Changes in platelet function, hemostasis, and prostaglandin expression after treatment with nonsteroidal anti-inflammatory drugs with various cyclooxygenase selectivities in dogs

OBJECTIVE: To determine the effects of nonsteroidal anti-inflammatory drugs of various cyclooxygenase selectivities on hemostasis and prostaglandin expression in dogs. ANIMALS: 8 client-owned dogs with clinical signs of osteoarthritis. PROCEDURES: Dogs received aspirin (5 mg/kg, PO, q 12 h), carprofen (4 mg/kg, PO, q 24 h), deracoxib (2 mg/kg, PO, q 24 h), and meloxicam (0.1 mg/kg, PO, q 24 h) for 10 days each, with an interval of at least 14 days between treatments. On days 0 and 10, blood was collected for platelet aggregation assays, thrombelastography, and measurement of lipopolysaccharide-stimulated prostaglandin E(2), platelet thromboxane B(2) (TXB(2)), and free serum TXB(2) and 6-keto-prostaglandin F (PGF)-1alpha concentrations. RESULTS: Platelet aggregation decreased after treatment with aspirin and carprofen, whereas significant changes from baseline were not detected for the other drugs tested. Thrombelastograms obtained after treatment with carprofen revealed decreased maximum amplitude and alpha-angle, suggesting hypocoagulability. Maximum amplitude and coagulation index increased after treatment with deracoxib. Plasma concentrations of prostaglandin E(2) decreased after treatment with carprofen or deracoxib, and platelet TXB(2) production increased after treatment with aspirin. Serum concentrations of the prostacyclin metabolite 6-keto-PGF-1alpha did not change significantly after treatment with any of the drugs, although the ratio of free TXB(2) to 6-keto-PGF-1alpha decreased slightly after treatment with carprofen and increased slightly after treatment with deracoxib. CONCLUSIONS AND CLINICAL RELEVANCE: At the dosages tested, treatment with meloxicam affected platelet function minimally in dogs with osteoarthritis. Treatment with carprofen decreased clot strength and platelet aggregation. Clot strength was increased after treatment with deracoxib.     

Genetic mapping in human disease

Genetic mapping provides a powerful approach to identify genes and biological processes underlying any trait influenced by inheritance, including human diseases. We discuss the intellectual foundations of genetic mapping of Mendelian and complex traits in humans, examine lessons emerging from linkage analysis of Mendelian diseases and genome-wide association studies of common diseases, and discuss questions and challenges that lie ahead.     

Two latent variable risk assessment approaches for mixed continuous and discrete outcomes from developmental toxicity data

Measurements of both continuous and discrete outcomes are encountered in many statistical problems. Here we consider the particular context of teratology studies, where quantitative risk asessment is aimed at determining the effect of dose on the probability that an individual fetus is malformed or of low birth weight, both being important measures of teratogenicity. We will introduce two different joint marginal mean models for outcomes of a mixed nature. First, we propose the Plackett-Dale approach, where for each binary outcome it is assumed that there exists an underlying glatent variable. The latent malformation outcomes are then assumed to follow a Plackett distribution. The second approach we consider is a probit approach. Here it is assumed that there exists an underlying continuous variable for each binary outcome, so the joint distribution for weight and malformation can be assumed to follow a multivariate normal distribution. In both cases, specification of the full distribution will be avoided using pseudolikelihood and generalized estimating equations methodology, respectively. Quantitative risk assessment is illustrated using data from two developmental toxicology experiments.     

What can mathematical models bring to the control of equine influenza?

Mathematical modelling of infectious disease is increasingly regarded as an important tool in the development of disease prevention and control measures. This article brings together key findings from various modelling studies conducted over the past 10 years that are of relevance to those on the front line of the battle against equine influenza. The Summary is available in Chinese – see Supporting information.     

Successful Management of a Case of Pregnancy Failure in a Degu (Octodon degus)

A 3-month-old female degu (Octodon degus) was presented because blood was noticed in its cage. On physical examination, firm masses were palpable within the caudal abdomen and traces of blood appeared to be coming from the patient’s vaginal opening. Radiographic images showed areas of ill-defined mineralization within the uterus, consistent with fetus formation. Three fetuses could be identified. Ultrasound examination of the degu failed to confirm viable fetal heartbeats. Pregnancy failure with fetal death was suspected. Overnight 1 fetus was passed, but medical therapy with oxytocin failed to induce delivery of the 2 remaining fetuses by the following morning. The degu was therefore anesthetized, an ovariohysterectomy was performed, and the patient made an uncomplicated recovery. Histopathological examination of the fetuses failed to identify any abnormalities. In the uterus, histology confirmed a minimal to mild diffuse, chronic active endometritis. The definitive cause of fetal death was not identified.     

Synthesis,Structural and Pharmacological Characterizations of CIC,a Novel α-Conotoxin with an Extended N-Terminal Tail

Cone snails are venomous marine predators that rely on fast-acting venom to subdue their prey and defend against aggressors. The conotoxins produced in the venom gland are small disulfide-rich peptides with high affinity and selectivity for their pharmacological targets. A dominant group comprises α-conotoxins, targeting nicotinic acetylcholine receptors. Here, we report on the synthesis, structure determination and biological activity of a novel α-conotoxin, CIC, found in the predatory venom of the piscivorous species Conus catus and its truncated mutant Δ-CIC. CIC is a 4/7 α-conotoxin with an unusual extended N-terminal tail. High-resolution NMR spectroscopy shows a major influence of the N-terminal tail on the apparent rigidity of the three-dimensional structure of CIC compared to the more flexible Δ-CIC. Surprisingly, this effect on the structure does not alter the biological activity, since both peptides selectively inhibit α3β2 and α6/α3β2β3 nAChRs with almost identical sub- to low micromolar inhibition constants. Our results suggest that the N-terminal part of α-conotoxins can accommodate chemical modifications without affecting their pharmacology.     

Brandt's cormorant diet (1994–2012) indicates the importance of fall ocean conditions for northern anchovy in central California

Effective ecosystem‐based management requires a comprehensive understanding of the functional links in the system. In many marine systems, forage species constitute a critical link between primary production and upper trophic level marine predators. As top predators, seabirds can be indicators of the forage species they consume and the ocean processes that influence these populations. We analyzed the diet and breeding success for the years 1994, 2003, 2005, and 2007–2012 of the Brandt's cormorant (Phalacrocorax penicillatus), a piscivorous diving seabird, breeding in central California, to evaluate the extent to which cormorant diet composition relates to prey availability, and how diet composition relates to breeding success and ocean conditions. Cormorant diet was primarily composed of young‐of‐the‐year (YOY) northern anchovy (Engraulis mordax), YOY rockfish (Sebastes spp.), and several species of small flatfish (order Pleuronectiformes). YOY rockfish consumption was positively related to their abundance as measured in a late spring pelagic midwater trawl survey. Northern anchovy appeared to be the most important prey as its consumption was positively related to cormorant breeding success. More northern anchovy were consumed in years where warm‐water conditions prevailed in the fall season before cormorant breeding. Thus, warm ocean conditions in the fall appear to be an important contributing factor in producing a strong year‐class of northern anchovy in central California and consequently a strong‐year class of Brandt's cormorant on the Farallon Islands.