Predation cues amplify the effects of parasites on the personality of a keystone grazer.

Parasites can alter species interactions either by modifying infected host behaviour or by influencing behavioural responses in uninfected individuals. Salt marsh ecosystems are characterized by a predator-prey interaction between the keystone grazer, Littoraria irrorata, and its main predator, Callinectes sapidus, both integral players in mediating the productivity of these habitats. Littoraria also acts as the first intermediate host for at least four species of digenetic trematode. Parasite infection has been shown to decrease grazing and climbing in populations of Littoraria, although effects on infected host response to predators have not been investigated. Moreover, how infection might increase or decrease among-individual variation in behaviour (i.e. animal personality) is still unknown. Here we ask how trematode infection affects the expression of boldness in the anti-predator responses of L. irrorata in both the absence and presence of a predator cue. We find that individual boldness varies substantially, and repeatability tends to increase as the number of stressors increases, with infected individuals exposed to a predator cue showing the strongest expression of behavioural types. Parasitism amplifies this effect, although the parasite itself does not appear to directly induce behavioural changes: infected snails show no evidence of decreased climbing or differences in refuge use as compared to their uninfected counterparts. Infection might therefore drive the expression of condition-dependent personality differences evident only under high-risk conditions. Group infection status strongly influenced behavioural reaction norms: uninfected individuals grouped with an infected snail were more responsive to predation risk, exhibiting increased climbing behaviour and spending less time in the water. Here parasites are influencing personality indirectly by inducing avoidance behaviours in healthy individuals, although only in high-risk environments. The potential for exposure to parasites and predators fluctuates greatly across marsh ecosystems. Given the ecological importance of this predator-prey relationship, trematode infection can act as an important, although indirect, determinant of overall salt marsh community structure, health and function.

The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT.

BACKGROUND: Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes. OBJECTIVE: The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure. METHODS: The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days. RESULTS: Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group. CONCLUSIONS: Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A(1)-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure.

Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure.

BACKGROUND: Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure. METHODS: We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient's clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes. RESULTS: Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists. CONCLUSIONS: Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.).

Combination angiotensin receptor blocker/hydrochlorothiazide as initial therapy in the treatment of patients with severe hypertension.

Patients with severe hypertension are at high risk for cardiovascular events. The authors hypothesized that initial treatment with a combination angiotensin receptor blocker/diuretic agent would be safe and more effective than initial treatment with a single agent for these patients. In this 6-week, double-blind trial, 585 patients were randomized to losartan/hydrochlorothiazide or losartan as monotherapy and titrated as needed at 2-week intervals to reach goal blood pressure (<90 mm Hg). Almost twice as many patients achieved goal at the primary end point of 4 weeks on 50 mg losartan/12.5 mg hydrochlorothiazide vs. the losartan regimen (50-100 mg; p=0.002). Additionally, almost three times as many patients achieved goal blood pressures at 6 weeks (p<0.001). Adverse experiences on losartan/hydrochlorothiazide (43%) were significantly less than with the angiotensin receptor blocker alone (52.6%). This study confirmed the efficacy and tolerability of initial use of a fixed combination of losartan/hydrochlorothiazide vs. losartan without a thiazide.