@article{brooks_landau_everitt_brown_grady_waskowicz_bass_d'angelo_asfaw_williams_et al._2018, title={Long-term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy}, volume={41}, ISSN={["1573-2665"]}, DOI={10.1007/s10545-018-0223-y}, abstractNote={Abstract}, number={6}, journal={JOURNAL OF INHERITED METABOLIC DISEASE}, author={Brooks, Elizabeth D. and Landau, Dustin J. and Everitt, Jeffrey I. and Brown, Talmage T. and Grady, Kylie M. and Waskowicz, Lauren and Bass, Cameron R. and D'Angelo, John and Asfaw, Yohannes G. and Williams, Kyha and et al.}, year={2018}, month={Dec}, pages={965–976} }
 @article{demaster_luo_curtis_williams_landau_drake_kozink_bird_crane_sun_et al._2012, title={Long-Term Efficacy Following Readministration of an Adeno-Associated Virus Vector in Dogs with Glycogen Storage Disease Type Ia}, volume={23}, ISSN={["1557-7422"]}, DOI={10.1089/hum.2011.106}, abstractNote={Glycogen storage disease type Ia (GSD-Ia) is the inherited deficiency of glucose-6-phosphatase (G6Pase), primarily found in liver and kidney, which causes life-threatening hypoglycemia. Dogs with GSD-Ia were treated with double-stranded adeno-associated virus (AAV) vectors encoding human G6Pase. Administration of an AAV9 pseudotyped (AAV2/9) vector to seven consecutive GSD-Ia neonates prevented hypoglycemia during fasting for up to 8 hr; however, efficacy eventually waned between 2 and 30 months of age, and readministration of a new pseudotype was eventually required to maintain control of hypoglycemia. Three of these dogs succumbed to acute hypoglycemia between 7 and 9 weeks of age; however, this demise could have been prevented by earlier readministration an AAV vector, as demonstrated by successful prevention of mortality of three dogs treated earlier in life. Over the course of this study, six out of nine dogs survived after readministration of an AAV vector. Of these, each dog required readministration on average every 9 months. However, two were not retreated until >34 months of age, while one with preexisting antibodies was re-treated three times in 10 months. Glycogen content was normalized in the liver following vector administration, and G6Pase activity was increased in the liver of vector-treated dogs in comparison with GSD-Ia dogs that received only with dietary treatment. G6Pase activity reached approximately 40% of normal in two female dogs following AAV2/9 vector administration. Elevated aspartate transaminase in absence of inflammation indicated that hepatocellular turnover in the liver might drive the loss of vector genomes. Survival was prolonged for up to 60 months in dogs treated by readministration, and all dogs treated by readministration continue to thrive despite the demonstrated risk for recurrent hypoglycemia and mortality from waning efficacy of the AAV2/9 vector. These preclinical data support the further translation of AAV vector-mediated gene therapy in GSD-Ia.}, number={4}, journal={HUMAN GENE THERAPY}, author={Demaster, Amanda and Luo, Xiaoyan and Curtis, Sarah and Williams, Kyha D. and Landau, Dustin J. and Drake, Elizabeth J. and Kozink, Daniel M. and Bird, Andrew and Crane, Bayley and Sun, Francis and et al.}, year={2012}, month={Apr}, pages={407–418} }
 @article{crane_luo_demaster_williams_kozink_zhang_brown_pinto_oka_sun_et al._2012, title={Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia}, volume={19}, ISSN={["0969-7128"]}, DOI={10.1038/gt.2011.86}, abstractNote={Glycogen storage disease type Ia (GSD-Ia) stems from glucose-6-phosphatase (G6Pase) deficiency and causes hypoglycemia, hepatomegaly, hypercholesterolemia and lactic acidemia. Three dogs with GSD-Ia were initially treated with a helper-dependent adenovirus encoding a human G6Pase transgene (HDAd-cG6Pase serotype 5) on postnatal day 3. Unlike untreated dogs with GSD-Ia, all three dogs initially maintained normal blood glucose levels. After 6-22 months, vector-treated dogs developed hypoglycemia, anorexia and lethargy, suggesting that the HDAd-cG6Pase serotype 5 vector had lost efficacy. Liver biopsies collected at this time revealed significantly elevated hepatic G6Pase activity and reduced glycogen content, when compared with affected dogs treated only by frequent feeding. Subsequently, the HDAd-cG6Pase serotype 2 vector was administered to two dogs, and hypoglycemia was reversed; however, renal dysfunction and recurrent hypoglycemia complicated their management. Administration of a serotype 2 HDAd vector prolonged survival in one GSD-Ia dog to 12 months of age and 36 months of age in the other, but the persistence of long-term complications limited HDAd vectors in the canine model for GSD-Ia.}, number={4}, journal={GENE THERAPY}, author={Crane, B. and Luo, X. and Demaster, A. and Williams, K. D. and Kozink, D. M. and Zhang, P. and Brown, T. T. and Pinto, C. R. and Oka, K. and Sun, F. and et al.}, year={2012}, month={Apr}, pages={443–452} }
 @article{fry_brown_lloyd_hansen_legleiter_robarge_spears_2011, title={Effect of dietary boron on physiological responses in growing steers inoculated with bovine herpesvirus type-1}, volume={90}, ISSN={["1532-2661"]}, DOI={10.1016/j.rvsc.2010.04.016}, abstractNote={Thirty-six Angus and Angus×Simmental steers were fed one of three dietary treatments; (1) control (no supplemental B), (2) 5 mg supplemental B/kg, and (3) 15 mg supplemental B/kg for 47 days to determine the effects of dietary boron (B) on disease resistance following an inoculation with bovine herpesvirus type-1 (BHV-1). On day 34 of the study steers were inoculated intranasally with BHV-1. Rectal temperatures began to elevate at day 2, and plasma tumor necrosis factor-α concentrations increased (P<0.05) by day 2 following BHV-1 inoculation. Plasma acute phase proteins were increased (P<0.01) while plasma interferon-γ was decreased (P<0.05) by day 4 post-inoculation. Supplementation of B increased (P<0.001) plasma B concentrations in a dose-responsive manner. However, dietary B did not affect the duration and severity of clinical signs of BHV-1 and had minimal effects on plasma acute phase proteins and cytokines.}, number={1}, journal={RESEARCH IN VETERINARY SCIENCE}, author={Fry, R. S. and Brown, T. T., Jr. and Lloyd, K. E. and Hansen, S. L. and Legleiter, L. R. and Robarge, W. P. and Spears, J. W.}, year={2011}, month={Feb}, pages={78–83} }
 @article{luo_hall_li_bird_lavin_winn_kemper_brown_koeberl_2011, title={Hepatorenal Correction in Murine Glycogen Storage Disease Type I With a Double-stranded Adeno-associated Virus Vector}, volume={19}, ISSN={["1525-0016"]}, DOI={10.1038/mt.2011.126}, abstractNote={Glycogen storage disease type Ia (GSD-Ia) is caused by the deficiency of glucose-6-phosphatase (G6Pase). Long-term complications of GSD-Ia include life-threatening hypoglycemia and proteinuria progressing to renal failure. A double-stranded (ds) adeno-associated virus serotype 2 (AAV2) vector encoding human G6Pase was pseudotyped with four serotypes, AAV2, AAV7, AAV8, and AAV9, and we evaluated efficacy in 12-day-old G6pase (−/−) mice. Hypoglycemia during fasting (plasma glucose <100 mg/dl) was prevented for >6 months by the dsAAV2/7, dsAAV2/8, and dsAAV2/9 vectors. Prolonged fasting for 8 hours revealed normalization of blood glucose following dsAAV2/9 vector administration at the higher dose. The glycogen content of kidney was reduced by >65% with both the dsAAV2/7 and dsAAV2/9 vectors, and renal glycogen content was stably reduced between 7 and 12 months of age for the dsAAV2/9 vector-treated mice. Every vector-treated group had significantly reduced glycogen content in the liver, in comparison with untreated G6pase (−/−) mice. G6Pase was expressed in many renal epithelial cells of with the dsAAV2/9 vector for up to 12 months. Albuminuria and renal fibrosis were reduced by the dsAAV2/9 vector. Hepatorenal correction in G6pase (−/−) mice demonstrates the potential of AAV vectors for the correction of inherited diseases of metabolism. Glycogen storage disease type Ia (GSD-Ia) is caused by the deficiency of glucose-6-phosphatase (G6Pase). Long-term complications of GSD-Ia include life-threatening hypoglycemia and proteinuria progressing to renal failure. A double-stranded (ds) adeno-associated virus serotype 2 (AAV2) vector encoding human G6Pase was pseudotyped with four serotypes, AAV2, AAV7, AAV8, and AAV9, and we evaluated efficacy in 12-day-old G6pase (−/−) mice. Hypoglycemia during fasting (plasma glucose <100 mg/dl) was prevented for >6 months by the dsAAV2/7, dsAAV2/8, and dsAAV2/9 vectors. Prolonged fasting for 8 hours revealed normalization of blood glucose following dsAAV2/9 vector administration at the higher dose. The glycogen content of kidney was reduced by >65% with both the dsAAV2/7 and dsAAV2/9 vectors, and renal glycogen content was stably reduced between 7 and 12 months of age for the dsAAV2/9 vector-treated mice. Every vector-treated group had significantly reduced glycogen content in the liver, in comparison with untreated G6pase (−/−) mice. G6Pase was expressed in many renal epithelial cells of with the dsAAV2/9 vector for up to 12 months. Albuminuria and renal fibrosis were reduced by the dsAAV2/9 vector. Hepatorenal correction in G6pase (−/−) mice demonstrates the potential of AAV vectors for the correction of inherited diseases of metabolism.}, number={11}, journal={MOLECULAR THERAPY}, author={Luo, Xiaoyan and Hall, Gentzon and Li, Songtao and Bird, Andrew and Lavin, Peter J. and Winn, Michelle P. and Kemper, Alex R. and Brown, Talmage T. and Koeberl, Dwight D.}, year={2011}, month={Nov}, pages={1961–1970} }
 @article{koeberl_pinto_brown_chen_2009, title={Gene Therapy for Inherited Metabolic Disorders in Companion Animals}, volume={50}, ISSN={["1084-2020"]}, DOI={10.1093/ilar.50.2.122}, abstractNote={Scientists first described inborn errors of metabolism, also termed inherited disorders of metabolism, early in the 20th century and since then have determined the biochemical and genetic bases of a great number of these disorders both in humans and in an increasing number of companion animals. The availability of metabolic screening tests has advanced the biochemical and genetic characterization in affected breeds of companion animals of inherited metabolic disorders involving amino acid, carbohydrate, fatty acid, and metal metabolism. Advances in gene therapy have led to the development of new treatments for inherited disorders of metabolism, and animal models have played a critical role in this research. For example, glycogen storage disease type Ia in dogs was highly responsive to adeno-associated viral vectormediated gene therapy, which prolonged survival and for more than a year prevented hypoglycemia during fasting. Gene therapy for other glycogen storage diseases and metabolic disorders will also be feasible. The establishment of a breeding colony and the ability to sustain affected animals are critical steps toward evaluating the safety and efficacy of gene therapy with clinically relevant endpoints. The further development of gene therapy for inherited disorders of metabolism could lead to curative therapy for affected humans and animals alike.}, number={2}, journal={ILAR JOURNAL}, author={Koeberl, Dwight D. and Pinto, Carlos and Brown, Talmage and Chen, Y. T.}, year={2009}, pages={122–127} }
 @article{hill_hopkins_davidson_bolt_diaz_brownie_brown_huntington_whitlow_2009, title={The addition of cottonseed hulls to the starter and supplementation of live yeast or mannanoligosaccharide in the milk for young calves}, volume={92}, ISSN={["1525-3198"]}, DOI={10.3168/jds.2008-1320}, abstractNote={The objectives of this study were to investigate the effects of the addition of cottonseed hulls (CSH) to the starter and the supplementation of live yeast product (YST) or mannanoligosaccharide product (MOS) to milk, on growth, intake, rumen development, and health parameters in young calves. Holstein (n = 116) and Jersey (n = 46) bull (n = 74) and heifer (n = 88) calves were assigned randomly within sex at birth to treatments. All calves were fed 3.8 L of colostrum daily for the first 2 d. Holstein calves were fed 3.8 L of whole milk, and Jersey calves were fed 2.8 L of whole milk through weaning at 42 d. Calves continued on trial through 63 d. Six treatments were arranged as a 2 x 3 factorial. Calves received either a corn-soybean meal-based starter (21% crude protein and 6% acid detergent fiber; -CSH) or a blend of 85% corn-soybean meal-based starter and 15% CSH (18% crude protein and 14% acid detergent fiber; +CSH) ad libitum. In addition, calves received whole milk with either no supplement (NONE) or supplemented with 3 g/d of mannanoligosaccharide product (MOS) or 4 g/d of live yeast product (YST) through weaning at 42 d. Twelve Holstein steers [n = 6 (per starter type); n = 4 (per supplement type)] were euthanized for collection and examination of rumen tissue samples. Dry matter intake (DMI) was greater for Holstein calves fed +CSH (0.90 kg/d) than -CSH (0.76 kg/d). Final body weight at 63 d of Holstein calves fed +CSH (75.8 kg) was greater than that of those fed -CSH (71.0 kg). Average daily gain (ADG) was greater for Holstein calves fed +CSH (0.58 kg/d) than -CSH (0.52 kg/d). However, Holstein calves fed -CSH had a greater feed efficiency (FE; 0.71 kg of ADG/kg of DMI) than those fed +CSH (0.65 kg of ADG/kg of DMI). Also, Holstein calves fed +CSH had narrower rumen papillae (0.32 mm) compared with those fed -CSH (0.41 mm). There were no significant effects of CSH on DMI, ADG, or FE in Jersey calves. There were no significant effects of YST or MOS on DMI, ADG, FE, or rumen papillae measures in Holstein calves. Jersey calves fed YST or MOS had greater final body weight at 63 d (51.2 kg and 51.0 kg, respectively) than calves fed NONE (47.5 kg). However, there were no significant effects of YST or MOS on DMI, ADG, or FE in Jersey calves.}, number={2}, journal={JOURNAL OF DAIRY SCIENCE}, author={Hill, S. R. and Hopkins, B. A. and Davidson, S. and Bolt, S. M. and Diaz, D. E. and Brownie, C. and Brown, T. and Huntington, G. B. and Whitlow, L. W.}, year={2009}, month={Feb}, pages={790–798} }
 @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 x 10(9) vp; 3 x 10(11) vp/kg). When the vector was pseudotyped with AAV1, survival was prolonged only at a higher dose (3 x 10(13) 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{sun_young_li_di_brown_salva_li_bird_yan_auten_et al._2008, title={Correction of multiple striated muscles in murine Pompe diseasethrough adeno-associated virus-mediated gene therapy}, volume={16}, ISSN={["1525-0016"]}, DOI={10.1038/mt.2008.133}, abstractNote={Glycogen storage disease type II (Pompe disease; MIM 232300) stems from the deficiency of acid alpha-glucosidase (GAA; acid maltase; EC 3.2.1.20), which primarily involves cardiac and skeletal muscles. An adeno-associated virus 2/8 (AAV2/8) vector containing the muscle creatine kinase (MCK) (CK1) reduced glycogen content by approximately 50% in the heart and quadriceps in GAA-knockout (GAA-KO) mice; furthermore, an AAV2/8 vector containing the hybrid alpha-myosin heavy chain enhancer-/MCK enhancer-promoter (MHCK7) cassette reduced glycogen content by >95% in heart and >75% in the diaphragm and quadriceps. Transduction with an AAV2/8 vector was higher in the quadriceps than in the gastrocnemius. An AAV2/9 vector containing the MHCK7 cassette corrected GAA deficiency in the distal hindlimb, and glycogen accumulations were substantially cleared by human GAA (hGAA) expression therein; however, the analogous AAV2/7 vector achieved much lower efficacy. Administration of the MHCK7-containing vectors significantly increased striated muscle function as assessed by increased Rotarod times at 18 weeks after injection, whereas the CK1-containing vector did not increase Rotarod performance. Importantly, type IIb myofibers in the extensor digitalis longus (EDL) were transduced, thereby correcting a myofiber type that is unresponsive to enzyme replacement therapy. In summary, AAV8 and AAV9-pseudotyped vectors containing the MHCK7 regulatory cassette achieved enhanced efficacy in Pompe disease mice.}, number={8}, journal={MOLECULAR THERAPY}, author={Sun, Baodong and Young, Sarah P. and Li, Ping and Di, Chunhui and Brown, Talmage and Salva, Maja Z. and Li, Songtao and Bird, Andrew and Yan, Zhen and Auten, Richard and et al.}, year={2008}, month={Aug}, pages={1366–1371} }
 @article{mackillop_olby_linder_brown_2007, title={Intramedullary cavernous malformation of the spinal cord in two dogs}, volume={44}, ISSN={["1544-2217"]}, DOI={10.1354/vp.44-4-528}, abstractNote={ Intramedullary cavernous malformations (CVMs) of the spinal cord were diagnosed in 2 adult dogs that presented for paraparesis. An intramedullary spinal cord lesion was identified on a myelogram in the first dog, and expansion of the vertebral canal was evident on radiographs in the second. Extensive intraparenchymal hemorrhage was found on gross postmortem examination in both dogs, and a distinct lobulated intramedullary mass was evident in the second dog. Microscopically, both lesions were composed of dilated, thin-walled vascular channels with little-to-no intervening neural parenchyma. Both dogs had evidence of channel thrombosis along with perilesional hemorrhage and hemosiderin accumulation. The second dog had additional degenerative changes, including thickened fibrous channel walls with hyalinization, foci of mineralization, and occasional tongues of entrapped gliotic neuropil. CVMs appear to be an uncommon cause of both acute and chronic spinal cord disease in the dog. }, number={4}, journal={VETERINARY PATHOLOGY}, author={Mackillop, E. and Olby, N. J. and Linder, K. E. and Brown, T. T.}, year={2007}, month={Jul}, pages={528–532} }
 @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{sun_zhang_benjamin_brown_bird_young_mcvie-wylie_chen_koeberl_2006, title={Enhanced efficacy of an AAV vector encoding chimeric, highly secreted acid alpha-glucosidase in glycogen storage disease type II}, volume={14}, ISSN={["1525-0024"]}, DOI={10.1016/j.ymthe.2006.08.001}, abstractNote={<h2>Abstract</h2> Glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) is an inherited muscular dystrophy caused by deficiency in the activity of the lysosomal enzyme acid α-glucosidase (GAA). We hypothesized that chimeric GAA containing an alternative signal peptide could increase the secretion of GAA from transduced cells and enhance the receptor-mediated uptake of GAA in striated muscle. The relative secretion of chimeric GAA from transfected 293 cells increased up to 26-fold. Receptor-mediated uptake of secreted, chimeric GAA corrected cultured GSD-II patient cells. High-level hGAA was sustained in the plasma of GSD-II mice for 24 weeks following administration of an AAV2/8 vector encoding chimeric GAA; furthermore, GAA activity was increased and glycogen content was significantly reduced in striated muscle and in the brain. Administration of only 1×10<sup>10</sup> vector particles increased GAA activity in the heart and diaphragm for >18 weeks, whereas 3×10<sup>10</sup> vector particles increased GAA activity and reduced glycogen content in the heart, diaphragm, and quadriceps. Furthermore, an AAV2/2 vector encoding chimeric GAA produced secreted hGAA for >12 weeks in the majority of treated GSD-II mice. Thus, chimeric, highly secreted GAA enhanced the efficacy of AAV vector-mediated gene therapy in GSD-II mice.}, number={6}, journal={MOLECULAR THERAPY}, author={Sun, Baodong and Zhang, Haoyue and Benjamin, Daniel K., Jr. and Brown, Talmage and Bird, Andrew and Young, Sarah P. and McVie-Wylie, Alison and Chen, Y. -T. and Koeberl, Dwight D.}, year={2006}, month={Dec}, pages={822–830} }
 @article{sun_zhang_franco_brown_bird_schneider_koeberl_2005, title={Correction of glycogen storage disease type II by an adeno-associated virus vector containing a muscle-specific promoter}, volume={11}, ISSN={["1525-0024"]}, DOI={10.1016/j.ymthe.2005.01.012}, abstractNote={Glycogen storage disease type II (Pompe disease) causes death in infancy from cardiorespiratory failure due to acid α-glucosidase (GAA; acid maltase) deficiency. An AAV2 vector pseudotyped as AAV6 (AAV2/6 vector) transiently expressed high-level human GAA in GAA-knockout (GAA-KO) mice without reducing glycogen storage; however, in immunodeficient GAA-KO/SCID mice the AAV2/6 vector expressed high-level GAA and reduced the glycogen content of the injected muscle for 24 weeks. A CD4+/CD8+ lymphocytic infiltrate was observed in response to the AAV2/6 vector in immunocompetent GAA-KO mice. When a muscle-specific creatine kinase promoter was substituted for the CB promoter (AAV-MCKhGAApA), that AAV2/6 vector expressed high-level GAA and reduced glycogen content in immunocompetent GAA-KO mice. Muscle-restricted expression of hGAA provoked only a humoral (not cellular) immune response. Intravenous administration of a high number of particles of AAV-MCKhGAApA as AAV2/7 reduced the glycogen content of the heart and skeletal muscle and corrected individual myofibers in immunocompetent GAA-KO mice 24 weeks postinjection. In summary, persistent correction of muscle glycogen content was achieved with an AAV vector containing a muscle-specific promoter in GAA-KO mice, and this approach should be considered for muscle-targeted gene therapy in Pompe disease.}, number={6}, journal={MOLECULAR THERAPY}, author={Sun, BD and Zhang, HY and Franco, LM and Brown, T and Bird, A and Schneider, A and Koeberl, DD}, year={2005}, month={Jun}, pages={889–898} }
 @article{franco_sun_yang_bird_zhang_schneider_brown_young_clay_amalfitano_et al._2005, title={Evasion of immune responses to introduced human acid alpha-glucosidase by liver-restricted expression in glycogen storage disease type II}, volume={12}, ISSN={["1525-0024"]}, DOI={10.1016/j.ymthe.2005.04.024}, abstractNote={Glycogen storage disease type II (GSD-II; Pompe disease) is caused by a deficiency of acid alpha-glucosidase (GAA; acid maltase) and manifests as muscle weakness, hypertrophic cardiomyopathy, and respiratory failure. Adeno-associated virus vectors containing either a liver-specific promoter (LSP) (AAV-LSPhGAApA) or a hybrid CB promoter (AAV-CBhGAApA) to drive human GAA expression were pseudotyped as AAV8 and administered to immunocompetent GAA-knockout mice. Secreted hGAA was detectable in plasma between 1 day and 12 weeks postadministration with AAV-LSPhGAApA and only from 1 to 8 days postadministration for AAV-CBGAApA. No anti-GAA antibodies were detected in response to AAV-LSPhGAApA (<1:200), whereas AAV-CBhGAApA provoked an escalating antibody response starting 2 weeks postadministration. The LSP drove approximately 60-fold higher GAA expression than the CB promoter in the liver by 12 weeks following vector administration. Furthermore, the detected cellular immunity was provoked by AAV-CBhGAApA, as detected by ELISpot and CD4+/CD8+ lymphocyte immunodetection. GAA activity was increased to higher than normal and glycogen content was reduced to essentially normal levels in the heart and skeletal muscle following administration of AAV-LSPhGAApA. Therefore, liver-restricted GAA expression with an AAV vector evaded immunity and enhanced efficacy in GSD-II mice.}, number={5}, journal={MOLECULAR THERAPY}, author={Franco, LM and Sun, BD and Yang, XY and Bird, A and Zhang, HY and Schneider, A and Brown, T and Young, SP and Clay, TM and Amalfitano, A and et al.}, year={2005}, month={Nov}, pages={876–884} }
 @misc{fuji_patton_steinbach_schulman_bradley_brown_wilson_summers_2005, title={Feline systemic reactive angioendotheliomatosis: Eight cases and literature review}, volume={42}, ISSN={["1544-2217"]}, DOI={10.1354/vp.42-5-608}, abstractNote={ A rare, multisystemic intravascular proliferative disorder was identified postmortem in eight cats. The majority of these cats died or were euthanized following episodes of dyspnea, lethargy, and anorexia. Microscopic examination revealed occlusive, intraluminal proliferations of spindle cells within small vessels. The heart was consistently involved, and myocardial dysfunction was the probable cause of illness in all cats. Immunohistochemically, the majority of intravascular cells expressed von Willebrand factor, and a smaller number expressed smooth muscle actin, compatible with a dual population of endothelial cells and pericytes, suggesting a reactive rather than a neoplastic process. Four cases of a similar feline vascular disorder from the veterinary literature are reviewed. The histopathology resembles reactive angioendotheliomatosis in humans, a benign cutaneous intravascular endothelial and pericytic proliferative condition. However, in contrast, this feline disease is multisystemic and fatal. We propose the name “feline systemic reactive angioendotheliomatosis” for this unique, idiopathic disorder of domestic cats. }, number={5}, journal={VETERINARY PATHOLOGY}, author={Fuji, RN and Patton, KM and Steinbach, TJ and Schulman, FY and Bradley, GA and Brown, TT and Wilson, EA and Summers, BA}, year={2005}, month={Sep}, pages={608–617} }
 @article{breitschwerdt_debroy_mexas_brown_remick_2005, title={Isolation of necrotoxigenic Escherichia coli from a dog with hemorrhagic pneumonia}, volume={226}, ISSN={0003-1488}, url={http://dx.doi.org/10.2460/javma.2005.226.2016}, DOI={10.2460/javma.2005.226.2016}, abstractNote={A 7-month-old sexually intact male Cocker Spaniel was admitted to the North Carolina State University Veterinary Teaching Hospital for evaluation of lethargy, panting, and excessive salivation that had become progressively severe during a 5-hour period. Despite intensive medical care, the dog died within the first 24 hours of hospitalization, and death was attributed to acute, severe, necrotizing pneumonia. Lung tissue collected at necropsy by use of swabs was cultured and yielded an isolate of Escherichia coli; because of the rapid progression of illness in an otherwise healthy dog, the isolate underwent virulence typing and was determined to be a necrotoxigenic E. coli. Necrotoxigenic E. coli produce a toxin called cytotoxic necrotizing factor and are known to be involved in extraintestinal infections, including urinary tract infection, in humans and animals. Virulence typing of E. coli isolates from dogs with peracute pneumonia is recommended to further characterize the epidemiologic characteristics and public health importance of necrotoxigenic E. coli.}, number={12}, journal={Journal of the American Veterinary Medical Association}, publisher={American Veterinary Medical Association (AVMA)}, author={Breitschwerdt, Edward B. and DebRoy, Chitrita and Mexas, Angela M. and Brown, Talmage T. and Remick, Amera K.}, year={2005}, month={Jun}, pages={2016–2019} }
 @article{hill_hopkins_davidson_bolt_diaz_brownie_brown_huntington_whitlow_2005, title={Technical note: Technique for dissection and analysis of the rumen in young calves}, volume={88}, ISSN={["1525-3198"]}, DOI={10.3168/jds.S0022-0302(05)72691-6}, abstractNote={This paper discusses a technique used to evaluate rumen development in young calves, including removal, dissection, and analysis of tissue. The method allowed for examination of the different sacs of the rumen (dorsal, ventral, cranial, and caudal) using scanning electron microscopy to measure papillae denseness and histology slides to measure papillae length and width. Computer software was used to produce accurate measurements of papillae. The rumens of young calves were dissected, and samples were taken from the cranial, caudal, ventral, and dorsal sections. Calves were part of a nutrition research study, and dietary treatments did have an effect on development measurements such as length, width, and papillae denseness.}, number={1}, journal={JOURNAL OF DAIRY SCIENCE}, author={Hill, SR and Hopkins, BA and Davidson, S and Bolt, SM and Diaz, DE and Brownie, C and Brown, T and Huntington, GB and Whitlow, LW}, year={2005}, month={Jan}, pages={324–326} }
 @article{olby_blot_thibaud_phillips_dp o'brien_burr_berg_brown_breen_2004, title={Cerebellar cortical degeneration in adult American Staffordshire Terriers}, volume={18}, ISSN={["1939-1676"]}, DOI={10.1892/0891-6640(2004)18<201:CCDIAA>2.0.CO;2}, abstractNote={Journal of Veterinary Internal MedicineVolume 18, Issue 2 p. 201-208 Open Access Cerebellar Cortical Degeneration in Adult American Staffordshire Terriers Natasha Olby, Corresponding Author Natasha Olby Department of Clinical Sciences, North Carolina State University, Raleigh, NC College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606;e-mail: [email protected].Search for more papers by this authorStephane Blot, Stephane Blot Ecole Nationale Ve-terinaire d'Alfort, Paris, FranceSearch for more papers by this authorJean-Laurent Thibaud, Jean-Laurent Thibaud Ecole Nationale Ve-terinaire d'Alfort, Paris, FranceSearch for more papers by this authorJeff Phillips, Jeff Phillips Department of Clinical Sciences, North Carolina State University, Raleigh, NCSearch for more papers by this authorDennis P. O'Brien, Dennis P. O'Brien Department of Clinical Sciences, University of Missouri, Columbia, MOSearch for more papers by this authorJeanne Burr, Jeanne Burr Department of Clinical Sciences, North Carolina State University, Raleigh, NCSearch for more papers by this authorJason Berg, Jason Berg VCA County Animal Clinic, Yonkers, NYSearch for more papers by this authorTalmage Brown, Talmage Brown Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NCSearch for more papers by this authorMatthew Breen, Matthew Breen Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC.Search for more papers by this author Natasha Olby, Corresponding Author Natasha Olby Department of Clinical Sciences, North Carolina State University, Raleigh, NC College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606;e-mail: [email protected].Search for more papers by this authorStephane Blot, Stephane Blot Ecole Nationale Ve-terinaire d'Alfort, Paris, FranceSearch for more papers by this authorJean-Laurent Thibaud, Jean-Laurent Thibaud Ecole Nationale Ve-terinaire d'Alfort, Paris, FranceSearch for more papers by this authorJeff Phillips, Jeff Phillips Department of Clinical Sciences, North Carolina State University, Raleigh, NCSearch for more papers by this authorDennis P. O'Brien, Dennis P. O'Brien Department of Clinical Sciences, University of Missouri, Columbia, MOSearch for more papers by this authorJeanne Burr, Jeanne Burr Department of Clinical Sciences, North Carolina State University, Raleigh, NCSearch for more papers by this authorJason Berg, Jason Berg VCA County Animal Clinic, Yonkers, NYSearch for more papers by this authorTalmage Brown, Talmage Brown Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NCSearch for more papers by this authorMatthew Breen, Matthew Breen Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC.Search for more papers by this author First published: 28 June 2008 https://doi.org/10.1111/j.1939-1676.2004.tb00161.xCitations: 47AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract Adult-onset cerebellar cortical degeneration recently has been reported in American Staffordshire Terriers. We describe the clinical and histopathologic features of this disease and examine its mode of inheritance in 63 affected dogs. The age at which neurologic deficits 1st were recognized varied from 18 months to 9 years, with the majority of dogs presented to veterinarians between 4 and 6 years of age. Time from onset of clinical signs to euthanasia varied from 6 months to 6.5 years, with the majority of affected dogs surviving from 2 to 4 years. Initial neurologic findings included stumbling, truncal sway, and ataxia exacerbated by lifting the head up and negotiating stairs. Signs progressed to obvious ataxia characterized by dysmetria, nystagmus, coarse intention tremor, variable loss of menace reaction, marked truncal sway, and falling with transient opisthotonus. With continued progression, dogs became unable to walk without falling repeatedly. Cerebellar atrophy was visible on magnetic resonance images and on gross pathology. Histopathologic findings included marked loss of Purkinje neurons with thinning of the molecular and granular layers and increased cellularity of the cerebellar nuclei. The closest common ancestor of the dogs was born in the 1950s and inheritance was most consistent with an autosomal recessive mode of transmission with a prevalence estimated at 1 in 400 dogs. This inherited disease is comparable to the group of diseases known as spinocerebellar ataxias in humans. Many spinocerebellar ataxias in humans are caused by nucleotide repeats, and this genetic aberration merits investigation as a potential cause of the disease in American Staffordshire Terriers. References 1 de Lahunta A. Abiotrophy in domestic animals: A review. Am J Vet Res 1990; 54: 65–67. 2 de Lahunta A., Averill DR Jr. Hereditary cerebellar cortical and extrapyramidal nuclear abiotrophy in Kerry Blue Terriers. J Am Vet Med Assoc 1976; 168: 1119–1124. 3 Hartley WJ, Barker JSF, Wanner RA, et al. Inherited cerebellar degeneration in the Rough Coated Collie. Aust Vet Pract 1978; 8: 79–85. 4 de Lahunta A., Fenner WR, Indrieri RJ, et al. Hereditary cere-bellar cortical abiotrophy in the Gordon Setter. J Am Vet Med Assoc 1980; 177: 538–541. 5 Steinberg HS, Troncoso JC, Cork LC, et al. Clinical features of inherited cerebellar degeneration in Gordon Setters. J Am Vet Med Assoc 1981; 179: 886–890. 6 Yasuba M., Okimoto K., Iida M., et al. Cerebellar cortical degeneration in Beagle dogs. Vet Pathol 1988; 25: 315–317. 7 Gill JM, Hewland M. Cerebellar degeneration in the Border Collie. N Z Vet J 1980; 28: 170. 8 Thomas JB, Robertson D. Hereditary cerebellar abiotrophy in Australian Kelpie dogs. 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Vet Radiol Ultrasound 2001; 42: 246–249. 15 Steinberg HS, Van Winkle T., Bell JS, de Lahunta A. Cerebellar degeneration in Old English Sheepdogs. Am Vet Med Assoc 2000; 217: 1162–1165. 16 Higgins RJ, LeCouteur RA, Kornegay JN, Coates JR. Late-onset progressive spinocerebellar degeneration in Brittany Spaniel dogs. Acta Neuropathol 1998; 96: 97–101. 17 Hanzlicek D., Kathman I., Bley T., et al. Cerebellar cortical abiotrophy in American Staffordshire Terriers: Clinical and pathological features of three cases. Schweiz Arch Tierheilkd 2003; 145: 369–375. 18 Thibaud J-L, Delisle F., Gray F., et al. Cerebellar ataxia in mer-ican Staffordshire Terriers. European Society of Veterinary Neurology 15th Annual Symposium, Philadelphia PA, September 2002. 19 Speciale J., de Lahunta A. Cerebellar degeneration in a mature Staffordshire Terrier. J Am Anim Hosp Assoc 2003; 39: 459–462. 20 Van der Merwe LL, Lane E. Diagnosis of cerebellar cortical degeneration in a Scottish Terrier using magnetic resonance imaging. J Small Anim Pract 2001; 42: 409–412. 21 Bonney GE. Regressive logistic models for familial disease and other binary traits. Biometrics 1986; 42: 611–625. 22 Akaike H. A new look at the statistical model identification. IEEE Trans Autom Control 1974; 19: 716–723. 23 Polo JM, Calleja J., Combarros O., Berciano J. Hereditary ataxias and paraplegias in Cantabria, Spain. An epidemiological and clinical study. Brain 1991; 114: 855–866. 24 Di Donato S., Gellera C., Mariotti C. The complex clinical and genetic classification of inherited ataxias. II Autosomal recessive ataxias. Neurol Sci 2001; 2: 219–228. 25 Koeppen AH. The hereditary ataxias. J Neuropathol Exp Neurol 1998; 57: 531–543. 26 Silveira I., Miranda C., Guimaraes L., et al. Trinucleotide repeats in 202 families with ataxia. A small expanded (CAG)n allele at the SCA17 locus. Arch Neurol 2002; 59: 623–629. 27 Vuillaume I., Devos D., Schraen-Maschke S., et al. A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3-p15.1. Ann Neurol 2002; 52: 666–670. 28 Jardim LB, Silveira I., Pereira ML, et al. A survey of spinocerebellar ataxia in South Brazil–6new caseswith Machado-Joseph disease, SCA7, SCA8, or unidentified disease-causing mutations. J Neurol 2001; 248: 870–876. 29 Zhuchenko O., Bailey J., Bonnen P., et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the a1A-voltage dependent calcium channel. Nat Genet 1997; 15: 62–69. 30 Sinke RJ, Ippel EF, Diepstraten CM, et al. Clinical and molecular correlations in spinocerebellar ataxia type 6. Arch Neurol 2001; 58: 1839–1844. 31 Pujana MA, Corral J., Gratacos M., et al. Spinocerebellar ataxias in Spanish patients: Genetic analysis of familial and sporadic cases. Hum Genet 1999; 104: 516–522. 32 Gabsi S., Gouider-Khouja N., Belal S., et al. Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency. Eur J Neurol 2001; 8: 477–481. 33 Van Swieten JC, Brusse E., de Graaf BM, et al. A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia. Am J Hum Genet 2003; 77: 191–199. Citing Literature Volume18, Issue2March 2004Pages 201-208 ReferencesRelatedInformation}, number={2}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Olby, N and Blot, S and Thibaud, JL and Phillips, J and DP O'Brien and Burr, J and Berg, J and Brown, T and Breen, M}, year={2004}, pages={201–208} }
 @article{noureddine_harder_olby_spaulding_brown_2004, title={Ultrasonographic appearance of Dandy Walker-like Syndrome in a Boston terrier}, volume={45}, DOI={10.1111/j.1740-8260.2004.04064.x}, number={4}, journal={Veterinary Radiology & Ultrasound}, author={Noureddine, C. and Harder, R. and Olby, Natasha and Spaulding, K. and Brown, T.}, year={2004}, pages={336–339} }
 @article{beaty_jackson_peterson_bird_brown_benjamin_juopperi_kishnani_boney_chen_et al._2002, title={Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors}, volume={9}, ISSN={["0969-7128"]}, DOI={10.1038/sj.gt.3301728}, abstractNote={Therapy in glycogen storage disease type Ia (GSD Ia), an inherited disorder of carbohydrate metabolism, relies on nutritional support that postpones but fails to prevent long-term complications of GSD Ia. In the canine model for GSD Ia, we evaluated the potential of intravenously delivered adeno-associated virus (AAV) vectors for gene therapy. In three affected canines, liver glycogen was reduced following hepatic expression of canine glucose-6-phosphatase (G6Pase). Two months after AAV vector administration, one affected dog had normalization of fasting glucose, cholesterol, triglycerides, and lactic acid. Concatamerized AAV vector DNA was confirmed by Southern blot analysis of liver DNA isolated from treated dogs, as head-to-tail, head-to-head, and tail-to-tail concatamers. Six weeks after vector administration, the level of vector DNA signal in each dog varied from one to five copies per cell, consistent with variation in the efficiency of transduction within the liver. AAV vector administration in the canine model for GSD Ia resulted in sustained G6Pase expression and improvement in liver histology and in biochemical parameters.}, number={15}, journal={GENE THERAPY}, author={Beaty, RM and Jackson, M and Peterson, D and Bird, A and Brown, T and Benjamin, DK and Juopperi, T and Kishnani, P and Boney, A and Chen, YT and et al.}, year={2002}, month={Aug}, pages={1015–1022} }
 @article{feng_tompkins_xu_brown_laster_zhang_mccaw_2002, title={Thymocyte and peripheral blood T lymphocyte subpopulation changes in piglets following in utero infection with porcine reproductive and respiratory syndrome virus}, volume={302}, ISSN={["0042-6822"]}, DOI={10.1006/viro.2002.1650}, abstractNote={Piglets infected in utero with porcine reproductive and respiratory syndrome virus (PRRSV) are born severely immunocompromised. In this article we more closely examine the effects of in utero PRRSV infection on circulating and thymic T cell populations. Numbers of CD4+, CD8+, and dual-positive lymphocytes were quantitated in circulation and in the thymus during the 2 weeks following birth. At birth we found that the number of circulating lymphocytes was suppressed by 60%. Lymphocyte numbers were also suppressed by 42% at day 7, but by day 14 the number of lymphocytes had rebounded and was actually 47% greater than controls. At birth and day 7, a drop in the number of CD4+ cells could partially explain the suppression we observed, while the rebound in total lymphocyte numbers seen at day 14 was due to a nearly fourfold increase in the number of circulating CD8+ cells. As a result, the normal CD4+:CD8+ ratio of between 1.4 and 2.2 for neonatal pigs was reduced to 0.1-0.5. The thymuses of infected piglets were found to be 50% smaller than those of control pigs and were characterized by cortical involution and severe cortical depletion of thymocytes. Analysis of the population of thymocytes revealed that double-positive thymocytes were suppressed to a greater degree than either single positive subpopulation. In addition, we show that the number of thymocytes undergoing apoptosis was increased twofold in piglets infected with PRRSV. Taken together, these results help explain the dramatic immunosuppression observed in neonatal animals infected in utero with PRRSV.}, number={2}, journal={VIROLOGY}, author={Feng, WH and Tompkins, MB and Xu, JS and Brown, TT and Laster, SM and Zhang, HX and McCaw, MB}, year={2002}, month={Oct}, pages={363–372} }
 @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{pappalardo_brown_tompkins_breitschwerdt_2001, title={Immunopathology of Bartonella vinsonii (berkhoffii) in experimentally infected dogs}, volume={83}, ISSN={["1873-2534"]}, DOI={10.1016/S0165-2427(01)00372-5}, abstractNote={Following natural infection with Bartonella, dogs and humans develop comparable disease manifestations including endocarditis, peliosis hepatis, and granulomatous disease. As the immunologic response to infection in these hosts has not been clearly established, data presented here was derived from the experimental infection of six specific pathogen free (SPF) beagles with a known pathogenic strain of Bartonella. Six dogs were inoculated intravenously with 10(9)cfu of B. vinsonii ssp. berkhoffii and six control dogs were injected intravenously with an equivalent volume of sterile saline. Despite production of substantial levels of specific antibody, blood culture and molecular analyses indicated that Bartonella established chronic infection in these dogs. Flow cytometric analysis of monocytes indicated impaired bacterial phagocytosis during chronic Bartonella infection. There was also a sustained decrease in the percentage of CD8+ lymphocytes in the peripheral blood. Moreover, modulation of adhesion molecule expression (downregulation of L-selectin, VLA-4, and LFA-1) on CD8+ lymphocytes suggested quantitative and qualitative impairment of this cell subset in Bartonella-infected dogs. When compared with control dogs, flow cytometric analysis of lymph node (LN) cells from B. vinsonii infected dogs revealed an expanded population of CD4+ T cells with an apparent naïve phenotype (CD45RA+/CD62L+/CD49D(dim)). However, fewer B cells from infected dogs expressed cell-surface MHC II, implicating impaired antigen presentation to helper T cells within LN. Taken together, results from this study indicate that B. vinsonii establishes chronic infection in dogs which may result in immune suppression characterized by defects in monocytic phagocytosis, an impaired subset of CD8+ T lymphocytes, and impaired antigen presentation within LN.}, number={3-4}, journal={VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY}, author={Pappalardo, BL and Brown, TT and Tompkins, M and Breitschwerdt, EB}, year={2001}, month={Dec}, pages={125–147} }
 @article{feng_laster_tompkins_brown_xu_altier_gomez_benfield_mccaw_2001, title={In utero infection by porcine reproductive and respiratory syndrome virus is sufficient to increase susceptibility of piglets to challenge by Streptococcus suis type II}, volume={75}, ISSN={["1098-5514"]}, DOI={10.1128/JVI.75.10.4889-4895.2001}, abstractNote={ABSTRACT}, number={10}, journal={JOURNAL OF VIROLOGY}, author={Feng, WH and Laster, SM and Tompkins, M and Brown, T and Xu, JS and Altier, C and Gomez, W and Benfield, D and McCaw, MB}, year={2001}, month={May}, pages={4889–4895} }
 @article{chittick_rotstein_brown_wolfe_2001, title={Pyometra and uterine adenocarcinoma in a melengestrol acetate- implanted captive coati (Nasua nasua)}, volume={32}, DOI={10.1638/1042-7260(2001)032[0245:pauaia]2.0.co;2}, abstractNote={Abstract A 9-yr and 3-mo-old captive female coati (Nasua nasua) was implanted with melengestrol acetate for contraception for 4.5 yr prior to presentation. During her annual examination, purulent vaginal discharge and a palpably prominent uterus were identified. Ancillary diagnostic tests including hematology, cystocentesis, radiographs, and abdominal ultrasound were consistent with pyometra. An ovariohysterectomy was performed and histologic examination revealed pyometra and uterine adenocarcinoma, similar to pathology that has been associated with melengestrol acetate contraception in felids, canids, and primates. Given the potential association between melengestrol acetate and uterine pathology in this case, we recommend caution with melengestrol acetate use in procyonids.}, number={2}, journal={Journal of Zoo and Wildlife Medicine}, author={Chittick, E. and Rotstein, D. and Brown, T. and Wolfe, B.}, year={2001}, pages={245–251} }
 @article{pappalardo_brown_gebhardt_sontakke_breitschwerdt_2000, title={Cyclic CD8+lymphopenia in dogs experimentally infected with Bartonella vinsonii subsp berkhoffii}, volume={75}, ISSN={["0165-2427"]}, DOI={10.1016/S0165-2427(00)00182-3}, abstractNote={Until recently, it was presumed that Bartonella vinsonii only infected voles, a species of North American rodents. In April of 1993, however, our laboratory isolated a novel subspecies of B. vinsonii (B. vinsonii subsp. berkhoffii) from the blood of a dog diagnosed with vegetative valvular endocarditis. Subsequently, based on a seroepidemiologic survey of dogs from North Carolina and Virginia presenting for a variety of medical problems, we found evidence supporting a potentially important association between B. vinsonii and Ehrlichia canis co-infection in dogs. In the following study, eight dogs were infected with B. vinsonii: four specific pathogen free dogs and four dogs that had previously been infected with E. canis. Flow cytometric analysis of peripheral blood lymphocytes revealed a cyclic elevation of the CD4/CD8 T-cell ratio that correlated with cyclic CD8+ lymphopenia in all dogs infected with B. vinsonii, regardless of prior exposure to E. canis.}, number={1-2}, journal={VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY}, author={Pappalardo, BL and Brown, T and Gebhardt, D and Sontakke, S and Breitschwerdt, EB}, year={2000}, month={Jun}, pages={43–57} }
 @article{luginbuhl_poore_spears_brown_2000, title={Effect of dietary copper level on performance and copper status of growing meat goats}, volume={16}, number={2000}, journal={Sheep & Goat Research Journal}, author={Luginbuhl, J. M. and Poore, M. H. and Spears, J. W. and Brown, T. T.}, year={2000}, pages={65–71} }
 @article{henry_schmader_brown_miller_howell_daley_hamilton_2000, title={Enhanced green fluorescent protein as a marker for localizing murine cytomegalovirus in acute and latent infection}, volume={89}, ISSN={["0166-0934"]}, DOI={10.1016/S0166-0934(00)00202-0}, abstractNote={A recombinant murine cytomegalovirus (mCMV) that expresses enhanced green fluorescent protein (EGFP) under control of the native immediate-early 1/3 promoter was constructed to detect directly sites of viral activity in latent and reactivated infections. The recombinant virus had acute and latent infection characteristics similar to those of wild-type mCMV. Rare green-fluorescing foci were observed in paraffin sections from lungs and spleens infected latently. Positive immunoperoxidase staining for EGFP in sections of the same lung tissues suggests that these cells may be sites of restricted viral gene expression. EGFP was detected easily in tissue explants reactivating from latent infection in vitro. Morphology and adhesion characteristics of fluorescing cells suggest that viral reactivation occurs in tissue macrophages in explant cultures. The observations presented in this study demonstrate the usefulness of EGFP-expressing recombinants as tools for direct tracking of mCMV activity in vivo and in vitro.}, number={1-2}, journal={JOURNAL OF VIROLOGICAL METHODS}, author={Henry, SC and Schmader, K and Brown, TT and Miller, SE and Howell, DN and Daley, GG and Hamilton, JD}, year={2000}, month={Sep}, pages={61–73} }
 @article{pappalardo_brown_gookin_morrill_breitschwerdt_2000, title={Granulomatous disease associated with Bartonella infection in 2 dogs}, volume={14}, ISSN={["0891-6640"]}, DOI={10.1892/0891-6640(2000)014<0037:GDAWII>2.3.CO;2}, abstractNote={Shortly after removal of an engorged tick from the left ear, a 4-year-old Greyhound was referred for evaluation of fever and a rapidly enlarging mass in the region of the left submandibular lymph node. Histopathologic evaluation of the lymph node resulted in a diagnosis of severe granulomatous lymphadenitis. An 11-year-old mixed-breed dog was referred for evaluation of a 6-week history of serous nasal discharge. Histologic examination of a surgical biopsy from a nasal mass indicated multifocal granulomatous inflammation with fibrosis. Serum samples obtained from both dogs were reactive by immunofluorescent assay to Bartonella vinsonii subsp. berkhoffii antigens (reciprocal titers of 128). Although Bartonella organisms were not isolated by lysis centrifugation blood culture, Bartonella DNA was amplified from tissue samples obtained from each dog (lymph node biopsy from dog 1 and nasal biopsy from dog 2) using primers that amplify a portion of the 16S rRNA gene followed by Southern blot hybridization using a genus-specific probe. Additionally, restriction fragment length polymorphism (RFLP) analysis of a Bartonella-specific citrate synthase gene product obtained from dog 2 resulted in a restriction pattern identical to B. vinsonii subsp. berkhoffii. This is the 1st report of granulomatous disease in dogs associated with Bartonella infection.}, number={1}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Pappalardo, BL and Brown, T and Gookin, JL and Morrill, CL and Breitschwerdt, EB}, year={2000}, pages={37–42} }
 @article{breitschwerdt_atkins_brown_kordick_snyder_1999, title={Bartonella vinsonii subsp berkhoffi and related members of the alpha subdivision of the Proteobacteria in dogs with cardiac arrhythmias, endocarditis, or myocarditis}, volume={37}, number={11}, journal={Journal of Clinical Microbiology}, author={Breitschwerdt, E. B. and Atkins, C. E. and Brown, T. T. and Kordick, D. L. and Snyder, P. S.}, year={1999}, pages={3618–3626} }
 @article{kordick_brown_shin_breitschwerdt_1999, title={Clinical and pathologic evaluation of chronic Bartonella henselae or Bartonella clarridgeiae infection in cats}, volume={37}, number={5}, journal={Journal of Clinical Microbiology}, author={Kordick, D. L. and Brown, T. T. and Shin, K. and Breitschwerdt, E. B.}, year={1999}, pages={1536–1547} }
 @article{rogers_poore_ferko_brown_deaton_bawden_1999, title={Dental wear and growth performance in steers fed sweetpotato cannery waste}, volume={214}, number={5}, journal={Journal of the American Veterinary Medical Association}, author={Rogers, G. M. and Poore, M. H. and Ferko, B. L. and Brown, T. T. and Deaton, T. G. and Bawden, J. W.}, year={1999}, pages={681–687} }
 @article{engle_spears_brown_lloyd_1999, title={Effect of breed (Angus Vs Simmental) on immune function and response to a disease challenge in stressed steers and preweaned calves}, volume={77}, DOI={10.2527/1999.773516x}, abstractNote={Two experiments were conducted with feeder steer calves and preweaned calves to determine the effects of breed on immune response. In Exp. 1, newly weaned Angus (n = 24) and Simmental (n = 24) steer calves were blocked by weight within breed and randomly assigned to 12 pens with four calves per pen. The basal diet consisted of 87% corn silage (DM basis) and 13% of a soybean meal-mineral-vitamin supplement. Steers were allowed ad libitum access to feed throughout the study. On d 2 following weaning, calves received an intranasal inoculation of infectious bovine rhinotraecheitis virus (IBRV; 2.7 x 10(8) CCID50). Rectal temperatures in response to the IBRV were higher (P < .05) in Angus calves. On d 9, calves were injected i.m. with 10 mL of a 25% pig red blood cell (PRBC) suspension. Total immunoglobulin (Ig) and IgM titers against PRBC were higher (P < .05) for the Angus calves. Breed did affect cell-mediated immune response to phytohemagglutinin (PHA). In Exp. 2, preweaned (16 Angus and 16 Simmental) calves were selected based on breed, body weight, and sex. On 0 d, all selected calves were injected i.m. with 10 mL of a 25% PRBC suspension. Total Ig and IgG titers against PRBC were higher (P < .05) for Angus calves. On d 28, lymphocytes were isolated from peripheral blood obtained from eight calves per breed. Peripheral lymphocytes from the Angus calves had a greater (P < .07) blastogenic response to 6.25 microg/mL of PHA than lymphocytes from Simmental calves. Results indicate that the immune response of Angus and Simmental calves may differ.}, number={3}, journal={Journal of Animal Science}, author={Engle, T. E. and Spears, J. W. and Brown, T. T. and Lloyd, K. E.}, year={1999}, pages={516–521} }
 @article{walker_ahmed_brown_ho_hodges_lucier_russo_weigel_weise_vandenbergh_1999, title={Species, interindividual, and tissue specificity in endocrine signaling}, volume={107}, DOI={10.1289/ehp.99107s4619}, abstractNote={The activity of endocrine-active agents exhibits specificity at many levels. Differential responsiveness to these agents has been observed between different species and extends to interindividual differences within a species and between different tissues as well. In cases where they have been identified, the biologic and molecular mechanisms underlying this specificity are quite diverse. Determinants of species specificity include differences that exist in receptor binding, gene transcription, and cellular responses to endocrine-active compounds between species. Interindividual differences in responsiveness may be determined at the level of genetic polymorphisms in hormone-metabolizing enzymes, hormone receptors, and in those genes that are transactivated by these receptors, as well as during changing windows of susceptibility that occur as a function of age, such as prenatal and postmenopausal exposures. Extrinsic factors such as diet can also impact individual susceptibility to endocrine-active agents. Tissue-specific determinants of susceptibility are well documented, but little is known regarding the mechanisms underlying these different responses. Differences in the expression of accessory proteins for steroid hormone receptors and different patterns of receptor expression, estrogen receptor alpha and estrogen receptor beta; for example, may contribute to tissue specificity, as may differences in the pattern of expression of other genes such as hormone-metabolizing enzymes. The use of animal model systems and development of appropriate mathematical models has the potential to yield additional valuable information for elucidating the role of these determinants of specificity at low-dose exposures and for improved risk assessments for the adverse health effects of endocrine-active compounds.}, number={1999 Aug.}, journal={Environmental Health Perspectives}, author={Walker, C. and Ahmed, S. A. and Brown, T. and Ho, S. M. and Hodges, L. and Lucier, G. and Russo, J. and Weigel, N. and Weise, T. and Vandenbergh, J.}, year={1999}, pages={619–624} }
 @article{fernandez_grindem_brown_sharp_saulnier_1997, title={Cytologic and histologic features of a poorly differentiated glioma in a dog}, volume={26}, ISSN={["1939-165X"]}, DOI={10.1111/j.1939-165X.1997.tb00733.x}, abstractNote={A 5‐year old female Boxer with a 1‐week history of progressive paresis and paraplegia had a T10‐13 subarachnoid filling defect on myelography. Exploratory hemilaminectomy revealed an intramedullary spinal cord tumor which was subsequently diagnosed as a poorly differentiated glioma, most likely an anaplastic ependymoma. The cytologic, histologic, and immunocytochemical staining characteristics of this neoplasm are described. Differential diagnoses, including primary and secondary tumors involving the central nervous system are discussed.}, number={4}, journal={VETERINARY CLINICAL PATHOLOGY}, author={Fernandez, FR and Grindem, CB and Brown, TT and Sharp, NJH and Saulnier, M}, year={1997}, pages={182–186} }
 @article{kegley_spears_brown_1997, title={Effect of shipping and chromium supplementation on performance, immune response, and disease resistance of steers}, volume={75}, DOI={10.2527/1997.7571956x}, abstractNote={Forty-eight Angus crossbred steers (263 +/- 2 kg initial BW) were blocked by weight and randomly assigned within weight group to treatment. Treatments consisted of control or .4 mg of supplemental Cr as Cr-nicotinic acid complex/kg of DM. Steers were fed diets containing 90% corn silage (DM basis) and 10% of a soybean meal-mineral-vitamin supplement. After 56 d on the dietary treatment, half of the steers in each treatment were transported 343 km and unloaded in an unfamiliar location. The next day, d 58, shipped steers were returned to the feedlot (50 km). On d 58 after shipped steers were returned to the feedlot, all steers were inoculated with infectious bovine rhinotracheitis virus (IBRV) intranasally. Average daily gain from d 0 to 80 was increased (P < .10) by supplemental Cr. There was a shipping x time interaction for serum cortisol concentrations. Shipping increased (P < .02) serum cortisol on d 58, but 7 d after transport there were no effects of shipping on serum cortisol. Transportation increased (P < .05) the ratio of neutrophils to lymphocytes. Supplemental Cr did not affect rectal temperature after the IBRV challenge or the antibody response to IBRV or porcine red blood cells. Immunoglobulin G antibody response to porcine red blood cells was decreased (P < .09) by shipping. Supplemental Cr as Cr-nicotinic acid improved ADG of growing steers, regardless of whether they had been stressed by shipping. Supplemental Cr did not affect any of the immune responses that were measured.}, number={7}, journal={Journal of Animal Science}, author={Kegley, E. B. and Spears, J. W. and Brown, T. T.}, year={1997}, pages={1956–1964} }
 @article{gengelbach_ward_spears_brown_1997, title={Effects of copper deficiency and copper deficiency coupled with high dietary iron or molybdenum on phagocytic cell function and response of calves to a respiratory disease challenge}, volume={75}, DOI={10.2527/1997.7541112x}, abstractNote={A study was conducted to determine the effects of supplementing a diet marginally deficient in copper (Cu) with iron (Fe), molybdenum (Mo), or Cu on phagocytic cell function and disease resistance of calves. Thirty-one calves were born to heifers fed a corn silage-based diet containing 4.5 mg of Cu/kg. Treatments consisted of 1) control (CON; no supplemental Cu, Fe, or Mo), 2) 600 mg of Fe added/kg (FE), 3) 5 mg of Mo added/kg (MO), or 4) 10 mg of Cu added/kg of DM (CU). Activity of superoxide dismutase was lower (P < .06) in neutrophils from MO vs CON or CU calves at 170 d of age. bactericidal activity of neutrophils from MO calves tended (P = .15) to be lower compared with those from CU calves at 70 d of age. Calves were inoculated intranasally with live infectious bovine rhinotracheitis virus (IBRV) 2 d after weaning, followed by intratracheal administration of Pasteurella hemolytica 5 d later. Iron- and Cu-supplemented calves exhibited higher (P < .01) body temperatures and lower (P < .06) feed intakes following IBRV inoculation compared with CON and MO calves. Copper-supplemented calves had higher levels of plasma tumor necrosis factor (TNF) than MO calves at weaning (P < .05) and tended to have higher plasma TNF (P = .11) than FE and MO calves 5 d after IBRV inoculation. These data indicate that dietary levels of Mo and Cu can affect body temperature and feed intake responses to disease by affecting TNF and perhaps other cytokines.}, number={4}, journal={Journal of Animal Science}, author={Gengelbach, G. P. and Ward, J. D. and Spears, J. W. and Brown, T.T.}, year={1997}, pages={1112–1118} }
 @article{ritchey_degernes_brown_1997, title={Exocrine pancreatic insufficiency in a yellow-naped Amazon (Amazona ochrocephala) with pancreatic adenocarcinoma}, volume={34}, ISSN={["0300-9858"]}, DOI={10.1177/030098589703400111}, abstractNote={ This report describes exocrine pancreatic insufficiency in a yellow-naped Amazon ( Amazona ochrocephala) with complete effacement of the pancreas by a pancreatic adenocarcinoma. The bird presented with a 3-month history of weight loss and voluminous, foul-smelling droppings. Clinically, routine hematologic findings were normal and fecal tests were performed to evaluate exocrine pancreatic function. The fecal function tests were positive for neutral and split fats and negative for trypsin. Oral administration of corn oil did not result in elevation of blood triglyceride levels. Two days later, the triglyceride tolerance test was repeated using corn oil mixed with pancreatic enzymes. This time, there was a 70% elevation of blood triglyceride levels. Because of a poor prognosis, the bird was euthanatized. At necropsy, the pancreas was diffusely enlarged, white, nodular, and firm. The liver contained multiple, 1-2-mm-diameter, randomly located, tan nodules. Microscopically, the pancreas was effaced by numerous lobules of neoplastic ductular structures surrounded by abundant fibrous connective tissue. In the liver, the hepatic parenchyma was replaced by multiple, well-demarcated, nonencapsulated foci of neoplastic tissue similar to that in the pancreas. }, number={1}, journal={VETERINARY PATHOLOGY}, author={Ritchey, JW and Degernes, LA and Brown, TT}, year={1997}, month={Jan}, pages={55–57} }
 @article{brown_shin_fuller_1995, title={Detection of pseudorabies viral DNA in tonsillar epithelial cells of latently infected pigs}, volume={56}, number={5}, journal={American Journal of Veterinary Research}, author={Brown, T. T. and Shin, K. O. and Fuller, F. J.}, year={1995}, pages={587} }
 @article{brown_shin_1990, title={Effect of bovine herpesvirus-1 or parainfluenza-3 virus on immune receptor-mediated functions of bovine alveolar macrophages in the presence or absence of virus-specific serum or pulmonary lavage fluids collected after virus infection}, volume={51}, number={10}, journal={American Journal of Veterinary Research}, author={Brown, T. T., Jr. and Shin, K.}, year={1990}, pages={1616} }
 @article{carver_shymodjeska_brown_rogers_riviere_1985, title={DOSE-RESPONSE STUDIES OF GENTAMICIN-NEPHROTOXICITY IN RATS WITH EXPERIMENTAL RENAL DYSFUNCTION .1. SUBTOTAL SURGICAL NEPHRECTOMY}, volume={80}, ISSN={["1096-0333"]}, DOI={10.1016/0041-008X(85)90082-1}, abstractNote={Gentamicin pharmacokinetics and nephrotoxicity have not been widely studied in animals with preexisting renal dysfunction, despite the fact that nephrotoxicity is a continuing manifestation of clinical therapy. The present study contrasted the dose-response nephrotoxicity of gentamicin in control rats with that of rats with renal insufficiency secondary to subtotal (2/3) surgical nephrectomy. Total daily doses ranging from 0 to 120 mg/kg were given in a divided regimen, every 8 hr and doses were reduced by doubling the interval in subtotally nephrectomized (Nx) rats, in proportion to impaired renal elimination on the first day of gentamicin administration. Estimates of renal function, including creatinine clearance, fractional sodium and potassium excretion, and serum creatinine and urea nitrogen, were collected after 6 and 12 days of dosing. In addition, urinary N-acetyl-beta-D-glucosaminidase excretion (6 days), in vitro renal cortical slice accumulation of tetraethylammonium (TEA) (6 days), quantified morphological lesions (12 days), and renal gentamicin concentrations (6 days) were examined. Pharmacokinetic data collected immediately after the first dose revealed a reduced gentamicin clearance and slightly reduced volume of distribution, with a corresponding prolonged half-life in the Nx rats. Based on statistical analysis of the dose-response relationships, Nx rats were functionally resistant to gentamicin nephrotoxicity after 6 days of dosing. This resistance was partially reversed by 12 days dosing, despite light-microscopic evidence of greater structural damage in the control rats. Renal parenchymal gentamicin concentrations were lower at some doses in the Nx rats, in contrast to the higher fractional reabsorption found in these rats at all doses. TEA transport was depressed at all doses in control rats but not at the lower doses in Nx rats, indicating that resistance was partially mediated at the level of the proximal tubular epithelium. This study demonstrates altered gentamicin pharmacokinetics and nephrotoxicity in a surgical model of renal dysfunction in rats.}, number={2}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={CARVER, MP and SHYMODJESKA, JS and BROWN, TT and ROGERS, RA and RIVIERE, JE}, year={1985}, pages={251–263} }