High levels of inflammatory phospholipase A2 activity in lumbar disc herniations.

Inflammation of neural elements is frequently mentioned clinically in association with lumbar radiculopathy. Mechanical embarrassment of neural elements by definable structural abnormalities is inadequate as a sole explanation of nerve injury in this condition. The purpose of this study was to demonstrate whether an enzymatic marker for inflammation (phospholipase A2) could be identified in human disc samples removed at surgery for radiculopathy due to lumbar disc disease. Samples were assayed for phospholipase A2 activity. The level of activity in the disc samples was compared with values obtained from other human tissues using the same assay. Specific activity (percent hydrolysis radiolabelled substrate) ranged from 238 to 1,014.5 nmol/min/mg. Mean activity for the human disc material was 568.7 nmol/min/mg, compared with 0.006 nmol/min/mg for human PMN, and 12.1 nmol/min/mg for inflammatory human synovial effusion. The pH and cation-related activity were identical to those demonstrated for phospholipase A2 inflammatory conditions. Human lumbar disc phospholipase A2 activity is from 20- to 100,000-fold more active than any other phospholipase A2 that has been described. As the enzyme responsible for the liberation of arachidonic acid from cell membranes, phospholipase A2 is the rate-limiting step in the production of prostaglandins and leukotrienes. These data establish biochemical evidence of inflammation at the site of lumbar disc herniations.

Modulation of phospholipase A2 activity in human synovial fluid by cations.

Cell-free, Ca2+-dependent phospholipase A2 activity (PLA2) was measured in human synovial fluid of patients with various kinds of arthritis using [1-14C] oleate-labelled autoclaved Escherichia coli as substrate. PLA2 activity at pH 7.0 and with 5 mM added Ca2+ was stimulated and then inhibited in a dose-dependent fashion by NaCl; maximal stimulation of 8.8 fold was found at 150 mM Na+. Similar effects were obtained with K+, Li+ and Ru+. In the absence of added Na+, PLA2 activity was maximal with 25 mM Ca2+ (145 nmols/hr/mg), but in the presence of 150 mM Na+, activity was maximal with 4 mM Ca2+ (415 nmols/hr/mg). PLA2 activity was optimal between pH 6.5-8.0 in presence of 150 mM Na+1 and 4 mM Ca2+. There was no significant difference between PLA2 activity in synovial fluids from rheumatoid and other types of arthritis. Neutral active, Ca2+-dependent PLA2 activity in acid extracts of human platelets, plasma, polymorphonuclear leukocytes and synovial fluid varied in response to added Na+. In presence of 150 mM added Na+ and 5 mM Ca2+, PLA2 activity in human synovial fluid was inhibited by all multivalent cations tested. In the absence of Na+, Cu2+ and Mg2+ stimulated PLA2 activity in a dose dependent fashion; whereas, Fe2+, Fe3+ and Al3+ were inhibitory. The extent of stimulation by Mg2+ was inversely related to the concentration of added Ca2+.

Randomized, double-blind, placebo-controlled study of the treatment of the painful shoulder.

The effect of triamcinolone subacromial bursa injection versus naproxen therapy was compared in a randomized, double-blind, placebo-controlled study of 100 patients who had painful shoulders. Outcome was compared using degree of active abduction, pain, limitation of function, and a clinical index that combined equally weighted measures of all of these. In a time-adjusted analysis, triamcinolone was superior to placebo in all clinical variables. Naproxen was superior to placebo in all variables except pain. Triamcinolone was superior to naproxen in the relief of pain (P = 0.04) and the clinical index (P = 0.04). Multiple linear regression analysis showed that naproxen and triamcinolone treatment accounted for only 16% of the variation in outcome, compared with 44% accounted for by the clinical index prior to treatment. Thus, patients with a poor pretreatment clinical index (those with the most room for improvement) were least likely to improve. We conclude that both triamcinolone (P = 0.00005) and naproxen (P = 0.02) are superior to placebo in the treatment of the painful shoulder.

Inositol trisphosphate is generated by a rat natural killer cell tumor in response to target cells or to crosslinked monoclonal antibody OX-34: possible signaling role for the OX-34 determinant during activation by target cells.

RNK-16 cells, rat leukemia cells with features of natural killer (NK) cells, were adapted for growth in vitro and used to examine the mechanism of NK-cell activation. Contact of RNK-16 cells with tumor cells (YAC-1) that are lysed by NK cells, but not with resistant tumor cells (EL-4, K562), led to an increase in inositol trisphosphate (InsP3), a Ca2+-mobilizing messenger. A similar increase in InsP3 could be elicited in RNK-16 cells by monoclonal antibody OX-34, when the antibody was crosslinked by F(ab')2 fragments of goat antibodies to mouse immunoglobulin. This reaction was accompanied by an increase in the concentration of cytoplasmic free calcium Ca2+, due primarily to the release of Ca2+ from intracellular stores. In contrast to the stimulatory effects of crosslinked OX-34, OX-34 alone did not affect the levels of either InsP3 or cytoplasmic free Ca2+. Moreover, OX-34 alone blocked the generation of InsP3 by RNK-16 cells in response to YAC-1 cells and prevented target-cell killing. These findings demonstrate that OX-34 identifies a structure on the surface of RNK-16 cells that can stimulate the generation of InsP3, and they suggest that this structure can regulate signal transduction during target-cell recognition by NK cells.

Phantom pacemaker programming.

Spurious or "phantom" programming of programmable pacemakers may occur as the result of two phenomena. One is change in rate and/or output of the generator from an anomalous source (dysprogramming); the other is a generator response different from that intended and set on the conventional programmer (misprogramming). In either case, the result is a nuisance, at best. Conceivably, at worst, an irreversible subthreshold output could be induced. Despite wide usage of such devices, neither event has been reported. In the routine follow-up of 95 implanted Cordis Omni-Stanicor generators, we have observed three instances of dysprogramming upon application of a magnet commonly used to induce the asynchronous mode. Subsequent in vitro studies revealed magnetically induced programming reed switch vibration in 9 of 6,680 units, which could account for the in vivo observations. We also describe many instances of misprogramming, attributable, in most cases, to a faulty programmer emission count. In this series, none of the anomalies was clinically detrimental. However, anyone involved in pacemaker follow-up should be alerted to the existence of these potentially hazardous phenomena.

Isolation and characterization of a phospholipase A2 from an inflammatory exudate.

Sterile peritoneal exudates produced in rabbits injected with 1% glycogen contain a phospholipase A activity in a cell-free supernatant fraction that hydrolyzed a synthetic phospholipid (1,2-diacyl-sn-glycero-3-phospho-ethanolamine) and phospholipids of autoclaved Escherichia coli. This phospholipase activity (phosphatidylacylhydrolase EC 3.1.1.4) exhibited an apparent bimodal pH optimum (pH 6.0 and pH 7.5) and was Ca(2+)-dependent; Mg(2+) and monovalent cations (Na(+) and K(+)) did not substitute for Ca(2+) in the reaction; EDTA was a potent inhibitor. The phospholipase hydrolyzed 1-[1-(14)C]palmitoyl-2-acyl-sn-glycero-3-phosphoethanolamine to form only radio-active lysophosphatidylethanolamine as the product, indicating that the enzyme had phospholipase A(2) specificity. The phospholipase A(2) was purified 302-fold by two successive chromatographic steps on carboxymethyl Sephadex. Gel filtration (Sephadex G75) of the purified enzyme resulted in a single peak of biological activity with a molecular weight of approximately 14,800. The same estimate of molecular weight was obtained by SDS-polyacrylamide gel electrophoresis, which yielded a single band. Polyacrylamide gel electrophoresis of this fraction at pH 4.3 revealed a single protein band migrating beyond lysozyme, with the dye front, suggesting that this protein was more basic than lysozyme (pI 10.5). The enzymatic and physical-chemical characteristics of this soluble enzyme were remarkably similar to a recently described phospholipase A(2) of rabbit polymorphonuclear leukocytes derived from glycogen-induced peritoneal exudates. The possible origin and physiological role of this soluble enzyme are discussed.

Spontaneous (pathologic) rupture of the spleen in previously undiagnosed Hodgkin's disease: report of a case with survival.

Spontaneous (pathologic) rupture of the spleen in lymphoma is a rare event. A 38-year-old man with a 6-week history of fever, night sweats, and weight loss, and with known splenomegaly presented in shock as a result of a ruptured spleen. There was no known antecedent trauma. Hodgkin's disease was demonstrated in the spleen and liver. Review of the literature failed to reveal any previous report of spontaneous rupture of the spleen due to undiagnosed Hodgkin's disease. Only one survivor of spontaneous rupture of the lymphomatous spleen has been reported previously.

Combination chemotherapy for acute nonlymphoblastic leukemia in adults.

Between January 1973 and February 1975, 77 adults with acute nonlymphoblastic leukemia were treated with a combination of daunorubicin, cytosine arabinoside, 6-thioguanine, prednisone, and vincristine in university-affiliated and private institutions. After 31 patients were treated (regimen 1) the doses of all drugs were significantly increased (regimen 2). Regimes 1 and 2 yielded CR rates of 59% (17 of 29 patients) and 70% (32 of 46 patients) respectively. With regimens 2 the mean number of courses and the median number of days to CR decreased from 3 to 1.4 and from 46 to 29 respectively. Failure to achieve CR was due to persistent leukemia during regimen 1 and fatal infections during regimen 2. With regimen 2 ten of 20 patients (50%) greater than 50 years had CR compared to 22 of 26 patients (85%) less than 50 years. CR rates were similar in community and university institutions.