Accelerators: Sparking Innovation and Transdisciplinary Team Science in Disparities Research.

Development and implementation of effective, sustainable, and scalable interventions that advance equity could be propelled by innovative and inclusive partnerships. Readied catalytic frameworks that foster communication, collaboration, a shared vision, and transformative translational research across scientific and non-scientific divides are needed to foster rapid generation of novel solutions to address and ultimately eliminate disparities. To achieve this, we transformed and expanded a community-academic board into a translational science board with members from public, academic and private sectors. Rooted in team science, diverse board experts formed topic-specific "accelerators", tasked with collaborating to rapidly generate new ideas, questions, approaches, and projects comprising patients, advocates, clinicians, researchers, funders, public health and industry leaders. We began with four accelerators-digital health, big data, genomics and environmental health-and were rapidly able to respond to funding opportunities, transform new ideas into clinical and community programs, generate new, accessible, actionable data, and more efficiently and effectively conduct research. This innovative model has the power to maximize research quality and efficiency, improve patient care and engagement, optimize data democratization and dissemination among target populations, contribute to policy, and lead to systems changes needed to address the root causes of disparities.

Development of a physiologically based pharmacokinetic model for flunixin in cattle (Bos taurus).

Frequent violation of flunixin residues in tissues from cattle has been attributed to non-compliance with the USFDA-approved route of administration and withdrawal time. However, the effect of administration route and physiological differences among animals on tissue depletion has not been determined. The objective of this work was to develop a physiologically based pharmacokinetic (PBPK) model to predict plasma, liver and milk concentrations of flunixin in cattle following intravenous (i.v.), intramuscular (i.m.) or subcutaneous (s.c.) administration for use as a tool to determine factors that may affect the withdrawal time. The PBPK model included blood flow-limited distribution in all tissues and elimination in the liver, kidney and milk. Regeneration of parent flunixin due to enterohepatic recirculation and hydrolysis of conjugated metabolites was incorporated in the liver compartment. Values for physiological parameters were obtained from the literature, and partition coefficients for all tissues but liver and kidney were derived empirically. Liver and kidney partition coefficients and elimination parameters were estimated for 14 pharmacokinetic studies (including five crossover studies) from the literature or government sources in which flunixin was administered i.v., i.m. or s.c. Model simulations compared well with data for the matrices following all routes of administration. Influential model parameters included those that may be age or disease-dependent, such as clearance and rate of milk production. Based on the model, route of administration would not affect the estimated days to reach the tolerance concentration (0.125 mg kg(-1)) in the liver of treated cattle. The majority of USDA-reported violative residues in liver were below the upper uncertainty predictions based on estimated parameters, which suggests the need to consider variability due to disease and age in establishing withdrawal intervals for drugs used in food animals. The model predicted that extravascular routes of administration prolonged flunixin concentrations in milk, which could result in violative milk residues in treated cattle.

Effects of exogenous sphinganine, sphingosine, and sphingosine-1-phosphate on relaxation and contraction of porcine thoracic aortic and pulmonary arterial rings.

Fumonisin mycotoxicosis in pigs causes a decrease in mean aortic pressure, an increase in mean pulmonary arterial pressure, and increases in serum concentrations of sphinganine (3.2 microM) and sphingosine (1.4 microM). To determine a causal relationship between the hemodynamic changes and sphingolipid alterations, we examined the in vitro effects of sphinganine, sphingosine, and sphingosine-1-phosphate on porcine aortic and pulmonary arterial rings. Both sphinganine and sphingosine relaxed un-contracted and phenylephrine-contracted aortic rings at > or = 10 microM and > or = 1 microM, respectively. Sphingosine (> or = 10 microM) relaxed un-contracted and phenylephrine-contracted pulmonary arterial rings, whereas sphingosine-1-phosphate (10 microM) contracted pulmonary arterial rings. Sphingosine (3 microM) also impaired the contractile response of pulmonary artery rings to 60 mM KCl. The results suggested that the systemic hypotension caused by fumonisin is mediated, in part, by increases in serum sphinganine and sphingosine concentrations, and the pulmonary hypertension is mediated, in part, by increased sphingosine-1-phosphate concentrations.

Effects of intravenous hyperosmotic sodium bicarbonate on arterial and cerebrospinal fluid acid-base status and cardiovascular function in calves with experimentally induced respiratory and strong ion acidosis.

The objectives of this study were to determine the effects of hyperosmotic sodium bicarbonate (HSB) administration on arterial and cerebrospinal fluid (CSF) acid-base balance and cardiovascular function in calves with experimentally induced respiratory and strong ion (metabolic) acidosis. Ten healthy male Holstein calves (30-47 kg body weight) were instrumented under halothane anesthesia to permit cardiovascular monitoring and collection of blood samples and CSE Respiratory acidosis was induced by allowing the calves to spontaneously ventilate, and strong ion acidosis was subsequently induced by i.v. administration of L-lactic acid. Calves were then randomly assigned to receive either HSB (8.4% NaHCO3; 5 ml/kg over 5 minutes, i.v.; n=5) or no treatment (controls, n=5) and monitored for 1 hour. Mixed respiratory and strong ion acidosis was accompanied by increased heart rate, cardiac index, mean arterial pressure, cardiac contractility (maximal rate of change of left ventricular pressure), and mean pulmonary artery pressure. Rapid administration of HSB immediately corrected the strong ion acidosis, transiently increased arterial partial pressure of carbon dioxide (P(CO2)), and expanded the plasma volume. The transient increase in arterial P(CO2) did not alter CSF P(CO2) or induce paradoxical CSF acidosis. Compared to untreated control calves, HSB-treated calves had higher cardiac index and contractility and a faster rate of left ventricular relaxation for 1 hour after treatment, indicating that HSB administration improved myocardial systolic function. We conclude that rapid i.v. administration of HSB provided an effective and safe method for treating strong ion acidosis in normovolemic halothane-anesthetized calves with experimentally induced respiratory and strong ion acidosis. Fear of inducing paradoxical CSF acidosis is not a valid reason for withholding HSB administration in calves with mixed respiratory and strong ion acidosis.

Abdominal fat necrosis in a pygmy goat associated with fescue toxicosis.

Abdominal fat necrosis was diagnosed in an 11-year-old female pygmy goat with a 10-day history of lethargy, anorexia, and progressive abdominal distension. Gross necropsy findings revealed multiple firm, dark yellow, nodular masses of fat throughout the abdominal cavity, which compressed several abdominal organs including the rumen, small intestine, spiral colon, and gall bladder. Histologically, multiple to coalescing adipocyte necrosis, saponification, and infiltration with variable numbers of macrophages, lymphocytes, and plasma cells was observed. Fat necrosis in this case was attributed to tall fescue toxicity based on the presence of high levels of endophyte (Neotyphodium coenophialum)-infected fescue identified in the goat's pasture. This is the first known report of abdominal fat necrosis in a goat and demonstrates the fat necrosis syndrome of fescue toxicosis in ruminants.

Neurologic abnormalities and cerebrospinal fluid changes in horses administered fumonisin B1 intravenously.

The objective of this experiment was to characterize a dose-dependent toxic effect of fumonisin B1 (FB1) and to document initial neurologic signs, clinical progression, and terminal cerebrospinal fluid (CSF) changes in horses administered FB1 IV. Seventeen healthy horses were administered 0.00 (n = 4), 0.01 (n = 3), 0.05 (n = 3), 0.10 (n = 3), or 0.20 mg (n = 4) of purified FB1 IV q24h. When neurologic abnormalities observed by a masked observer became severe, atlanto-occipital CSF taps were performed and CSF pressure, cell count, cytology, protein, albumin and glucose concentrations, and creatine kinase activity were measured. Changes in CSF and number of days to 1st observation of neurologic abnormalities were compared between doses by ANOVA, with the level of significance set at P < .05. Control horses and low-dose horses (0.01 mg/kg) remained neurologically normal. In higher dose FB1-treated horses (n = 10), initial clinical signs (days 4-10) included hindlimb ataxia, delayed forelimb placing, and decreased tongue tone and movement. Hindlimb and trunkal ataxia, depression, hyperesthesia, and intermittent dementia gradually became apparent. When data from all horses with neurologic abnormalities were pooled (0.05-0.20 mg/kg FB1), mild clinical signs (mean day 6.3) occurred significantly earlier than did more severe (mean day 8.9) clinical signs (P = .009). Neurologic horses had high CSF protein, albumin, and IgG concentrations and increased albumin quotients (P < .05). It was concluded that FB1-induced neurologic and CSF changes in a dose-dependent manner, with a no-observable-limit of 0.01 mg FB1/kg IV q24h for 28 days. The neurologic and CSF changes were consistent with vasogenic cerebral edema.

The effects of oral magnesium hydroxide administration on rumen fluid in cattle.

This study was conducted to determine the effects of oral magnesium hydroxide administration on rumen fluid in cattle. Six lactating Holstein cows (4-7 years of age) with rumen fistulas were studied. Cattle were randomly assigned to receive boluses of magnesium hydroxide (162 g) or a powdered form (450 g dissolved in 3.5 L of water) PO daily for 3 days. Analysis of rumen fluid, blood gas tensions, and pH and measurement of serum magnesium concentrations were conducted daily. The study was discontinued after 72 hours, or sooner if rumen pH exceeded 8.0. After at least 3 weeks, the study was repeated with each cow receiving the other form of magnesium hydroxide (powder or bolus). Compared with baseline rumen pH (mean +/- SD: 6.22 +/- 0.28), magnesium hydroxide boluses caused a significant increase (P < .05) in rumen pH after 48 (7.27 +/- 0.11) and 72 (8.01 +/- 0.16) hours of administration, whereas the powdered form caused a significant increase (P < .05) in rumen pH after 24 (7.54 +/- 0.19) and 48 (8.43 +/- 0.22) hours of administration. Both the powdered and bolus forms of magnesium hydroxide decreased rumen protozoal numbers and increased methylene blue reduction times compared with baseline values. There was no change in blood pH, bicarbonate, or base excess values. Serum magnesium concentrations were significantly increased (P < .05) in cows that received the magnesium hydroxide powder. The results of this study indicate that magnesium hydroxide has a potent alkalinizing effect on rumen pH and significantly decreases rumen microbial activity.

Fumonisin-induced blockade of ceramide synthase in sphingolipid biosynthetic pathway alters aortic input impedance spectrum of pigs.

The sphingolipid signaling pathway appears to play an important role in regulating vascular tone. We examined the effect of fumonisin B(1), a fungal toxin in corn that blocks ceramide synthase in the sphingolipid signaling pathway, on the ascending aortic impedance spectrum of pigs. Sixteen pigs were fed culture material containing fumonisin B(1) (20 mg/kg body wt) (n = 7) or a control diet (n = 9) daily for 3 days and then instrumented under alpha-chloralose anesthesia for measurement of ascending aortic pressure and flow. Fumonisin ingestion increased serum sphinganine and sphingosine concentrations. Fumonisin ingestion also decreased cardiac output and characteristic impedance and increased the frequency of the first minimum impedance modulus, systemic vascular resistance, and the terminal, first, and second harmonic reflection coefficients, without changing mean arterial pressure. Thus blockade of ceramide synthase is accompanied by decreased vascular tone in systemic conduit arteries and increased vascular tone in systemic resistance vessels. The results indicate that the sphingolipid signaling pathway influences vascular tone in alpha-chloralose-anesthetized pigs.

Suspected pokeweed toxicity in a boer goat.

A 5-y-old Boer goat buck was presented to a University veterinary hospital with a history of acute bloody diarrhea. Pokeweed toxicitywas diagnosed from history of plant ingestion and by ruling out other possible diagnoses. The goat responded to supportive therapy and was discharged after 4 d.

Atypical parapoxvirus infection in sheep.

This report describes the clinical and laboratory findings for 5 sheep from 3 different flocks with extensive proliferative skin lesions grossly resembling warts on the distal limbs. The lesions affected the front and rear extremities in all sheep, and 2 sheep also had lesions around the head. The sheep exhibited signs of pain when the lesions were touched, and most sheep were reluctant to move. Various empirical treatments, including systemic antibiotics, topical antibiotics, and antifungal ointments, were administered without clinical improvement. Diagnostic tests including skin biopsy and histopathology, examination of skin scrapings, bacteriology, mycology, electron microscopy of lesions, and immunohistochemical analysis demonstrated that the lesions were the result of parapoxvirus infection. All 5 animals were euthanized either because of the lack of resolution of clinical signs or a decision by the owner. These animals illustrate an atypical presentation of parapoxvirus infection in sheep (orf, contagious ecthyma, and scabby mouth). The infection appeared to be minimally contagious; however, the lesions did not spontaneously resolve. This appears to be the 1st report of such lesions in multiple sheep in North America, although similar lesions have been reported in Israel and the United Kingdom.

Cardiovascular changes associated with intravenous administration of fumonisin B1 in horses.

OBJECTIVE: To determine whether cardiovascular dysfunction is evident in horses with leukoencephalomalacia experimentally induced by administration of fumonisin B1. ANIMALS: 11 healthy horses of various breeds (body weight, 252 to 367 kg). PROCEDURE: Horses were randomly assigned to 3 groups and administered fumonisin B1 daily. Horses received IV injections of 0 (control horses; n = 4), 0.01 (3), or 0.20 mg (4) of fumonisin B1/kg for 7 to 28 days. Horses were examined daily for evidence of neurologic disease. When neurologic signs consistent with leukoencephalomalacia were evident, horses were anesthetized, and catheters were inserted for evaluation of the cardiovascular system. After recovery from anesthesia, hemodynamic measurements were obtained. RESULTS: Fumonisin-treated horses with clinical signs of neurologic disease had evidence of cardiovascular dysfunction manifested as decreases in heart rate, cardiac output, right ventricular contractility (assessed by measuring the maximal rate of change of right ventricular pressure), coccygeal artery pulse pressure, and pH and base excess in venous blood as well as increases in systemic vascular resistance, compared with values for control horses. Fumonisin-treated horses with and without clinical signs of neurologic disease also had higher serum and right ventricular sphinganine and sphingosine concentrations than control horses. CONCLUSIONS AND CLINICAL RELEVANCE: An association was detected among fumonisin-induced neurologic disease, increased serum and myocardial sphinganine and sphingosine concentrations, and decreased cardiovascular function in horses. Fumonisin-induced decreases in cardiovascular function may contribute to the pathophysiologic development of leukoencephalomalacia in horses.