Modeling potential masking of echolocating sperm whales exposed to continuous 1-2 kHz naval sonar.

Modern active sonar systems can (almost) continuously transmit and receive sound, which can lead to more masking of important sounds for marine mammals than conventional pulsed sonar systems transmitting at a much lower duty cycle. This study investigated the potential of 1-2 kHz active sonar to mask echolocation-based foraging of sperm whales by modeling their echolocation detection process. Continuous masking for an echolocating sperm whale facing a sonar was predicted for sonar sound pressure levels of 160 dB re 1 µPa2, with intermittent masking at levels of 120 dB re 1 µPa2, but model predictions strongly depended on the animal orientation, harmonic content of the sonar, click source level, and target strength of the prey. The masking model predicted lower masking potential of buzz clicks compared to regular clicks, even though the energy source level is much lower. For buzz clicks, the lower source level is compensated for by the reduced two-way propagation loss to nearby prey during buzzes. These results help to predict what types of behavioral changes could indicate masking in the wild. Several key knowledge gaps related to masking potential of sonar in echolocating odontocetes were identified that require further investigation to assess the significance of masking.

Paroxysmal Dyskinesia in Border Terriers: Clinical, Epidemiological, and Genetic Investigations.

BACKGROUND: In the last decade, a disorder characterized by episodes of involuntary movements and dystonia has been recognized in Border Terriers. OBJECTIVES: To define clinical features of paroxysmal dyskinesia (PD) in a large number of Border Terriers and to study the genetics of the disease. ANIMALS: 110 affected and 128 unaffected client-owned Border Terriers. METHODS: A questionnaire regarding clinical characteristics of PD was designed at Utrecht University and the University of Helsinki. Thirty-five affected Border Terriers underwent physical examination and blood testing (hematology and clinical biochemistry). Diagnostic imaging of the brain was performed in 17 affected dogs and electroencephalograms (EEG) between episodes were obtained in 10 affected dogs. A genomewide association study (GWAS) was performed with DNA of 110 affected and 128 unaffected dogs. RESULTS: One hundred forty-seven questionnaires were included in the study. The most characteristic signs during episodes were dystonia, muscle fasciculations, and falling over. The majority of owners believed that their dogs remained conscious during the episodes. A beneficial effect of anti-epileptic therapy was observed in 29 of 43 dogs. Fifteen owners changed their dogs' diet to a hypoallergenic, gluten-free diet, and all reported reasonable to good improvement of signs. Clinical examinations and diagnostic test results were unremarkable. The GWAS did not identify significantly associated chromosome regions. CONCLUSIONS AND CLINICAL IMPORTANCE: The survey results and EEG studies provided further evidence that the observed syndrome is a PD rather than epilepsy. Failure to achieve conclusive results by GWAS indicates that inheritance of PD in Border Terriers probably is complex.

Canine lymphoma: a review.

Canine lymphoma (cL) is a common type of neoplasia in dogs with an estimated incidence rate of 20-100 cases per 100,000 dogs and is in many respects comparable to non-Hodgkin lymphoma in humans. Although the exact cause is unknown, environmental factors and genetic susceptibility are thought to play an important role. cL is not a single disease, and a wide variation in clinical presentations and histological subtypes is recognized. Despite this potential variation, most dogs present with generalized lymphadenopathy (multicentric form) and intermediate to high-grade lymphoma, more commonly of B-cell origin. The most common paraneoplastic sign is hypercalcemia that is associated with the T-cell immunophenotype. Chemotherapy is the treatment of choice and a doxorubicin-based multidrug protocol is currently the standard of care. A complete remission is obtained for most dogs and lasts for a median period of 7-10 months, resulting in a median survival of 10-14 months. Many prognostic factors have been reported, but stage, immunophenotype, tumor grade, and response to chemotherapy appear of particular importance. Failure to respond to chemotherapy suggests drug resistance, which can be partly attributed to the expression of drug transporters of the ABC-transporter superfamily, including P-gp and BCRP. Ultimately, most lymphomas will become drug resistant and the development of treatments aimed at reversing drug resistance or alternative treatment modalities (e.g. immunotherapy and targeted therapy) are of major importance. This review aims to summarize the relevant data on cL, as well as to provide an update of the recent literature.

A longitudinal study of ABC transporter expression in canine multicentric lymphoma.

Canine lymphoma is typically treated with a doxorubicin-based multidrug chemotherapy protocol. Although this is often initially successful, tumour recurrence is common and frequently refractory to treatment. Failure to respond to chemotherapy is thought to represent drug resistance and has been associated with active efflux of cytostatic drugs by transporter proteins of the ATP-binding cassette (ABC) family, including P-glycoprotein (ABCB1), MRP1 (ABCC1) and BCRP (ABCG2). In this study, ABC transporter mRNA expression was assessed in 63 dogs diagnosed with multicentric lymphoma that were treated with a doxorubicin-based chemotherapy protocol. Expression of ABCB1, ABCB5, ABCB8, ABCC1, ABCC3, ABCC5 and ABCG2 mRNA was quantified in tumour samples (n = 107) obtained at the time of diagnosis, at first tumour relapse and when the tumour was no longer responsive to cytostatic drugs while receiving chemotherapy. Expression data were related to patient demographics, staging, treatment response and drug resistance (absent, intrinsic, acquired). ABC transporter expression was independent of sex, weight, age, stage or substage, but T cell lymphoma and hypercalcaemia were associated with increased ABCB5 and ABCC5 expression, and decreased ABCC1 mRNA expression. Drug resistance occurred in 35/63 (55.6%) dogs and was associated with increased ABCB1 mRNA expression in a subset of dogs with B cell lymphoma, and with increased ABCG2 and decreased ABCB8, ABCC1 and ABCC3 mRNA expression in T cell lymphomas. ABC transporter expression in the pre-treatment sample was not predictive of the length of the first disease-free period or overall survival. Glucocorticoids had no effect on ABC transporter mRNA expression. In conclusion, drug resistance in canine multicentric lymphoma is an important cause of treatment failure and is associated with upregulation of ABCB1 and ABCG2 mRNA.

Multi-drug resistance in a canine lymphoid cell line due to increased P-glycoprotein expression, a potential model for drug-resistant canine lymphoma.

Canine lymphoma is routinely treated with a doxorubicin-based multidrug chemotherapy protocol, and although treatment is initially successful, tumor recurrence is common and associated with therapy resistance. Active efflux of chemotherapeutic agents by transporter proteins of the ATP-Binding Cassette superfamily forms an effective cellular defense mechanism and a high expression of these transporters is frequently observed in chemotherapy-resistant tumors in both humans and dogs. In this study we describe the ABC-transporter expression in a canine lymphoid cell line and a sub-cell line with acquired drug resistance following prolonged exposure to doxorubicin. This sub-cell line was more resistant to doxorubicin and vincristine, but not to prednisolone, and had a highly increased P-glycoprotein (P-gp/abcb1) expression and transport capacity for the P-gp model-substrate rhodamine123. Both resistance to doxorubicin and vincristine, and rhodamine123 transport capacity were fully reversed by the P-gp inhibitor PSC833. No changes were observed in the expression and function of the ABC-transporters MRP-1 and BCRP. It is concluded that GL-40 cells represent a useful model for studying P-gp dependent drug resistance in canine lymphoid neoplasia, and that this model can be used for screening substances as potential P-gp substrates and their capacity to modulate P-gp mediated drug resistance.

Prednisolone inclusion in a first-line multidrug cytostatic protocol for the treatment of canine lymphoma does not affect therapy results.

Chemotherapy protocols for canine lymphoma include the routine use of glucocorticoids for their lympholytic effect. However, glucocorticoids are associated with side effects (e.g. polyphagia, polyuria, and weight gain), limit the use of non-steroidal anti-inflammatory drugs, and can induce drug transporter expression that could lead to drug resistance. Despite these negative effects, there are no data to support the use of glucocorticoids as part of a multidrug chemotherapy protocol for the treatment of canine lymphoma. A prospective, randomized clinical trial was conducted in 81 dogs with multicentric lymphoma and no history of recent glucocorticoid use. All dogs were staged and treated with the same chemotherapy protocol (L-asparaginase, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with half of the dogs receiving prednisolone. Both treatment groups were similar with respect to demographics, immunophenotype, and clinical stage, except for a higher number of substage b patients in the prednisolone group (5 vs. 14; P=0.015). Treatment results obtained with the initial treatment (complete response rate 75%, disease-free period 176 days) and rescue treatment (complete response rate 45%, disease-free period 133 days), overall survival (283 days) and adverse events (number and grade) were similar for both groups. In conclusion, prednisolone, as part of a multidrug chemotherapy protocol, has no additional effect on treatment results and can be omitted from first-line multidrug protocols used for the treatment of canine lymphoma.

Masitinib reverses doxorubicin resistance in canine lymphoid cells by inhibiting the function of P-glycoprotein.

Overexpression of ABC-transporters including Pgp, MRP1, and BCRP has been associated with multidrug resistance (MDR) in both human and canine oncology. Therapeutic interventions to reverse MDR are limited, but include multidrug protocols and the temporary concomitant use of inhibitors of ABC-transporters. Recently, the use of tyrosine kinase inhibitors has been proposed to overcome MDR in human oncology. One of the tyrosine kinase inhibitors, masitinib, is licensed for veterinary use in the treatment of canine mast cell tumors. Therefore, this study aimed to assess the potential of masitinib to revert MDR in canine malignant lymphoma using an in vitro model with canine lymphoid cell lines. Masitinib had a mild antiproliferative effect on lymphoid cells, inhibited Pgp function at concentrations equal to or exceeding 1 µm and was able to reverse doxorubicin resistance. The current findings provide the rationale for a combined use of masitinib with doxorubicin in the treatment of dogs with doxorubicin-resistant malignant lymphoma but await confirmation in clinical trials.

Transient hyperammonemia due to urea cycle enzyme deficiency in Irish wolfhounds.

BACKGROUND: Irish Wolfhounds frequently have a congenital portosystemic shunt, but a considerable proportion of the 6- to 8-wk-old pups has hyperammonemia in the absence of portosystemic shunting. This hyperammonemia causes no signs and is transient, normalizing at the age of 3-4 months. HYPOTHESIS: Transient hyperammonemia has a metabolic basis in Irish Wolfhounds. ANIMALS: Two related (same sire) litters of Irish Wolfhounds (17 pups) and their parents were studied. METHODS: Integrity of the portal circulation was examined by ultrasonography and scintigraphy. Absence of parenchymal liver disease was verified by liver biopsy. Amino acid profiles were measured in 4 pups and repeated in 2 of these pups when ammonia concentrations had normalized. The amino acid profiles were compared with those of healthy Irish Wolfhound pups. RESULTS: Fasting venous ammonia concentrations were high (113-622 microg/dL, 65-345 micromol/L) in all pups, whereas bile acids were within reference range in all but 1. The ammonia and bile acid concentrations from all parents were within reference range. Portosystemic shunting was excluded in all but 1 pup. Liver biopsy excluded significant lesions in all 10 pups examined. Hypercitrullinemia was found and persisted even when ammonia had normalized, at the expense of an increase in glutamine and asparagine. CONCLUSIONS AND CLINICAL IMPORTANCE: Citrulline concentrations are controlled by the urea cycle enzymes argininosuccinase and argininosuccinate synthetase, and a defect in either of these enzymes may be responsible for the transient hyperammonemia in Irish Wolfhounds. Resolution of the hyperammonemia is associated with increased activity of alternative metabolic pathways forming glutamine and asparagine. Confirmation requires measurement of enzyme activities in liver tissue.

[Ehrlichia and Babesia infections in dogs in The Netherlands]. / Ehrlichia- en Babesia-infecties bij de hond in Nederland.

A retrospective study was performed at the Department of Clinical Sciences of Companion Animals at Utrecht University amongst 75 dogs diagnosed with a Babesia canis and/or an Ehrlichia canis infection. The majority of the dogs had visited an endemic area (most often the Mediterranean area or the Dutch Antilles), but two dogs became infected with Babesia in the Netherlands. Babesia infections were associated with a stay in an endemic area and an incubation period that are both significantly shorter (less than 3 months) than those for Ehrlichia and co-infections (more than 3 months). Reasons for the owner to seek veterinary attention (lethargy, anorexia, fever), findings from the physical examination (pale mucous membranes, hepato-/splenomegaly) and laboratory results (anemia, thrombocytopenia, hypo-albuminemia) were highly aspecific, making serology or PCR mandatory for diagnosing infections. Antigenic stimulation by the parasite sometimes resulted in immune-mediated diseases such as immune-mediated hemolytic anemia, thrombocytopenia, glomerulonefritis, and polyarthritis and in the case of ehrlichiosis in hypergammaglobulinemia. Specific therapy (imidocarb-diproprionate and/or doxycycline) was necessary, and because combined infections were common, it was considered appropriate to administer both drugs while the definitive diagnosis was being established. The prognosis was reasonably good, with almost half of all patients showing no clinical signs after treatment, although Babesia and co-infections were associated with a significantly longer survival sometimes resulted than Ehrlichia infections.

Chronic pulmonary interstitial fibrosis in Amazon parrots.

In the Netherlands, a syndrome affecting several species of older Amazon parrots (Amazona sp.) has been described. This syndrome was characterized as a chronic respiratory disease resulting in exercise intolerance. Pathological examination revealed loss of functional lung tissue, pulmonary interstitial fibrosis, and right heart failure. Haematology revealed an elevated packed cell volume as a result of an increase in erythrocyte size and an increased haemoglobin mass per erythrocyte. In two patients, hypoxia and hypercapnia were demonstrated. The aetiology of this syndrome is currently not known. The microscopic lesions resemble those found in Diffuse Interstitial Fibrosis in humans.