Using accelerometers to identify a high risk of catastrophic musculoskeletal injury in three racing Thoroughbreds.

OBJECTIVE: To describe the process whereby the screening of racing Thoroughbreds with accelerometer-based inertial measurement unit (IMU) sensors followed by clinical evaluation and advanced imaging identified potentially catastrophic musculoskeletal injuries in 3 horses. ANIMALS: 3 Thoroughbred racehorses. CLINICAL PRESENTATION: All cases demonstrated an abnormal stride pattern either during racing (cases 1 and 2) or while breezing (case 3) and were identified as being at very high risk of catastrophic musculoskeletal injury by an algorithm derived from IMU sensor files from > 20,000 horses' race starts. Veterinary examination and 18F-sodium fluoride (18F-NaF) positron emission tomography were performed within 10 days of the respective race or breeze in each of the cases. RESULTS: The intensity and location of the 18F-NaF uptake in the condyles of the third metacarpal bone in cases 1 and 2 identified them as at potential increased risk of condylar fracture. The pattern and intensity of the 18F-NaF uptake in case 3 indicated that the third carpal bone was likely responsible for the horse's lameness, with an impending slab fracture subsequently identified on radiographs. Following periods of convalescence, cases 1 and 2 returned to racing and were identified by the sensor system as no longer being at high risk of catastrophic musculoskeletal injury. Case 3 returned to training but has yet to return to racing. CLINICAL RELEVANCE: When worn by Thoroughbreds while racing or breezing, these IMU sensors can identify horses at high risk of catastrophic musculoskeletal injury, allowing for veterinary intervention and the potential avoidance of such injuries.

Effects of hyperthermia and acidosis on mitochondrial production of reactive oxygen species.

Exercise is associated with the development of oxidative stress, but the specific source and mechanism of production of pro-oxidant chemicals during exercise has not been confirmed. We used equine skeletal muscle mitochondria to test the hypothesis that hyperthermia and acidosis affect mitochondrial oxygen consumption and production of reactive oxygen species (ROS). Skeletal muscle biopsies were obtained at rest, after an acute episode of fatiguing exercise, and after a 9-wk conditioning program to increase aerobic fitness. Mitochondrial oxygen consumption and ROS production were measured simultaneously using high-resolution respirometry. Both hyperthermia and acidosis increased nonphosphorylating (LEAK) respiration (5.8× and 3.0×, respectively, P < 0.001) and decreased efficiency of oxidative phosphorylation. The combined effects of hyperthermia and acidosis resulted in large decreases in phosphorylating respiration, further decreasing oxidative phosphorylation efficiency from 97% to 86% (P < 0.01). Increased aerobic fitness reduced the effects of acidosis on LEAK respiration. Hyperthermia increased and acidosis decreased ROS production (2× and 0.23×, respectively, P < 0.001). There was no effect of acute exercise, but an aerobic conditioning program was associated with increased ROS production during both nonphosphorylating and phosphorylating respiration. Hyperthermia increased the ratio of ROS production to O2 consumption during phosphorylating respiration, suggesting that high-temperature impaired transfer of energy through the electron transfer system despite relatively low mitochondrial membrane potential. These data support the role of skeletal muscle mitochondria in the development of exercise-induced oxidative stress, particularly during forms of exercise that result in prolonged hyperthermia without acidosis.NEW & NOTEWORTHY The results of this study provide evidence for the role of mitochondria-derived ROS in the development of systemic oxidative stress during exercise as well as skeletal muscle diseases such as exertional rhabdomyolysis.

Effects of Feeding Coenzyme Q10-Ubiquinol on Plasma Coenzyme Q10 Concentrations and Semen Quality in Stallions.

Although coenzyme Q10 (CoQ10) serves as an antioxidant and energy source for spermatozoa when added to stallion semen before cooling or freezing, the effects of feeding CoQ10 on semen quality have not been studied. We assessed the effects of daily oral ingestion of CoQ10-ubiquinol by stallions on their plasma CoQ10 concentrations and semen quality. Seven mature Andalusian stallions ate 1g ubiquinol/day for 4 weeks followed by a 4-week washout period. Four horses initially completed an additional 4-week control period without ubiquinol. Blood was sampled weekly for determination of plasma CoQ10 concentrations. Ejaculates were collected every two weeks and assessed for total motility (TM), progressive motility (PM), and viability (V) after cooling for 24hours (T1), immediate cryopreservation (T2), and cryopreservation after 24hours cooling (T3). Ingesting ubiquinol resulted in an increase in plasma CoQ10 concentration (P < .001). Two weeks of CoQ10-ubiquinol resulted in improved V with all treatments (T1: P = .007; T2: P = .05; T3: P = .01) and PM with T3 (P = .04). In five stallions, TM and PM were also improved for T1 (P = .01 and P = .02, respectively) and TM increased with T2 (P = .03). Overall, semen quality parameters increased within the first 2 weeks of supplementation, plateaued at the end of the 4-week supplementation period and persisted after discontinuing ubiquinol until the end of the sampling period (8 weeks). Feeding 1 g CoQ10-ubiquinol for 4 weeks to breeding stallions improved semen quality after cooling and freezing in 5 of 7 stallions. This could be important for improving reproductive efficiency in stallions.

Validation of a Rapid Bronchoalveolar Lavage Fluid Colorimetric Evaluation for Assessing the Severity of Exercise-Induced Pulmonary Hemorrhage in Horses in Field Conditions.

Diagnosis and assessment of severity of exercise-induced pulmonary hemorrhage (EIPH) relies on postexercise visualization of fresh blood in the airways via tracheobronchoscopic examination (TBE) and/or counting erythrocytes in bronchoalveolar lavage fluid (BALFRBC). Determining the BALFRBC is more sensitive than TBE but its usefulness is hampered by the need to have BALFRBC counted at a laboratory. We explored the feasibility of evaluating the severity of EIPH by using a color chart comprised of five shades of red and matching those colors with the color of BALF immediately following collection. To validate the technique, sets of ten BALF samples with known BALFRBC numbers were created and randomly shown to two groups of 18 observers who independently matched the color of the BALF with one of the shades of red displayed on the screen of a smartphone. Interobserver and intra-observer agreements regarding colors were > 0.9. The utility of the color chart was further validated under field conditions at two barrel racing events where 63 BALF samples were collected from 21 horses and BALF color was graded independently by three observers. The number of BALFRBC in the 63 samples ranged from 25-1,100,000/µL. EIPH was diagnosed in 39 samples based on the detection of color, and all 5 colors were matched multiple times with BALF samples. Overall, the color of the BALF was related to the number of BALFRBC. Colorimetric evaluation of BALF represents a practical and reliable option for rapid postexercise assessment of the presence and severity of EIPH.

Effects of exercise, furosemide, blood depletion, and reinfusion on body fluid compartment volumes in horses.

High pulmonary blood pressure contributes to exercise-induced pulmonary hemorrhage. The objective of this study was to use bioimpedance spectroscopy to assess body fluid compartment volumes under 3 conditions in 6 racehorses: i) Pre- and post-supramaximal treadmill exercise (control); ii) Exercise 4 hours after furosemide (0.5 mg/kg body weight, IV); iii) Exercise, removal of ~14 L of blood and subsequent reinfusion of the blood. Statistical analysis used linear mixed effects models. Body compartment volumes did not change during the control runs. Total body water (TBW) (P = 0.007, P = 0.007), extracellular fluid (ECF) (P = 0.003, P = 0.003), and intracellular fluid (ICF) volumes (P = 0.04, P = 0.04) decreased pre- and post-exercise following furosemide administration. The ICF trended to decrease (P = 0.07) after slow removal of blood. Blood reinfusion increased TBW (P = 0.02, P = 0.02) and ICF (P = 0.005, P = 0.005) pre- and post-exercise.

Effets de l'exercice, du furosémide, de la diminution sanguine et de la ré-infusion sur les volumes des liquides corporels compartimentés chez les chevaux. Une pression sanguine pulmonaire élevée contribue à des hémorragies pulmonaires induites par l'exercice. L'objectif de la présente étude était d'utiliser la spectroscopie à bio-impédance pour évaluer les volumes des liquides corporels compartimentés sous trois conditions chez six chevaux de course : i) Pré- et post-supramaximal exercice au tapis roulant (témoin); ii) Exercice 4 h après administration de furosémide (0,5 mg/kg de poids corporel, IV); iii) Exercice, retrait d'environ 14 L de sang et ré-infusion subséquente du sang. Les analyses statistiques utilisaient des modèles linéaires à effets mixtes. Les volumes des compartiments corporels n'ont pas changé durant les essais témoins. Les volumes de la quantité totale d'eau corporelle (TBW) (P = 0,007, P = 0,007), de liquide extracellulaire (ECF) (P = 0,003, P = 0,003) et liquide intracellulaire (ICF) (P = 0,04, P = 0,04) ont diminué pré- et post-exercice à la suite de l'administration de furosémide. L'ICF avait tendance à diminuer (P = 0,07) à la suite du lent retrait de sang. La ré-infusion de sang augmenta la TBW (P = 0,02, P = 0,02) et l'ICF (P = 0,005, P = 0,005) pré- et post-exercice.(Traduit par Dr Serge Messier).

Relationship between tracheobronchoscopic score and bronchoalveolar lavage red blood cell numbers in the diagnosis of exercise-induced pulmonary hemorrhage in horses.

BACKGROUND: Exercise-induced pulmonary hemorrhage (EIPH) is diagnosed and its severity assessed by post-exercise tracheobronchoscopy, and enumeration of bronchoalveolar lavage fluid red blood cells (BALFRBC). Minimal information is available regarding the relationship of tracheobronchoscopy score to BALFRBC number. OBJECTIVE: Evaluate the relationship between BALFRBC number and tracheobronchoscopy scores and determine their diagnostic sensitivities. ANIMALS: Nine sedentary horses, 21 fit Thoroughbreds, 129 Barrel Racers. METHODS: Normal BALFRBC number and the effect of bronchoalveolar lavage (BAL) on it were evaluated by performing 2 BALs 24 hours apart in sedentary horses. Tracheobronchoscopy followed by BAL was performed 247 times on 150 horses after treadmill, racetrack, or barrel racing exercise. Lastly, a BALFRBC diagnostic threshold number that optimized the geometric mean of the sensitivity and precision (F1-score) was determined using Bayesian analysis. RESULTS: No increase in BALFRBC occurred after the second BAL (mean ± SD, 304 ± 173/µL). Tracheobronchoscopy scores ranged from 0 (n = 112) to 4 (n = 4) and BALFRBC ranged from 102 to 4605268/µL. Spearman correlation between tracheobronchoscopy score and BALFRBC was weak (P < .001; rs = 0.42) with large ranges of BALFRBC associated with each tracheobronchoscopy score. The highest F1-score occurred for a BALFRBC threshold number = 992/µL. Seventy-five tracheobronchoscopy scores equaled 0 although BALFRBC number was ≥992/µL. Sensitivity of tracheobronchoscopy for diagnosing EIPH was poor (0.59; 95% confidence intervals [CI], 0.49-0.68), compared to BALFRBC number ≥992/µL (0.93; 95% CI, 0.88-0.96). CONCLUSIONS AND CLINICAL IMPORTANCE: False negatives are common with tracheobronchoscopy. Follow-up determination of BALFRBC may be indicated for tracheobronchoscopy scores = 0 before EIPH can be ruled out.

Assessment of two methods to determine the relative contributions of the aerobic and anaerobic energy systems in racehorses.

A prospective, randomized, controlled study was designed to determine relative aerobic and anaerobic (lactic and alactic) contributions at supramaximal exercise intensities using two different methods. Thoroughbred racehorses (n = 5) performed a maximal rate of oxygen consumption (V̇o2max) test and three supramaximal treadmill runs (105, 115, and 125% V̇o2max). Blood lactate concentration (BL) was measured at rest, every 15 s during runs, and 2, 5, 10, 20, 30, 40, 50, and 60 min postexercise. In method 1, oxygen demand was calculated for each supramaximal intensity based on the V̇o2max test, and relative aerobic and anaerobic contributions were calculated from measured V̇o2 and the accumulated oxygen deficit. In method 2, aerobic contribution was calculated using the trapezoidal method to determine V̇o2 during exercise. A monoexponential model was fitted to the postexercise V̇o2 curve. Alactic contribution was calculated using the coefficients of this model. Lactate anaerobic contribution was calculated by multiplying the peak to resting change in BL by 3. Linear mixed-effects models were used to examine the effects of exercise intensity and method (as fixed effects) on measured outcomes (P ≤ 0.05). Relative aerobic and anaerobic contributions were not different between methods (P = 0.20). Horses' mean contributions were 81.4, 77.6, and 72.5% (aerobic), and 18.5, 22.3, and 27.4% (anaerobic) at 105, 115, and 125% V̇o2max, respectively. Individual alactic anaerobic energy was not different between supramaximal exercise intensities (P = 0.43) and was negligible, contributing a mean of 0.11% of the total energy. Relative energy contributions can be calculated using measured V̇o2 and BL in situations where the exercise intensity is unknown. Understanding relative metabolic demands could help develop tailored training programs. NEW & NOTEWORTHY Relative energy contributions of horses can be calculated using measured V̇o2 and BL in situations where the exercise intensity is unknown. Horses' mean contributions were 81.4, 77.6, and 72.5% (aerobic), and 18.5, 22.3, and 27.4% (anaerobic) at 105, 115, and 125% of V̇o2max, respectively. Individual alactic capacity was unaltered between supramaximal exercise intensities and accounted for a mean contribution of 0.11% of energy use.

Exercise-induced pulmonary hemorrhage in barrel racing horses in the Pacific Northwest region of the United States.

BACKGROUND: Exercise-induced pulmonary hemorrhage (EIPH) refers to bleeding from the lungs in association with strenuous exercise. It has been documented in race horses but little information exists on EIPH in barrel racing horses. HYPOTHESIS/OBJECTIVES: Our goals were to evaluate the presence of EIPH in barrel racing horses and estimate its prevalence in the Pacific Northwest. ANIMALS: 149 barrel racing horses enrolled at events in WA (11), ID (3), and MT (33). METHODS: Observational cross-sectional study. Data collected included signalment, history of illness, respiratory disease, race division, and pre-race medications. Endoscopy was performed and tracheobronchoscopic (TBE) EIPH score was assigned based on quantity of blood in the trachea (0 = no blood to 4 = abundance of blood within the trachea). After TBE, bronchoalveolar lavage (BAL) was performed. Erythrocyte (red blood cell, RBC) counts were obtained from bronchoalveolar lavage fluid (BALF). Statistical analysis included linear and logistic regression, Fisher's exact t test, and calculation of correlation coefficient. Significance was set at P < .05. RESULTS: The prevalence of EIPH based on TBE EIPH score was 54%. When based on BALF RBC count >1,000 cells, EIPH prevalence was 66%. Race time did not significantly affect the presence of EIPH. A significant (P < .0001) positive linear relationship between the TBE and BAL erythrocyte count was identified, but its strength was poor (r2 = .15). CONCLUSIONS AND CLINICAL IMPORTANCE: EIPH occurs in over 50% of barrel racing horses in the Pacific Northwest. Precise determination of the impact of EIPH on health of barrel racers requires further study.

Linking Auxin with Photosynthetic Rate via Leaf Venation.

Land plants lose vast quantities of water to the atmosphere during photosynthetic gas exchange. In angiosperms, a complex network of veins irrigates the leaf, and it is widely held that the density and placement of these veins determines maximum leaf hydraulic capacity and thus maximum photosynthetic rate. This theory is largely based on interspecific comparisons and has never been tested using vein mutants to examine the specific impact of leaf vein morphology on plant water relations. Here we characterize mutants at the Crispoid (Crd) locus in pea (Pisum sativum), which have altered auxin homeostasis and activity in developing leaves, as well as reduced leaf vein density and aberrant placement of free-ending veinlets. This altered vein phenotype in crd mutant plants results in a significant reduction in leaf hydraulic conductance and leaf gas exchange. We find Crispoid to be a member of the YUCCA family of auxin biosynthetic genes. Our results link auxin biosynthesis with maximum photosynthetic rate through leaf venation and substantiate the theory that an increase in the density of leaf veins coupled with their efficient placement can drive increases in leaf photosynthetic capacity.

The role of strigolactones and ethylene in disease caused by Pythium irregulare.

Plant hormones play key roles in defence against pathogen attack. Recent work has begun to extend this role to encompass not just the traditional disease/stress hormones, such as ethylene, but also growth-promoting hormones. Strigolactones (SLs) are the most recently defined group of plant hormones with important roles in plant-microbe interactions, as well as aspects of plant growth and development, although the knowledge of their role in plant-pathogen interactions is extremely limited. The oomycete Pythium irregulare is a poorly controlled pathogen of many crops. Previous work has indicated an important role for ethylene in defence against this oomycete. We examined the role of ethylene and SLs in response to this pathogen in pea (Pisum sativum L.) at the molecular and whole-plant levels using a set of well-characterized hormone mutants, including an ethylene-insensitive ein2 mutant and SL-deficient and insensitive mutants. We identified a key role for ethylene signalling in specific cell types that reduces pathogen invasion, extending the work carried out in other species. However, we found no evidence that SL biosynthesis or response influences the interaction of pea with P. irregulare or that synthetic SL influences the growth or hyphal branching of the oomycete in vitro. Future work should seek to extend our understanding of the role of SLs in other plant interactions, including with other fungal, bacterial and viral pathogens, nematodes and insect pests.

Oviposition preference and larval performance of Epiphyas postvittana (Lepidoptera: Tortricidae) on Botrytis cinerea (Helotiales: Sclerotiniaceae) infected berries of Vitis vinifera (Vitales: Vitaceae).

In this paper we tested the behavior of gravid Epiphyas postvittana in selecting the most-appropriate site for oviposition thus benefitting offspring performance. Our hypothesis was built on Jaenike's preference-performance hypothesis (also referred to as the "mother-knows-the-best" hypothesis). To test this, we used the interacting Epiphyas postvittana, its host Vitis vinifera, and the pathogenic microbe Botrytis cinerea system. Populations of E. postvittana and B. cinerea often exist concurrently on V. vinifera in Australasia and their interaction and mutual influence are currently being explored, although the suggestion presently is that the relationship between E. postvittana and B. cinerea is mutualistic. We tested the effect of volatiles from B. cinerea-infected berries and uninfected (control) berries of V. vinifera on the oviposition behavior of E. postvittana. We also characterized the effects of B. cinerea infection on the berries of V. vinifera on the growth and development of E. postvittana. Contrary to the preference-performance hypothesis, oviposition choices made by gravid E. postvittana did not result in the best offspring survival, development, and performance. The preference for oviposition by E. postvittana was strongly influenced by the olfactory and tactile cues. She laid fewer eggs on B. cinerea-infected berries compared to uninfected berries of V. vinifera. The larvae of E. postvittana showed no preference to uninfected berries of V. vinifera. The larvae fed on B. cinerea-infected berries of V. vinifera showing greater survival rate, shorter time to pupation, greater pupal mass, and on becoming adults they laid more numbers of eggs than the larvae that were enabled to feed on uninfected berries. The larvae of E. postvittana transport the conidia of B. cinerea and transmit grey-mould disease to uninfected berries of V. vinifera.

Pt-functionalized Fe2O3 photoanodes for solar water splitting: the role of hematite nano-organization and the platinum redox state.

Pt/α-Fe2O3 nanocomposites were synthesized on fluorine-doped tin oxide (FTO) substrates by a sequential plasma enhanced-chemical vapor deposition (PE-CVD)/radio frequency (RF) sputtering approach, tailoring the overall Pt content as a function of sputtering time. The chemico-physical properties of the as-prepared systems were extensively investigated by means of complementary techniques, including X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), field emission-scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDXS), secondary ion mass spectrometry (SIMS), and optical absorption spectroscopy, and compared to those of the homologous Pt/α-Fe2O3 systems annealed in air prior and/or after sputtering. The obtained results evidenced that the material compositional, structural and morphological features, with particular regard to the Pt oxidation state and hematite nano-organization, could be finely tailored as a function of the adopted processing conditions. Pt/α-Fe2O3 systems were finally tested as photoanodes in photoelectrochemical (PEC) water splitting experiments, evidencing a remarkable interplay between functional performances and the above-mentioned material properties, as also testified by transient absorption spectroscopy (TAS) results.

Long-term efficacy of an imidacloprid 10 % / flumethrin 4.5 % polymer matrix collar (Seresto®, Bayer) against the Australian paralysis tick (Ixodes holocyclus) in dogs.

Two placebo-controlled pen studies were conducted to assess the efficacy of an imidacloprid 10 %/flumethrin 4.5 % polymer matrix collar (Seresto®, Bayer; Investigational Veterinary Product (IVP)) against the Australian paralysis tick (Ixodes holocyclus). Dogs assigned to the placebo (n = 8) or IVP (n ≥ 8) groups had collars (placebo or IVP) attached on Day 0 and were infested with 30 unfed, adult, female I. holocyclus at 14­28 day intervals over 227 days. Ticks were counted 24, 48 and 72 h post infestation to determine the acaricidal efficacy of the IVP. The acaricidal efficacy of the IVP 72 h post infestation exceeded 95 % on Days 17 (99.3 %), 59 (99.7 %), 73 (96.6 %), 87 (100.0 %), 101 (96.4 %), 115 (99.1 %) and 171 (95.8 %), but dropped on Days 45 (94.0 %) and 143 (77.8 %), and declined from Day 199 (79.9 %) to 227 (65.5 %). No adverse events related to treatment were observed. This study has demonstrated the excellent acaricidal efficacy (97.9 %) of the IVP collar against I. holocyclus 72 h post infestation over 16 weeks.

Using excised leaves to screen lucerne for salt tolerance: physiological and cytological evidence.

Salinity affects many physiological processes at all levels of plant structural organization. Being a physiologically and genetically complex trait, salinity tolerance implies a coordinated contribution of multiple mechanisms, making plant screening for salt tolerance extremely difficult. In this work, we show how the use of excised leaves can fulfill that task. We argue that, by adding NaCl directly to the transpiration stream, the protective effects of several mechanisms regulating Na(+) delivery to the shoot are eliminated, enhancing PSII exposure to salinity treatment and resulting in a significant decline in leaf photochemistry (Fv/Fm characteristics). We suggest that measuring Fv/Fm characteristics on excised salt-treated leaves provides an opportunity to evaluate the efficiency of vacuolar Na(+) compartmentation, arguably the most important feature for salt tolerance. We also explain the observed decline in Fv/Fm values as salt-induced structural damage to chloroplasts caused by oxidative stress.

Comparison of Fick and thermodilution cardiac output determinations in standing horses.

The Fick and thermodilution (TD) methods are two currently popular techniques for determination of cardiac output (CO) in adult horses. To our knowledge, a comparison of these two techniques has not been reported. Six healthy, resting, fit, adult horses of either sex and weighing 516.5+/-33.2 kg (mean+/-SD) were instrumented to enable measurement of cardiac output. Resting CO was determined by the Fick method and by thermodilution while the horses stood quietly in the stocks. Fick and thermodilution CO measurements were repeated under conditions of increased cardiac output achieved with the use of a dobutamine infusion (5 microg kg(-1) min(-1), IV), and again under conditions of decreased CO induced by administration of xylazine (0.5 mg/kg, IV). Fick and thermodilution cardiac outputs were compared using Bland-Altman analysis for repeated measures. The mean of the differences+/-1.96SD (bias and precision) between the two techniques was 1.88+/-24.17 L/min. Variability between measurements with the two techniques was decreased to 3.41+/-46.78 mL kg(-1) min(-1) when CO was normalized for body size by calculation of cardiac index.

Auxin-Induced Resistance to Common Scab Disease of Potato Linked to Inhibition of Thaxtomin A Toxicity.

Production of the phytotoxin thaxtomin A by pathogenic Streptomyces spp. is essential for induction of common scab disease in potato. Prior studies have shown that foliar application of sublethal concentrations of 2,4-dichlorophenoxyacetic acid (2,4-D) and other auxin or auxin-like compounds significantly reduced severity and occurrence of common scab in subsequently produced tubers. However, the means of disease suppression by these compounds was not known. We confirm the disease suppressive activity of 2,4-D. Detailed tuber physiological examination showed that lenticel numbers, lenticel external dimensions, and periderm thickness and structure, physiological features believed to be critical to Streptomyces scabiei infection, were not substantially changed by 2,4-D treatments, negating a possible mechanism for disease suppression through alteration of these structures. In contrast, our studies show accumulation of 2,4-D in tubers of treated plants occurs and is associated with an enhanced tolerance to thaxtomin A. Applying 2,4-D to cultures of S. scabiei did not significantly alter in vitro growth of the pathogen. Thaxtomin A production by the pathogen was inhibited by 2,4-D, but only at the highest rate tested (1.0 mM), which is at least 200-fold more than is found in 2,4-D treated tubers. These data suggest 2,4-D has no direct effect on the pathogen or its virulence. Confirmatory evidence from studies with Arabidopsis thaliana seedlings demonstrated that the auxins 2,4-D and IAA ameliorate thaxtomin A toxicity. The evidence presented whereby auxin treatment inhibits toxicity of thaxtomin A secreted by the pathogen suggests a novel indirect means of disease suppression.

Blastomycosis in Missouri: epidemiology and risk factors for endemic disease.

Between 1992 and 1999, 93 cases of blastomycosis, including 25 laboratory confirmed cases, were identified in Missouri (annual incidence, 0.2/100,000 population). Mississippi County in southeastern Missouri had the highest incidence (12/100,000) with a much higher rate among blacks than whites in this county (43.21/100,000). The mortality rate, 44% was also higher among blacks. To determine risk factors for endemic blastomycosis, a case-control study was conducted among southeastern Missouri residents. Independent risk factors for blastomycosis were black race and a prior history of pneumonia. No environmental exposures or socioeconomic factors were significantly associated with increased risk. The increased risk among blacks may possibly be related to genetic factors, but further studies are needed to clarify this. However, heightened awareness of the disease and a better understanding of the risk factors are important and may lead to earlier diagnosis and start of treatment, possibly improving outcome.

The effect of erythromycin on the pharmacokinetics of rosuvastatin.

RATIONALE OBJECTIVE: To examine in vivo the effect of erythromycin on the pharmacokinetics of rosuvastatin [an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase]. Erythromycin is a potent inhibitor of CYP3A4 that markedly increases circulating levels of some other HMG-CoA reductase inhibitors. METHODS: In this randomised, double-blind, two-way cross-over, placebo-controlled trial 14 healthy volunteers were given 500 mg erythromycin or placebo four times daily for 7 days. A single dose of 80 mg rosuvastatin was co-administered on day 4 of dosing. Plasma concentrations of rosuvastatin and active and total HMG-CoA reductase inhibitors were measured up to 96 h after dosing. RESULTS: Eleven volunteers had data available from both dosing periods. There was no increase in rosuvastatin plasma exposure following co-administration with erythromycin compared to placebo. In fact, following co-administration with erythromycin, rosuvastatin geometric least square mean AUC((0-t)) and C(max) were 20% and 31%, respectively, lower than with placebo. Individual treatment ratios for AUC((0-t)) ranged from 0.48 to 1.17, and for C(max) ranged from 0.33 to 2.19. Essentially all of the circulating active HMG-CoA reductase inhibitors and most (>94%) of the total inhibitors were accounted for by rosuvastatin. Erythromycin did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. CONCLUSIONS: Erythromycin did not produce any increase in rosuvastatin plasma exposure. This indicates that CYP3A4 metabolism is not an important clearance mechanism for rosuvastatin, a result consistent with previous findings. The small decreases in rosuvastatin AUC((0-t)) and C(max) that occurred as a consequence of short-term treatment with erythromycin are unlikely to have relevance to long-term treatment with rosuvastatin.

Pharmacokinetics and pharmacodynamics of rosuvastatin in subjects with hepatic impairment.

OBJECTIVE: To assess the effect of chronic hepatic impairment on rosuvastatin disposition, pharmacodynamic activity and tolerability. METHODS: This was an open-label, non-randomised, parallel-group trial. Six subjects were enrolled in each of three hepatic-function strata: Child-Pugh class A (CP-A, mild impairment), Child-Pugh class B (CP-B, moderate impairment) and normal hepatic function; the latter two strata were age, weight, race, sex and smoking history matched. All subjects were given rosuvastatin 10 mg for 14 days. RESULTS: In subjects with CP-A, and in four of six subjects with CP-B, rosuvastatin steady-state AUC(0-24) and C(max) were similar to subjects with normal hepatic function (geometric mean values 60.7 ng h/ml and 6.02 ng/ml, respectively). Two of six subjects with CP-B who had the highest CP scores (i.e. the highest degrees of hepatic impairment) had the highest AUC(0-24) (128 ng h/ml and 242 ng h/ml) and C(max) (23.4 ng/ml and 96.7 ng/ml) values. Low-density lipoprotein cholesterol (LDL-C) was decreased in all strata, but the response was more variable in the CP-B group. Rosuvastatin was well tolerated, and the safety profile was similar in subjects with hepatic impairment and normal hepatic function. CONCLUSION: In most subjects with mild-to-moderate hepatic impairment, the steady-state pharmacokinetics of rosuvastatin were similar to subjects with normal hepatic function (more extensive hepatic impairment may increase systemic exposure to rosuvastatin), and most had LDL-C reductions similar to subjects with normal hepatic function.