Paraherquamide is a novel natural anthelmintic product with a mode of action that is incompletely characterized. Nicotine and cholinergic-anthelmintic agonists of different chemical classes were used to produce contraction in Ascaris muscle strips. Paraherquamide and a semisynthetic derivative, 2-deoxy-paraherquamide, antagonized these responses. Analysis of the actions of the antagonists was made using the simple competitive model and nonlinear regression to estimate the pK B values of the antagonists. The analysis was tested using Clark plots. The pK B values for paraherquamide were: nicotine, 5.86 Ϯ 0.14; levamisole, 6.61 Ϯ 0.19; pyrantel, 6.50 Ϯ 0.11; and bephenium, 6.75 Ϯ 0.15. The pK B of nicotine was significantly different from the pK B values for levamisole, pyrantel, and bephenium, showing that paraherquamide can distinguish a subtype of cholinergic receptors sensitive to nicotine and a subtype of cholinergic receptors sensitive to levamisole, pyrantel, and bephenium. The pK B values for 2-deoxy-paraherquamide were: levamisole, 5.31 Ϯ 0.13; pyrantel, 5.63 Ϯ 0.10; and bephenium, 6.07 Ϯ 0.13. The Clark plots of the antagonism illustrated the degree of fit to the competitive model for 2-deoxy-paraherquamide. 2-Deoxy-paraherquamide selectively antagonized the effects of bephenium; the pK B values of levamisole and pyrantel were significantly different from the pK B of bephenium. Paraherquamide and 2-deoxy-paraherquamide are selective competitive cholinergic antagonists that distinguish subtypes of cholinergic receptor in Ascaris muscle corresponding to nicotine-, levamisole-, and bephenium-sensitive receptors.Nematode parasite infections of humans and animals cause disease with loss of productivity, debility, and occasionally death. Ascariasis and hookworm infections are carried by 1.6 billion people throughout the world and in 2% of cases cause loss of life. The use of therapeutic compounds forms a major component of control, and the development of novel therapeutic agents is required to deal with the increasing levels of resistance to existing drugs.Paraherquamide (Fig. 1) is a novel anthelmintic (Yamazaki et al., 1981) that is an alkaloid fermentation product originally isolated from Penicillium paraherquii. The anthelmintic property of paraherquamide was first identified using jirds infected with Trichostrongylus colubriformis (Ostlind et al., 1990). Paraherquamide produces paralysis of parasitic nematodes in culture, without an effect on ATP, suggesting that it does not act as a metabolic poison (Thompson et al., 1996). Interestingly, one of the toxic effects of paraherquamide in the dog (Shoop et al., 1990) is a prolapsed nictitating membrane, an effect that suggests antagonism of neuronal nicotinic receptors (nAChRs). Recently, it has been reported (E.

BackgroundThe original equine sepsis score provided a method of identifying foals with sepsis. New variables associated with sepsis have been evaluated, but the sepsis score has not been updated.ObjectivesTo evaluate the sensitivity and specificity of 2 updated sepsis scores and the systemic inflammatory response syndrome (SIRS) criteria in regard to detecting sepsis in foals.AnimalsTwo‐hundred and seventy‐three ill foals and 25 healthy control foals.MethodsHistorical, physical examination, and clinicopathologic findings were used to calculate the original sepsis score and 2 updated sepsis scores. SIRS criteria were also evaluated. Sepsis scores and positive SIRS scores were statistically compared to foals with sepsis.ResultsOne‐hundred and twenty‐six foals were septic and 147 sick‐nonseptic. The original and updated sepsis scores were significantly higher in septic foals as compared to sick‐nonseptic and healthy foals. The sensitivity and specificity of the updated sepsis scores to predict sepsis were not significantly better than those of the original sepsis score. One‐hundred and twenty‐seven of 273 (46.5%) foals met the original SIRS criteria and 88/273 (32%) foals met the equine neonatal SIRS criteria. The original SIRS criteria had similar sensitivity and specificity for predicting sepsis as did the 3 sepsis scores in our study.Conclusions and Clinical ImportanceThe updated sepsis scores did not provide improved ability in predicting sepsis. Fulfilling the original SIRS criteria provided similar sensitivity and specificity in predicting sepsis as the modified sepsis score and might serve as a diagnostic aid in identifying foals at risk for sepsis.

Background: Insulin resistance has been associated with risk of laminitis in horses. Genes coding for proinflammatory cytokines and chemokines are expressed more in visceral adipose tissue than in subcutaneous adipose tissue of insulin-resistant (IR) humans and rodents.Hypothesis/Objectives: To investigate adipose depot-specific cytokine and chemokine gene expression in horses and its relationship to insulin sensitivity (SI).Animals: Eleven light breed mares. Methods: Animals were classified as IR (SI 5 0.58 AE 0.31 Â 10 À4 L/min/mU; n 5 5) or insulin sensitive (IS; SI 5 2.59 AE 1.21 Â 10 À4 L/min/mU; n 5 6) based on results of a frequently sampled intravenous glucose tolerance test. Omental, retroperitoneal, and mesocolonic fat was collected by ventral midline celiotomy; incisional nuchal ligament and tail head adipose tissue biopsy specimens were collected concurrently. The expression of tumor necrosis factor-a (TNF-a), interleukin (IL)-1b, IL-6, plasminogen activator inhibitor-1 (PAI-1), and monocyte chemoattractant protein-1 (MCP-1) in each depot was measured by real-time quantitative polymerase chain reaction. Data were analyzed by 2-way analysis of variance for repeated measures (P o .05).Results: No differences in TNF-a, IL-1b, IL-6, PAI-1, or MCP-1 mRNA concentrations were noted between IR and IS groups for each depot. Concentrations of mRNA coding for IL-1b (P 5 .0005) and IL-6 (P 5 .004) were significantly higher in nuchal ligament adipose tissue than in other depots.Conclusions and Clinical Importance: These data suggest that the nuchal ligament depot has unique biological behavior in the horse and is more likely to adopt an inflammatory phenotype than other depots examined. Visceral fat may not contribute to the pathogenesis of obesity-related disorders in the horse as in other species.

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Background: Insulin resistance (IR) has been widely recognized in humans, and more recently in horses, but its underlying mechanisms are still not well understood. The translocation of glucose transporter 4 (GLUT4) to the cell surface is the limiting step for glucose uptake in insulin-sensitive tissues. Although the downstream signaling pathways regulating GLUT translocation are not well defined, AS160 recently has emerged as a potential key component. In addition, the role of GLUT12, one of the most recently identified insulin-sensitive GLUTs, during IR is unknown.Hypothesis/Objectives: We hypothesized that cell-surface GLUT will be decreased in muscle by an AS160-dependent pathway in horses with IR.Animals: Insulin-sensitive (IS) or IR mares (n 5 5/group). Methods: Muscle biopsies were performed in mares classified as IS or IR based on results of an insulin-modified frequently sampled IV glucose tolerance test. By an exofacial bis-mannose photolabeled method, we specifically quantified active cellsurface GLUT4 and GLUT12 transporters. Total GLUT4 and GLUT12 and AS160 protein expression were measured by Western blots.Results: IR decreased basal cell-surface GLUT4 expression (P 5 .027), but not GLUT12, by an AS160-independent pathway, without affecting total GLUT4 and GLUT12 content. Cell-surface GLUT4 was not further enhanced by insulin stimulation in either group.Conclusions and Clinical Importance: IR induced defects in the skeletal muscle glucose transport pathway by decreasing active cell-surface GLUT4.