Protein kinase C regulation of ATP-induced phosphoinositide hydrolysis in bovine aorta endothelial cells

This study investigated the mechanism of protein kinase C-mediated inhibition of ATP-induced phospholipase C activation in cultured bovine aorta endothelial cells (BAEC). In BAEC labeled with 3H-inositol, phorbol myristate acetate (PMA) prevented ATP-induced inositol bisphosphate and inositol trisphosphate formation. In membranes prepared from these PMA-treated cells, Ca(2+)-, sodium fluoride-, GTP gamma S-, and ATP plus GTP gamma S-stimulated inositol bisphosphate, but not inositol trisphosphate, formation was inhibited. Inositol trisphosphate phosphatase activity was not altered in membranes from PMA-treated BAEC. These results suggest that 1) protein kinase C inhibits ATP-induced phospholipase C activation in BAEC through interference with the coupling of phospholipase C with a G-protein and through an effect on phospholipase C itself, and 2) different mechanisms are responsible for the inhibition by protein kinase C of the phospholipase C-mediated hydrolysis of phosphatidylinositol bisphosphate and phosphatidyl-inositol phosphate.     

In memoriam. Raymond Millard Cable 1909-1995

1. This experiment was designed to pharmacologically characterize a novel calcium channel blocker, AE0047. 2. After 1-hr treatment with each drug (10(-6) M), K(+)-induced contraction in rat aortic strip was clearly depressed by nifedipine and manidipine and slightly depressed by AE0047. After a wash out of the preparation in drug-free medium, the inhibition of K(+)-induced contraction by nifedipine or manidipine was abolished or unchanged, respectively. In contrast, AE0047-produced inhibition was reinforced with time after removal of the drug. 3. A cell membrane depolarization-induced 45Ca uptake into tissue was depressed completely by nifedipine, but, if it was washed out, merely 20% inhibition of control remained. AE0047-produced inhibition became prominent after drug removal. Manidipine did not have the same inhibitory effect after wash out. 4. A receptor-binding study indicated that affinity of AE0047 and manidipine for the dihydropyridine-sensitive Ca channel receptor was lower than that of nifedipine. AE0047, unlike nifedipine and manidipine, inhibited [3H]PN200-110 binding more strongly when a 4-hr preincubation was used than without extended incubation. 5. The drug molecule of AE0047 was highly partitioned into the lipid bilayer of the synaptosome in canine cerebral cortices. In the synaptic membrane and liposomes, both prepared from canine cerebral cortices, the respective partition coefficients of the drug were 6997 +/- 2309 and 422 +/- 28 against 1395 +/- 161 and 24 +/- 2 of nitrendipine. 6. AE0047 showed slower onset of inhibition against K(+)-induced contraction and enhanced Ca influx compared with manidipine and nifedipine. These results may suggest that AE0047 requires a long period of time to occupy the dihydropyridine-sensitive sites within the Ca channel, which was detected by decreased specific [3H]PN200-110 binding, and to inhibit K(+)-induced Ca influx into rat aorta.     

Genomic organization of the human TIMP-1 gene. Investigation of a causative role in the pathogenesis of X-linked retinitis pigmentosa 2

PURPOSE: To evaluate the role of TIMP-1 in inherited retinal degeneration. METHODS: The genomic structure of the TIMP-1 gene was established and male patients with x-linked retinitis pigmentosa 2 from five families were screened for sequence alterations by direct sequencing in all exons, exon-intron boundaries, and the 5' upstream region of the gene. RESULTS: TIMP-1 appears to be expressed in the retina at low levels and consists of six exons spanning a genomic region of approximately 4.5 kb on Xp11.23. No disease-specific sequence alterations were identified. A site substitution in exon 5 was observed in samples from control subjects and patients, but it did not alter the amino acid sequence of the protein product. CONCLUSIONS: The results of this study exclude mutations in the TIMP-1 coding sequence, splice sites, and the 5' upstream region as a cause of retinal degeneration in x-linked retinitis pigmentosa 2. However, an as yet unidentified regulatory element that lies outside these intervals may be implicated. The role of this tightly regulated protein in the normal functioning of the retina has yet to be determined.     

Mild traumatic brain injury--the Fife perspective

Excretion was studied of catecholamines and diphenilamine (DOPA) in 310 patients with carcinoma of the stomach and large intestine and 43 patients with non-malignant diseases. The oncological patients showed decrease in activity of the mediator link of the sympathoadrenal system (SAS) as well as its reserves but there was no association with sex, age, location or histological structure. Three types of SAS functioning were identified, such as compensation, overstrain and emaciation. Surgical intervention led to activation of the hormonal link and exhaustion of the system's reserves. Two kinds of sympathoadrenal response to stress were described--adequate and inadequate. In the former type, phases of stress remain as they are, unchanged, as are time periods of formation thereof, while under the latter one time periods of the phases formation or formation thereof get disordered.     

Rehabilitation from the economic viewpoint--basic geriatric considerations

Idiopathic Systemic Capillary Leak Syndrome (SCLS) is a rare entity characterised by idiopathic increasing of capillary permeability associated with recurrent attacks of hypovolaemic shock. We report the case of a 39-year-old man with a SCLS fourteen years after a cadaveric renal transplantation. The clinical evolution was rapidly fatal despite treatment with corticoids, aminophylline and terbutaline which are the most efficient drugs known to prevent attacks.     

Inducible gene expression in mammalian cells and transgenic mice

The discovery of the superantigens (SAgs) offered new insights on the interaction between microorganisms and the host immune system. Associated to Major Histocompatibility Complex (MHC) class II molecules, SAgs bind to the variable domain of the beta chain (V beta) of the TCR alpha beta engaged in the family specificity of lymphocytes. Therefore, these molecules are able to activate a high number of T lymphocytes as well as surface MHC class II bearing cells, leading to an overriding release of cytokines and inflammatory mediators, which have been related to their toxic effects. Endogenous SAgs are encoded by murine tumor proviruses (Mtv) which are integrated in the genome of mice. Bacteria and viruses produce exogenous SAgs and those related to food poisoning have been widely studied. The presence of parasite SAgs is still unclear and further studies are required to establish their existence and effects on the corresponding infections.     

Reference range and repeatability of a combined intestinal permeability and function test in clinically healthy Irish setter dogs

We investigated the influence of nutrition and exercise interventions within cognitive/behavioral and public health formats on weight and blood lipid profiles in obese children. Compliance was also examined as well as the relationship of the compliance measures with clinical outcome variables. Three conditions were compared over 16 sessions: nutrition and eating-habit change followed by exercise (NE), exercise followed by nutrition and eating-habit change (EN), and an information control (INFO). NE and EN were presented in a cognitive/ behavioral framework which focused on the development of self-regulation whereas the INFO condition received the same material in a public health/educational model. NE and EN participants evidenced modest, yet significant, reductions in weight and blood lipids, and the impact of these two interventions endured at a five-year follow-up. In contrast, INFO participants displayed stable weight and blood lipids during the course of the program, and most remained morbidly obese at follow-up. Improved nutrition, increased physical activity and fitness were significantly correlated with weight and lipid reductions.