Establishment of CD1b-restricted immunity to lipid antigens in the pulmonary response to Mycobacterium tuberculosis infection.

CD1 is an antigen presenting glycoprotein homologous to MHC I; however, CD1 proteins present lipid rather than peptide antigen. CD1 proteins are well established to present lipid antigens of Mycobacterium tuberculosis (Mtb) to T cells, but understanding the role of CD1-restricted immunity in vivo in response to Mtb infection has been limited by availability of animal models naturally expressing the CD1 proteins implicated in human response: CD1a, CD1b and CD1c. Guinea pigs, in contrast to other rodent models, express four CD1b orthologs, and here we utilize the guinea pig to establish the kinetics of gene and protein expression of CD1b orthologs, as well as the Mtb lipid-antigen and CD1b-restricted immune response at the tissue level over the course of Mtb infection. Our results indicate transient upregulation of CD1b expression during the effector phase of adaptive immunity that wanes with disease chronicity. Gene expression indicates that upregulation of CD1b is the result of transcriptional induction across all CD1b orthologs. We show high CD1b3 expression on B cells, and identify CD1b3 as the predominant CD1b ortholog in pulmonary granuloma lesions. We identify ex vivo cytotoxic activity directed against CD1b that closely paralleled the kinetic changes in CD1b expression in Mtb infected lung and spleen. This study confirms that CD1b expression is modulated by Mtb infection in lung and spleen, leading to pulmonary and extrapulmonary CD1b-restricted immunity as a component of the antigen-specific response to Mtb infection.

The Impact of Vitamin A Deficiency on Tuberculosis Progression.

BACKGROUND: Although previous studies have shown that vitamin A deficiency is associated with incident tuberculosis (TB) disease, the direction of the association has not been established. We investigated the impact of vitamin A deficiency on TB disease progression. METHODS: We conducted a longitudinal cohort study nested within a randomized clinical trial among HIV-infected patients in Haiti. We compared serial vitamin A levels in individuals who developed TB disease to controls matched on age, gender, follow-up time, and time to antiretroviral therapy initiation. We also evaluated histopathology, bacterial load, and immune outcomes in TB infection in a guinea pig model of dietary vitamin A deficiency. RESULTS: Among 773 participants, 96 developed incident TB during follow-up, 62.5% (60) of whom had stored serum samples obtained 90-365 days before TB diagnosis. In age- and sex- adjusted and multivariate analyses, respectively, incident TB cases were 3.99 times (95% confidence interval [CI], 2.41 to 6.60) and 3.59 times (95% CI, 2.05 to 6.29) more likely to have been vitamin A deficient than matched controls. Vitamin A-deficient guinea pigs manifested more extensive pulmonary pathology, atypical granuloma morphology, and increased bacterial growth after experimental TB infection. Reintroduction of dietary vitamin A to deficient guinea pigs after established TB disease successfully abrogated severe disease manifestations and altered cellular immune profiles. CONCLUSIONS: Human and animal studies support the role of baseline vitamin A deficiency as a determinant of future TB disease progression.

The use of force plate measurements to titrate the dosage of a new COX-2 inhibitor in lame horses.

REASONS FOR PERFORMING STUDY: Lameness is a highly prevalent condition in horses and the principal cause of removal from athletic activity. In clinical studies to evaluate nonsteroidal anti-inflammatory drug therapies, force plates are commonly used to assess improvement of lameness objectively. HYPOTHESIS: To use a force plate to determine the optimal dose of a new COX-2 inhibitor (firocoxib) that will reduce lameness, when administered orally to horses once daily. METHODS: Sixty-four horses that exhibited chronic lameness presumed due to osteoarthritis, including navicular disease, in at least one of the frontlimbs and at a stable level of severity, were included. Horses were treated per os s.i.d. for 7 days as follows: vehicle control, firocoxib at 0.05, 0.1 or 0.25 mg/kg bwt. Force plate analysis of each horse was done for the selected (most) lame frontlimb at trot. Once between Days -19 and -4 (initial examination), and again on Day -2 or -1 (baseline), pretreatment force plate assessments were performed, and thereafter horses were assessed on Days 0, 2 and 6, approximately 10 h post treatment each time. Peak vertical force (PVF) and lameness grades at initial examination and at baseline, and their change from baseline in the 4 different treatment groups were analysed statistically at a significance level of P < 0.05. RESULTS: The PVF results were found to be superior to vehicle control already at Day 0 for 0.25 mg/kg bwt and at Days 2 and 6 for 0.1 and 0.25 mg/kg bwt (P < 0.05). Mean clinical lameness for both concentrations decreased > 1 grade at Day 6. CONCLUSIONS AND CLINICAL RELEVANCE: With the dosage of 0.25 mg/kg bwt lameness did not improve more than with 0.1 mg/kg bwt. Thus, 0.1 mg/kg bwt s.i.d. was considered to be the effective dose at reducing chronic lameness in horses presumed due to osteoarthritis, including navicular disease.

Effect of repeated oral administration of hypertonic electrolyte solution on equine gastric mucosa.

REASONS FOR PERFORMING STUDY: Electrolyte supplementation is common in horses during endurance competitions, but the effect on the gastric mucosa is unknown. HYPOTHESIS: Repeated oral administration of hypertonic electrolyte solution is associated with exacerbation of gastric ulcers in mature horses. METHODS: The study design was a randomised, blinded, crossover trial. Fourteen horses were divided randomly into equal groups and administered either 60 ml water (placebo) or 56.7 g commercial electrolyte supplement mixed with 60 ml water by dose syringe orally once an hour for 8 h. The minimum concentration of individual constituent electrolytes/28.35 g dry commercial product used was: sodium (5528 mg); chloride (11,886 mg); potassium (3657 mg); calcium (754 mg); and magnesium (153 mg). Gastric lesions were scored prior to and after oral treatments, and analysis of variance procedures were then performed. RESULTS: Administration of hypertonic electrolytes resulted in a significant increase in mean ulcer number (P = 0.0174) and severity (P = 0.0006) scores in the nonglandular stomach. Mean ulcer number score was 3.6 and mean ulcer severity score 2.7 after hypertonic electrolyte treatment. CONCLUSIONS: Oral hypertonic electrolyte administration to horses in this model was associated with exacerbation of gastric ulcers. POTENTIAL RELEVANCE: Our findings suggest that one schedule of electrolyte supplementation used commonly in endurance horses may be harmful to the gastric mucosa.

Comparison of topical lidocaine/prilocaine anesthetic cream and local infiltration of 2% lidocaine for episioplasty in mares.

Local anesthesia and tissue inflammation associated with lidocaine infiltration and lidocaine/prilocaine topical anesthetic cream for episioplasty in mares were compared. Twenty-two mares were randomly assigned to lidocaine or lidocaine/prilocaine topical anesthetic cream treatment groups. Perineum and vulva were cleaned, 8-12 g (approximately 1 g/cm per side of vulva) of topical anesthetic cream was applied, and the area was covered by plastic wrap 30 min prior to beginning procedure. Alternately, lidocaine was injected (1 mL) every centimeter just prior to the procedure. Episioplasty was conducted using standard methods, but employing simple interrupted sutures. Horses were not sedated and use of a twitch was recorded. Four millimeter punch biopsies were harvested 1, 3, and 10 days following episioplasty and scored for degree of inflammation by a blinded pathologist. Clinical inflammation scores were assigned when biopsies were obtained. Seven of 11 horses receiving lidocaine infiltration required twitching, but none of the horses that received the anesthetic cream required twitching. Six of 11 and seven of 11 of the lidocaine and anesthetic cream groups, respectively, required twitching for episioplasty. Except for the clinical scores on day 3, no statistical differences for clinical and histopathologic scores between samples from the two treatment groups for a given day were identified. Use of lidocaine/prilocaine topical anesthetic cream was as effective as lidocaine infiltration in providing local anesthesia when performing episioplasty in mares. Its use decreased the need for twitching horses as well as the risk of deformation of the labia caused by lidocaine infiltration.

Isoxsuprine hydrochloride in the horse: a review.

Isoxsuprine hydrochloride has been suggested for use in horses for treatment of navicular syndrome and laminitis. The drug has been shown to be a beta-adrenoreceptor antagonist with beta-adrenoreceptor agonistic properties, with both characteristics contributing to vasodilation and uterine relaxation. In addition, the drug is capable of decreasing blood viscosity and platelet aggregation. Studies have shown i.v. isoxsuprine to have a plasma half-life of <3 h with a large apparent volume of distribution. Cardiovascular effects resolve rapidly following i.v. administration, but are absent with oral dosing. Oral bioavailability is 2.2% with a high first pass effect. Isoxsuprine has an apparent affinity for melanin that may contribute to extended renal excretion. Clinical trials appear to support the use of isoxsuprine for treatment of navicular disease. However, poor bioavailability, lack of cardiovascular effects following oral administration, superficial support in clinical trials, and new evidence regarding the pathogenesis of navicular syndrome indicate that the use of isoxsuprine for treatment of navicular syndrome or laminitis is questionable at best.

Failure of holmium:yttrium-aluminum-garnet laser lithotripsy in two horses with calculi in the urinary bladder.

Holmium:yttrium-aluminum-garnet (Ho:YAG) laser lithotripsy was attempted in a mare and a gelding with calculi in the urinary bladder. The procedure was unsuccessful in producing adequate fragmentation of the calculi. In the gelding, pulsed dye laser lithotripsy was subsequently used to fragment the urolith. Manual removal of the urolith via the urethra was performed in the mare.

Pharmacokinetics of acetazolimide after intravenous and oral administration in horses.

OBJECTIVE: To determine the pharmacokinetics of acetazolamide administered IV and orally to horses. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Horses received 2 doses of acetazolamide (4 mg/kg of body weight, IV; 8 mg/kg, PO), and blood samples were collected at regular intervals before and after administration. Samples were assayed for acetazolamide concentration by high-performance liquid chromatography, and concentration-time data were analyzed. RESULTS: After IV administration of acetazolamide, data analysis revealed a median mean residence time of 1.71 +/- 0.90 hours and median total body clearance of 263 +/- 38 ml/kg/h. Median steady-state volume of distribution was 433 +/- 218 ml/kg. After oral administration, mean peak plasma concentration was 1.90 +/- 1.09 microg/ml. Mean time to peak plasma concentration was 1.61 +/- 1.24 hours. Median oral bioavailability was 25 +/- 6%. CONCLUSIONS AND CLINICAL RELEVANCE: Oral pharmacokinetic disposition of acetazolamide in horses was characterized by rapid absorption, low bioavailability, and slower elimination than observed initially after IV administration. Pharmacokinetic data generated by this study should facilitate estimation of appropriate dosages for acetazolamide use in horses with hyperkalemic periodic paralysis.

Sexual harassment in the veterinary academic environment.

OBJECTIVE: To survey faculty and house officers of clinical departments of colleges of veterinary medicine (CVM) to identify characteristics of sexual harassment (SH) in the veterinary academic environment, to report the opinions of survey respondents on how SH is being handled, and to determine how the process can be improved at veterinary academic institutions. PROCEDURE: On the basis of lists obtained from 25 CVM, a survey was mailed to 1,294 academic veterinarians. Four hundred seventy-eight completed surveys were returned. RESULTS: The prevalence of SH in the population of respondents was 31%. Nonphysical forms of SH were reported 6 times as often as physical forms of harassment, with the most common type reported being offensive sexual comments and unwanted attention. Fear of reprisal was the most prevalent reason cited by respondents for not confronting the harasser. Survey respondents rated the following as very important to improve the system of dealing with SH at their academic institution: guarantee of protection from retaliation, assurance of confidentiality, clear explanation of what will happen to you, and a clearer definition of SH. CONCLUSION: A clear definition of SH is the first step in preventing SH. Other cited steps include professional development programs to educate the academic population as to what constitutes SH, inform the entire academic population what the institution's SH policy is, and enforce this policy with sensitivity, fairness, confidentiality, and quick resolve to protect the victim.

Effects of omeprazole paste on healing of spontaneous gastric ulcers in horses and foals: a field trial.

A multicentre, blinded, randomised complete-block, field trial was conducted with 140 horses and foals age 4 weeks-28 years to determine if omeprazole paste is effective and safe in promoting healing of spontaneous gastric ulcers under a variety of field conditions and in different breeds and ages of horses. Horses in the study had gastric ulceration as determined by gastroscopy and were divided into replicates of 4 or 5 animals. One horse in each replicate was assigned randomly to receive an empty omeprazole syringe (sham-dosed control) and the remaining horses received omeprazole paste once daily for 28 days. Gastroscopy was repeated at the end of the study. Horses treated with omeprazole had significantly (P < 0.01) more improvement in ulcer scores at the end of the study compared with controls. Ulcers were improved in 32.4 and 99.0% of the control and omeprazole groups, respectively. Ulcers were completely healed in 8.9 and 86.7% of the control and omeprazole groups, respectively. Under typical field conditions, omeprazole was effective at enhancing healing of spontaneous gastric ulcers in horses of a variety of ages and breeds.

Pharmacokinetics of cefepime and comparison with those of ceftiofur in horses.

OBJECTIVE: To determine pharmacokinetics of i.v., i.m., and oral administration of cefepime in horses and to compare pharmacokinetics of i.m. administration of cefepime with those of ceftiofur sodium. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Horses received 3 doses of cefepime (11 mg/kg of body weight, PO; 2.2 mg/kg, i.v.; and 2.2 mg/kg, i.m.) and 1 dose of ceftiofur (2.2 mg/kg, i.m.). Two horses also received L-arginine, p.o. and i.v., at doses identical to those contained in the cefepime dihydrochloride-L-arginine preparations previously administered. Blood samples were collected for 24 hours after administration of cefepime or ceftiofur and were assayed for cefepime and ceftiofur concentrations. RESULTS: Pharmacokinetic analysis of disposition data indicated that i.v. administration data were best described by a 2-compartment open model, whereas i.m. administration data were best described by a 1-compartment absorption model. Median elimination half-life and volume of distribution after i.v. administration of cefepime were 125.7 minutes and 225 ml/kg, respectively. After i.m. administration of cefepime, mean maximal plasma concentration of (8.13 microg/ml) was reached at a mean time of 80 minutes. Absorption of cefepime after i.m. administration was complete, with a median bioavailability of 1.11. Intramuscular administration of ceftiofur resulted in similar mean maximal plasma concentration (7.98 microg/ml) and mean time to this concentration (82 minutes). Cefepime was not detected in samples collected after oral administration. Adverse effects consisting principally of gastrointestinal disturbances were observed after oral and i.m. administration of cefepime and after 1 i.m. administration of ceftiofur. CONCLUSIONS AND CLINICAL RELEVANCE: Cefepime, administered i.v. or i.m. at a dosage of 2.2 mg/kg, every 8 hours is likely to provide effective antibacterial therapy for cefepime-sensitive organisms in horses. Further studies are needed to evaluate adverse effects on the gastrointestinal tract.

A scoring system for gastric ulcers in the horse.

Five investigators familiar with gastric ulcer disease in horses met to establish a scoring system that could be utilised in future studies. Slides of gastric lesions were viewed and discussed and a scoring system established that required the nonglandular and glandular portions of the stomach to be graded separately. Each portion of the stomach (glandular and nonglandular) received a score for number of ulcers present and a score for severity of ulcers which resulted in each stomach receiving 4 separate scores. After the grading system was developed, each investigator independently graded 16 horses with gastric ulcer disease that had been previously recorded on video tape. The results of each investigator's scores were then compared. There was a variability between observers in the scores for severity of both nonglandular and glandular lesions but the variability was not significant. The variability between observers for the number of glandular lesions was also not significant. This implied that there was consistency between the 5 observers in the way severity of lesions was scored and the number of glandular lesions. However, there was a significant variability between observers for the number of nonglandular lesions which implied agreement on this observation was more variable.

Thrombosis resulting in rectal perforation in a horse.

A 12-year-old Quarter Horse gelding was admitted to the veterinary medical teaching hospital with a 2-day history of signs of abdominal pain. Initial findings on physical examination included signs of lethargy, dehydration, diarrhea, and gastric reflux. Results of laboratory testing indicated that the horse had panleukopenia with neutrophilic toxic changes, was dehydrated, and was hypocalcemic. During the first 48 hours of hospitalization, 1 abdominal palpation per rectum and 3 analyses of peritoneal fluid were performed; abnormalities were not detected. A preliminary diagnosis of enterocolitis was made. Salmonella anatum was isolated from the feces. The horse's condition improved during a 5-day period, although left jugular thrombosis did develop. On day 8 of hospitalization, the gelding was found dead. Necropsy revealed acute severe fibrinous peritonitis as the result of vasculitis and thrombosis of the caudal mesenteric artery and its cranial rectal branch with rectal infarction and perforation. Immediate classification of rectal tears and perforation as iatrogenic should be avoided. Ischemic vascular disease is a consideration, and horses with thromboembolic disorders may be at risk for rectal perforations.

Laryngospasm, dysphagia, and emaciation associated with hyperkalemic periodic paralysis in a horse.

An 18-month-old Quarter Horse gelding was examined because of weight loss and dysphagia of 1 month's duration. Clinical signs included lethargy, dehydration, ptyalism, and probable aspiration pneumonia. Severe dyspnea and cyanosis were evident after mild exercise. Endoscopy revealed laryngospasm and pharyngospasm. Because clinical signs and endoscopic findings were suggestive of hyperkalemic periodic paralysis (HPP), acetazolamide treatment was instituted. Marked improvement was observed within 48 hours. The horse was determined to be homozygous for HPP. It is likely that this horse's dysphagia, with resultant weight loss and aspiration pneumonia, were clinical manifestations and consequences of HPP. Regardless of age and serum potassium concentration, HPP should be considered as a differential diagnosis for pharyngeal and laryngeal abnormalities and dysphagia in horses with Quarter Horse breeding.

Hepatic disease associated with administration of tetanus antitoxin in eight horses.

Seven horses developed clinical or subclinical hepatitis 48 to 87 days after administration of tetanus antitoxin. One horse had mildly high hepatic enzyme activity 120 days after inoculation with tetanus antitoxin. The first horse developed signs of depression, lethargy, and anorexia. During hospitalization, signs of hepatoencephalopathy were noticed, and laboratory data were consistent with hepatic disease. Another horse that was found dead had gross and histologic lesions compatible with serum hepatitis. Screening of serum gamma-glutamyltransferase (GGT) and aspartate transaminase activities were used to investigate the remaining horses in the herd. High GGT activities (71 to 206 IU/L) were detected in 5 additional herd members. These horses appeared clinically normal, apart from 2 reports of nasal photosensitization and an aborted fetus. In 3 horses, high serum GGT activity persisted over a 44-day testing period. All affected horses had been given tetanus antitoxin within 12 hours of parturition, and a common source of vaccine was identified for 7 horses. Findings in this group of horses indicate that clinical and subclinical serum hepatitis can develop after administration of tetanus antitoxin.

Mercury toxicosis caused by ingestion of a blistering compound in a horse.

Mercury toxicosis by ingestion was diagnosed in a 3-year-old Quarter Horse mare with a history of anorexia and signs of abdominal discomfort. Ten and 9 days prior to admission, an inorganic mercuric blistering agent has been applied for topical treatment of dorsal metacarpal disease. At referral, signs of depression, dependent edema, pollakiuria, nonproductive cough, and oral ulceration were noticed. Laboratory data were consistent with renal dysfunction. Mercury content of blood and urine was high, confirming the diagnosis. The horse responded to intensive care, consisting primarily of IV fluid treatment, and mercury-chelating agents. However, acute laminitis developed, and the owners elected to euthanatize the horse 18 days after mercury exposure. Necropsy findings included renal tubulonephrosis and ulcerative colitis and enteritis. Mercury concentration was highest in kidney and liver tissues. The potential for mercury toxicosis in horses currently exists, and although the prognosis is grave, some horses may recover with appropriate treatment and long-term supportive medical care.

Transendoscopic electrocautery-induced gastric ulcers as a model for gastric healing studies in ponies.

The ponies were apparently healthy and 6-20 months of age. In Study 1, gastric lesions were created by transendoscopic electrocautery in the non-glandular gastric mucosa, adjacent to the margo plicatus in 9 ponies which were then treated with water, 12 mg cimetidine HCl/kg bwt or 18 mg cimetidine HCl/kg bwt per os every 12 h for 35 days. In Study 2, gastric lesions were similarly induced in 9 ponies in the non-glandular mucosa and also in the glandular mucosa just below the non-glandular lesion on the greater curvature of the stomach. The ponies were treated with water, 8 mg cimetidine/kg bwt or 16 mg cimetidine/kg bwt per os every 8 h for 21 days. In both studies gastric lesion healing was monitored twice weekly by video gastroscopy. There was no apparent difference in healing times between the water and cimetidine treatment groups in either study. These results indicate that uniform gastric ulcers can be created by transendoscopic electrocautery in the non-glandular mucosa of ponies and that these ulcers heal at a predictable rate which should be useful in studying compounds that might accelerate healing of gastric mucosal lesions. However, cimetidine was not effective in accelerating the rate of healing under the conditions of this study.

Pneumocystis carinii pneumonia in foals.

Pneumocystis carinii pneumonia was diagnosed in 3 foals. In 2 foals (No. 1 and 2), diagnosis was by histologic evaluation of pulmonary tissue. On retrospective evaluation, P carinii cysts were found on sediment smears of bronchoalveolar lavage fluid in 1 foal (No. 1). A different foal (No. 3) was diagnosed as having pneumocytosis by finding P carinii cysts in bronchoalveolar lavage fluid, and was treated successfully. Definitive diagnosis of pneumocytosis in animals is usually made at necropsy. However, careful cytologic evaluation in bronchoalveolar lavage fluid sediment can provide a diagnosis in some cases, allowing for initiation of appropriate treatment.