Effect of clinical signs, endocrinopathies, timing of surgery, hyperlipidemia, and hyperbilirubinemia on outcome in dogs with gallbladder mucocele.

Gallbladder mucocele (GBM) is a common extra-hepatic biliary syndrome in dogs with death rates ranging from 7 to 45%. Therefore, the aim of this study was to identify the association of survival with variables that could be utilized to improve clinical decisions. A total of 1194 dogs with a gross and histopathological diagnosis of GBM were included from 41 veterinary referral hospitals in this retrospective study. Dogs with GBM that demonstrated abnormal clinical signs had significantly greater odds of death than subclinical dogs in a univariable analysis (OR, 4.2; 95% CI, 2.14-8.23; P<0.001). The multivariable model indicated that categorical variables including owner recognition of jaundice (OR, 2.12; 95% CI, 1.19-3.77; P=0.011), concurrent hyperadrenocorticism (OR 1.94; 95% CI, 1.08-3.47; P=0.026), and Pomeranian breed (OR, 2.46; 95% CI 1.10-5.50; P=0.029) were associated with increased odds of death, and vomiting was associated with decreased odds of death (OR, 0.48; 95% CI, 0.30-0.72; P=0.001). Continuous variables in the multivariable model, total serum/plasma bilirubin concentration (OR, 1.03; 95% CI, 1.01-1.04; P<0.001) and age (OR, 1.17; 95% CI, 1.08-1.26; P<0.001), were associated with increased odds of death. The clinical utility of total serum/plasma bilirubin concentration as a biomarker to predict death was poor with a sensitivity of 0.61 (95% CI, 0.54-0.69) and a specificity of 0.63 (95% CI, 0.59-0.66). This study identified several prognostic variables in dogs with GBM including total serum/plasma bilirubin concentration, age, clinical signs, concurrent hyperadrenocorticism, and the Pomeranian breed. The presence of hypothyroidism or diabetes mellitus did not impact outcome in this study.

Characterisation and outcome of idiopathic pyogranulomatous lymphadenitis in 64 English springer spaniel dogs.

OBJECTIVES: To describe the history, clinicopathological abnormalities, diagnostic imaging findings, lymph node cytological/histological appearance, treatment and outcome of English springer spaniels diagnosed with idiopathic pyogranulomatous lymphadenitis. MATERIALS AND METHODS: In this retrospective UK-based multicentre study, 64 dogs were recruited from 10 referral centres, 32 first-opinion practices and three histopathology/cytology laboratories, between 2010 and 2016. RESULTS: The median age at presentation was 6 years (range: 0.17 to 11.75). Neutered females were frequently affected. Pyrexia (83.8%), peripheral lymphadenomegaly (78.4%), dermatological lesions (72.9%), lethargy (67.6%), hyporexia (54%), diarrhoea (29.7%), coughing (24.3%), epistaxis, sneezing or nasal discharge (21.6%), ocular signs (21.6%) and vomiting (16.2%) were reported in dogs for which the history and physical examination records were available. Popliteal (45.3%), superficial cervical (35.9%) and submandibular (37.5%) lymphadenomegaly were frequently reported. Haematology and serum biochemistry revealed non-specific changes. When undertaken, testing for infectious diseases was negative in all cases. Lymph node cytology, histopathology or both demonstrated mixed inflammatory (27%), pyogranulomatous (24%), neutrophilic (20%) or granulomatous (11%) lymphadenitis. Treatment details were available for 38 dogs, with 34 receiving prednisolone for a median duration of 15 weeks (range: 1 to 28 weeks). A good to excellent clinical response was reported in all but one case. Ten dogs relapsed after discontinuing prednisolone. CLINICAL SIGNIFICANCE: Idiopathic pyogranulomatous lymphadenitis should be considered as a differential diagnosis for lymphadenopathy and pyrexia in English springer spaniels. The characteristics of the disease, absence of identifiable infectious aetiology and response to glucocorticoid therapy suggest an immune-mediated aetiology.

Gall bladder mucoceles in Border terriers.

BACKGROUND: Gall bladder mucoceles (GBM) are a leading cause of biliary disease in dogs with several breeds, including the Shetland Sheepdog, American Cocker Spaniel, Chihuahua, Pomeranian, and Miniature Schnauzer apparently predisposed. OBJECTIVE: To determine risk factors, clinical features, and response to treatment of GBM in Border terriers (BT). ANIMALS: Medical records of 99 dogs (including 51 BT) with an ultrasonographic (±histopathologic) diagnosis of GBM from three referral centers in the United Kingdom were collected. A control group of 87 similar-aged BT with no ultrasonographic evidence of gall bladder disease was selected for comparison. METHOD: Retrospective case-control study. Odds ratios were calculated to establish breed predisposition. Signalment, presence of endocrine disease, clinicopathologic results, and outcome were compared between the BT, other breeds, and control BTs. RESULTS: The odds of identifying a GBM in a BT in this hospital population was 85 times that of all other breeds (95% confidence interval 56.9-126.8). BT had similar clinical signs and clinicopathologic changes to other breeds with GBM. There was no evidence that endocrinopathies were associated with GBM in BT. CLINICAL SIGNIFICANCE: A robust breed predisposition to GBM is established for the BT.

Evaluation of different shape-memory staple configurations against crossed screws for first metatarsophalangeal joint arthrodesis: A biomechanical study.

BACKGROUND: The first metatarsophalangeal joint may be fused in order to treat arthritis or instability. The use of shape-memory staples for fixation is well recognised, but little work has been done into the optimal configuration of staples. METHODS: The structural behaviour of first metatarsophalangeal joint (MTPJ) arthrodeses using shape-memory staples or crossed screws was studied using cadaveric porcine joints. Five fixation configurations were tested: single vertical or horizontal staple, paired staples in dorsal-medial configuration (0-90° to the sagittal plane), paired staples in oblique orthogonal configuration (45-135°); or two crossed screws. Specimens were loaded in cyclical dorsiflexion for 1000 cycles. Plantar gapping and shearing were measured. Specimens were then loaded to failure. RESULTS: Cyclic testing caused more shear in the 45-135° staples than the crossed screws (1.0mm±0.5mm compared to 0.14mm±0.4mm, p<0.01). No significant difference was found in plantar gap formation. Single vertical and horizontal single staples failed at 15N and 19. CONCLUSIONS: N, respectively. Paired 0-90° staples failed at 43N±9N, significantly lower than the 45-135° staples (141N±25N; p<0.001) and crossed screws (180N±67N; p<0.001). There was no significant difference between the 45-135° staples and crossed screws. Screws failed by sudden cortical fracture; staples displayed gradual pull-out and shearing. First MTPJ arthrodeses fixed with single staples are not recommended. Arthrodeses fixed with staples at 0-90° to the sagittal plane were significantly less strong than two crossed screws. However, positioning oblique staples at 45-135° significantly improved stability, creating a construct as strong as, crossed screws. None of the constructs was strong enough for immediate weight bearing.

A Remote Assay for Measuring Canine Platelet Activation and the Inhibitory Effects of Antiplatelet Agents.

BACKGROUND: Antiplatelet medications are increasingly used in dogs. Remote analysis of platelet activity is challenging, limiting assessment of antiplatelet drug efficacy. HYPOTHESIS/OBJECTIVES: To evaluate a method used in humans for stimulation and remote analysis of canine platelet activity. ANIMALS: Forty-five dogs of various ages without a coagulopathy or thrombocytopenia. Six were receiving antiplatelet medication. METHODS: Prospective observational study. Platelets were stimulated with combinations of arachidonic acid (AA) and epinephrine (Epi) or adenosine diphosphate (ADP) and the thromboxane A2 -mimetic U46619 (U4). PAMFix was added to the blood samples to facilitate delayed analysis of platelet activity. Activity was assessed by flow cytometric measurement of surface P-selectin (CD62P) expression. RESULTS: Canine platelets could be stimulated with both AA/Epi and ADP/U4. The levels of P-selectin were significantly greater than paired, unstimulated samples (P < 0.001). Inhibition of P-selectin expression occurred after this stimulation by adding antiplatelet drugs in vitro. The efficacy of antiplatelet drugs in samples from treated dogs was also measurable ex vivo using this method. Delayed analysis of platelet activity at time points up to 22 days demonstrated excellent correlation between respective mf values at each time point (r2  = 0.92, P < 0.0001). CONCLUSIONS AND CLINICAL IMPORTANCE: This study evaluated a new method to remotely assess canine platelet activity. It shows that PAMFix can be used for this purpose. This provides opportunities to interrogate the inhibitory action of antiplatelet drugs in clinical settings.

Preliminary investigation of urine N-telopeptide concentration as a biomarker of bone resorption in dogs receiving glucocorticoids.

OBJECTIVES: The influence of glucocorticoid therapy on bone resorption in dogs using a urine N-telopeptide assay was investigated. MATERIALS AND METHODS: Thirty-one dogs receiving oral glucocorticoids and 31 age-matched healthy control dogs were enrolled. Urine N-telopeptide concentration was measured using a commercially available immunoassay and results were expressed as a ratio against urinary creatinine concentration. Dogs receiving glucocorticoids were divided into three subgroups based on daily glucocorticoid dose and three subgroups based on treatment duration. Urine N-telopeptide concentration was then compared between groups. RESULTS: Urine N-telopeptide concentration was significantly higher in dogs receiving glucocorticoids compared to the control group. CLINICAL SIGNIFICANCE: This preliminary study demonstrates significant increase in urine N-telopeptide concentration in dogs receiving glucocorticoid therapy compared to control dogs. Further studies are needed to assess whether this increase in urine N-telopeptide concentration correlates with decreases in bone mineral density as has been identified in humans.

Polyglandular endocrinopathy type II (Schmidt's syndrome) in a Dobermann pinscher.

A three-year-old, female neutered, Dobermann pinscher was presented for investigation of lethargy, episodic collapse, ataxia and myxoedema. Primary hypothyroidism and primary cortisol-deficient hypoadrenocorticism were diagnosed based on history, physical examination and compatible hormonal analysis. Increased serum concentrations of thyroglobulin autoantibodies and 21-hydroxylase autoantibodies indicated an immune-mediated aetiology. The case was complicated by lymphadenopathy with hand-mirror lymphocytes, classically identified in lymphoma. A polymerase chain reaction test for antigen receptor rearrangement indicated polyclonality and therefore reactive lymphadenopathy. The dog's clinical signs resolved following introduction of levothyroxine and prednisolone. Prioritising the problem-based approach in this case facilitated the diagnosis of hypoadrenocorticism in addition to hypothyroidism due to the persistence of clinical signs despite thyroxine replacement. Importantly, atypical adrenal gland dysfunction was not misinterpreted as inadequate therapeutic response to thyroxine supplementation. The observation that polyglandular endocrinopathy type II can occur in dogs suggests that in dogs with a suboptimal response to treatment for hypothyroidism or hypoadrenocorticism comorbid endocrinopathies should be investigated.

Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study.

BACKGROUND: Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome. METHODS: In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone. FINDINGS: We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions. INTERPRETATION: For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts.

First characterization of coherent optical vortices from harmonic undulator radiation.

We describe the experimental generation and measurement of coherent light that carries orbital angular momentum from a relativistic electron beam radiating at the second harmonic of a helical undulator. The measured helical phase of the light is shown to be in agreement with predictions of the sign and magnitude of the phase singularity and is more than 2 orders of magnitude greater than the incoherent signal. Our setup demonstrates that such optical vortices can be produced in modern free-electron lasers in a simple afterburner arrangement for novel two-mode pump-probe experiments.

Colonic vascular ectasia (angiodysplasia) in a juvenile dog.

An eight-month-old female English springer spaniel was presented with weight loss and severe haematochezia. Upper and lower endoscopy identified small intestinal inflammatory bowel disease and a vascular malformation within the descending colon. The colonic lesion was excised at coeliotomy and identified histopathologically as a colonic vascular ectasia. All clinical signs resolved following surgery and continued dietary management. To the authors' knowledge this is only the second published report of CVE in a juvenile dog and the first to survive to long term follow up.

COX-2 expression and outcome in canine nasal carcinomas treated with hypofractionated radiotherapy.

The expression of cyclooxygenase isoform 2 (COX-2) in canine nasal carcinomas has been well documented. COX-2 expression has proven to be a prognostic factor in several human tumours. The aims of this study were to assess the correlation between immunohistochemical COX-2 expression and prognosis using rhinoscopic biopsies from 42 dogs with nasal carcinomas treated with hypofractionated radiotherapy, and to establish a replicable COX-2 scoring system. Ninety per cent of sections evaluated were COX-2 positive with a mean score of 6.6 (median 8.0; range 0-12). Neither COX-2 expression nor tumour type had a significant correlation with survival. There are likely to be many as yet unidentified variants which contribute to length of survival in dogs with nasal carcinomas. Immunohistochemical COX-2 expression appears unlikely to be of prognostic significance for canine nasal carcinoma.

Exogenous insulin treatment after hypofractionated radiotherapy in cats with diabetes mellitus and acromegaly.

BACKGROUND: The optimal treatment for feline acromegaly has yet to be established. Surgical and medical therapies are minimally effective although radiotherapy might have greater efficacy. The purpose of this study was to review the response and outcome of cats with acromegaly and insulin-resistant diabetes mellitus (DM) to radiotherapy. HYPOTHESES: That radiotherapy improves glycemic control in cats with acromegaly and that improved glycemic control is due to remission of clinical acromegaly; demonstrated by a fall in serum insulin-like growth factor-1 (IGF-1) concentrations. ANIMALS: Fourteen cats with naturally occurring acromegaly. METHODS: Retrospective case review; records of all cats treated for acromegaly with radiotherapy were reviewed from 1997 to 2008. Cats were selected on the basis of compatible clinical signs, laboratory features, and diagnostic imaging findings. Fourteen cats received radiotherapy, delivered in 10 fractions, 3 times a week to a total dose of 3,700 cGy. RESULTS: Thirteen of 14 cats had improved diabetic control after radiotherapy. These improvements were sustained for up to 60 months. DM progressed in 2 cats and 1 did not respond. Seven cats responded before the final treatment. Ten cats were euthanized, 1 as a consequence of radiotherapy. In 8 cats in which IGF-1 was measured after treatment, changes in its concentration did not reflect the clinical improvement in glycemic control. CONCLUSIONS AND CLINICAL IMPORTANCE: Radiotherapy represents an effective treatment for cats with insulin-resistant DM resulting from acromegaly. IGF-1 concentration after treatment does not provide a suitable method by which remission from either acromegaly or insulin-resistant DM may be assessed.

Bone marrow augmentation in kidney transplantation: a large animal study.

Specific immunomodulatory strategies are required to eliminate the need for lifelong dependence on debilitating immunosuppressants. One proposed strategy is to simultaneously transplant the kidney and infuse donor-specific bone marrow cells. We prospectively studied the effect of unmodified donor-specific bone marrow infusion (DSBMI) on rejection, infection, graft-versus-host disease (GvHD), and graft survival. We performed 57 kidney transplants in mixed lymphocyte culture (MLC)-reactive, outbred pigs. The groups of recipient pigs differed according to the use of (1) indefinite versus short-term tacrolimus-based immunosuppression, (2) DSBMI, and (3) recipient preconditioning (RPC: whole body irradiation with 400 rads on day 0 and horse anti-pig thymocyte globulin (ATG) on days -2, -1, and 0). In all, we studied eight groups: group 1, nonimmunosuppressed control pigs (n = 8); group 2, nonimmunosuppressed DSBMI pigs (n = 7); group 3, nonimmunosuppressed RPC + DSBMI pigs (n = 5); group 4, tacrolimus (indefinite) pigs (n = 11); group 5, tacrolimus (10 days only) pigs (n = 5); group 6, DSBMI + tacrolimus (indefinite) pigs (n = 8); group 7, DSBMI + tacrolimus (10 days only) pigs (n = 6); and group 8, RPC + DSBMI + tacrolimus (indefinite) pigs (n = 7). DSBMI alone (group 2) or in combination with RPC (group 3) did not prolong graft survival, as compared with nonimmunosuppressed controls (group 1). In groups 1, 2, and 3, all but one pig died from rejection; in group 3 only, 45% of the pigs died from concurrent infection or GvHD, indicating that RPC in combination with DSBMI aggravated the risk of generalized infection and GvHD. Post-transplant immunosuppression--irrespective of indefinite or short-term administration--was required for prolonged graft survival. With indefinite use of immunosuppression, graft survival rates and death rates from rejection were not different for pigs with (group 6) versus without (group 4) DSBMI; however, the death rate from infection was higher in group 6, suggesting that the bone marrow inoculum increased the risk of systemic infection. With short-term use of immunosuppression, graft survival rates were higher and death rates from rejection lower for pigs with (group 7) versus without (group 5) DSBMI. But DSBMI and short-term immunosuppression (group 7) failed to prolong survival beyond that achieved with indefinite immunosuppression (groups 4 and 6). Although the combination of DSBMI and short-term immunosuppression (group 7) reduced the risk of infection, it did not avert severe rejection. The addition of RPC to DSBMI and indefinite immunosup- pression (group 8) significantly decreased graft survival, as compared with groups 4, 6, and 7. It also increased the incidence of death from rejection, GvHD, and infection, or a combination thereof. Unmodified DSBMI did not prolong graft survival after kidney transplantation, nor did it decrease the incidence of rejection. But it aggravated the risk of GvHD and infection. Short-term immunosuppression with DSBMI reduced the incidence of death from infection or GvHD, but it resulted in a higher incidence of death from rejection (as compared with indefinite use of immunosuppression). RPC, combined with DSBMI and indefinite immunosuppression, increased the death rate from rejection, GvHD, infection, or a combination thereof. In this large animal study, the effect of unmodified DSBMI has been disappointing. The search continues for the optimal way to successfully perform bone marrow augmentation in solid organ transplants.

Acute smoking increases ST depression in humans during general anesthesia.

UNLABELLED: We tested the hypothesis that acute smoking is associated with ST segment depression during general anesthesia in patients without ischemic heart disease. The carbon monoxide (CO) concentration in expired gas and hemodynamic data was measured during general anesthesia for noncardiac or nonperipheral vascular surgery in patients without symptoms or evidence of ischemic heart disease. Increased expired CO concentrations are indicators of recent smoking. Logistic regression analysis identified significant predictors of ST segment depression > or = 1 mm. Both rate pressure product (odds ratio 1.20 for each increase of 1000, 95% confidence interval = 1.04-1.41, P = 0.007) and expired CO concentration (odds ratio 1.05 for each part per million increase, 95% confidence interval = 1.03-1.08, P = 0.001) were significant predictors of ST segment depression when considered simultaneously. Males demonstrated a lower probability of having an episode of ST depression (odds ratio = 0.16, P = 0.01), but this did not change the relationship between rate pressure product and CO as predictors of ST depression. Approximately 25% of chronically smoking patients smoked on the morning of surgery despite instructions not to smoke. IMPLICATIONS: Patients under age 65 without symptoms of ischemic heart disease who smoked shortly before surgery had more episodes of rate pressure product-related ST segment depression than nonsmokers, prior smokers, or chronic smokers who did not smoke before surgery. Females were at greater risk of ST depression than males.

Testosterone metabolism in benign and malignant breast lesions.

Tissues from a variety of breast lesions were incubated with 14C-testosterone (17beta-hydroxy-4-androsten-3-one). Conversion to 14C-5alpha-dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one) and 14C-androstenedione (4-androsten-3,17-dione) was measured. Normal breast tissue showed formation of 14C-androstenedione but no formation of 14C-5alpha-dihydrotestosterone. Fibroadenomas showed a high degree of testosterone metabolism forming both 14C-androstenedione and 14C-5alpha-dihydrotestosterone. The adenocarcinomas of the breast, contrary to a previous report in the literature, showed no conversion to 14C-5alpha-dihydrotestosterone. The data suggest that formation of 5alpha-dihydrotestosterone is a predominant metabolic pathway in fibroadenoma.