Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by background methotrexate dose group.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post hoc analysis investigated the effect of methotrexate (MTX) dose on the efficacy of tofacitinib in patients with RA. ORAL Scan (NCT00847613) was a 2-year, randomized, Phase 3 trial evaluating tofacitinib in MTX-inadequate responder (IR) patients with RA. Patients received tofacitinib 5 or 10 mg twice daily (BID), or placebo, with low (≤12.5 mg/week), moderate (>12.5 to <17.5 mg/week), or high (≥17.5 mg/week) stable background MTX. Efficacy endpoints (at months 3 and 6) included American College of Rheumatology (ACR) 20/50/70 response rates, and mean change from baseline in Clinical Disease Activity Index (CDAI), Disease Activity Score in 28 joints (DAS28)-4(erythrocyte sedimentation rate [ESR]), Health Assessment Questionnaire-Disability Index (HAQ-DI), and modified Total Sharp score. 797 patients were treated with tofacitinib 5 mg BID (N = 321), tofacitinib 10 mg BID (N = 316), or placebo (N = 160); 242, 333, and 222 patients received low, moderate, and high MTX doses, respectively. At months 3 and 6, ACR20/50/70 response rates were greater for both tofacitinib doses vs placebo across all MTX doses. At month 3, mean changes from baseline in CDAI and HAQ-DI were significantly greater for both tofacitinib doses vs placebo, irrespective of MTX category; improvements were maintained at month 6. Both tofacitinib doses demonstrated improvements in DAS28-4(ESR), and less structural progression vs placebo, across MTX doses at month 6. Tofacitinib plus MTX showed greater clinical and radiographic efficacy than placebo in MTX-IR patients with RA, regardless of MTX dose.

Using diurnal intraocular pressure fluctuation to assess the efficacy of fixed-combination latanoprost/timolol versus latanoprost or timolol monotherapy.

AIM: To evaluate differences in diurnal intraocular pressure (IOP) fluctuation in glaucoma/ocular hypertension patients treated with once-daily fixed-combination latanoprost/timolol, once-daily latanoprost or twice-daily timolol. METHODS: In two 6-month, double-masked, parallel-group studies, patients received run-in timolol (2-4 weeks) and randomised (1:1:1) to therapy. IOP was measured three times/day at baseline and weeks 2, 13 and 26. In posthoc analyses, diurnal IOP fluctuation = highest daily IOP-lowest daily IOP at baseline and week 26. Fluctuation also was dichotomised: high (>6 mm Hg), low (< or =6 mm Hg). RESULTS: 854 patients were randomised (fixed combination = 278; latanoprost = 287; timolol = 289). Diurnal fluctuation was significantly reduced from baseline to week 26 with the fixed combination (p = 0.002) but not with latanoprost or timolol monotherapy (p = 0.601; p = 0.097). Relative to baseline, the percentage with high diurnal IOP fluctuation at week 26 was reduced by 48% with fixed combination but increased 13% with latanoprost and 48% with timolol. Changes in IOP fluctuation and in mean IOP were significantly correlated for the monotherapies but not the fixed combination. CONCLUSIONS: Fixed-combination latanoprost/timolol results in lower diurnal IOP fluctuation and significantly fewer patients with a high fluctuation than treatment with latanoprost or timolol monotherapy. The fixed combination may have an independent effect on reducing IOP fluctuation in addition to lowering IOP.

Efficacy and tolerability of celecoxib compared with diclofenac slow release in the treatment of acute ankle sprain in an Asian population.

INTRODUCTION: Cyclooxygenase (COX)-2 selective inhibitors are attractive candidates for treatment of ankle sprain because of their efficacy as anti-inflammatory and analgesic agents and their overall safety, including lack of effect on platelet aggregation. The objective of this study was to assess the efficacy and tolerability of celecoxib compared with diclofenac slow release (SR) in the treatment of acute ankle sprain in an Asian population. METHODS: In this seven-day, multicentre, double-blind, randomised, parallel-group trial, 370 patients with first- or second-degree ankle sprain occurring at or less than 48 hours prior to the first dose of study medication were randomised to receive celecoxib 200 mg bid (189 patients) after a 400 mg loading dose or diclofenac SR 75 mg bid (181 patients). Patients were required to demonstrate moderate to severe ankle pain on weight bearing (45 mm or greater on a 100 mm visual analogue scale [VAS]) at baseline. The primary efficacy end point was the patient's assessment of ankle pain (VAS on full weight bearing) on day 4. RESULTS: Celecoxib was as effective as diclofenac SR in improving the signs and symptoms of ankle sprain. At day 4, mean VAS scores for celecoxib and diclofenac SR had decreased to 28 mm and 30 mm, respectively. Treatment differences were not statistically significant. Incidence of upper gastrointestinal adverse events was low in both treatment groups (0.5 percent versus 2.2 percent for celecoxib and diclofenac SR, respectively). CONCLUSION: Celecoxib, a COX-2 selective inhibitor, is as effective as diclofenac SR in treating ankle sprains. With its platelet-sparing properties, celecoxib may offer an advantage over diclofenac SR in managing musculoskeletal injuries.

Variability in systolic blood pressure--a risk factor for coronary heart disease?

Among 1,433 men of Japanese ancestry living in Hawaii with blood pressure measured at four different physical examinations over a 10-year period, 110 events of definite coronary heart disease (CHD) occurred during 11.6 years of subsequent follow-up. Each subject's mean blood pressure, the slope of the regression of his blood pressure on age, and the variance of blood pressure about this regression line were tested for association with subsequent incident definite CHD. Adjusted for mean systolic blood pressure (SBP), the variance of SBP was significantly associated with CHD (p < 0.001); however, the slope was not significantly associated with CHD. Variation in body weight was an independent risk factor for CHD. The effect of variation in SBP was significantly higher among men not taking antihypertensive medication; among men taking antihypertension medication, the standardized relative risk was 1.00. Comparing men in the highest quintile of SBP variation with those in the lowest quintile, the relative risk of CHD was 2.0 among all subjects and 5.3 among the 1,007 men not taking antihypertensive medication (95% confidence interval 1.8-15.4). Some of the beneficial effect of taking antihypertensive medication may have been due to reducing the effect of SBP variance rather than simply lowering the average SBP.

Characteristics associated with rapid decline in forced expiratory volume.

Cigarette smoking is known to accelerate decline of pulmonary function; however, the role of other factors is less clear. Characteristics of individuals who experienced rapid decline in forced expiratory volume in 1-sec (FEV1) were examined in 4451 Japanese-American men from the Honolulu Heart Program who were aged 45 to 68 years at baseline (1965-1968) and who produced three acceptable FEV1 measures over a 6-year period. Average annual rates of FEV1 decline were calculated by use of within-person regression and were categorized as rapid (> or = 60 ml/y), moderate (30 to 59 ml/y) or slow (< 30 ml/y). Lifestyle and biologic factors were compared by FEV1 decline categories after adjustment for age. A logistic regression model showed that continued smoking during follow-up, cigarette pack-years, wheezing, coronary heart disease, alcohol intake, and reduced subscapular skinfold were significantly associated with rapid FEV1 decline, after adjustment for age, height, cholesterol, an indicator of Japanese diet, and education. When analyses were restricted to continuous smokers, cigarette pack-years, wheezing, and reduced subscapular skinfold were found to be independent predictors. Among never smokers, lower educational attainment was a predictor of rapid FEV1 decline, and the association involving subscapular skinfold approached significance (P < 0.07). These characteristics may be useful in identifying subgroups of the population who are at increased risk of accelerated decline in pulmonary function and thus would be most likely to benefit from appropriate intervention.

Combined effects of HDL cholesterol, triglyceride, and total cholesterol concentrations on 18-year risk of atherosclerotic disease.

BACKGROUND: Whether the combination of a low level of HDL cholesterol (HDL-C) and high level of triglyceride (TG) confers increased risk of cardiovascular disease and whether risk varies across levels of total cholesterol (TC) are not well established. Combined effects of HDL-C, TG, and TC on the incidence of atherosclerotic disease were examined prospectively in Japanese-American men from the Honolulu Heart Program. METHODS AND RESULTS: Among 1,646 men aged 51 to 72 years who were free of coronary heart disease (CHD), stroke, and cancer and were not taking lipid-lowering medication, 318 developed atherosclerotic events (angina, coronary insufficiency, aortic aneurysm, definite CHD, or thromboembolic stroke) and 170 developed definite CHD between 1970 and 1988. Subjects were stratified by TC level (desirable, < 200 mg/dL; borderline high, 200 to 239 mg/dL; high, > or = 240 mg/dL), HDL-C level (< 35 and > or = 35 mg/dL), and TG level (< 200 and > or = 200 mg/dL). With Cox regression with high HDL-C and low TG as reference, age-adjusted relative risks (RR) of atherosclerotic events were significantly elevated in men with low HDL-C and high TG at borderline-high (RR, 2.46; 95% CI, 1.48 to 4.09) and high (RR, 2.21; 95% CI, 1.34 to 3.66) TC levels but not in men with desirable TC levels (RR, 0.89; 95% CI, 0.38 to 2.09). Elevated risks were independent of blood pressure, obesity, fat distribution, diabetes, smoking, and alcohol. Results were not materially altered by exclusion of subjects with angina alone and were similar but somewhat weaker for CHD. CONCLUSIONS: Risk of atherosclerotic disease appears elevated in subjects with low HDL-C and high TG levels when TC is borderline high or high, independent of other cardiovascular risk factors. These findings support recent cholesterol screening recommendations and suggest that joint effects of HDL-C and TG may be important to consider.

Physical activity and incidence of diabetes: the Honolulu Heart Program.

Few prospective studies have assessed the relation between physical activity and diabetes. The authors examined this relation prospectively among 6,815 Japanese-American men in the Honolulu Heart Program who were aged 45-68 years and initially free of diagnosed diabetes in 1965-1968. A physical activity index was calculated based on time spent per day in different activity levels and a weighting factor correlated with estimated oxygen consumption. Incidence of clinically recognized diabetes was based on self-reported use of diabetic medication at one of two subsequent examinations. The age-adjusted 6-year cumulative incidence of diabetes decreased progressively with increasing quintile of physical activity from 73.8 to 34.3 per 1,000 (p < 0.0001, trend) in all men and from 53.9 to 21.7 per 1,000 (p < 0.0001, trend) among men with a non-fasting glucose level < 225 mg/dl one hour after a 50-gm load, the latter group being less likely to have unrecognized diabetes at baseline. When stratified by tertile of baseline glucose, trends in incidence across physical activity quintiles were statistically significant in the low and middle tertiles but not in the high tertile. Similar inverse trends were observed for men in the lower four quintiles of body mass index, however, these trends were weaker and not significant for men in the upper quintile of body mass index. Age-adjusted odds ratios for diabetes comparing the upper with the lower four quintiles of physical activity were 0.55 (95% confidence interval (CI) 0.41-0.75) for all men and 0.50 (95% CI 0.33-0.74) for men with glucose < 225 mg/dl. After adjustment for age, body mass index, subscapular/triceps skinfold ratio, systolic blood pressure, triglycerides, glucose, hematocrit, and parental history of diabetes, odds ratios were still statistically significant and similar in magnitude. Restriction of analyses to men who remained free of cardiovascular disease during the study period produced similar results, which suggests that inactivity due to subclinical cardiovascular disease is unlikely to be responsible for these findings. Risk factor-adjusted odds ratios for older men (55-68 years) demonstrated that physical activity confers at least the same degree of protection as in younger men (45-54 years). These results indicate that physical activity is associated inversely with incident diabetes and that the beneficial effect does not appear to be mediated through improvements in other risk factors assessed in this study.

Incidence and predictors of diabetes in Japanese-American men. The Honolulu Heart Program.

Reports on the incidence and predictors of diabetes in minority populations are infrequent. The 6-year cumulative incidence of diabetes between 1965 and 1974 was estimated among 7210 Japanese-American men aged 45 to 68 years who were enrolled in the Honolulu Heart Program and were free of clinically recognized diabetes at baseline. The incidence of "possible" diabetes (based on history, medication, or hospital diagnosis) was 12.8% and the incidence of "probable" diabetes (based on diabetic medication) was 5.7%. Estimates of incidence in subjects with a nonfasting glucose concentration less than 225 mg/dL 1 hour after a 50-g load were 9.7 and 4.0%, respectively. Multivariate adjusted odds ratios (ORs) for probable diabetes in all subjects comparing the upper quintile with the lower four quintiles combined for continuous variables indicated statistically significant direct associations with body mass index (OR, 1.69; 95% confidence interval (CI), 1.31 to 2.18), 1-hour postchallenge glucose level (OR, 5.79; 95% CI, 4.58 to 7.33), triglyceride levels (OR, 1.47; 95% CI, 1.14 to 1.91), systolic blood pressure (OR, 1.36; 95% CI, 1.05 to 1.76), and parental history of diabetes (OR, 1.73; 95% CI, 1.29 to 2.33), and an inverse association with physical activity (OR, 0.49; 95% CI, 0.34 to 0.72), using logistic regression models including these variables as well as age, subscapular/triceps skinfold ratio, and hematocrit simultaneously. Associations were similar but slightly weaker in men with glucose levels less than 225 mg/dL and in those who remained free of cardiovascular disease. When older men (55 to 68 years old) were compared with younger (45 to 54 years old) men, associations among the older group were stronger for body mass index, physical activity, and systolic blood pressure and they were weaker for glucose levels, triglyceride values, and parental diabetes. Results suggest that body mass index, physical inactivity, glucose level, and parental diabetes appear to be independent risk factors for diabetes, while triglyceride and systolic blood pressure levels may be markers for an adverse cardiovascular risk factor profile associated with diabetes and may reflect an insulin resistance syndrome.

Fish consumption may limit the damage of smoking on the lung.

High fish consumption is characteristic of Japanese-American men of the Honolulu Heart Program (HHP). Analyses of data from the Atherosclerosis Risk in Communities (ARIC) study suggest high fish intake protects the lung against smoking damage. Measurements of forced expiratory volume in 1 s (FEV1) and smoking status in the HHP cohort were done at the first examination in 1965-68. Among 8,006 men, 45 to 68 yr, 6,346 had acceptable spirograms. Within current smokers, 1,545 men consumed fish less than twice a week, and 1,264 ate fish twice a week or more. Controlling for cigarettes/d, age, height, and daily calories, separate regression models indicated an average decrease of -10.1 ml for each additional yr of smoking (95% Confidence Interval [CI]: -13.6, -6.5) at low levels of fish intake, and a decrease of -4.4 ml (95% CI: -8.2, -0.6) at high levels. The coefficients were significantly different (p = 0.03). These differences reflect a predicted FEV1 144 ml (95% CI: 62, 227) higher in the high fish group at > or = 40 yr of smoking, but no difference at < or = 35 yr. Similar analyses were conducted for cigarettes/d. On average, the FEV1 decline for each additional cigarette/d was not significantly different among subjects with low versus high fish intake. However, the predicted FEV1 at < or = 30 cigarettes/d was 52 ml (95% CI: 17, 87) higher in the high fish consumption group. No significant difference in FEV1 was noted between groups at > 30 cigarettes/d. These findings suggest that the protective role of fish is "saturated" at higher "doses" of cigarette smoking.

To what extent do cardiovascular risk factor values measured in elderly men represent their midlife values measured 25 years earlier? A preliminary report and commentary from the Honolulu Heart Program.

In a Honolulu Heart Program cohort of 1,604 elderly men aged 70-90 years who were sampled from the most recent follow-up examination (1991-1992), current risk factor values were compared with those obtained 25 years earlier when the same men were between ages 45-64 and free of clinically diagnosed cardiovascular disease. Cardiovascular disease risk factors studied included systolic blood pressure, diastolic blood pressure, serum cholesterol, cigarette smoking, body mass index, and alcohol intake. For systolic pressure, 65% of the men had moved into a different quartile by old age, with 25% changing by more than one quartile. For diastolic pressure, 68% had moved into another quartile, with 28% moving more than one quartile, and for body mass index, 53% had moved into another quartile, with 14% moving more than a quartile. Less than 1% started to smoke, while 27% were reclassified from smokers to nonsmokers. Only 4% started to drink alcohol, while 30% were reclassified from drinkers to nondrinkers. When the men were stratified into cardiovascular disease, noncardiovascular disease, and healthy follow-up groups, modest deviations from the overall pattern were observed, with morbidity groups showing a greater tendency to reduction in risk factor levels. The results show that there is a substantial redistribution of major cardiovascular disease risk factor values between midlife and old age. Since midlife values are more likely to represent lifelong exposure values that, in turn, make the main contribution to the development of atherosclerosis, investigators and clinicians may need to be cautious in using risk factor values measured late in life as the only means of assessing risk for subsequent disease.

Elevated serum cholesterol is a risk factor for both coronary heart disease and thromboembolic stroke in Hawaiian Japanese men. Implications of shared risk.

BACKGROUND AND PURPOSE: The relation between total serum cholesterol level and thromboembolic or nonhemorrhagic stroke is controversial. The Honolulu Heart Program cohort of Japanese-American men provides data which show that elevated serum cholesterol is an independent predictor of thromboembolic stroke as well as coronary heart disease (CHD). The data are presented to suggest that the association of elevated cholesterol with stroke is sometimes underestimated or underreported partly because of competing or shared risk with CHD, the other major atherosclerotic end point. METHODS: The data are based on 6352 men (aged 51 to 74 years) at baseline examination (1971 to 1974) who were free of clinical CHD and stroke and were followed an average of 15 years for new cases of both end points. Relative risks of serum cholesterol for CHD and thromboembolic stroke were calculated, controlling for other major cardiovascular covariates. RESULTS: There was a continuous and progressive increase in both CHD and thromboembolic stroke rates with increasing levels of serum cholesterol. The relative risk between the highest and lowest quartiles of serum cholesterol was 1.7 (95% confidence interval, 1.4 to 2.0) for CHD and 1.4 (95% confidence interval, 1.1 to 1.9) for thromboembolic stroke. There was a decline in the difference in relative risks between CHD and thromboembolic stroke in older men (aged 60 years and older) compared with younger men (aged younger than 60 years). CONCLUSIONS: These data provide additional evidence that elevated serum cholesterol should be considered a primary risk factor for thromboembolic stroke, presumably through its effect on both coronary and cerebrovascular atherosclerosis. It is suggested that this association is sometimes underestimated or underreported partly because of shared or competing risk with CHD, the clinical manifestation of atherosclerosis that generally occurs earlier in life and with greater frequency than thromboembolic stroke.

Role of serotonin and catecholamines in sympathetic responses evoked by stimulation of rostral medulla.

In halothane-anesthetized, paralyzed rats, single-pulse stimulation of nucleus raphe pallidus/obscurus (NR) evoked an inhibition followed by a single wave of excitation in 1) the mass discharge of lumbar and splanchnic sympathetic nerves (modal onset latencies: LSND 210 +/- 14 ms, SSND 161 +/- 5 ms) and 2) the unit activity of lumbar sympathetic vasoconstrictor neurons (LSVNs). Stimulation of the rostral ventrolateral medulla (RVL) produced two excitatory responses in LSND, SSND, and LSVN units (modal onset latencies: RVL peak I 98 +/- 8 ms for LSND and 62 +/- 2 ms for SSND; RVL peak II 210 +/- 15 ms for LSND and 160 +/- 6 ms for SSND). Most LSVNs received excitatory inputs from both raphe and RVL. NR peak was selectively attenuated (76%) by 5,7-dihydroxytryptamine [intracisternally (ic), 2-wk] and acute intrathecal (it) methiothepine (10 micrograms, 69%) or methysergide (40 micrograms, 72%). 6-Hydroxydopamine (2-wk ic) produced no effect. Phentolamine (20 micrograms it) or prazosin (20 micrograms it) reduced RVL peak II by > 94% and attenuated NR peak (phentolamine 67%, prazosin 46%). Intrathecal kynurenic acid produced proportionately larger reduction of RVL peak I than raphe peak or RVL peak II. Our interpretations are 1) LSVNs receive convergent excitatory inputs from midline raphe, parphyramidal area, and RVL, 2) bulbospinal serotonergic neurons mediate most of the sympathoexcitation evoked from NR and a portion of RVL peak II, 3) a catecholamine probably released by C1 cells mediates most of RVL peak II and a portion of the NR response, and 4) RVL peak I is predominantly mediated by an excitatory amino acid.

Altered growth hormone (GH) secretion in vivo and in vitro in the diabetes-prone BB/Worcester rat.

Diminished concentrations of growth hormone (GH) have been observed in the male BB/Wor rat with diabetes mellitus (DM). The precise mechanism(s) responsible for the altered GH levels is not entirely understood. We have therefore employed independent techniques to investigate potential alterations in: 1) the peripheral metabolism of the hormone; 2) GH release by somatotropes; and 3) hypothalamic regulation of GH secretion. An extra group of insulin-untreated animals was included for the studies of acute DM. The results demonstrate diminished circulating mean concentrations of GH (35 +/- 4 vs. 16 +/- 4 micrograms/l; mean +/- SEM; control vs. animal with DM; P = 0.006) due to impaired GH secretion. In particular, there was a decrease in the mass of GH secreted per burst (230 +/- 22 vs. 136 +/- 34 micrograms/l; P = 0.04) and in the GH secretory rate (24 +/- 4 vs. 9 +/- 3 micrograms/l/min; P < 0.01). No differences in the secretory burst frequency, (5.3 +/- 0.3 vs. 5.2 +/- 0.5 #/8-h; P = 0.68), secretory half-duration (10 +/- 2 vs. 17 +/- 2 min; P = 0.09), or serum GH half-life (8 +/- 1 vs. 6 +/- 1 min; P = 0.13) were observed. In vitro studies of acutely dispersed somatotropes obtained from rats with DM demonstrated increased sensitivity to GHRH (1 nM), as detected by a greater mean hemolytic plaque area following exposure to an EC50 dose of the secretagogue (14.3 +/- 3.3 vs. 17.4 +/- 3.5 microns 2 x 10(3); P = 0.049), and diminished sensitivity to SRIH (1 nM) inhibition of GH release following exposure to an EC50 dose of the secretagogue (10.0 +/- 1.2 vs. 14.9 +/- 2.3 microns2 x 10(3); P = 0.026). The number of the pituitary cells (18.0 +/- 2.8 vs. 15.3 +/- 1.0 x 10(5) cells; P = 0.38) as well as the number of somatotropes (7.3 +/- 1.4 vs. 7.6 +/- 0.9 x 10(5) cells; P = 0.87) were indistinguishable between experimental groups. Hypothalamic gene transcript levels for GH-releasing hormone (GHRH) and somatotropin release-inhibiting hormone (SRIH) were evaluated by in situ hybridization histochemistry to assess cellular synthetic activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of antifibrinolytic agents on the life span of fibrin sealant.

Fibrin sealant, a biologic glue consisting of fibrinogen and thrombin, has been used in a variety of surgical procedures. The usefulness of fibrin sealant may be prolonged by the addition of antifibrinolytic agents. This study compared the efficacy of transexamic acid (30 mg/ml), epsilon-aminocaproic acid (25 mg/ml), and aprotinin (3000 KIU/ml) to provide data on the choice of an appropriate antifibrinolytic agent for use with fibrin sealant. By use of a modified in vitro plasma euglobulin lysis time (hours), all agents were found to be superior (n = 10 for each agent, P < 0.05, analysis of variance for completely randomized design followed by Dunnett's test for multiple comparisons) to control. Lysis times (mean +/- SE) were (control) 50.9 +/- 0.5, (tranexamic acid) 402.6 +/- 25.4, (epsilon-aminocaproic acid) 433.5 +/- 21.2, and (aprotinin) 393.9 +/- 26.0. Using the in vivo implantation of fibrin sealant supplemented with 125I-fibrinogen in the rat peritoneum significant improvement in percentage clot (mean +/- SE) remaining was found (P < 0.05, analysis for repeated measures followed by tests for multiple comparisons) under the following conditions: at 3 hr by weight (n = 15), tranexamic acid (70.13 +/- 2.02%) was superior to aprotinin (61.22 +/- 2.21%) and control (61.28 +/- 2.36%); at 3 hr by radioactivity counts (n = 19), tranexamic acid (76.29 +/- 0.75%) was superior to epsilon-aminocaproic acid (72.52 +/- 1.28%) and aprotinin (73.84 +/- 0.78%); at 72 hr by radioactivity counts (n = 10), aprotinin (27.30 +/- 2.45%) was superior to epsilon-aminocaproic acid 19.76 +/- 3.09% and control (20.38 +/- 3.01%). These data suggest the early (3-hr) superiority of tranexamic acid as an inhibitor of plasminogen activation and the late (72-hr) effectiveness of aprotinin as an inhibitor of plasmin. The possibility of a synergistic effect of tranexamic acid and aprotinin is suggested.

Splanchnic nerve response to A5 area stimulation in rats.

Microinjection of the excitatory amino acid N-methyl-D-aspartate (NMDA, 0.5 nmol) into ventrolateral pons (the A5 area) of halothane-anesthetized, paralyzed rats increased splanchnic (sSND) and renal sympathetic nerve discharges (approximately 45%) and usually decreased lumbar SND. These effects were accompanied by 1) regionally specific changes in vascular resistances, 2) an increase in the gain of the sympathetic baroreflex, and 3) modest reductions in blood pressure and heart rate. sSND activation was greatest when NMDA injections were made in the vicinity of A5 noradrenergic (NE) cells. Injection of 6-hydroxydopamine (6-OH-DA) into A5 area (after 15 days) destroyed 83% of NE neurons and reduced NMDA activation of sSND by 76%. Stimulation of sSND by NMDA in A5 area was reduced 1) 1-2 h after bilateral intraspinal injection of 6-OHDA, but not vehicle or 5,7-dihydroxytryptamine, and 2) by administration of prazosin [alpha 1-NE receptor antagonist, 1 mg/kg iv or 10-20 micrograms intrathecal (it)], but not by idazoxan (alpha 2-NE receptor antagonist, 10-20 micrograms it) or propranolol (0.2 mg/kg iv). We conclude that A5 NE cells have a visceral vasomotor sympathoexcitatory function mediated in large part by their spinal projection.

Value and limitations of current methods of evaluating patients presenting to the emergency room with cardiac-related symptoms for determining long-term prognosis.

The goal of this study was to determine the value and limitations of the current approach for evaluating patients in the emergency room (ER) with cardiac-related symptoms in terms of predicting long-term outcome. Accordingly, 274 consecutive prospectively identified patients presenting to the ER with such symptoms were evaluated, and follow-up was obtained at 20 +/- 9 months in 265 of them (97%). Adverse cardiovascular events were defined as: nonfatal myocardial infarction, death, cerebrovascular accident with neurologic deficit, life-threatening arrhythmia and cardiac surgery. Eighty-three patients (31%) had a cardiovascular event during follow-up; 42 occurred within 48 hours of ER presentation, whereas 41 occurred in the ensuing months. Findings on physical examination and electrocardiogram provided additional prognostic information, compared with that of history alone, when added sequentially into a Cox model. However, by discriminant function analysis, only 63% of actual events were correctly predicted by the model. Events occurring after 48 hours of ER presentation were correctly predicted only 50% of the time compared with those occurring within 48 hours of ER presentation, which were correctly predicted 75% of the time (p = 0.04). It is concluded that patients presenting to the ER with cardiac-related symptoms are at high risk for adverse cardiovascular events. The likelihood of an event occurring after 48 hours of presentation is as high as one occurring within 48 hours. Current methods of evaluating such patients have limited prognostic value, particularly for those at long-term risk for events.

alpha-Fibrinogenase from Agkistrodon rhodostoma (Malayan pit viper) snake venom.

By means of DEAE-Sephadex A-50 column chromatography, Agkistrodon rhodostoma (Malayan pit viper) snake venom was separated into eleven fractions. Fraction II had fibrinogenolytic activity, and when further purified by gel filtration was homogeneous, as judged by sodium dodecylsulfate polyacrylamide gel electrophoresis. It had a single peptide chain with a molecular weight of 25,360 and an isoelectric point greater than 10. The fibrinogenolytic activity was completely destroyed after heating for 30 min at 60 degrees C at pH 5.6, 7.4 or 8.8. This enzyme cleaved specifically the alpha(A) chain of monomeric fibrinogen, without cleaving the beta(B) chain or gamma chain. The specific fibrinogenolytic activity was 51 mg fibrinogen/min per mg protein. This enzyme showed proteolytic activities toward fibrinogen, fibrin and casein, but was devoid of phospholipase A and tosyl-L-arginine methylester esterase activities which are found in the crude venom. The fibrinogenolytic activity was inhibited by EDTA and cysteine, but not by epsilon-aminocaproic acid.