluorescence detection. RESULTS: In Sørenson's phosphate buffer, cisatracurium degraded spontaneously by a chemical process commonly referred to as "Hofmann elimination." The rate of degradation increased with increasing pH. From pH 6.4 to 7.8 there was a 6.5-fold increase in the rate of degradation of cisatracurium and, on a molar basis, the final decomposition product laudanosine accounted for all of the drug. At a pH of 7.4, cisatracurium degraded with a half-life of about 34.1 +/- 2.1 minutes. Cisatracurium incubated in human plasma degraded with a mean (+/- SD) half-life of 29.2 +/- 3.8 minutes, which is consistent with Hofmann elimination. Besides laudanosine, and unlike that observed in Sørenson's phosphate buffer, significant amounts of the monoquaternary alcohol were formed that slowly degraded to laudanosine. The micromoles of laudanosine formed eventually accounted for the total amount of cisatracurium incubated with human plasma. The monoquaternary alcohol appears to be a product of ester hydrolysis of a monoquaternary acrylate formed during the first step in Hofmann elimination. Evidence for esterase involvement at this step in the degradation of cisatracurium was based on inhibition studies with O-cresyl benzodioxaphosphorin oxide (CBDP), a specific carboxylesterase inhibitor. The addition of CBDP to human plasma completely blocked the formation of monoquaternary alcohol and converted the degradation of cisatracurium to total Hofmann elimination. In rat plasma cisatracurium was hydrolyzed, with a half-life of only 3 1/2 minutes, by carboxylesterases. The addition of CBDP increased the half-life to 25 minutes, which is consistent with Hofmann elimination. CONCLUSION: In human plasma the rate-limiting step in the degradation of cisatracurium is Hofmann elimination, with the initial formation of a monoquaternary acrylate. The observation that the monoquaternary alcohol results from ester hydrolysis of the monoquaternary acrylate by plasma esterase(s) explains the presence of the monoquaternary alcohol metabolite in human plasma during clinical studies with cisatracurium. The rapid hydrolysis of cisatracurium by rat plasma relative to human indicates a major species difference in plasma esterase(s).

Alcohols↗

Pharmacokinetics and pharmacodynamics of a new cardiotonic vasodilator agent, 349U85, in normal subjects.

OBJECTIVE: To assess the pharmacodynamics and pharmacokinetics of single oral doses of a new vasodilator-cardiotonic agent, 349U85 hydrochloride [6-piperidino-2(1H)-quinolinone hydrochloride], in healthy male subjects. METHODS: This randomized, parallel, double-blind, placebo-controlled, dose escalation trial was conducted at a university-based clinical research center among 27 healthy male subjects. Data measurements used in the study included cardiac index, supine and standing blood pressure, 24-hour ambulatory electrocardiography, and 12-lead electrocardiography. RESULTS: Doses from 2 mg to 250 mg were well tolerated. Cardiac index, supine heart rate, and orthostatic hypotension, indicators of inotropic, chronotropic, and vasodilator effects, respectively, correlated to plasma concentrations of 349U85 and of its metabolite, 661U88. Results suggest that 349U85 may be more responsible for inotropic effects, whereas 661U88 may be more responsible for vasodilatory and chronotropic effects. These results are consistent with the preclinical pharmacologic profile for these two compounds. Headache, orthostatic dizziness, and hypotension tended to occur more frequently at higher doses and were temporally related to drug administration. Pharmacokinetic analyses indicate nonlinearity of 349U85 and 661U88, suggestive of saturation of metabolism and large interindividual variability in maximum plasma drug concentration and area under the plasma concentration-time curve. The source of the variability is not known. The time to maximum distribution was approximately 0.7 hours for both 349U85 and 661U88; the terminal elimination half-life was 1 hour for 349U85 and 3 hours for 661U88. Holter monitoring revealed asymptomatic increases in ventricular and supraventricular ectopic activity in some volunteers; ectopy appeared to be related to the dose of 349U85 and generally occurred at higher doses.

Adult↗

Stereoselective high-performance liquid chromatographic assay with fluorometric detection for the isomers of mivacurium in human plasma.

A high-performance liquid chromatographic assay with fluorometric detection was developed for the analysis of the stereoisomers of mivacurium, a new short-acting neuromuscular blocker, in plasma. The isomers were isolated from plasma by solid-phase extraction with C18 and anion-exchange cartridges. The extracts were chromatographed on a LiChrosphere 60 RP Select B column (125 mm x 4.6 mm I.D.) using a mobile phase of acetonitrile-water (4:6, v/v) containing 0.005 M octanesulfonic acid. The fluorescence excitation and emission wavelengths were 202 and 320 nm, respectively. The accuracy and precision of the assay, expressed as the percentage deviation of measured values from true values and the percentage coefficient of variation, respectively, were less than or equal to 10% at all concentrations except for the percentage coefficient of variation at the lower limit of quantitation (5 ng/ml). The assay has been successfully used for the analysis of plasma samples from a pharmacokinetic study in human volunteers.

Chromatography, High Pressure Liquid↗

Pharmacokinetics of mivacurium in normal patients and in those with hepatic or renal failure.

We have determined the pharmacokinetics and duration of action of a bolus dose of mivacurium (0.15 mg kg-1) during isoflurane and nitrous oxide anaesthesia in nine patients with normal renal and liver function, nine patients undergoing cadaveric kidney transplantation and nine patients undergoing cadaveric liver transplantation. Total plasma concentrations of mivacurium were measured for 2.5 h after administration using a high-pressure liquid chromatographic assay. Plasma concentration vs time data for what were presumed to be the two active mivacurium isomers were analysed by a non-compartmental method based on statistical moments. Neuromuscular block was assessed by measuring the electromyographic evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. The mean time to recovery of 25% neuromuscular transmission, T25, was greater in the patients with liver failure (57.2 min) than in control patients (18.7 min). The volume of distribution at steady rate (Vdss) was comparable in the three groups. Patients with impaired liver function had significantly longer mean residence time and smaller plasma clearance than did patients with renal failure or control patients. There were significant negative correlations between plasma cholinesterase activity and both T25 (r = 0.79) and mean residence time (r = 0.62).

Adult↗

Pharmacokinetics and pharmacodynamics of doxacurium in normal patients and in those with hepatic or renal failure.

We determined the pharmacokinetics and duration of action of a bolus dose of doxacurium (15 micrograms/kg) in 27 patients anesthetized with isoflurane and nitrous oxide. Nine patients had normal renal and liver functions and were undergoing a variety of surgical procedures, nine were undergoing cadaveric kidney transplantation because of end-stage renal disease, and nine were undergoing cadaveric liver transplantation because of end-stage hepatocellular disease. Plasma concentrations of doxacurium were measured for 6 h after administration using a sensitive and specific capillary gas chromatographic assay. Plasma concentration versus time data were analyzed by a noncompartmental method based on statistical moments. Neuromuscular blockade was assessed by measuring the electromyographic evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. The degree of neuromuscular blockade after doxacurium administration was described as the percent of control of the first train-of-four response. The pharmacokinetic variables were (normal vs hepatic failure vs renal failure, respectively): volume of distribution at steady state (220 +/- 110 vs 290 +/- 60 vs 270 +/- 130 mL/kg [mean +/- SD]), plasma clearance (2.7 +/- 1.6 vs 2.3 +/- 0.4 vs 1.2 +/- 0.7 mL.kg-1.min-1), mean residence time (95.2 +/- 57 vs 129.4 +/- 30 vs 270 +/- 210 min), and elimination half-life (99 +/- 54 vs 115 +/- 31 vs 221 +/- 156 min). Plasma clearance and mean residence time differed significantly between patients with renal failure and control patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Accumulation of apoplastic iron in plant roots : a factor in the resistance of soybeans to iron-deficiency induced chlorosis?

We hypothesized that the resistance of Hawkeye (HA) soybean (Glycine max L.) to iron-deficiency induced chlorosis (IDC) is correlated to an ability to accumulate a large pool of extracellular-root iron which can be mobilized to shoots as the plants become iron deficient. Iron in the root apoplast was assayed after efflux from the roots of intact plants in nutrient solution treated with sodium dithionite added under anaerobic conditions. Young seedlings of HA soybean accumulated a significantly larger amount of extracellular iron in their roots than did either IDC-susceptible PI-54619 (PI) soybean or IDC-resistant IS-8001 (IS) sunflower (Helianthus annus L.). Concurrently, HA soybean had much higher concentrations of iron in their shoots than either PI soybean or IS sunflower. The concentration of iron in the root apoplast and in shoots of HA soybean decreased sharply within days after the first measurements of extracellular root iron were made, in both +Fe and -Fe treatments. The accumulation of short-term iron reserves in the root apoplast and translocation of iron in large quantities to the shoot may be important characteristics of IDC resistance in soybeans.

Journal Article↗

Pleiotropic Effects of brz: A Mutation in Pisum sativum (L.) cv ;Sparkle' Conditioning Decreased Nodulation and Increased Iron Uptake and Leaf Necrosis.

Treatment of Pisum sativum (L.) cv ;Sparkle' with ethylmethane sulfonic acid produced a stable mutant, E107, which forms few nodules. The mutant allele exhibits other pleiotropic properties including bronze necrotic spots on the leaflets and high accumulation of iron in the shoot. The mutant phenotype is under monogenic recessive control. The gene, designated brz (bronze), is nonallelic with two other genes conditioning necrotic spots on leaves of other mutants of P. sativum. The brz allele was located on chromosome 4 by linkage with wax production controlled by alleles at the was locus.

Journal Article↗