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1.
Genes Brain Behav ; 15(5): 514-26, 2016 06.
Article in English | MEDLINE | ID: mdl-26991152

ABSTRACT

Temperament is a key criterion in the selection of horses for both leisure and competitive riding to ensure optimal performance and safety. The Tennessee Walking Horse (TWH) is described as a calm, docile breed and is often used as a trail, show and pleasure horse. However, among horse owners and caretakers, there are anecdotes supporting familial and disciplinal typical behaviors and personalities. To investigate the contribution of genetics to temperament, we collected a behavior questionnaire, brief training history and identifying information for 276 TWH, as well as blood or hair samples for DNA. Factor analysis was conducted on the 20-item questionnaire for the set of 216 horses that met inclusion thresholds. Factor analysis identified four temperament factors in TWH: 'anxious', 'tractable', 'agonistic' and 'gregarious'. These four factors account for 64% of the total trait variance. DNA from 113 TWHs were selected and genotyped using the Equine SNP70 bead chip for three separate genome-wide association studies (GWAs) using the factor 1-anxious, factor 2-tractable and factor 3-agonistic scores as the phenotype. Quantitative association analysis identified significant candidate loci for each factor that warrant further investigation.


Subject(s)
Behavior, Animal , Genetic Loci , Horses/genetics , Temperament , Animals , Genome-Wide Association Study , Phenotype
2.
Equine Vet J ; 48(6): 727-731, 2016 Nov.
Article in English | MEDLINE | ID: mdl-26537825

ABSTRACT

REASONS FOR PERFORMING STUDY: Crib-biting is a common oral stereotypy. Although most treatments involve prevention, the efficacy of various anti-crib devices, including surgically implanted gingival rings, has thus far not been empirically tested. OBJECTIVES: Demonstrate the effect that 2 anti-crib collars, muzzle and gingival rings have on crib-biting, other maintenance behaviours, and cortisol levels in established crib-biting horses. STUDY DESIGN: Randomised, crossover clinical trial. METHODS: In Experiment I, 2 anti-crib collars and a muzzle were used on 8 established crib-biting horses; horses wore each of 3 devices for 7 days, with a 7-day device-free period between treatments. Horses were video recorded for 24 h at least 3 times each week prior to any device placement, and always the day after a device was removed. In Experiment II, gingival rings were used in 6 established crib-biting horses; horses were video recorded for 3 days prior to ring implantation and the day after surgery until the rings became ineffective. Plasma cortisol levels were assessed every day during Experiment II and on Days 1, 3 and 5 of each week during Experiment I. RESULTS: All devices significantly reduced crib-biting compared with control periods. There was no significant difference in crib-bite reduction amongst devices in Experiment I, or between pre-device periods and the first day the device was removed. The only increase in plasma cortisol occurred on the day of surgery in Experiment II. CONCLUSIONS: Common anti-crib devices are effective in reducing crib-biting and significant distress was not evident from our findings. We did not find a post inhibitory rebound effect. Surgical rings were successful only temporarily and implantation was probably painful to the horses. Because stereotypies involve suboptimal environmental conditions, efforts should be made to improve husbandry factors previously shown to contribute to crib-biting, and research into decreasing horses' motivation to crib-bite should continue.


Subject(s)
Behavior, Animal , Horse Diseases/prevention & control , Horses/physiology , Stereotyped Behavior , Animals
3.
Equine Vet J ; 41(5): 455-8, 2009 May.
Article in English | MEDLINE | ID: mdl-19642405

ABSTRACT

REASONS FOR PERFORMING STUDY: Crib-biting is an equine stereotype that may result in diseases such as colic. Certain breeds and management factors have been associated. OBJECTIVES: To determine: breed prevalence of crib-biting in US horses; the likelihood that one horse learns to crib-bite from another; and owner perceptions of causal factors. METHODS: An initial postal survey queried the number and breed of crib-biting horses and if a horse began after being exposed to a horse with this habit. In a follow-up survey, a volunteer subset of owners was asked the number of affected and nonaffected horses of each breed and the extent of conspecific contact. The likelihood of crib-biting given breed and extent of contact was quantified using odds ratio (OR) and significance of the association was assessed using the Chi-squared test. RESULTS: Overall prevalence was 4.4%. Thoroughbreds were the breed most affected (133%). Approximately half of owners believed environmental factors predominantly cause the condition (54.4%) and crib-biting is learned by observation (48.8%). However, only 1.0% of horses became affected after being exposed to a crib-biter. The majority (86%) of horses was turned out in the same pasture with other horses and extent of contact with conspecifics was not statistically related to risk. CONCLUSION: This is the first study to report breed prevalence for crib-biting in US horses. Thoroughbreds were the breed more likely to be affected. More owners believed either environmental conditions were a predominant cause or a combination of genetic and environmental factors contributes to the behaviour. Only a small number of horses reportedly began to crib-bite after being exposed to an affected individual, but approximately half of owners considered it to be a learned behaviour; most owners did not isolate affected horses. POTENTIAL RELEVANCE: Genetic predisposition, not just intensive management conditions and surroundings, may be a factor in the high crib-biting prevalence in some breeds, and warrants further investigation. Little evidence exists to suggest horses learn the behaviour from other horses, and isolation may cause unnecessary stress.


Subject(s)
Horses , Stereotyped Behavior/physiology , Animals , Data Collection , Horses/genetics , Horses/physiology , Surveys and Questionnaires , United States
5.
Am J Sports Med ; 29(4): 410-4, 2001.
Article in English | MEDLINE | ID: mdl-11476377

ABSTRACT

We evaluated 18 of 23 patients who had undergone cryopreserved meniscal allograft transplantation for compartmental pain after total meniscectomy 2 to 8 years (mean, 5.4) after the operation. The Short Form-36 scores revealed a decrease in pain with a significant improvement in function, although function remained limited. There was no significant decrease in joint space on 45 degrees posteroanterior weightbearing radiographs through the duration of the study. Eight of 22 allograft menisci (36%) tore during the study period, necessitating 6 partial and 2 total meniscectomies. Two patients subsequently underwent reimplantation. Histologic examination of the removed tissue revealed reduced cellularity as compared with normal or torn native menisci. Four specimens also underwent detailed cytokine evaluation and demonstrated reduced cytokine expression compared with controls. While successful in alleviating compartmental pain that may be a late consequence of major meniscectomy, allograft menisci are repopulated with fewer cells than are present in normal or torn native menisci. These cells also demonstrate potentially reduced function, as measured by decreased growth factor production. This decreased biologic activity may be a factor that contributes to the high frequency of retears noted in this and prior studies.


Subject(s)
Menisci, Tibial/transplantation , Adult , Anterior Cruciate Ligament/surgery , Anterior Cruciate Ligament Injuries , Arthralgia/etiology , Arthralgia/prevention & control , Arthroscopy , Female , Follow-Up Studies , Humans , Joint Instability/etiology , Joint Instability/physiopathology , Joint Instability/prevention & control , Knee Joint/diagnostic imaging , Male , Menisci, Tibial/diagnostic imaging , Menisci, Tibial/pathology , Prospective Studies , Radiography , Recovery of Function , Reoperation , Tibial Meniscus Injuries , Transplantation, Homologous , Treatment Outcome
6.
Bioorg Med Chem Lett ; 10(8): 695-8, 2000 Apr 17.
Article in English | MEDLINE | ID: mdl-10782666

ABSTRACT

Synthesis and SAR of N-[4-[(4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-y l)carbonyl]phenyl]benzamides as arginine vasopressin (AVP) receptor antagonists are discussed. Potent orally active AVP receptor antagonists are produced when the benzamide moiety contains a phenyl group at the 2-position. Similar analogues of 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepine and VPA-985 are reported.


Subject(s)
Arginine Vasopressin/antagonists & inhibitors , Azepines/chemical synthesis , Azepines/pharmacology , Animals , Arginine Vasopressin/metabolism , Azepines/chemistry , Azepines/metabolism , Rats , Receptors, Vasopressin/metabolism , Structure-Activity Relationship
7.
Ann N Y Acad Sci ; 878: 61-72, 1999 Jun 30.
Article in English | MEDLINE | ID: mdl-10415720

ABSTRACT

Experimental evidence confirms that the matrix metalloproteinases (MMPs) play a fundamental role in a wide variety of pathologic conditions that involve connective tissue destruction including osteoarthritis and rheumatoid arthritis, tumor metastasis and angiogenesis, corneal ulceration, multiple sclerosis, periodontal disease, and atherosclerosis. Modulation of MMP regulation is possible at several biochemical sites, but direct inhibition of enzyme action provides a particularly attractive target for therapeutic intervention. Hypotheses concerning inhibition of specific MMP(s) with respect to disease target and/or side-effect profile have emerged. Examples are presented of recent advances in medicinal chemistry approaches to the design of matrix metalloproteinase inhibitors (MMPIs), approaches that address structural requirements and that influence potency, selectivity, and bioavailability. Two important approaches to the design, synthesis, and biological evaluation of MMPIs are highlighted: (1) the invention of alternatives to hydroxamic acid zinc chelators and (2) the construction of nonpeptide scaffolds. One current example in each of these two approaches from our own work is described.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Metalloendopeptidases/antagonists & inhibitors , Animals , Arteriosclerosis/drug therapy , Arteriosclerosis/pathology , Arteriosclerosis/physiopathology , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/pathology , Arthritis, Rheumatoid/physiopathology , Connective Tissue/enzymology , Connective Tissue/pathology , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Extracellular Matrix/enzymology , Humans , Neoplasm Metastasis , Osteoarthritis/drug therapy , Osteoarthritis/pathology , Osteoarthritis/physiopathology , Periodontal Diseases/drug therapy , Periodontal Diseases/pathology , Periodontal Diseases/physiopathology
8.
Bioorg Med Chem Lett ; 9(13): 1733-6, 1999 Jul 05.
Article in English | MEDLINE | ID: mdl-10406632

ABSTRACT

Synthesis and structure-activity relationships (SAR) of arginine vasopressin receptor (AVP) antagonists are described. Potent and orally active compounds are prepared when tricyclic 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine moiety in VPA-985 1 is replaced with a compound 7 or 12.


Subject(s)
Antidiuretic Hormone Receptor Antagonists , Azepines/chemical synthesis , Azepines/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Benzazepines/chemical synthesis , Thiophenes/chemical synthesis , Administration, Oral , Animals , Benzazepines/pharmacology , Fibroblasts , Inhibitory Concentration 50 , Mice , Pyrroles , Structure-Activity Relationship , Thiophenes/pharmacology
13.
J Med Chem ; 26(10): 1393-411, 1983 Oct.
Article in English | MEDLINE | ID: mdl-6604817

ABSTRACT

The synthesis of a series of analogues in which the carboxylic acid group of cetaben is replaced by carboxylate ester, carboxamide, or a variety of other substituent groups is described. Also reported are the syntheses of analogues in which the phenyl ring of cetaben is either modified by the presence of additional substituents or replaced entirely by another moiety. Structure-activity relationships of these compounds both as hypolipidemic agents and as inhibitors of the enzyme fatty acyl-CoA:cholesterol acyltransferase (ACAT) are discussed. Analogue syntheses designed to produce compounds that would be better absorbed orally than cetaben failed to yield any congeners of enhanced biological activity. In contrast, analogue syntheses directed toward non carboxylic acids of similar acidity to cetaben produced a very active class of sulfonamides.


Subject(s)
4-Aminobenzoic Acid/chemical synthesis , Aminobenzoates/chemical synthesis , Arteriosclerosis/drug therapy , 4-Aminobenzoic Acid/pharmacology , 4-Aminobenzoic Acid/therapeutic use , Animals , Benzoates/therapeutic use , Drug Evaluation, Preclinical , Hyperlipidemias/drug therapy , Male , Methods , Rats , Rats, Inbred Strains , Sterol O-Acyltransferase/antagonists & inhibitors , Sterols/blood , Structure-Activity Relationship , Triglycerides/blood , para-Aminobenzoates
14.
J Med Chem ; 26(10): 1378-93, 1983 Oct.
Article in English | MEDLINE | ID: mdl-6604816

ABSTRACT

The syntheses of a series of (aralkylamino)- and (alkylamino)benzoic acids, as well as the corresponding esters and sodium salts, are described. The compounds were evaluated in vivo in rats for serum sterol and triglyceride lowering activity and in vitro for activity in inhibiting the principle cholesterol-esterifying enzyme of the arterial wall, fatty acyl-CoA:cholesterol acyltransferase (ACAT). Based on a combination of these two activities, cataben sodium (150) was selected for development as a hypolipidemic and potential antiatherosclerotic agent.


Subject(s)
4-Aminobenzoic Acid/chemical synthesis , Acyltransferases/antagonists & inhibitors , Aminobenzoates/chemical synthesis , Arteriosclerosis/drug therapy , Sterol O-Acyltransferase/antagonists & inhibitors , 4-Aminobenzoic Acid/pharmacology , 4-Aminobenzoic Acid/therapeutic use , Animals , Drug Evaluation, Preclinical , Hyperlipidemias/drug therapy , Indicators and Reagents , Male , Methods , Rats , Rats, Inbred Strains , Sterols/blood , Structure-Activity Relationship , Triglycerides/blood , para-Aminobenzoates
15.
J Med Chem ; 26(3): 381-93, 1983 Mar.
Article in English | MEDLINE | ID: mdl-6298428

ABSTRACT

A series of 1-[3-(acylthio)-3-aroylpropionyl]-L-proline derivatives was synthesized. A number of these compounds are potent angiotensin converting enzyme (ACE) inhibitors that lowered blood pressure in aorta-coarcted renal hypertensive rats. The most active derivatives are 1-[3(R)-(acetylthio) -3-substituted-benzoyl)-2(S)-methyl-propionyl]-L-prolines with an in vivo activity equivalent to SQ 14,225 (captopril). Structure-activity relationships are discussed. Changes in the configuration of the alpha-methyl group and the S-acetyl group affect the ACE activity. Coupling of 3-(substituted-benzoyl)-2-methylpropionic acids to L-proline via enol lactones is described.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Antihypertensive Agents , Proline/analogs & derivatives , Pyrrolidines/pharmacology , Animals , Blood Pressure/drug effects , Magnetic Resonance Spectroscopy , Proline/pharmacology , Rabbits , Rats , Structure-Activity Relationship , X-Ray Diffraction
16.
J Med Chem ; 24(5): 592-600, 1981 May.
Article in English | MEDLINE | ID: mdl-6113284

ABSTRACT

The synthesis of a series of 6-(substituted-phenyl)-1,2,4-triazolo[4,3-b]pyridazines (VIII) is reported. Some of these derivatives show activity in tests predictive of anxiolytic activity [(a) protection against pentylenetetrazole-induced convulsions; (b) thirsty rat conflict procedure]. They also represent a new class of compound which inhibits [3H]diazepam binding. Structure--activity correlations, as well as the ability of structures VIII to inhibit [3H]diazepam binding (in vitro), are discussed.


Subject(s)
Anti-Anxiety Agents/chemical synthesis , Triazoles/chemical synthesis , Animals , Anticonvulsants , Antihypertensive Agents/chemical synthesis , Binding, Competitive , Chemical Phenomena , Chemistry , Conflict, Psychological , Diazepam/metabolism , Male , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Rats , Triazoles/pharmacology
17.
J Med Chem ; 22(9): 1068-74, 1979 Sep.
Article in English | MEDLINE | ID: mdl-490551

ABSTRACT

A series of (aryloxy)[p-(aryloxy)phenyl]- and (aryloxy)[p-(arylthio)phenyl]acetic acids and esters of general structure 8 were prepared and tested for lipid-lowering activity in normal rats. At a dose of 0.1% of the diet (ca. 100 mg/kg), approximately half of the compounds reduced serum sterols in the range of 20--30% and lowered serum triglycerides by 40--60%. Over 35 analogues lowered serum sterols by 15--25% when fed at 0.03% of diet, and 15 of these maintained their activity at 0.01% of the diet (10 mg/kg). Synthetic methodology and structure-activity relationships are discussed.


Subject(s)
Hypolipidemic Agents/chemical synthesis , Phenylacetates/chemical synthesis , Animals , Esters/chemical synthesis , Esters/pharmacology , Male , Phenylacetates/pharmacology , Rats , Structure-Activity Relationship
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