Effect of nabumetone on hemostasis during arthroscopic knee surgery

The known effects of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) on hemostatic parameters have led to concern over their use in the perioperative period. Nabumetone, unlike other NSAIDs, has little effect on collagen-induced platelet aggregation. To evaluate the effect of nabumetone 2000 mg daily on other hemostatic parameters (e.g., bleeding time, prothrombin time, and partial thromboplastin time) in the clinical setting, this double-masked study was conducted in patients with osteoarthritis undergoing arthroscopic knee surgery. After a 1-week placebo washout period, 58 patients were randomized to receive nabumetone and 53 were randomized to receive placebo. They were assessed before surgery (after 1 to 2 weeks of treatment) and again after surgery (after an additional 3 weeks of treatment). The study was designed to have 90% power to show equivalence in bleeding time to within 1.5 minutes, a difference assumed to be of no clinical importance. No meaningful differences were observed between the groups in any of the measured hemostatic parameters. Before surgery, the bleeding time increased by only 0.3 minutes with nabumetone and decreased by 0.2 minutes with placebo. The mean (+/- SD) difference between the groups in change from baseline was 0.5 +/- 0.3 minutes. After surgery, the changes were 0.1 minutes and 0.0 minutes, respectively, and the difference between groups was 0.2 +/- 0.3 minutes. These differences were neither statistically nor clinically significant, and maximum individual increases were similar in each group. Furthermore, there were no reports of abnormal bleeding in the operative knees. The results of this study show that nabumetone had little or no effect on hemostasis and suggest that this drug can be used safely in the perioperative period.     

A patient's perspective on the management of peptic esophageal stricture: experience and results in 113 consecutive cases

A retrospective analysis of 113 consecutive cases of benign esophageal stricture, all secondary to gastroesophageal reflux, 100 treated conservatively, 13 treated surgically, has been carried out in conjunction with a postal questionnaire of patients. Patients were requested to grade both their swallowing ability and the acceptability of their treatment. Of those responding to questionnaire, 88% of patients treated conservatively found their treatment acceptable or better, and 72% were left with either no or minimal restriction of diet. There was no correlation between either the total number or frequency of dilatations and the result achieved. Similarly, patient satisfaction appears largely independent of these variables. Doctors should be wary of taking recurrence of a stricture after initial dilatation as indicating a poor eventual outcome or a dissatisfied patient. There was no difference in terms of either the result or patient satisfaction between conservatively treated and surgically treated patients.     

The genotype of the human cancer cell: implications for risk analysis

An extremely large database describes genotypes associated with the human cancer phenotype and genotypes of human populations with genetic predisposition to cancer. Aspects of this database are examined from the perspective of risk analysis, and the following conclusions and hypotheses are proposed: (1) The genotypes of human cancer cells are characterized by multiple mutated genes. Each type of cancer is characterized by a set of mutated genes, a subset from a total of more than 80 genes, that varies between tissue types and between different tumors from the same tissue. No single cancer-associated gene nor carcinogenic pathway appears suitable as an overall indicator whose induction serves as a quantitative marker for risk analysis. (2) Genetic defects that predispose human populations to cancer are numerous and diverse, and provide a model for associating cancer rates with induced genetic changes. As these syndromes contribute significantly to the overall cancer rate, risk analysis should include an estimation of the effect of putative carcinogens on individuals with genetic predisposition. (3) Gene activation and inactivation events are observed in the cancer genotype at different frequencies, and the potency of carcinogens to induce these events varies significantly. There is a paradox between the observed frequency for induction of single mutational events in test systems and the frequency of multiple events in a single cancer cell, suggesting events are not independent. Quantitative prediction of cancer risk will depend on identifying rate-limiting events in carcinogenesis. Hyperproliferation and hypermutation may be such events. (4) Four sets of data suggest that hypermutation may be an important carcinogenic process. Current mechanisms of risk analysis do not properly evaluate the potency of putative carcinogens to induce the hypermutable state or to increase mutation in hypermutable cells. (5) High-dose exposure to carcinogens in model systems changes patterns of gene expression and may induce protective effects through delay in cell progression and other processes that affect mutagenesis and toxicity. Paradigms in risk analysis that require extrapolation over wide ranges of exposure levels may be flawed mechanistically and may underestimate carcinogenic effects of test agents at environmental levels. Characteristics of the human cancer genotype suggest that approaches to risk analysis must be broadened to consider the multiplicity of carcinogenic pathways and the relative roles of hyperproliferation and hypermutation. Further, estimation of risk to general human populations must consider effects on hypersusceptible individuals. The extrapolation of effects over wide exposure levels is an imprecise process.     

Autoxidation of ubiquinol-6 is independent of superoxide dismutase

Ubiquinone (Q) is an essential, lipid soluble, redox component of the mitochondrial respiratory chain. Much evidence suggests that ubiquinol (QH2) functions as an effective antioxidant in a number of membrane and biological systems by preventing peroxidative damage to lipids. It has been proposed that superoxide dismutase (SOD) may protect QH2 form autoxidation by acting either directly as a superoxide-semiquinone oxidoreductase or indirectly by scavenging superoxide. In this study, such an interaction between QH2 and SOD was tested by monitoring the fluorescence of cis-parinaric acid (cPN) incorporated phosphatidylcholine (PC) liposomes. Q6H2 was found to prevent both fluorescence decay and generation of lipid peroxides (LOOH) when peroxidation was initiated by the lipid-soluble azo initiator DAMP, dimethyl 2,2'-azobis (2-methylpropionate), while Q6 or SOD alone had no inhibitory effect. Addition of either SOD or catalase to Q6H2-containing liposomes had little effect on the rate of peroxidation even when incubated in 100% O2. Hence, the autoxidation of QH2 is a competing reaction that reduces the effectiveness of QH2 as an antioxidant and was not slowed by either SOD or catalase. The in vivo interaction of SOD and QH2 was also tested by employing yeast mutant strains harboring deletions in either CuZnSOD and/or MnSOD. The sod mutant yeast strains contained the same percent Q6H2 per cell as wild-type cells. These results indicate that the autoxidation of QH2 is independent of SOD.     

Bioavailability of phenytoin acid and phenytoin sodium with enteral feedings

In the absence of E1B, the 289-amino acid product of human adenovirus type 5 13S E1A induces p53-independent apoptosis by a mechanism that requires viral E4 gene products (Marcellus, R.C., J.C. Teodoro, T. Wu, D.E. Brough, G. Ketner, G.C. Shore, and P.E. Branton. 1996. J. Virol. 70:6207-6215) and involves a mechanism that includes activation of caspases (Boulakia, C.A., G. Chen, F.W. Ng, J. G. Teodoro, P.E. Branton, D.W. Nicholson, G.G. Poirier, and G.C. Shore. 1996. Oncogene. 12:529-535). Here, we show that one of the E4 products, E4orf4, is highly toxic upon expression in rodent cells regardless of the p53 status, and that this cytotoxicity is significantly overcome by coexpression with either Bcl-2 or Bcl-XL. Conditional expression of E4orf4 induces a cell death process that is characterized by apoptotic hallmark features, such as externalization of phosphatidylserine, loss of mitochondrial membrane potential, cytoplasmic vacuolation, condensation of chromatin, and internucleosomal DNA degradation. However, the wide-spectrum inhibitor of caspases, tetrapeptide zVAD-fmk, does not affect any of these apoptogenic manifestations, and does not alter the kinetics of E4orf4-induced cell death. Moreover, E4orf4 expression does not result in activation of the downstream effector caspase common to most apoptosis-inducing events, caspase-3 (CPP32). We conclude, therefore, that in the absence of E1A, E4orf4 is sufficient by itself to trigger a p53-independent apoptosis pathway that may operate independently of the known zVAD-inhibitable caspases, and that may involve an as yet uncharacterized mechanism.     

MEASUREMENT OF THE SPECIFIC SURFACE AREA OF POWDERS BY THIN LAYER WICKING

The specific surface areas (A) of different clay mineral powders were measured by both the BET method and by thin layer wicking. The values of A for the BET and the wicking experiments coincided within a few percent. Thus, the simple and inexpensive thin layer wicking approach may well suffice to obtain reliable specific surface area values for most powders. From the wicking data it is also possible to obtain a rough estimate of the average particle size.     

The significance of spinal cord compression as the initial manifestation of lymphoma

Sex hormones have profound effects on immune responses and may influence the outcome of autoimmune diseases such as rheumatoid arthritis (RA). We investigated the effect of gonadal steroids on the production of interleukin-1 (IL-1) and IL-6, cytokines believed to be important in the pathogenesis of RA. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy male donors and male patients with RA, and were stimulated with lipopolysaccharide (LPS) in the presence of different concentrations of 17-beta-estradiol, progesterone or testosterone. In studies of cells from normal male donors, 17-beta-estradiol at pharmacological concentrations (> or = 10(-6) M) enhanced IL-1 and IL-6 secretion as well as the production of cell-associated IL-1. Progesterone and testosterone at similar concentrations inhibited IL-1 secretion but had no significant effect on IL-6 secretion or on the production of cell-associated IL-1. In studies of male RA donors, 17-beta-estradiol failed to enhance IL-1 or IL-6 secretion and progesterone failed to inhibit IL-1 secretion. The inhibitory effects of testosterone, however, appeared to be similar to that in normal donors. It is suggested that 17-beta-estradiol may promote IL-1 and IL-6 production and release, while gestation hormone, progesterone, and testosterone may inhibit IL-1 release in vivo. These data may partly explain the gender and age differences in the incidence of RA and the development of the disease in men with low and androgen levels.