Effect of cholesterol deprivation on piglet small intestine and serum lipids

Using the neonatal piglet, the effects of dietary cholesterol deprivation on growth, intestinal enzyme activity, intestinal and hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), and serum lipid were studied. Six litters of piglets were randomly assigned to one of two feeding regimens: restricted (800 ml of formula/24 h) versus unrestricted (1,200 ml of formula/24 h). Within litters, piglets were separated by sex, then randomly assigned to a formula containing low cholesterol (less than 2 mg/dl) or high cholesterol (145 mg/dl). Piglets were fed for 2 weeks. Male piglets in the restricted low cholesterol group gained significantly less weight per milliliter of formula than the restricted high cholesterol males. No effect was observed in the females. Microvillus membrane lactase activity was greater in males fed a high versus low cholesterol diet. Intestinal and hepatic HMG-CoA reductase activities and serum lipid profiles showed a trend toward compensation for dietary cholesterol deprivation but did not differ statistically between the cholesterol-fed versus -deprived groups. It is concluded that dietary cholesterol deprivation in the male neonatal pig causes alterations in growth, but no other statistically significant responses were detectable in this study.     

Pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase.

1. This paper describes the pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase which is undergoing clinical evaluation. 2. ICI D2138 potently inhibited leukotriene synthesis in murine peritoneal macrophages (IC50 = 3 nM) and human blood (IC50 = 20 nM). In human and dog blood, ICI D2138 did not inhibit thromboxane B2 synthesis at a concentration of 500 microM, thus the selectivity ratio (cyclo-oxygenase: 5-lipoxygenase) was greater than 20,000. In contrast, zileuton (a 5-lipoxygenase inhibitor also undergoing clinical evaluation) exhibited a selectivity ratio of 15-100. 3. ICI D2138 potently and dose-dependently inhibited ex vivo leukotriene B4 (LTB4) synthesis by rat blood with ED50 values of 0.9, 4.0 and 80.0 mg kg-1 p.o. at 3, 10 and 20 h respectively after dosing. Similar activity was observed for inhibition of LTB4 production in a zymosan-inflamed rat air pouch model. Zileuton produced ED50 values of 5 and 20 mg kg-1 at 3 and 10 h respectively. 4. Oral administration of 1, 3 or 10 mg kg-1 ICI D2138 to dogs produced maximal inhibition of ex vivo LTB4 synthesis by blood for 5, 9 and 31 h respectively. A dose of 5 mg kg-1 p.o. of zileuton caused maximal inhibition of LTB4 for 24 h. 5. Oral administration of 10 mg kg-1 ICI D2138 caused total inhibition of LTB4 production in zymosan-inflamed rabbit knee joint. 6. Topical administration of ICI D2138 to rabbit skin caused a dose-related inhibition of arachidonic acid-induced plasma extravasation with an ID30 of 1.08 nmol per site.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of methoprene (Altosid XR) sustained-release briquets for control of culex mosquitoes in urban catch basins.

A sustained-release, briquet formulation of methoprene (Altosid XR), applied at a rate of one briquet per catch basin in Saginaw, Michigan, provided ca. 70% reduction in emergence of Culex pipiens and Cx. restuans adults, compared with nontreated catch basins, during a period of 15 wk in the summer of 1990. In a parallel study using one briquet per 10.5 liter bucket, there was 99% reduction in adult emergence of these species for a period of 12 weeks. The difference between catch basins and buckets may be attributable to water movement through the catch basins with each rainfall, causing a dilution of methoprene through time. However, both studies indicated that the briquets released methoprene for 12-15 wk, suggesting that this formulation may offer season-long control of Culex mosquitoes from urban catch basins in Michigan, with a single treatment of insecticide.     

Quality of life in surgically palliated complex congenital heart disease.

The outcome of surgical palliation was evaluated in 26 children with complex cyanotic congenital heart disease. Outcome was examined in terms of ongoing symptoms, exercise tolerance, and the ability to participate in normal childhood activities. An activity score was calculated and each child performed graded treadmill exercise testing. Breathlessness (24 (92%) children), respiratory infections (nine (35%) children), and leg cramps (eight 31%) children) were the most common physical disorders. Although formal exercise testing showed a clear reduction in exercise tolerance compared with age and sex matched controls, palliation had allowed 23 (89%) to function with moderate exercise limitation, three (11%) having severely limited activity. Parents underestimated the child's exercise tolerance in 80% of cases. Sixteen (62%) patients attended school full time, eight (31%) attended part time, and two (8%) received only home tuition. Palliative surgery can give children with a single functional ventricle a level of activity which allows them to take part in most childhood activities. Subjective estimates of exercise tolerance are inaccurate in this group of children, and formal exercise testing can contribute useful information to decision making about further surgical intervention.     

Only patients with dysplasia progress to adenocarcinoma in Barrett''s oesophagus.

Columnar lined oesophagus (Barrett's oesophagus) carries a risk for the development of adenocarcinoma. Epithelial dysplasia appears to be a precursor but the utility of this marker for predicting subsequent adenocarcinoma is unsettled. We therefore prospectively studied 81 patients with histologically proven columnar epithelium of at least the distal 3 cm of the tubular oesophagus with regular endoscopic biopsies for a total of 289.2 patient years (mean 3.6 years, range 0.5-8). Twenty three patients (28%) had epithelial dysplasia detected during follow up. Both patients with persistent high grade dysplasia present on initial biopsies developed adenocarcinoma after 2.6-4.5 years, despite the absence of gross macroscopic change. The initial single layer pleomorphic high grade dysplasia in one patient regressed to low grade dysplasia which has persisted for 1.5 years. Of 10 patients with initial low grade dysplasia, one progressed to adenocarcinoma in 4.3 years. The low grade dysplasia persisted unchanged in seven patients for 1.5-7 years and appears to have regressed in two patients after three to five years. Ten patients developed low grade dysplasia during the surveillance period. This has persisted unchanged in six patients from 0.5-5 years, regressed in three for 0.5-5 years and has appeared after the first yearly biopsy in one patient. No patient without dysplasia has developed adenocarcinoma. The incidence of adenocarcinoma in Barrett's oesophagus in this study is one case per 96 patient years. This is 61 times (95% confidence limits 12-176) the age adjusted incidence of oesophageal cancer in Australia. Persistent high grade dysplasia appears to be a sensitive indicator for the development of subsequent adenocarcinoma.     

An optimal viral peptide recognized by CD8+ T cells binds very tightly to the restricting class I major histocompatibility complex protein on intact cells but not to the purified class I protein.

CD8+ cytotoxic T lymphocytes recognize cell surface complexes formed by class I major histocompatibility complex (MHC-I) glycoproteins and antigenic peptides. We have identified a peptide nonamer (termed IV9) derived from the human immunodeficiency virus that is over a millionfold more active (at subpicomolar concentrations) than peptide analogues longer or shorter by one or two amino acid residues. Although IV9 does not detectably bind to isolated MHC-I molecules as measured by equilibrium dialysis, we quantitated its specific binding in unaltered form to MHC-I on intact cells. Less than 1% of cell surface MHC-I forms complexes with IV9, which suffices to trigger maximal cytotoxic T-lymphocyte activity. By contrast, a peptide dodecamer that includes the IV9 sequence and is active at micromolar concentrations does not bind to MHC-I on intact cells, raising the possibility that this longer peptide undergoes processing. Using stoichiometrically iodinated IV9 to obviate the ambiguities associated with trace labeling methods, we measured the dissociation kinetics of purified peptide/MHC-I complexes isolated by affinity chromatography and found these complexes to be exceedingly stable (t1/2 = 200-600 hr).