@article{koeberl_pinto_sun_li_kozink_benjamin_demaster_kruse_vaughn_hillman_et al._2008, title={AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia}, volume={16}, ISSN={["1525-0016"]}, DOI={10.1038/mt.2008.15}, abstractNote={Glycogen storage disease type Ia (GSD-Ia) profoundly impairs glucose release by the liver due to glucose-6-phosphatase (G6Pase) deficiency. An adeno-associated virus (AAV) containing a small human G6Pase transgene was pseudotyped with AAV8 (AAV2/8) to optimize liver tropism. Survival was prolonged in 2-week-old G6Pase (–/–) mice by 600-fold fewer AAV2/8 vector particles (vp), in comparison to previous experiments involving this model (2 × 109 vp; 3 × 1011 vp/kg). When the vector was pseudotyped with AAV1, survival was prolonged only at a higher dose (3 × 1013 vp/kg). The AAV2/8 vector uniquely prevented hypoglycemia during fasting and fully corrected liver G6Pase deficiency in GSD-Ia mice and dogs. The AAV2/8 vector has prolonged survival in three GSD-Ia dogs to >11 months, which validated this strategy in the large animal model for GSD-Ia. Urinary biomarkers, including lactate and 3-hydroxybutyrate, were corrected by G6Pase expression solely in the liver. Glycogen accumulation in the liver was reduced almost to the normal level in vector-treated GSD-Ia mice and dogs, as was the hepatocyte growth factor (HGF) in GSD-Ia mice. These preclinical data demonstrated the efficacy of correcting hepatic G6Pase deficiency, and support the further preclinical development of AAV vector–mediated gene therapy for GSD-Ia. Glycogen storage disease type Ia (GSD-Ia) profoundly impairs glucose release by the liver due to glucose-6-phosphatase (G6Pase) deficiency. An adeno-associated virus (AAV) containing a small human G6Pase transgene was pseudotyped with AAV8 (AAV2/8) to optimize liver tropism. Survival was prolonged in 2-week-old G6Pase (–/–) mice by 600-fold fewer AAV2/8 vector particles (vp), in comparison to previous experiments involving this model (2 × 109 vp; 3 × 1011 vp/kg). When the vector was pseudotyped with AAV1, survival was prolonged only at a higher dose (3 × 1013 vp/kg). The AAV2/8 vector uniquely prevented hypoglycemia during fasting and fully corrected liver G6Pase deficiency in GSD-Ia mice and dogs. The AAV2/8 vector has prolonged survival in three GSD-Ia dogs to >11 months, which validated this strategy in the large animal model for GSD-Ia. Urinary biomarkers, including lactate and 3-hydroxybutyrate, were corrected by G6Pase expression solely in the liver. Glycogen accumulation in the liver was reduced almost to the normal level in vector-treated GSD-Ia mice and dogs, as was the hepatocyte growth factor (HGF) in GSD-Ia mice. These preclinical data demonstrated the efficacy of correcting hepatic G6Pase deficiency, and support the further preclinical development of AAV vector–mediated gene therapy for GSD-Ia.}, number={4}, journal={MOLECULAR THERAPY}, author={Koeberl, Dwight D. and Pinto, Carlos and Sun, Baodong and Li, Songtao and Kozink, Daniel M. and Benjamin, Daniel K., Jr. and Demaster, Amanda K. and Kruse, Meghan A. and Vaughn, Valerie and Hillman, Steven and et al.}, year={2008}, month={Apr}, pages={665–672} } @article{koeberl_sun_damodaran_brown_millington_benjamin_bird_schneider_hillman_jackson_et al._2006, title={Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia}, volume={13}, ISSN={["1476-5462"]}, DOI={10.1038/sj.gt.3302774}, abstractNote={The deficiency of glucose-6-phosphatase (G6Pase) underlies life-threatening hypoglycemia and growth retardation in glycogen storage disease type Ia (GSD-Ia). An adeno-associated virus (AAV) vector encoding G6Pase was pseudotyped as AAV8 and administered to 2-week-old GSD-Ia mice (n=9). Median survival was prolonged to 7 months following vector administration, in contrast to untreated GSD-Ia mice that survived for only 2 weeks. Although GSD-Ia mice were initially growth-retarded, treated mice increased fourfold in weight to normal size. Blood glucose was partially corrected by 2 weeks following treatment, whereas blood cholesterol normalized. Glucose-6-phosphatase activity was partially corrected to 25% of the normal level at 7 months of age in treated mice, and blood glucose during fasting remained lower in treated, affected mice than in normal mice. Glycogen storage was partially corrected in the liver by 2 weeks following treatment, but reaccumulated to pre-treatment levels by 7 months old (m.o.). Vector genome DNA decreased between 3 days and 3 weeks in the liver following vector administration, mainly through the loss of single-stranded genomes; however, double-stranded vector genomes were more stable. Although CD8+ lymphocytic infiltrates were present in the liver, partial biochemical correction was sustained at 7 m.o. The development of efficacious AAV vector-mediated gene therapy could significantly reduce the impact of long-term complications in GSD-Ia, including hypoglycemia, hyperlipidemia and growth failure.}, number={17}, journal={GENE THERAPY}, author={Koeberl, D. D. and Sun, B. D. and Damodaran, T. V. and Brown, T. and Millington, D. S. and Benjamin, D. J., Jr. and Bird, A. and Schneider, A. and Hillman, S. and Jackson, M. and et al.}, year={2006}, month={Sep}, pages={1281–1289} } @article{bunch_ford_hawkins_jackson_vaden_breitschwerdt_2004, title={The Clinician Investigator Program in Companion Animal Internal Medicine at North Carolina State University}, volume={31}, ISSN={0748-321X 1943-7218}, url={http://dx.doi.org/10.3138/jvme.31.4.425}, DOI={10.3138/jvme.31.4.425}, abstractNote={ A retrospective study was conducted to describe the development and evolution of the combined internal medicine/PhD program, the Clinician Investigator (CI) Program, at North Carolina State University. Separate survey instruments were developed for individuals who had committed to completing both the residency and PhD components and for graduate advisors of individuals who were granted the PhD degree. Results are summarized here. Most CIs reported believing that each component of the program (clinical training and research training) provided mutual benefits and that their teaching skills were enhanced, particularly as a result of instructing students in the Veterinary Teaching Hospital. Opinions among both the CIs and the graduate advisors were divided about the benefits of a combined program compared with a sequential program; however, all but one of 11 CIs who completed the survey would enroll in the combined program again. The graduate advisors were overwhelmingly positive about the CIs they had advised and indicated that they would welcome a CI as a PhD student in their laboratory again. Suggested areas for improvement included guaranteed salary/stipend support for the average time to completion (six years) instead of for five years, as well as more emphasis on and guidance in identifying a graduate advisor earlier in the CI program so as to smooth the transition between the clinical and research training components of the program. It is hoped that other training programs will benefit from the summary of our experience with this program. }, number={4}, journal={Journal of Veterinary Medical Education}, publisher={University of Toronto Press Inc. (UTPress)}, author={Bunch, Susan E. and Ford, Richard B. and Hawkins, Eleanor C. and Jackson, Mark W. and Vaden, Shelly L. and Breitschwerdt, Edward B.}, year={2004}, month={Dec}, pages={425–434} } @article{jackson_jackson_coblentz_hammerberg_2003, title={Evaluation of the clinical and allergen specific serum immunoglobulin E responses to oral challenge with cornstarch, corn, soy and a soy hydrolysate diet in dogs with spontaneous food allergy}, volume={14}, ISSN={["0959-4493"]}, DOI={10.1046/j.1365-3164.2003.00338.x}, abstractNote={Abstract Fourteen dogs with known clinical hypersensitivity to soy and corn were maintained on a limited antigen duck and rice diet until cutaneous manifestations of pruritus were minimal (78 days). Sequential oral challenges with cornstarch, corn and soy were then performed. Subsequently, the dogs were fed a diet containing hydrolysed soy protein and cornstarch. Throughout the study period the dogs were examined for cutaneous manifestations of pruritus and, additionally, serum was collected for measurement of allergen‐specific and total immunoglobulin (Ig)E concentrations. Intradermal testing with food antigens was performed prior to entry into the study and after 83 days. A statistically significant clinical improvement was measured between days 0 and 83. Significant pruritus was induced after oral challenge with cornstarch, corn and soy (P = 0.04, 0.002, 0.01, respectively) but not with the hydrolysed diet (P = 0.5). The positive predictive value of the skin test for soy and corn allergy was reduced after feeding a soy and corn free diet. Although increases in soy and corn‐specific serum IgE concentrations were measured in individual dogs post challenge they were not statistically significant and could not be used to predict clinical hypersensitivity.}, number={4}, journal={VETERINARY DERMATOLOGY}, author={Jackson, HA and Jackson, MW and Coblentz, L and Hammerberg, B}, year={2003}, month={Aug}, pages={181–187} } @article{savary-bataille_bunch_spaulding_jackson_mac law_stebbins_2003, title={Percutaneous ultrasound-guided cholecystocentesis in healthy cats}, volume={17}, ISSN={["1939-1676"]}, DOI={10.1892/0891-6640(2003)017<0298:PUCIHC>2.3.CO;2}, number={3}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Savary-Bataille, KCM and Bunch, SE and Spaulding, KA and Jackson, MW and Mac Law, J and Stebbins, ME}, year={2003}, pages={298–303} } @article{pressler_rotstein_law_rosol_leroy_keene_jackson_2002, title={Hypercalcemia and high parathyroid hormone-related protein concentration associated with malignant melanoma in a dog}, volume={221}, ISSN={["0003-1488"]}, DOI={10.2460/javma.2002.221.263}, abstractNote={A 12-year-old Cocker Spaniel with an oral malignant melanoma was evaluated for progressive lethargy and anorexia. No metastases were identified during antemortem evaluation, but severe hypercalcemia was evident. Antemortem diagnostic testing failed to identify a cause for the hypercalcemia. No neoplasms other than the melanoma were identified on postmortem examination. Serum parathyroid hormone-related protein concentration was markedly high, and the melanoma had moderate to marked immunostaining for this protein. Paraneoplastic syndromes are rare in dogs with malignant melanoma.}, number={2}, journal={JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION}, author={Pressler, BM and Rotstein, DS and Law, JM and Rosol, TJ and LeRoy, B and Keene, BW and Jackson, MW}, year={2002}, month={Jul}, pages={263-+} } @article{kishnani_faulkner_vancamp_jackson_brown_boney_koeberl_chen_2001, title={Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia)}, volume={38}, ISSN={["0300-9858"]}, DOI={10.1354/vp.38-1-83}, abstractNote={ A canine model of glycogen storage disease Ia (GSD Ia), similar clinically, biochemically, and pathologically to the human disease, was established by crossbreeding Maltese and Beagle dogs carrying a mutated, defective glucose-6-phosphatase (G-6-Pase) gene. Ten puppies were born in three litters from these crossbreedings. Six were homozygous for the previously described M121I GSD Ia mutation. Of these six affecteds, two were stillborn, and one died at 2, 32, and 60 days of life, respectively (puppies A, B, C, D, E), while one is alive at age 15 months (puppy F). Affected puppies exhibited tremors, weakness, and neurologic signs when hypoglycemic. They had postnatal growth retardation and progressive hepatomegaly. Biochemical abnormalities included fasting hypoglycemia, hyperlactacidemia, hypercholesterolemia, hypertriglyceridemia, and hyperuricemia. Microscopic examination of tissues from affected puppies showed diffuse, marked hepatocellular vacuolation, with distended clear hepatocytes and central to marginally located rounded nuclei. In the kidneys of puppies D and E, there was segmental glomerular sclerosis and vacuolation of proximal convoluted tubular epithelium. Biochemical analysis revealed increased liver glycogen content and isolated markedly reduced G-6-Pase enzyme activity in liver and kidney. The canine G-6-Pase gene was characterized by screening a canine genomic library. It spans ~ 11.8 kb and consists of five exons with >90% amino acid sequence homology to the derived human sequence. The first 1.5 kb of the 5′ region was sequenced and contains several putative response element motifs homologous to the human 5′ region. Establishment of this canine colony of GSD Ia that closely resembles human disease and isolation of the canine genomic gene provides an excellent model for studying pathophysiology and long-term complications and an opportunity to develop novel therapeutic approaches such as drug and gene therapy. }, number={1}, journal={VETERINARY PATHOLOGY}, author={Kishnani, PS and Faulkner, E and VanCamp, S and Jackson, M and Brown, T and Boney, A and Koeberl, D and Chen, YT}, year={2001}, month={Jan}, pages={83–91} } @article{bush_kimmel_wosar_jackson_2001, title={Secondary hypoparathyroidism attributed to hypomagnesemia in a dog with protein-losing enteropathy}, volume={219}, ISSN={["0003-1488"]}, DOI={10.2460/javma.2001.219.1732}, abstractNote={Severe hypomagnesemia (0.8 mg/dl; reference range, 1.6 to 2.3 mg/dl), hypocalcemia, and protein-losing enteropathy were identified in a 5-year-old castrated male 3-kg (6.6 lb) Shih Tzu examined because of anorexia, lethargy, paresis, and abdominal distention. Histologic examination of intestinal biopsy specimens revealed lymphangiectasia and lymphocytic, plasmacytic, neutrophilic infiltrates. Initial treatment included administration of magnesium (0.80 mEq/kg [0.36 mEq/lb]) of body weight in a balanced electrolyte solution. This treatment resulted in normalization of the serum magnesium concentration (1.7 mg/dl); resolution of the lethargy, paresis, and tachycardia; and an increase in the serum parathyroid hormone and ionized calcium concentrations. Findings were consistent with secondary hypoparathyroidism attributable to hypomagnesemia. Magnesium concentration should be monitored in all dogs with gastrointestinal tract disease, especially those with protein-losing enteropathy, anorexia, and weakness.}, number={12}, journal={JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION}, author={Bush, WW and Kimmel, SE and Wosar, MA and Jackson, MW}, year={2001}, month={Dec}, pages={1732-+} }