Classification of back muscle impairment based on the surface electromyographic signal.

A surface electromyographic (EMG) procedure for classifying muscle impairments in persons with low back pain (LBP) is described. The procedure was studied using a device, the Back Analysis System (BAS), to acquire and process EMG signals from six bilateral muscle sites during sustained isometric contractions designed to progressively fatigue the lower back. Back muscle impairment was determined on the basis of the different ways in which the EMG median frequency parameters change as a function of contraction duration and muscle site. The article describes a series of studies that have been useful in developing an automated procedure for identifying back muscle impairment by comparing individual test results to a normative database. To date, the research results have produced multivariate discriminant functions that have identified two muscle impairment categories associated with deconditioning and imbalances secondary to LBP. We have found that the functions can distinguish individuals with and without LBP with an accuracy of approximately 90%. Other studies are described in which the technique is applied to monitoring changes in muscle performance capability that occur following rehabilitation for LBP. Many of our findings here are also compared to the results of independent studies by others using similar procedures. The need for further research and development of the technique to improve its clinical applicability is also described.

Intermittent spinal ischemia. A reversible cause of neurologic dysfunction and back pain.

A woman who presented with leg claudication and neurologic dysfunctions is described. Aortic obstruction was defined by aortography, with large collateral vessels observed above the obstruction extending to the femoral arteries and small collaterals extending to the spinal cord. Aorto-femoral bypass surgery resulted in resolution of the patient's symptoms. Prompt recognition and treatment of spinal cord ischemia is essential if permanent and disabling neurologic damage is to be avoided.

Immune surveillance, organophosphorus exposure, and lymphomagenesis.

Prevalence of lymphoproliferative disorders is increased in populations with various chemical exposures, including organophosphorus compounds. Lymphomas are also more common in individuals with a substantially decreased monocyte esterase activity. Organophosphorus compounds inhibit esterases associated with monocytes, natural killer (NK) cells, lymphokine-activated killer (LAK) cells, and cytotoxic T lymphocytes, and these inhibitory effects impair immune surveillance and cytotoxic functions mediated by such cells. Lymphoma development is also associated with Epstein-Barr virus (EBV) and human herpesvirus-6 (HHV-6) infections, which are regulated by cytotoxic immune responses mediated by monocytes, T cells, and NK cells. My hypothesis is that lymphomagenesis is a multistep process, and the absence or inhibition of monocyte esterase and perhaps other immune cell esterases alters esterase-dependent detoxification of a factor critical for the early steps of oncogenesis. Also, such an enzyme deficit might impair the processes that regulate the dissemination and limit the total burden of pathogens such as the lymphoma-associated herpesviruses. An added risk to any viral-mediated lymphoproliferation might be an organophosphorus-induced oncogenic genetic change.

Chiral stereoisomeric molecules in the treatment of arthritis.

Pharmacokinetic and pharmacodynamic properties of drugs and their ultimate therapeutic effects are often significantly influenced by interactions between the geometry of host receptors, host enzymes, and the three-dimensional structure of drugs. Drug molecules that are mirror images of each other are chiral stereoisomers, and such chiral isomer compounds are commonly used as therapeutic agents by rheumatologists either as racemates (mixtures of chiral isomers) or as pure stereoisomers. Understanding and using such stereoisomeric drugs may lead to lower risks of drug toxicity, better therapeutic indices, and newer approaches for the treatment of articular disorders. A review of the properties of these special isomers is presented, and their therapeutic advantages are discussed.

Structural requirements for the inhibition of human monocyte carboxylesterase by organophosphorus compounds.

Human blood monocyte carboxylesterase (CBE) is inhibited by a variety of organophosphorus compounds including arylphosphates and arylphosphites and some alkylphosphites. Triphenyl phosphate and triphenyl phosphite with Ki values of 8 x 10(-9) M and 4.8 x 10(-8) M, respectively, are the most potent inhibitors of this enzyme evaluated by this study. The arylphosphates vary in their capacity to inhibit carboxylesterase activity. Diphenyl phosphate with its strong negative charge is not a potent inhibitor (Ki = 1 x 10(-4) M), whereas if its negative charge is neutralized, as in diphenyl methyl phosphate, its capacity to inhibit carboxylesterase is significantly increased. Compounds with increased bulk, such as trinaphthyl phosphate, only inhibit the enzyme at concentrations of 10(-5) M or greater. Arylphosphites have inhibitory capacities similar to the arylphosphates. Alkylphosphites (tributyl phosphite/triethyl phosphite) inhibit carboxylesterase activity, whereas alkylphosphates (tributyl phosphate/triethyl phosphate) have no inhibitory effect. Arylphosphines and arylphosphine oxides do not inhibit carboxylesterase activity. This study demonstrates that organophosphates and organophosphites are relatively effective inhibitors of human monocyte CBE activity with the exception of the alkylphosphates which have no inhibitory activity. We conclude that molecular bulk and charge have a significant role in determining the potency of organophosphorus inhibitors of monocyte CBE. The observed variations in the degree of esterase inhibition by organophosphorus compounds as well as the differences in the pathological expression of neuropathic disorders associated with such chemicals suggest that different esterase enzymes derived from the family of esterase genes may mediate the different neuropathies observed with organophosphorus exposures. Such data also provide the rationale for the kinetic analyses of esterases and the design of non-toxic organophosphorus compounds with low or no monocyte CBE inhibitory capacity to reduce the potential of these commonly used chemicals for human toxicity.

Human monocyte carboxylesterase. Purification and kinetics.

Human peripheral blood monocytes were isolated by density gradient centrifugation and purified by counterflow centrifugation elutriation. Membrane-localized carboxylesterase (CBE) was extracted with nonionic detergent (Triton X-100) and purified by ion exchange (DEAE-cellulose), gel filtration (Sephacryl S-300), hydroxylapatite column, and high performance liquid chromatography. The purified enzyme migrated on 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a single protein band with a molecular weight of 60,000. Under nondenaturing conditions, monocyte CBE formed a trimer and eluted from a gel filtration column as a protein with an approximate molecular weight of 200,000. Electrophoretic patterns of the enzyme on polyacrylamide gels run a neutral pH did not vary during enzyme purification. At least four major isoenzymes of human monocyte CBE were observed with isoelectric points between 7.5 and 7.8. Pure human monocyte CBE hydrolyzed short chain alpha-naphthyl, o-nitrophenyl, and p-nitrophenyl esters. Amide esters and thioesters were not hydrolyzed by the enzyme. Short chain alcohols activated the enzyme and organophosphorus compounds, diphenyl carbonate, sodium fluoride, and phenylmethylsulfonyl fluoride inhibited the enzyme. EDTA and sulfhydryl reagents had no effect on enzyme activity. The amino acid content of the enzyme was consistent with other CBEs. Inhibitors reacted either with the active or effector site of the enzyme. Purified enzyme now permits the characterization of CBE structure and regulation.

Successful management of Mycoplasma hominis septic arthritis involving a cementless prosthesis.

PIP: Prompt identification of the infectious agent and antibiotic treatment are essential to the prevention of mortality or serious morbidity in patients with septic arthritis. Of concern is the increasing incidence of Mycoplasma hominis saprophytes as a cause of joint infections given the problems in isolating these microbes. The case of a 32-year-old black woman with a 9-year history of systemic lupus erythematous who presented with an M hominis-related septic arthritis involving hip and knee joint protheses offers guidelines on the predisposing factors and characteristic clinical and laboratory findings in such cases. The literature indicates that hypogammaglobulinemia, immunocompromise, postpartum or postabortion fever, and urinary tract manipulation are the risk factors most commonly associated with mycoplasmal septic arthritis. Typical laboratory results include a synovial fluid white blood cell count exceeding 80,000/mm3, a synovial fluid smear greater than 95% neutrophils, negative Gram's stain of synovial fluid smear, positive acridine-orange stain, and slow or absent growth in standard culture media. M hominis infections respond to tetracyclines, lincomycin, and clindamycin, but are resistant to erythromycin. Risk factors in the patient described here included longterm corticosteroid treatment, prior urinary tract infection, and an abortion 2 months prior to presentation for which antibiotic prophylaxis was not administered. The results of synovial tissue, bone, and irrigation fluid cultures were initially negative, but more sophisticated testing ("fried egg" morphology) isolated M hominis. This microorganism was also isolated in endometrial tissue cultures, and retained products of conception are considered the most likely source of the patient's joint infection. A 10-week course of tetracycline eliminated the infection.^ieng

Immunotoxicity of organophosphorus compounds. Modulation of cell-mediated immune responses by inhibition of monocyte accessory functions.

Several organophosphorus compounds (OP) used commercially as flame retardants and plasticizers and related chemicals were evaluated for their effects on human in vitro cell-mediated immune responses. At nontoxic concentrations ranging from 0.1 to 20 microM, two of the tested compounds, triphenylphosphine oxide (TPPO) and tetra-o-cresylpiperazinyl diphosphoamidate (TCPD) caused significant suppression of antigen-specific lymphocyte proliferation (P less than 0.01). Mitogenesis was less sensitive to OP treatment and was affected only by TCPD. When monocytes and lymphocytes were treated separately with OP, washed, and recombined, it appeared that these OP mediated their suppressive effects by interfering with a monocyte function rather than acting directly on lymphocytes. Further, triphenyl phosphate (TPP), triphenyl thiophosphate (TPTP) as well as TPPO and TCPD were tested for direct inhibition of monocyte antigen presentation, and all four compounds were found to cause significant inhibition at concentrations as low as 1 microM (P less than 0.001).

Glucocorticoid inhibition of zymosan-induced arachidonic acid release by rat alveolar macrophages.

The phospholipase-dependent liberation of arachidonic acid (AA) from membrane phospholipids has been proposed as the rate-limiting step in the synthesis of bioactive AA metabolites, which play an important role in the expression of inflammatory and immune reactions. We have examined the effects of steroids in vitro on the release of AA by rat alveolar macrophages exposed to zymosan. Fluocinolone (1 microM) significantly inhibited the zymosan-induced release of radiolabeled AA from phosphatidylcholine as well as the production of radiolabeled prostaglandin E2. (PGE2). Dose-response curves gave the following rank order of potency: fluocinolone greater than dexamethasone greater than hydrocortisone. The maximal degree of inhibition of radiolabeled AA release observed was approximately 70%. Inhibition was not observed after 3 h of glucocorticoid pretreatment, but maximal inhibition was achieved after 10 h of pretreatment. Pretreatment with gonadal sex hormones (1 microM) did not inhibit AA release. Concurrent incubation of macrophages with hydrocortisone and excess concentrations of the partial glucocorticoid agonist, progesterone, blunted the degree of inhibition observed with hydrocortisone alone. These data are consistent with a receptor-mediated process. The time course suggests a response dependent on new protein synthesis, and the increased concentration of the phospholipase-inhibitory protein, lipomodulin, in steroid-treated cultures is putative evidence of new protein synthesis.

The role of the human synovial fibroblast in monosodium urate crystal-induced synovitis.

Human synovial fibroblasts (HSF) have been cultured to identify and quantitate arachidonate metabolites released after exposure to monosodium urate (MSU) crystals. These crystals caused a significant release of PGE2 and 6-keto-PGF1 alpha. Media lactate dehydrogenase levels from MSU-exposed HSF were equal to controls. Serum was required for the increase in metabolite release. Indomethacin and dexamethasone inhibited metabolite release, whereas colchicine increased metabolite release. MSU (1 mg/ml) released hydroxyeicosatetraenoic acids (HETE) from HSF whereas 20-fold higher doses were required to release these metabolites from human polymorphonuclear leukocytes. Colchicine increased but lipoxygenase inhibitors decreased HETE synthesis. Arachidonate metabolites from HSF may contribute to the pathogenesis of crystal-provoked synovitides.

Human alveolar macrophages: a lesion in arachidonic acid metabolism in cigarette smokers.

Human pulmonary macrophages (PAM) recovered from young cigarette smokers and from age- and sex-matched subjects who had never smoked were used to investigate arachidonic acid metabolism. The uptake of radiolabeled arachidonic acid by PAM obtained from smokers and nonsmokers was not significantly different. The phagocytic indexes of the smoker and nonsmoker macrophages were 17.4 X 3.9% and 18.5 +/- 5.0%, respectively. Both smoker and nonsmoker macrophages produced prostaglandin E2 (PGE2), thromboxane B2 (TXB2) and prostaglandin F2 alpha (PGF2 alpha). A significant decrease in PGE2 and TXB2 synthesis but not in PGF2 alpha synthesis by the smoker PAM compared PAM compared with the nonsmoker PAM was observed using 2 different assays to measure prostaglandin production. Nonsmoker macrophages produced 644 +/- 128,239 +/- 53, and 29 +/- 12 ng/1.5 X 10(6) cells of PGE2, TXB2, and PGF2 alpha, respectively, whereas smoker macrophages synthesized 168 +/- 20, 41 +/- 3, and 17 +/- 1 ng/1.5 X 10(6) cells, as measured by radioimmunoassay. Similar differences were observed using isotopic assays. A cigarette-smoke-induced lesion in phospholipid hydrolysis or the mechanism regulating phospholipid hydrolysis seem most consistent with these findings.

Regulation of bradykinin-induced cyclic amp response by quinacrine and prostaglandin E2 and F2 alpha in human synovial fibroblasts.

Bradykinin induces an increment in intracellular cyclic AMP concentrations of human synovial fibroblasts and evokes the release of [3H]arachidonic acid and [3H]-E prostaglandins from human synovial fibroblasts pre-labeled in their phospholipids. Both these bradykinin-induced reactions are inhibited by quinacrine, an inhibitor of phospholipase A activity. The cyclic AMP response of human synovial fibroblasts to bradykinin is potentiated by prostaglandin E2 and inhibited by prostaglandin F2 alpha. These data emphasize the critical role of the prostaglandin system in reactions induced by bradykinin and suggest mechansims by which inflammatory reactions due to bradykinin may be modulated.

The effect of 7-oxa-13 prostynoic acid on the mechanism of action of bradykinin in human synovial fibroblasts.

Bradykinin, a potent inflammatory mediator, induces an increment in intracellular cyclic AMP concentrations of human synovial fibroblasts and evokes the synthesis and release of 3H-arachidonic acid and 3H-E prostaglandins from these cells pre-labeled in their phospholipids. Fetal calf serum in the media also stimulates the synthesis and release of these labeled lipids from pre-labeled human synovial fibroblasts and potentiates the bradykinin-induced cyclic AMP response. The PGE1 analogue, 7-oxa-13 prostynoic acid, completely abrogates both the bradykinin-induced cyclic AMP response and the bradykinin- and fetal calf serum-evoked release of labeled E-prostaglandins from pre-labeled cells. In serum-free media, the prostaglandin antagonist stimulated the release of 3H-arachidonic acid from pre-labeled human synovial fibroblasts and did not inhibit the bradykinin-induced release of this lipid.

Human synovial fibroblasts: the relationships between cyclic AMP, bradykinin, and prostaglandins.

Human synovial fibroblasts in culture respond to bradykinin (8 X 10(-9) M) with an increment in intracellular cyclic AMP concentration. These bradykinin (BK) concentrations are comparable to levels of the nonapeptide found in pathological synovial effusions. The cyclic AMP response to BK is enhanced by a heat stable factor(s) in fetal calf serum (FCS) and by the addition of arachidonic acid (AA) to monolayer cultures incubated in serum-free media. Synovial fibroblasts initially treated with BK are refractory to rechallenge with this agent as measured by the absence of an increment in cyclic AMP. These BK refractory cells do respond with significant increment in cyclic AMP to challenge with prostaglandin E1 (PGE1). Cells that have become refractory to PGE1 stimulation respond to BK. this suggests that a receptor or activator system different from the one for PGE1 and PGE2 exists for BK. When both BK and PGE1 are incubated together with synovial fibroblasts, the cyclic AMP response elicited is more than additive as compared to the response of each hormone separately. Indomethacin (IM) inhibits the BK evoked cyclic AMP response unless cell cultures are pretreated with PGE1. The PGE1 analog, 7-oxa-13-prostynoic acid, is a better inhibitor of the cyclic AMP response induced by BK than by PGE1. BK does not elicit a cyclic AMP response solely by elaborating PGE1, yet the prostaglandin pathway and its products seem to have a role in the degree of the cyclic AMP response to BK challenge.

Hydrocortisone inhibition of the bradykinin activation of human synovial fibroblasts.

Human synovial fibroblasts in culture respond to bradykinin with a 20-fold increment in intracellular cyclic AMP concentrations, however bradykinin does not directly activate adenylate cyclase activity in a particulate fraction derived from these cells. Bradykinin evokes a release of labeled arachidonic acid and prostaglandins E and F from synovial fibroblasts pre-labeled with 3H-arachidonic acid. Hydrocortisone inhibits the bradykinin induced increment in cyclic AMP and the release of arachidonic acid and prostaglandins E and F from synovial fibroblasts. Indomethacin, which also inhibits the cyclic AMP response to bradykinin, has no effect on the release of arachidonic acid from synovial fibroblasts. Indomethacin does, however, inhibit the quantity of prostaglandins released into the medium. These studies support the hypothesis that bradykinin does not activate human synovial fibroblast adenylate cyclase, but presumably activates a phospholipase whose products in turn result in the synthesis of prostaglandins. These and other investigations also suggest that a product(s) of the prostaglandin pathway causes the increment in cyclic AMP.

The effect of anti-inflammatory agents on human synovial fibroblast prostaglandin synthetase.

Human synovial fibroblast prostaglandin synthetase activity is inhibited by many different non-steroidal anti-inflammatory agents. Aspirin, indomethacin and phenylbutazone significantly inhibit both PGE1, PGE2 and PGF1alpha and PGF2alpha synthesis; whereas penicillamine and aurothioglucose are more potent inhibitors of the F prostaglandins. Histidine and antimalarials do not inhibit, to a significant degree, human synovial prostaglandin synthetase activity. Hydrocortisone has no direct effect on prostaglandin synthetase activity. No changes in synthetase activity are observed when synovial cells are incubated with hydrocortisone, and the prostaglandin synthetase system subsequently isolated and assayed. The proposed inhibitory effects of hydrocortisone on prostaglandin production by synovium may be the resulf of an alteration of enzyme substrate or cofactor concentration rather than a direct effect on prostaglandin synthetase.

Epiphyseal cartilage cyclic nucleotide phosphodiesterase: partial purification and kinetic characteristics of multiple enzymes.

Partial purification of chicken epiphyseal PDE activity by centrifugation and column chromatography has defined two distinct peaks of PDE activity. The faster eluting peak (I) has a higher apparent Km for cyclic AMP than the slower eluting major peak (IIs and II). Peak I has greater activity towards cyclic AMP as a substrate than towards cyclic GMP but does use both substrates. Peak I is not inhibited by T-3 or indomethacin at physiological concentrations. Substrates studies demonstrate the presence of at least two overlapping PDE species in the major peak(IIs and II). There is suggestive evidence that indomethacin is a more potent inhibitor of peak IIs which can use either cyclic AMP or cyclic GMP as substrates, whereas T-3 is a more potent inhibitor of fractions eluting where the enzyme only has activity with cyclic AMP.