Response to sulfasalazine in rheumatoid arthritis: life table analysis of a 5-year followup.

Eighty-six patients with rheumatoid arthritis treated with sulfasalazine were followed for 5 years, or until treatment was discontinued. At the end of 5 years, there was a 22% probability of successfully continuing treatment. Most adverse effects developed in the first 3 months of treatment. In 38 patients treatment was discontinued because of inefficacy. In 18 of these, a brief period of improvement was followed by clinical relapse. Twenty were regarded as having no useful response to sulfasalazine. The treatment continuation rate of 22% at 5 years is in marked contrast to the pessimistic longterm evaluations of second line drugs that have recently been reported.

Vagal stimulation reduces the severity of maximal electroshock seizures in intact rats: use of a cuff electrode for stimulating and recording.

J. Zabara showed that repetitive vagal stimulation (VS) prevents or ameliorates convulsive seizures in dogs. We have studied the effects of VS on maximal electroshock seizures (MES) in intact rats: (1) A 5 wire cuff electrode was developed for stimulating and recording from the vagus. Compound action potentials (AP) were recorded and strength-duration curves obtained for A and C fibers. There is a monotonic relationship with a negative slope between heart rate (HR) and AP amplitude. C fibers remain excitable for 25 days after cuff implant. (2) The anticonvulsant efficacy of VS is directly related to the fraction of vagal C fibers stimulated and the frequency of stimulation. (3) The anticonvulsant efficacy of VS has been established using two rat models of human epilepsy. VS abolishes the extensor component of the tonic phase of a MES and shortens or prevents tonic seizures induced by pentylenetetrazol (PTZ). (4) VS appears to act via release of large quantities of the inhibitory mediators GABA and glycine throughout large volumes of the brain. (5) It is rational to test VS in man as a treatment for intractable seizures.

Effects of vagal stimulation on experimentally induced seizures in rats.

Repetitive stimulation of the vagus nerve inhibits chemically induced seizures in dogs. We report here the results and conclusions from studies designed to answer some of the immediate questions raised by this finding. (1) Maximal stimulation of vagal C fibers at frequencies greater than 4 Hz prevents or reduces chemically and electrically induced seizures in young male rats. (2) Antiepileptic potency is directly related to the fraction of vagal C fibers stimulated. (3) Vagal stimulation shortens but does not shut down a chemical seizure once it has begun. (4) In rats, optimal stimulus frequency is approximately 10-20 Hz; duration of stimulus, 0.5-1 ms; and stimulus strength, 0.2-0.5 mA/mm2 of nerve cross-section. These results, when taken together with similar results obtained from dogs, monkeys, and humans, strongly suggest that periodic stimulation of the vagus nerve using appropriate stimulation parameters is a powerful method for preventing seizures. The data from the literature suggest that the antiepileptic actions of vagal stimulation are largely mediated by widespread release of GABA and glycine in the brainstem and cerebral cortex. The probable pathway is via projections from the nucleus of the solitary tract to the reticular formation and thence by diffuse projections to the cortex and other areas. Intermittent vagal stimulation has the potentiality of reducing the number and/or the intensity of seizures in patients with intractable epilepsy. These results indicate that feasibility studies in humans should be continued and expanded.

Effects of Putative Neurotransmitters of the Carotid Body on its Own Glomus Cells.

Carotid body glomus cells produce and release acetylcholine (ACh), catecholamines, and neuropeptides, and there is biochemical evidence that these cells possess receptors for these substances. Thus, we studied the effects of cholinergics [ACh, nicotine (Nic), bethanechol (BN)] and peptides [met-enkephalin (ME), substance P (SP)] on the membrane potential (Em), voltage noise (Erms), and input resistance (Ro) of glomus cells. Sliced carotid bodies (for cell visualization) of cats, rabbits, and mice were used. The mean Em and Ro of rabbit glomus cells were lower than those of cat and mouse. Ro of mouse cells was the largest, whereas Erms was similar in all species. The various agents had qualitatively similar effects on the cells of the three species although some quantitative differences were sometimes observed. But, for simplicity, results were pooled. ACh depolarized most cells (effect depressed by zero [Ca2+]o and Mn2+), reduced their resistance, and induced variable changes in Erms. Different ACh doses produced non-linear effects on DeltaEm. Nic and BN also depolarized most cells, reducing Ro and Erms. Atropine depressed the cell responses to BN; alpha-bungarotoxin the depolarizing response to Nic. ME and SP depolarized most cells, but only ME significantly reduced Ro. Neither peptide significantly changed voltage noise. Comparing the effects of all drugs showed that BN was the most effective depolarizing agent, producing the largest reductions in Ro. There were negative correlations between DeltaEm and DeltaRo with the cholinergics and SP; correlations between DeltaErms and DeltaRo were significant and positive only with the cholinergics. These results confirm the presence of nicotinic, muscarinic, and peptidergic receptors in glomus cells. The similar effects of cholinergics and peptides and those of flow interruption and anoxia suggest that the latter may partly act via autoreceptors for the released transmitters.

Radiolabelling of Mycobacterium avium oligosaccharide determinant and use in macrophage studies.

Internal radiolabelling procedures were used to radiolabel the oligosaccharide determinant of the glycopeptidolipids (GPL) from serovars 4 and 20 of the Mycobacterium avium complex. Mycobacteria were cultured in the presence of [6-3H]fucose, [2-3H]mannose or [methyl-3H]methionine, after which radiolabelled native lipid was extracted and distribution of radioactivity in native and deacetylated lipid was determined by thin-layer chromatographic methods. Incorporation of radiolabel was confirmed by examining acid hydrolysates of purified GPL for 3H-labelled sugars on cellulose thin-layer plates. Least incorporation of radiolabel into GPL was observed with [6-3H]fucose, whereas better incorporation was obtained with [2-3H]mannose and [methyl-3H]methionine. Use of [methyl-3H]methionine resulted in the radiolabelling of the methylated sugars in both the oligosaccharide determinant and the 3,4-di-O-methylrhamnose located at the terminus of the peptide core. Use of [2-3H]mannose resulted in the incorporation of radioactivity into the oligosaccharide determinant as 2-O-methylfucose, found in the GPL of both serovars 4 and 20. GPL radiolabelled with [2-3H]mannose were subsequently examined in macrophage cultures and found to be relatively inert to degradation by those phagocytic cells. These results substantiate earlier findings with the GPL of serovar 20 and indicate that these mycobacterial components may play a role in pathogenesis.

Changes in glomus cell membrane properties in response to stimulants and depressants of carotid nerve discharge.

Intracellular recordings were made from glomus cells in the excised, intact or sliced (150-200 microns) carotid body. Carotid nerve discharge was also recorded from intact preparations. Slices were prepared for visual (Nomarski) control of microelectrode impalement. Resting potential (Em), input resistance (Ro) and voltage noise (Erms) were measured in control conditions and in response to several stimulants (interruption of flow, hypoxic and histotoxic [NaCN]anoxia, hypercapnia, asphyxia and acidity) and depressants (alkalinity, cooling) of the carotid nerve sensory discharge. Different glomus cells responded differently to the same stimulus but significant trends were found. The more common responses to zero flow and anoxia (hypoxic and histotoxic) were depolarization (64%) and decreases in Erms (63%) and Ro (71%). When extracellular pH was varied from 8.5 to 5.0, the preponderant responses were cell depolarization, and increases in noise and input resistance as pH decreased. Consequently, cell depolarization induced by zero flow and anoxia tended to be accompanied by reduced Ro, whereas that induced by acidity generally showed increased Ro. Changes in voltage noise usually followed variations in Ro. When nerve discharge frequency was plotted against delta Em or delta Erms there were positive correlations during acid stimulation. However, these correlations were complex (parabolic) during flow interruption and anoxia: an increase in discharge occurred in response to cell depolarization and to hyperpolarization. These results suggest that hypoxia and hypercapnic or acidic stimuli act on glomus cells by different mechanisms. This finding is consistent with evidence obtained by recording carotid nerve discharges in intact animals.

Scleroderma and hemolytic anemia in a patient with deficiency of IgA and C4: a hitherto undescribed association.

We describe a 66-year-old women with CREST variant of scleroderma who developed autoimmune hemolytic anemia responsive to prednisone and demonstrated a deficiency of IgA and the C4 component of complement. This association of clinical, immunologic and genetic findings has not previously been reported. The literature relating to these findings is reviewed and possible mechanisms are discussed.

Liquid chromatographic determination of piroxicam in serum.

A sensitive method for monitoring serum piroxicam (Feldene) is described. The assay requires 1.0 ml of specimen and involves chloroform extraction from an acidified mixture followed by concentration and injection into a liquid chromatograph. Column effluent is monitored at 330 nm. Retention times of piroxicam and the internal standard (naproxen) are 6.6 and 11.0 min, respectively. The lower limit of detection in serum is 0.5 mg/L. Within-day precision (coefficient of variation, CV) of piroxicam in serum (5-13 mg/L range) varied from 3.6 to 6.3%; between-day CV at concentrations of 5 to 20 mg/L varied from 6.5 to 9.8%. Analytical recovery of piroxicam at 20 mg/L was 88%. Several other drugs were analyzed but none interfered with the assay. Serum concentrations found in 28 patients on a 20-30 mg/day dose ranged from 1.5 to 15.2 mg/L.

Costs of managing patients at a Canadian rheumatic disease unit.

Financial and other costs of managing 194 inpatients and 433 outpatients referred to the rheumatology service of a Canadian general teaching hospital during 1978 were assessed. The tax financed institutional cost/outpatient visit was $102, compared to $112/inpatient day, which was 62% of the hospital's $180 cost/inpatient day. Hospital financial costs represent 78% of RDU outpatient costs and 85% of substantially lower than per diem rates. Our findings caution against relying solely on hospital data in assessing total economic costs of any diagnostic subset of patients.

Interaction in vitro between synovial cells and autologous lymphocytes and sera from arthritis patients.

Synovial cells from patients with rheumatoid arthritis (RA) when grown in vitro in media supplemented with 20% fetal calf serum failed to show any difference in growth rate, life span, uptake of tritiated thymidine or cellular and nuclear characteristics when compared with synovial cells from patients with osteoarthritis or other joint diseases grown similarly in 20% serum enriched medium. There was also no evidence that lymphocytes and/or sera from RA patients were more cytotoxic to autologous synovial cells than sera and/or lymphocytes from OA patients. It is unlikely that antisynovial antibodies or lymphocytes from RA patients act as triggers for synovial damage.

Immunopathological changes in rheumatoid arthritis and other joint diseases.

A comparative study of the distribution of immunoglobulins G, M, and A and C3 in the synovium and inside synovial fluid leucocytes and of the relative levels of IgG, IgM, AND C3 in paired samples of serum and synovial fluid from both seropositive and seronegative patients with rheumatoid arthritis and other types of non-infective synovitis shows that although there is no distinctive immunopathological feature of rheumatoid arthritis, the incidence of immune complexes containing IgG and IgM with and without detectable C3 in the affected synovium or inside synovial fluid granulocytes is higher in rheumatoid arthritis and especially so in seropositive cases. The mean level of C3 in synovial fluid from patients with rheumatoid arthritis is lower than that from the group without rheumatoid arthritis. In contrast to previous reports, extracellular clumps of IgA could be detected in the affected synovium of a number of affected patients. Aggretated human IgG could be bound by some of the synovial biopsies and synovial fluid leucocytes from both seropositive and seronegative rheumatoid arthritis patients. Antinuclear factor and rheumatoid factor could be detected in the synovial fluid but not in the serum of several patients suggesting either selective sequestration or local synthesis of antinuclear and rheumatoid factors in the affected joints.

Arthritis, deformities, and runting in C5-deficient mice injected with human rheumatoid arthritis synovium.

The pathogenesis of rheumatoid arthritis might be more easily understood and the efficacy of therapeutic measures might be more accurately assessed if a convenient animal replica of this disease were available for laboratory study. Intraperitoneal injection of homogenates of inflamed synovium taken at operation from patients with rheumatoid arthritis produces inflammatory swelling and deformity in the tail and extremities of a proportion of injected mice from a complement (C5)-deficient inbred strain. Swelling of the paws leads to limping of the affected mice. The lesions are transmissible from generation to generation. The results support the theory of a transmissible agent in the inflamed synovium of rheumatoid arthritis patients.

Anion conductance of frog muscle membranes: one channel, two kinds of pH dependence.

Anion conductance and permeability sequences were obtained for frog skeletal muscle membranes from the changes in characteristic resistance and transmembrane potential after the replacement of one anion by another in the bathing solution. Permeability and conductance sequences are the same. The conductance sequence at pH = 7.4 is Cl(-) Br(-) > NO(3) (-) > I(-) > trichloroacetate >/= benzoate > valerate > butyrate > proprionate > formate > acetate >/= lactate > benzenesulfonate >/= isethionate > methylsulfonate > glutamate >/= cysteate. The anions are divided into two classes: (a) Chloride-like anions (Cl(-) through trichloroacetate) have membrane conductances that decrease as pH decreases. The last six members of the complete sequence are also chloride like. (b) Benzoate-like anions (benzoate through acetate) have conductances that increase as pH decreases. At pH = 6.7 zinc ions block Cl(-) and benzoate conductances with inhibitory dissociation constants of 0.12 and 0.16 mM, respectively. Chloride-like and benzoate-like anions probably use the same channels. The minimum size of the channel aperture is estimated as 5.5 x 6.5 A from the dimensions of the largest permeating anions. A simple model of the channel qualitatively explains chloride-like and benzoate-like conductance sequences and their dependence on pH.

Fecal excretion of bile acids: a new technique for studying bile acid kinetics in patients with ileal resection.

The fecal elimination and enterohepatic circulation of bile acid was studied in 11 patients. 10 patients with varying degrees of ileal disease or resection and 1 patient with pancreatic insufficiency and no ileal disease. A new technique was employed which involved the nearly simultaneous administration of cholic acid-(14)C and a nonabsorbable marker. (51)CrCl(3). Each individual stool specimen was collected for 36-96 hr and analyzed separately. Assay of the radioactivity of each isotope allowed the accurate determination of an excretion rate for both cholic acid and (51)Cr. The difference between these rates was used to calculate an absorption coefficient for cholic acid. In addition, bile acid concentration measured by the steroid dehydrogenase technique, and the water content of each stool was determined. THE PATIENTS WERE DIVIDED INTO GROUPS DEPENDING UPON HOW MUCH SMALL INTESTINE WAS RESECTED OR DISEASED: six patients with less than 100 cm of ileal resection or disease (group A), and five patients with more than 100 cm of ileal disease or resection (group B). The (51)Cr excretion rate was similar in the two groups, but cholic acid-(24)C excretion rates were significantly more rapid in group B than in group A. The cholic acid absorption coefficient was essentially normal in the patient with pancreatic insufficiency, moderately decreased in group A patients, and extremely low or zero in group B patients. It was inversely related to the length of intestine diseased or resected. Daily fecal bile acid excretion was normal to twice normal in group A patients and 2-8 times normal in group B patients. In all patients with ileal disease or resection, there was a direct correlation between fecal bile acid, fecal mass, and fecal water. Each millimole of additional bile acid in the stool was associated with an increase in stool water of 11 moles (P < 0.01). These studies show that the kinetics of bile acids in the enterohepatic circulation can be accurately studied in patients with extensive ileal resection. The regular relationship between fecal bile acid and fecal mass and water suggests, but does not prove, a critical role of bile acid in determining stool water.