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Biomedical subjects

R Wilson

Publications and source records attributed to R Wilson.

At least 865 records · Page 48Linked to original sources
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Structural and conformational modifications of alpha-MSH/ACTH4-10 provide melanotropin analogues with highly potent behavioral activities.

Previous studies have identified the (4-10) heptapeptide sequence as the central core of alpha-MSH/ACTH peptides required for mediation of important biological activities. In the present study, the structure-activity relationships of Nle4-substituted and Cys4,Cys10-bridged cyclic alpha-MSH analogues, which were previously shown to exhibit a wide range of melanotropic potencies from weak agonism to super potency, were examined for grooming behavioral activity in the rat following intracerebroventricular injections. The results showed that stepwise C-terminal elongation of the linear Nle4-substituted Ac-alpha-MSH4-10-NH2 increased grooming potencies of the peptides in a manner similar to their actions on melanocytes. The most interesting finding was the observation that cyclization of the inactive linear "central (4-10) core" of alpha-MSH (Ac-alpha-MSH4-10) to form Ac-[Cys4,Cys10]-alpha-MSH4-10-NH2 resulted in a super potent agonist in the grooming assay. However, while cyclization of the (4-10) heptapeptide produced potent agonists on grooming behavior, the structure-activity relationships were different than the frog skin bioassay. These findings support the hypothesis that appropriate structural and confirmational modifications of alpha-MSH-related peptides can produce profound effects on the bioactivities of the peptides, and suggest that different structural-conformational requirements exist for alpha-MSH interactions with its various receptors.

Adrenocorticotropic Hormone↗
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Factors influencing maternal behavior in the hubb/hubb mutant mouse.

We examined the maternal behavior of hubb/hubb mutant mice and normal control (+/hubb) siblings. From previous observations we noted that mutants groom their pups less, suckle less than normal, and often cannibalize the young. To date, these observations had not been quantified. Although prolactin (PRL) is linked to maternal behavior, it was difficult to measure because of the hyperirratibility of the mutant mice. Consequently, dopamine (DA) and its metabolite, dihydroxyphenylacetic acid (DOPAC), were measured in the median eminence in brains of both normal and mutant mice. Tyrosine hydroxylase, the rate-determining step in dopamine synthesis, was localized in the brain by immunohistochemistry. Five mutant and nine normal dams were observed for pup retrieval and crouching. Mean time for pup retrieval was slower (p < 0.06) for mutants (28.09 s) than for normal dams (18.49 s). Crouching was the same for both strains. Mutant pups were cold to the touch, and not well groomed. Brains from both strains were examined at Day 11 and Day 18 of gestation and Day 2 and Day 11 of lactation. Qualitatively, tyrosine hydroxylase localization in the arcuate nucleus and median eminence was the same in both strains for the gestation samples. The decrease in staining observed from gestation to lactation in the normal mice was increased in the mutants. Dopamine was similar in both strains at all stages, but DOPAC was significantly higher at early lactation in the mutants. We do not assume an absolute inverse relationship between dopaminergic activities and prolactin, but it is likely that the increase in DOPAC in the mutant reflects a decrease in prolactin, which could contribute to the diminished maternal care in the mutants.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

The fate of ingested glyceran esters of condensed castor oil fatty acids [polyglycerol polyricinoleate (PGPR)] in the rat.

Samples of the emulsifier polyglycerol polyricinoleate (PGPR) were synthesized using the radiolabelled precursors [1-14C]glycerol ([14C]polyglycerol PGPR), [9,10-3H] or [12-3H]ricinoleic acid ([3H] PGPR) or [1-14C]stearic acid ([14C]stearyl PGPR). The absorption, tissue distribution, metabolism and excretion of these 14C- or tritium-labelled PGPR samples administered to rats was studied. The effects of intestinal and porcine pancreatic lipases on PGPR preparations were examined. Rats were dosed with [1-14C]glycerol, [14C]polyglycerol and ([14C]polyglycerol)PGPR by gavage and their urine. faeces and expired CO2 monitored for 14C. The results from the [1-14C]glycerol treated animals showed extensive metabolism of glycerol. For [14C]polyglycerols, the lower polyglycerols were preferentially absorbed from the intestine and were excreted unchanged in the urine while the higher polyglycerols were found in the faeces. After 4 days, 93% of the dose of polyglycerols was recovered, of which some 30% was found in the urine and 60% in the faeces. Traces of 14C activity were found in depot fat and liver. The excretory pattern and urinary metabolites from ([14C]polyglycerol) PGPR was very similar to that of [14C]polyglycerol. Analysis of urinary and faecal 14C material indicated that the PGPR polymer was digested to give free polyglycerol and polyricinoleic acid. PGPR was synthesised incorporating [1-14C]stearic into polyricinoleic acid which was then esterified with polyglycerol. The resulting [14C]PGPR or [1-14C] stearic acid in a dietary slurry was administered to groups of fed or starved rats by gavage. The results indicated complete digestion of PGPR and absorption of the fatty acids. The 14C-material absorbed was extensively laid down in depot fat and some metabolism to 14CO2 was demonstrated. The fate of the stearic acid was similar whether dosed alone or incorporated into the PGPR polymer. Samples of PGPR were synthesized containing 3H-labelled ricinoleic acid. The resulting [3H]PGPR was intubated into rats as a component of a dietary slurry. The results indicated that the polymer is extensively digested and 90% of the administered tritium is absorbed. The absorbed material was extensively metabolized within 24 hr so that large amounts of tritium were present in the aqueous phase of the tissues examined. After 24 hr, less than 5% of the administered material was present as lipid material, of which a large proportion was as non-hydroxy fatty acids. No traces of polymer material were found in the tissues examined. In vitro digestion of PGPR by porcine pancreatic lipase and rat intestinal fractions was demonstrated. The results indicate very extensive digestion of the PGPR polymer to polyglycerols and fatty acids. The fatty acids are metabolized extensively. The mono-, di- and triglycerols are extensively absorbed from the intestinal tract and rapidly excreted in the urine unchanged but the hexa-, penta- and higher polyglycerols are essentially not absorbed and excreted in the faeces unchanged.

Animals↗
PubMedDate not supplied

Assessment of the carcinogenic potential of polyglycerol polyricinoleate (PGPR) in rats and mice.

The carcinogenic potential of the food emulsifier ADMUL WOL brand of polyglycerol polyricinoleate (PGPR) was evaluated in rats and mice. Groups of 60 male and 60 female rats were given purified diets containing 5% of either PGPR or groundnut oil for 2 years. Groups of 25 male and 25 female mice were given purified diets containing 5% of either PGPR or groundnut oil for 80 weeks. No carcinogenic effect of PGPR was observed. In addition, dietary PGPR had no adverse effect on growth, food consumption, longevity and haematology. Organ weight analysis revealed an increase in liver and kidney weight in both male and female rats and female mice. Histological analysis of tissues revealed no treatment related adverse effects.

Animals↗
PubMedDate not supplied

Overview of the preparation, use and biological studies on polyglycerol polyricinoleate (PGPR).

The esterification of condensed castor oil fatty acids with polyglycerol gives a powerful water-in-oil emulsifier which is used by the food industry in tin-greasing emulsions and as an emulsifier with lecithin in chocolate couverture and block chocolate. A safety evaluation programme was undertaken in the late 1950s and early 1960s to determine whether this food emulsifier polyglycerol polyricinoleate (PGPR). (Quest International trade name ADMUL WOL) presented any health implications for consumers. This programme included acute toxicity tests, subacute rat and chicken toxicity studies, a rat chronic toxicity/multigeneration reproduction study, rodent metabolism, carcinogenicity testing in rat and mouse and a human clinical evaluation. PGPR was found to be 98% digested by rats and utilized as a source of energy superior to starch and nearly equivalent to groundnut oil. There was no interference with normal fat metabolism in rats or in the utilization of fat-soluble vitamins. Despite the intimate relationship with fat metabolism, no evidence was found of any adverse effects on such vital processes as growth, reproduction and maintenance of tissue homeostasis. PGPR was not carcinogenic in either 2-year rat or 80-week mouse feeding studies. The human studies showed no adverse effects on tolerance, liver and kidney function, and fat balance at levels up to 10 g/day PGPR. The acceptable daily intake for PGPR which was set by JECFA in 1974 and the EC/SCF in 1979 is 7.5 mg/kg body weight/day. The UK FAC in 1992 estimated that the maximum per capita mean daily intake of PGPR is 2.64 mg/kg body weight/day. It can be concluded that the use of ADMUL WOL brand of PGPR in tin-greasing emulsions or in chocolate couverture does not constitute a human health hazard.

Animals↗
PubMedDate not supplied

Human studies on polyglycerol polyricinoleate (PGPR).

A series of toxicology studies was conducted in the 1950s and 1960s to investigate the toxicity of ADMUL WOL, a brand of polyglycerol polyricinoleate (PGPR). A component of these investigations included studies in human subjects. During 1964 and 1965, PGPR was fed to 19 human volunteers whose diet contained constant levels of fat and protein. Up to 10 g/day PGPR was fed to each volunteer in soups, cakes and toffee bars for 2 weeks. Pre-exposure normal values of biochemical parameters were established. Fat balance tests confirmed that digestion and absorption of PGPR took place. No consistent effect of PGPR on the various biochemical parameters was observed, nor had PGPR any toxic effect on liver and kidneys. The consumption of PGPR by humans produced no adverse effects. The quantities consumed, up to 10g/day, was equivalent to approximately 63 times the estimated maximum per capita mean daily intake by man of 2.64 mg kg body weight/day. It is therefore concluded from this study that the consumption of ADMUL WOL, a brand of PGPR, has no adverse effects in man.

Administration, Oral↗
PubMedDate not supplied

A three-generation reproduction study on polyglycerol polyricinoleate (PGPR) in Wistar rats.

A series of toxicology studies were conducted in the 1950s and 1960s to investigate the toxicity of ADMUL WOL, a brand of polyglycerol polyricinoleate (PGPR). Included as part of these investigations was a three-generation reproduction study in rats. The control rats received a commercial pelletted stock diet and the treated rats were given the same diet ground with 1.5% (w/w) PGPR. A continuous breeding protocol was adopted, in which the breeding pairs were maintained until the female had produced five litters or when it became evident that breeding had ceased. The main focus of the study design was to observe any effect on breeding. The parameters measured in each of the three generations included number of litters per dam, average litter size, average weaning weights of males and females, litters per group showing 100% survival and total survival (%) at day 21. Growth was normal throughout the three generations and there were no deaths or clinical signs associated with the consumption of PGPR. The only significant change in breeding performance was a reduction in the percentage of animals weaned in the second generation, but as this occurred in the control group to a similar extent it was concluded that this was due to an unknown environmental factor and was not treatment related. A histological examination of selected tissues from those rats continued for 1 year failed to show any lesions which could be ascribed to the consumption of PGPR. In conclusion, rats fed 1.5% (w/w) PGPR showed no evidence of a cumulative effect on breeding performance over three generations.

Administration, Oral↗
PubMedDate not supplied

Risk analysis.

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Accidents↗
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Interaction between mycobacteria and mucus on a human respiratory tissue organ culture model with an air interface.

Mycobacteria adhere specifically to extracellular matrix (ECM) and mucus with a fibrous, but not globular, appearance, in organ cultures of human respiratory mucosa examined by scanning electron microscopy. Previously, light microscopy sections made of tissue infected for 7 days demonstrated mycobacteria associated with mucus on the organ culture surface, and within submucosal glands in areas of damaged epithelium. The authors have now investigated the interactions between Mycobacterium avium complex (MAC), Mycobacterium tuberculosis (MTB), and Mycobacterium smegmatis (MS) and mucus by preincubating bacteria with purified mucins MUC5AC and MUC5B prior to inoculation onto the organ culture mucosal surface. They have also measured mucin production by the organ culture after mycobacterial infection. Mucus did not cause clumping of mycobacteria. There was a significant (P=.03) increase in the amount of fibrous mucus, but not globular mucus, observed on tissue inoculated with mucins compared to controls. The number of bacteria adhering to ECM was markedly reduced after incubation with mucins, which could indicate a protective effect. Mycobacterial infection did not increase mucin production by the organ culture. Mycobacterial adherence to mucins may play a role in the pathogenicity of mycobacteria in diseases such as cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease (COPD), in which there are changes in mucus composition and clearance.

Air↗
PubMedDate not supplied

The role of Haemophilus influenzae in the pathogenesis of pneumonia.

Haemophilus influenzae, one of the bacteria comprising the commensal flora of the human upper respiratory tract, is also pathogenic and causes both localized and invasive (septicemic) infections. The major focus of attention and research has been on infections caused by serotype b organisms, which cause several life-threatening illnesses in children, including meningitis and acute respiratory infection (ARI; e.g., epiglottitis, pneumonia). Type b polysaccharide-protein conjugate vaccines are at an advanced stage of development and implementation; however, these vaccines will not protect against noncapsulated (nontypable) strains of H. influenzae or strains expressing capsular polysaccharides other than serotype b, strains which cause a substantial proportion of ARI (especially pneumonia) among infants, particularly in developing countries. The magnitude of this problem, which contributes to many thousands-perhaps millions-of deaths each year, emphasizes the need for research on the epidemiology, pathogenesis, virulence factors, immune mechanisms, and forms of treatment relevant to ARI caused by H. influenzae in infants and implies that such studies should be given a high priority.

Carrier State↗
PubMedDate not supplied

Effect of alinidine on experimental cardiac arrhythmias.

Alinidine (2.9 +/- 0.7 mg/kg) prevented an adrenaline-induced ventricular arrhythmia in dogs respired with halothane. In ouabain-induced ventricular tachycardia, a cumulative dose of alinidine (15.5 mg/kg) reduced the number of ventricular beats by 91.6 +/- 1.9%. The drug was much less effective in abolishing the ventricular tachycardia 24 h after ligation of a coronary artery, with only a 36 +/- 15% reduction in ventricular ectopic beats after 15.5 mg/kg. The administration of alinidine (0.5-1.0 mg/kg) to anaesthetized dogs with no cardiac arrhythmia reduced sinus node rate with little effect on the response of the node to vagal stimulation.

Animals↗