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Hip resurfacing offers advantages for young active patients afflicted with hip osteoarthritis, and may also be a beneficial treatment for adult canines. Conventional hip resurfacing uses metal-on-metal bearings to preserve bone stock, but it may be feasible to use metal-on-polyethylene bearings to reduce metal wear debris, while still preserving bone. This study characterized the short-term wear behavior of a novel hip resurfacing implant for canines that uses a 1.5 mm thick liner of highly cross-linked polyethylene in the acetabular component. This implant was tested in an orbital bearing machine that simulated canine gait for 1.1 million cycles. Wear of the liner was evaluated using gravimetric analysis and by measuring wear depth with an optical scanner. The liners had a steady-state mass wear rate of 0.99 ± 0.17 mg per million cycles, and an average wear depth in the central liner region of 0.028 mm. No liners, shells, or femoral heads had any catastrophic failure due to yielding or fracture. These results suggest that the thin liners will not prematurely crack after implantation in canines. This is the first hip resurfacing device developed for canines, and this study is the first to characterize the in vitro wear of highly cross-linked polyethylene liners in a hip resurfacing implant. The canine implant developed in this study may be an attractive treatment option for canines afflicted with hip osteoarthritis, and can serve as a valuable animal model to support the development of metal-on-polyethylene hip resurfacing technology for human patients. This article is protected by copyright. All rights reserved

• Osteoarthritis is a “total joint disease,” with many different tissue types contributing to the pain response. • Cyclooxygenase-2, prostaglandin E2, interleukin-1, matrix metalliproteinase-13, inducible nitric oxide synthase, and tumor necrosis factor- are all major players in the catabolic process of degenerative joint disease. • Osteoarthritis cannot be cured, but can be managed quite effectively with a multi-modal approach. • As cancer progresses, changing factors may complicate the pain state. Only through an understanding of the mechanisms associated with dynamic cancer pain, can we manage patients’ pain with evidence-based confidence.

Background Induced sputum is used to sample inflammatory cells, predominantly neutrophils and macrophages, from the airways of COPD patients. The author’s aim was to identify candidate genes associated with the degree of airflow obstruction and the extent of emphysema by expression profiling, and then to confirm these findings for selected candidates using PCR and protein analysis. Methods Two sputum studies were performed in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2e4 COPD ex-smokers from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort. First, gene array profiling at baseline in samples from 148 patients. The findings were replicated in a separate population of 176 patients using real-time PCR. The findings for one selected gene IL-18R were further analysed using immunohistochemistry in lung tissue and induced sputum from patients outside the ECLIPSE cohort. Results Gene expression profiling revealed changes in 277 genes associated with GOLD stage 2v ersus 3a nd 4, and 198 genes with changes associated with the degree of emphysema (p

What role should the extended sectors of the U.S. bond market—specifically high-yield bonds (HY) and emerging market debt (EMD)—play in a well-diversified portfolio of a U.S.-based institutional investor? Should these sectors be considered separate asset classes? At what point should the decision be made on whether to allocate assets to HY and EMD, and what are the important considerations that should guide the decision? An answer to these questions tests the relationships between these sectors and the major asset classes customarily held by U.S. institutional investors.

The authors use a simulation methodology to assess the potential value added and residual risk from active management in the Japanese bond market. They examine the performance potential of taking bets on both credit sectors and interest rates, as well as combination strategies. They compare the results from taking bets of different sizes and skill levels to the returns of actual managers and to simulated U.S. strategies over the same period. Illiquidity in Japanese spread sectors severely limits the opportunity for managers to add value using credit strategies instead of the established broad market benchmark, even at high skill levels.

Objective—To determine the cardiorespiratory effects of preemptive atropine administration in dogs sedated with medetomidine. Design—Randomized crossover trial. Animals—12 healthy adult dogs. Procedures—Dogs underwent 6 treatments. Each treatment consisted of administration of atropine (0.04 mg/kg [0.018 mg/lb] of body weight, IM) or saline solution (0.9% NaCl, 1 ml, IM) and administration of medetomidine (10, 20, or 40 µg/kg [4.5, 9.1, or 18.2µg/lb], IM) 10 minutes later. Treatments were administered in random order, with a minimum of 1 week between treatments. Cardiorespiratory effects before and after atropine and medetomidine administration were assessed. Duration of lateral recumbency and quality of sedation and recovery were assessed. Results—Bradycardia (heart rate < 60 beats/min) was seen in all dogs when saline solution was administered followed by medetomidine, and the dose of medetomidine was not associated with severity or frequency of bradycardia or second-degree heart block. However, a medetomidine dose-dependent increase in mean and diastolic blood pressures was observed, regardless of whether dogs received saline solution or atropine. Preemptive atropine administration effectively prevented bradycardia and seconddegree heart block but induced pulsus alternans and hypertension. The protective effects of atropine against bradycardia lasted 50 minutes. Blood gas values were within reference limits during all treatments and were not significantly different from baseline values. Higher doses of medetomidine resulted in a longer duration of lateral recumbency. Conclusions and Clinical Relevance—Preemptive administration of atropine in dogs sedated with medetomidine effectively prevents bradycardia for 50 minutes but induces hypertension and pulsus alternans. ( J Am Vet Med Assoc 2001;218:52–58)

Objective—To evaluate effects of medetomidine on anesthetic dose requirements, cardiorespiratory variables, plasma cortisol concentrations, and behavioral pain scores in dogs undergoing ovariohysterectomy. Design—Randomized, prospective study. Animals—12 healthy Walker-type hound dogs. Procedure—Dogs received medetomidine (40 µg/kg [18.2 µg/lb] of body weight, IM; n = 6) or saline (0.9% NaCl) solution (1 ml, IM; 6) prior to anesthesia induction with thiopental; thiopental dose needed for endotracheal intubation was compared between groups. Ovariohysterectomy was performed during halothane anesthesia. Blood samples were obtained at various times before drug administration until 300 minutes after extubation. Various physiologic measurements and end-tidal halothane concentrations were recorded. Results—In medetomidine-treated dogs, heart rate was significantly lower than in controls, and blood pressure did not change significantly from baseline. Plasma cortisol concentrations did not increase significantly until 60 minutes after extubation in medetomidine-treated dogs, whereas values in control dogs were increased from time of surgery until the end of the recording period. Control dogs had higher pain scores than treated dogs from extubation until the end of the recording period. Conclusion and Clinical Relevance—Administration of medetomidine reduced dose requirements for thiopental and halothane and provided postoperative analgesia up to 90 minutes after extubation. Dogs undergoing ovariohysterectomy by use of thiopental induction and halothane anesthesia benefit from analgesia induced by medetomidine administered prior to anesthesia induction. Additional analgesia is appropriate 60 minutes after extubation. (J Am Vet Med Assoc 2000;217:509–514)

For U.S. two-way tactical asset allocation (TAA) managers, performance is a function of at least two factors: forecasting ability and tilt size. Assessing the relative performance across a universe of managers is made difficult because of small peer group and relative short return histories. Simulated performance universes are used to decompose the source of relative performance and to overcome the small sample problems. Surprising, little forecasting ability is required, on average, to provide positive excess returns. Portfolio risk, measured as the probability of underperforming the benchmark, decreases with forecasting skill of U.S. TAA managers and demonstrates that after accounting for equity tilt, size, sample period, and length, seemingly equivalent managers possess vastly different levels of forecasting ability.

Patients with chronic obstructive pulmonary disease (COPD) who are defined as frequent exacerbators suffer with 2 or more exacerbations every year. The molecular mechanisms responsible for this phenotype are poorly understood. We investigated gene expression profile patterns associated with frequent exacerbations in sputum and blood cells in a well-characterised cohort. Samples from subjects from the ECLIPSE COPD cohort were used; sputum and blood samples from 138 subjects were used for microarray gene expression analysis, while blood samples from 438 subjects were used for polymerase chain reaction (PCR) testing. Using microarray, 150 genes were differentially expressed in blood (>±1.5 fold change, p≤0.01) between frequent compared to non-exacerbators. In sputum cells, only 6 genes were differentially expressed. The differentially regulated genes in blood included downregulation of those involved in lymphocyte signalling and upregulation of pro-apoptotic signalling genes. Multivariate analysis of the microarray data followed by confirmatory PCR analysis identified 3 genes that predicted frequent exacerbations; B3GNT, LAF4 and ARHGEF10. The sensitivity and specificity of these 3 genes to predict the frequent exacerbator phenotype was 88% and 33% respectively. There are alterations in systemic immune function associated with frequent exacerbations; down-regulation of lymphocyte function and a shift towards pro-apoptosis mechanisms are apparent in patients with frequent exacerbations.

Chronic obstructive pulmonary disease (COPD) is an increasing health problem primarily associated with cigarette smoking, and one of the leading causes of morbidity and mortality worldwide. Despite recent advances in understanding the pathogenesis of the disease, overall patient outcome remains poor with limited therapeutic intervention. Chronic inflammation, an imbalance between proteolytic and anti-proteolytic activities (leading to lung parenchyma destruction) and excessive oxidative stress contribute to COPD pathophysiology. Oxidative stress-triggered apoptosis of alveolar structural cells, including epithelial cells, may be an important event in the development of COPD. In this study, we developed a cell-based oxidative stress-induced apoptosis assay and performed a high-throughput screen (HTS) using a human druggable genome siRNA library. Our results have identified potential novel pathways (e.g. unfolded protein response, proteosomal activity) and targets (e.g. MAP3K14, HMGB2) that regulate the response of lung epithelial cells to oxidative stress. This assay has proven to be a useful tool for the identification of potential new therapeutic targets for lung disease.

This study examines the feasibility and potential benefits of implementing a blood management program at the Mike O'Callaghan Federal Hospital (MOFH). The study evaluated two major courses of action for potential implementation of blood utilization practices. Analyses indicated that implementation of a full-scale program in the surgical setting would not significantly impact the MOFH from a strict cost-benefit standpoint. In the medical services segments, however, implementing consistent, evidence-based peer review procedures and eliminating autologous donations could potentially save the MOFH more than $120,000 over the next three years. Integral to the potential savings is the initiation of a blood management committee. The oversight and guidance provided by the committee would be the driving force for reducing the number of allogeneic transfusions occurring in the facility. Fewer transfusions correlate to fewer transfusion reactions, reduced risk of infection, and fewer surgical complications. Reducing the number of transfusions will have widespread benefits for both patient safety and the bottom line of the MOFH. Following through with the blood management committee recommendation also opens the door for several future studies which could also provide financial and operational benefits to the MOFH.

Recent advances in clinical, pathological and neuroscience studies have identified disease-modifying therapeutic approaches for Alzheimer's disease that are now in clinical trials. This has highlighted the need for reliable and convenient biomarkers for both early disease diagnosis and a rapid signal of drug efficacy. We describe the identification and assessment of a number of candidate biomarkers in patients with Alzheimer's disease and the correlation of those biomarkers with rosiglitazone therapeutic efficacy, as represented by a change in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). Plasma from 41 patients with Alzheimer's disease were analysed by open platform proteomics at baseline and after receiving 8 mg rosiglitazone for 24 weeks. From a comparison of protein expression following treatment with rosiglitazone, 97 proteins were observed to be differentially expressed with a p-value

Emerging disease modifying therapeutic strategies for Alzheimer's disease (AD) have generated a critical need for biomarkers of early stage disease. Here, we describe the identification and assessment of a number of candidate biomarkers in patients with mild to moderate probable AD. Plasma from 47 probable Alzheimer's patients and 47 matched controls were analysed by proteomics to define a significant number of proteins whose expression appeared to be associated with AD. These were compared to a similar proteomic comparison of a mouse transgenic model of amyloidosis, which showed encouraging overlap with the human data. From these studies a prioritised list of 31 proteins were then analysed by immunoassay and/or functional assay in the same human cohort to verify the changes observed. Eight proteins continued to show significance by either immunoassay or functional assay in the human plasma and these were tested in a further set of 100 probable AD patients and 100 controls from the original cohort. From our data it appeared that two proteins, serpin F1 (pigment epithelium-derived factor) and complement C1 inhibitor are down-regulated in plasma from AD patients.

Objective—To identify factors associated with gastrointestinal tract perforation in dogs being treated with a selective cyclooxygenase-2 (COX-2) inhibitor (deracoxib). Design—Retrospective study. Animals—29 dogs. Procedure—The Novartis Animal Health pharmacovigilance database was searched for records of dogs treated with deracoxib in which gastrointestinal tract perforation was documented. Results—16 of the 29 (55%) dogs had received deracoxib at a dosage higher than that approved by the FDA for the particular indication being treated, with 25 (86%) dogs having received deracoxib at a dosage > 2 mg/kg/d (0.9 mg/lb/d). Seventeen (59%) dogs had received at least 1 other nonsteroidal anti-inflammatory drug (NSAID) or a corticosteroid in close temporal association (within 24 hours) with deracoxib administration (ie, immediately before or following). In all, 26 (90%) dogs had received deracoxib at a higher-than-approved dosage or had received at least 1 other NSAID or corticosteroid in close temporal association with deracoxib administration. Twenty dogs died or were euthanatized, and 9 survived. Conclusions and Clinical Relevance—In dogs with gastrointestinal tract perforation and that had been treated with deracoxib, perforation was most likely attributable to a number of factors. Deracoxib should only be used at approved dosages. Cortico-steroids and other less selective NSAIDs should not be administered in close temporal association with selective COX-2 inhibitors, including deracoxib. Further study is required to define this problem. (J Am Vet Med Assoc 2005;227:1112–1117)

Objective—To determine sedative and cardiorespiratory effects of IM administration of medetomidine alone and in combination with butorphanol or ketamine in dogs. Design—Randomized, crossover study. Animals—6 healthy adult dogs. Procedure—Dogs were given medetomidine alone (30 µg/kg [13.6 µg/lb] of body weight, IM), a combination of medetomidine (30 µg/kg, IM) and butorphanol (0.2 mg/kg [0.09 mg/lb], IM), or a combination of medetomidine (30 µg/kg, IM) and ketamine (3 mg/kg [1.36 mg/lb], IM). Treatments were administered in random order with a minimum of 1 week between treatments. Glycopyrrolate was given at the same time. Atipamezole (150 µg/kg [68 µg/lb], IM) was given 40 minutes after administration of medetomidine. Results—All but 1 dog (given medetomidine alone) assumed lateral recumbency within 6 minutes after drug administration. Endotracheal intubation was significantly more difficult when dogs were given medetomidine alone than when given medetomidine and butorphanol. At all evaluation times, percentages of dogs with positive responses to tail clamping or to needle pricks in the cervical region, shoulder region, abdominal region, or hindquarters were not significantly different among drug treatments. The PaCO2 was significantly higher and the arterial pH and PaO2 were significantly lower when dogs were given medetomidine and butorphanol or medetomidine and ketamine than when they were given medetomidine alone. Recovery quality following atipamezole administration was unsatisfactory in 1 dog when given medetomidine and ketamine. Conclusion and Clinical Relevance—Results suggested that a combination of medetomidine with butorphanol or ketamine resulted in more reliable and uniform sedation in dogs than did medetomidine alone. (J Am Vet Med Assoc 2000;216:1578–1583)

Total gastric emptying time was determined in nine mongrel dogs using a barium meal contrast procedure. Within the group, total gastric emptying time ranged from 7.0–15.0 hours. Comparison of the population mean showed a statistical difference (p − 0.01) from previously published values. Individual dogs showed consistent total gastric emptying time over three trials. The technique can be used to test the effect of a procedure on total gastric emptying time when a normal value has been established for the dog. Due to the wide range of normal values observed, evaluation of clinical patients could be difficult unless there is a gross abnormality in function.