The selective oestrogen receptor modulator, LY362321, is not neuroprotective in a rat model of transient focal ischaemia.

Selective oestrogen receptor modulators (SERMs) may offer improved alternatives to oestrogen as neuroprotectants in experimental stroke. The present study investigated the role of a novel SERM, LY362321, in a rat model of transient middle cerebral artery occlusion (MCAO). Female Sprague-Dawley rats were ovariectomised and began receiving daily s.c. injections of either 1 mg/kg (n = 13), 10 mg/kg (n = 14) of LY362321, or vehicle (n = 13). The left MCA was temporarily occluded (90 min), with cortical blood flow monitoring, at 12 days post ovariectomy. Sensorimotor function was assessed using a neurological score prior to the MCAO and daily for 3 days following the MCAO. Tissue was processed for infarct volume assessment using 2,3,5-triphenyltetra-zolium chloride staining. The results indicated that there were no significant differences amongst groups in cortical blood flow during the MCAO. Furthermore, there was no significant difference in infarct size amongst vehicle, 1, and 10 mg/kg treated animals: 22.9 +/- 5.0, 16.7 +/- 4.2, and 21.1 +/- 4.1, respectively, one-way anova [F(2,32) = 0.542, P = 0.587]. The MCAO induced a significant decline in neurological score in the vehicle group (from 14 to 7 at 24 h post-MCAO) but this was not significantly affected by LY362321 at either dose. In conclusion, pretreatment with a low or high dose of the novel SERM LY362321 did not significantly influence cerebral blood flow, infarct volume, or sensorimotor function in rats exposed to transient MCAO.

Fibrosing colonopathy in cystic fibrosis: results of a case-control study.

Fibrosing colonopathy was first described in cystic fibrosis (CF) children in 1994. We have done a nested case-control study to identify possible associations with this condition. A case ascertainment within the UK CF population to identify any cases that occurred between January, 1984, and April, 1994, found 14 cases, all under 14 years and confirmed by independent histopathological review. All had presented since April, 1993; 12 were boys and six had received some or all of their care in Liverpool. Each case was matched, by date of birth, with four controls from the UK CF Registry. Information was obtained about cases and controls from their case records and by a structured interview with the families. In the 12 months before surgery, there was an association between the occurrence of fibrosing colonopathy and use of high-strength pancreatic enzyme preparations. This association was dose related. Odds ratio per extra 1000 high-strength capsules was 1.45 (95% CI 1.14-1.84). For use of protease, the odds ratio per million extra units per kg was 1.55 (1.19-2.03). For usage of individual high-strength products at any time during the 12 months before surgery some differences were observed; for Creon 25000 the odds ratio was 0.38 (0.10-1.42), for Nutrizym 22 43.4 (2.51-751), and for Pancrease HL 8.4 (1.95-36.1). These last two confidence intervals are extremely wide and compatible with these two products having the same odds ratios. Laxative use was independently predictive (odds ratio 2.42 [1.20-4.94]). We conclude that there is a dose-related association between high-strength pancreatic enzyme preparations and fibrosing colonopathy.

A complex biochemical modulation of intestinal ion transport in rats fed on high-fat diets.

This study investigates the relationship between dietary fat and ion transport in rat intestine. Animals were fed isocaloric diets with high fat content as corn oil, evening primrose oil (Efamol), fish oil, Efamol/fish oil, olive oil, coconut oil, and butter. A low-fat (corn oil) diet was used in a control group. Biopsies of the small intestine from these animals were mounted in an Ussing chamber, and the intestinal mucosal to serosal ion transport was measured as short-circuit current (SCC). The SCC was stimulated in rats fed on diets high in polyunsaturated fatty acids such as corn oil, Efamol, fish oil, and Efamol/fish oil. SCC was also stimulated in rats fed on diets high in monosaturated fatty acids such as olive oil. Animals fed on diets high in saturated fatty acids such as coconut oil and butter, on the other hand, showed an inhibition in the SCC. To determine whether the effect of membrane lipids was mediated by a differential effect on membrane receptor proteins, the response to secretogogue challenge was studied. Biochemical agents and secretogogues including acetylcholine, noradrenaline, dibutyryl-cAMP, calcium ionophore A2318, and prostaglandin E2 were analysed and compared. These agents were able to influence the SCC, showing responses with marked differences between diet groups.

Kinetics of viral replication in experimental rotavirus infection: effects of high dietary fat.

Epidemiological studies suggest that dietary fat can affect the frequency and severity of diarrhoeal illnesses in childhood. To study the effects of dietary fat on the kinetics of rotavirus antigen, 3-week-old mice of rotavirus-seronegative mothers were fed isocaloric diets with 40% of the total calories as fat [either butter (high saturated fat), olive oil (high monounsaturated fat), or corn oil (high polyunsaturated fat)] with one group on low fat (10% of calories) standard diet as controls. Seven-day-old mice from the first litter were killed and their stomach contents (milk) analyzed for total fatty acids. Seven-day-old mice from the second litter were inoculated with EDIM rotavirus, and some were killed at 48 h and others at 120 h postinoculation. The stool was removed from the distal colon of each mouse and examined for evidence of diarrhoea. The small intestine was removed, the contents washed, and the intestine divided into equal thirds. All stool and tissue samples were made to 10% (wt/vol), homogenised, and tested for rotavirus antigen by ELISA. We found that (a) dietary fat markedly altered the fatty acid profile of milk, (b) high saturated dietary fat (butter) delayed the onset of diarrhoea, reduced the excretion of rotavirus antigen in stool, and reduced mucosal antigen in the lower third of the small intestine at 120 h compared to 48 h postinoculation, (c) high polyunsaturated dietary fat initially increased the frequency of diarrhoea and viral antigen in the middle and lower segment at 120 h, followed by a reduction in rotavirus excretion in stool.(ABSTRACT TRUNCATED AT 250 WORDS)

Paradoxical effects of essential fatty acid supplementation on lipid profiles and sweat electrolytes in cystic fibrosis.

Supplements of evening primrose oil (Oenothera biennis), which contains at least 72% linoleic (18:2n-6) and 7% gamma-linolenic (18:3 n-6) acids (expressed as % fatty acid methyl esters) were given to sixteen cystic fibrosis patients for a period of 12 months. Clinical observations showed no significant changes in patients' weights or respiratory function throughout. Linoleic acid levels in plasma and erythrocyte membranes increased significantly during the first 6 months but this increase was not sustained at its initial level. After supplementation was discontinued reversion to baseline (low) levels occurred within 4 months. Levels of plasma prostaglandins (PG) and urinary PG metabolites varied among individuals over a wide range, and urinary PGF2 alpha metabolites fell during the supplementation. There was a significant fall in sweat sodium concentrations after 6 weeks of supplementation, but sweat chloride was unchanged. It is not known whether the effect of essential fatty acids on sweat Na+ reflects changes in cell membrane conformation or if there is a direct effect on Na+ pump activity.

The nutritional state and nutrition.

Cystic fibrosis children tend to have a low birth weight and their mean height and weight during childhood is below that for the general population. They also tend to have a delayed bone age and puberty. The degree of underweight correlates more closely with the respiratory condition than with the degree of malabsorption. There is evidence that their nutritional requirements are increased, perhaps up to 150% of the recommended daily allowance, but in later childhood their food intake is frequently low and maybe the major reasons for their poor growth and development. Specific deficiencies of vitamins, minerals and essential fatty acids occasionally present as clinical problems. New approaches to nutrition include increasing dietary fat, which was traditionally low because of malabsorption, and this change has been made possible with the development of modern pancreatic supplements. Supplementary nutrition with elemental diets or intravenous hyperalimentation have given promising results in some studies and might be expected to improve the patient's resistance to infection as well as his nutritional state. The place of oral essential fatty acid supplements is still being evaluated, but intravenous infusions of fat emulsion are not justifiable in themselves.