RESUMEN
Appaloosa horses are predisposed to equine recurrent uveitis (ERU), an immune-mediated disease characterized by recurring inflammation of the uveal tract in the eye, which is the leading cause of blindness in horses. Nine genetic markers from the ECA1 region responsible for the spotted coat color of Appaloosa horses, and 13 microsatellites spanning the equine major histocompatibility complex (ELA) on ECA20, were evaluated for association with ERU in a group of 53 Appaloosa ERU cases and 43 healthy Appaloosa controls. Three markers were significantly associated (corrected P-value <0.05): a SNP within intron 11 of the TRPM1 gene on ECA1, an ELA class I microsatellite located near the boundary of the ELA class III and class II regions and an ELA class II microsatellite located in intron 1 of the DRA gene. Association between these three genetic markers and the ERU phenotype was confirmed in a second population of 24 insidious ERU Appaloosa cases and 16 Appaloosa controls. The relative odds of being an ERU case for each allele of these three markers were estimated by fitting a logistic mixed model with each of the associated markers independently and with all three markers simultaneously. The risk model using these markers classified ~80% of ERU cases and 75% of controls in the second population as moderate or high risk, and low risk respectively. Future studies to refine the associations at ECA1 and ELA loci and identify functional variants could uncover alleles conferring susceptibility to ERU in Appaloosa horses.
Asunto(s)
Enfermedades de los Caballos/genética , Uveítis/veterinaria , Alelos , Animales , Marcadores Genéticos , Caballos , Repeticiones de Microsatélite , Modelos Genéticos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Uveítis/genéticaRESUMEN
Recurrent exertional rhabdomyolysis is a heritable disorder that results in painful skeletal muscle cramping with exercise in up to 10% of all Thoroughbred racehorses. Here, we report a genome-wide association study with 48 282 SNPs analyzed among 48 case and 37 control Thoroughbreds. The most significant SNPs spanned approximately 13 Mb on ECA16, and the P-value of the most significant SNP after correcting for population structure was 8.0 × 10(-6) . This region on ECA16 was further evaluated by genotyping 247 SNPs in both the initial population and a second population of 34 case and 98 control Thoroughbreds. Several SNPs across the 13-Mb region on ECA16 showed significance when each population was analyzed separately; however, the exact positions of the most significant SNPs within this region on ECA16 varied between populations. This variability in location may be attributed to lack of power owing to insufficient sample sizes within each population individually, or to the relative distribution of long, conserved haplotypes, characteristic of the Thoroughbred breed. Future genome-wide association studies with additional horses would likely improve the power to resolve casual loci located on ECA16 and increase the likelihood of detecting any additional loci on other chromosomes contributing to disease susceptibility.
Asunto(s)
Mapeo Cromosómico/veterinaria , Estudio de Asociación del Genoma Completo/veterinaria , Enfermedades de los Caballos/genética , Rabdomiólisis/veterinaria , Animales , Cromosomas de los Mamíferos/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Caballos , Masculino , Músculo Esquelético/patología , Esfuerzo Físico , Polimorfismo de Nucleótido Simple , Rabdomiólisis/genéticaRESUMEN
Quetiapine is a new antipsychotic drug that has been available in the United States since September 1997. It belongs to a new chemical class of drugs called the dibenzothiazepine derivatives and is easily detected with a basic drug screen. The Los Angeles County Department of Coroner Toxicology Laboratory has encountered quetiapine in seven postmortem cases. Tissue distributions were determined in each of the seven cases. The analysis of quetiapine from postmortem specimens consisted of an n-butylchloride basic extraction with presumptive identification and quantitation on a gas chromatograph-nitrogen-phosphorus detector. Linearity was achieved from 0.10 to 3.0 mg/L with a limit of quantitation of 0.10 mg/L. Confirmation of quetiapine was performed on a gas chromatograph-mass spectrometer by comparison with a pure analytical standard. The tissue distribution of quetiapine was as follows: heart blood present, but less than (+<) 0.10-49 mg/L (seven cases); femoral blood +< 0.10-1.4 mg/L (five cases); liver +< 0.10-112 mg/kg (five cases); spleen 4.0 mg/kg (one case); urine 0-3.0 mg/L (two cases); bile 0.60-7.5 mg/L (three cases); and gastric contents +< 0.01-18 mg total (five cases). To our knowledge, this is the first report of the presence of quetiapine in postmortem specimens.
Asunto(s)
Antipsicóticos/sangre , Dibenzotiazepinas/sangre , Adulto , Autopsia , Femenino , Medicina Legal/métodos , Cromatografía de Gases y Espectrometría de Masas , Humanos , Masculino , Fumarato de Quetiapina , Valores de Referencia , Sensibilidad y EspecificidadRESUMEN
Mirtazapine is a new antidepressant agent that entered the United States market in April 1996. To date, the literature provides limited information about therapeutic blood concentrations and virtually no information about postmortem levels. The Los Angeles County Coroner's Toxicology Laboratory has encountered 13 cases where postmortem tissue distributions of mirtazapine were determined. The analysis of mirtazapine from postmortem specimens (2-mL sample size) consisted of an n-butylchloride basic extraction procedure with identification and quantitation on a gas chromatograph-nitrogen-phosphorus detector. Linearity was achieved from 0.025 mg/L to 3.0 mg/L with a limit of quantitation of 0.025 mg/L. Confirmation of mirtazapine was performed on a gas chromatograph-mass spectrometer by comparison with a pure analytical standard. The tissue distribution of mirtazapine are in the following concentration ranges: heart blood 0.03-0.57 mg/L (13 cases), femoral blood 0.04-0.24 mg/L (9 cases), vitreous 0.06-0.10 mg/L (3 cases), liver 0.32-2.1 mg/kg (12 cases), bile 0.40-6.6 mg/L (7 cases), urine 0.12-2.5 mg/L (11 cases), kidney 0.23 mg/kg (1 case), spleen 0.17 mg/kg (1 case), and gastric 0.001-2.7 mg total (9 cases). Mirtazapine was not implicated in the cause of death in any of the 13 cases studied. These cases are being presented to aid the forensic toxicologist in the evaluation of postmortem mirtazapine levels.
Asunto(s)
Antidepresivos Tricíclicos/farmacocinética , Mianserina/análogos & derivados , Distribución Tisular/fisiología , Adulto , Anciano , Autopsia , Cromatografía de Gases , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Masculino , Mianserina/farmacocinética , Persona de Mediana Edad , MirtazapinaRESUMEN
The objective of this study was to determine the effect of high stearic acid (SA) diets versus high polyunsaturated fatty acid (PUFA) diets on several measures of lipid peroxidation in vivo. Sprague-Dawley rats were fed diets that differed only in the fat source (8% by weight) for 19 weeks. High SA fats were beef tallow (BT) and cocoa butter (CB), high PUFA fats were soybean oil (SO) and menhaden oil (MO). Urine was analyzed for lipophilic aldehydes, the secondary products of lipid peroxidation, by HPLC. Decreases (P<0.05) were found for 4 nonpolar lipophilic aldehydes and related carbonyl compounds (NPC) and 4 polar lipophilic aldehydes and related carbonyl compounds (PC) when the BT-fed group was compared to the SO-fed group. Decreases were also found to be significant for total NPC (P<0.01) and total PC (P<0.05) between BT and SO-fed groups. Serum increase in resistance to oxidation (P<0.01) was found in the BT group when compared to the SO group. The differences in urine and serum measurements in the present experiment indicate lower level of lipid peroxidation in vivo due to the consumption of high SA containing BT diet compared to high PUFA containing SO diet without raising serum triglycerides and cholesterol levels significantly for the BT-fed groups.
Asunto(s)
Grasas de la Dieta/farmacología , Peroxidación de Lípido/efectos de los fármacos , Ácidos Esteáricos/farmacología , Aldehídos/orina , Animales , Peso Corporal/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/análisis , Grasas Insaturadas en la Dieta/administración & dosificación , Grasas Insaturadas en la Dieta/análisis , Grasas Insaturadas en la Dieta/farmacología , Ingestión de Alimentos/efectos de los fármacos , Grasas/química , Ácidos Grasos/análisis , Femenino , Oxidación-Reducción/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Ácidos Esteáricos/administración & dosificaciónRESUMEN
Although selenium or vitamin E deficiencies or changing from cereal-based to purified diets augments paraquat toxicity, the action of other dietary components in normal animals fed nutritionally adequate diets is not clear. Upon injection of mice with antiinflammatory agents, a protective action of the corn oil vehicle against paraquat lethalities was noted. This preventive action of a large parenteral administration of unknown components in oils served as the basis for this study. Intramuscular injection of various vegetable oils protected similarly, indicating that in mixtures, the degree of lipid saturation did not seem to be an important factor. Injection of the monounsaturated fatty acid oleic acid decreased oral paraquat lethalities in mice, but linoleic, gamma-linoleic or linolenic acids were not protective in either male or female mice. Measurement of paraquat concentrations in various tissues at various times after administration indicated no effect of corn oil on paraquat distribution. Although the exact mechanism of the complex nature of oil protection against paraquat toxicity in mice is still unknown, this study provides evidence for in vivo oxidant protection by a monounsaturated fatty acid.
Asunto(s)
Aceites/administración & dosificación , Ácidos Oléicos/administración & dosificación , Paraquat/envenenamiento , Animales , Ácidos Grasos/administración & dosificación , Femenino , Inyecciones Intramusculares , Masculino , Ratones , Ácido Oléico , Paraquat/análisis , Intoxicación/prevención & control , Distribución TisularRESUMEN
Combined whole body hyperthermia (WBHT) and interleukin-2 (IL-2) significantly reduces the growth rate of subcutaneous 10 day MCA-105 tumors in C57BL/6 mice, but not in 3-day tumors. Others have shown that macroscopic tumors show reduced growth with tumor necrosis factor alpha (TNF alpha) therapy compared with microscopic tumors. We sought to determine if the antitumor effect of combined WBHT+IL-2 is mediated by TNF alpha. After inducing MCA-105 sarcoma in the right hind limb on Day 0, C57BL/6 mice were randomized to treatment groups (six each) on Day 10: control, WBHT alone, IL-2 alone, and WBHT+IL-2. Pooled serum was assessed by ELISA for TNF alpha level: control (350 pg/ml), WBHT (250 pg/ml), IL-2 alone (>2450 pg/ml), and WBHT+IL-2 (>2450 pg/ml). Using the same tumor model, animals were treated in the following groups: control, WBHT+IL-2, anti-TNF alpha Ab alone, and WBHT+IL-2+Ab. Mice in the control, Ab alone, and WBHT+IL-2+Ab groups had similar tumor growth rates (P > 0.05). However, the growth rate for WBHT+IL-2 was significantly lower (P < 0.05) compared to the other three groups. These data demonstrate significantly increased TNF alpha levels in mice treated with combined therapy and abrogation of the antitumor effect of WBHT+IL-2 therapy by the addition of anti-TNF alpha Ab with a tumor growth rate similar to that observed in untreated mice, suggesting that the antitumor effect of WBHT+IL-2 is mediated at least in part by TNF alpha.