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2. An oral form of methylglyoxal-bis-guanylhydrazone reduces monocyte activation and traffic to the dorsal root ganglia in a primate model of HIV-peripheral neuropathy

Author

Lakritz, Jessica R, Yalamanchili, Samshita, Polydefkis, Michael J, Miller, Andrew D, McGrath, Michael S, Williams, Kenneth C, and Burdo, Tricia H

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Infectious Diseases, Neurodegenerative, Pain Research, Chronic Pain, Neurosciences, HIV/AIDS, Peripheral Neuropathy, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Aetiology, Infection, Administration, Oral, Animals, CD8-Positive T-Lymphocytes, Cell Movement, DNA, Viral, Enzyme Inhibitors, Ganglia, Spinal, HIV Core Protein p24, Lymphocyte Depletion, Macaca mulatta, Macrophages, Male, Mitoguazone, Monocytes, Nerve Fibers, Peripheral Nervous System Diseases, Polyamines, Simian Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus, HIV, Rhesus, Peripheral neuropathy, Dorsal root ganglia, Monocyte, Polyamine biosynthesis inhibitor, Simian immunodeficiency virus, Virology, Clinical sciences, Medical microbiology
Abstract

Peripheral neuropathy (PN) is a major comorbidity of HIV infection that is caused in part by chronic immune activation. HIV-PN is associated with infiltration of monocytes/macrophages to the dorsal root ganglia (DRG) causing neuronal loss and formation of Nageotte nodules. Here, we used an oral form of methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine biosynthesis inhibitor, to specifically reduce activation of myeloid cells. MGBG is selectively taken up by monocyte/macrophages in vitro and inhibits HIV p24 expression and DNA viral integration in macrophages. Here, MGBG was administered to nine SIV-infected, CD8-depleted rhesus macaques at 21 days post-infection (dpi). An additional nine SIV-infected, CD8-depleted rhesus macaques were used as untreated controls. Cell traffic to tissues was measured by in vivo BrdU pulse labeling. MGBG treatment significantly diminished DRG histopathology and reduced the number of CD68+ and CD163+ macrophages in DRG tissue. The number of recently trafficked BrdU+ cells in the DRG was significantly reduced with MGBG treatment. Despite diminished DRG pathology, intraepidermal nerve fiber density (IENFD) did not recover after treatment with MGBG. These data suggest that MGBG alleviated DRG pathology and inflammation.

Published
2017

3. Pain Hypersensitivity in SLURP1 and SLURP2 Knock-out Mouse Models of Hereditary Palmoplantar Keratoderma.

Author

Weinberg, Rachel L., Suyeon Kim, Zixuan Pang, Awad, Sandy, Hanback, Tyger, Baohan Pan, Bettin, Leonie, Chang, Dennis, Polydefkis, Michael J., Lintao Qu, and Caterina, Michael J.

Subjects
KNOCKOUT mice, PALMOPLANTAR keratoderma, LABORATORY mice, ECTODERMAL dysplasia, ALLERGIES, DYSPLASIA, SKIN
Abstract

SLURP1 and SLURP2 are both small secreted members of the Ly6/u-PAR family of proteins and are highly expressed in keratinocytes. Loss-of-function mutations in SLURP1 lead to a rare autosomal recessive palmoplantar keratoderma (PPK), Mal de Meleda (MdM), which is characterized by diffuse, yellowish palmoplantar hyperkeratosis. Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin. By comparison, other hereditary PPKs such as pachyonychia congenita and Olmsted syndrome show prevalent pain in PPK lesions. Two mouse models of MdM, Slurp1 knock-out and Slurp2X knock-out, exhibit robust PPK in all four paws. However, whether the sensory experience of these animals includes augmented pain sensitivity remains unexplored. In this study, we demonstrate that both models exhibit hypersensitivity to mechanical and thermal stimuli as well as spontaneous pain behaviors in males and females. Anatomical analysis revealed slightly reduced glabrous skin epidermal innervation and substantial alterations in palmoplantar skin immune composition in Slurp2X knock-out mice. Primary sensory neurons innervating hindpaw glabrous skin from Slurp2X knock-out mice exhibit increased incidence of spontaneous activity and mechanical hypersensitivity both in vitro and in vivo. Thus, Slurp knock-out mice exhibit polymodal PPK-associated pain that is associated with both immune alterations and neuronal hyperexcitability and might therefore be useful for the identification of therapeutic targets to treat PPK-associated pain. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations

Author

Gewandter, Jennifer S., Dworkin, Robert H., Turk, Dennis C., Farrar, John T., Fillingim, Roger B., Gilron, Ian, Markman, John D., Oaklander, Anne Louise, Polydefkis, Michael J., Raja, Srinivasa N., Robinson, James P., Woolf, Clifford J., Ziegler, Dan, Ashburn, Michael A., Burke, Laurie B., Cowan, Penney, George, Steven Z., Goli, Veeraindar, Graff, Ole X., Iyengar, Smriti, Jay, Gary W., Katz, Joel, Kehlet, Henrik, Kitt, Rachel A., Kopecky, Ernest A., Malamut, Richard, McDermott, Michael P., Palmer, Pamela, Rappaport, Bob A., Rauschkolb, Christine, Steigerwald, Ilona, Tobias, Jeffrey, and Walco, Gary A.

Published
2021
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6. Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update

Author

Brannagan, Thomas H., Coelho, Teresa, Wang, Annabel K., Polydefkis, Michael J., Dyck, Peter J., Berk, John L., Drachman, Brian, Gorevic, Peter, Whelan, Carol, Conceição, isabel, Plante-Bordeneuve, Violaine, Merlini, Giampaolo, Obici, Laura, Plana, Josep Maria Campistol, Gamez, Josep, Kristen, Arnt V., Mazzeo, Anna, Gentile, Luca, Narayana, Arvind, Olugemo, Kemi, Aquino, Peter, Benson, Merrill D., Gertz, Morie, and Repositório da Universidade de Lisboa

Subjects
Peripheral neuropathies, Amyloid Neuropathies, Familial, Oligonucleotides, Hereditary transthyretin amyloidosis, Clinical trial, Polyneuropathies, Neurology, Familial amyloid polyneuropathy, Polyneuropathy, Quality of Life, Humans, Prealbumin, Neurology (clinical), Inotersen
Abstract

© The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/, Background: Hereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years. Methods: Patients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004. Results: In the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen-inotersen) and 39 switched from placebo to inotersen (placebo-inotersen). The placebo-inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen-inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo-inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study. Conclusion: Inotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.

Published
2022

7. Long-Term Update from the Open-Label Extension of the NEURO-TTR Study in Patients with Hereditary Transthyretin Amyloidosis

Author

Brannagan, Thomas, primary, Wang, Annabel K., additional, Coelho, Teresa, additional, Waddington Cruz, Marcia, additional, Polydefkis, Michael J., additional, Dyck, Peter J., additional, Plante-Bordeneuve, Violaine, additional, Berk, John L., additional, Barroso, Fabio, additional, Merlini, Giampaolo, additional, Conceição, Isabel, additional, Hughes, Steven G., additional, Kwoh, Jesse G., additional, Jung, Shiangtung W., additional, Guthrie, Spencer, additional, Pollock, Michael, additional, Benson, Merrill D., additional, and Gertz, Morie A., additional

Published
2018
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8. Research design considerations for chronic pain prevention clinical trials:IMMPACT recommendations

Author

Gewandter, Jennifer S, Dworkin, Robert H, Turk, Dennis C, Farrar, John T, Fillingim, Roger B, Gilron, Ian, Markman, John D, Oaklander, Anne Louise, Polydefkis, Michael J, Raja, Srinivasa N, Robinson, James P, Woolf, Clifford J, Ziegler, Dan, Ashburn, Michael A, Burke, Laurie B, Cowan, Penney, George, Steven Z, Goli, Veeraindar, Graff, Ole X, Iyengar, Smriti, Jay, Gary W, Katz, Joel, Kehlet, Henrik, Kitt, Rachel A, Kopecky, Ernest A, Malamut, Richard, McDermott, Michael P, Palmer, Pamela, Rappaport, Bob A, Rauschkolb, Christine, Steigerwald, Ilona, Tobias, Jeffrey, Walco, Gary A, Gewandter, Jennifer S, Dworkin, Robert H, Turk, Dennis C, Farrar, John T, Fillingim, Roger B, Gilron, Ian, Markman, John D, Oaklander, Anne Louise, Polydefkis, Michael J, Raja, Srinivasa N, Robinson, James P, Woolf, Clifford J, Ziegler, Dan, Ashburn, Michael A, Burke, Laurie B, Cowan, Penney, George, Steven Z, Goli, Veeraindar, Graff, Ole X, Iyengar, Smriti, Jay, Gary W, Katz, Joel, Kehlet, Henrik, Kitt, Rachel A, Kopecky, Ernest A, Malamut, Richard, McDermott, Michael P, Palmer, Pamela, Rappaport, Bob A, Rauschkolb, Christine, Steigerwald, Ilona, Tobias, Jeffrey, and Walco, Gary A

Abstract

Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials., Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

Published
2015

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