Urinary 11-dehydrothromboxane B2 concentrations in 20 dogs with primary immune-mediated hemolytic anemia.

BACKGROUND: Thromboembolic disease is a major cause of mortality in dogs with immune-mediated hemolytic anemia (IMHA). At present, no reliable biomarkers of individual patient thrombotic risk are available. In human medicine, increased urinary thromboxane concentrations have utility as markers of prothrombotic tendency in various situations. HYPOTHESIS/OBJECTIVES: First, to determine if urinary 11-dehydrothromboxane B2 (u11-dTXB) concentrations are increased in dogs with primary IMHA compared to normal dogs; second, to assess whether u11-dTXB concentration is associated with survival, known prognostic indicators, or frequency of thrombosis in dogs with IMHA. ANIMALS: Twenty client-owned dogs diagnosed with primary IMHA and 17 healthy dogs volunteered by hospital staff. METHODS: Prospective case-control study. A previously validated ELISA was used to measure urine 11-dTXB concentrations, which were normalized to urine creatinine concentration (u11-dTXB:Cr). Samples were obtained at presentation from patients with primary IMHA. Standard clincopathological data at baseline and survival data were collected. Urinary 11-dTXB:Cr was compared between outcome subgroups, and correlated with known markers of disease severity. RESULTS: Baseline u11-dTXB:Cr was significantly higher in dogs with IMHA than in healthy dogs (median, 3.75; range, 0.83-25.36 vs 0.65; 0.24-2.57; P = .003) but did not differ between dogs with IMHA that survived and did not survive to 30 days after presentation, nor between dogs with and without clinical suspicion of thrombotic disease. CONCLUSIONS AND CLINICAL IMPORTANCE: Urinary 11-dTXB:Cr is increased in dogs with IMHA compared to healthy controls, consistent with a prothrombotic state. However, in this IMHA population u11-dTXB:Cr was not associated with survival or suspected thrombosis.

Retrospective investigation of the neutrophil-to-lymphocyte ratio in dogs with pneumonia: 49 cases (2011-2016).

OBJECTIVE: To assess the utility of the neutrophil-to-lymphocyte ratio (NLR) in predicting outcome in canine pneumonia compared with routine hematological parameters and systemic inflammatory response syndrome (SIRS) scores. DESIGN: Retrospective study. SETTING: University teaching hospital. ANIMALS: Forty-nine client-owned dogs. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Medical records were reviewed to identify dogs with a diagnosis of pneumonia from July 2011 to December 2016. Signalment, clinical findings, laboratory characteristics, and outcome were recorded. Inclusion criteria were a clinical and radiographic diagnosis of pneumonia, plus reference laboratory hematology at diagnosis. Cases that received steroids were excluded. Euthanized dogs were only included in statistical analysis if euthanized solely due to pneumonia severity. The NLR, total WBC count, neutrophil count, lymphocyte count, band neutrophil percent of total WBC count (%-bands), and percentage of cases diagnosed with SIRS were compared between survivors and nonsurvivors. Receiver operating characteristic curves were generated to identify optimal sensitivity and specificity cutoffs for nonsurvival to discharge. Two hundred records were retrieved; 49 cases fulfilled the inclusion criteria. Of these, 33 (67%) survived to discharge. The NLR did not differ significantly between the survivors and nonsurvivors, nor did total WBC count or neutrophil count. Survivors had a significantly lower %-bands than nonsurvivors (P < 0.001) and higher lymphocyte count (P = 0.004). The mortality rate did not differ significantly between dogs with and without SIRS. Receiver operating characteristic analysis identified a %-bands cutoff of 2.5% or higher had an 83% sensitivity and 79% specificity for nonsurvival. CONCLUSIONS: Unlike in human medicine, neither NLR nor SIRS scores predicted outcome in this cohort of dogs with pneumonia. However, survivors had a lower %-bands and higher lymphocyte count than nonsurvivors, which may be helpful prognostically in clinical cases.

A case of T-cell chronic lymphocytic leukemia progressing to Richter syndrome with central nervous system involvement in a dog.

An 8-year-old neutered Beagle dog was presented with polyuria and polydipsia. Routine clinicopathologic testing showed a significant lymphocytosis and proteinuria. Lymphocytes were of small to intermediate in size with a mature morphology. Infectious disease screening was negative. PCR for antigen receptor gene rearrangements showed a clonal T-cell receptor (TCR) rearrangement consistent with T-cell chronic lymphocytic leukemia (CLL). Bone marrow cytology showed <30% lymphocytes, while the proportion in splenic fine-needle aspirate cytology was considered increased. The dog was initially monitored but started on prednisolone and chlorambucil therapy 2 months later due to worsening clinical signs and progressive lymphocytosis. After an additional 2 weeks, the dog developed multifocal spinal pain and single-node lymphadenomegaly. Cytology of the lymph node showed a monomorphic population of large lymphoblasts consistent with lymphoma. Cytology of a cerebrospinal fluid sample also showed large lymphoblasts. PCR for antigen receptor gene rearrangement at both sites showed a clonal TCR rearrangement of the same molecular size as in the initial leukemic cells. The dog was diagnosed with a transformation of the CLL to Richter syndrome (RS) with involvement of the central nervous system (CNS). Therapy was started with L-asparaginase and an increased dose of prednisolone; however, the dog was euthanized due to progressive clinical signs. To our knowledge, this is the first report of canine RS with direct involvement of the CNS.

Identification of small molecule agonists of the motilin receptor.

High-throughput screening resulted in the identification of a series of novel motilin receptor agonists with relatively low molecular weights. The series originated from an array of biphenyl derivatives designed to target 7-transmembrane (7-TM) receptors. Further investigation of the structure-activity relationship within the series resulted in the identification of compound (22) as a potent and selective agonist at the motilin receptor.

The discovery of biaryl carboxamides as novel small molecule agonists of the motilin receptor.

Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.

A cost-effectiveness analysis of adding a human papillomavirus vaccine to the Australian National Cervical Cancer Screening Program.

BACKGROUND: The cost-effectiveness of adding a human papillomavirus (HPV) vaccine to the Australian National Cervical Screening Program compared to screening alone was examined. METHODS: A Markov model of the natural history of HPV infection that incorporates screening and vaccination was developed. A vaccine that prevents 100% of HPV 16/18-associated disease, with a lifetime duration of efficacy and 80% coverage offered through a school program to girls aged 12 years, in conjunction with current screening was compared with screening alone using cost (in Australian dollars) per life-year (LY) saved and quality-adjusted life-year (QALY) saved. Sensitivity analyses included determining the cost-effectiveness of offering a catch-up vaccination program to 14-26-year-olds and accounting for the benefits of herd immunity. RESULTS: Vaccination with screening compared with screening alone was associated with an incremental cost-effectiveness ratio (ICER) of $51 103 per LY and $18 735 per QALY, assuming a cost per vaccine dose of $115. Results were sensitive to assumptions about the duration of vaccine efficacy, including the need for a booster ($68 158 per LY and $24 988 per QALY) to produce lifetime immunity. Accounting for herd immunity resulted in a more attractive ICER ($36 343 per LY and $13 316 per QALY) for girls only. The cost per LY of vaccinating boys and girls was $92 052 and the cost per QALY was $33 644. The cost per LY of implementing a catch-up vaccination program ranged from $45 652 ($16 727 per QALY) for extending vaccination to 14-year-olds to $78 702 ($34 536 per QALY) for 26-year-olds. CONCLUSIONS: These results suggest that adding an HPV vaccine to Australia's current screening regimen is a potentially cost-effective way to reduce cervical cancer and the clinical interventions that are currently associated with its prevention via screening alone.

Paired associate performance in the early detection of DAT.

Subjects underwent longitudinal neuropsychological assessment in order to retrospectively determine which measures of cognitive function best predicted later development of dementia of the Alzheimer type (DAT). Three groups of subjects were studied: normal controls, patients with early DAT, and questionable dementia subjects (QD). All subjects were assessed using a battery of standard neuropsychological measures and two subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB), paired associate learning and delayed matching to sample. A structured interview was also used to elicit a profile of the subject's daily functioning. Subjects were assessed every 6 months for 2 years. At the 6 month assessment, almost half of the QD group exhibited significant deterioration in scores on the computerized paired associate learning subtest, while maintaining their scores on standard measures. At the conclusion of the study, all of this QD subgroup fulfilled the NINCDS-ADRDA criteria for probable DAT pertaining to significant cognitive and functional deterioration. Performance on the C