Publications by authors named "Alonso Guedes"

32 Publications

Novel Pathway of Adenosine Generation in the Lungs from NAD: Relevance to Allergic Airway Disease.

Molecules 2020 Oct 27;25(21). Epub 2020 Oct 27.

Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.

Adenosine and uric acid (UA) play a pivotal role in lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). In the present experiments, we measured adenosine synthesis from nicotinamide adenine dinucleotide (NAD) in membranes prepared from wild type (WT) and CD38 knockout (CD38KO) mouse lungs, from cultured airway smooth muscle and epithelial cells, and in bronchoalveolar lavage fluid after airway challenge with epidemiologically relevant allergens. Adenosine was determined using an enzymatically coupled assay that produces ATP and is detected by luminescence. Uric acid was determined by ELISA. Exposure of cultured airway epithelial cells to extract caused significant nucleotide (NAD and ATP) release in the culture media. The addition of NAD to membranes prepared from WT mice resulted in faster generation of adenosine compared to membranes from CD38KO mice. Formation of adenosine from NAD affected UA and ATP concentrations, its main downstream molecules. Furthermore, NAD and adenosine concentrations in the bronchoalveolar lavage fluid decreased significantly following airway challenge with house-dust mite extract in WT but not in CD38KO mice. Thus, NAD is a significant source of adenosine and UA in the airways in mouse models of allergic airway disease, and the capacity for their generation from NAD is augmented by CD38, a major NADase with high affinity for NAD. This novel non-canonical NAD-adenosine-UA pathway that is triggered by allergens has not been previously described in the airways.
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http://dx.doi.org/10.3390/molecules25214966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663290PMC
October 2020

Owner evaluation of quality of life and mobility in osteoarthritic cats treated with amantadine or placebo.

J Feline Med Surg 2021 Jun 28;23(6):568-574. Epub 2020 Oct 28.

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA.

Objectives: The aim of the study was to determine if amantadine improves owner-identified mobility impairment and quality of life associated with osteoarthritis in cats.

Methods: Using a blinded, placebo-controlled, randomized, crossover design, 13 healthy client-owned cats with clinical and radiographic evidence of osteoarthritis and owner-identified mobility impairment were studied. Cats received 5 mg/kg amantadine or placebo q24h PO for 3 weeks each with no washout period in between. Locomotor activity was continuously assessed with a collar-mounted activity monitor system, and owners chose and rated two mobility-impaired activities using a client-specific outcome measures (CSOM) questionnaire on a weekly basis. Locomotor activity on the third treatment week was analyzed with two-tailed paired -tests. The CSOM scores were analyzed using a mixed-effect model and the Bonferroni post-hoc test. Owner-perceived changes in quality of life were compared between treatments using the χ test. Statistical significance was set at 0.05.

Results: Mean ± SD activity counts during the third week of each treatment were significantly lower with amantadine (240,537 ± 53,880) compared with placebo (326,032 ± 91,759). CSOM scores assigned by the owners were significantly better with amantadine on the second (3 ± 1) and third (3 ± 1) weeks compared with placebo (5 ± 2 and 5 ± 1, respectively). A significantly greater proportion of owners reported improvement in quality of life with amantadine compared with placebo.

Conclusions And Relevance: Amantadine significantly decreased activity, but improved owner-identified impaired mobility and owner-perceived quality of life in cats with osteoarthritis. Amantadine appears to be an option for the symptomatic treatment of osteoarthritis in cats.
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http://dx.doi.org/10.1177/1098612X20967639DOI Listing
June 2021

Selection of Potent Inhibitors of Soluble Epoxide Hydrolase for Usage in Veterinary Medicine.

Front Vet Sci 2020 26;7:580. Epub 2020 Aug 26.

Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States.

The veterinary pharmacopeia available to treat pain and inflammation is limited in number, target of action and efficacy. Inhibitors of soluble epoxide hydrolase (sEH) are a new class of anti-inflammatory, pro-resolving and analgesic drugs being tested in humans that have demonstrated efficacy in laboratory animals. They block the hydrolysis, and thus, increase endogenous concentrations of analgesic and anti-inflammatory signaling molecules called epoxy-fatty acids. Here, we screened a library of 2,300 inhibitors of the sEH human against partially purified feline, canine and equine hepatic sEH to identify inhibitors that are broadly potent among species. Six very potent sEH inhibitors (IC < 1 nM for each enzyme tested) were identified. Their microsomal stability was then measured in hepatic extracts from cat, dog and horse, as well as their solubility in solvents suitable for the formulation of drugs. The -4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB, ) appears to be the best compromise between stability and potency across species. Thus, it was selected for further testing in veterinary clinical trials of pain and inflammation in animals.
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http://dx.doi.org/10.3389/fvets.2020.00580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479175PMC
August 2020

Role of CD38/cADPR signaling in obstructive pulmonary diseases.

Curr Opin Pharmacol 2020 04 29;51:29-33. Epub 2020 May 29.

Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, United States.

The worldwide socioeconomical burden associated with chronic respiratory diseases is substantial. Enzymes involved in the metabolism of nicotinamide adenine dinucleotide (NAD) are increasingly being implicated in chronic airway diseases. One such enzyme, CD38, utilizes NAD to produce several metabolites, including cyclic ADP ribose (cADPR), which is involved in calcium signaling in airway smooth muscle (ASM). Upregulation of CD38 in ASM caused by exposure to cytokines or allergens leads to enhanced calcium mobilization by agonists and the development of airway hyperresponsiveness (AHR) to contractile agonists. Glucocorticoids and microRNAs can suppress CD38 expression in ASM, whereas cADPR antagonists such as 8Br-cADPR can directly antagonize intracellular calcium mobilization. Bronchodilators act via CD38-independent mechanisms. CD38-dependent mechanisms could be developed for chronic airway diseases therapy.
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http://dx.doi.org/10.1016/j.coph.2020.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529733PMC
April 2020

Pharmacokinetics and clinical effects of xylazine and dexmedetomidine in horses recovering from isoflurane anesthesia.

J Vet Pharmacol Ther 2020 Jul 12;43(4):369-376. Epub 2020 Mar 12.

Veterinary Clinical Sciences Department, College of Veterinary Medicine, University of Minnesota, Minneapolis, MN, USA.

This study determined the pharmacokinetics and compared the clinical effects of xylazine and dexmedetomidine in horses recovering from isoflurane anesthesia. Six healthy horses aged 8.5 ± 3 years and weighing 462 ± 50 kg were anesthetized with isoflurane for 2 hr under standard conditions on two occasions one-week apart. In recovery, horses received 200 μg/kg xylazine or 0.875 μg/kg dexmedetomidine intravenously and were allowed to recover without assistance. These doses were selected because they have been used for postanesthetic sedation in clinical and research studies. Serial venous blood samples were collected for quantification of xylazine and dexmedetomidine, and the pharmacokinetic parameters were calculated. Two individuals blinded to treatment identity evaluated recovery quality with a visual analog scale. Times to stand were recorded. Results (mean ± SD) were compared using paired t tests or Wilcoxon signed-ranked test with p < .05 considered significant. Elimination half-lives (62.7 ± 21.8 and 30.1 ± 8 min for xylazine and dexmedetomidine, respectively) and steady-state volumes of distribution (215 ± 123 and 744 ± 403 ml/kg) were significantly different between xylazine and dexmedetomidine, whereas clearances (21.1 ± 17.3 and 48.6 ± 28.1 ml/minute/kg), times to stand (47 ± 24 and 53 ± 12 min) and recovery quality (51 ± 24 and 61 ± 22 mm VAS) were not significantly different. When used for postanesthetic sedation following isoflurane anesthesia in healthy horses, dexmedetomidine displays faster plasma kinetics but is not associated with faster recoveries compared to xylazine.
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http://dx.doi.org/10.1111/jvp.12855DOI Listing
July 2020

Controlled, non-inferiority trial of bupivacaine liposome injectable suspension.

J Feline Med Surg 2020 10 13;22(10):916-921. Epub 2019 Dec 13.

Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.

Objectives: Recently, a bupivacaine liposome injectable suspension (BLIS) became commercially available in the veterinary market that may provide local analgesia for 72 h. The purpose of this study was to compare a BLIS incisional block with a control protocol in cats after ovariohysterectomy (OHE). The hypothesis was that a BLIS block would provide equivalent pain relief.

Methods: This study was designed as a randomized, double-blind, non-inferiority trial. Students performed an OHE followed by a two-layer incisional and body wall block with either standard bupivacaine (control) or BLIS. Postoperatively, cats in the control group received robenacoxib, whereas the BLIS cats received saline. All cats were evaluated using the feline Glasgow Composite Measure Pain Scale (GCMPS) at multiple time points postoperatively.

Results: There were 24 control cats and 23 BLIS cats. One cat from each group required rescue medication. The mean GCMPS scores were low and the groups were equivalent at all time points ( <0.05). This study showed that BLIS was equivalent to the control group up to 42 h and pain scores remained low up to 68 h after surgery.

Conclusions And Relevance: BLIS incisional block is equivalent to a control pain protocol and reduces the need for continued postoperative drug administration.
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http://dx.doi.org/10.1177/1098612X19892355DOI Listing
October 2020

Mast Cells Induce Blood Brain Barrier Damage in SCD by Causing Endoplasmic Reticulum Stress in the Endothelium.

Front Cell Neurosci 2019 19;13:56. Epub 2019 Feb 19.

Vascular Biology Center, Division of Hematology, Oncology and Transplantation, Department of Medicine, Medical School, University of Minnesota, Minneapolis, MN, United States.

Endothelial dysfunction underlies the pathobiology of cerebrovascular disease. Mast cells are located in close proximity to the vasculature, and vasoactive mediators released upon their activation can promote endothelial activation leading to blood brain barrier (BBB) dysfunction. We examined the mechanism of mast cell-induced endothelial activation endoplasmic reticulum (ER) stress mediated P-selectin expression in a transgenic mouse model of sickle cell disease (SCD), which shows BBB dysfunction. We used mouse brain endothelial cells (mBECs) and mast cells-derived from skin of control and sickle mice to examine the mechanisms involved. Compared to control mouse mast cell conditioned medium (MCCM), mBECs incubated with sickle mouse MCCM showed increased, structural disorganization and swelling of the ER and Golgi, aggregation of ribosomes, ER stress marker proteins, accumulation of galactose-1-phosphate uridyl transferase, mitochondrial dysfunction, reactive oxygen species (ROS) production, P-selectin expression and mBEC permeability. These effects of sickle-MCCM on mBEC were inhibited by Salubrinal, a reducer of ER stress. Histamine levels in the plasma, skin releasate and in mast cells of sickle mice were higher compared to control mice. Compared to control BBB permeability was increased in sickle mice. Treatment of mice with imatinib, Salubrinal, or P-selectin blocking antibody reduced BBB permeability in sickle mice. Mast cells induce endothelial dysfunction ER stress-mediated P-selectin expression. Mast cell activation contributes to ER stress mediated endothelial P-selectin expression leading to increased endothelial permeability and impairment of BBB. Targeting mast cells and/or ER stress has the potential to ameliorate endothelial dysfunction in SCD and other pathobiologies.
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http://dx.doi.org/10.3389/fncel.2019.00056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389721PMC
February 2019

Assessment of the effects of gabapentin on activity levels and owner-perceived mobility impairment and quality of life in osteoarthritic geriatric cats.

J Am Vet Med Assoc 2018 Sep;253(5):579-585

OBJECTIVE Toevaluate effects of gabapentin on activity levels and owner-perceived mobility impairment and quality of life (QOL) in osteoarthritic geriatric cats. DESIGN Blinded, placebo-controlled, randomized crossover-design study. ANIMALS 20 osteoarthritic cats (≥ 10 years old). PROCEDURES Cats received gabapentin (10 mg/kg [4.5 mg/lb]) or placebo treatment, PO, every 12 hours for 2 weeks, followed by the alternate treatment (with no washout period). Activity was assessed with a collar-mounted accelerometer. A client-specific outcome measure (CSOM) questionnaire was used weekly to collect owner assessments of 3 selected activities in which their cats had impaired mobility; QOL ratings (worse, the same, or improved) following crossover to each treatment and for the overall study period were collected at the end of the investigation. Activity counts, CSOM and QOL data, and deterioration in impaired activities (ie, decrease of ≥ 2 points in CSOM scores) associated with treatment crossover were assessed statistically. Adverse events were recorded. RESULTS Gabapentin administration was associated with significantly lower mean daily activity counts (48,333 vs 39,038 counts/d) and significantly greater odds (approx 3-fold change) of CSOM ratings indicating improvement in impaired activities, compared with results for the placebo treatment. A greater proportion of cats had deterioration in impaired activities after the crossover from gabapentin to placebo than when the opposite occurred, but the proportion of cats with worsened QOL did not differ between sequences. Adverse events were noted for 10 cats (9 that completed the study) during gabapentin treatment (sedation, ataxia, weakness, and muscle tremors) and 1 cat during placebo treatment (lethargy). CONCLUSIONS AND CLINICAL RELEVANCE Gabapentin treatment was associated with improvement in owner-identified impaired activities of osteoarthritic cats. Activity levels were lower than those during placebo treatment, and sedation was the most common adverse effect.
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http://dx.doi.org/10.2460/javma.253.5.579DOI Listing
September 2018

Preliminary appraisal of the reliability and validity of the Colorado State University Feline Acute Pain Scale.

J Feline Med Surg 2019 04 31;21(4):335-339. Epub 2018 May 31.

1 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA.

Objectives: The objective of this study was to determine the inter-rater reliability and convergent validity of the Colorado State University Feline Acute Pain Scale (CSU-FAPS) in a preliminary appraisal of its performance in a clinical teaching setting.

Methods: Sixty-eight female cats were assessed for pain after ovariohysterectomy. A cohort of 21 cats was examined independently by four raters (two board-certified anesthesiologists and two anesthesia residents) with the CSU-FAPS, and intra-class correlation coefficient (ICC) was used to determine inter-rater reliability. Weighted Cohen's kappa was used to determine inter-rater reliability centered on the 'need to reassess analgesic plan' (dichotomous scale). A separate cohort of 47 cats was evaluated independently by two raters (one board-certified anesthesiologist and one veterinary small animal rotating intern) using the CSU-FAPS and the Glasgow Composite Measure Pain Scale (CMPS-Feline), and Spearman rank-order correlation was determined to assess convergent validity. Reliability was interpreted using Altman's classification as very good, good, moderate, fair and poor. Validity was considered adequate if correlation coefficients were between 0.4 and 0.8.

Results: The ICC was 0.61 for anesthesiologists and 0.67 for residents, indicating good reliability. Weighted Cohen's kappa was 0.79 for anesthesiologists and 0.44 for residents, indicating moderate to good reliability. The Spearman rank correlation indicated a statistically significant ( P = 0.0003) positive correlation (0.31; 95% confidence interval 0.14-0.46) between the CSU-FAPS and the CMPS-Feline.

Conclusions And Relevance: The CSU-FAPS showed moderate-to-good inter-rater reliability when used by veterinarians to assess pain level or need to reassess analgesic plan after ovariohysterectomy in cats. The validity fell short of current guidelines for correlation coefficients and further refinement and testing are warranted to improve its performance.
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http://dx.doi.org/10.1177/1098612X18777506DOI Listing
April 2019

CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms.

Mediators Inflamm 2018 7;2018:8942042. Epub 2018 Feb 7.

Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA.

Asthma is an inflammatory disease in which proinflammatory cytokines have a role in inducing abnormalities of airway smooth muscle function and in the development of airway hyperresponsiveness. Inflammatory cytokines alter calcium (Ca) signaling and contractility of airway smooth muscle, which results in nonspecific airway hyperresponsiveness to agonists. In this context, Ca regulatory mechanisms in airway smooth muscle and changes in these regulatory mechanisms encompass a major component of airway hyperresponsiveness. Although dynamic Ca regulation is complex, phospholipase C/inositol tris-phosphate (PLC/IP3) and CD38-cyclic ADP-ribose (CD38/cADPR) are two major pathways mediating agonist-induced Ca regulation in airway smooth muscle. Altered CD38 expression or enhanced cyclic ADP-ribosyl cyclase activity associated with CD38 contributes to human pathologies such as asthma, neoplasia, and neuroimmune diseases. This review is focused on investigations on the role of CD38-cyclic ADP-ribose signaling in airway smooth muscle in the context of transcriptional and posttranscriptional regulation of CD38 expression. The specific roles of transcription factors NF-kB and AP-1 in the transcriptional regulation of CD38 expression and of miRNAs miR-140-3p and miR-708 in the posttranscriptional regulation and the underlying mechanisms of such regulation are discussed.
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http://dx.doi.org/10.1155/2018/8942042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821947PMC
September 2018

Transversus abdominis plane block in ponies: a preliminary anatomical study.

Vet Anaesth Analg 2018 May 7;45(3):392-396. Epub 2018 Feb 7.

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA.

Objective: To describe a single-site transversus abdominis plane (TAP) block technique in horses.

Study Design: Prospective, descriptive, experimental anatomical study.

Animals: Four adult pony cadavers.

Methods: Freshly euthanized ponies were positioned in dorsal recumbency. A 6-13 MHz linear ultrasonic probe was used to scan the abdominal wall bilaterally midway between the last rib and iliac crest in search of the TAP location. By modifying the technique to accommodate the equine anatomy, the TAP was successfully visualized with the transducer positioned in a transverse plane with its side indicator over the intercept of two lines, one connecting the most cranial aspect of the iliac crest and the most caudal extent of the last rib and another originating just caudal to the umbilicus and extending laterally. Each hemiabdomen was injected with 0.5 mL kg of a 1:1 solution of 1% methylene blue and 0.5% bupivacaine via a 21 gauge 10 cm stimulating needle inserted ventral-dorsally and in plane with the ultrasound beam. Approximately 3 hours after injection, the abdomen was dissected and nerves stained over 1 cm in length were identified.

Results: Staining was evident from the fourteenth thoracic (T14) to the third lumbar (L3) nerves. The ventral branches of the fifteenth to the eighteenth thoracic nerves (T15-T18) and first and second lumbar nerves (L1 and L2) were stained in three, six, eight, eight, eight and seven of eight injections, respectively.

Conclusions And Clinical Relevance: Nerves T16-L2 had over 75% success rate in staining, suggesting that this technique would block transmission from T16 to L2, assuming that staining indicates potential nerve block. Dorsal spread occurred in three of eight hemiabdomens. Further studies developing techniques for the cranial abdomen and adjusting volume and concentration of injectate are warranted.
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http://dx.doi.org/10.1016/j.vaa.2018.01.009DOI Listing
May 2018

Evaluation of tramadol for treatment of osteoarthritis in geriatric cats.

J Am Vet Med Assoc 2018 Mar;252(5):565-571

OBJECTIVE To evaluate tramadol for treatment of signs of pain and impaired mobility in geriatric cats with osteoarthritis. DESIGN Randomized controlled crossover trial. ANIMALS 24 client-owned geriatric (≥ 10 years old) cats with osteoarthritis. PROCEDURES Otherwise healthy cats with owner-identified mobility impairment and clinical and radiographic evidence of osteoarthritis involving at least 1 appendicular joint were enrolled in the study. Cats were treated with tramadol orally at dosages of 0 (placebo), 1, 2, and 4 mg/kg (0, 0.45, 0.9, and 1.8 mg/lb) twice a day for 5 days, with a 2-day (weekend) washout period between treatments. Mobility was assessed with a collar-mounted activity monitor system, and impairments in activity were assessed with a client-completed questionnaire. RESULTS 17 cats completed the study; 7 cats were withdrawn. There was a significant increase in activity with the 2-mg/kg dosage of tramadol, compared with activity when cats received the placebo. Significantly more owners (11/18) considered their cats to have improved with the 2-mg/kg treatment, compared with all other dosages (6/19 to 8/21). Most owners (17/20 [85%]) considered their cat's global quality of life to have improved during the study. Adverse events, predominantly euphoria, dysphoria, sedation, decreased appetite, and diarrhea, were significantly more frequent with the 4-mg/kg (8/19) and 2-mg/kg (6/18) treatments but not with the 1-mg/kg (2/21) treatment, compared with frequency of adverse events with the placebo (0/21). CONCLUSIONS AND CLINICAL RELEVANCE Results suggested a beneficial effect of twice-daily oral administration of tramadol at a dosage of 2 mg/kg in geriatric cats with osteoarthritis. Adverse events were dose dependent, and caution should be exercised in cats that have concurrent disease or are receiving other drugs that may produce adverse gastrointestinal effects.
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http://dx.doi.org/10.2460/javma.252.5.565DOI Listing
March 2018

Inhibition of soluble epoxide hydrolase attenuates eosinophil recruitment and food allergen-induced gastrointestinal inflammation.

J Leukoc Biol 2018 07 17;104(1):109-122. Epub 2018 Jan 17.

Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, USA.

Prevalence of food allergies in the United States is on the rise. Eosinophils are recruited to the intestinal mucosa in substantial numbers in food allergen-driven gastrointestinal (GI) inflammation. Soluble epoxide hydrolase (sEH) is known to play a pro-inflammatory role during inflammation by metabolizing anti-inflammatory epoxyeicosatrienoic acids (EETs) to pro-inflammatory diols. We investigated the role of sEH in a murine model of food allergy and evaluated the potential therapeutic effect of a highly selective sEH inhibitor (trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]-cyclohexyloxy}-benzoic acid [t-TUCB]). Oral exposure of mice on a soy-free diet to soy protein isolate (SPI) induced expression of intestinal sEH, increased circulating total and antigen-specific IgE levels, and caused significant weight loss. Administration of t-TUCB to SPI-challenged mice inhibited IgE levels and prevented SPI-induced weight loss. Additionally, SPI-induced GI inflammation characterized by increased recruitment of eosinophils and mast cells, elevated eotaxin 1 levels, mucus hypersecretion, and decreased epithelial junction protein expression. In t-TUCB-treated mice, eosinophilia, mast cell recruitment, and mucus secretion were significantly lower than in untreated mice and SPI-induced loss of junction protein expression was prevented to variable levels. sEH expression in eosinophils was induced by inflammatory mediators TNF-α and eotaxin-1. Treatment of eosinophils with t-TUCB significantly inhibited eosinophil migration, an effect that was mirrored by treatment with 11,12-EET, by inhibiting intracellular signaling events such as ERK (1/2) activation and eotaxin-1-induced calcium flux. These studies suggest that sEH induced by soy proteins promotes allergic responses and GI inflammation including eosinophilia and that inhibition of sEH can attenuate these responses.
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http://dx.doi.org/10.1002/JLB.3MA1017-423RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020675PMC
July 2018

Pain Management in Horses.

Authors:
Alonso Guedes

Vet Clin North Am Equine Pract 2017 Apr;33(1):181-211

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, 1352 Boyd Avenue, St Paul, MN 55108, USA. Electronic address:

There has been great progress in the understanding of basic neurobiologic mechanisms of pain, but this body of knowledge has not yet translated into new and improved analgesics. Progress has been made regarding pain assessment in horses, but more work is needed until sensitive and accurate pain assessment tools are available for use in clinical practice. This review summarizes and updates the knowledge concerning the cornerstones of pain medicine (understand, assess, prevent, and treat). It highlights the importance of understanding pain mechanisms and expressions to enable a rational approach to pain assessment, prevention, and management in the equine patient.
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http://dx.doi.org/10.1016/j.cveq.2016.11.006DOI Listing
April 2017

Comparison between the effects of postanesthetic xylazine and dexmedetomidine on characteristics of recovery from sevoflurane anesthesia in horses.

Vet Anaesth Analg 2017 Mar 11;44(2):273-280. Epub 2017 Jan 11.

Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.

Objective: To compare postanesthetic xylazine and dexmedetomidine on recovery characteristics from sevoflurane anesthesia in horses.

Study Design: Randomized, crossover study.

Animals: Six geldings, mean±standard deviation (SD) (range), 17±4 (11-24) years and 527±80 (420-660) kg.

Methods: Horses were anesthetized with sevoflurane for 60 minutes under standardized conditions for a regional limb perfusion study. In recovery, horses were administered either xylazine (200 μg kg) or dexmedetomidine (0.875 μg kg) intravenously. Recoveries were unassisted and were video-recorded for later evaluation of recovery events and quality by two individuals unaware of treatment allocation. Recovery quality was assessed using a 100 mm visual analog scale (VAS) (0=poor recovery, 100=excellent recovery), the Edinburgh Scoring System (ESS) (0-100; 100=excellent recovery) and the mean attempt interval (MAI) (longer=better). Data are mean±SD.

Results: All recovery quality assessments (xylazine and dexmedetomidine, respectively: VAS: 71±21 mm, 84±13 mm; ESS: 65±22, 67±30; MAI: 52±24 minutes, 60±32 minutes) and events (first limb movement: 37±8 minutes, 42±10 minutes; first attempt to lift head: 44±12 minutes, 48±9 minutes; first attempt to sternal posture: 57±28 minutes, 50±7 minutes; number of head bangs: 2.0±3.0, 0.5±0.5; time to first attempt to stand: 72±6 minutes, 78±13 minutes; time to standing: 79±14 minutes, 84±13 minutes) did not differ significantly between treatments (p>0.05).

Conclusions And Clinical Relevance: Recovery characteristics did not differ significantly between postanesthetic xylazine and dexmedetomidine following 1 hour of sevoflurane anesthesia in horses in this study. Further evaluations in more horses and in younger horses are required to confirm these results.
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http://dx.doi.org/10.1016/j.vaa.2016.04.002DOI Listing
March 2017

CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets.

Pharmacol Ther 2017 Apr 7;172:116-126. Epub 2016 Dec 7.

Department of Veterinary and Biomedical Sciences, University of Minnesota at Twin Cities, USA. Electronic address:

CD38 is an ectoenzyme that catalyzes the conversion of β-nicotinamide adenine dinucleotide (β-NAD) to cyclic adenosine diphosphoribose (cADPR) and adenosine diphosphoribose (ADPR) and NADP to nicotinic acid adenine dinucleotide phosphate (NAADP) and adenosine diphosphoribose-2'-phosphate (ADPR-P). The metabolites of NAD and NADP have roles in calcium signaling in different cell types including airway smooth muscle (ASM) cells. In ASM cells, inflammatory cytokines augment CD38 expression and to a greater magnitude in cells from asthmatics, indicating a greater capacity for the generation of cADPR and ADPR in ASM from asthmatics. CD38 deficient mice develop attenuated airway responsiveness to inhaled methacholine following allergen sensitization and challenge compared to wild-type mice indicating its potential role in asthma. Regulation of CD38 expression in ASM cells is achieved by mitogen activated protein kinases, specific isoforms of PI3 kinases, the transcription factors NF-κB and AP-1, and post-transcriptionally by microRNAs. This review will focus on the role of CD38 in intracellular calcium regulation in ASM, contribution to airway inflammation and airway hyperresponsiveness in mouse models of allergic airway inflammation, the transcriptional and post-transcriptional mechanisms of regulation of expression, and outline approaches to inhibit its expression and activity.
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http://dx.doi.org/10.1016/j.pharmthera.2016.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346344PMC
April 2017

Cardiovascular, respiratory and metabolic responses to apnea induced by atlanto-occipital intrathecal lidocaine injection in anesthetized horses.

Vet Anaesth Analg 2016 Nov 5;43(6):590-598. Epub 2016 Feb 5.

William R Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, CA, USA.

Objective: To determine physiologic responses to apnea-induced severe hypoxemia in anesthetized horses.

Study Design: Prospective experimental study.

Animals: Six university-owned horses with a median (range) body weight of 500 (220-510) kg and aged 13.5 (0.8-24.0) years scheduled for euthanasia.

Methods: Xylazine-midazolam-ketamine-anesthetized horses breathing room air spontaneously were instrumented with a facial artery catheter for pressure measurement and blood sampling, and were made apneic with atlanto-occipital intrathecal lidocaine (4 mg kg ). Cardiopulmonary, biochemical and hematologic variables were recorded before (baseline) and every minute for 10 minutes after lidocaine injection.

Results: PaO values were: baseline, 55 mmHg (7.3 kPa); 1 minute, 28 mmHg (3.8 kPa); 2 minutes, 18 mmHg (2.4 kPa); 3 minutes, 15 mmHg (2.0 kPa), and 4-10 minutes, (8-11 mmHg (1.1-1.5 kPa). PaCO values were: baseline, 50 mmHg (6.7 kPa); 1 minute, 61 mmHg (8.1 kPa), and 2-10 minutes, 64-66 mmHg (8.5-8.8 kPa). Base excess values at baseline, 1 minute and 2-10 minutes were 5.3 mmol L , 6.5 mmol L and 7.0-8.1 mmol L , respectively. Pulse rates at baseline, 1 minute and 2-7 minutes were 36, 53 and 54-85 beats minute , respectively. Asystole occurred at 8 minutes. Pulse pressures were 50 mmHg at baseline and 1 minute, and 39 mmHg, 31 mmHg, 22 mmHg, 17 mmHg and 1-9 mmHg at 2, 3, 4, 5 and 6-10 minutes, respectively. Lactate was 0.9 mmol L at baseline, progressively increasing to 1.7-2.4 mmol L at 7-10 minutes. Packed cell volume increased after 7 minutes of apnea. There were no other major changes.

Conclusions And Clinical Relevance: Apnea immediately exacerbated hypoxemia and hypercapnia and rapidly caused hemodynamic instability. Apnea in hypoxemic anesthetized horses is associated with a serious risk for progress to cardiovascular collapse.
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http://dx.doi.org/10.1111/vaa.12344DOI Listing
November 2016

Desflurane and sevoflurane elimination kinetics and recovery quality in horses.

Am J Vet Res 2015 Mar;76(3):201-7

William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

Objective: To evaluate pharmacokinetics, recovery times, and recovery quality in horses anesthetized with 1.2 times the minimum alveolar concentration of sevoflurane or desflurane.

Animals: 6 healthy adult horses.

Procedures: Anesthesia was maintained with sevoflurane or desflurane for 2 hours at 1.2 times the minimum alveolar concentration. Horses recovered without assistance. During recovery, end-tidal gas samples were collected until horses spontaneously moved. Anesthetic concentrations were measured by use of gas chromatography. After a 1-week washout period, horses were anesthetized with the other inhalation agent. Video recordings of anesthetic recovery were evaluated for recovery quality on the basis of a visual analogue scale by investigators who were unaware of the anesthetic administered. Anesthetic washout curves were fit to a 2-compartment kinetic model with multivariate nonlinear regression. Normally distributed interval data were analyzed by means of paired Student t tests; ordinal or nonnormally distributed data were analyzed by means of Wilcoxon signed rank tests.

Results: Horses recovered from both anesthetics without major injuries. Results for subjective recovery evaluations did not differ between anesthetics. Area under the elimination curve was significantly smaller and time to standing recovery was significantly less for desflurane than for sevoflurane, although distribution and elimination constants did not differ significantly between anesthetics.

Conclusions And Clinical Relevance: Differences in area under elimination the curve between anesthetics indicated more rapid clearance for desflurane than for sevoflurane in horses, as predicted by anesthetic blood solubility differences in this species. More rapid elimination kinetics was associated with faster recovery times, but no association with improved subjective recovery quality was detected.
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http://dx.doi.org/10.2460/ajvr.76.3.201DOI Listing
March 2015

CD38 and airway hyper-responsiveness: studies on human airway smooth muscle cells and mouse models.

Can J Physiol Pharmacol 2015 Feb 9;93(2):145-53. Epub 2014 Dec 9.

a Department of Surgical & Radiological Sciences, University of California, Davis, CA 95616, USA.

Asthma is an inflammatory disease in which altered calcium regulation, contractility, and airway smooth muscle (ASM) proliferation contribute to airway hyper-responsiveness and airway wall remodeling. The enzymatic activity of CD38, a cell-surface protein expressed in human ASM cells, generates calcium mobilizing second messenger molecules such as cyclic ADP-ribose. CD38 expression in human ASM cells is augmented by cytokines (e.g., TNF-α) that requires the activation of MAP kinases and the transcription factors, NF-κB and AP-1, and is post-transcriptionally regulated by miR-140-3p and miR-708 by binding to 3' Untranslated Region of CD38 as well as by modulating the activation of signaling mechanisms involved in its regulation. Mice deficient in Cd38 exhibit reduced airway responsiveness to inhaled methacholine relative to the response in wild-type mice. Intranasal challenge of Cd38-deficient mice with TNF-α or IL-13, or the environmental fungus Alternaria alternata, causes significantly attenuated methacholine responsiveness compared with wild-type mice, with comparable airway inflammation. Reciprocal bone marrow transfer studies revealed partial restoration of airway hyper-responsiveness to inhaled methacholine in the Cd38-deficient mice. These studies provide evidence for CD38 involvement in the development of airway hyper-responsiveness; a hallmark feature of asthma. Future studies aimed at drug discovery and delivery targeting CD38 expression and (or) activity are warranted.
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http://dx.doi.org/10.1139/cjpp-2014-0410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648235PMC
February 2015

Airway responsiveness in CD38-deficient mice in allergic airway disease: studies with bone marrow chimeras.

Am J Physiol Lung Cell Mol Physiol 2015 Mar 9;308(5):L485-93. Epub 2015 Jan 9.

Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota

CD38 is a cell-surface protein involved in calcium signaling and contractility of airway smooth muscle. It has a role in normal airway responsiveness and in airway hyperresponsiveness (AHR) developed following airway exposure to IL-13 and TNF-α but appears not to be critical to airway inflammation in response to the cytokines. CD38 is also involved in T cell-mediated immune response to protein antigens. In this study, we assessed the contribution of CD38 to AHR and inflammation to two distinct allergens, ovalbumin and the epidemiologically relevant environmental fungus Alternaria. We also generated bone marrow chimeras to assess whether Cd38(+/+) inflammatory cells would restore AHR in the CD38-deficient (Cd38(-/-)) hosts following ovalbumin challenge. Results show that wild-type (WT) mice develop greater AHR to inhaled methacholine than Cd38(-/-) mice following challenge with either allergen, with comparable airway inflammation. Reciprocal bone marrow transfers did not change the native airway phenotypic differences between WT and Cd38(-/-) mice, indicating that the lower airway reactivity of Cd38(-/-) mice stems from Cd38(-/-) lung parenchymal cells. Following bone marrow transfer from either source and ovalbumin challenge, the phenotype of Cd38(-/-) hosts was partially reversed, whereas the airway phenotype of the WT hosts was preserved. Airway inflammation was similar in Cd38(-/-) and WT chimeras. These results indicate that loss of CD38 on hematopoietic cells is not sufficient to prevent AHR and that the magnitude of airway inflammation is not the predominant underlying determinant of AHR in mice.
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http://dx.doi.org/10.1152/ajplung.00227.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346775PMC
March 2015

Effects of pre-operative administration of medetomidine on plasma insulin and glucose concentrations in healthy dogs and dogs with insulinoma.

Vet Anaesth Analg 2013 Sep 29;40(5):472-81. Epub 2013 May 29.

Veterinary Clinical Sciences Department, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA.

Objective: To investigate the effect of medetomidine on plasma glucose and insulin concentrations in dogs with insulinoma and in healthy dogs undergoing anesthesia and surgery.

Animals: Twenty-five dogs with insulinoma and 26 healthy dogs.

Methods: In dogs with insulinoma, medetomidine (5 μg kg(-1) ) was randomly included (n = 12) or omitted (n = 13) from the pre-anesthetic medication protocol, which typically contained an opioid and an anticholinergic. Healthy dogs received medetomidine (5 μg kg(-1) ; n = 13) or acepromazine (0.04 mg kg(-1) ; n = 13) plus an opioid (morphine 0.5 mg kg(-1) ) and an anticholinergic (atropine 0.04 mg kg(-1) ) as pre-anesthetic medications. Pre-anesthetic medications were given intramuscularly. Plasma glucose and insulin concentrations were measured before (sample 1) and 30 minutes after pre-anesthetic medication (sample 2), and at the end of surgery in dogs with insulinoma or at 2 hours of anesthesia in healthy dogs (sample 3). Glucose requirement to maintain intra-operative normoglycemia in dogs with insulinoma was quantified and compared. Data were analyzed with anova and Bonferroni post-test, t-tests or chi-square tests as appropriate with p < 0.05 considered significant. Data are shown as mean ± SD.

Results: Medetomidine significantly decreased plasma insulin concentrations and increased plasma glucose concentrations in healthy dogs and those with insulinoma. These variables did not change significantly in the dogs not receiving medetomidine. In the dogs with insulinoma, intra-operative glucose administration rate was significantly less in the animals that received medetomidine compared to those that did not.

Conclusions: Pre-anesthetic administration of medetomidine significantly suppressed insulin secretion and increased plasma glucose concentration in dogs with insulinoma and in healthy dogs undergoing anesthesia and surgery.

Clinical Relevance: These findings support the judicious use of medetomidine at low doses as an adjunct to the anesthetic management of dogs with insulinoma.
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http://dx.doi.org/10.1111/vaa.12047DOI Listing
September 2013

Potential role of the CD38/cADPR signaling pathway as an underlying mechanism of the effects of medetomidine on insulin and glucose homeostasis.

Vet Anaesth Analg 2013 Sep 9;40(5):512-6. Epub 2013 Apr 9.

Veterinary Clinical Sciences Department, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA.

Objective: To investigate the CD38/cADPR signaling pathway as possible underlying mechanism of the effects of medetomidine on insulin and glucose homeostasis.

Animals: Thirty-two C57BL/6 mice of both sexes.

Methods: Wild-type (WT) and CD38-knockout (CD38(-/-) ) mice received medetomidine (50 μg kg(-1) ) or a similar volume of 0.9% NaCl (control) by intraperitoneal (IP) injection (each group n = 8). The mice were euthanized 45 minutes later with sodium pentobarbital IP and blood was sampled via cardiac puncture. Insulin and glucose concentrations were measured by radioimmunoassay and by the oxygen rate method, respectively. Data were analyzed with anova and Bonferroni post hoc (5% significance) and are shown as mean ± SD.

Results: Plasma insulin and glucose concentrations were similar between WT and CD38(-/-) mice under control conditions. As compared to controls, medetomidine administration produced a statistically significant decrease in plasma insulin concentrations in the WT mice whereas the decrease in the CD38(-/-) mice was not statistically significant. Correspondingly, medetomidine caused a significantly greater increase in plasma glucose concentrations in the WT than in the CD38(-/-) mice.

Conclusion: The CD38/cADPR signaling pathway may be one underlying mechanism of the glucose and insulin effects of the alpha-2 adrenergic receptor agonist medetomidine and likely other drugs of its class.
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http://dx.doi.org/10.1111/vaa.12039DOI Listing
September 2013

Use of a soluble epoxide hydrolase inhibitor as an adjunctive analgesic in a horse with laminitis.

Vet Anaesth Analg 2013 Jul 7;40(4):440-8. Epub 2013 Mar 7.

Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.

History: A 4-year old, 500 kg Thoroughbred female horse diagnosed with bilateral forelimb laminitis and cellulitis on the left forelimb became severely painful and refractory to non-steroidal anti-inflammatory therapy (flunixin meglumine on days 1, 2, 3 and 4; and phenylbutazone on days 5, 6 and 7) alone or in combination with gabapentin (days 6 and 7).

Physical Examination: Pain scores assessed independently by three individuals with a visual analog scale (VAS; 0 = no pain and 10 = worst possible pain) were 8.5 on day 6, and it increased to 9.5 on day 7. Non-invasive blood pressure monitoring revealed severe hypertension.

Management: As euthanasia was being considered for humane reasons, a decision was made to add an experimental new drug, trans-4-{4-[3-(4-Trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB), which is a soluble epoxide hydrolase (sEH) inhibitor, to the treatment protocol. Dose and frequency of administration were selected based on the drug potency against equine sEH to produce plasma concentrations within the range of 30 nmol L(-1) and 2.5 μmol L(-1) . Pain scores decreased sharply and remarkably following t-TUCB administration and blood pressure progressively decreased to physiologic normal values. Plasma concentrations of t-TUCB, measured daily, were within the expected range, whereas phenylbutazone and gabapentin plasma levels were below the suggested efficacious concentrations.

Follow Up: No adverse effects were detected on clinical and laboratory examinations during and after t-TUCB administration. No new episodes of laminitis have been noted up to the time of writing (120 days following treatment).

Conclusions: Inhibition of sEH with t-TUCB was associated with a significant improvement in pain scores in one horse with laminitis whose pain was refractory to the standard of care therapy. No adverse effects were noticed. Future studies evaluating the analgesic and protective effects of these compounds in painful inflammatory diseases in animals are warranted.
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http://dx.doi.org/10.1111/vaa.12030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956586PMC
July 2013

Effect of ketamine hydrochloride on the analgesic effects of tramadol hydrochloride in horses with signs of chronic laminitis-associated pain.

Am J Vet Res 2012 May;73(5):610-9

Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.

Objective: To investigate the effects of ketamine hydrochloride on the analgesic effects of tramadol hydrochloride in horses with signs of pain associated with naturally occurring chronic laminitis.

Animals: 15 client-owned adult horses with chronic laminitis.

Procedures: Each horse received tramadol alone or tramadol and ketamine in a randomized, crossover study (≥ 2 months between treatments). Tramadol (5 mg/kg) was administered orally every 12 hours for 1 week. When appropriate, ketamine (0.6 mg/kg/h) was administered IV for 6 hours on each of the first 3 days of tramadol administration. Noninvasive systemic blood pressure values, heart and respiratory rates, intestinal sounds, forelimb load and off-loading frequency (determined via force plate system), and plasma tumor necrosis factor-α and thromboxane B(2) concentrations were assessed before (baseline) during (7 days) and after (3 days) each treatment.

Results: Compared with baseline data, arterial blood pressure decreased significantly both during and after tramadol-ketamine treatment but not with tramadol alone. Forelimb off-loading frequency significantly decreased during the first 3 days of treatment with tramadol only, returning to baseline frequency thereafter. The addition of ketamine to tramadol treatment reduced off-loading frequency both during and after treatment. Forelimb load did not change with tramadol alone but increased with tramadol-ketamine treatment. Plasma concentrations of tumor necrosis factor-α and thromboxane B(2) were significantly reduced with tramadol-ketamine treatment but not with tramadol alone.

Conclusions And Clinical Relevance: In horses with chronic laminitis, tramadol administration induced limited analgesia, but this effect was significantly enhanced by administration of subanesthetic doses of ketamine.
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http://dx.doi.org/10.2460/ajvr.73.5.610DOI Listing
May 2012

Role of CD38 in TNF-alpha-induced airway hyperresponsiveness.

Am J Physiol Lung Cell Mol Physiol 2008 Feb 30;294(2):L290-9. Epub 2007 Nov 30.

Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, 1971 Commonwealth Avenue, St. Paul, MN 55108, USA.

CD38 is involved in normal airway function, IL-13-induced airway hyperresponsiveness (AHR), and is also regulated by tumor necrosis factor (TNF)-alpha in airway smooth muscle (ASM) cells. This study aimed to determine whether TNF-alpha-induced CD38 upregulation in ASM cells contributes to AHR, a hallmark of asthma. We hypothesized that AHR would be attenuated in TNF-alpha-exposed CD38-deficient (CD38KO) mice compared with wild-type (WT) controls. Mice (n = 6-8/group) were intranasally challenged with vehicle control or TNF-alpha (50 ng) once and every other day during 1 or 4 wk. Lung inflammation and AHR, measured by changes in lung resistance after inhaled methacholine, were assessed 24 h following the last challenge. Tracheal rings were incubated with TNF-alpha (50 ng/ml) to assess contractile changes in the ASM. While a single TNF-alpha challenge caused no airway inflammation, both multiple-challenge protocols induced equally significant inflammation in CD38KO and WT mice. A single intranasal TNF-alpha challenge induced AHR in the WT but not in the CD38KO mice, whereas both mice developed AHR after 1 wk of challenges. The AHR was suppressed by extending the challenges for 4 wk in both mice, although to a larger magnitude in the WT than in the CD38KO mice. TNF-alpha increased ASM contractile properties in tracheal rings from WT but not from CD38KO mice. In conclusion, CD38 contributes to TNF-alpha-induced AHR after a brief airway exposure to the cytokine, likely by mediating changes in ASM contractile responses, and is associated with greater AHR remission following chronic airway exposure to TNF-alpha. The mechanisms involved in this remission remain to be determined.
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http://dx.doi.org/10.1152/ajplung.00367.2007DOI Listing
February 2008

The impact of animal age, bacterial coinfection, and isolate pathogenicity on the shedding of porcine reproductive and respiratory syndrome virus in aerosols from experimentally infected pigs.

Can J Vet Res 2006 Oct;70(4):297-301

Swine Disease Eradication Center, Room 385C, Animal Science/Veterinary Medicine Building, 1988 Fitch Avenue, St. Paul, Minnesota 55108, USA.

The objective of this study was to evaluate the role of different variables (animal age, bacterial coinfection, and isolate pathogenicity) on the shedding of Porcine reproductive and respiratory syndrome virus (PRRSV) in aerosols. Animals were grouped according to age (2 versus 6 mo) and inoculated with a PRRSV isolate of either low (MN-30100) or high (MN-184) pathogenicity. Selected animals in each group were also inoculated with Mycoplasma hyopneumoniae. The pigs were anesthetized and aerosol samples (1000 breaths/sample) collected on alternating days from 1 to 21 after PRRSV inoculation. The results indicated that animal age (P = 0.09), M. hyopneumoniae coinfection (P = 0.09), and PRRSV isolate pathogenicity (P = 0.15) did not significantly influence the concentration of PRRSV in aerosols. However, inoculation with the PRRSV MN-184 isolate significantly increased the probability of aerosol shedding (P = 0.00005; odds ratio = 3.22). Therefore, the shedding of PRRSV in aerosols may be isolate-dependent.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1562537PMC
October 2006

CD38-deficient mice have reduced airway hyperresponsiveness following IL-13 challenge.

Am J Physiol Lung Cell Mol Physiol 2006 Dec 4;291(6):L1286-93. Epub 2006 Aug 4.

Department of Veterinary Clinicial Sciences, University of Minnesota, St. Paul, MN 55108, USA.

The transmembrane glycoprotein CD38 in airway smooth muscle is the source of cyclic-ADP ribose, an intracellular calcium-releasing molecule, and is subject to regulatory effects of cytokines such as interleukin (IL)-13, a cytokine implicated in asthma. We investigated the role of CD38 in airway hyperresponsiveness using a mouse model of IL-13-induced airway disease. Wild-type (WT) and CD38-deficient (CD38KO) mice were intranasally challenged with 5 microg of IL-13 three times on alternate days under isoflurane anesthesia. Lung resistance (R(L)) in response to inhaled methacholine was measured 24 h after the last challenge in pentobarbital-anesthetized, tracheostomized, and mechanically ventilated mice. Bronchoalveolar cytokines, bronchoalveolar and parenchymal inflammation, and smooth muscle contractility and relaxation using tracheal segments were also evaluated. Changes in methacholine-induced R(L) were significantly greater in the WT than in the CD38KO mice following intranasal IL-13 challenges. Airway reactivity after IL-13 exposure, as measured by the slope of the methacholine dose-response curve, was significantly higher in the WT than in the CD38KO mice. The rate of isometric force generation in tracheal segments (e.g., smooth muscle reactivity) was greater in the WT than in the CD38KO mice following incubation with IL-13. IL-13 treatment reduced isoproterenol-induced relaxations to similar magnitudes in tracheal segments obtained from WT and CD38KO mice. Both WT and CD38KO mice developed significant bronchoalveolar and parenchymal inflammation after IL-13 challenges compared with naïve controls. The results indicate that CD38 contributes to airway hyperresponsiveness in lungs exposed to IL-13 at least partly by increasing airway smooth muscle reactivity to contractile agonists.
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http://dx.doi.org/10.1152/ajplung.00187.2006DOI Listing
December 2006

Evaluation of the effects of animal age, concurrent bacterial infection, and pathogenicity of porcine reproductive and respiratory syndrome virus on virus concentration in pigs.

Am J Vet Res 2006 Mar;67(3):489-93

Swine Disease Eradication Center, College of Veterinary Medicine, University of Minnesota, Saint Paul, 55108, USA.

Objective: To evaluate the influences of animal age, bacterial coinfection, and porcine reproductive and respiratory syndrome virus (PRRSV) isolate pathogenicity on virus concentration in pigs.

Animals: Twenty-one 2-month-old pigs and eighteen 6-month-old pigs.

Procedure: Pigs were grouped according to age and infected with mildly virulent or virulent isolates of PRRSV. The role of concurrent bacterial infection was assessed by infecting selected pigs with Mycoplasma hyopneumoniae 21 days prior to inoculation with PRRSV. On alternating days, blood and swab specimens of nasal secretions and oropharyngeal secretions were collected. On day 21 after inoculation with PRRSV, selected tissues were harvested. Concentrations of PRRSV were determined by use of quantitative real-time PCR and expressed in units of TCID(50) per milliliter (sera and swab specimens) or TCID(50) per gram (tissue specimens).

Results: Concentrations of virus were higher in blood and tonsils of pigs infected with virulent PRRSV. Pigs infected with virulent PRRSV and M hyopneumoniae had significantly higher concentrations of viral RNA in lymphoid and tonsillar tissue. Coinfection with M hyopneumoniae resulted in a higher viral load in oropharyngeal swab specimens and blood samples, independent of virulence of the PRRSV isolate. Two-month-old pigs had significantly higher viral loads in lymph nodes, lungs, and tracheal swab specimens than did 6-month-old pigs, independent of virulence of the PRRSV isolate.

Conclusions And Clinical Relevance: Multiple factors affect PRRSV concentration in pigs, including pathogenicity of the PRRSV isolate, age, and concurrent infection with M hyopneumoniae.
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http://dx.doi.org/10.2460/ajvr.67.3.489DOI Listing
March 2006

Effects of preoperative epidural administration of racemic ketamine for analgesia in sheep undergoing surgery.

Am J Vet Res 2006 Feb;67(2):222-9

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108-1016, USA.

Objective: To investigate the effects of preoperative epidural administration of racemic ketamine to provide analgesia in sheep undergoing experimental hind limb orthopedic surgery.

Animals: 12 adult sheep (weight range, 51.4 to 67.2 kg).

Procedure: Sheep were anesthetized with guaifenesin, thiopental, and isoflurane; after induction of anesthesia, sheep received a lumbosacral epidural injection of ketamine (1 mg/kg; n = 6) or saline (0.9% NaCl) solution (1 mL/7 kg; 6 [control group]). Respiratory and cardiovascular variables were recorded before and at intervals during and for 6 hours after anesthesia. During that 6-hour postoperative period, analgesia was evaluated subjectively with a numeric ranking scale that included assessments of comfort, posture, movement, and response to wound palpation; buprenorphine was administered when a score > 3 (maximum score, 10) was achieved. Rectal temperature, heart and respiratory rates, and lameness were evaluated daily for 2 weeks after surgery.

Results: At all evaluations, cardiovascular and respiratory variables were comparable between the 2 groups. Compared with control sheep, time to first administration of rescue analgesic was significantly longer and total dose of buprenorphine administered during the 6- hour postoperative period was significantly decreased for ketamine-treated sheep. During the second week following surgery, ketamine-treated sheep had significantly less lameness than control sheep.

Conclusions And Clinical Relevance: In sheep undergoing hind limb surgery, preoperative epidural administration of ketamine appears to provide analgesia in the immediate postoperative period and has residual analgesic effects, which may contribute to more rapid return of normal function in surgically treated limbs.
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http://dx.doi.org/10.2460/ajvr.67.2.222DOI Listing
February 2006

Evaluation of histamine release during constant rate infusion of morphine in dogs.

Vet Anaesth Analg 2006 Jan;33(1):28-35

Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108-1016, USA.

Objective: To evaluate histamine release and selected physiologic variables during constant rate infusion (CRI) of morphine in dogs.

Animals: Five healthy, conscious, intact female dogs.

Material And Methods: Using a Latin square, repeated-measures design, dogs were randomly assigned to three treatment groups to receive a 4-hour CRI of saline (SAL), or a loading dose of morphine at 0.3 mg kg(-1) (LM), or 0.6 mg kg(-1) (HM), followed by an infusion of 0.17 mg kg(-1) hour(-1) (LM) and 0.34 mg kg(-1) hour(-1) (HM) respectively. Dogs received each of the three treatments at intervals of at least 7 days. Plasma histamine concentration, skin flushing, edema and wheals, heart rate and rhythm and non-invasive arterial blood pressure were measured before the loading dose and at 1, 2, 5, 15, 30, 60, 120, 180 and 240 minutes during the CRI, or at the time of occurrence.

Results: The loading dose induced the highest histamine release in the HM group being statistically higher than the SAL group. The histamine release obtained in the LM group after the loading dose did not differ from SAL. During the infusion, plasma histamine levels were numerically higher in the LM group. Besides one dog that developed hypotension for 2 minutes after the loading dose in the HM group and one dog that showed occasional ventricular premature contractions during both morphine infusions, cardiovascular variables were similar among the three treatment groups.

Conclusions And Clinical Relevance: Both doses of morphine induced variable histamine release with minimal adverse cardiovascular effects in these conscious, healthy dogs. The plasma histamine levels obtained may be associated with significant hemodynamic changes in patients with limited cardiovascular reserve and sympathetic nervous tone.
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http://dx.doi.org/10.1111/j.1467-2995.2005.00218.xDOI Listing
January 2006
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