@article{sai_nakanishi_scofield_tokarz_linder_cohen_ninomiya-tsuji_2023, title={Aberrantly activated TAK1 links neuroinflammation and neuronal loss in Alzheimer?s disease mouse models}, volume={136}, ISSN={["1477-9137"]}, url={http://dx.doi.org/10.1242/jcs.260102}, DOI={10.1242/jcs.260102}, abstractNote={ABSTRACT}, number={6}, journal={JOURNAL OF CELL SCIENCE}, publisher={The Company of Biologists}, author={Sai, Kazuhito and Nakanishi, Aoi and Scofield, Kimberly M. and Tokarz, Debra A. and Linder, Keith E. and Cohen, Todd J. and Ninomiya-Tsuji, Jun}, year={2023}, month={Mar} }
 @article{krane_shockley_malarkey_miller_miller_tokarz_jensen_janardhan_breen_mariani_2022, title={Inter-pathologist agreement on diagnosis, classification and grading of canine glioma}, volume={7}, ISSN={["1476-5829"]}, url={https://doi.org/10.1111/vco.12853}, DOI={10.1111/vco.12853}, abstractNote={Abstract}, journal={VETERINARY AND COMPARATIVE ONCOLOGY}, author={Krane, Gregory A. and Shockley, Keith R. and Malarkey, David E. and Miller, Andrew D. and Miller, C. Ryan and Tokarz, Debra A. and Jensen, Heather L. and Janardhan, Kyathanahalli S. and Breen, Matthew and Mariani, Christopher L.}, year={2022}, month={Jul} }
 @article{krane_carly a. o'dea_malarkey_miller_miller_tokarz_jensen_janardhan_shockley_flagler_et al._2021, title={Immunohistochemical evaluation of immune cell infiltration in canine gliomas}, volume={7}, ISSN={["1544-2217"]}, DOI={10.1177/03009858211023946}, abstractNote={Evasion of the immune response is an integral part of the pathogenesis of glioma. In humans, important mechanisms of immune evasion include recruitment of regulatory T cells (Tregs) and polarization of macrophages toward an M2 phenotype. Canine glioma has a robust immune cell infiltrate that has not been extensively characterized. The purpose of this study was to determine the distribution of immune cells infiltrating spontaneous intracranial canine gliomas. Seventy-three formalin-fixed, paraffin-embedded tumor samples were evaluated using immunohistochemistry for CD3, forkhead box 3 (FOXP3), CD20, Iba1, calprotectin (Mac387), CD163, and indoleamine 2,3-dioxygenase (IDO). Immune cell infiltration was present in all tumors. Low-grade and high-grade gliomas significantly differed in the numbers of FoxP3+ cells, Mac387+ cells, and CD163+ cells ( P = .006, .01, and .01, respectively). Considering all tumors, there was a significant increase in tumor area fraction of CD163 compared to Mac387 ( P < .0001), and this ratio was greater in high-grade tumors than in low-grade tumors ( P = .005). These data warrant further exploration into the roles of macrophage repolarization or Treg interference therapy in canine glioma.}, journal={VETERINARY PATHOLOGY}, author={Krane, Gregory A. and Carly A. O'Dea and Malarkey, David E. and Miller, Andrew D. and Miller, C. Ryan and Tokarz, Debra A. and Jensen, Heather L. and Janardhan, Kyathanahalli S. and Shockley, Keith R. and Flagler, Norris and et al.}, year={2021}, month={Jul} }
 @article{bomba_sheets_valdivia_khagi_ruterbories_mariani_borst_tokarz_hingtgen_2021, title={Personalized-induced neural stem cell therapy: Generation, transplant, and safety in a large animal model}, volume={6}, ISSN={["2380-6761"]}, DOI={10.1002/btm2.10171}, abstractNote={Abstract}, number={1}, journal={BIOENGINEERING & TRANSLATIONAL MEDICINE}, author={Bomba, Hunter N. and Sheets, Kevin T. and Valdivia, Alain and Khagi, Simon and Ruterbories, Laura and Mariani, Christopher L. and Borst, Luke B. and Tokarz, Debra A. and Hingtgen, Shawn D.}, year={2021}, month={Jan} }
 @article{reece_varikuti_kilburg-basnyat_dunigan-russell_hodge_luo_madenspacher_thomas_tokarz_tighe_et al._2021, title={Scavenger Receptor BI Attenuates IL-17A-Dependent Neutrophilic Inflammation in Asthma}, volume={64}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2020-0007OC}, abstractNote={Asthma is a common respiratory disease currently affecting more than 300 million worldwide and is characterized by airway inflammation, hyperreactivity, and remodeling. It is a heterogeneous disease consisting of corticosteroid-sensitive Th2-driven eosinophilic and corticosteroid-resistant Th17-driven neutrophilic phenotypes. One pathway recently described to regulate asthma pathogenesis is cholesterol trafficking. Scavenger receptors, in particular scavenger receptor class B type I (SR-BI), are known to direct cellular cholesterol uptake and efflux. We recently defined SR-BI functions in pulmonary host defense, however, the function of SR-BI in asthma pathogenesis is unknown. To elucidate the role of SR-BI in allergic asthma, SR-BI sufficient (SR-BI+/+) and deficient (SR-BI-/-) mice were sensitized (days 0, 7) and then challenged (days 14, 15, 16) with HDM (house dust mite) by oropharyngeal aspiration. Airway inflammation and cytokine production were quantified on day 17. When compared to SR-BI+/+ mice, HDM-challenged SR-BI-/- mice had increased bronchoalveolar lavage (BAL) neutrophils and pulmonary IL-17A production. This augmented IL-17A production in SR-BI-/- mice originated from a non-T cell source including neutrophils and alveolar macrophages. Given that SR-BI regulates adrenal steroid hormone production, we tested if the changes in SR-BI-/- mice were glucocorticoid-dependent. Indeed, SR-BI-/- mice were adrenally insufficient during HDM challenge and corticosterone replacement decreased pulmonary neutrophilia and IL-17A production in SR-BI-/- mice. Taken together, these data indicate that SR-BI dampens pulmonary neutrophilic inflammation and IL-17A production in allergic asthma at least in part by maintaining adrenal function.}, number={6}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Reece, Sky W. and Varikuti, Sanjay and Kilburg-Basnyat, Brita and Dunigan-Russell, Katelyn and Hodge, Myles X. and Luo, Bin and Madenspacher, Jennifer H. and Thomas, Seddon Y. and Tokarz, Debra A. and Tighe, Robert M. and et al.}, year={2021}, month={Jun}, pages={698–708} }
 @article{yaeger_reece_kilburg-basnyat_hodge_pal_dunigan-russell_luo_you_bonner_spangenburg_et al._2021, title={Sex Differences in Pulmonary Eicosanoids and Specialized Pro-Resolving Mediators in Response to Ozone Exposure}, volume={183}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfab081}, abstractNote={Abstract}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Yaeger, Michael J. and Reece, Sky W. and Kilburg-Basnyat, Brita and Hodge, Miles X. and Pal, Anandita and Dunigan-Russell, Katelyn and Luo, Bin and You, Dorothy J. and Bonner, James C. and Spangenburg, Espen E. and et al.}, year={2021}, month={Sep}, pages={170–183} }
 @article{mohan_neequaye_malur_soliman_mcpeek_leffler_ogburn_tokarz_knudson_gharib_et al._2020, title={Matrix Metalloproteinase-12 Is Required for Granuloma Progression}, volume={11}, ISSN={["1664-3224"]}, DOI={10.3389/fimmu.2020.553949}, abstractNote={Background Sarcoidosis is a chronic inflammatory disease of unknown cause characterized by granuloma formation. Mechanisms for chronic persistence of granulomas are unknown. Matrix Metalloproteinase-12 (MMP12) degrades extracellular matrix elastin and enables infiltration of immune cells responsible for inflammation and granuloma formation. Previous studies report increased MMP12 in sarcoidosis patients and association between MMP12 expression and disease severity. We also observed elevated MMP12 in our multiwall carbon nanotube (MWCNT) murine model of granulomatous inflammation. Here we hypothesized that MMP12 is important to acute and late phases of granuloma pathogenesis. To test this hypothesis, we analyzed granulomatous and inflammatory responses of Mmp12 knock-out (KO) mice at 10 (acute) and 60 days (late) after MWCNT instillation. Methods C57BL/6 (wildtype) and Mmp12 KO mice underwent oropharyngeal instillation of MWCNT. Lungs were harvested at 3, 10, 20, and 60 days post instillation for evaluation of MMP12 expression and granulomatous changes. Bronchoalveolar lavage (BAL) cells were analyzed 60 days after MWCNT instillation for expression of mediators thought to play a role in sarcoid granulomatosis: peroxisome proliferator-activated receptor-gamma (PPARγ), interferon-gamma (IFN-γ), and CCL2 (MCP-1). Results Pulmonary granuloma appearance at 10 days after MWCNT instillation showed no differences between wildtype and Mmp12 KO mice. In contrast, by 60 days after MWCNT instillation, Mmp12 KO mice revealed markedly attenuated granuloma formation together with elevated PPARγ and reduced IFNγ expression in BAL cells compared to wildtype. Unexpectedly, Mmp12 KO mice further demonstrated increased alveolar macrophages with increased CCL2 at 60 days. Conclusions The striking reduction of granuloma formation at day 60 in Mmp12 KO mice suggests that MMP12 is required to maintain chronic granuloma pathophysiology. The increased PPARγ and decreased IFNγ findings suggest that these mediators also may be involved since previous studies have shown that PPARγ suppresses IFNγ and PPARγ deficiency amplifies granuloma formation. Interestingly, a role of MMP12 in granuloma resolution is also suggested by increases in both macrophage influx and CCL2. Overall, our results strongly implicate MMP12 as a key factor in granuloma persistence and as a possible therapeutic target in chronic pulmonary sarcoidosis.}, journal={FRONTIERS IN IMMUNOLOGY}, author={Mohan, Arjun and Neequaye, Nicole and Malur, Anagha and Soliman, Eman and McPeek, Matthew and Leffler, Nancy and Ogburn, David and Tokarz, Debra A. and Knudson, Warren and Gharib, Sina A. and et al.}, year={2020}, month={Sep} }
 @article{mcpeek_malur_tokarz_lertpiriyapong_gowdy_murray_wingard_fessler_barna_thomassen_2019, title={Alveolar Macrophage ABCG1 Deficiency Promotes Pulmonary Granulomatous Inflammation}, volume={61}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2018-0365OC}, abstractNote={Pulmonary granuloma formation is a complex and poorly understood response to inhaled pathogens and particulate matter. To explore the mechanisms of pulmonary granuloma formation and maintenance our laboratory has developed a multi-wall carbon nanotube (MWCNT) induced murine model of chronic granulomatous inflammation. We have demonstrated that the MWCNT model closely mimics pulmonary sarcoidosis pathophysiology, including the deficiency of alveolar macrophage ATP-binding cassette (ABC) lipid transporters ABCA1 and ABCG1. We hypothesized that deficiency of alveolar macrophage ABCA1 and ABCG1 would promote pulmonary granuloma formation and inflammation. To test this hypothesis, the effects of MWCNT instillation were evaluated in ABCA1, ABCG1 and ABCA1/ABCG1 myeloid-specific knockout mice. Histological examination revealed significantly larger pulmonary granulomas in ABCG1-KO and ABCA1/ABCG1 double knockout animals when compared to wild-type animals. Evaluation of bronchoalveolar lavage cells indicated increased expression of CCL2 and osteopontin, genes shown to be involved in the formation and maintenance of pulmonary granulomas. Single deficiency of alveolar macrophage ABCA1 did not affect MWCNT induced granuloma formation or pro-inflammatory gene expression. These observations indicate that the deficiency of alveolar macrophage ABCG1 promotes pulmonary granulomatous inflammation and that this is augmented by additional deletion of ABCA1.}, number={3}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={McPeek, Matthew and Malur, Anagha and Tokarz, Debra A. and Lertpiriyapong, Kvin and Gowdy, Kymberly M. and Murray, Gina and Wingard, Christopher J. and Fessler, Michael B. and Barna, Barbara P. and Thomassen, Mary Jane}, year={2019}, month={Sep}, pages={332–340} }
 @article{schreeg_evans_allen_lewis_luckring_evola_richard_piner_thompson_adin_et al._2019, title={Cardiac Leiomyosarcoma in a Cat Presenting for Bilateral Renal Neoplasia}, volume={168}, ISSN={["1532-3129"]}, DOI={10.1016/j.jcpa.2019.02.005}, abstractNote={A 10-year-old neutered female domestic longhair cat was presented to a tertiary care veterinary hospital for evaluation of a right renal mass that was identified incidentally on abdominal radiographs and classified further as a sarcoma based on fine needle aspiration cytology. Further diagnostic workup, including ultrasound and cytology, identified a sarcoma in the left kidney. After approximately 1 month of conservative medical management, the clinical condition deteriorated and the cat was humanely destroyed. Post-mortem examination confirmed bilateral renal masses with multifocal infarction and extensive necrosis, and further identified a large mass at the apex of the heart as well as multiple pulmonary nodules. Microscopical examination of the masses identified a population of poorly-differentiated neoplastic spindle cells, consistent with sarcoma. Immunohistochemically, the neoplastic cells expressed smooth muscle actin and muscle-specific actin, but were negative for myoglobin and factor VIII. Phosphotungstic acid–haematoxylin staining was unable to identify cross-striations in the neoplastic cells. Based on these results and the pattern of lesion distribution, the cat was diagnosed with cardiac leiomyosarcoma with pulmonary and bilateral renal metastasis.}, journal={JOURNAL OF COMPARATIVE PATHOLOGY}, author={Schreeg, M. E. and Evans, B. J. and Allen, J. and Lewis, M. C. and Luckring, E. and Evola, M. and Richard, D. K. and Piner, K. and Thompson, E. M. and Adin, D. B. and et al.}, year={2019}, month={Apr}, pages={19–24} }
 @article{friedenberg_vansteenkiste_yost_treeful_meurs_tokarz_olby_2018, title={A de novo mutation in the EXT2 gene associated with osteochondromatosis in a litter of American Staffordshire Terriers}, volume={32}, ISSN={0891-6640}, url={http://dx.doi.org/10.1111/jvim.15073}, DOI={10.1111/jvim.15073}, abstractNote={BackgroundWe aimed to identify mutations associated with osteochondromatosis in a litter of American Staffordshire Terrier puppies.}, number={3}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Friedenberg, Steven G. and Vansteenkiste, Daniella and Yost, Oriana and Treeful, Amy E. and Meurs, Kathryn M. and Tokarz, Debra A. and Olby, Natasha J.}, year={2018}, month={Feb}, pages={986–992} }
 @article{messenger_hall_jima_house_tam_tokarz_smart_2018, title={C/EBPβ deletion in oncogenic Ras skin tumors is a synthetic lethal event}, volume={9}, ISSN={2041-4889}, url={http://dx.doi.org/10.1038/S41419-018-1103-Y}, DOI={10.1038/s41419-018-1103-y}, abstractNote={Abstract}, number={11}, journal={Cell Death & Disease}, publisher={Springer Science and Business Media LLC}, author={Messenger, Zachary J. and Hall, Jonathan R. and Jima, Dereje D. and House, John S. and Tam, Hann W. and Tokarz, Debra A. and Smart, Robert C.}, year={2018}, month={Oct} }
 @article{mcpeek_malur_tokarz_murray_barna_thomassen_2018, title={PPAR-gamma pathways attenuate pulmonary granuloma formation in a carbon nanotube induced murine model of sarcoidosis}, volume={503}, ISSN={["1090-2104"]}, DOI={10.1016/j.bbrc.2018.06.061}, abstractNote={Peroxisome proliferator activated receptor gamma (PPARγ), a ligand activated nuclear transcription factor, is constitutively expressed in alveolar macrophages of healthy individuals. PPARγ deficiencies have been noted in several lung diseases including the alveolar macrophages of pulmonary sarcoidosis patients. We have previously described a murine model of multiwall carbon nanotubes (MWCNT) induced pulmonary granulomatous inflammation which bears striking similarities to pulmonary sarcoidosis, including the deficiency of alveolar macrophage PPARγ. Further studies demonstrate alveolar macrophage PPARγ deficiency exacerbates MWCNT-induced pulmonary granulomas. Based on these observations we hypothesized that activation of PPARγ via administration of the PPARγ-specific ligand rosiglitazone would limit MWCNT-induced granuloma formation and promote PPARγ-dependent pathways. Results presented here show that rosiglitazone significantly limits the frequency and severity of MWCNT-induced pulmonary granulomas. Furthermore, rosiglitazone attenuates alveolar macrophage NF-κB activity and downregulates the expression of the pro-inflammatory mediators, CCL2 and osteopontin. PPARγ activation via rosiglitazone also prevents the MWCNT-induced deficiency of PPARγ-regulated ATP-binding cassette lipid transporter-G1 (ABCG1) expression. ABCG1 is crucial to pulmonary lipid homeostasis. ABCG1 deficiency results in lipid accumulation which promotes pro-inflammatory macrophage activation. Our results indicate that restoration of homeostatic ABCG1 levels by rosiglitazone correlates with both reduced pulmonary lipid accumulation, and decreased alveolar macrophage activation. These data confirm and further support our previous observations that PPARγ pathways are critical in regulating MWCNT-induced pulmonary granulomatous inflammation.}, number={2}, journal={BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS}, author={McPeek, Matthew and Malur, Anagha and Tokarz, Debra A. and Murray, Gina and Barna, Barbara P. and Thomassen, Mary Jane}, year={2018}, month={Sep}, pages={684–690} }
 @article{duke_thompson_ihrie_taylor-just_ash_shipkowski_hall_tokarz_cesta_hubbs_et al._2018, title={Role of p53 in the chronic pulmonary immune response to tangled or rod-like multi-walled carbon nanotubes}, volume={12}, ISSN={["1743-5404"]}, DOI={10.1080/17435390.2018.1502830}, abstractNote={Abstract The fiber-like shape of multi-walled carbon nanotubes (MWCNTs) is reminiscent of asbestos, suggesting they pose similar health hazards when inhaled, including pulmonary fibrosis and mesothelioma. Mice deficient in the tumor suppressor p53 are susceptible to carcinogenesis. However, the chronic pathologic effect of MWCNTs delivered to the lungs of p53 heterozygous (p53+/−) mice has not been investigated. We hypothesized that p53+/− mice would be susceptible to lung tumor development after exposure to either tangled (t-) or rod-like (r-) MWCNTs. Wild-type (p53+/+) or p53+/− mice were exposed to MWCNTs (1 mg/kg) via oropharyngeal aspiration weekly over four consecutive weeks and evaluated for cellular and pathologic outcomes 11-months post-initial exposure. No lung or pleural tumors were observed in p53+/+ or p53+/− mice exposed to either t- or rMWCNTs. In comparison to tMWCNTs, the rMWCNTs induced the formation of larger granulomas, a greater number of lymphoid aggregates and greater epithelial cell hyperplasia in terminal bronchioles in both p53+/− and p53+/+ mice. A constitutively larger area of CD45R+/CD3+ lymphoid tissue was observed in p53+/− mice compared to p53+/+ mice. Importantly, p53+/− mice had larger granulomas induced by rMWCNTs as compared to p53+/+ mice. These findings indicate that a combination of p53 deficiency and physicochemical characteristics including nanotube geometry are factors in susceptibility to MWCNT-induced lymphoid infiltration and granuloma formation.}, number={9}, journal={NANOTOXICOLOGY}, author={Duke, Katherine S. and Thompson, Elizabeth A. and Ihrie, Mark D. and Taylor-Just, Alexia J. and Ash, Elizabeth A. and Shipkowski, Kelly A. and Hall, Jonathan R. and Tokarz, Debra A. and Cesta, Mark F. and Hubbs, Ann F. and et al.}, year={2018}, month={Oct}, pages={975–991} }
 @article{tokarz_heffelfinger_jima_gerlach_shah_rodriguez-nunez_kortum_fletcher_nordone_law_et al._2017, title={Disruption of Trim9 function abrogates macrophage motility in vivo}, volume={102}, ISSN={0741-5400 1938-3673}, url={http://dx.doi.org/10.1189/jlb.1A0816-371R}, DOI={10.1189/jlb.1a0816-371r}, abstractNote={Abstract}, number={6}, journal={Journal of Leukocyte Biology}, publisher={Wiley}, author={Tokarz, Debra A. and Heffelfinger, Amy K. and Jima, Dereje D. and Gerlach, Jamie and Shah, Radhika N. and Rodriguez-Nunez, Ivan and Kortum, Amanda N. and Fletcher, Ashley A. and Nordone, Shila K. and Law, J. McHugh and et al.}, year={2017}, month={Oct}, pages={1371–1380} }
 @article{chernyavskaya_mudbhary_zhang_tokarz_jacob_gopinath_sun_wang_magnani_madakashira_et al._2017, title={Loss of DNA methylation in zebrafish embryos activates retrotransposons to trigger antiviral signaling}, volume={144}, ISSN={0950-1991 1477-9129}, url={http://dx.doi.org/10.1242/dev.147629}, DOI={10.1242/dev.147629}, abstractNote={Complex cytoplasmic nucleotide sensing mechanisms can recognize foreign DNA based on a lack of methylation and initiate an immune response to clear the infection. Zebrafish embryos with global DNA hypomethylation caused by mutations in the ubiquitin-like, with PHD and RING finger domains 1 (uhrf1) or DNA methyltransferase 1 (dnmt1) genes exhibit a robust interferon induction characteristic of first line of defense against viral infection. We found that this interferon induction occurred in non-immune cells and asked whether intracellular viral sensing pathways in these cells were the trigger. RNA-seq analysis of uhrf1 and dnmt1 mutants revealed widespread induction of Class I retrotransposons and activation of cytoplasmic DNA viral sensors. Attenuating Sting, pTbk1 and, importantly, blocking reverse transcriptase activity suppressed the expression of interferon genes in uhrf1 mutants. Thus, activation of transposons in cells with global DNA hypomethylation mimics a viral infection by activating cytoplasmic DNA sensors. This suggests that antiviral pathways serve as surveillance of cells that have derepressed intragenomic parasites due to DNA hypomethylation.}, number={16}, journal={Development}, publisher={The Company of Biologists}, author={Chernyavskaya, Yelena and Mudbhary, Raksha and Zhang, Chi and Tokarz, Debra and Jacob, Vinitha and Gopinath, Smita and Sun, Xiaochen and Wang, Shuang and Magnani, Elena and Madakashira, Bhavani P. and et al.}, year={2017}, month={Jul}, pages={2925–2939} }
 @article{allen_gracieux_talib_tokarz_hensley_cores_vandergriff_tang_de andrade_dinh_et al._2016, title={Angiopellosis as an Alternative Mechanism of Cell Extravasation}, volume={35}, ISSN={1066-5099}, url={http://dx.doi.org/10.1002/stem.2451}, DOI={10.1002/stem.2451}, abstractNote={Abstract}, number={1}, journal={STEM CELLS}, publisher={Wiley}, author={Allen, Tyler A. and Gracieux, David and Talib, Maliha and Tokarz, Debra A. and Hensley, M. Taylor and Cores, Jhon and Vandergriff, Adam and Tang, Junnan and de Andrade, James B.M. and Dinh, Phuong-Uyen and et al.}, year={2016}, month={Jul}, pages={170–180} }
 @article{kol_christopher_skorupski_tokarz_vernau_2012, title={B-cell lymphoma with plasmacytoid differentiation, atypical cytoplasmic inclusions, and secondary leukemia in a dog}, volume={42}, ISSN={0275-6382}, url={http://dx.doi.org/10.1111/vcp.12003}, DOI={10.1111/vcp.12003}, abstractNote={Abstract}, number={1}, journal={Veterinary Clinical Pathology}, publisher={Wiley}, author={Kol, A. and Christopher, M.M. and Skorupski, K.A. and Tokarz, D. and Vernau, W.}, year={2012}, month={Dec}, pages={40–46} }
 @article{yamout_tokarz_magdesian_le jeune_2012, title={Intrathoracic pulsion diverticulum in a horse}, volume={53}, journal={Canadian Veterinary Journal}, author={Yamout, S. and Tokarz, D. and Magdesian, K.G. and le Jeune, S.S.}, year={2012}, pages={408–411} }
 @article{tokarz_poppenga_kaae_filigenzi_lowenstine_pesavento_2011, title={Amanitin Toxicosis in Two Cats with Acute Hepatic and Renal Failure}, volume={49}, ISSN={0300-9858 1544-2217}, url={http://dx.doi.org/10.1177/0300985811429307}, DOI={10.1177/0300985811429307}, abstractNote={ Amanitin is a toxic cyclopeptide present in several species of poisonous mushrooms. Amanitin toxicosis was diagnosed in 2 cats from separate premises. Both cats initially had lethargy and vomiting, and they rapidly developed depression and neurological signs over 24–48 hours. Marked elevation of alanine aminotransferase was the primary finding, with subsequent serum chemistry values compatible with hepatic and renal failure. Histopathological findings consisted of submassive to massive acute hepatic necrosis, renal proximal tubular epithelial necrosis, and foci of necrosis and inflammation in the gastrointestinal tract. Amanitin exposure was confirmed postmortem by detection of α-amanitin in the kidney by liquid chromatography–mass spectrometry. A similar clinical course and pathological changes are reported in human and canine amanitin intoxication; however, gastrointestinal lesions are not typically described. }, number={6}, journal={Veterinary Pathology}, publisher={SAGE Publications}, author={Tokarz, D. and Poppenga, R. and Kaae, J. and Filigenzi, M. and Lowenstine, L. J. and Pesavento, P.}, year={2011}, month={Dec}, pages={1032–1035} }
 @article{sykes_marks_mapes_schultz_pollard_tokarz_pesavento_lindsay_foley_2010, title={Salmon Poisoning Disease in Dogs: 29 Cases}, volume={24}, ISSN={0891-6640 1939-1676}, url={http://dx.doi.org/10.1111/j.1939-1676.2010.0493.x}, DOI={10.1111/j.1939-1676.2010.0493.x}, abstractNote={BACKGROUND
Salmon poisoning disease (SPD) is a trematode-borne disease of dogs caused by Neorickettsia helminthoeca.


OBJECTIVES
To determine risk factors and spatial epidemiology of SPD in dogs from northern California; to describe the clinicopathologic, microbiologic, and imaging findings of SPD in these dogs; and to evaluate treatments and outcomes for SPD.


ANIMALS
Twenty-nine dogs with SPD based on the finding of trematode ova in the feces, or organisms consistent with N. helminthoeca in specimens submitted for microscopic examination.


METHODS
Information regarding signalment, fish exposure, clinical signs, diagnostic evaluation, treatments, and outcomes was obtained for each dog. Archived lymph node aspirates and histopathology specimens were subjected to polymerase chain reaction (PCR) testing for Neorickettsia spp.


RESULTS
Labrador Retrievers and intact male dogs were overrepresented. Exposure locations were often distant from the dogs' residence. Some dogs had neurologic signs, including twitching and seizures. Dogs lacking peripheral lymphadenomegaly had abdominal lymphadenomegaly on ultrasound examination. A combination of centrifugation fecal flotation and sedimentation had greatest sensitivity for finding fluke ova. N. helminthoeca DNA was amplified by PCR from 4/10 dogs. Penicillins, cephalosporins, and chloramphenicol did not appear to be effective treatments. Mortality rate was 4/29 (14%).


CONCLUSIONS AND CLINICAL IMPORTANCE
SPD should be suspected in dogs with inappetence, gastrointestinal, or neurologic signs, with or without fever or peripheral lymphadenomegaly in the appropriate geographical setting. Diagnosis is facilitated by a combination of fecal sedimentation and centrifugal flotation, abdominal ultrasonography, and PCR-based assays on lymphoid tissue. The treatment of choice is tetracycline antimicrobials.}, number={3}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Sykes, J.E. and Marks, S.L. and Mapes, S. and Schultz, R.M. and Pollard, R.E. and Tokarz, D. and Pesavento, P.P. and Lindsay, L.L. and Foley, J.E.}, year={2010}, month={Mar}, pages={504–513} }
 @article{rainier_bui_mark_thomas_tokarz_ming_delaney_richardson_albers_matsunami_et al._2008, title={Neuropathy Target Esterase Gene Mutations Cause Motor Neuron Disease}, volume={82}, ISSN={0002-9297}, url={http://dx.doi.org/10.1016/j.ajhg.2007.12.018}, DOI={10.1016/j.ajhg.2007.12.018}, abstractNote={The possibility that organophosphorus (OP) compounds contribute to motor neuron disease (MND) is supported by association of paraoxonase 1 polymorphisms with amyotrophic lateral sclerosis (ALS) and the occurrence of MND in OP compound-induced delayed neuropathy (OPIDN), in which neuropathy target esterase (NTE) is inhibited by organophosphorylation. We evaluated a consanguineous kindred and a genetically unrelated nonconsanguineous kindred in which affected subjects exhibited progressive spastic paraplegia and distal muscle wasting. Affected subjects resembled those with OPIDN and those with Troyer Syndrome due to SPG20/spartin gene mutation (excluded by genetic linkage and SPG20/spartin sequence analysis). Genome-wide analysis suggested linkage to a 22 cM homozygous locus (D19S565 to D19S884, maximum multipoint LOD score 3.28) on chromosome 19p13 to which NTE had been mapped (GenBank AJ004832 ). NTE was a candidate because of its role in OPIDN and the similarity of our patients to those with OPIDN. Affected subjects in the consanguineous kindred were homozygous for disease-specific NTE mutation c.3034A→G that disrupted an interspecies conserved residue (M1012V) in NTE's catalytic domain. Affected subjects in the nonconsanguineous family were compound heterozygotes: one allele had c.2669G→A mutation, which disrupts an interspecies conserved residue in NTE's catalytic domain (R890H), and the other allele had an insertion (c.2946_2947insCAGC) causing frameshift and protein truncation (p.S982fs1019). Disease-specific, nonconserved NTE mutations in unrelated MND patients indicates NTE's importance in maintaining axonal integrity, raises the possibility that NTE pathway disturbances contribute to other MNDs including ALS, and supports the role of NTE abnormalities in axonopathy produced by neuropathic OP compounds. The possibility that organophosphorus (OP) compounds contribute to motor neuron disease (MND) is supported by association of paraoxonase 1 polymorphisms with amyotrophic lateral sclerosis (ALS) and the occurrence of MND in OP compound-induced delayed neuropathy (OPIDN), in which neuropathy target esterase (NTE) is inhibited by organophosphorylation. We evaluated a consanguineous kindred and a genetically unrelated nonconsanguineous kindred in which affected subjects exhibited progressive spastic paraplegia and distal muscle wasting. Affected subjects resembled those with OPIDN and those with Troyer Syndrome due to SPG20/spartin gene mutation (excluded by genetic linkage and SPG20/spartin sequence analysis). Genome-wide analysis suggested linkage to a 22 cM homozygous locus (D19S565 to D19S884, maximum multipoint LOD score 3.28) on chromosome 19p13 to which NTE had been mapped (GenBank AJ004832 ). NTE was a candidate because of its role in OPIDN and the similarity of our patients to those with OPIDN. Affected subjects in the consanguineous kindred were homozygous for disease-specific NTE mutation c.3034A→G that disrupted an interspecies conserved residue (M1012V) in NTE's catalytic domain. Affected subjects in the nonconsanguineous family were compound heterozygotes: one allele had c.2669G→A mutation, which disrupts an interspecies conserved residue in NTE's catalytic domain (R890H), and the other allele had an insertion (c.2946_2947insCAGC) causing frameshift and protein truncation (p.S982fs1019). Disease-specific, nonconserved NTE mutations in unrelated MND patients indicates NTE's importance in maintaining axonal integrity, raises the possibility that NTE pathway disturbances contribute to other MNDs including ALS, and supports the role of NTE abnormalities in axonopathy produced by neuropathic OP compounds. Exposure to neurotoxic organophosphorous (OP) compounds of sufficient magnitude and duration causes neurodegeneration in humans, livestock, and laboratory animals.1Abou-Donia M.B. Organophosphorus ester-induced delayed neurotoxicity.Annu. Rev. Pharmacol. Toxicol. 1981; 21: 511-548Crossref PubMed Scopus (350) Google Scholar OP compound exposures occur in industrial or agricultural environments and as the consequences of terrorism, accidents, suicide attempts, or chemical warfare. Recent attention has focused on OP neurotoxicity after the use of Sarin in the 1995 Tokyo subway terrorist incident2Lotti M. Becker C.E. Aminoff M.J. Organophosphate polyneuropathy; pathogenesis and prevention.Neurology. 1984; 34: 658-662Crossref PubMed Google Scholar and because of concerns about persistent neurological effects after exposures to neurotoxic OP agents in the Gulf War. During the Prohibition era in the United States, consumption of Jamaica ginger extract (“Ginger Jake”) adulterated with triorthocresyl phosphate (TOCP) led to OP compound-induced delayed neuropathy (OPIDN) in an estimated 50,000 Americans.3Woolf A.D. Ginger Jake and the blues: A tragic song of poisoning.Vet. Hum. Toxicol. 1995; 37: 252-254PubMed Google Scholar, 4Morgan J.P. Penovich P. Jamaica ginger paralysis. Forty-seven-year follow-up.Arch. Neurol. 1978; 35: 530-532Crossref PubMed Scopus (97) Google Scholar, 5Morgan J.P. Tulloss T.C. The Jake Walk Blues. A toxicologic tragedy mirrored in American popular music.Ann. Intern. Med. 1976; 85: 804-808Crossref PubMed Scopus (31) Google Scholar Additional outbreaks of OPIDN causing paralysis of tens of thousands of individuals have occurred in Morocco, Fiji, and India due to consumption of cooking oil contaminated with lubricating oil (containing triorthocresyl phosphate).6Smith H.V. Spalding J.M. Outbreak of paralysis in Morocco due to ortho-cresyl phosphate poisoning.Lancet. 1959; 2: 1019-1021Abstract PubMed Scopus (106) Google Scholar, 7Taylor P. Anticholinesterase agents. Goodman and Gilman's Pharmacologic Basis of Therapeutics.Ninth Edition. McGraw Hill, New York1996Google Scholar, 8Sorokin M. Orthocresyl phosphate neuropathy: Report of an outbreak in Fiji.Med. J. Aust. 1969; 1: 506-508PubMed Google Scholar, 9Srivastava A.K. Das M. Khanna S.K. An outbreak of tricresyl phosphate poisoning in Calcutta, India.Food Chem. Toxicol. 1990; 28: 303-304Crossref PubMed Scopus (12) Google Scholar, 10Sarkar J.K. Outbreaks of paralystic disease in West Bengal due to tricresyl phosphate poisoning.J. Indian Med. Assoc. 1974; 63: 359-361PubMed Google Scholar, 11Mehta R.S. Dixit I.P. Khakharia S.J. Toxic neuropathy in Raipur due to triorthocresylphosphate (TOCP).J. Assoc. Physicians India. 1975; 23: 133-138PubMed Google Scholar Neurologic syndromes following OP toxicity are highly variable and depend on such factors as the specific OP compound, dose and duration of exposure, species, age, and various physiologic factors at the time of OP exposure. Whereas acute OP toxicity usually produces acute cholinergic crisis,7Taylor P. Anticholinesterase agents. Goodman and Gilman's Pharmacologic Basis of Therapeutics.Ninth Edition. McGraw Hill, New York1996Google Scholar acute cholinergic crises are often absent in OPIDN. In contrast, OPIDN often begins with sensory impairment, ataxia, weakness, muscle fasciculation, and hyporeflexia and may progress to complete flaccid paralysis followed by progressive spastic paraplegia.4Morgan J.P. Penovich P. Jamaica ginger paralysis. Forty-seven-year follow-up.Arch. Neurol. 1978; 35: 530-532Crossref PubMed Scopus (97) Google Scholar, 7Taylor P. Anticholinesterase agents. Goodman and Gilman's Pharmacologic Basis of Therapeutics.Ninth Edition. McGraw Hill, New York1996Google Scholar, 12Inoue N. Fujishiro K. Mori K. Matsuoka M. Triorthocresyl phosphate poisoning - A review of human cases.J. UOEH. 1988; 10: 433-442PubMed Google Scholar Neuropathologic analyses of OPIDN have shown distal degeneration of the longest central- and peripheral-nervous-system axons.1Abou-Donia M.B. Organophosphorus ester-induced delayed neurotoxicity.Annu. Rev. Pharmacol. Toxicol. 1981; 21: 511-548Crossref PubMed Scopus (350) Google Scholar, 12Inoue N. Fujishiro K. Mori K. Matsuoka M. Triorthocresyl phosphate poisoning - A review of human cases.J. UOEH. 1988; 10: 433-442PubMed Google Scholar Distal axon degeneration is also the primary neuropathologic feature of hereditary spastic paraplegia (HSP) (reviewed in13Fink J.K. Hereditary spastic paraplegia.in: Rimoin D. Connor J.M. Pyeritz R.E. Korf B.R. Emery and Rimoin's Principles and Practice of Medical Genetics. 5 ed. Churchill Livingstone Elsevier, Philadelphia2007: 2771-2801Google Scholar). Some complicated forms of HSP,13Fink J.K. Hereditary spastic paraplegia.in: Rimoin D. Connor J.M. Pyeritz R.E. Korf B.R. Emery and Rimoin's Principles and Practice of Medical Genetics. 5 ed. Churchill Livingstone Elsevier, Philadelphia2007: 2771-2801Google Scholar such as Troyer syndrome (MIM 275900), also exhibit lower-motor neuron involvement.14Patel H. Cross H. Proukakis C. Hershberger R. Bork P. Ciccarelli F.D. Patton M.A. McKusick V.A. Crosby A.H. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia.Nat. Genet. 2002; 31: 347-348Crossref PubMed Scopus (198) Google Scholar OPIDN pathogenesis involves neuropathy target esterase (NTE), a neuronal membrane protein, either through direct OP-induced inhibition of NTE or through generation of OP-NTE neurotoxic complexes (“aged NTE”). NTE's functions are incompletely understood. NTE is capable of hydrolyzing several intrinsic membrane lipids and thus may be a factor in determining the composition of neuronal membranes.15van Tienhoven M. Atkins J. Li Y. Glynn P. Human neuropathy target esterase catalyzes hydrolysis of membrane lipids.J. Biol. Chem. 2002; 277: 20942-20948Crossref PubMed Scopus (138) Google Scholar NTE's catalytic domain for esterase activity has been mapped to a 489 amino acid region between residues 727 and 1216.16Forshaw P.J. Atkins J. Ray D.E. Glynn P. The catalytic domain of human neuropathy target esterase mediates an organophosphate-sensitive ionic conductance across liposome membranes.J. Neurochem. 2001; 79: 400-406Crossref PubMed Scopus (12) Google Scholar Participation of NTE in a cell-signaling pathway controlling interactions between neurons and accessory glial cells in the developing nervous system has also been proposed.17Glynn P. Neuropathy target esterase.Biochem. J. 1999; 344: 625-631Crossref PubMed Scopus (107) Google Scholar, 18Glynn P. Neural development and neurodegeneration: Two faces of neuropathy target esterase.Prog. Neurobiol. 2000; 61: 61-74Crossref PubMed Scopus (107) Google Scholar We studied a consanguineous family of Ashkenazi Jewish ancestry (Figure 1A) and a nonconsanguineous family of northern European ancestry (Figure 1B) in which affected subjects developed childhood onset of insidiously progressive lower-extremity spastic weakness and progressive wasting of distal upper- and lower-extremity muscles. Electrophysiologic studies were consistent with a motor axonopathy affecting upper and lower extremities. Magnetic resonance imaging demonstrated spinal cord atrophy, particularly in the thoracic region. The affected phenotype in each family conformed both to OPIDN and to “Troyer syndrome,” an autosomal-recessive form of HSP associated with distal muscle wasting.14Patel H. Cross H. Proukakis C. Hershberger R. Bork P. Ciccarelli F.D. Patton M.A. McKusick V.A. Crosby A.H. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia.Nat. Genet. 2002; 31: 347-348Crossref PubMed Scopus (198) Google Scholar, 19Cross H.E. McKusick V.A. The Troyer syndrome. A recessive form of spastic paraplegia with distal muscle wasting.Arch. Neurol. 1967; 16: 473-485Crossref PubMed Scopus (93) Google Scholar Troyer syndrome patients variably exhibit additional neurologic and systemic abnormalities (delayed milestone acquisition, skeletal abnormalities, and cerebellar, extrapyramidal, and cognitive impairment). These features were not observed in our patients. The University of Michigan Institutional Review Board approved this study. We analyzed the SPG20/spartin gene (MIM 607111) coding sequence, mutations in which cause Troyer syndrome (SPG20 HSP),14Patel H. Cross H. Proukakis C. Hershberger R. Bork P. Ciccarelli F.D. Patton M.A. McKusick V.A. Crosby A.H. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia.Nat. Genet. 2002; 31: 347-348Crossref PubMed Scopus (198) Google Scholar, 19Cross H.E. McKusick V.A. The Troyer syndrome. A recessive form of spastic paraplegia with distal muscle wasting.Arch. Neurol. 1967; 16: 473-485Crossref PubMed Scopus (93) Google Scholar and found no mutations in the index (consanguineous) family (data not shown), and we excluded the SPG2014Patel H. Cross H. Proukakis C. Hershberger R. Bork P. Ciccarelli F.D. Patton M.A. McKusick V.A. Crosby A.H. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia.Nat. Genet. 2002; 31: 347-348Crossref PubMed Scopus (198) Google Scholar locus in the consanguineous family by genetic-linkage analysis (Table 1). Two-point linkage analyses for exclusion mapping were performed with the MLINK subroutine of the LINKAGE program20Lathrop G.M. Lalouel J. Julient C. Ott J. Multipoint linkage analysis in humans: Detection of linkage and estimation of recombination.Am. J. Hum. Genet. 1985; 37: 482-498PubMed Google Scholar with an autosomal-recessive model of disease inheritance and a disease allele frequency of 0.001. We assigned a genetic penetrance of 0.90 for LOD-score calculations.Table 1Genetic-Linkage Analysis Excludes Chromosome 13q12.3MarkerLOD θ = 00.010.020.030.040.05D13S1841−3.4−1.23−0.94−0.77−0.66−0.57D13S1842−2.19−1.19−0.92−0.76−0.64−0.56D13S1851−3.4−1.23−0.94−0.77−0.66−0.57D13S1843−3.4−1.23−0.94−0.77−0.66−0.57D13S2190.080.070.070.060.060.06D13S1844−2.19−1.19−0.92−0.76−0.64−0.56Genetic-linkage analysis excludes SPG20 “Troyer syndrome” locus on chromosome 13q12.3. Open table in a new tab Genetic-linkage analysis excludes SPG20 “Troyer syndrome” locus on chromosome 13q12.3. We then initiated genome-wide linkage analysis (Figure 2) in the larger, consanguineous family with ten subjects (three living affected subjects, seven living unaffected subjects, no spouses of descendants) and in the second smaller, nonconsanguineous family. Marrying-in spouses were asymptomatic and had no evidence of similar neurologic disorders in their families. Maximum-likelihood estimates of marker allele frequencies were estimated from all 15 subjects in both families. The average number of alleles was 4 (range = 3–7), and the average observed heterozygosity of these markers in the families was 0.64 (range = 0.32–0.84). We analyzed 400 polymorphic microsatellite markers spaced ∼10 cM apart (ABI MD-10 Linkage Mapping Set), of which 164 markers heterozygous for at least one affected individual excluded 41% of the genome. Six of these markers were homozygous for all affected individuals in the consanguineous family. We analyzed adjacent markers for each homozygous marker. Only markers adjacent to D19S209 yielded an extended linked haplotype that spanned 22 cM between D19S565 and D19S884 on chromosome 19p13 (Figure 1A). In the smaller, nonconsanguineous family, these same markers also resulted in haplotype sharing in affected subjects consistent with genetic linkage of this region (Figure 1B). The positive chromosome 19 region was analyzed with multipoint methods to incorporate information from all 27 informative markers. The GeneHunter program21Kruglyak L. Daly M.J. Reeve-Daly M.P. Lander E.S. Parametric and nonparametric linkage analysis: A unified multipoint approach.Am. J. Hum. Genet. 1996; 58: 1347-1363PubMed Google Scholar was used to obtain exact multipoint LOD scores and multipoint nonparametric linkage (NPL) scores. The NPL score is based on allele sharing identical by descent (IBD) and does not assume a transmission model. The NPL analysis allows an assessment of the robustness of the result to model misspecification. Because of the size and complexity of the largest pedigree, it had to be trimmed for analysis in GeneHunter. Therefore, analyses were also performed with SimWalk2.22Sobel E. Lange K. Descent graphs in pedigree analysis: Applications to haplotyping, location scores, and marker sharing statistics.Am. J. Hum. Genet. 1996; 58: 1323-1337PubMed Google Scholar, 23Sobel E. Sengul H. Weeks D.E. Multipoint estimation of identity-by-descent probablilities at arbitrary positions among marker loci on general pedigrees.Hum. Hered. 2001; 52: 121-131Crossref PubMed Scopus (145) Google Scholar, 24Sobel E. Papp J.C. Jange K. Detection and integration of genotyping errors in statistical genetics.Am. J. Hum. Genet. 2002; 70: 496-508Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar SimWalk2 uses Markov chain Monte Carlo (MCMC) and simulated annealing methods to perform multipoint analyses, allowing computation on large, complex pedigrees. Although the method is not exact, all pedigree members could be included in the analysis. We performed parametric LOD score and NPL analyses in SimWalk2. For each analysis, we set the “parallel runs” flag to generate two simulated annealing runs of the data. The runs produced a maximum score at the same location with the same scores within rounding error. p values given by SimWalk2 were calculated with 10,000 simulations. For nonparametric analyses, p values were used to generate the reported scores (score = −log10 [p value]). Multipoint LOD score and nonparametric analyses of the two families clearly mirrored the shared haplotype region (Figure 2). With all methods (model-based parametric analysis or nonparametric analysis with either GeneHunter or SimWalk2) used, the maximum LOD score occurred near marker D19S869. Maximum multipoint parametric LOD scores were 2.58 with GeneHunter and 3.82 with SimWalk2. The maximum NPL scores were 3.30 with GeneHunter and 3.36 with SimWalk2. The p value associated with the GeneHunter statistics is 0.002; the simulation-based p value for the SimWalk2 statistics is 0.0004. The index family contributed most to these scores (3.28 and 3.09 for the parametric and NPL SimWalk2 analyses, respectively, and 2.07 and 3.07 for the GeneHunter parametric and NPL analyses, respectively). It is important to note that the second small, nonconsanguineous family supported this peak, with scores close to the maximum expected for an affected-sibling-pair family. To further characterize the region on chromosome 19 and to fully characterize all shared chromosomal regions, we carried out high-density SNP typing with the Affymetrix 250K NspI chips on all family members for whom DNA was available: 12 subjects in the consanguineous family (including all three affected individuals and two additional unaffected subjects ascertained after the initial microsatellite linkage analysis had been performed) and five subjects in the nonconsanguineous family. We analyzed the SNP data by looking for regions of autozygosity in the entire genome with the Find Autozygous Regions program in the GeneSpring GT analysis package (Agilent). The results of this analysis are shown in Figure 3; they clearly show a single major autozygosity region on chromosome 19 in the three affected individuals. This 4.7 megabase region is defined by the map location from 2784431 to 7541689 bp (NCBI build 35). This region corresponds to the same region identified by the microsatellite markers. The region includes the interesting candidate gene neuropathy target esterase (NTE) (GenBank AJ004832 ), whose location on chromosome 19 is from 7505075—7532647 bp (UCSC Genome Browser on NCBI build 35). The NTE gene was an obvious candidate because of its role in OPIDN and the similarity of symptoms seen in our patients to those reported for OPIDN. Analysis of NTE's coding sequence in the index family showed that each affected subject was homozygous for (and each obligate carrier heterozygous for) substitution of guanine for adenine at NTE cDNA 3034. This mutation was absent in 105 control subjects (data not shown) and caused substitution of valine for methionine at amino acid position 1012 (M1012V). This mutation disrupts an interspecies conserved residue within NTE's catalytic domain (Figure 4C).25Lush M.J. Li Y. Read D.J. Willis A.C. Glynn P. Neuropathy target esterase and a homologous Drosophila neurodegeneration-associated mutant protein contain a novel domain conserved from bacteria to man.Biochem. J. 1998; 332: 1-4Crossref PubMed Scopus (122) Google Scholar Mouse, Drosophila, and C. elegans species all contain M at residue 1012. Polyphen analysis of M1012V mutation gave a PSIC profile-difference score of 2.590 predicting that the mutation would be damaging. On the other hand, SIFT analysis predicted that M1012V substitution would be tolerated. We then analyzed the NTE coding sequence in the second, unrelated, nonconsanguineous family (Figure 1B). Analysis of NTE's coding sequence in affected subjects in this second family showed that they were compound heterozygotes for two NTE mutations. Like the mutation in the index family, these mutations also occurred within NTE's catalytic domain. One allele had a 2669G→A mutation corresponding to an R890H substitution in NTE's catalytic domain. Human and mouse contain R at residue 890, whereas Drosophila and C.elegans contain K at residue 890. Polyphen analysis (PSIC profile-difference score = 0.184) and SIFT analysis predicted that R890H would be a tolerated substitution. The other allele had a four base pair insertion (NTE mRNA position 2946) that caused a frameshift and protein truncation after residue 1019. The truncated protein is predicted to be missing the last 235 residues of NTE's catalytic domain (which extends from amino acid position 727 to position 1216). These mutations were present separately in each carrier parent and absent in 105 control subjects and the unaffected sibling. In summary, we identified homozygous and compound heterozygous NTE mutations in subjects from two unrelated families with autosomal-recessive progressive spastic paraplegia associated with distal upper- and lower-extremity wasting. Because of its clinical similarity with SPG20 HSP (Troyer syndrome), we reserved for this disease the next-available HSP locus designation (SPG39) and refer to this disorder as NTE-related Motor Neuron Disorder (NTE-MND). These NTE mutations are disease-specific and considered pathogenic for several reasons. First, they were present in affected subjects in two unrelated kindreds and absent in control subjects. Second, they affect amino acid residues within NTE's catalytic domain. Third, NTE plays a central role in OPIDN, an upper- and lower-motor neuron disorder whose symptoms bear a striking resemblance to those exhibited by our NTE-MND patients. Two mechanisms for NTE involvement in OPIDN have been proposed. The first mechanism proposes that neurotoxicity is the consequence of OP-induced inhibition of NTE. The second mechanism proposes that OP-NTE complexes are toxic. These proposed mechanisms are not mutually exclusive because OP interaction with NTE could both be toxic as well as interfere with NTE activity. The fact that identified NTE mutations in NTE-MND subjects disturb NTE's catalytic domain suggests that they could result in altered NTE activity in vivo. This suggests that modified NTE activity alone could be sufficient to cause corticospinal tract and peripheral motor axonopathy. Nonetheless, it is also possible that the NTE mutations identified result in neurotoxic or “aged” NTE. Observations that NTE mutations are associated with progressive upper- and lower-motor neuron disease indicate the importance of NTE in maintaining the integrity of corticospinal tract and peripheral motor axons. The finding that NTE mutations underlie corticospinal tract and peripheral motor axon degeneration raises the possibility that other NTE polymorphisms (or genetic variation in factors that regulate or interact with NTE) could contribute to other motor neuron disorders including amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). We have shown that two NTE mutations are the likely cause of autosomal-recessive motor neuron disease that closely resembles OPIDN. These NTE mutations were sufficient to cause the disorder even in the absence of apparent exposure to neurotoxic OP compounds. It will be important to determine whether other polymorphisms in NTE and/or proteins with which it interacts influence the susceptibility to OP-induced neurologic disease. Our findings, together with the recently identified association of PON1 polymorphisms with ALS,26Slowik A. Tomik B. Wolkow P.P. Partyka D. Turaj W. Malecki M.T. Pera J. Dziedzic T. Szczudlik A. Figlewicz D.A. Paraoxonase gene polymorphisms and sporadic ALS.Neurology. 2006; 67: 766-770Crossref PubMed Scopus (72) Google Scholar further support the possibility that neurotoxic OP compounds contribute to motor neuron disease. This research is supported by grants from the University of Michigan Institute of Gerontology (to S.R.); and the Veterans Affairs Merit Review, the National Institutes of Health (National Institute of Neurological Disorders and Stroke [NINDS] R01-NS053917 and R01-NS045163), the Spastic Paraplegia Foundation, and the National Organization for Rare Disorders (to J.K.F.). Those funding this study did not play any role in design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. We are grateful for the Elderly Subjects Program of the University of Michigan Institute of Gerontology through which control subjects were ascertained, the technical assistance of Shalini Guduri, the expert secretarial assistance of Lynette Girbach, and the participation of research subjects and their families without whom this investigation would not be possible. Download .xls (.1 MB) Help with xls files Document S1. Table of Genescan Data The URL for online data listed herein is as follows:Online Mendelian Inheritance in Man, http://www.ncbi.nlm.nih.gov/Omim/.}, number={3}, journal={The American Journal of Human Genetics}, publisher={Elsevier BV}, author={Rainier, Shirley and Bui, Melanie and Mark, Erin and Thomas, Donald and Tokarz, Debra and Ming, Lei and Delaney, Colin and Richardson, Rudy J. and Albers, James W. and Matsunami, Nori and et al.}, year={2008}, month={Mar}, pages={780–785} }
 @article{schrenzel_maalouf_gaffney_tokarz_keener_mcclure_griffey_mcaloose_rideout_2005, title={Molecular characterization of isosporoid coccidia (Isospora and Atoxoplasma spp.) in passerine birds.}, volume={91}, ISSN={0022-3395 1937-2345}, url={http://dx.doi.org/10.1645/ge-3310}, DOI={10.1645/ge-3310}, abstractNote={Prevalence and disease caused by isosporoid coccidia in passerine birds are well recognized, but confusion about the life cycles of the parasites has led to taxonomic inconsistencies. In this study, we characterized segments of the chromosomal small and large-subunit ribosomal RNA (rRNA) genes of coccidial parasites from 23 species of passerine birds, as well as heat shock protein 70, apicoplast rRNA, and chromosomal 5.8s rRNA genes from a subgroup of these animals, and we correlated genetic data with morphologic findings for different parasite developmental stages, host phylogeny, and overall taxonomic relations within the phylum Apicomplexa. Our findings indicate that isosporoid coccidia of passerine birds are monophyletic but exhibit substantial diversity, with most avian species having one or several unique parasite lineages that underwent synchronous speciation with their hosts, interrupted by sporadic episodes of lateral transmission across species and families. Molecular analyses support a homoxenous life cycle, with sexual forms occurring chiefly in the intestines and asexual merozoites present systemically. Rarely, extraintestinal sexual stages can occur. The passerine coccidia are genetically most closely related to species of Eimeria rather than Isospora. We suggest that these parasites, whether identified from blood merozoite stages or fecal oocysts, be provisionally grouped as a homogeneous clade of individual species in a single taxon and formally named when reliable criteria allowing reclassification of related genera in the suborder Eimeriina are clarified.}, number={3}, journal={Journal of Parasitology}, publisher={American Society of Parasitologists}, author={Schrenzel, Mark D. and Maalouf, Gabriel A. and Gaffney, Patricia M. and Tokarz, Debra and Keener, Laura L. and McClure, Diane and Griffey, Stephen and McAloose, D. and Rideout, Bruce A.}, year={2005}, month={Jun}, pages={635–647} }
 @article{rainier_thomas_tokarz_ming_bui_plein_zhao_lemons_albin_delaney_et al._2004, title={Myofibrillogenesis Regulator 1 Gene Mutations Cause Paroxysmal Dystonic Choreoathetosis}, volume={61}, ISSN={0003-9942}, url={http://dx.doi.org/10.1001/archneur.61.7.1025}, DOI={10.1001/archneur.61.7.1025}, abstractNote={BACKGROUND
Paroxysmal dystonic choreoathetosis (PDC) is characterized by attacks of involuntary movements that occur spontaneously while at rest and following caffeine or alcohol consumption. Previously, we and others identified a locus for autosomal dominant PDC on chromosome 2q33-2q35.


OBJECTIVE
To identify the PDC gene.


DESIGN
Analysis of PDC positional candidate genes by exon sequencing and reverse transcription-polymerase chain reaction.


SETTING
Outpatient clinical and molecular genetic laboratory at a university hospital. Patients Affected (n = 12) and unaffected (n = 26) subjects from 2 unrelated families with PDC and 105 unrelated control subjects.


RESULTS
We identified missense mutations in the myofibrillogenesis regulator gene (MR-1) in affected subjects in 2 unrelated PDC kindreds. These mutations were absent in control subjects and caused substitutions of valine for alanine at amino acid positions 7 and 9. The substitutions disturb interspecies conserved residues and are predicted to alter the MR-1 gene's amino-terminal alpha helix. The MR-1 exon containing these mutations (exon 1) was expressed only in the brain, a finding that explains the brain-specific symptoms of subjects with these mutations.


CONCLUSIONS
Although MR-1 gene function is unknown, the precedence of ion channel disturbance in other episodic neurologic disorders suggests that the pathophysiologic features of PDC also involve abnormal ion localization. The discovery that MR-1 mutations underlie PDC provides opportunities to explore this condition's pathophysiologic characteristics and may provide insight into the causes of other paroxysmal neurologic disorders as well as the neurophysiologic mechanisms of alcohol and caffeine, which frequently precipitate PDC attacks.}, number={7}, journal={Archives of Neurology}, publisher={American Medical Association (AMA)}, author={Rainier, S. and Thomas, D. and Tokarz, D. and Ming, L. and Bui, M. and Plein, E. and Zhao, X. and Lemons, R. and Albin, R. and Delaney, C. and et al.}, year={2004}, month={Jul}, pages={1025–1029} }
 @article{rainier_chai_tokarz_nicholls_fink_2003, title={NIPA1 Gene Mutations Cause Autosomal Dominant Hereditary Spastic Paraplegia (SPG6)}, volume={73}, ISSN={0002-9297}, url={http://dx.doi.org/10.1086/378817}, DOI={10.1086/378817}, abstractNote={The hereditary spastic paraplegias (HSPs) are genetically heterogeneous disorders characterized by progressive lower-extremity weakness and spasticity. The molecular pathogenesis is poorly understood. We report discovery of a dominant negative mutation in the NIPA1 gene in a kindred with autosomal dominant HSP (ADHSP), linked to chromosome 15q11-q13 (SPG6 locus); and precisely the same mutation in an unrelated kindred with ADHSP that was too small for meaningful linkage analysis. NIPA1 is highly expressed in neuronal tissues and encodes a putative membrane transporter or receptor. Identification of the NIPA1 function and ligand will aid an understanding of axonal neurodegeneration in HSP and may have important therapeutic implications.}, number={4}, journal={The American Journal of Human Genetics}, publisher={Elsevier BV}, author={Rainier, Shirley and Chai, Jing-Hua and Tokarz, Debra and Nicholls, Robert D. and Fink, John K.}, year={2003}, month={Oct}, pages={967–971} }