Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo: The EPIC Study.

BACKGROUND: Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described. OBJECTIVES: To investigate the effect of pimobendan on clinical variables and the relationship between a change in heart size and the time to congestive heart failure (CHF) or cardiac-related death (CRD) in dogs with MMVD and cardiomegaly. To determine whether pimobendan-treated dogs differ from dogs receiving placebo at onset of CHF. ANIMALS: Three hundred and fifty-four dogs with MMVD and cardiomegaly. MATERIALS AND METHODS: Prospective, blinded study with dogs randomized (ratio 1:1) to pimobendan (0.4-0.6 mg/kg/d) or placebo. Clinical, laboratory, and heart-size variables in both groups were measured and compared at different time points (day 35 and onset of CHF) and over the study duration. Relationships between short-term changes in echocardiographic variables and time to CHF or CRD were explored. RESULTS: At day 35, heart size had reduced in the pimobendan group: median change in (Δ) LVIDDN -0.06 (IQR: -0.15 to +0.02), P < 0.0001, and LA:Ao -0.08 (IQR: -0.23 to +0.03), P < 0.0001. Reduction in heart size was associated with increased time to CHF or CRD. Hazard ratio for a 0.1 increase in ΔLVIDDN was 1.26, P = 0.0003. Hazard ratio for a 0.1 increase in ΔLA:Ao was 1.14, P = 0.0002. At onset of CHF, groups were similar. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan treatment reduces heart size. Reduced heart size is associated with improved outcome. At the onset of CHF, dogs treated with pimobendan were indistinguishable from those receiving placebo.

Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study-A Randomized Clinical Trial.

BACKGROUND: Pimobendan is effective in treatment of dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD). Its effect on dogs before the onset of CHF is unknown. HYPOTHESIS/OBJECTIVES: Administration of pimobendan (0.4-0.6 mg/kg/d in divided doses) to dogs with increased heart size secondary to preclinical MMVD, not receiving other cardiovascular medications, will delay the onset of signs of CHF, cardiac-related death, or euthanasia. ANIMALS: 360 client-owned dogs with MMVD with left atrial-to-aortic ratio ≥1.6, normalized left ventricular internal diameter in diastole ≥1.7, and vertebral heart sum >10.5. METHODS: Prospective, randomized, placebo-controlled, blinded, multicenter clinical trial. Primary outcome variable was time to a composite of the onset of CHF, cardiac-related death, or euthanasia. RESULTS: Median time to primary endpoint was 1228 days (95% CI: 856-NA) in the pimobendan group and 766 days (95% CI: 667-875) in the placebo group (P = .0038). Hazard ratio for the pimobendan group was 0.64 (95% CI: 0.47-0.87) compared with the placebo group. The benefit persisted after adjustment for other variables. Adverse events were not different between treatment groups. Dogs in the pimobendan group lived longer (median survival time was 1059 days (95% CI: 952-NA) in the pimobendan group and 902 days (95% CI: 747-1061) in the placebo group) (P = .012). CONCLUSIONS AND CLINICAL IMPORTANCE: Administration of pimobendan to dogs with MMVD and echocardiographic and radiographic evidence of cardiomegaly results in prolongation of preclinical period and is safe and well tolerated. Prolongation of preclinical period by approximately 15 months represents substantial clinical benefit.

Oxidative degradation of glyphosate and aminomethylphosphonate by manganese oxide.

Glyphosate (N-(phosphonomethyl)glycine), the most commonly used herbicide worldwide, degrades relatively rapidly in soils under most conditions, presumably by microbial processes. The most frequently detected degradation product in soil and water is AMPA (aminomethylphosphonic acid). We report the first evidence for an abiotic pathway of glyphosate and AMPA degradation under environmentally realistic conditions. Both glyphosate and AMPA degraded at 20 degrees C in dilute aqueous suspensions of birnessite, a manganese oxide common in soils, as evidenced by the accumulation of orthophosphate in solution over a period of several days. It is concluded that the abiotic degradation involved C-P bond cleavage at the Mn oxide surface, although evidence for C-N bond cleavage in the case of glyphosate and sarcosine, a likely degradation product of glyphosate, was found. The degradation of glyphosate was faster than that of AMPA, and higher temperature (50 degrees C) resulted in faster degradation of both glyphosate and AMPA. The addition of sulfate to the solution had no marked effect on the reaction rate, although Cu2+ addition inhibited degradation. As this metal ion complexes strongly with glyphosate, the inhibition can be attributed to the ability of Cu2+ to limit glyphosate coordination to reactive oxidation sites at the Mn oxide surface. Using a similar experimental design, we were unable to detect glyphosate degradation in an equimolar solution of MnCl2 (0.5 mM). However, we demonstrated that the oxidation of Mn2+ is enhanced both in solution and on an inert surface, in the presence of glyphosate (4:1 Mn-glyphosate molar ratio). This result suggests that the oxidative breakdown of glyphosate in the presence of Mn2+ may ultimately occur following the spontaneous oxygen-mediated oxidation of manganese.

Reduced progesterone metabolites are not critical for plus-maze performance of lactating female rats.

Lactation has been associated with anxiolysis in several tests of anxiety. These observations, considered together with observations that progesterone and its 5alpha-reduced metabolites are anxiolytic in cycling, nonlactating females, raised the question of whether the changes in anxiety-related behaviors that accompany lactation are driven by reduced progesterone metabolites. Lactating female rats were tested on the plus-maze on postpartum days 2 or 7, and demonstrated enhanced open-arm performance relative to cycling, nonlactating females. Hormonal analysis indicated that while serum levels of both progesterone and its 3alpha,5alpha-reduced metabolite were increased in lactating females, the turnover of progesterone to the metabolite was markedly reduced during lactation. Furthermore, treatment with a 5alpha-reductase inhibitor for 3 days prior to testing potentiated the open-arm performance in lactating females, implying that enhanced open-arm performance was not mediated by the reduction of progesterone or other steroids. Additionally, analysis of GABA(A) receptor function indicated that parturition and lactation did not alter the sensitivity of the receptor to GABA or to modulation by reduced steroids. The mechanisms driving enhanced plus-maze behavior in lactating females appear to differ from mechanisms identified in nonlactating females.

Effect of gender on the mismatch negativity auditory evoked potential.

Mismatch negativity (MMN) was measured on normal-hearing young adult women and men to determine the effect of gender on this auditory evoked potential (AEP). In the experimental condition, recordings were obtained for 1000-Hz tone bursts presented at 75 dB nHL (standard stimuli) and 60 dB nHL (deviant stimuli). AEPs also were obtained in a control condition in which all stimuli were presented at 60 dB nHL; however, 15 percent of these responses were averaged to represent a response analogous to the experimental deviant response. The MMN was derived by subtracting the analogous control waveform from the experimental deviant waveform. Measures of peak-to-peak amplitude, peak latency, and area-under-the-curve were obtained for each derived waveform. Analysis of these data indicated no significant gender differences in peak latency of the MMN response. However, peak-to-peak amplitude and area-under-the-curve were significantly larger for women than for men.

Test-retest reliability in tympanometry.

Test-retest reliability for tympanometric measures was evaluated across five sessions in 20 subjects with normal hearing and normal middle-ear function. Tympanograms were obtained on each ear for probe frequencies of 226, 678, and 1000 Hz using both ascending and descending directions of pressure change. Across all conditions, the tympanometric measure that consistently demonstrated the highest test-retest reliability was compensated static acoustic admittance. Test-retest correlations for peak compensated static acoustic admittance measures were higher than those for ambient measures across all probe frequencies and both directions of pressure change; the differences in correlations for peak and ambient measures, however, reached significance only for 226-Hz conditions. Across-session correlations for tympanogram width did not differ significantly for measures referenced to the lowest tympanogram tail and those referenced to +200 daPa.

Statistical conclusion validity of rehabilitation research. A quantitative analysis.

The findings of 100 data-based studies exploring the effectiveness of rehabilitation procedures were reviewed and analyzed. The statistical conclusion validity was determined by computing post hoc power coefficients for the statistical hypotheses tests included in the review studies. The data analysis revealed that the median power to detect a small effect size in the studiesreviewed was 0.08. The median power to detect medium and large effect sizes was 0.26 and 0.56, respectively. The results suggest the possibility of a high rate of type II experimental errors in the rehabilitation research. A type II error represents a false-negative conclusion and occurs when a researcher supports a null hypothesis that was false and should have been rejected.

Measures of effect size in the reporting of rehabilitation research.

Effect size measures were computed for a sample of 100 research studies published in four leading rehabilitation journals. The effect size measures were categorized as small, medium, or large according to established criteria. Analysis of the effect size measures revealed that the average treatment effect was in the medium range (0.69). Further data analysis exposed a statistically significant difference in mean effect size values across articles contained in the four rehabilitation journals. A regression analysis indicated that characteristics of the study design were not significant predictors of effect size values in the 100 studies. The interpretation of effect size measures in relation to statistical significance testing is discussed and the argument made that reporting measures of effect size will assist researchers in determining the sensitivity of experimental manipulations in rehabilitation research.

Comparative anatomy of eustachian tube and middle ear cavity in animal models for otitis media.

The comparative anatomy of the normal eustachian tube (ET) and normal middle ear cavity of three animal species (rat, gerbil, and chinchilla) is described relating to the usefulness of these animals as models for otitis media (OM). Routine histological and anatomical techniques and procedures were used. The gerbil and chinchilla, although of different sizes, are quite similar, having hypertrophied middle ear bullae, nearly vertical ET, and similar histology including seromucous glands draining directly into the ET. In contrast, the rat has a small bulla, a nearly horizontal ET, and a large concentration of goblet cells but few mucous glands in the ET. It appears that the chinchilla and the gerbil may serve as alternative models for OM research. Chinchillas and gerbils are relatively free of naturally occurring OM, while the rat has a high incidence of naturally occurring OM.

Effects of PCA and DMAE on the namatode Caenorhabditis briggsae.

Concentration of 6.8 mM DMAE did not retard age pigment accumulation in Caenorhabditis briggsae. However, when the nematodes were exposed to 6.8 mM PCA + 6.8 mM DMAE combined, the accumulation of age pigment was significantly retarded. A combination of 3.4 mM DMAE + 3.4 mM PCA had no effect on age pigment. It is concluded from this study that PCA and DMAE act in concert to produce the observed effect on age pigment. In respect to this parameter neither molecule was effective alone. The results indicate that the effect of centrophenoxine on age pigment might be enhanced by retarding the hydrolysis of centrophenoxine. The accumulation of electron dense aggregates, thought to be aggregates of cross-linked molecules, was reduced by 6.8 PCA + 6.8 DMAE. It is suggested that centrophenoxine be tested for its ability to remove random, unwanted cross-linkages in higher animals.