An 8-month-old Ayrshire heifer had a rapidly growing mass in the axillary region of the left thor... more An 8-month-old Ayrshire heifer had a rapidly growing mass in the axillary region of the left thoracic limb. The mass surrounded the distal humerus and entrapped nerves of the brachial plexus, causing an abnormal gait. Histologically, the mass was composed of clusters and cords of round to polygonal cells with scattered, spindle-shaped cells. The neoplastic cells stained positively for vimentin and cytokeratin. No staining was found with S-100 protein, kappa and lambda light chains, or T-cell markers by immunohistochemistry. On electron microscopic evaluation, the cytoplasm of the neoplastic cells contained few organelles, principally rough and smooth endoplasmic reticulum and mitochondria. This synovial sarcoma has histologic and ultrastructural features characteristic of the poorly differentiated subtype of synovial sarcoma in the human classification system.
To evaluate the ability of commercial, chromogenic kits designed to measure human fibrinolytic pa... more To evaluate the ability of commercial, chromogenic kits designed to measure human fibrinolytic pathway components to measure the canine plasma fibrinolytic pathway enzymes, tissue plasminogen activator (tPA) and plasminogen (PLG), and their respective inhibitors, plasminogen activator inhibitor 1 (PAI) and alpha 2-antiplasmin (AP). 20 healthy dogs of various ages and breeds. The commercial procedure was adapted to a microtitration plate. Standard curves were generated by use of a canine plasma pool. Modifications of the commercial kit consisted of change in incubation periods and the substitution of urokinase for the streptokinase. Plasminogen and AP procedures yielded intra- and interassay coefficients of variation (CV) ranging from 2 to 6.4%. The tPA activity gave an acceptable intra-assay CV of 4.2%, but an equivocal interassay CV of 18%. The PAI assay gave unacceptable intra-assay and interassay CV of 59 and 66%, respectively. Modifications of the commercial PLG and AP procedure...
The Canadian veterinary journal. La revue vétérinaire canadienne, 2001
The purpose of this review was to provide the reader with an updated overview of small animal tra... more The purpose of this review was to provide the reader with an updated overview of small animal transfusion medicine, and an approach to integrating it into private practice, based on a review of the veterinary and human literature spanning the last 3 decades. Electronic, online databases that were searched included CAB International and Medline; multiple keywords or subject headings were searched that were appropriate to each of the sections reviewed: canine and feline blood groups, blood-typing and crossmatching, donors, blood collection, storage, blood components, blood transfusion, blood component therapy, blood substitutes, and adverse reactions. The safe use of blood component therapy requires knowledge of blood groups and antibody prevalence, and knowledge of the means to minimize the risk of adverse reactions by including the use of proper donors and screening assays that facilitate detection of serological incompatibility. The 2 assays available to the practitioner are crossm...
The Canadian veterinary journal. La revue vétérinaire canadienne, 1998
A 7-month-old calf with a firm, diffuse infiltration of the left hind limb with sciatic nerve mot... more A 7-month-old calf with a firm, diffuse infiltration of the left hind limb with sciatic nerve motor deficit was presented. The cytology indicated a malignant, round cell tumor and at necropsy, tissues were positive to a Kappa-lambda immunohistochemistry test. The final diagnosis was sporadic bovine leukosis, juvenile form.
Journal of the American Veterinary Medical Association, Jan 15, 1996
A 5-month-old sexually intact male Chesapeake Bay Retriever was evaluated for lameness of 2 weeks... more A 5-month-old sexually intact male Chesapeake Bay Retriever was evaluated for lameness of 2 weeks' duration and lymphocytosis. Acute lymphoblastic leukemia was diagnosed on the basis of results of cytologic and cytochemical evaluation of a bone marrow aspirate. Serum biochemical abnormalities included hypercalcemia and hyperkalemia. Hypercalcemia was likely paraneoplastic; hyperkalemia was believed to be a result of release of potassium from large numbers of lymphocytes in vitro (pseudohyperkalemia). The dog was euthanatized, and necropsy revealed infiltration of the hepatic vasculature and sinusoids, renal parenchyma, mesenteric and peripheral lymph nodes, bone marrow, and iridial tissue with neoplastic cells. Unique features of this case include the young age of the dog and the hypercalcemia and hyperkalemia associated with acute lymphoblastic anemia.
Certain compounds that induce liver injury clinically are not readily identified from earlier pre... more Certain compounds that induce liver injury clinically are not readily identified from earlier preclinical studies. Novel biomarkers are being sought to be applied across the pharmaceutical pipeline to fill this knowledge gap and to add increased specificity for detecting drug-induced liver injury in combination with aminotransferases (alanine and aspartate aminotransferase) – the current reference-standard biomarkers used in the clinic. The gaps in the qualification process for novel biomarkers of regulatory decision-making are assessed and compared with aminotransferase activities to guide the determination of safe compound margins for drug delivery to humans where monitoring for potential liver injury is a cause for concern. Histopathologic observations from preclinical studies are considered the principal reference standard to benchmark and assess subtle aminotransferase elevations. This approach correlates quite well for many developmental compounds, yet cases of discordance cre...
To determine whether alterations in the fibrinolytic pathway analytes, plasminogen (PLG), tissue ... more To determine whether alterations in the fibrinolytic pathway analytes, plasminogen (PLG), tissue plasminogen activator, and alpha 2-antiplasmin are significant in dogs subjected to minor and major surgical trauma. 18 dogs in 3 groups of 6 each. Plasma fibrinolytic pathway analytes were measured in dogs with trauma of ovariohysterectomy (minor trauma) or orthopedic surgery (major trauma) and halothane anesthesia (control group). A commercial procedure adapted to a microtitration plate was used to measure the analytes. Blood was obtained 24 hours before anesthesia, at extubation (0 hours), and again at 2, 24, and 48 hours after extubation. An analyte quality-control strategy was maintained. In the major trauma group, there was a significant, transient, postsurgical decrease in PLG activity at 0 and 24 hours and a return to presurgical values by 48 hours. The minor trauma group had a similar trend without significant changes, including an increase in PLG values at 48 hours that exceede...
Recently, in early clinical development, a few biologics and small molecules intended as antitumo... more Recently, in early clinical development, a few biologics and small molecules intended as antitumor or anti-inflammatory agents have caused a severe adverse pro-inflammatory systemic reaction also known as systemic inflammatory response syndrome (SIRS). This toxicity could result from expected pharmacological effects of a therapeutic antibody and/or from interaction with antigens expressed on cells/tissues other than the intended target. Clinical monitoring of SIRS is challenging because of the narrow diagnostic window to institute a successful intervening therapeutic strategy prior to acute circulatory collapse. Furthermore, for these classes of therapeutic agents, studies in animals have low predictive ability to identify potential human hazards. In vitro screens with human cells, though promising, need further development. Therefore, identification of improved preclinical diagnostic markers of SIRS will enable clinicians to select applicable markers for clinical testing and avoid potentially catastrophic events. There is limited preclinical toxicology data describing the interspecies performance of acute-phase proteins because the response time, type, and duration of major acute-phase proteins vary significantly between species. This review will attempt to address this intellectual gap, as well as the use and applicability of acute-phase proteins as preclinical to clinical translational biomarkers of SIRS.
associated with some pathology, and possibly clinical signs. There are no reports of an associati... more associated with some pathology, and possibly clinical signs. There are no reports of an association between the size of the worm burden and clinical signs with this nematode. It should be noted that, in most reported infections, no clinical signs were observed. However, Ollulanus tricuspis has been associated with vomiting, illthrift, and associated chronic gastritis (7,9,10), and should be considered in the differential diagnoses of cats with this type of history.
Regulatory Toxicology and Pharmacology, Apr 30, 2010
Drug-induced liver injury (DILI) is the most frequent cause of discontinuation of new chemical en... more Drug-induced liver injury (DILI) is the most frequent cause of discontinuation of new chemical entities during development. DILI can either be intrinsic/predictable or an idiosyncratic type. These two forms of DILI are contrasted in their manifestation and diagnosis. Even with regulatory guidance (FDA, 2009), there is still a gap in our ability to identify predictable DILI, both specifically and sensitively. Alanine aminotransferase (ALT) is the principal reference standard biomarker to diagnose DILI, yet its current application in preclinical to clinical translation for decision-making purposes has imperfections: (1) analytical ALT assay uniformity across industry would be aided by common analytical processes; (2) assessment of ALT toxicological performance in a large preclinical analysis would help to establish a true threshold of elevation for predictable DILI and improve translational use across various stages of pharmaceutical development and finally, (3) clinical evaluation of ALT elevations prospectively and retrospectively is recommended to define and manage variations in clinical study subjects including rising body mass index (BMI) range and ALT upper limit of normal (ULN) in the broader population over time. The emergence of new hepatotoxicity biomarkers necessitates a parallel and equivalent assessment to the aminotransferases in a regulatory qualification model.
The objective of this study was to determine the relationship between the number of transferable ... more The objective of this study was to determine the relationship between the number of transferable embryos (TE) and various blood chemistry parameters as a reflection of the metabolic state of cows after superovulatory treatment. Forty-nine Holstein cows were subjected to superovulatory treatment for commercial embryo production. At the time of embryo harvest, individual blood samples were taken from cows for biochemical analysis. All embryos including dead ones as well as non-fertilized oocytes were counted in uterine lavage. Feed samples collected daily for a period of two weeks before embryo harvest, were analyzed for mycotoxins: vomitoxin, zearalenone and T-2 toxin. On average, cows produced 9.45+/-5.60 embryos and oocytes of which 5.27+/-4.20 were TE, 0.37+/-0.80 were dead embryos and 3.82+/-3.78 were non-fertilized oocytes. Higher concentrations of Mg and K were associated with a higher production of TE (p=0.005 and p=0.043, respectively) and higher activity of creatinine kinase was associated with a lower production of TE (p=0.011).
Certain compounds that induce liver injury clinically are not readily identified from earlier pre... more Certain compounds that induce liver injury clinically are not readily identified from earlier preclinical studies. Novel biomarkers are being sought to be applied across the pharmaceutical pipeline to fill this knowledge gap and to add increased specificity for detecting drug-induced liver injury in combination with aminotransferases (alanine and aspartate aminotransferase)--the current reference-standard biomarkers used in the clinic. The gaps in the qualification process for novel biomarkers of regulatory decision-making are assessed and compared with aminotransferase activities to guide the determination of safe compound margins for drug delivery to humans where monitoring for potential liver injury is a cause for concern. Histopathologic observations from preclinical studies are considered the principal reference standard to benchmark and assess subtle aminotransferase elevations. This approach correlates quite well for many developmental compounds, yet cases of discordance crea...
Veterinary Clinical Pathology American Society For Veterinary Clinical Pathology, Feb 1, 1996
Canine serum was used to compare seven chemistry analytes on two tabletop clinical dry chemistry ... more Canine serum was used to compare seven chemistry analytes on two tabletop clinical dry chemistry analyzers, Boehringer's Reflotron and Kodak's Ektachem. Results were compared to those obtained on a wet chemistry reference analyzer, Roche Diagnostic's Cobas Mira. Analytes measured were urea nitrogen (BUN), creatinine, glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol, and bilirubin. Nine to 12 canine sera with values in the low, normal, and high range were evaluated. The correlations were acceptable for all comparisons with correlation coefficients greater than 0.98 for all analytes. Regression analysis resulted in significant differences for both tabletop analyzers when compared to the reference analyzer for cholesterol and bilirubin, and for glucose andAST on the Kodak Ektachem. Differences appeared to result from proportional systematic error occurring at high analyte concentrations.
An 8-month-old Ayrshire heifer had a rapidly growing mass in the axillary region of the left thor... more An 8-month-old Ayrshire heifer had a rapidly growing mass in the axillary region of the left thoracic limb. The mass surrounded the distal humerus and entrapped nerves of the brachial plexus, causing an abnormal gait. Histologically, the mass was composed of clusters and cords of round to polygonal cells with scattered, spindle-shaped cells. The neoplastic cells stained positively for vimentin and cytokeratin. No staining was found with S-100 protein, kappa and lambda light chains, or T-cell markers by immunohistochemistry. On electron microscopic evaluation, the cytoplasm of the neoplastic cells contained few organelles, principally rough and smooth endoplasmic reticulum and mitochondria. This synovial sarcoma has histologic and ultrastructural features characteristic of the poorly differentiated subtype of synovial sarcoma in the human classification system.
To evaluate the ability of commercial, chromogenic kits designed to measure human fibrinolytic pa... more To evaluate the ability of commercial, chromogenic kits designed to measure human fibrinolytic pathway components to measure the canine plasma fibrinolytic pathway enzymes, tissue plasminogen activator (tPA) and plasminogen (PLG), and their respective inhibitors, plasminogen activator inhibitor 1 (PAI) and alpha 2-antiplasmin (AP). 20 healthy dogs of various ages and breeds. The commercial procedure was adapted to a microtitration plate. Standard curves were generated by use of a canine plasma pool. Modifications of the commercial kit consisted of change in incubation periods and the substitution of urokinase for the streptokinase. Plasminogen and AP procedures yielded intra- and interassay coefficients of variation (CV) ranging from 2 to 6.4%. The tPA activity gave an acceptable intra-assay CV of 4.2%, but an equivocal interassay CV of 18%. The PAI assay gave unacceptable intra-assay and interassay CV of 59 and 66%, respectively. Modifications of the commercial PLG and AP procedure...
The Canadian veterinary journal. La revue vétérinaire canadienne, 2001
The purpose of this review was to provide the reader with an updated overview of small animal tra... more The purpose of this review was to provide the reader with an updated overview of small animal transfusion medicine, and an approach to integrating it into private practice, based on a review of the veterinary and human literature spanning the last 3 decades. Electronic, online databases that were searched included CAB International and Medline; multiple keywords or subject headings were searched that were appropriate to each of the sections reviewed: canine and feline blood groups, blood-typing and crossmatching, donors, blood collection, storage, blood components, blood transfusion, blood component therapy, blood substitutes, and adverse reactions. The safe use of blood component therapy requires knowledge of blood groups and antibody prevalence, and knowledge of the means to minimize the risk of adverse reactions by including the use of proper donors and screening assays that facilitate detection of serological incompatibility. The 2 assays available to the practitioner are crossm...
The Canadian veterinary journal. La revue vétérinaire canadienne, 1998
A 7-month-old calf with a firm, diffuse infiltration of the left hind limb with sciatic nerve mot... more A 7-month-old calf with a firm, diffuse infiltration of the left hind limb with sciatic nerve motor deficit was presented. The cytology indicated a malignant, round cell tumor and at necropsy, tissues were positive to a Kappa-lambda immunohistochemistry test. The final diagnosis was sporadic bovine leukosis, juvenile form.
Journal of the American Veterinary Medical Association, Jan 15, 1996
A 5-month-old sexually intact male Chesapeake Bay Retriever was evaluated for lameness of 2 weeks... more A 5-month-old sexually intact male Chesapeake Bay Retriever was evaluated for lameness of 2 weeks' duration and lymphocytosis. Acute lymphoblastic leukemia was diagnosed on the basis of results of cytologic and cytochemical evaluation of a bone marrow aspirate. Serum biochemical abnormalities included hypercalcemia and hyperkalemia. Hypercalcemia was likely paraneoplastic; hyperkalemia was believed to be a result of release of potassium from large numbers of lymphocytes in vitro (pseudohyperkalemia). The dog was euthanatized, and necropsy revealed infiltration of the hepatic vasculature and sinusoids, renal parenchyma, mesenteric and peripheral lymph nodes, bone marrow, and iridial tissue with neoplastic cells. Unique features of this case include the young age of the dog and the hypercalcemia and hyperkalemia associated with acute lymphoblastic anemia.
Certain compounds that induce liver injury clinically are not readily identified from earlier pre... more Certain compounds that induce liver injury clinically are not readily identified from earlier preclinical studies. Novel biomarkers are being sought to be applied across the pharmaceutical pipeline to fill this knowledge gap and to add increased specificity for detecting drug-induced liver injury in combination with aminotransferases (alanine and aspartate aminotransferase) – the current reference-standard biomarkers used in the clinic. The gaps in the qualification process for novel biomarkers of regulatory decision-making are assessed and compared with aminotransferase activities to guide the determination of safe compound margins for drug delivery to humans where monitoring for potential liver injury is a cause for concern. Histopathologic observations from preclinical studies are considered the principal reference standard to benchmark and assess subtle aminotransferase elevations. This approach correlates quite well for many developmental compounds, yet cases of discordance cre...
To determine whether alterations in the fibrinolytic pathway analytes, plasminogen (PLG), tissue ... more To determine whether alterations in the fibrinolytic pathway analytes, plasminogen (PLG), tissue plasminogen activator, and alpha 2-antiplasmin are significant in dogs subjected to minor and major surgical trauma. 18 dogs in 3 groups of 6 each. Plasma fibrinolytic pathway analytes were measured in dogs with trauma of ovariohysterectomy (minor trauma) or orthopedic surgery (major trauma) and halothane anesthesia (control group). A commercial procedure adapted to a microtitration plate was used to measure the analytes. Blood was obtained 24 hours before anesthesia, at extubation (0 hours), and again at 2, 24, and 48 hours after extubation. An analyte quality-control strategy was maintained. In the major trauma group, there was a significant, transient, postsurgical decrease in PLG activity at 0 and 24 hours and a return to presurgical values by 48 hours. The minor trauma group had a similar trend without significant changes, including an increase in PLG values at 48 hours that exceede...
Recently, in early clinical development, a few biologics and small molecules intended as antitumo... more Recently, in early clinical development, a few biologics and small molecules intended as antitumor or anti-inflammatory agents have caused a severe adverse pro-inflammatory systemic reaction also known as systemic inflammatory response syndrome (SIRS). This toxicity could result from expected pharmacological effects of a therapeutic antibody and/or from interaction with antigens expressed on cells/tissues other than the intended target. Clinical monitoring of SIRS is challenging because of the narrow diagnostic window to institute a successful intervening therapeutic strategy prior to acute circulatory collapse. Furthermore, for these classes of therapeutic agents, studies in animals have low predictive ability to identify potential human hazards. In vitro screens with human cells, though promising, need further development. Therefore, identification of improved preclinical diagnostic markers of SIRS will enable clinicians to select applicable markers for clinical testing and avoid potentially catastrophic events. There is limited preclinical toxicology data describing the interspecies performance of acute-phase proteins because the response time, type, and duration of major acute-phase proteins vary significantly between species. This review will attempt to address this intellectual gap, as well as the use and applicability of acute-phase proteins as preclinical to clinical translational biomarkers of SIRS.
associated with some pathology, and possibly clinical signs. There are no reports of an associati... more associated with some pathology, and possibly clinical signs. There are no reports of an association between the size of the worm burden and clinical signs with this nematode. It should be noted that, in most reported infections, no clinical signs were observed. However, Ollulanus tricuspis has been associated with vomiting, illthrift, and associated chronic gastritis (7,9,10), and should be considered in the differential diagnoses of cats with this type of history.
Regulatory Toxicology and Pharmacology, Apr 30, 2010
Drug-induced liver injury (DILI) is the most frequent cause of discontinuation of new chemical en... more Drug-induced liver injury (DILI) is the most frequent cause of discontinuation of new chemical entities during development. DILI can either be intrinsic/predictable or an idiosyncratic type. These two forms of DILI are contrasted in their manifestation and diagnosis. Even with regulatory guidance (FDA, 2009), there is still a gap in our ability to identify predictable DILI, both specifically and sensitively. Alanine aminotransferase (ALT) is the principal reference standard biomarker to diagnose DILI, yet its current application in preclinical to clinical translation for decision-making purposes has imperfections: (1) analytical ALT assay uniformity across industry would be aided by common analytical processes; (2) assessment of ALT toxicological performance in a large preclinical analysis would help to establish a true threshold of elevation for predictable DILI and improve translational use across various stages of pharmaceutical development and finally, (3) clinical evaluation of ALT elevations prospectively and retrospectively is recommended to define and manage variations in clinical study subjects including rising body mass index (BMI) range and ALT upper limit of normal (ULN) in the broader population over time. The emergence of new hepatotoxicity biomarkers necessitates a parallel and equivalent assessment to the aminotransferases in a regulatory qualification model.
The objective of this study was to determine the relationship between the number of transferable ... more The objective of this study was to determine the relationship between the number of transferable embryos (TE) and various blood chemistry parameters as a reflection of the metabolic state of cows after superovulatory treatment. Forty-nine Holstein cows were subjected to superovulatory treatment for commercial embryo production. At the time of embryo harvest, individual blood samples were taken from cows for biochemical analysis. All embryos including dead ones as well as non-fertilized oocytes were counted in uterine lavage. Feed samples collected daily for a period of two weeks before embryo harvest, were analyzed for mycotoxins: vomitoxin, zearalenone and T-2 toxin. On average, cows produced 9.45+/-5.60 embryos and oocytes of which 5.27+/-4.20 were TE, 0.37+/-0.80 were dead embryos and 3.82+/-3.78 were non-fertilized oocytes. Higher concentrations of Mg and K were associated with a higher production of TE (p=0.005 and p=0.043, respectively) and higher activity of creatinine kinase was associated with a lower production of TE (p=0.011).
Certain compounds that induce liver injury clinically are not readily identified from earlier pre... more Certain compounds that induce liver injury clinically are not readily identified from earlier preclinical studies. Novel biomarkers are being sought to be applied across the pharmaceutical pipeline to fill this knowledge gap and to add increased specificity for detecting drug-induced liver injury in combination with aminotransferases (alanine and aspartate aminotransferase)--the current reference-standard biomarkers used in the clinic. The gaps in the qualification process for novel biomarkers of regulatory decision-making are assessed and compared with aminotransferase activities to guide the determination of safe compound margins for drug delivery to humans where monitoring for potential liver injury is a cause for concern. Histopathologic observations from preclinical studies are considered the principal reference standard to benchmark and assess subtle aminotransferase elevations. This approach correlates quite well for many developmental compounds, yet cases of discordance crea...
Veterinary Clinical Pathology American Society For Veterinary Clinical Pathology, Feb 1, 1996
Canine serum was used to compare seven chemistry analytes on two tabletop clinical dry chemistry ... more Canine serum was used to compare seven chemistry analytes on two tabletop clinical dry chemistry analyzers, Boehringer's Reflotron and Kodak's Ektachem. Results were compared to those obtained on a wet chemistry reference analyzer, Roche Diagnostic's Cobas Mira. Analytes measured were urea nitrogen (BUN), creatinine, glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol, and bilirubin. Nine to 12 canine sera with values in the low, normal, and high range were evaluated. The correlations were acceptable for all comparisons with correlation coefficients greater than 0.98 for all analytes. Regression analysis resulted in significant differences for both tabletop analyzers when compared to the reference analyzer for cholesterol and bilirubin, and for glucose andAST on the Kodak Ektachem. Differences appeared to result from proportional systematic error occurring at high analyte concentrations.
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