Dependence of adaptative regulation for IL-1 beta action on system A activity in human synovial cells

Human synovial cells are a suitable model for estimating the physiopathological effects of IL-1 beta (IL-1) in joint. Given the importance of this cytokine in the modulation of cell metabolic activities, we set out to study the action of IL-1 on the neutral amino acid transport A system, using the methyl (aminoisobutyric) acid (MeAIB), the most highly specific and nonmetabolizable substrate for the A system. Stimulation of system A activity by adaptative regulation is a prerequisite to obtain an increase of MeAIB uptake in IL-1-treated cells, since cells which had been grown in a normal medium did not express stimulation of system A activity when IL-1 was added. The IL-1-mediated MeAIB uptake is independent of protein synthesis, since cycloheximide (CHX) did not inhibit MeAIB uptake, and characterized by a decrease in the Michaelis constant K(m) (0.147 vs. 0.270 mmol/l, IL-1 vs. control) and a slight increase in maximal velocity (Vmax) (4.59 vs. 3.89 nmol/mg prot/10 min, IL-1 vs. control). These observations indicate that IL-1 induces modifications in both system A transporter affinity and number. Moreover, we indicate that system A should be responsive in vivo to IL-1 in the same way since derepression and IL-1 action occurred in the presence of human synovial fluid.     

Inhibition of pigeon breast muscle alpha-ketoglutarate dehydrogenase by structural analogs of alpha-ketoglutarate

Inhibition of alpha-ketoglutarate dehydrogenase (KGD) by dicarboxylates with (oxaloacetate and ketomalonate) and without (malonate, succinate, and glutarate) alpha-keto group was studied. Ketodicarboxylates at low concentrations inhibit KGD in competitive manner. Increase in their concentrations results in appearance of the noncompetitive component. The extent of KGD inhibition by keto dicarboxylates increases with structural similarity of the inhibitor and the substrate, irrespective of preliminary incubation of the enzyme with the inhibitor. This is indicative of blocking the substrate-binding site of KGD by dicarboxylates. In contrast, inhibitory effect of dicarboxylates which contain no keto group increases as their structural similarity with the substrate decreases. Saturation of KGD with dicarboxylates of this type does not completely suppress the enzymatic activity. Alternatively, these analogs display competitive mode of inhibition. Analysis of the data obtained suggests that these dicarboxylates produce catalytically active triple complex keto substrate-KGD-dicarboxylate and that KGD which enters the composition of such a complex inhibits a decreased affinity for the keto substrate as a result of the inhibitor binding.     

Re: invited discussion on "spontaneous autoinflation of saline mammary implants"

Weights of total hip and total knee components from 4 major orthopaedic device manufacturers are compared. These data provide surgeons with information that is not readily available and may serve as a reference for patient information or possibly biomechanical studies in the future.     

A twenty-year review of malignant colorectal neoplasms at University College Hospital, Ibadan, Nigeria

PURPOSE: Colorectal malignancies are less common in developing than developed nations because of lower per capita income and higher dietary fiber consumption. This clinicopathologic study attempts to determine changes in the pattern of these neoplasms in Ibadan, Nigeria, during the last two decades. METHODS: The present study is based on the clinical Cancer Registry records and gross and morphologic surgical pathology findings of 526 patients with histologically verified malignant colorectal neoplasms received in the Department of Pathology, University College Hospital, Ibadan, between 1971 and 1990. RESULTS: Colonic malignancies increased by 81 percent, whereas rectal malignancies decreased 16.1 percent in frequency (P < 0.05). The modal ages were 55 to 60 years and 45 to 50 years for colonic and rectal neoplasms, respectively, in contrast to reported peak occurrence in the seventh decade among Caucasians. Colonic neoplasms were predominantly right-sided (34.3 percent cecal), abdominal mass and pain being major clinical manifestations. This differs from the pattern in American Negroes, among whom colonic carcinomas are predominantly left-sided, dyschezia being an important presentation. As in most other studies, adenocarcinomas were the predominant neoplasms. CONCLUSIONS: Further work is required to determine prognostically significant features of colorectal cancer in our environment.     

Effects of chronic combined treatment with captopril and pravastatin on the progression of insulin resistance and cardiovascular alterations in an experimental model of obesity in dogs

BACKGROUND: Cyclic nucleotides mediate intracellular signal transduction of several vasodilators. In addition to its vascular relaxant effects, cAMP is known to protect endothelial cells and to suppress Kupffer cell activation. On the other hand, cGMP potently ameliorates adhesion of leukocytes and platelets. We tested the effects of two analogs of cyclic nucleotides (8bromo cyclic adenosine monophosphate [8br-cAMP] and 8bromo cyclic guanosine monophosphate [8br-cGMP]) in rat liver preservation. METHODS: In experiment 1, either analog (0.1-1.0 mM) alone was added to University of Wisconsin (UW) solution in a survival study. In experiment 2, donors and recipients were also treated with 8br-cAMP or 8br-cGMP, with the following three groups tested: group 1=control; group 2=administration of 8br-cAMP to donors, UW solution, and recipients; group 3=administration of 8br-cGMP to donors, UW solution, and recipients. Experiment 3 tested combined treatments: group 4=administration of 8br-cGMP to donors and UW solution, and cAMP to recipients; group 5=administration of 8br-cAMP to donors and UW solution, and 8br-cGMP to recipients. To elucidate the roles of each nucleotide, two further groups were tested: group 6=administration of 8br-cAMP to donors and UW solution; group 7=administration of 8br-cGMP to recipients. In experiment 4, rats in groups 1, 5, 6, and 7 were killed at several time points after reperfusion, and percent graft blood flow (%BF), number of accumulated neutrophils, plasma levels of tumor necrosis factor-alpha and interleukin-1, and serum alanine aminotransferase levels were examined. RESULTS: In experiments 1 and 2, no significant effect was observed on animal survival. In experiment 3, a significant increase in animal survival was observed only in group 5 (100%, 7/7, P=0.0004 vs. group 1: 16.7%, 2/12). In group 5, no improvement of %BF was observed during the early phase of reperfusion (15 and 30 min) compared with that in group 1. On the other hand, the %BF of group 5 was significantly higher in the later phase (6 hr), consistent with the decrease in accumulation of neutrophils observed then. Production of tumor necrosis factor-alpha and serum alanine aminotransferase levels were also reduced with this treatment. Histologically, the bleeding and segmental necrosis, observed in group 1, were completely prevented in group 5. CONCLUSIONS: We conclude that restoration of grafts with cAMP and administration of cGMP to recipients led to successful transplantation, and that the two analogs acted synergistically in opposing preservation and reperfusion injury without improvement of graft blood flow during the early phase of reperfusion. The effect was due to their regulation of neutrophil activation and sequestration.     

Effect of para-aminobenzoic acid on the fibrinolytic activity of blood

In an infant with transient neonatal diabetes mellitus, control of the blood glucose concentration was attained with ultralente insulin treatment, without any episodes of hypoglycemia. We recommend subcutaneous injection of ultralente insulin, rather than lente or isophane (NPH) insulin, to avoid hypoglycemia during the treatment of transient neonatal diabetes mellitus.