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BACKGROUND This study is the first to evaluate the short-term efficacy and long-term safety of AZD0585, a mixture of omega-3 free fatty acids, in Japanese patients with dyslipidemia.Methods and Results:In this randomized double-blind placebo-controlled Phase III study, 383 patients were randomized to 2 g AZD0585, 4 g AZD0585, or placebo once daily for 52 weeks. Eligible patients had low-density lipoprotein cholesterol (LDL-C) levels controlled regardless of statin use, and triglyceride levels between 150 and 499 mg/dL. The least-squares (LS) mean percentage changes in triglyceride concentrations from baseline to the 12-week endpoint (mean of measurements at Weeks 10 and 12) in the 2 and 4 g AZD0585 and placebo groups were -15.57%, -21.75%, and 11.15% respectively (P

Importance It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk. Objective To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk. Design, Setting, and Participants A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa. Interventions Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins. Main Outcomes and Measures The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. Results When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09];P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil–treated patients (14.7%). Conclusions and Relevance Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients. Trial Registration ClinicalTrials.gov Identifier:NCT02104817

Background The role of saliva composition and dietary sugar in development of infundibular caries in equine cheek teeth is not fully understood. This study analysed electrolyte and urea concentrations in saliva in relation to different forage and measured pH changes after sucrose application in vivo in sound and carious cheek teeth. Results Forage type had no effect on the equine saliva electrolyte concentrations, which varied considerably both intra- and inter-individually. Chewing resulted in increased values for all electrolytes except bicarbonate. Compared with stimulated human saliva, horse saliva after mastication, contained higher amounts of potassium, calcium and bicarbonate, and less phosphate. The in vivo pH measurements showed a lower resting pH and a more pronounced pH drop after sucrose application in carious teeth compared to sound teeth. Conclusions No large differences were found between the composition of equine saliva and human saliva. A more pronounced acidogenicity was found for the carious than sound teeth. Thus, the caries process in equine cheek teeth seems to follow the same pattern as in human teeth, caused by acid production by oral microorganisms after sugar consumption.

Aims: Omega-3-carboxylic acids (OM3-CA) contain omega-3 free fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as carboxylic acids. Food intake is known to affect the bioavailability of ethyl ester fatty acid formulations. We conducted a phase I study to investigate the effects of the timing of OM3-CA administration relative to food intake on the pharmacokinetics of EPA and DHA. Methods: In this randomized, open-label, three-period crossover study, Japanese healthy male subjects were administered 4 × 1 g OM3-CA capsules with continued fasting, before a meal, or after a meal. All subjects fasted for ≥ 10 h prior to drug/meal administration. The primary objective was to examine the effect of meal timing on the pharmacokinetics of EPA and DHA after OM3-CA administration. The secondary objectives were to examine the safety and tolerability of OM3-CA. Results: A total of 42 Japanese subjects was enrolled in the study. The baseline-adjusted maximum concentration and area under the concentration–time curve from 0 to 72 h for EPA, DHA, and EPA + DHA were lower in the fasting and before meal conditions than in the after meal condition. The maximum total EPA, total DHA, and total EPA + DHA concentrations were reached later when administered in fasting conditions than in fed conditions, indicating slower absorption in fasting conditions. Diarrhea was reported by five, six, and no subjects in the fasting, before meal, and after meal conditions, respectively. Conclusions: The timing of OM3-CA administration relative to food intake influences the systemic bioavailability of EPA and DHA in healthy Japanese male subjects. Trial registration: NCT02372344

This study aimed to increase the knowledge on salivary antibodies in the horse since these constitute an important part of the immune defence of the oral cavity. For that purpose assays to detect horse immunoglobulin A (IgA) including secretory IgA (SIgA) were set up and the molecular weights of different components of the horse IgA system were estimated. Moreover, samples from 51 clinically healthy horses were tested for total SIgA and IgG amounts in saliva and relative IgG3/5 (IgG(T)) and IgG4/7 (IgGb) content were tested in serum and saliva. Results showed a mean concentration of 74μg SIgA/ml horse saliva and that there was a large inter-individual variation in salivary SIgA concentration. For total IgG the mean concentration was approx. 5 times lower than that of SIgA, i.e. 20μg IgG/ml saliva and the inter-individual variation was lower than that observed for SIgA. The saliva-serum ratio for IgG isotypes IgG3/5 and IgG4/7 was also assessed in the sampled horses and this analysis showed that the saliva-serum ratio of IgG4/7 was in general approximately 4 times higher than that of IgG3/5. The large inter-individual variation in salivary SIgA levels observed for the normal healthy horses in the present study emphasises the need for a large number of observations when studying this parameter especially in a clinical setting. Moreover, our results also indicated that some of the salivary IgG does not originate from serum but may be produced locally. Thus, these results provide novel insight, and a base for further research, into salivary antibody responses of horses.

It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to 4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels.

This study assesses the efficacy and exposure–response relationship of omega-3-carboxylic acids (OM-3 CA) in models of crystal-based inflammation. Human THP-1 macrophages and primary peripheral blood mononuclear cells exposed to multiple inflammatory crystal types were used to determine the anti-inflammatory potential of omega-3 (OM-3) fatty acids in vitro. Anti-inflammatory effects of OM-3 CA in vivo were tested in rat monosodium urate (MSU) crystal air pouch and rat knee intra-articular MSU injection models. Acute treatment with the OM-3 fatty acid docosahexaenoic acid suppressed MSU-, cholesterol crystal-, and calcium pyrophosphate crystal-mediated interleukin-1β (IL-1β) production in vitro. In vivo, OM-3 CA dose-dependently reduced crystal-mediated cell migration, exudate volume, and levels of IL-1β and prostaglandin E2. Following intra-articular injection of MSU, treatment with OM-3-CA (1 mL/kg) and indomethacin (1 mg/kg) resulted in similar mean reductions in pain (23% and 41%, respectively) and swelling (58% and 50%, respectively), compared with controls. Additionally, in complex formulations of OM-3 fatty acids, high levels of palmitic acid could reduce the in vivo effect on crystal-mediated IL-1β elevation. OM-3 CA has a broadly efficacious anti-inflammatory effect with a strong exposure–response relationship that could be beneficial in prevention and treatment of crystal arthritis, with potential applications in other IL-1β-mediated diseases.

Objective To compare the effects of bisoprolol and metoprolol CR/ZOK (metoprolol succinate controlled release) on systolic blood pressure (bpsys) over a 24-h period in an in silico model. Methods On the basis of the observed data from ambulatory blood pressure measurements (ABPM), a model with an appropriate distribution and correlation structure was derived for simulation of 24-h bpsys patterns during treatment with commonly studied doses, assumed to be equipotent, of bisoprolol and metoprolol CR/ZOK. Input into the simulations was aligned with the available data on the diurnal efficacy and pharmacology profiles of these substances. The validity of the model was tested in a bootstrap model. Results The simulation model reproduced the observed data with high congruence (p = 1.0). The mean 24-h bpsys values did not significantly differ between the two simulated groups (estimated overall change in bpsys [∆bpsys] for metoprolol versus bisoprolol = 2.7 mmHg [95 % confidence interval −0.3 to 5.7 mmHg]; p = 0.08). There were clear diurnal differences, with bisoprolol being more effective earlier and metoprolol CR/ZOK being more effective later in the 24-h day. A validity test with 100 repeated samples gave an overall mean group difference of 1.4 ± 3.59 mmHg (p = 0.63 relative to simulation). Conclusion In a robust model for the simulation of 24-h ABPM, comparisons between bisoprolol and metoprolol CR/ZOK indicate a comparable overall blood pressure-lowering effect but different diurnal patterns, consistent with the pharmacokinetics of the two drugs. This difference may be of clinical relevance, given the recognized diurnal pattern of cardiovascular events.

OM3-CA (omega-3-carboxylic acids) is a complex mixture of omega-3 carboxylic acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which is approved in the United States for the treatment of hypertriglyceridemia. As part of its clinical development in Japan, we performed a phase 1 study to investigate the safety, tolerability, and pharmacokinetics after single and multiple doses of OM3-CA in healthy male Japanese subjects. Eighteen Japanese subjects were allocated to receive 2 or 4 g/day OM3-CA, or placebo (n = 6 per group). In addition, 6 white subjects received 4 g/day OM3-CA. The primary objective was to determine the safety and tolerability of OM3-CA. Plasma concentrations of EPA and DHA were adjusted for baseline values for pharmacokinetic analysis. Overall, OM3-CA was well tolerated in healthy Japanese subjects. Two Japanese subjects in each group and 5 white subjects experienced adverse events (AEs). Alanine aminotransferase increase was the most common AE in Japanese subjects, also seen with placebo, and diarrhea was the most common AE in white subjects. The maximum plasma concentrations of EPA and DHA were observed 5-6 hours postdose. The pharmacokinetic profiles of EPA and DHA after administration of OM3-CA were comparable between Japanese and white subjects.

Data from two clinical studies (hyperCholesterolaemia in cHildren and Adolescents taking Rosuvastatin OpeN label [CHARON; NCT01078675] and Study 4522IL/0086) were used to describe rosuvastatin pharmacokinetics in patients with heterozygous familial hypercholesterolemia aged ≥6 to

One hundred consecutive patients admitted in 1980-82 for direct current conversion of chronic atrial fibrillation (AF) were followed. The first attempt to convert was made without the institution of class I antiarrhythmics. If AF relapsed, patients were selected for further conversions, in connection with which quinidine or disopyramide treatment was instituted. The proportion of patients maintaining sinus rhythm (SR) one and two years after the first conversion was 23% and 16%, after the second conversion 40% and 33% and after any number of conversions [1-12] 54% and 41%. Fifty-three per cent of the patients were symptomless before at least one conversion. Of the patients maintaining SR two years after conversion, 46% did not receive antiarrhythmic therapy. More than two conversions should be exceptional since symptoms of AF are often absent and the additional effect of further conversions is minor. A first attempt to convert without antiarrhythmics identifies a substantial proportion of patients maintaining SR without any prophylactic antiarrhythmic therapy.

Oral soft tissue ulcers are common disorders of horses, but it is unclear if their prevalence is increased by riding horses with a bit and bridle. Oral examinations were performed on 113 horses and ponies, all which had received routine dental floating, that were divided into four groups depending on when they had last been ridden with a bit and bridle. The subjects comprised: group 1, a randomly selected population of ridden horses; group 2, a group of horses examined after being rested at pasture for 5 weeks; group 3, the previous group following 7 weeks of riding with a bit and bridle, and group 4, brood mares that had not been ridden for at least 11 months. Lip and intraoral soft tissue lesions were recorded at seven pre-determined locations, with lesions classified as large or small; acute or chronic. The examinations showed that horses that were currently being ridden with a bit and bridle had a significantly higher prevalence of large and acute buccal ulcers opposite the maxillary Triadan 06 teeth and of the commissures of the lips, as compared to horses that were not being currently ridden. It was concluded that using a bit and bridle can cause oral ulceration even in horses that have regular prophylactic dental floating. It is suggested that riding tack should be individually fitted for each horse and also that prophylactic dental treatments should be individually adapted for each horse.

Introduction: STRENGTH (NCT02104817) is a 13,000-patient cardiovascular (CV) outcomes trial testing the hypothesis that high-CV-risk patients on statins with hypertriglyceridemia paired with low levels of high-density lipoprotein cholesterol (HDL-C) will have a reduction in incidence of major adverse CV events with omega-3 carboxylic acids (OM3-CA) 4 g/day compared with corn oil control. At present, the triglyceride (TG)-lowering mechanisms by which OM3-CA therapy may reduce CV risk are uncertain. Methods: In the ESPRIT trial (NCT01408303), patients (n=277) on statins who had fasting TG ≥200 mg/dL and Results: Least-squares mean difference in HDL2:HDL3 ratio increased by 12% (p=0.004), while apolipoprotein (Apo)B100, ApoB48 and PCSK9 were not significantly affected. The sum of the change in the highly atherogenic subfractions, very-low-density lipoprotein cholesterol (VLDL-C) + small LDL-C + remnant lipoprotein-C, was strongly correlated with TG reduction (0.732; p Conclusions: Compared with OO, OM3-CA 4 g/day significantly lowers non-HDL-C in patients with hypertriglyceridemia and low HDL-C by lowering VLDL-C, small LDL-C and remnant lipoprotein-C. Large LDL-C is raised without modifying ApoB100, ApoB48 or PCSK9 levels. STRENGTH will determine whether these lipoprotein compositional changes in this high-risk population will result in a CV benefit.

The impact of prothrombotic abnormalities on the risk of recurrent venous thromboembolism (VTE) and bleeding in patients receiving long-term anticoagulation remains unclear. This analysis evaluated the influence of potential prothrombotic risk factors (antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin gene G20210A mutation, cardiolipin antibodies, number of risk factors) on the risk of recurrent VTE or bleeding during treatment with oral ximelagatran (24 mg twice daily) or placebo for 18 months [THRombin Inhibitor in Venous thromboEmbolism (THRIVE) III trial]. Of the 1223 patients in the intention-to-treat population, prothrombotic state was analysed in 559 patients receiving ximelagatran and 540 patients receiving placebo. It is possible that patients at a high risk of recurrent VTE were poorly represented in this analysis because of selection bias. Prothrombotic risk factors were reported in 41% of patients (8% had > or = 2 factors). No significant interactions were found between ximelagatran treatment and potential prothrombotic risk factors for the risk of recurrent VTE or bleeding by Cox proportionate hazard modelling. There was no clear evidence for a higher risk of recurrent VTE or bleeding across subgroups according to the potential prothrombotic factors analysed in this study.

SummaryThe oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in theTHRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initialVTE event, and history of previousVTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49, 4.17), and in patients with one or more than one previous VTE event (HR: 1.73, 95% CI 1.00, 2.99). There was a higher risk of bleeding among women than men in both the ximelagatran (HR: 1.49, 95% CI 1.06, 2.09) and placebo (HR: 1.48, 95% CI 1.01, 2.15) groups, and in placebo-treated patients with an initial pulmonary embolism (HR: 1.53, 95% CI 1.06, 2.23) compared to those with initial deep vein thrombosis. There were no significant interactions between treatment effect and any of the potential prognostic factors. In conclusion, the superior efficacy of ximelagatran vs. placebo was maintained in all subgroups. Long-term use of oral ximelagatran, without coagulation monitoring or dose adjustment, should be feasible and well tolerated in a wide cross-section of patients for the secondary prevention of VTE.

SummaryIn the randomized, double-blind THRIVE III trial, the oral direct thrombin inhibitor ximelagatran (24 mg twice daily) significantly reduced the incidence of recurrent venous thromboembolism (VTE) versus placebo over 18 months or until premature study drug discontinuation. A complementary follow-up analysis (intention-to-treat) was conducted post-study to evaluate the cumulative risks of locally-confirmed recurrent VTE and death (Kaplan-Meier procedure) over the full 18-month study period, regardless of whether patients discontinued study drug prematurely. Hazard ratios (HRs) between treatments were estimated using Cox proportional hazard modeling. Of 612 and 611 patients receiving ximelagatran and placebo, respectively, 149 and 181 discontinued treatment prematurely. Of these discontinuations, further information could not be collected for 14 and 13patients in the ximelagatran and placebo groups, respectively; among the remaining patients, four VTE events and four deaths occurred in the ximelagatran group, and oneVTE event and five deaths occurred in the placebo group. The resulting cumulative risks of VTE (3.2% vs. 12.7%; HR 0.21; 95% confidence interval [CI], 0.12, 0.36;P < 0.0001) and pulmonary embolism (0.8% vs. 5.2%; HR 0.13; 95% CI 0.04, 0.36;P < 0.0001) were significantly lower in the ximelagatran than in the placebo group over 18 months. Death from any cause over 18 months occurred in 10 and 12 patients, respectively (HR 0.83;95% CI 0.36,1.93;P = 0.7). This complementary follow-up analysis confirms the benefit of oral ximelagatran 24 mg twice daily, administered without coagulation monitoring or dose adjustment, for the long-term secondary prevention of VTE.

Background: Atrial filling pressures are increased in acute atrial fibrillation, which stimulates the release of atrial natriuretic factor pro-hormone, proANF. Methods: In a randomized trial comparing digoxin with placebo in 216 patients, we investigated whether the baseline plasma level of N-terminal proANF is a predictor for conversion to sinus rhythm and the relation among N-terminal proANF, conversion to sinus rhythm, and changes in heart rate. Results: N-terminal proANF was increased at baseline and decreased significantly in patients converting to sinus rhythm, whereas it was mainly unchanged in nonconverters. N-terminal proANF was not a predictor of conversion to sinus rhythm. A relation was found between relative changes in heart rate and N-terminal proANF in nonconverters. Conclusion: The level of N-terminal proANF does not predict conversion to sinus rhythm, which indicates that hemodynamics per se is not important. There is a correlation between relative changes in heart rate and N-terminal proANF in nonconverters. (Am Heart J 1998;135:1040-7.)

The purpose of this study was to assess hemodynamic and respiratory measures of submaximal and maximal exercise performance in patients with chronic atrial fibrillation, before and one month after cardioversion to sinus rhythm. Restoration of sinus rhythm (n = 16) produced significant reductions in resting and exercise heart rates, 14 percent to 20 percent (p0.01). Due to a proportionately larger increase in stroke volume, cardiac output increased by 9 percent during low-level exercise (p0.01) and by 7 percent during exercise above the anaerobic threshold (p0.05). Minute ventilation was reduced by 7 percent during low-level exercise (p0.01) and by 9 percent above the anaerobic threshold (p0.05). The ratio between minute ventilation and carbon dioxide elimination was significantly reduced (p0.01). Maximum oxygen uptake (+8 percent; p0.01) and maximal tolerated work load (+6 percent; p0.05) increased. Hemodynamic changes during exercise were similar in patients with (n = 7) or without (n = 9) disopyramide prophylaxis. Restoration of sinus rhythm induced improvement in hemodynamics and in efficiency of ventilation, thereby reducing the ventilatory demand during submaximal exercise.

In a placebo-controlled study the effects on ventricular rate regulation and exercise performance of xamoterol, 100 mg two times a day and 200 mg two times a day, and slow-release verapamil, 240 mg once a day, were assessed in 21 patients with chronic atrial fibrillation. The mean ventricular rate from noon to 6:00 PM was 101 +/- 20 beats/min with placebo, 95 +/- 17 beats/min with xamoterol 100 mg two times a day (not significant), 90 +/- 16 beats/min with xamoterol 200 mg two times a day (p less than 0.001 vs placebo) and 78 +/- 19 beats/min with verapamil (p less than 0.001 vs each other treatment). The mean ventricular rate from midnight to 6:00 AM was 69 +/- 16 beats/min with placebo, increased with xamoterol 100 mg two times a day and 200 mg two times a day to 75 +/- 15 beats/min and 74 +/- 16 beats/min, respectively (p less than 0.001 vs placebo), but decreased with verapamil to 62 +/- 15 beats/min (p less than 0.001 vs each other treatment). The number of ventricular pauses greater than 2.0 seconds was increased by verapamil (p less than 0.05). All active treatments reduced exercise ventricular rates (p less than 0.001), but the decrease was more pronounced with verapamil. The anaerobic threshold was reached significantly earlier with verapamil than with placebo (72 +/- 32 W vs 79 +/- 37 W; p less than 0.01). Xamoterol is preferable to verapamil for treatment of patients with chronic atrial fibrillation who exhibit both bradycardia at rest and excessive tachycardia during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of two calcium channel blockers, diltiazem (270 mg/day) and verapamil (240 mg/day), were studied in 18 patients with chronic atrial fibrillation. During 24 h Holter electrocardiographic monitoring, mean ventricular rate (beats/min) decreased from 88 +/- 14 with placebo to 76 +/- 13 (p less than 0.001) with diltiazem and 80 +/- 11 (p less than 0.01) with verapamil. Maximal symptom-limited exercise tolerance (W) increased from 127 +/- 39 during the placebo period to 136 +/- 42 (p less than 0.01) with diltiazem and 137 +/- 39 (p less than 0.01) with verapamil. Ventricular rate and rate-pressure product were lower at rest and during exercise with diltiazem and verapamil than with placebo (p less than 0.001), with the drugs being similarly effective. Ventricular rate at maximal exercise (beats/min) was 179 +/- 13 with placebo compared with 159 +/- 21 with diltiazem and 158 +/- 23 with verapamil. Maximal oxygen uptake (ml/kg per min) was 22.3 +/- 4.5 with placebo, 23.7 +/- 4.9 (p less than 0.05) with diltiazem and 22.9 +/- 4.5 with verapamil (p = NS). Respiratory gas exchange anaerobic threshold was reached at a work load (W) of 76 +/- 21 with placebo, 84 +/- 27 (p less than 0.05) with diltiazem and 85 +/- 23 (p less than 0.01) with verapamil. In conclusion, patients with chronic atrial fibrillation have modestly improved exercise tolerance with calcium channel blockade therapy. The dromotropic responses and the effects on physical performance are of similar magnitude for diltiazem and verapamil.

Background Swedish equine dental practices have empirically found that the prevalence of infundibular caries as a primary disorder in the first permanent premolar teeth (P2) of the horse upper jaw has increased during the last 10 years. A previously unknown bacterial species, Streptococcus devriesei (CCUG 47155T), which is related to Streptococcus mutans, has recently been isolated from these carious lesions. To understand the aetiology of caries in horses, it is essential to elucidate the relationship between S. devriesei and P2 infundibular caries. Methods The anterior infundibulum of maxillary P2, or the occlusal surface at the site of the infundibulum, in 117 horses and ponies, 77 with and 40 without caries in this tooth, was sampled for bacteriological analyses between 1990 and 2004. Samples were transported in VMGA III medium and then inoculated onto MSB agar. The approximate number of bacteria was counted in each sample and the isolates were characterised biochemically, using a commercial kit. Results All 50 samples taken from carious lesions after 2002 were positive for an S. mutans-like strain, i.e. S. devriesei. The bacteria were also found in four of the control animals, but were much less numerous than in samples from caries-affected horses. None of the swabs taken prior to 2002 were positive for this bacteria. Conclusion Our results demonstrate that S. devriesei can colonise the infundibulum of P2 of the horse upper jaw, which can be fatal for the dental tissue. We conclude that S. devriesei is strongly associated with P2 caries in horses.

Phenotypic and phylogenetic studies were performed on four unidentified Gram-positive staining, catalase-negative, alpha-hemolytic Streptococcus-like organisms recovered from the teeth of horses. SDS PAGE analysis of whole-cell proteins and comparative 16S rRNA gene sequencing demonstrated the four strains were highly related to each other but that they did not correspond to any recognised species of the genus Streptococcus. Phylogenetic analysis based on 16S rRNA gene sequences showed the unidentified organisms form a hitherto unknown sub-line within the Streptococcus genus, displaying a close affinity with Streptococcus mutans, Streptococcus ferus and related organisms. Sequence divergence values of > 5% with these and other reference streptococcal species however demonstrated the organisms from equine sources represent a novel species. Based on the phenotypic distinctiveness of the new bacterium and molecular chemical and molecular genetic evidence, it is proposed that the unknown species be classified as Streptococcus devriesei sp. nov. The type strain of Streptococcus devriesei is CCUG 47155T (= CIP 107809T).

For many patients with venous thromboembolism, secondary prevention with vitamin K antagonists is not extended beyond six months, since the risk of recurrence may be outweighed by the risk of major bleeding.In a double-blind, multicenter trial, we randomly assigned 1233 patients with venous thromboembolism who had undergone six months of anticoagulant therapy to extended secondary prevention with the oral direct thrombin inhibitor ximelagatran (24 mg) or placebo, taken twice daily, for 18 months without monitoring of coagulation. At base line, bilateral ultrasonography of the legs and perfusion lung scanning were performed.Data from 612 patients in the ximelagatran group and 611 in the placebo group were analyzed. The occurrence of the primary end point, symptomatic recurrent venous thromboembolism, was confirmed in 12 patients assigned to ximelagatran and 71 patients assigned to placebo (hazard ratio, 0.16; 95 percent confidence interval, 0.09 to 0.30; P0.001). Death from any cause occurred in 6 patients in the ximelagatran group and 7 patients in the placebo group, and bleeding occurred in 134 patients and 111 patients, respectively (hazard ratio, 1.19; 95 percent confidence interval, 0.93 to 1.53; P=0.17). The incidence of major hemorrhage was low (six events in the ximelagatran group and five in the placebo group), and none of these hemorrhages were fatal. The cumulative risk of a transient elevation of the alanine aminotransferase level to more than three times the upper limit of normal was 6.4 percent in the ximelagatran group, as compared with 1.2 percent in the placebo group (P0.001).Oral ximelagatran was superior to placebo for the extended prevention of venous thromboembolism. There was no significant increase in the frequency of bleeding complications, but there was an increase in the number of patients with a transient elevation in the alanine aminotransferase level.

tients with acute venousthromboembolismconsistsof5to7daysofunfractionatedheparinorlow-molecular-weighthep-arin,overlappedwithandfollowedbylong-term oral anticoagulation with avitamin K antagonist such as warfa-rin. Heparins must be given parenter-ally, and their administration requiresconsiderable health care resources.Warfarinhasanunpredictabledosere-sponse,interactswithmanydrugs,andcanbeaffectedbychangesindiet;thus,continuedcoagulationmonitoringanddose adjustment are necessary.

Background Oral lesions related to the use of the bit and bridle are reported to be common findings in horses worldwide and represent an important animal welfare issue. In order to provide an overview of bit-related lesions in Icelandic competition horses, a field examination of the rostral part of the oral cavity was performed in 424 competition horses coming to the two major national horse events in Iceland in 2012. Records from repeated examination of 77 horses prior to the finals were used to assess potential risk factors. Results Mild lesions were recorded in 152 horses (36%) prior to the preliminary rounds. They were most often located in the commissures of the lips and the adjacent buccal mucosa (n = 111). Severe lesions were found in 32 (8%) horses. For 77 horses examined prior to the finals, the frequency of findings in the area of the mandibular interdental space (bars of the mandible) had increased from 8% to 31% (P