The safety and tolerability of daily infergen plus ribavirin in the treatment of naíïve chronic hepatitis C patients.

The treatment of chronic hepatitis C patients was enhanced when the combination of interferon alfa-2b and ribavirin was shown to be safe and more effective than interferon monotherapy. To date, no published reports have addressed the use of consensus interferon (CIFN) when combined with ribavirin. We conducted a pilot study to compare the safety and tolerability of daily CIFN plus ribavirin to CIFN monotherapy for the initial treatment of chronic hepatitis C patients. Forty subjects were randomized to two treatment groups; CIFN 9 microg daily, or CIFN 9 microg daily plus ribavirin 1000 or 1200 mg daily. All subjects received 48 weeks of therapy except for nongenotype 1 subjects in the combination treatment group who received only 24 weeks of therapy. The results show that at baseline, age, gender, risk factors, race, RNA titres, and liver histology were not different between the two groups. The proportion of subjects with genotype 1 infection was 50% (10/20) and 55% (11/20) for the monotherapy and combination therapy groups, respectively. Fifty (10/20) and sixty-five (13/20) per cent of subjects in the monotherapy and combination therapy groups exhibited a 2-log or greater decrease in viral titre at week 12 (P = NS). Using intent-to-treat analysis, 20% and 40% of enrolled subjects exhibited a sustained viral response in the monotherapy and combination therapy groups, respectively (P = NS). The proportion of subjects requiring dose reduction was 55% (11/20) and 65% (13/20), respectively. Study discontinuations for any reason were 25% (5/20) and 35% (7/20) for the monotherapy and combination groups, respectively. Discontinuations due to adverse events related to study drug were 20% (4/20) and 25% (5/20), respectively. A total of four serious adverse events occurred, two in each treatment group, only one of which was determined to be study-drug related. It is concluded that the safety and tolerability profiles of the two treatments were similar suggesting that daily dosing of CIFN may be difficult to tolerate resulting in discontinuation of therapy in a significant proportion of patients. The combination regimen resulted in a trend towards a higher viral response rate than monotherapy treatment. These data suggest that CIFN may be safely combined with ribavirin and may enhance the sustained response rate but is not well tolerated in US patients when given in a daily dosing regimen.

Multilevel performance probability: a meta-analytic integration of expectancy and self-efficacy.

A meta-analysis of one approach to measuring expectancy and self-efficacy was conducted. Although used for over 25 years, this measure has yet to be named or integrated across the two theoretical domains. We proposed to label this measure a Multilevel Performance Probability and conducted a meta-analysis. The search for empirical tests of expectancy and self-efficacy using this procedure yielded 16 studies with ratings which could be subjected to meta-analysis. Five studies with 8 tests were taken from expectancy studies and 11 studies with 47 tests from studies of self-efficacy. In total, the analyses involved 7,444 subjects across 55 tests of the Multilevel Performance Probability to performance relationship. Examination of the measure as a predictor of performance gave a mean r of .51 (p<.001) which is in the same direction and larger than values from other meta-analyses conducted within each of the two theoretical domains (rs of .21 and .38).

Differential human renal tubular responses to dopamine type 1 receptor stimulation are determined by blood pressure status.

We performed the present studies to determine whether a proximal renal tubular dopamine D1-like receptor defect exists in human essential hypertension. Twenty-four subjects were studied (13 normotensive and 11 hypertensive) in a randomized, double-blind, vehicle-controlled study using fenoldopam, a selective D1-like receptor agonist. Subjects were studied in sodium metabolic balance at 300 mEq/d, after which the salt sensitivity of their blood pressure was determined. Fenoldopam at peak doses of 0.1 to 0.2 microgram/kg per minute decreased mean arterial pressure in hypertensive subjects but did not change mean pressure in normotensive subjects. Fenoldopam increased renal plasma flow to a greater extent in hypertensive than normotensive subjects. Fenoldopam increased both urinary and fractional sodium excretions in the hypertensive and normotensive groups. In normotensive but not hypertensive subjects, fenoldopam increased the fractional excretion of lithium and distal sodium delivery. In contrast, both distal fractional sodium reabsorption and sodium-potassium exchange fell significantly in hypertensive subjects. We conclude that human essential hypertension is associated with a reduction in the proximal tubular response to D1-like receptor stimulation compared with normotensive subjects. Hypertensive subjects appear to have a compensatory upregulation of renal vascular and distal tubular D1-like receptor function that offsets the proximal tubular defect, resulting in an enhanced natriuretic response to D1-like receptor stimulation.

Circulating dihydroxyphenylglycol and norepinephrine concentrations during sympathetic nervous system activation in patients with pheochromocytoma.

Although increased plasma norepinephrine (NE) concentrations mediate vasoconstriction during episodic hypertension and hypertensive crises in patients with pheochromocytoma (Pheo), the precise origin of this circulating NE (tumor or sympathetic nerves) is not known. Dihydroxyphenylglycol (DHPG), a deaminated metabolite of NE, is formed principally in sympathetic nerve endings. Under basal conditions, plasma NE and DHPG concentrations correlate closely, and during sympathetic nervous system activation, both plasma NE and DHPG concentrations increase. This observation suggests that plasma DHPG concentrations may reflect the source of circulating NE (tumor or sympathetic nerves) during hypertensive episodes in patients with Pheo. Plasma NE and DHPG concentrations were measured simultaneously, and the NE/DHPG ratio was calculated in seven patients with Pheo during 20 min of sympathetic nervous system activation (treadmill exercise) before and after surgical resection of the tumor. Age- and sex-matched normal subjects were also studied. Exercise resulted in a significant increase in plasma NE and DHPG concentrations in patients with Pheo and in normal subjects (Pheo: basal NE, 1827 +/- 639; peak NE, 3016 +/- 769 pg/mL (P = 0.02); normal subjects: basal NE, 266 +/- 27; peak NE, 1166 +/- 197 pg/mL (P = 0.01); Pheo: basal DHPG, 1521 +/- 280; peak DHPG, 2313 +/- 252 pg/mL (P = 0.007); normal subjects: basal DHPG, 870 +/- 50; peak DHPG, 1630 +/- 180 pg/mL (P = 0.01)]. The NE/DHPG ratio increased with exercise in normal subjects (basal, 0.30 +/- 0.02; peak, 0.83 +/- 12; P = 0.005), but did not change in patients with Pheo (basal, 1.22 +/- 0.32; peak, 1.54 +/- 0.27). Exercise also increased plasma NE and DHPG concentrations and the NE/DHPG ratio in five patients studied after surgical resection of the tumor. Systolic blood pressure and heart rate increased significantly during exercise in all three study groups. The increase in plasma NE and HDPG concentrations during exercise-induced sympathetic nervous system stimulation in patients with Pheo is similar to that in normal subjects and may indicate that the sympathetic nervous system plays an important role in the pathogenesis of hypertension and hypertensive crises in patients with Pheo.

Effects of exercise and exercise conditioning on blood platelet function.

The effects of exercise and exercise conditioning on blood platelet function were investigated in six healthy individuals who had not engaged in regular exercise for at least 1 yr prior to the study. The subjects (three men and three women) had a mean age of 28 (range 23-32) and participated in a supervised program of treadmill exercise. Subjects exercised for 20 min, three times weekly, for 12 wk at 70-80% of estimated maximum heart rate. Samples for platelet counts, platelet aggregation, and plasma beta-thromboglobulin (beta-TG) were obtained prior to training and after 6 and 12 wk of training. All subjects responded with an increase in aerobic capacity during training. Resting mean systolic and diastolic blood pressures decreased after training (P less than 0.05). Platelet counts increased after exercise, and the increment in week 12 exceeded that in the 1st wk by 57%. Platelet aggregation studies in platelet rich plasma (PRP) showed an increase in slope after exercise (week 1, P less than 0.05) which decreased with training (week 1 vs week 12, P less than 0.01). Aggregation studies utilizing impedance aggregometry in diluted native whole blood showed an acceleration of both spontaneous aggregation (P less than 0.01 weeks 6 and 12) and aggregation using epinephrine as an agonist (P less than 0.05) following exercise. Plasma beta-TG levels did not increase significantly after exercise; however, resting concentrations of beta-TG decreased with training (P less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Observations on human platelet aggregation in native whole blood: synergism and sensitivity to aggregating agents in vitro.

Threshold sensitivity levels, as well as the synergistic effects of agonists for blood platelets have been evaluated by impedance aggregometry using whole blood without anticoagulation. Platelet aggregation was studied using adenosine diphosphate (ADP), epinephrine, and thrombin. Threshold responses to ADP, epinephrine, and thrombin were observed at lower concentrations in diluted native whole blood (NWB) than reported values for citrated whole blood, and appear to be similar to those of citrated platelet rich plasma (PRP). Potentiation of aggregation occurred when both ADP and epinephrine, or epinephrine and thrombin but not ADP and thrombin were present in combination. Synergism between agonists thus is similar but not identical to that of PRP, and NWB appears to provide a sensitive system with a more physiologic milieu than other in vitro aggregation systems.

Fetal expression of muscle-specific isoactins in multiple organs of the Wistar-Kyoto rat.

Actin, a cytoskeletal and contractile protein, is expressed in six different isoforms that exhibit striking specificity. No studies have considered the muscle-specific actin expression in multiple organ systems in the intact fetus. Using a monoclonal antibody (B4) which reacts specifically with the isoactins of the smooth and skeletal muscle our immunohistochemical study examined whole fetal body sections to follow the development of actin expression throughout the last third of gestation in the Wistar-Kyoto rat. B4 staining was exclusively localized to muscle, confirming its high specificity and its usefulness for studying the ontogeny of muscle-specific isoactins. At 15 days of gestation, B4 staining was detected in the heart, the thoracic aorta and the skeletal muscle of the chest wall. The distribution and intensity of staining in the heart were initially higher than in the aorta or skeletal muscle and remained unchanged throughout the remainder of gestation, suggesting that the maturation of cardiac actin expression is well developed, although not fully completed before birth. Expression of muscle-specific actins in skeletal muscle was age-dependent and correlated with the maturational changes of muscle cell precursors. B4 staining in the fetal kidney was not apparent until day 20 of gestation and was localized to the inner cortical vessels. in association with the most mature nephrons, suggesting a centrifugal maturation of the intrarenal vasculature. The intensity of B4 staining in most tissues including bronchi, bowel, diaphragm, chest wall muscle and peripheral and pulmonary arteries increased by the end of gestation.

Cognitive impairment in patients with obstructive sleep apnea and associated hypoxemia.

Twenty-six patients with sleep apnea had neuropsychologic testing prior to nocturnal sleep study in a sleep disorders clinic. The cognitive functioning of patients who had sleep apnea with associated hypoxemia was compared to nonhypoxemic patients with sleep apnea. The patients who had sleep apnea with hypoxemia had more severe cognitive impairment than those with sleep apnea without hypoxemia. The hypoxemic patients with sleep apnea had significantly poorer cognitive functioning on four of eight tests (p less than 0.05). In addition, the patients who had sleep apnea with hypoxemia had mean performance scores in the impaired range on measures of attention, concentration, complex problem-solving, and short-term recall of verbal and spatial information. In contrast, the patients who had sleep apnea without hypoxemia had no mean performance score in the impaired range. The degree of hypoxemia during sleep and wakefulness significantly correlated with the degree of overall cognitive impairment as rated by a neuropsychologist; however, measures of sleep fragmentation did not significantly correlate with overall cognitive impairment in patients with sleep apnea. We conclude that patients who have sleep apnea with associated hypoxemia have cognitive impairment which is more severe than those with sleep apnea without hypoxemia.

Relationship of disembedding ability to performance in volleyball, tennis, and badminton.

The study was designed to determine the relationship between different perceptual abilities and performance in volleyball, badminton, and tennis. 41 boys and 37 girls enrolled in a Grade 10 physical education program served as subjects. Performance in the three sports and four perceptual ability measures were determined. A multiple regression analysis indicated that the Group Embedded Figures Test was the most consistent perceptual measure for predicting significant motor performance but accounted for only 8 to 20% of the actual variance. Further, multiple regression analysis confirmed the importance of previous experience in a specific sport which accounted for 24 to 50% of the variance.