Virginia R. Fajt

Analgesic drug administration and attitudes about analgesia in cattle among bovine practitioners in the United States

OBJECTIVE To determine current attitudes and practices related to pain and analgesia in cattle among US veterinarians in bovine practice and to identify factors associated with these attitudes and practices. DESIGN Web-based survey. Sample-3,019 US members of the American Association of Bovine Practitioners (AABP) with e-mail addresses. PROCEDURES Veterinarians were invited via e-mail to participate in a Web-based survey. Respondents replied to questions related to pain and analgesia and supplied personal, professional, and demographic information. Descriptive statistical analysis was performed, and associations among various factors were examined. RESULTS 666 surveys (25.5% response rate) were analyzed. Among common procedures and medical conditions of cattle listed on the survey, castration of dairy calves < 6 months old was subjectively estimated as causing the least pain; abdominal surgery, toxic mastitis, and dehorning of calves > 6 months old were assessed as causing the greatest pain. Respondents reported not providing analgesic drugs to approximately 70% of calves castrated at < 6 months of age. The most commonly administered analgesics were NSAIDs, local anesthetics, and α(2)-adrenergic receptor agonists. Significant associations were detected among respondent characteristics and pain ratings, percentages of cattle treated, and opinions regarding analgesia. CONCLUSIONS AND CLINICAL RELEVANCE Results provide information on current attitudes and practices related to pain and analgesia in cattle among US veterinarians in bovine practice and can be considered in the development of policies and protocols for pain management in cattle. These data can be compared with those of future studies to examine changes over time.

effect of mir-142-3p on the M2 Macrophage and therapeutic efficacy Against Murine Glioblastoma

BACKGROUND The immune therapeutic potential of microRNAs (miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis. METHODS An miRNA microarray was used to compare expression profiles between human glioblastoma-infiltrating macrophages and matched peripheral monocytes. The effects of miR-142-3p on phenotype and function of proinflammatory M1 and immunosuppressive M2 macrophages were determined. The therapeutic effect of miR-142-3p was ascertained in immune-competent C57BL/6J mice harboring intracerebral GL261 gliomas and in genetically engineered Ntv-a mice bearing high-grade gliomas. Student t test was used to evaluate the differences between ex vivo datasets. Survival was analyzed with the log-rank test and tumor sizes with linear mixed models and F test. All statistical tests were two-sided. RESULTS miR-142-3p was the most downregulated miRNA (approximately 4.95-fold) in glioblastoma-infiltrating macrophages. M2 macrophages had lower miR-142-3p expression relative to M1 macrophages (P = .03). Overexpression of miR-142-3p in M2 macrophages induced selective modulation of transforming growth factor beta receptor 1, which led to subsequent preferential apoptosis in the M2 subset (P = .01). In vivo miR-142-3p administration resulted in glioma growth inhibition (P = .03, n = 5) and extended median survival (miR-142-3p-treated C57BL/6J mice vs scramble control: 31 days vs 23.5 days, P = .03, n = 10; miR-142-3p treated Ntv-a mice vs scramble control: 32 days vs 24 days, P = .03, n = 9), with an associated decrease in infiltrating macrophages (R (2) = .303). CONCLUSIONS These data indicate a unique role of miR-142-3p in glioma immunity by modulating M2 macrophages through the transforming growth factor beta signaling pathway.

Comparison of three treatment regimens for sheep and goats with caseous lymphadenitis.

OBJECTIVE To compare the effectiveness of 3 treatment regimens for small ruminants with caseous lymphadenitis. DESIGN Randomized clinical trial. ANIMALS 44 client-owned sheep and goats. PROCEDURES Aspirates were obtained from 48 lesions of 44 enrolled animals and submitted for bacterial culture. Animals were randomly assigned to 1 of 3 treatment groups. Treatment for group A (n = 15 lesions) consisted of opening, draining, and flushing the lesions and SC administration of procaine penicillin G. Treatment for group B (n = 15 lesions) consisted of closed-system lavage and intralesional administration of tulathromycin. Treatment for group C (n = 18 lesions) consisted of closed-system lavage and SC administration of tulathromycin. All animals were reexamined approximately 1 month after treatment, unless treatment failure was detected prior to that time. RESULTS 43 animals with lesions had positive results (Corynebacterium pseudotuberculosis) for bacterial culture. Proportions of lesions that had resolution of infection by 1 month after treatment did not differ significantly among the treatment groups (group A, 13/14 [92.9%]; 95% confidence interval [CI], 69.5% to 99.6%; group B, 10/12 [83.3%]; 95% CI, 54.9% to 97.1%; and group C, 14/17 [82.4%]; 95% CI, 59.1% to 95.3%). CONCLUSIONS AND CLINICAL RELEVANCE Acceptable alternatives to opening, draining, and flushing of lesions may exist for treatment of sheep and goats with caseous lymphadenitis. Use of tulathromycin and penicillin in this study constituted extralabel drug use, which would require extended withholding times before milk or meat of treated sheep and goats can be sold for human consumption.

Antimicrobial Issues in Bovine Lameness

This article reviews some of the issues surrounding antimicrobial use in treating diseases that cause lameness in cattle. The discussion includes sections on selection of an antimicrobial, regimen design, and medication of multiple animals. Pathogen susceptibility testing is covered, along with empiric selection of antimicrobials. Other issues covered include regional perfusion and topical application of antimicrobials, antimicrobials in footbaths and in feed, and withdrawal time estimates.

Efficacy of a Metalloproteinase Inhibitor in Spinal Cord Injured Dogs

Matrix metalloproteinase-9 is elevated within the acutely injured murine spinal cord and blockade of this early proteolytic activity with GM6001, a broad-spectrum matrix metalloproteinase inhibitor, results in improved recovery after spinal cord injury. As matrix metalloproteinase-9 is likewise acutely elevated in dogs with naturally occurring spinal cord injuries, we evaluated efficacy of GM6001 solubilized in dimethyl sulfoxide in this second species. Safety and pharmacokinetic studies were conducted in naïve dogs. After confirming safety, subsequent pharmacokinetic analyses demonstrated that a 100 mg/kg subcutaneous dose of GM6001 resulted in plasma concentrations that peaked shortly after administration and were sustained for at least 4 days at levels that produced robust in vitro inhibition of matrix metalloproteinase-9. A randomized, blinded, placebo-controlled study was then conducted to assess efficacy of GM6001 given within 48 hours of spinal cord injury. Dogs were enrolled in 3 groups: GM6001 dissolved in dimethyl sulfoxide (n = 35), dimethyl sulfoxide (n = 37), or saline (n = 41). Matrix metalloproteinase activity was increased in the serum of injured dogs and GM6001 reduced this serum protease activity compared to the other two groups. To assess recovery, dogs were a priori stratified into a severely injured group and a mild-to-moderate injured group, using a Modified Frankel Scale. The Texas Spinal Cord Injury Score was then used to assess long-term motor/sensory function. In dogs with severe spinal cord injuries, those treated with saline had a mean motor score of 2 (95% CI 0–4.0) that was significantly (P<0.05; generalized linear model) less than the estimated mean motor score for dogs receiving dimethyl sulfoxide (mean, 5; 95% CI 2.0–8.0) or GM6001 (mean, 5; 95% CI 2.0–8.0). As there was no independent effect of GM6001, we attribute improved neurological outcomes to dimethyl sulfoxide, a pleotropic agent that may target diverse secondary pathogenic events that emerge in the acutely injured cord.

Pharmacokinetics of an orally administered methylcellulose formulation of gallium maltolate in neonatal foals

Gallium is a trivalent semi-metal with anti-microbial effects because of its incorporation into crucial iron-dependent reproductive enzyme systems. Gallium maltolate (GaM) provides significant gallium bioavailability to people and mice following oral administration and to neonatal foals following intragastric administration. To study the prophylactic and therapeutic effects of GaM against Rhodococcus equi pneumonia in foals, we developed a methylcellulose formulation of GaM (GaM-MCF) for oral administration to neonatal foals. Normal neonatal foals were studied. Six foals received 20 mg/kg and another six foals received 40 mg/kg of GaM-MCF orally. Serial serum samples were collected and serum gallium concentrations were determined using inductively coupled plasma mass spectroscopy. Gallium was rapidly absorbed (T(max) of 4 h), and a mean C(max) of 0.90 or 1.8 microg/mL was achieved in foals receiving 20 or 40 mg/kg respectively. Marked variability existed in C(max) among foals: only half of the foals receiving 20 mg/kg attained serum concentrations of >0.7 microg/mL, a level suggested to be therapeutic against R. equi by previous studies. Mean elimination half-life was 32.8 or 32.4 h for foals receiving 20 or 40 mg/kg respectively. The results of this study suggest that at least 30 mg/kg orally every 24 h should be considered in future pharmacodynamic and efficacy studies.

Prevalence and patterns of antimicrobial resistance in Campylobacter spp isolated from pigs reared under antimicrobial-free and conventional production methods in eight states in the Midwestern United States

OBJECTIVE To compare apparent prevalence and patterns of antimicrobial resistance in Campylobacter spp in feces collected from pigs reared with antimicrobial-free versus conventional production methods in 8 states in the Midwestern United States. DESIGN Cross-sectional study. SAMPLE POPULATION 95 swine farms that used antimicrobial-free (n = 35) or conventional (60) production methods. PROCEDURES Fecal samples from 15 pigs/farm were collected. Biochemical and multiplex-PCR analyses were used to identify Campylobacter spp. The minimal inhibitory concentrations of erythromycin, azithromycin, ciprofloxacin, nalidixic acid, gentamicin, and tetracycline for these organisms were determined by use of a commercially available antimicrobial gradient strip. The data were analyzed by use of population-averaged statistical models. RESULTS Campylobacter spp were isolated from 512 of 1,422 pigs. A subset (n = 464) of the 512 isolates was available for antimicrobial susceptibility testing. The apparent prevalence of Campylobacter spp isolates from pigs on conventional farms (35.8%) and antimicrobial-free farms (36.4%) did not differ significantly. Resistances to azithromycin, erythromycin, and tetracycline were significantly higher on conventional farms (70.0%, 68.3%, and 74.5%, respectively) than antimicrobial-free farms (20.1%, 21.3%, and 48.8%, respectively). Resistances to azithromycin, erythromycin, and tetracycline declined as the number of years that a farm was antimicrobial-free increased. CONCLUSIONS AND CLINICAL RELEVANCE Production method did not affect the apparent prevalence of Campylobacter spp on swine farms. However, antimicrobial-free farms had a significantly lower prevalence of antimicrobial resistance. Although cessation of antimicrobial drug use will lower resistance over time, investigation of other interventions designed to reduce resistance levels is warranted.

Label and Extralabel Drug use in Small Ruminants

The small ruminant practitioner has a small arsenal of approved drugs in the United States, so the practitioner must be familiar with the laws and regulations related to extra label use. Drugs can be used extra label in food animals only under specific circumstances and can be used only for therapeutic purposes. Drugs that are illegal in small ruminants include chloramphenicol; clenbuterol; diethylstilbestrol; dimetridazole, ipranidazole, and other nitroimidazoles such as metronidazole; dipyrone; fluoroquinolones; glycopeptides; nitrofurans; furazolidone; and extra label use of medication in feed. It is also illegal to use any drug that results in residues above established tolerances or safe levels.

Cilostazol blocks pregnancy in naturally cycling mice

BACKGROUND Administration of a phosphodiesterase three enzyme inhibitor (PDE3-I) in rodents and primates results in ovulation of immature oocytes. Concerns regarding inhibition of PDE3 enzymes that are expressed in heart and blood vessels discouraged further development of PDE3-Is as nonsteroidal contraceptives. Cilostazol (CLZ) is a PDE3A-I that is approved for medical indications in humans and has an additional effect of adenosine uptake inhibition that is believed to counterbalance the undesirable outcomes resulting from PDE inhibition. STUDY DESIGN Cycling mature female mice were treated with 7.5 or 15 mg CLZ, dimethyl sulfoxide or water beginning on the day of proestrus. Animals were placed with fertility-proven males after 3 days of treatment. Treatments were continued until 1 day after detection of a vaginal plug, and then females were monitored up to 30 days postbreeding to assess the effects of the compounds on pregnancy. Each of the treated female with CLZ was then remated with the same male and again monitored up to 30 days. RESULTS None of the CLZ-treated mice produced offspring, whereas all of the control animals maintained pregnancy and delivered normal pups (p<.0001). Remating of the previously CLZ-treated females exhibited normal pregnancies and gave birth to live offspring that were not different from the controls. CONCLUSION CLZ is a potential nonsteroidal contraceptive agent that merits further evaluation in other mammals.

The effect of intramuscular injection of dinoprost or gonadotropin-releasing hormone in dairy cows on beef quality

Intramuscular injections of drugs and vaccines cause tissue damage and subsequent effects on tenderness and consumer acceptability of beef. In the 2007 National Market Cow and Bull Beef Quality Audit, 100% of plants reported fabricating subprimal cuts such as rib eyes and tenderloins from cow and bull carcasses. Dairy beef quality should therefore be a consideration when injections are given to dairy animals. The discussion about injection site reactions and tenderness has focused on vaccines and antimicrobial drugs with little concern for the effects of reproductive hormones. The objective of this study was to quantify antemortem the effects of semimembranosis/semitendinosis muscle injection of dinoprost and GnRH in lactating dairy cows by estimating the weight of tissue damaged and comparing that with a drug known to cause extensive tissue damage, flunixin meglumine. Tissue damage was estimated from previously reported equations for grams of muscle tissue damage based on area under the curve of serum concentrations of the muscle enzyme creatine kinase over time. Dinoprost and flunixin injection both caused a significantly increased estimate of muscle tissue damaged compared with needle only (P = 0.0351 and 0.0355, respectively). Dinoprost and flunixin caused a marginally significant increased muscle tissue damage compared with GnRH (P = 0.1394 and 0.1475, respectively). No statistically significant difference was found between the estimated weight of muscle tissue damaged by flunixin compared with dinoprost (P = 1.0000), or by saline compared with GnRH (P = 0.7736) or needle only (P = 0.4902). The assumption that reproductive hormones are less damaging than vaccines and antimicrobial drugs should be examined more closely, including postmortem evaluation of injection site lesions and effects on tenderness.