Genetic improvement of hip-extended scores in 3 breeds of guide dogs using estimated breeding values: Notable progress but more improvement is needed.

Two hip quality phenotypes-a hip-extended score assigned by a board certified radiologist and the PennHIP distraction index-were analyzed to estimate genetic parameters and to calculate estimated breeding values used for selecting replacement breeders. Radiographs obtained at 12-18 months of age were available on 5,201 German Shepherd Dogs, 4,987 Labrador Retrievers and 2,308 Golden Retrievers. Obtained by fitting a two-trait model using Bayesian techniques, estimates of heritability for the hip-extended score were 0.76, 0.72, and 0.41 in German Shepherd Dogs, Labrador Retrievers, and Golden Retrievers, respectively, while estimated heritabilities for distraction index were 0.60, 0.66 and 0.59, respectively. Genetic correlations between the two hip quality measures were -0.28 in German Shepherd Dogs, -0.21 in Labrador Retrievers, and -0.29 in Golden Retrievers. Genetic selection for improved hip quality based upon the hip extended score phenotype began in 1980. Among first generation puppies, 34% of 273 German Shepherd Dogs, 55% of 323 Labrador Retrievers, and 43% of 51 Golden Retrievers had an Excellent hip extended score. After 8 generations of selection, mostly based on estimated breeding values derived from the hip extended score, over 93% of 695 German Shepherd Dogs, 94% of 528 Labrador Retrievers, and 87% of 116 Golden Retrievers received an Excellent hip extended score. With respect to PennHIP distraction index values among these same dogs, median values were at or above 0.30 for all 3 breeds meaning that half or more of dogs possessing the Excellent hip-extended-score phenotype remained susceptible to developing the osteoarthritis of canine hip dysplasia. Genetic improvement of the hip-extended-view phenotype to its desired biological endpoint left a surprising proportion of dogs expressing sufficient joint laxity to place them in an osteoarthritis at-risk state as they age. Only by directly applying selection pressure to reduce distraction index was marked reduction in joint laxity noted.

Lymphoma in cats treated with a weekly cyclophosphamide-, vincristine-, and prednisone-based protocol: 114 cases (1998-2008).

OBJECTIVE: To evaluate the clinical response rate, progression-free survival time, overall survival time, and possible prognostic factors associated with a cyclophosphamide-, vincristine-, and prednisone (COP)-based chemotherapy protocol in cats with lymphoma. DESIGN: Retrospective case series. ANIMALS: 114 cats with lymphoma. PROCEDURES: Medical records of cats receiving a weekly COP-based chemotherapy protocol from 1998 to 2008 at the Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania were evaluated for information regarding signalment, anatomic site of involvement, cell morphology, treatment, and outcome. Retroviral status, baseline weight, substage, anatomic location, dose delays, dose reductions, and response to treatment were evaluated for prognostic importance. RESULTS: The majority of cases (94 [82.4%]) were substage b, and the most common anatomic site was the gastrointestinal tract (57 [50%]). Clinical response rate after the first chemotherapy cycle was 47.4%. Response to treatment was significantly associated with progression-free survival time and overall survival time, whereas substage was significantly associated with progression-free survival time. The median progression-free survival time and overall survival time were 65.5 and 108 days, respectively. Compared with nonresponders, responders had significantly longer median progression-free survival time (364 vs 31 days) and median overall survival time (591 vs 73 days). CONCLUSIONS AND CLINICAL RELEVANCE: Clinical response after 1 cycle of COP-based chemotherapy was predictive for progression-free survival time and overall survival time in cats with lymphoma; therefore, response after 1 cycle of chemotherapy could be used to guide decisions about further treatment. No new prognostic factors were identified.

Chronology of hip dysplasia development in a cohort of 48 Labrador retrievers followed for life.

OBJECTIVE: To determine the chronology of radiographic signs of canine hip dysplasia (CHD), specifically joint laxity and secondary osteoarthritis (OA). STUDY DESIGN: Longitudinal cohort study. ANIMALS: Paired littermates, 48 Labrador retrievers. METHODS: Conventional, ventrodorsal, hip-extended (HE) radiographs were evaluated yearly for CHD according to the subjective criteria of the Orthopedic Foundation for Animals (OFA). PennHIP screening was performed at 2 years of age to assess joint laxity by distraction index (DI). Histopathologic evaluation of coxofemoral joints was performed at the dogs' natural end of life. RESULTS: Coxofemoral subluxation, as identified on the HE radiograph occurred by 2 years of age and not thereafter. Accuracy of OFA-criteria scoring was poor: 55% of dogs scored "normal" at 2 years of age became radiographically dysplastic by the end of life (45% negative predictive value, NPV); 92% of the dogs scored as normal at 2 years of age had histopathologic OA of CHD (8% NPV). The DI predicted all 48 dogs to be susceptible to OA of CHD and 98% had radiographic or histopathologic OA by the end of life. CONCLUSION: OFA-criteria score was profoundly influenced by environmental factors, such as diet restriction and age, reducing its value as a selection criterion. DI measurements were not influenced by dietary treatment suggesting higher trait heritability.

Radiographic hip joint phenotype of the Pembroke Welsh Corgi.

OBJECTIVE: To investigate the radiographic hip joint phenotype of the Pembroke Welsh Corgi. STUDY DESIGN: Prospective and retrospective cross-sectional study. ANIMALS: Pembroke Welsh Corgis (n = 399). METHODS: Ventrodorsal, hip-extended radiographs were evaluated for subluxation, osteoarthritis (OA), caudolateral curvilinear osteophytes (CCO), and circumferential femoral head osteophytes (CFHO) of PennHIP evaluated Corgis. Joint laxity was measured by distraction index (DI). RESULTS: All Corgis had DI > 0.30 (mean, 0.66), 6.8% had OA, 18% had subluxation, 22.3% had CCO, and 74.4% had CFHO. Higher DI increased the odds for subluxation and canine hip dysplasia (CHD) but not for OA, CCO, or CFHO. The presence of CCO increased the odds for OA by 4.6 times (P = .002) and 2.2 times (P = .01) for hip dysplasia. All dogs with OA had CFHO. The presence of CFHO increased the odds for subluxation by 8.7 times (p < .001) and 8.9 times (P < .001) for hip dysplasia. Subluxation increased the odds for OA by 15.4 times (P < .001). CONCLUSION: Corgis had a low frequency of conventional OA despite having hip laxity that has been shown to correlate with hip OA and hip dysplasia in large-breed dogs. The relationship between CCO and OA was similar to published findings in nonchondrodystrophic large-breed dogs and the CFHO was significantly associated with subluxation. Both CCO and CFHO are associated with hip dysplasia in this small chondrodystrophic breed.

CD40-activated B cell cancer vaccine improves second clinical remission and survival in privately owned dogs with non-Hodgkin's lymphoma.

Cell-based active immunotherapy for cancer is a promising novel strategy, with the first dendritic cell (DC) vaccine achieving regulatory approval for clinical use last year. Manufacturing remains arduous, especially for DC vaccines, and the prospect of using cell-based immunotherapy in the adjuvant setting or in combination with chemotherapy remains largely untested. Here, we used a comparative oncology approach to test the safety and potential efficacy of tumor RNA-loaded, CD40-activated B cells in privately owned dogs presenting with non-Hodgkin's lymphoma (NHL), a clinical scenario that represents not only a major problem in veterinary medicine but also a bona fide spontaneous animal model for the human condition. When administered to NHL dogs in remission after induction chemotherapy, CD40-B cells electroporated ex vivo with autologous tumor RNA safely stimulated immunity in vivo. Although chemotherapy plus CD40-B vaccination did not improve time-to-progression or lymphoma-specific survival compared to dogs treated with chemotherapy alone, vaccination potentiated the effects of salvage therapy and improved the rate of durable second remissions as well as subsequent lymphoma-specific survival following salvage therapy. Several of these relapsed dogs are now long-term survivors and free of disease for more than a year. Overall, these clinical and immunological results suggest that cell-based CD40 cancer vaccination is safe and synergizes with chemotherapy to improve clinical outcome in canine NHL. More broadly, our findings underscore the unique value of clinical investigations in tumor-bearing companion animals.

Evaluation of the relationship between Orthopedic Foundation for Animals' hip joint scores and PennHIP distraction index values in dogs.

OBJECTIVE: To compare 2 screening methods for detecting evidence of hip dysplasia (Orthopedic Foundation for Animals [OFA] and PennHIP) in dogs. DESIGN: Diagnostic test evaluation study. Animals-439 dogs >or= 24 months of age that received routine hip joint screening from June 1987 through July 2008. PROCEDURES: Dogs were sedated, and PennHIP radiography was performed (hip joint- extended [HE], compression, and distraction radiographic views). The HE radiographic view was submitted for OFA evaluation. A copy of the HE radiographic view plus the compression and distraction radiographic views were submitted for routine PennHIP evaluation, including quantification of hip joint laxity via the distraction index (DI). RESULTS: 14% (60/439) of dogs had hip joints scored as excellent by OFA standards; however, 52% (31/60) of those had a DI >or= 0.30 (range, 0.14 to 0.61). Eighty-two percent of (183/223) dogs with OFA-rated good hip joints had a DI >or= 0.30 (range, 0.10 to 0.77), and 94% (79/84) of dogs with OFA-rated fair hip joints had a DI >or= 0.30 (range, 0.14 to 0.77). Of all dogs with fair to excellent hip joints by OFA standards, 80% (293/367) had a DI >or= 0.30. All dogs with OFA-rated borderline hip joints or mild, moderate, or severe hip dysplasia had a DI >or= 0.30 (range, 0.30 to 0.83). CONCLUSION AND CLINICAL RELEVANCE: Dogs judged as phenotypically normal by the OFA harbored clinically important passive hip joint laxity as determined via distraction radiography. Results suggested that OFA scoring of HE radiographs underestimated susceptibility to osteoarthritis in dogs, which may impede progress in reducing or eliminating hip dysplasia through breeding.

Effects of osteoarthritis on radiographic measures of laxity and congruence in hip joints of Labrador Retrievers.

OBJECTIVE- To determine effects of hip joint osteoarthritis on radiographic measures of hip joint laxity and congruence. DESIGN- Longitudinal study. ANIMALS- 40 Labrador Retrievers. PROCEDURES- Dogs were assigned to 2 groups based on radiographic evidence of osteoarthritis. Dogs in the osteoarthritis group were free of osteoarthritis at initial radiographic evaluation (t(1)) and developed osteoarthritis by a subsequent radiographic evaluation (t(2)). Dogs in the nonosteoarthritis group had no radiographic osteoarthritis at either evaluation. Hip joint laxity was quantified by use of the distraction index (DI) from a distraction radiographic view and use of the Norberg angle (NA) from a ventrodorsal hip-extended radiographic view. The compression index (CI) from a compression radiographic view was used as a measure of joint congruence (concentricity). RESULTS- Hip joint laxity (NA or DI) did not change over time in the nonosteoarthritis group. Mean hip joint laxity (NA and DI) for the osteoarthritis group was greater at t(1) than for the nonosteoarthritis group. With the onset of osteoarthritis, mean NA decreased significantly and mean CI increased significantly, but mean DI remained unchanged. CONCLUSIONS AND CLINICAL RELEVANCE- No radiographic evidence for compensatory hip joint tightening associated with osteoarthritis was detected. Hip-extended radiography revealed that hip joints got looser with osteoarthritis and NA decreased. Hip joint laxity (DI) on distraction radiographs was unchanged by the onset of osteoarthritis and remained constant in the osteoarthritis and nonosteoarthritis groups at both evaluations. However, the CI increased with osteoarthritis, as reflected in nonzero indices (incongruence). The CI may be a valid marker for early hip joint osteoarthritis.

Un-united medial epicondyle of the humerus: radiographic prevalence and association with elbow osteoarthritis in a cohort of labrador retrievers.

OBJECTIVE: To longitudinally characterize the radiographic appearance of un-united medial epicondyle (UME) of the humerus, evaluate UME association with osteoarthritis (OA) and consider its relevance to the elbow dysplasia complex. STUDY DESIGN: Longitudinal cohort study. ANIMALS: Labrador retrievers (n=48) from 7 litters. METHODS: Forty-eight same-sex littermates were paired for this lifetime feeding study. One of each pair was control-fed; the pair mate was fed 25% less than the control each day. Elbows of 46 surviving dogs were radiographed at ages 6 and 8 years, and/or at end-of-life (EOL). Elbow histopathology was done EOL, although UME lesions were not evaluated histologically. RESULTS: Seven dogs (15%) had UME, representing 5 litters; 4 were control-fed, 3 diet-restricted. Six (86%) dogs had unilateral lesions; 1 was bilateral. UME was evident on craniocaudal (CrCd) radiographic projections by 8 years in all dogs. UME was detected in only 1 elbow by mediolateral radiographic projection. Elbow OA frequency in UME affected dogs was not significantly different from the remaining study population. Histopathologic lesions were bilateral in dogs with unilateral UME. CONCLUSIONS: UME may be more common than previously thought. Most cases were unilateral and diet restriction had no effect on frequency. The CrCd view was critical for diagnosis. Elbow OA was not directly associated with UME. CLINICAL RELEVANCE: Infrequent diagnosis of UME could result from infrequent radiography and use of only the flexed lateral radiographic projection required by the Orthopedic Foundation for Animals for elbow screening. Like hip evaluations, screening for UME should be continued for life, until genetics are better understood. Lack of association between UME and elbow OA suggests that UME is not likely a component of elbow dysplasia.

A longitudinal study of the influence of lifetime food restriction on development of osteoarthritis in the canine elbow.

OBJECTIVE: To report the effects of age and lifetime calorie restriction on development and progression of osteoarthritis (OA) in elbow joints of Labrador retrievers. STUDY DESIGN: Longitudinal cohort study. ANIMALS: Labrador retriever dogs (n=48). METHODS: Puppies from 7 litters were allotted to 2 groups of 24 dogs each. Diet-restricted (DR) dogs received 25% fewer calories than control-fed (CF) pair mates. Elbow radiographs were taken at 6 and 8 years of age and end of life (EOL). Gross and histopathologic evaluations for OA occurred at EOL. RESULTS: There was no statistical difference in radiographic OA frequency between groups at any of the time points. Radiographic OA severity was greater for CF dogs at 6 years only (P<.05). There was no significant difference between feeding groups for histopathologic prevalence or severity of OA. Similarly, there were no differences in gross OA lesions between the groups (P>.05). Fragmented medial coronoid process, un-united anconeal process, and osteochondrosis were not present in any elbow. CONCLUSION: No differences in prevalence or severity of radiographic and histopathologic elbow OA were found between feeding groups. Diet restriction resulted in a 1.8-year extension in median lifespan but no additional incremental worsening of elbow disease. Evaluation at time points <6 years may have revealed larger differences in OA prevalence and severity between the dietary groups. CLINICAL RELEVANCE: These findings support calorie restriction as a clinical tool to slow progression of elbow OA.

The effects of lifetime food restriction on the development of osteoarthritis in the canine shoulder.

OBJECTIVE: To report effects of age and lifetime food restriction on development and progression of shoulder joint osteoarthritis (OA) in Labrador retriever dogs. STUDY DESIGN: Longitudinal life-span, cohort study. ANIMALS: Labrador retriever dogs (n=48). METHODS: Littermates were paired (gender, weight) to make 24 pairs of genetically similar dogs. Each diet-restricted (DR) pair-mate was fed daily 75% of the same diet consumed by its control-fed (CF) pair-mate for life. Shoulders were evaluated radiographically at years 6, 8, and end of life (EOL). At EOL shoulders were evaluated grossly and by histopathology for OA. RESULTS: Radiographic evidence of shoulder OA was identified in 78% of dogs. Severity of radiographic shoulder OA at 6 (P<.03) and 8 years (P<.02) was significantly lower among DR dogs compared with CF dogs. Pooled gross evaluation results revealed 40 of 46 dogs had cartilage erosion on the caudal aspect of the humeral head. By EOL, 91% of dogs had histopathologic changes consistent with OA. CONCLUSION: There was a high overall prevalence of radiographic, gross, and histologic OA among dogs. Substantial disparity was found between radiographic evidence of OA (at EOL) and characteristic changes visible by gross and histologic examination. CLINICAL RELEVANCE: Radiographic evaluation correlates poorly with severity of shoulder joint pathology. The benefits of DR on shoulder OA are consistent with the demonstrated effect of DR in delaying species- and strain-specific diseases of aging.

Evaluation of the Norberg angle threshold: a comparison of Norberg angle and distraction index as measures of coxofemoral degenerative joint disease susceptibility in seven breeds of dogs.

OBJECTIVE: To evaluate the thresholds of 2 radiographic methods used to determine coxofemoral joint laxity in 7 breeds of dogs. ANIMALS: Three hundred and fifty clinically normal dogs. STUDY DESIGN: Retrospective study. METHODS: Hip radiographs from 7 breeds of dogs were randomly selected from a database. None of the dogs had radiographic evidence of degenerative joint disease (DJD). Distraction index (DI) and Norberg angle (NA) were measured on these radiographs and compared with DI and NA thresholds for diagnosing DJD susceptibility derived from the literature and from evaluated Borzois. Dogs with a NA<105 degrees and a DI of < or =0.32 were considered false-positives and dogs with a NA> or =105 degrees and a DI of >0.32 were considered false-negatives. RESULTS: Mean age of all dogs was 22.9 months. Mean NA for all dogs was 99.37 degrees, and mean DI for all dogs was 0.44. Borzoi mean DI of was significantly less than the mean DI of the other 6 breeds. The highest (most hip laxity) Borzoi DI was 0.32, and the lowest (most hip laxity) Borzoi NA was 99 degrees. False-positive and false-negative diagnoses were identified in 6 of the 7 breeds. CONCLUSIONS: Using the NA threshold of 105 degrees (literature established threshold of susceptibility to DJD) resulted in a high percentage of false-negative and false-positive diagnoses. Breeds like the Labrador Retriever and Rottweiler would have large numbers of hip dysplasia susceptible dogs remain in the breeding population based on this NA threshold. False-positive diagnoses were common in breeds like the Australian Shepherd, Borzoi, and German Shepherd effectively eliminating hip dysplasia nonsusceptible dogs from the breeding population. CLINICAL RELEVANCE: The NA was not an accurate predictor of DJD susceptibility in these 7 breeds of dogs when using a NA threshold of 105 degrees.

Estimates of prevalence of hip dysplasia in Golden Retrievers and Rottweilers and the influence of bias on published prevalence figures.

OBJECTIVE: To estimate prevalence of canine hip dysplasia (CHD) in Golden Retrievers and Rottweilers and identify sources of bias in published reports. DESIGN: Prospective study. ANIMALS: 200 clinically normal Golden Retrievers and 140 clinically normal Rottweilers between 24 and 60 months of age referred for hip evaluation (group 1) and 93 clinically normal dogs evaluated for Orthopedic Foundation for Animals (OFA) hip certification (group 2). PROCEDURE: Hip-extended pelvic radiographs from group 1 dogs were screened for CHD. Radiographs were evaluated twice; the first interpretation used an OFA-type subjective 7-point scoring system, and the second included the caudolateral curvilinear osteophyte as an additional sign of degenerative joint disease. The OFA submission rate of group 2 dogs was determined from the number of official reports returned from the OFA. RESULTS: Prevalence of CHD in Golden Retrievers ranged from 53% to 73% and in Rottweilers ranged from 41% to 69%. Among dogs referred for OFA evaluation, radiographs from 49 (53%) were submitted to OFA. Of submitted radiographs, 45 (92%) were normal; of radiographs not submitted, 22 (50%) were normal. Radiographs with normal-appearing hips were 8.2 times as likely to be submitted to the OFA. Compared with Golden Retrievers, Rottweiler radiographs were significantly more likely to be submitted for OFA certification. CONCLUSIONS AND CLINICAL RELEVANCE: Prevalence of CHD in these 2 breeds may be much higher than previously reported in the United States. Results suggest substantial bias in the OFA database, which causes lower estimates of prevalence of CHD.

Use of the caudolateral curvilinear osteophyte as an early marker for future development of osteoarthritis associated with hip dysplasia in dogs.

OBJECTIVE: To determine the relationship between the caudolateral curvilinear osteophyte (CCO) and osteoarthritis associated with hip dysplasia in dogs. DESIGN: Longitudinal cohort study. ANIMALS: 48 Labrador Retrievers from 7 litters. PROCEDURE: In each of 24 sex- and size-matched pairs fed the same diet, a restricted-fed dog was fed 25% less than a control dog for life. The dogs' hips were evaluated in the standard ventrodorsal hip-extended radiographic projection at 16, 30, and 52 weeks of age and then yearly for life. Histologic examination of hip joint tissues was performed on 45 dogs. RESULTS: Median age at death was 11.2 years. Adjusting for feeding group, dogs with a CCO were 3.7 times as likely to develop radiographic signs of osteoarthritis than those without a CCO. Stratified by diet, 100% of the control dogs with a CCO developed radiographic signs of osteoarthritis and 55% of restricted-fed dogs with a CCO developed radiographic signs of osteoarthritis. The CCO was the first radiographic change seen in 22 of 29 (76%) dogs with osteoarthritis. Overall, 35 of 37 (95%) dogs with a CCO had histopathologic lesions of osteoarthritis. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate a relationship between a CCO on the femoral neck and subsequent development of radiographic signs of osteoarthritis in Labrador Retrievers evaluated over their life span. A CCO is an important early radiographic indication of osteoarthritis associated with canine hip dysplasia.

Comparison of two radiographic techniques for evaluation of hip joint laxity in 10 breeds of dogs.

OBJECTIVE: To evaluate hip joint laxity in 10 breeds of dogs via 2 radiographic techniques. ANIMALS: 500 clinically normal dogs. DESIGN: Prospective study. PROCEDURE: Radiographs obtained via routine hip joint evaluations performed in sedated dogs of 10 popular breeds were randomly selected from a database. Measurements of distraction index (DI) and hip-extended index (HEI) on 1 hip joint radiograph randomly chosen from each dog were made. RESULTS: Mean age of dogs was 20.7 months. Mean HEI was 0.17 (range, 0.0 to 0.72) and mean DI was 0.44 (range, 0.07 to 0.96). Borzois had uniformly tight hip joints as judged by use of both methods and were considered the gold standard by which hip joint laxity was judged (all Borzois had DI < or = 0.32). Overall, DI was significantly greater than HEI. Within each breed, mean DI was always greater than mean HEI. Significant differences were detected among breeds for HEI; however, compared with DI, the magnitude of differences among breeds was less. CONCLUSIONS AND CLINICAL RELEVANCE: Distraction radiography detected the greatest range and magnitude of passive hip laxity in the 10 breeds of dogs. The difference in values between breeds known to have high prevalence of canine hip dysplasia and those in Borzois was greater for DI than for HEI. Breeds must be evaluated individually because of inherent differences in hip joint laxity.