Dry/wet cycling reduces spore germination and viability in six peatland bryophytes.

Dry/wet cycling driven by water level fluctuation in wetlands may strongly influence the destiny of seeds. However, how dry/wet cycling affects spore survival and germinability in peatland bryophytes is poorly understood. Six peatland bryophytes, three hummock- and three hollow-dwelling Sphagnum species, were chosen as study species. We tested the effects of dry (60% air RH)/wet (waterlogging) cycle frequency (once per 12, 8 or 4 days for low, medium or high, respectively) and ratio (3:1, 1:1 or 1:3 dry:wet time per cycle) on spore germinability, viability, dormancy percentage and protonema development. Dry/wet cycling significantly reduced spore germination percentage and viability and slowed protonema development in all Sphagnum species, being more pronounced with higher dry/wet cycling frequencies. The hummock species S. capillifolium and S. fuscum had higher spore germination percentage after the continuous dry treatment, while the hollow species S. angustifolium, S. squarrosum and S. subsecundum showed the opposite response, compared to the continuously wet treatment. Except for S. squarrosum, spore viability was higher after the dry than after the wet treatment. Spore viability and dormancy percentage were higher after a dry/wet ratio of 1:3 than after ratios of 3:1 and 1:1. Our study shows that both germinability and viability of bryophyte spores are reduced by dry/wet cycling (especially when frequent) in peatlands. This emphasizes the need to ensure constant water levels and low frequencies of water level fluctuation, which are relevant in connection with wetland restoration, to promote Sphagnum spore survival and establishment in peatlands after disturbances.

The hemodynamic and pharmacokinetic interactions between chronic use of oral levosimendan and digoxin in patients with NYHA Classes II-III heart failure.

OBJECTIVE: Levosimendan is a calcium-sensitizing drug for the treatment of heart failure. The aim of this exploratory study was to assess the hemodynamic and pharmacokinetic interactions between digoxin and oral levosimendan as well as the proarrhythmic potential of this combination in patients with chronic heart failure. MATERIALS: Male or female patients (n = 24) with chronic heart failure of NYHA Classes II-III. METHODS: A randomized, placebo-controlled, double-blind, parallel-group trial. After a 1-week digoxin-free washout period, the patients were randomized to receive either digoxin and levosimendan (digoxin + levosimendan), or digoxin and placebo (digoxin) orally for 14 +/- 2 days. The levosimendan dose was 1 mg 3 times daily, and the digoxin dose was 0.125-0.25 mg once daily. Systolic time intervals, electrocardiography (ECG), magneto-cardiography (MCG) and 24-h ambulatory ECG were performed at baseline and at the end of each treatment period. Pharmacokinetic variables of levosimendan and digoxin were calculated in both treatment periods. Steady-state concentrations of the active metabolites OR-1855 and OR-1896 were determined at baseline at Visit 2. RESULTS: There tended to be a greater shortening of QS2i (suggesting trend to positive inotropy) in the digoxin + levosimendan group (-14ms) compared with the digoxin group (-5ms), although the difference was not statistically significant (p=0.359). However, the change from baseline in QS2i after digoxin + levosimendan was of statistically borderline significance (p=0.05). The change from baseline in the digoxin group was not statistically significant. ECG and MCG repolarization measures and occurrence of nonsustained ventricular tachycardia showed no substantial differences. After 2 weeks of digoxin + levosimendan treatment, mean area under the curve (AUC) of levosimendan increased approximately by 49% (p<0.01). The maximum plasma concentration (Cmax) of levosimendan increased from 17 to 23 ng/ml. The mean concentrations of the metabolites OR-1855 and OR-1896 in plasma were 4.3 and 8.3 ng/ml, respectively. CONCLUSIONS: The addition of oral levosimendan to digoxin therapy produced only a modest statistically nonsignificant additive inotropic effect. In contrast to the earlier data with intravenous levosimendan, the results indicate a pharmacokinetic interaction between levosimendan and digoxin. Data obtained from repolarization analyses and ambulatory ECG did not indicate any possible proarrhythmic effects of the combination.

High-throughput and ultra-high-throughput screening: solution- and cell-based approaches.

The trend towards assay miniaturization for high-throughput and ultra-high-throughput screening continues to spur development of homogeneous, fluorescence-based assays in higher density, smaller volume microplate formats. Recently, first-generation microfluidic devices have been designed for performing continuous-flow biochemical and cell-based assays. These devices provide orders-of-magnitude reduction in reagent consumption, and offer the potential for implementing high-throughput screening in formats that integrate up-front compound handling with unique assay functionality.

Simultaneous inhibition of catechol-O-methyltransferase and monoamine oxidase A: effects on hemodynamics and catecholamine metabolism in healthy volunteers.

OBJECTIVE: To evaluate the effects of simultaneous pharmacologic inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase type A (MAO-A) on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during exercise. BACKGROUND: Entacapone, a COMT inhibitor, is studied as an adjunct to levodopa treatment in patients with Parkinson's disease. Moclobemide, an MAO-A inhibitor, is already in clinical use as an antidepressant. It is likely that entacapone and moclobemide will be used concomitantly in the future in patients who have both Parkinson's disease and depression. It was therefore considered to be important to investigate the tolerability of combined COMT and MAO-A inhibition with entacapone and moclobemide. DESIGN AND METHODS: This was a randomized, single-dose, double-blind crossover study of 12 healthy male volunteers. The treatments were either placebo, 200 mg entacapone, 150 mg moclobemide, or the combination of entacapone and moclobemide in single doses. Heart rate, blood pressure, impedance cardiography, and plasma concentrations of catecholamines and their metabolites were measured both at rest and during submaximal standardized bicycle exercise. RESULTS: Entacapone and moclobemide (either alone or in combination) did not change heart rate, blood pressure, or any hemodynamic parameter at rest or during exercise compared with placebo. Neither were the concentrations of norepinephrine and epinephrine in plasma influenced. Both drugs had the expected effects on catecholamine metabolite concentrations in plasma. The decrease in the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG) induced by moclobemide was not potentiated by entacapone. CONCLUSION: The combined use of therapeutic single doses of entacapone and moclobemide in healthy volunteers did not affect the hemodynamics or concentrations of unconjugated norepinephrine and epinephrine in plasma. Other mechanisms are capable of regulating the concentrations of norepinephrine and epinephrine in circulating blood (and apparently also at receptors in the heart and vascular tissue) when both COMT and MAO-A activity are inhibited to a significant extent. This was also the case during marked sympathetic stimulation. The changes in the catecholamine metabolite concentrations provide evidence of effective COMT and MAO inhibition. Concentrations of MHPG in plasma are determined mainly by MAO-A activity because COMT inhibition did not have an additional effect on the moclobemide-induced decrease in plasma MHPG.

The effect of entacapone on the disposition and hemodynamic effects of intravenous isoproterenol and epinephrine.

BACKGROUND: Entacapone is a potent, selective catechol-O-methyltransferase (COMT) inhibitor. Entacapone could potentiate the hemodynamic effects of exogenously administered catecholamines, which are substrates of the COMT enzyme. DESIGN AND METHODS: Originally, the study was to follow a placebo-controlled, randomized crossover design. Because of two cases of ventricular arrhythmia, a decision was made to terminate the study before its completion. Six subjects went through the isoproterenol and epinephrine infusions while taking placebo and five other subjects while taking entacapone. The actual design was thus one with two parallel groups with random allocation and double-blind drug administration. The subjects were given either a single dose of 400 mg entacapone or placebo 30 minutes before the start of isoproterenol or epinephrine infusions. Four dosages of epinephrine (1.5, 3, 6, or 12 micrograms/min) and isoproterenol (0.5, 1, 1.5, or 2 micrograms/min) were infused (5 minutes for each level). Heart rate and blood pressure were measured and ECG was monitored. The concentrations of isoproterenol and epinephrine in plasma were determined by HPLC. RESULTS: The maximal increase in heart rate during isoproterenol infusion after entacapone administration (40 +/- 11 beats/min, mean +/- SD) was statistically greater (p = 0.0496) than after placebo administration (27 +/- 7 beats/min). The increase in heart rate during epinephrine infusion was 25 +/- 13 beats/min after entacapone administration and 14 +/- 9 beats/min after placebo administration (p = 0.127). There were no statistically significant differences between entacapone and placebo in blood pressure or in plasma concentrations of isoproterenol and epinephrine. CONCLUSION: We conclude that entacapone may potentiate the chronotropic and arrhythmogenic effects of exogenously administered isoproterenol and epinephrine.

Exercise hemodynamics and catecholamine metabolism after catechol-O-methyltransferase inhibition with nitecapone.

The effect of catechol-O-methyltransferase inhibition with nitecapone (OR-462) on the hemodynamic responses to exercise and catecholamine metabolism was studied in 10 healthy male volunteers (aged 19 to 26 years). Nitecapone, a new specific and selective catechol-O-methyltransferase inhibitor, was given at increasing single oral doses up to 100 mg. Nitecapone did not influence resting or exercise heart rate, blood pressure, systolic time intervals, or plasma catecholamine levels. It altered the metabolic profile of catecholamines as shown by (1) an increase of 140% in the plasma concentration of the monoamine oxidase-dependent metabolite 3,4-dihydroxyphenylethyleneglycol (p less than 0.001), (2) a decrease of 27% in the plasma concentration of its methylation product 3-methoxy-4-hydroxyphenylethyleneglycol (p less than 0.05), and (3) a 25% reduction in the urinary excretion of the methylated metabolites 3-methoxy-4-hydroxymandelic acid and homovanillic acid (p less than 0.05). Nitecapone was well tolerated and seemed to be hemodynamically safe in humans.

Rapid reversal of circadian blood pressure rhythm in shift workers.

The blood pressure and heart rates of seven normotensive shift workers were monitored automatically for 24 h with a non-invasive ambulatory method on 3 different days. The first monitoring session took place at the end of an ordinary work period of morning shifts, the second on the first day of a period of night shifts, and the third on the last day of a period of night shifts. The circadian blood pressure rhythm, which showed a normal pattern during the daytime work shift, was totally reversed from the first day of the night shift. The blood pressure rhythm closely followed the sleep-wakefulness cycle. The changes in circadian heart rate rhythm were not as pronounced as those in blood pressure but showed a similar trend.

Influence of beta blockade and intrinsic sympathomimetic activity on hemodynamics, inotropy and respiration at rest and during exercise.

The degree of intrinsic sympathomimetic activity (ISA) is reported to influence the effects of beta blockade at rest, but the effects during exercise are not well documented. Heart rate, blood pressure and left ventricular (LV) function (as assessed by systolic time intervals) were measured at rest and during upright bicycle exercise as well as with flow-volume spirometry at rest in 13 healthy volunteers. The measurements were performed before and 4 and 24 hours after a single oral dose of pindolol (10 mg), nadolol (80 mg) and acebutolol (400 mg) in a double-blind, randomized, crossover manner. All drugs reduced heart rate, but nadolol had the most pronounced and longest bradycardic effect at rest. Diastolic blood pressure was only slightly influenced by the drugs, whereas systolic pressure was significantly lower compared with control values, especially during exercise (p less than 0.001). Neither preejection period (PEP) nor LV ejection time (LVETc) was changed at rest after pindolol, but PEP increased and LVETc decreased significantly after nadolol (p less than 0.05 for PEP and p less than 0.01 for LVETc) and acebutolol (p less than 0.05 for both). During exercise, PEP and LVET were significantly longer after all 3 drugs compared with control values. Only nadolol, which lacks ISA, significantly decreased expiratory flow values (p less than 0.05). Thus, unlike the other beta blockers, pindolol (with strong ISA) did not depress LV function at rest, while during exercise all 3 beta blockers had equal adverse effects. The degree of ISA appears to be important in determining the hemodynamic effects of beta-blocking drugs.

Hemodynamic and neurohumoral effects of levosimendan, a new calcium sensitizer, at rest and during exercise in healthy men.

Levosimendan is a novel inodilator that increases the calcium sensitivity of troponin C in a calcium-dependent way. Cardiac function (impedance cardiography, systolic time intervals), neurohumoral responses at rest and during exercise at 2 workloads, and peripheral blood flow (plethysmography) were studied in 14 healthy young men. Vehicle and 2 doses of levosimendan (6.5 micrograms/kg, low dose [LD]; and 25 micrograms/kg, high dose [HD]) were given intravenously in a crossover study. Measurements taken 15 minutes after a supine rest showed HD levosimendan shortened electromechanical systole (QS2i) by 16 ms maximally (p < 0.001), and decreased systemic vascular resistance by 25% (p < 0.001), compared with baseline values. Diastolic blood pressure fell by 9 mm Hg (p < 0.01). When the changes after vehicle were compared with the changes after HD levosimendan, the difference was 2.1 L/min after 25 micrograms/kg (p < 0.001), caused by an increase in stroke volume, with the heart rate being unaffected. Leg blood flow increased by 35% (p < 0.001). During exercise at the lower workload, HD levosimendan increased cardiac output by 1.5 L/min (p < 0.05), compared with that caused by vehicle, by an increase in heart rate, with the stroke volume being unchanged. Electromechanical systole was shortened significantly (20 ms, p < 0.001 after HD; 12 ms, p < 0.01 after LD). At the higher workload, no effects on electromechanical systole or cardiac output compared with that associated with administration of vehicle were seen, but the mean heart rate increased (p < 0.001, LD and HD) and mean diastolic blood pressure decreased (p < 0.01, HD).(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise capacity and hemodynamics in persons aged 20 to 50 years with systemic hypertension treated with diltiazem and atenolol.

Hemodynamic responses and exercise capacity were studied during maximal exercise in 25 young hypertensive persons (mean age 40 years) taking placebo, diltiazem (mean 216 mg/day) and atenolol (mean 80 mg/day). The study was a crossover, double-blind, randomized trial, each medication period lasting 2 months. Sitting blood pressure (BP) was 160 +/- 19/109 +/- 8 mm Hg after run-in. Both drugs decreased BP significantly, diltiazem by 10/ 11 mm Hg and atenolol by 16/14 mm Hg (difference not significant between drugs). During exercise there were no differences among patients taking placebo, diltiazem and atenolol in peak workload and rating of perceived exertion. Atenolol significantly attenuated the increase in heart rate, BP and heart rate-BP product at each workload. Diastolic BP during exercise was significantly lower (6 to 10 mm Hg) during diltiazem therapy than during placebo at each workload. Thus, both diltiazem and atenolol decrease rest BP significantly without impairing exercise capacity.

Experimental evidence for a persistent spore bank in Sphagnum.

Spore capsules of four Sphagnum species were buried at different depths in peat on a bog. Spore viability was determined after 0, 1, 2 and 3 yr. Viability generally declined with time, but viable spores were still found at all depths after 3 yr. The light-coloured spores of S. balticum and S. tenellum retained their viability better than the darker spores of S. fuscum and S. lindbergii. Survival was highest under wet but aerobic conditions, but was also high under humid or periodically desiccated conditions. By contrast, most spores stored under wet, anaerobic conditions died within 2-3 yr. These results, and predictions from them, are not consistent with earlier results for spores of long-lived and dominant bryophytes, or for seeds of phanerogams of undisturbed wetlands and forests. There was no correlation between spore size and longevity across species, but the small spores from small capsules of S. balticum and S. tenellum generally showed higher viability than those from the medium-sized and large capsules of the same species. This suggests a positive intraspecific relationship between longevity and dispersal distance. There was an indication of conditional dormancy, controlled by weather, in Sphagnum spores. The experiments indicate that Sphagnum spores can form a long-term persistent spore bank under suitable conditions, with a half-life of between 1 and 20 yr (mean across species of 2.6 and 5.0 yr at two depths studied), and with potential values in individual spore capsules of several decades, or even of centuries. Sphagnum spores kept refrigerated showed 15-35% viable spores after 13 yr. The capacity to form a persistent spore bank that can be activated whenever favourable conditions occur might help explain the wide geographical distribution of many Sphagnum species in the boreal and temperate zones, where they have managed to colonize almost every suitable patch of acidic, nutrient-poor wetland.

Effect of hydroxyethyl starch and dextran on plasma volume and blood hemostasis and coagulation.

Six healthy male subjects were given in a crossover fashion medium molecular weight (HES 125) and low molecular weight (HES 40) hydroxyethyl starch, dextran, and balanced salt solution by intravenous infusion. The plasma volumes were determined using labeled albumin and plasma protein measurements. Three properties of factor VIII protein complex and indices of blood coagulation and hemostasis were measured before and after the infusions. Both the salt solution and HES 40 increased plasma volume, but their effect wore off within 3 hours. Dextran and HES 125 increased plasma volume significantly (P less than 0.001) more than the salt solution did, and the expansion was maintained for 24 hours. Plasma volume increases (dextran and HES 125) were associated with high nonglucose carbohydrate levels in plasma and low levels in urine. No or slight increases in plasma volumes (HES 40), on the other hand, were associated with low and high carbohydrate levels in plasma and urine, respectively. Serum alpha-amylase activity increased significantly after both HES preparations as compared to salt solution. Dextran and HES 125 decreased all the three values of factor VIII, these decreases being maximal 3 to 6 hours after administration and highest (about 25 per cent) for F VIII R:Ag and F VIII R:cof. It is concluded that HES 125 and dextran are equally effective plasma expanders.

Functional characteristics of unmyelinated fibres in the hippocampal cortex.

(1) In transverse hippocampal slices (350 micrometer thick), taken from guinea pigs initially anaesthetized with ether, intracortical afferent fibres were activated by small current pulses delivered through tungsten microelectrodes. Extracellular potentials were recorded from the zone of activated fibres in dendritic layers while intracellular recordings were made from the soma of CA1 pyramidal cells. (2) When recording was made from the same level as the stimulating cathode, the extracellular potential consisted of a diphasic deflection followed by a larger negative wave with a superimposed population spike. The negative wave corresponded to an intracellularly recorded EPSP, and is called an extracellular EPSP, whereas the initial diphasic deflection had no intracellular counterpart. (3) The initial diphasic deflection was linearly related to the size of both the intracellular and extracellular EPSP. It was not changed by removal of calcium ions from the bathing fluid, whereas all postsynaptic activity disappeared. The diphasic deflection was propagated along fibres lying parallel to the pyramidal layer with a velocity of 0.3 m/sec. It could follow short bursts of stimulation at 300 Hz. The absolute refractory period was 2.0 msec. (4) The initial diphasic deflection is interpreted as the compound action potential of the largely unmyelinated afferent fibres to the CA1 neurones.

Management of common pediatric fractures.

Pediatric fractures are seen commonly in emergency departments. Pediatricians are usually the first physicians to assess injured children. Pediatricians should be comfortable in evaluating the fracture and interpreting radiographs prior to consulting an orthopedist. An understanding of the differences between pediatric and adult bone makes the assessment of children and their radiographs easier. Musculoskeletal injuries, fractures, and sprains are common, most of which require minimal care. Growth plate injuries, however, pose a risk for permanent deformity and must be managed with care.

Assessment of cardiac performance: short- and medium-term variability of impedance cardiography at rest and during dynamic exercise.

Short- and medium-term variability of impedance cardiography at rest and during exercise at a heart rate of 155-160 beats/min were assessed in 12 healthy men aged 21-28 years. Two consecutive measurements within 1 min were performed 4 times at 2-hour intervals on 2 days 14 days apart. Ejection fraction was the most reproducible of all impedance cardiography parameters, the CV ranging from 3.3-5.9%. The short-term reproducibility of cardiac output and stroke volume at rest was good, the between-repeats coefficient of variation (CV) being 4-6%. The reproducibility weakened with longer time span (between-day CV being about 12%) and higher heart rates (exercise). However, even the between-day reproducibility at rest was as good as that of heart rate. Between-day CV during exercise were about 20%.

COMT inhibition by high-dose entacapone does not affect hemodynamics but changes catecholamine metabolism in healthy volunteers at rest and during exercise.

We studied the effects of catechol-O-methyltransferase (COMT) inhibition with entacapone on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during a bicycle exercise test. Entacapone was given orally during two periods of seven days each to eleven healthy male volunteers; on the first period 400 mg t.i.d. and on the second 800 mg t.i.d. A submaximal exercise test giving a heart rate of about 163-167 beats/min with the highest predetermined work load was performed on a bicycle ergometer, and blood pressure, heart rate and ECG were recorded. The concentrations of adrenaline, noradrenaline, 3,4-dihydroxyphenylglycol (DHPG), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) in plasma were determined. Blood pressure, heart rate, ECG, and plasma concentrations of unconjugated adrenaline and noradrenaline were not influenced after single and repeated dosing of entacapone. The plasma concentrations of DHPG (a monoamine oxidase (MAO)-dependent metabolite) increased maximally by 245% compared to the control day. DOPAC (a MAO-dependent metabolite) increased maximally by 144% and MHPG (a COMT-dependent metabolite) decreased by 54%. The increase in DHPG and DOPAC was significantly greater with the 800 mg dose than with the 400 mg dose. The decrease in MHPG was significantly greater with the repeated dosing than with the single dose of entacapone. COMT inhibition by entacapone seems not to affect hemodynamics or plasma concentrations of unconjugated adrenaline and noradrenaline in healthy volunteers either at rest or during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Integrated pharmacokinetics and pharmacodynamics of the novel calcium sensitizer levosimendan as assessed by systolic time intervals.

BACKGROUND: Levosimendan is a new calcium sensitizer, acting calcium-dependently on cardiac troponin C. In the present study pharmacokinetic-pharmacodynamic interrelations of levosimendan were assessed. SUBJECTS AND METHODS: Ten healthy subjects (22-27 years) were given single doses of 2 mg of levosimendan in 4 different formulations: intravenous (i.v.), conventional tablet (CT), conventional capsule (CC), and slow-release tablet (SR) on different days. Systolic time intervals and impedance cardiography were recorded up to 4 hours post drug. Plasma concentrations of levosimendan and its metabolite OR-1855 were analyzed using HPLC. Hysteresis loops were constructed by connecting the effect-concentration points in time order. In addition, pharmacokinetic-pharmacodynamic modelling was performed with the i.v. data. RESULTS: The i.v. administration, giving a maximal levosimendan concentration of 180 ng x ml(-1), increased heart rate by 8 beats min(-1) and cardiac output by 18%. It shortened heart rate corrected electromechanical systole QS2i by 23 ms, indicating a fairly strong positive inotropic effect. The conventional oral formulations (giving maximal drug concentrations of about 70-80 ng x ml(-1)) increased heart rate by 4-5 beats min(-1) and cardiac output by 5-8%, while QS2i shortened by 9-13 ms. The SR formulation resulted in low drug concentrations and generally weaker effects than the other formulations. The bioavailability of CT and CC was 83 and 87%, while that of SR was only 31%. QS2i showed counter-clockwise hysteresis after all formulations (p < 0.01). The mean equilibration half-time (ln(2)/k(e0)) after i.v. administration was 9.6 min. Only after SR, OR-1855 was detected in appreciable amounts in plasma, the highest value being 2.2 ng x ml(-1) which occurred 24 hours after drug intake. CONCLUSION: In conclusion, the pharmacokinetic-dynamic behavior of the inotropy index QS2i indicates an equilibration delay of levosimendan, which most probably reflects the time the drug requires to distribute from plasma to its cardiac site of action. The deviant kinetic-dynamic profile of the oral slow-release formulation suggests a different absorption pattern of levosimendan from this formulation.

Pharmacokinetic-pharmacodynamic interrelationships of intravenous and oral levosimendan in patients with severe congestive heart failure.

OBJECTIVE: To assess the pharmacokinetic-pharmacodynamic (PK-PD) interrelations after a 6-hour continuous infusion and a 2 mg single oral dose of levosimendan in patients with congestive heart failure (CHF). METHODS: This was an open-label, non-randomized Phase II trial in 29 patients with New York Heart Association (NYHA) class III-IV CHF, comprising 2 study days. On the first day, patients were given 6-hour levosimendan infusion with the dose 0.2 microg/kg/min. After a 1-week washout, the patients received a 2 mg single oral dose of levosimendan. Heart rate-corrected electromechanical systole QS2i was the primary variable. Secondary variables were heart rate (HR), systolic (sBP) and diastolic blood pressure (dBP) and 24-hour ambulatory ECG (Holter). RESULTS: QS2i shortened from 515 ms at baseline to 506 ms at the end of 6-hour infusion (p = 0.007). After 2 mg single dose, QS2i shortened at 2 h after drug intake from 532 ms at baseline to 525 ms (p = 0.006). The effect was similar also at 8 h (532 ms vs 526 ms, p = 0.017). Mean of maximum shortening of QS2i observed during the infusion was 22 ms (p < 0.0001) and 17 ms after 2 mg single oral dose (p < 0.0001). The concentration-effect loops for QS2i showed a clear counter-clockwise hysteresis with both modes of administration. sBP and dBP decreased both during infusion and after 2 mg oral dose. HR remained unchanged during both modes of administration. CONCLUSIONS: Both 6-hour infusion and 2 mg single dose of levosimendan showed that levosimendan possesses moderate inotropic and vasodilatory effects in patients with severe congestive heart failure, which could be described as counter-clockwise hysteresis. It seemed that the vasodilatory effect appeared earlier than the inotropic effect.

Effects of flunarizine and pentoxifylline on walking distance and blood rheology in claudication.

Thirty-one patients, mean age 60 years (range 45-80 years), with a typical history and objective symptoms of intermittent claudication with a reported maximal walking distance less than 500 m, were included in a cross-over study. After a one month's run-in period on placebo, the patients were randomized into two groups: one group started with flunarizine (5 mg t.i.d.) and the other with pentoxifylline (400 mg t.i.d.). The treatment lasted 3 months, whereafter the medications were changed. The trial followed a double-blind design. The median of the maximal walking distance was 255 m after the placebo period, increasing significantly (p less than 0.01) during both medication periods: by 43% and 18% during flunarizine and pentoxifylline, respectively. No changes were recorded in the ankle systolic blood pressure ratio ( ASBP -ratio) after placebo or either medication period. Red cell rigidity (Pmax), which was initially elevated, decreased significantly (p less than 0.05) during both medication periods, but there were no significant differences between the two drugs. No changes were found in whole blood or plasma viscosity. We conclude that the decrease in red cell rigidity may have contributed to the increased walking distance.

Victim blame and the disinhibition of sexual arousal to rape vignettes.

The present study examined the effects of differing levels of victim blame on the sexual arousal of males to rape vignettes. In the first experiment, a between-subjects experimental design was used to compare four groups of eight university males for their erectile responses to vignettes rated as low, medium, and high along a victim blame continuum. All groups found a consenting vignette more arousing than a nonconsenting vignette, however, this difference was significantly smaller for subjects in the high blame condition compared to the low and medium blame conditions. A second experiment supported the disinhibiting effect of the high victim blame manipulation using 12 university males in a within-subjects experimental design. The disinhibiting influence of victim blame on male sexual arousal to rape cues was discussed in relation to our broader understanding of sexual assault.