Protein arginine deiminase 4 inhibition is sufficient for the amelioration of collagen-induced arthritis.

Citrullination of joint proteins by the protein arginine deiminase (PAD) family of enzymes is recognized increasingly as a key process in the pathogenesis of rheumatoid arthritis. This present study was undertaken to explore the efficacy of a novel PAD4-selective inhibitor, GSK199, in the murine collagen-induced arthritis model of rheumatoid arthritis. Mice were dosed daily from the time of collagen immunization with GSK199. Efficacy was assessed against a wide range of end-points, including clinical disease scores, joint histology and immunohistochemistry, serum and joint citrulline levels and quantification of synovial autoantibodies using a proteomic array containing joint peptides. Administration of GSK199 at 30 mg/kg led to significant effects on arthritis, assessed both by global clinical disease activity and by histological analyses of synovial inflammation, pannus formation and damage to cartilage and bone. In addition, significant decreases in complement C3 deposition in both synovium and cartilage were observed robustly with GSK199 at 10 mg/kg. Neither the total levels of citrulline measurable in joint and serum, nor levels of circulating collagen antibodies, were affected significantly by treatment with GSK199 at any dose level. In contrast, a subset of serum antibodies reactive against citrullinated and non-citrullinated joint peptides were reduced with GSK199 treatment. These data extend our previous demonstration of efficacy with the pan-PAD inhibitor Cl-amidine and demonstrate robustly that PAD4 inhibition alone is sufficient to block murine arthritis clinical and histopathological end-points.

Role of antithrombotic therapy in unstable angina, myocardial infarction and sudden death.

The role of platelets and the clotting system in the initiation and progression of atherosclerosis has received significant attention. Most importantly, platelets and thrombosis play a pivotal role in the pathogenesis of the acute coronary syndromes of unstable angina, myocardial infarction and sudden death. In each stage of the development of coronary artery disease, from the early symptomatic stage through the growing lesion and finally to the complicated plaque that results in the precipitation of the acute coronary syndromes, platelets and the clotting system serve as a common link among them. Antithrombotic therapy aimed at halting the progression of these syndromes, preventing their occurrence or even reversing them (such as in the early stages of acute myocardial infarction), has provided exciting new modalities to treat these disorders. The use of aspirin in unstable angina in two well designed studies has clearly shown a reduction in fatal as well as nonfatal cardiac events compared with control groups not treated with aspirin. Although demonstration of a benefit of anticoagulant and antiplatelet therapy is difficult owing to a low event rate of thrombotic events (low sensitivity) and other nonthrombotic fatal events (low specificity) after myocardial infarction, pooled results have shown a favorable effect with their use. The usefulness of thrombolytic therapy in the early stages of acute myocardial infarction depends on the timing of initiation of therapy, the severity of the residual stenosis and possible use of agents that protect the ischemic myocardium. Other potential therapies for the acute coronary syndromes are also suggested. Further studies are in progress to establish the clinical benefits of antithrombotic agents in acute coronary syndromes.

Myxomatous degeneration and cystic medial necrosis associated with acromegaly.

Although valvular lesions are rare in acromegaly, two patients with click-murmur syndrome and one patient with aortic insufficiency secondary to myxomatous degeneration and cystic medial necrosis of the aorta have been reported. Growth hormone excess has been postulated to potentiate these connective tissue defects. Excess mucopolysaccharide deposition is stimulated by growth hormone and is characteristic of both cystic medial necrosis and myxomatous degeneration. Both lesions are found in experimental lathyrism, which is potentiated by growth hormone. We observed a patient with mitral insufficiency, acromegaly documented by growth hormone levels, myxomatous degeneration of all four cardiac valves, and cystic medial necrosis of the aorta and pulmonary artery. This case presents further evidence that excess growth hormone may potentiate the connective tissue cardiovascular lesions in acromegaly.

Effect of aspirin on exercise-induced angina.

Suspecting that platelet thromboemboli could play a role in the pathogenesis of myocardial ischemia, we did a random-order, double-blind, crossover study of the effect of the platelet aggregation inhibitor, aspirin, on treadmill exercise-induced angina in 13 men with coronary artery disease. Although collagen-induced platelet aggregation and the second phase of adenosine diphosphate (ADP)-induced platelet aggregation were significantly decreased and the rate of disaggregation of ADP-induced platelet aggregates was significantly increased after 650 mg aspirin in buffered solution, there was no delay in onset of exercise-induced angina, change in heart rate-blood pressure product at onset of angina, or change in S-T segment depression at onset of angina. Regardless of whether the patients had received placebo or aspirin on the preceding day, treadmill exercise until angina was followed by no changes in platelet aggregation or disaggregation, platelet count in blood or platelet-rich plasma, or of the plasma concentration of nonesterified fatty acids.

Hepatitis B infection in hospital personnel during an eight-year period; policies for screening and pregnancy in high risk areas.

From 1972 through 1979, acute hepatitis, type B, or asymptomatic hepatitis B surface (HBs) antigenemia developed in 34 employees at Yale-New Haven Hospital. The average yearly incidence of the infection was 1.2 cases per 1,000 employees. The incidence was highest in those administering venipunctures followed, respectively, by those in the emergency room, hemodialysis unit, housestaff, laboratory, general nursing, and support service personnel. Three cases were detected during eight years of routine screening of personnel; in 1972, one of these, a pregnant nurse working in the hemodialysis unit, was moved from that unit. Subsequently, seven personnel in the unit have been transferred during pregnancy. However, staphylococcal pneumonia was acquired by one of them on a medical floor, and another nurse, seeking work in oncology, was not hired while pregnant. Both cases resulted in administrative complaints. Currently, we screen personnel in the hemodialysis and venipuncture units quarterly for hepatitis B surface antigen (HBsAg) and antibody (anti-HBs) (participation is optional for those in the emergency room and oncology) and strongly urge seronegative pregnant women to transfer from these areas.

Prosthetic valve endocarditis: reviewing the problem.

Bacterial endocarditis is a serious complication of valve replacement, with an overall mortality of 59%. Fever, although a constant feature of the condition, is a nonspecific finding; other manifestations may or may not be present and the diagnosis may be overlooked. Any patient with a prosthetic heart valve and bacteremia should be considered to have endocarditis and should be treated accordingly.

Unstable angina: status of aspirin and other forms of therapy.

A randomized, double-blind clinical trial in 1266 men with unstable angina showed that 324 mg of aspirin daily for 12 weeks reduced the incidence of myocardial infarction by 51% (p = .001), and the data suggested a similar reduction in mortality. The only other therapy for unstable angina that has been studied in randomized trials of adequate size to evaluate mortality and rate of infarction is aortocoronary bypass surgery. Results with heparin therapy have been encouraging, but the studies in which this drug has been tested have been flawed. Nitrates, beta-blockers, calcium blockers, fibrinolytic therapy, and coronary angioplasty have not been adequately evaluated. Randomized trials of aortocoronary bypass surgery have not demonstrated decreased mortality or rates of myocardial infarction in patients with unstable angina. Although surgical techniques have improved since these trials were conducted, medical management has also improved. Mortality and infarct rate in patients with unstable angina are now lower than in the early 1970s. New well-controlled clinical trials are needed.

Which role for antiplatelet and anticoagulant drugs in unstable angina pectoris?

Two large placebo-controlled, randomized, double-blind clinical trials have demonstrated the benefit of aspirin therapy in preventing myocardial infarction and death in patients with unstable angina. The Veterans Administration Cooperative Study of 1266 men hospitalized with unstable angina showed that 324 mg of aspirin daily for 12 weeks reduced the incidence of myocardial infarction by 51% (p = 0.001), and the data suggested a similar reduction in mortality. The Canadian McMaster University multicenter trial of 555 patients showed that treatment with 1300 mg of aspirin per day for a mean of 18 months reduced the incidence of cardiac death and nonfatal myocardial infarction together by 51% (p = 0.008). The reduction in death alone was 71% (p = 0.004). In the Canadian study there was no observed benefit of sulfinpyrazone. The Canadian trial confirmed the results of the VA Cooperative Study and showed statistical significance for reduction by aspirin of death as well as of myocardial infarction. It showed similar benefits in women as in men with unstable angina. The life-table curves for aspirin-treated and control patients continued to separate throughout the 2-year study period, demonstrating the value of continued treatment. The VA study showed no evidence of gastrointestinal side effects from 324 mg of aspirin daily administered in a buffered solution. Heparin therapy for unstable angina has appeared promising, but no properly conducted randomized trial has been accomplished.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic impedance measurements in cleft-palate children.

Clinical acoustic impedance findings in a group of 40 children with cleft lip or palate and a group of 20 noncleft children are presented. The cleft subjects exhibited a high incidence of hearing loss and aural pathology. The data suggest that impedance measurements lend pertinent supportive information to routine puretone audiometric testing in the detection and management of middle-ear disease in the cleft-palate population.

Prevention of exercise-induced endothelemia by isradipine in men with angina pectoris.

The primary purpose of this study was to determine whether treatment with isradipine would prevent an exercise-induced increase in the concentration of anuclear carcasses of endothelial cells in the blood of men with angina pectoris. Endothelial cells were prepared for microscopic counting by a method involving differential centrifugation of venous blood. The endothelial cell count of 20 men increased from 0.78 +/- (SD) 0.41 per counting chamber approximately 2 h before exercise to 1.28 +/- 0.54 three minutes after moderate angina was induced by treadmill exercise (p = 0.003). After treatment with isradipine, the endothelial cell count decreased with or without treadmill exercise. These results suggest that exercise caused an increase in the endothelial cell count of men with coronary artery disease and that isradipine caused an acute decrease and prevented the exercise-induced increase in the endothelial cell count.

The effect of sulfinpyrazone on treadmill exercise-induced angina pectoris.

Suspecting that platelet thromboemboli could play a role in the pathogenesis of myocardial ischemia, we have done a random-order, double-blind, crossover study of the effect of the platelet-active drug sulfinpyrazone on treadmill exercise-induced angina pectoris in 30 men with coronary artery disease. The mean duration of exercise before onset of angina was 43 s longer after taking sulfinpyrazone than before and 11 s shorter after taking placebo than before. Analysis of variance for crossover design showed that the mean difference between the values obtained before and after sulfinpyrazone was significantly different (p < 0.01) from the mean difference between the values before and after placebo. Sulfinpyrazone had no effect on the mean heart rate-blood pressure product at onset of angina, change in ST segment during exercise, or preexercise platelet aggregate ratio and bleeding time. Exercise until angina occurred did not affect the platelet aggregate ratio.

Babble and random-noise masking of speech in high and low context cue conditions.

"Perceptual" masking of speech by multitalker speech (babble) has been widely reported but poorly quantified. Furthermore, the validity of the construct of perceptual masking is questionable. This report describes an experiment using a newly standardized test of speech perception in noise (SPIN) with both babble and spectrally matched random-noise maskers. Classical psychophysical ogive curves were used to model speech recognition as a function of signal-to-noise ratio (S/N). The two maskers yielded speech recognition functions of the same steepness but different locations on the S/N axis. The high-context items of SPIN yielded speech recognition curves with steeper slope and different locations on the S/N axis than the low-context items. These data are used to argue that perceptual masking was not documented (under certain assumptions) and that the superior masking of babble may be explained in purely acoustical terms. Speculations are offered about the possible acoustical differences that could be responsible for the differences in masking effect.

Platelet aggregation. Adult-onset diabetes mellitus and coronary artery disease.

Using a turbidimetric technique, we determined 1.7 micrometer adenosine diphosphate--induced platelet aggregation and disaggregation at 37 degrees C in the platelet-rich plasmas of two groups of men with coronary artery disease. Eleven men were nondiabetic and 11 had adult-onset diabetes mellitus without retinopathy. There were no significant differences (P greater than .05) between diabetics and nondiabetics of the following variables: age, platelet count in platelet-rich plasma, first and second phases of platelet aggregation, maximum extent of aggregation, and percent disaggregation at three minutes after maximum aggregation occurred. Although the mean adenosine diphosphate--induced platelet aggregation in the platelet-rich plasmas of adult-onset diabetic men with coronary artery disease and no retinopathy was not enhanced, and the mean rate of disaggregation was not reduced, when compared with nondiabetic men with coronary artery disease or with healthy men; a slow rate of platelet disaggregation (less than 10%) occurred more frequently in the platelet-rich plasmas of men with coronary artery disease.

Cigarette smoking--induced enhancement of platelet function: lack of prevention by aspirin in men with coronary artery disease.

Increased cardiovascular morbidity and mortality among cigarette smokers may be mediated in part by enhanced platelet function. Previous data showed that cigarette smoking--induced lowering of the platelet aggregate ratio of normal individuals was prevented by taking aspirin before smoking. Our study was undertaken to determine whether similar results would occur in men with coronary artery disease and whether platelet factor 4 would be released. A random-order, double-blind crossover study comparing the effects of placebo, 0.15 gm aspirin, and 0.30 gm aspirin was done in 30 male habitual smokers with coronary artery disease. Each man took a tablet containing placebo or aspirin and then abstained from smoking for 12 hours before each of three 20-minute periods of smoking two tobacco cigarettes. Immediately before and after smoking, the platelet aggregate ratio and the concentration of platelet factor 4 in platelet-poor plasma were determined from antecubital venous blood. Twelve hours after placebo, the geometric mean concentration of platelet factor 4 was 13.6 ng/ml before and 19.7 ng/ml after smoking (P = 0.0006). The mean platelet aggregate ratio was 0.77 and 0.72, respectively (P less than 0.00001). Neither dose of aspirin affected the presmoking value of or the smoking-induced change in either variable. The data indicate that smoking stimulated platelet aggregate formation and release of the contents of platelet alpha-granules, which were unaffected by preadministration of aspirin. This contrasts with the previous study of normal habitual smokers whose ingestion of 0.32 gm aspirin prevented a smoking-induced decrease in the platelet aggregate ratio.