24 results on '"Schmidt, Brian P."'
Search Results
2. SARS-CoV-2 infects neurons and induces neuroinflammation in a non-human primate model of COVID-19
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Beckman, Danielle, Bonillas, Alyssa, Diniz, Giovanne B, Ott, Sean, Roh, Jamin W, Elizaldi, Sonny R, Schmidt, Brian A, Sammak, Rebecca L, Van Rompay, Koen KA, Iyer, Smita S, and Morrison, John H
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Biological Sciences ,Infectious Diseases ,Coronaviruses ,Emerging Infectious Diseases ,Lung ,Neurosciences ,Brain Disorders ,Neurological ,Good Health and Well Being ,Animals ,SARS-CoV-2 ,COVID-19 ,Neuroinflammatory Diseases ,Nervous System Diseases ,Neurons ,Primates ,CP: Microbiology ,CP: Neuroscience ,NHP ,astrocytes ,coronavirus ,macaque ,microglia ,neurotropism ,rhesus ,neuroinflammation ,high-resolution microscopy ,Biochemistry and Cell Biology ,Medical Physiology ,Biological sciences - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), can induce a plethora of neurological complications in some patients. However, it is still under debate whether SARS-CoV-2 directly infects the brain or whether CNS sequelae result from systemic inflammatory responses triggered in the periphery. By using high-resolution microscopy, we investigated whether SARS-CoV-2 reaches the brain and how viral neurotropism can be modulated by aging in a non-human primate model of COVID-19. Seven days after infection, SARS-CoV-2 was detected in the olfactory cortex and interconnected regions and was accompanied by robust neuroinflammation and neuronal damage exacerbated in aged, diabetic animals. Our study provides an initial framework for identifying the molecular and cellular mechanisms underlying SARS-CoV-2 neurological complications, which will be essential to reducing both the short- and long-term burden of COVID-19.
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- 2022
3. Rendering Spatial Sound for Interoperable Experiences in the Audio Metaverse
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Jot, Jean-Marc, Audfray, Rémi, Hertensteiner, Mark, and Schmidt, Brian
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Computer Science - Sound ,Electrical Engineering and Systems Science - Audio and Speech Processing - Abstract
Interactive audio spatialization technology previously developed for video game authoring and rendering has evolved into an essential component of platforms enabling shared immersive virtual experiences for future co-presence, remote collaboration and entertainment applications. New wearable virtual and augmented reality displays employ real-time binaural audio computing engines rendering multiple digital objects and supporting the free navigation of networked participants or their avatars through a juxtaposition of environments, real and virtual, often referred to as the Metaverse. These applications require a parametric audio scene programming interface to facilitate the creation and deployment of shared, dynamic and realistic virtual 3D worlds on mobile computing platforms and remote servers. We propose a practical approach for designing parametric 6-degree-of-freedom object-based interactive audio engines to deliver the perceptually relevant binaural cues necessary for audio/visual and virtual/real congruence in Metaverse experiences. We address the effects of room reverberation, acoustic reflectors, and obstacles in both the virtual and real environments, and discuss how such effects may be driven by combinations of pre-computed and real-time acoustic propagation solvers. We envision an open scene description model distilled to facilitate the development of interoperable applications distributed across multiple platforms, where each audio object represents, to the user, a natural sound source having controllable distance, size, orientation, and acoustic radiation properties., Comment: International Conference on Immersive and 3D Audio (i3DA), September 2021
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- 2021
4. Mice expressing fluorescent PAR2 reveal that endocytosis mediates colonic inflammation and pain
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Latorre, Rocco, Hegron, Alan, Peach, Chloe J, Teng, Shavonne, Tonello, Raquel, Retamal, Jeffri S, Klein-Cloud, Rafael, Bok, Diana, Jensen, Dane D, Gottesman-Katz, Lena, Rientjes, Jeanette, Veldhuis, Nicholas A, Poole, Daniel P, Thomsen, Alex RB, Schmidt, Brian L, Pothoulakis, Charalabos H, Rankin, Carl, Xie, Ying, Koon, Wai, and Bunnett, Nigel W
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Digestive Diseases ,Biotechnology ,Pain Research ,Chronic Pain ,Neurosciences ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Arrestins ,Cell Membrane ,Colon ,Endocytosis ,Endosomes ,Female ,Fluorescent Dyes ,Ganglia ,Spinal ,Humans ,Inflammation ,Mice ,Mice ,Inbred C57BL ,Nociception ,Pain ,Receptor ,PAR-2 ,Signal Transduction ,signaling ,receptors ,proteases ,endocytosis ,inflammation - Abstract
G protein-coupled receptors (GPCRs) regulate many pathophysiological processes and are major therapeutic targets. The impact of disease on the subcellular distribution and function of GPCRs is poorly understood. We investigated trafficking and signaling of protease-activated receptor 2 (PAR2) in colitis. To localize PAR2 and assess redistribution during disease, we generated knockin mice expressing PAR2 fused to monomeric ultrastable green fluorescent protein (muGFP). PAR2-muGFP signaled and trafficked normally. PAR2 messenger RNA was detected at similar levels in Par2-mugfp and wild-type mice. Immunostaining with a GFP antibody and RNAScope in situ hybridization using F2rl1 (PAR2) and Gfp probes revealed that PAR2-muGFP was expressed in epithelial cells of the small and large intestine and in subsets of enteric and dorsal root ganglia neurons. In healthy mice, PAR2-muGFP was prominently localized to the basolateral membrane of colonocytes. In mice with colitis, PAR2-muGFP was depleted from the plasma membrane of colonocytes and redistributed to early endosomes, consistent with generation of proinflammatory proteases that activate PAR2 PAR2 agonists stimulated endocytosis of PAR2 and recruitment of Gαq, Gαi, and β-arrestin to early endosomes of T84 colon carcinoma cells. PAR2 agonists increased paracellular permeability of colonic epithelial cells, induced colonic inflammation and hyperalgesia in mice, and stimulated proinflammatory cytokine release from segments of human colon. Knockdown of dynamin-2 (Dnm2), the major colonocyte isoform, and Dnm inhibition attenuated PAR2 endocytosis, signaling complex assembly and colonic inflammation and hyperalgesia. Thus, PAR2 endocytosis sustains protease-evoked inflammation and nociception and PAR2 in endosomes is a potential therapeutic target for colitis.
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- 2022
5. Early post-infection treatment of SARS-CoV-2 infected macaques with human convalescent plasma with high neutralizing activity had no antiviral effects but moderately reduced lung inflammation
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Van Rompay, Koen KA, Olstad, Katherine J, Sammak, Rebecca L, Dutra, Joseph, Watanabe, Jennifer K, Usachenko, Jodie L, Immareddy, Ramya, Roh, Jamin W, Verma, Anil, Lakshmanappa, Yashavanth Shaan, Schmidt, Brian A, Di Germanio, Clara, Rizvi, Nabeela, Liu, Hongwei, Ma, Zhong-Min, Stone, Mars, Simmons, Graham, Dumont, Larry J, Allen, A Mark, Lockwood, Sarah, Pollard, Rachel E, de Assis, Rafael Ramiro, Yee, JoAnn L, Nham, Peter B, Ardeshir, Amir, Deere, Jesse D, Jain, Aarti, Felgner, Philip L, Coffey, Lark L, Iyer, Smita S, Hartigan-O’Connor, Dennis J, Busch, Michael P, and Reader, J Rachel
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Pneumonia & Influenza ,Infectious Diseases ,Coronaviruses Therapeutics and Interventions ,Immunization ,Emerging Infectious Diseases ,Coronaviruses ,Lung ,Infection ,Good Health and Well Being ,Animals ,Antibodies ,Neutralizing ,Antiviral Agents ,COVID-19 ,Humans ,Immunization ,Passive ,Macaca mulatta ,RNA ,Viral ,SARS-CoV-2 ,COVID-19 Serotherapy ,Microbiology ,Virology ,Medical microbiology - Abstract
Early in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable but low levels of antiviral antibodies after infusion. In comparison to the control animals, CCP-treated animals had similar levels of viral RNA in upper and lower respiratory tract secretions, similar detection of viral RNA in lung tissues by in situ hybridization, but lower amounts of infectious virus in the lungs. CCP-treated animals had a moderate, but statistically significant reduction in interstitial pneumonia, as measured by comprehensive lung histology. Thus overall, therapeutic benefits of CCP were marginal and inferior to results obtained earlier with monoclonal antibodies in this animal model. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses.
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- 2022
6. SARS-CoV-2 Infection of Rhesus Macaques Treated Early with Human COVID-19 Convalescent Plasma
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Deere, Jesse D, Carroll, Timothy D, Dutra, Joseph, Fritts, Linda, Sammak, Rebecca Lee, Yee, JoAnn L, Olstad, Katherine J, Reader, J Rachel, Kistler, Amy, Kamm, Jack, Di Germanio, Clara, Lakshmanappa, Yashavanth Shaan, Elizaldi, Sonny R, Roh, Jamin W, Simmons, Graham, Watanabe, Jennifer, Pollard, Rachel E, Usachenko, Jodie, Immareddy, Ramya, Schmidt, Brian A, O’Connor, Shelby L, DeRisi, Joseph, Busch, Michael P, Iyer, Smita S, Van Rompay, Koen KA, Hartigan-O’Connor, Dennis J, and Miller, Christopher J
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Microbiology ,Biological Sciences ,Coronaviruses Therapeutics and Interventions ,Coronaviruses ,Lung ,Vaccine Related ,Immunization ,Emerging Infectious Diseases ,Infectious Diseases ,Infection ,Good Health and Well Being ,Animals ,Antibodies ,Neutralizing ,Antibodies ,Viral ,Antiviral Agents ,COVID-19 ,Disease Models ,Animal ,Humans ,Immunity ,Immunization ,Passive ,Macaca mulatta ,Pandemics ,SARS-CoV-2 ,Spike Glycoprotein ,Coronavirus ,Viral Load ,Virus Replication ,convalescent plasma ,passive immunization ,nonhuman primate ,animal models of infectious diseases ,microbial pathogenesis ,virology - Abstract
Human clinical studies investigating use of convalescent plasma (CP) for treatment of coronavirus disease 2019 (COVID-19) have produced conflicting results. Outcomes in these studies may vary at least partly due to different timing of CP administration relative to symptom onset. The mechanisms of action of CP include neutralizing antibodies but may extend beyond virus neutralization to include normalization of blood clotting and dampening of inflammation. Unresolved questions include the minimum therapeutic titer in the CP units or CP recipient as well as the optimal timing of administration. Here, we show that treatment of macaques with CP within 24 h of infection does not reduce viral shedding in nasal or lung secretions compared to controls and does not detectably improve any clinical endpoint. We also demonstrate that CP administration does not impact viral sequence diversity in vivo, although the selection of a viral sequence variant in both macaques receiving normal human plasma was suggestive of immune pressure. Our results suggest that CP, administered to medium titers, has limited efficacy, even when given very early after infection. Our findings also contribute information important for the continued development of the nonhuman primate model of COVID-19. These results should inform interpretation of clinical studies of CP in addition to providing insights useful for developing other passive immunotherapies and vaccine strategies. IMPORTANCE Antiviral treatment options for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain very limited. One treatment that was explored beginning early in the pandemic (and that is likely to be tested early in future pandemics) is plasma collected from people who have recovered from coronavirus disease 2019 (COVID-19), known as convalescent plasma (CP). We tested if CP reduces viral shedding or disease in a nonhuman primate model. Our results demonstrate that administration of CP 1 day after SARS-CoV-2 infection had no significant impact on viral loads, clinical disease, or sequence diversity, although treatment with normal human plasma resulted in selection of a specific viral variant. Our results demonstrate that passive immunization with CP, even during early infection, provided no significant benefit in a nonhuman primate model of SARS-CoV-2 infection.
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- 2021
7. Monoclonal antibodies protect aged rhesus macaques from SARS-CoV-2-induced immune activation and neuroinflammation.
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Verma, Anil, Hawes, Chase E, Lakshmanappa, Yashavanth Shaan, Roh, Jamin W, Schmidt, Brian A, Dutra, Joseph, Louie, William, Liu, Hongwei, Ma, Zhong-Min, Watanabe, Jennifer K, Usachenko, Jodie L, Immareddy, Ramya, Sammak, Rebecca L, Pollard, Rachel, Reader, J Rachel, Olstad, Katherine J, Coffey, Lark L, Kozlowski, Pamela A, Hartigan-O'Connor, Dennis J, Nussenzweig, Michel, Van Rompay, Koen KA, Morrison, John H, and Iyer, Smita S
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NeuroCOVID ,inflammation ,SARS-CoV-2 ,cerebrospinal fluid ,effector CD4 T cells ,interstitial pneumonia ,lymph node ,neuroinflammation ,pathogenesis ,rhesus macaques ,Aging ,Animals ,Antibodies ,Monoclonal ,COVID-19 ,Diabetes Complications ,Diabetes Mellitus ,Experimental ,Female ,Humans ,Lymphocyte Activation ,Macaca mulatta ,Male ,Neuritis ,Pre-Exposure Prophylaxis ,T-Lymphocytes ,Virus Replication ,Prevention ,Biodefense ,Infectious Diseases ,Pneumonia ,Immunization ,Biotechnology ,Pneumonia & Influenza ,Emerging Infectious Diseases ,Lung ,Diabetes ,Vaccine Related ,receptor binding domain ,aged ,type 2 diabetic ,neutrophils ,mucosal-associated invariant T cells ,Biochemistry and Cell Biology ,Medical Physiology - Abstract
Anti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from coronavirus disease 2019 (COVID-19) in high-risk populations, such as people with diabetes and the elderly; however, data on their efficacy in these populations are limited. We demonstrate that prophylactic mAb treatment blocks viral replication in both the upper and lower respiratory tracts in aged, type 2 diabetic rhesus macaques. mAb infusion dramatically curtails severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing development of interstitial pneumonia. Furthermore, mAb infusion significantly dampens the greater than 3-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data show that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.
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- 2021
8. Oral health-related quality of life after radiation therapy for head and neck cancer: the OraRad study
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Patton, Lauren L., Helgeson, Erika S., Brennan, Michael T., Treister, Nathaniel S., Sollecito, Thomas P., Schmidt, Brian L., Lin, Alexander, Chera, Bhishamjit S., and Lalla, Rajesh V.
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- 2023
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9. Review of applications and challenges of quantitative systems pharmacology modeling and machine learning for heart failure
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Cheng, Limei, Qiu, Yuchi, Schmidt, Brian J., and Wei, Guo-Wei
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- 2022
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10. Oral cancer induced TRPV1 sensitization is mediated by PAR2 signaling in primary afferent neurons innervating the cancer microenvironment
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Scheff, Nicole N., Wall, Ian M., Nicholson, Sam, Williams, Hannah, Chen, Elyssa, Tu, Nguyen H., Dolan, John C., Liu, Cheng Z., Janal, Malvin N., Bunnett, Nigel W., and Schmidt, Brian L.
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- 2022
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11. Oral cancer patients experience mechanical and chemical sensitivity at the site of the cancer
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Sawicki, Caroline M., Janal, Malvin N., Nicholson, Samuel J., Wu, Angie K., Schmidt, Brian L., and Albertson, Donna G.
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- 2022
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12. Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice
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De Logu, Francesco, Nassini, Romina, Hegron, Alan, Landini, Lorenzo, Jensen, Dane D., Latorre, Rocco, Ding, Julia, Marini, Matilde, Souza Monteiro de Araujo, Daniel, Ramírez-Garcia, Paulina, Whittaker, Michael, Retamal, Jeffri, Titiz, Mustafa, Innocenti, Alessandro, Davis, Thomas P., Veldhuis, Nicholas, Schmidt, Brian L., Bunnett, Nigel W., and Geppetti, Pierangelo
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- 2022
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13. SARS-CoV-2 induces robust germinal center CD4 T follicular helper cell responses in rhesus macaques
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Shaan Lakshmanappa, Yashavanth, Elizaldi, Sonny R., Roh, Jamin W., Schmidt, Brian A., Carroll, Timothy D., Weaver, Kourtney D., Smith, Justin C., Verma, Anil, Deere, Jesse D., Dutra, Joseph, Stone, Mars, Franz, Sergej, Sammak, Rebecca Lee, Olstad, Katherine J., Rachel Reader, J., Ma, Zhong-Min, Nguyen, Nancy K., Watanabe, Jennifer, Usachenko, Jodie, Immareddy, Ramya, Yee, JoAnn L., Weiskopf, Daniela, Sette, Alessandro, Hartigan-O’Connor, Dennis, McSorley, Stephen J., Morrison, John H., Tran, Nam K., Simmons, Graham, Busch, Michael P., Kozlowski, Pamela A., Van Rompay, Koen K. A., Miller, Christopher J., and Iyer, Smita S.
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- 2021
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14. Reduced mouth opening in patients with head and neck cancer treated with radiation therapy: an analysis of the Clinical Registry of Dental Outcomes in Head and Neck Cancer Patients (OraRad).
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Sollecito, Thomas P., Helgeson, Erika S., Lalla, Rajesh V., Treister, Nathaniel S., Schmidt, Brian L., Patton, Lauren L., Lin, Alexander, and Brennan, Michael T.
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Trismus/reduced mouth opening (RMO) is a common side effect of radiotherapy (RT) for head and neck cancer (HNC). The objective was to measure RMO, identify risk factors for RMO, and determine its impact on quality of life (QOL). OraRad is an observational, prospective, multicenter cohort study of patients receiving curative intent RT for HNC. Interincisal mouth opening measurements (n = 565) and patient-reported outcomes were recorded before RT and every 6 months for 2 years. Linear mixed-effects models were used to evaluate change in mouth opening and assess the relationship between trismus history and change in QOL measures. Interincisal distance decreased from a mean (SE) of 45.1 (0.42) mm at baseline to 42.2 (0.44) at 6 months, with slight recovery at 18 months (43.3, 0.46 mm) but no additional improvement by 24 months. The odds of trismus (opening <35 mm) were significantly higher at 6 months (odds ratio [OR] = 2.21, 95% CI: 1.30 to 3.76) and 12 months (OR = 1.87, 95% CI: 1.08 to 3.25) compared with baseline. Females were more likely to experience trismus at baseline and during follow-up (P <.01). Patients with oral cavity cancer had the highest risk for trismus at baseline and post-RT (P <.01). RMO was associated with higher RT dose to the primary site and receiving concomitant chemotherapy (P <.01). Trismus was associated with self-reported difficulty opening the mouth and dry mouth (P <.01). A decrease in mouth opening is a common treatment-related toxicity after RT, with some recovery by 18 months. Trismus has a significant impact on survivor QOL. [ABSTRACT FROM AUTHOR]
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- 2024
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15. The interactive performance of SLIM
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Schmidt, Brian K., Lam, Monica S., and Northcutt, J. Duane
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- 2024
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16. Radiation therapy for head and neck cancer leads to gingival recession associated with dental caries.
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Lalla, Rajesh V., Treister, Nathaniel S., Sollecito, Thomas P., Schmidt, Brian L., Patton, Lauren L., Helgeson, Erika S., Lin, Alexander, Rybczyk, Cynthia, Dowsett, Robert, Hegde, Upendra, Boyd, Timothy S., Duplinsky, Thomas G., and Brennan, Michael T.
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Objective: The aim of this study was to examine effects of radiation therapy (RT) for head and neck cancer (HNC) on periodontal disease and relationships to caries.Study Design: A multicenter prospective observational cohort study (OraRad) was conducted in patients undergoing RT for HNC. Assessments were conducted by calibrated examiners at the pre-RT (baseline) visit (n = 533), the 12-month visit (n = 414), and the 24-month visit (n = 365).Results: The average whole mouth mean (standard error (SE)) distance from the cementoenamel junction to the gingival margin (CEJ-GM) decreased significantly from 0.43 (0.04) mm at baseline to 0.24 (0.04) mm at 12 months and 0.11 (0.04) mm at 24 months (P ≤ .001). Whole mouth mean (SE) percentage of sites with CEJ-GM distance of <0 mm increased significantly from 23.3% (1.0%) at baseline to 28.5% (1.0%) at 12 months and 30.5% (1.1%) at 24 months (P ≤ .02). Higher mean radiation dose to the mandible was associated with a greater increase in the percentage of mandibular sites with CEJ-GM distance of <0 mm (P = .003). Both mean CEJ-GM distance and the percentage of sites with a CEJ-GM distance <0 mm were strongly associated with whole mouth mean proportion of decayed, missing, and filled surfaces, as well as proportion of decayed or filled facial/buccal surfaces specifically, (P < .001), with greater gingival recession associated with increased caries.Conclusions: RT for HNC leads to mandibular gingival recession in a dose-dependent manner. This gingival recession may contribute to increased risk for cervical caries seen in these patients. [ABSTRACT FROM AUTHOR]- Published
- 2022
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17. Angler Choices That Help Catch Lots of Big Fish
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Bade, Andrew P., Dippold, David A., Schmidt, Brian A., DuFour, Mark R., Hartman, Travis J., and Ludsin, Stuart A.
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A primary goal of fisheries management is to maximize angler satisfaction (e.g., by catching more and bigger fish), while maintaining sustainable populations. In addition to environmental and ecological factors, angler choices may influence recreational catches. Using interviews (92,838) from Walleye Sander vitreusanglers in Lake Erie during 1989–2017, we identified how angler behavior influences catch outcomes. Angler behaviors were associated with changes in catch rate and the length of harvested fish. For example, trolling resulted in a 50% increase in median catch and a 24‐mm increase in length, relative to casting. Other behaviors led to tradeoffs between catch rate and size, such as the time of year anglers fished. We identified behaviors that maximize fishing success with respect to anglers’ desired catch outcomes. Our results can help increase angler satisfaction by providing realistic catch expectations, given the environmental and fishery conditions, while improving recreational catch outcomes through more informed angler decision making.
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- 2022
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18. Factors associated with oral hygiene compliance in patients treated with radiation therapy for head and neck cancer
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Lim, Jiwon, Helgeson, Erika S., Lalla, Rajesh V., Sollecito, Thomas P., Treister, Nathaniel S., Schmidt, Brian L., Patton, Lauren L., Lin, Alexander, Milas, Zvonimir, and Brennan, Michael T.
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Patients who are oral hygiene noncompliant (OHNC) are more likely to lose teeth after radiation therapy (RT) for head and neck cancer (HNC), which increases the risk of developing osteoradionecrosis. A previous study revealed that patients who were OHNC at baseline (BL) who became oral hygiene compliant during follow-up had the best tooth-failure outcomes. The purpose of this study was to identify factors associated with oral hygiene compliance (OHC), overall, and among those who were BL OHNC.
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- 2024
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19. Agonist that activates the µ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects
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Jiménez-Vargas, Nestor Nivardo, Yu, Yang, Jensen, Dane D, Bok, Diana Daeun, Wisdom, Matthew, Latorre, Rocco, Lopez, Cintya, Jaramillo-Polanco, Josue O, Degro, Claudius, Guzman-Rodriguez, Mabel, Tsang, Quentin, Snow, Zachary, Schmidt, Brian L, Reed, David E, Lomax, Alan Edward, Margolis, Kara Gross, Stein, Christoph, Bunnett, Nigel W, and Vanner, Stephen J
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ObjectiveThe effectiveness of µ-opioid receptor (MOPr) agonists for treatment of visceral pain is compromised by constipation, respiratory depression, sedation and addiction. We investigated whether a fentanyl analogue, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), which preferentially activates MOPr in acidified diseased tissues, would inhibit pain in a preclinical model of inflammatory bowel disease (IBD) without side effects in healthy tissues.DesignAntinociceptive actions of NFEPP and fentanyl were compared in control mice and mice with dextran sodium sulfate colitis by measuring visceromotor responses to colorectal distension. Patch clamp and extracellular recordings were used to assess nociceptor activation. Defecation, respiration and locomotion were assessed. Colonic migrating motor complexes were assessed by spatiotemporal mapping of isolated tissue. NFEPP-induced MOPr signalling and trafficking were studied in human embryonic kidney 293 cells.ResultsNFEPP inhibited visceromotor responses to colorectal distension in mice with colitis but not in control mice, consistent with acidification of the inflamed colon. Fentanyl inhibited responses in both groups. NFEPP inhibited the excitability of dorsal root ganglion neurons and suppressed mechanical sensitivity of colonic afferent fibres in acidified but not physiological conditions. Whereas fentanyl decreased defecation and caused respiratory depression and hyperactivity in mice with colitis, NFEPP was devoid of these effects. NFEPP did not affect colonic migrating motor complexes at physiological pH. NFEPP preferentially activated MOPr in acidified extracellular conditions to inhibit cAMP formation, recruit β-arrestins and evoke MOPr endocytosis.ConclusionIn a preclinical IBD model, NFEPP preferentially activates MOPr in acidified microenvironments of inflamed tissues to induce antinociception without causing respiratory depression, constipation and hyperactivity.
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- 2022
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20. Expanded microbiome niches of RAG-deficient patients
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Blaustein, Ryan A., Shen, Zeyang, Kashaf, Sara Saheb, Lee-Lin, ShihQueen, Conlan, Sean, Thomas, Jim, Mullikin, James, Young, Alice, Bouffard, Gerry, Barnabas, Betty, Brooks, Shelise, Buchter, Chloe, Crawford, Juyun, Han, Joel, Ho, Shi-ling, Legaspi, Richelle, Maduro, Quino, Marfani, Holly, Montemayor, Casandra, Schandler, Karen, Schmidt, Brian, Sison, Christina, Stantripop, Mal, Black, Sean, Dekhtyar, Mila, Masiello, Cathy, McDowell, Jenny, Park, Morgan, Thomas, Pam, Vemulapalli, Meg, Bosticardo, Marita, Delmonte, Ottavia M., Holmes, Cassandra J., Taylor, Monica E., Banania, Glenna, Nagao, Keisuke, Dimitrova, Dimana, Kanakry, Jennifer A., Su, Helen, Holland, Steven M., Bergerson, Jenna R.E., Freeman, Alexandra F., Notarangelo, Luigi D., Kong, Heidi H., and Segre, Julia A.
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The complex interplay between microbiota and immunity is important to human health. To explore how altered adaptive immunity influences the microbiome, we characterize skin, nares, and gut microbiota of patients with recombination-activating gene (RAG) deficiency—a rare genetically defined inborn error of immunity (IEI) that results in a broad spectrum of clinical phenotypes. Integrating de novoassembly of metagenomes from RAG-deficient patients with reference genome catalogs provides an expansive multi-kingdom view of microbial diversity. RAG-deficient patient microbiomes exhibit inter-individual variation, including expansion of opportunistic pathogens (e.g., Corynebacterium bovis, Haemophilus influenzae), and a relative loss of body site specificity. We identify 35 and 27 bacterial species derived from skin/nares and gut microbiomes, respectively, which are distinct to RAG-deficient patients compared to healthy individuals. Underscoring IEI patients as potential reservoirs for viral persistence and evolution, we further characterize the colonization of eukaryotic RNA viruses (e.g., Coronavirus 229E, Norovirus GII) in this patient population.
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- 2023
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21. Letter to the Editor Regarding "Evaluation of Proposed Protocol Changing Statistical Significance From 0.05 to 0.005 in Foot and Ankle Randomized Controlled Trials".
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O'Dell, Brennen L., Rothenberg, Gary M., and Schmidt, Brian M.
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- 2023
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22. Tooth-level predictors of tooth loss and exposed bone after radiation therapy for head and neck cancer
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Lalla, Rajesh V., Hodges, James S., Treister, Nathaniel S., Sollecito, Thomas P., Schmidt, Brian L., Patton, Lauren L., Lin, Alexander, and Brennan, Michael T.
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The objective of this study was to identify tooth-level risk factors for use during preradiation dental care management to predict risk of tooth failure (tooth lost or declared hopeless) and exposed bone after radiation therapy (RT) for head and neck cancer (HNC).
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- 2023
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23. Tackling diabetic foot: limb salvage during the COVID-19 pandemic
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Schmidt, Brian M. and Shin, Laura
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Purpose: Lower extremity amputation resulting from diabetic foot ulcer, with neuropathic and/or ischemic etiologies, remains a devastating and costly complication of diabetes mellitus. This study evaluated changes in care delivery of diabetic foot ulcer patients during the COVID-19 pandemic. A longitudinal assessment evaluating the ratio of major lower extremity amputation to minor lower extremity amputations after implementation of novel strategies to combat access restrictions was compared to the pre-COVID-19 era.Methods: The ratio of major to minor lower extremity amputation (i.e. the high-to-low ratio) was assessed at two academic institutions, the University of Michigan, and University of Southern California, in a population of patients with diabetes who had direct access to multidisciplinary foot care clinics in the 2 years prior to the pandemic and the first 2 years of the COVID-19 pandemic.Results: Patient characteristics and volumes including patients with diabetes and those with a diabetic foot ulcer were similar between eras. In addition, inpatient diabetic foot-related admissions were similar, but were suppressed by government shelter in placed mandates and subsequent COVID-19 variants surges (e.g. delta, omicron). In the control group, the Hi-Lo ratio increased every 6 months by an average of 11.8%. Meanwhile, following STRIDE implementation during the pandemic, the Hi-Lo ratio reduced by (−)11% (p< 0.001) and doubled limb salvage efforts as compared to the baseline era. The reduction of the Hi-Lo ratio was not influenced significant by patient volumes or inpatient admissions for foot infections.Conclusion: These findings signify the importance of podiatric care in the at-risk diabetic foot population. Through strategic planning and rapid implementation of at-risk diabetic foot ulcer triage, multidisciplinary teams were able to maintain accessible care during the pandemic which resulted in a reduction of amputations. Furthermore, this manuscript highlights the value of the Hi-Lo ratio as an indicator of institutional limb salvage efforts.
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- 2023
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24. Exposure to crop production alters cecal prokaryotic microbiota, inflates virulome and resistome in wild prairie grouse.
- Author
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Drovetski, Serguei V., Schmidt, Brian K., Lai, Jonas E., Gross, Michael S., Hladik, Michelle L., Matterson, Kenan O., and Karouna-Renier, Natalie K.
- Subjects
AGRICULTURAL productivity ,GROUSE ,GUT microbiome ,WILDLIFE resources ,PRAIRIES ,EMERGING infectious diseases - Abstract
Chemically intensive crop production depletes wildlife food resources, hinders animal development, health, survival, and reproduction, and it suppresses wildlife immune systems, facilitating emergence of infectious diseases with excessive mortality rates. Gut microbiota is crucial for wildlife's response to environmental stressors. Its composition and functionality are sensitive to diet changes and environmental pollution associated with modern crop production. In this study we use shotgun metagenomics (median 8,326,092 sequences/sample) to demonstrate that exposure to modern crop production detrimentally affects cecal microbiota of sharp-tailed grouse (Tympanuchus phasianellus : 9 exposed, 18 unexposed and greater prairie chickens (T. cupido ; 11, 11). Exposure to crop production had greater effect on microbiota richness (t = 6.675, P < 0.001) and composition (PERMANOVA r
2 = 0.212, P = 0.001) than did the host species (t = 4.762, P < 0.001; r2 = 0.070, P = 0.001) or their interaction (t = 3.449; r2 = 0.072, both P = 0.001), whereas sex and age had no effect. Although microbiota richness was greater in exposed (T. cupido chao1 = 152.8 ± 20.5; T. phasianellus 115.3 ± 17.1) than in unexposed (102.9 ± 15.1 and 101.1 ± 17.2, respectively) birds, some beneficial bacteria dropped out of exposed birds' microbiota or declined and were replaced by potential pathogens. Exposed birds also had higher richness and load of virulome (mean ± standard deviation; T. cupido 24.8 ± 10.0 and 10.1 ± 5.5, respectively; T. phasianellus 13.4 ± 6.8/4.9 ± 2.8) and resistome (T. cupido 46.8 ± 11.7/28.9 ± 10.2, T. phasianellus 38.3 ± 16.7/18.9 ± 14.2) than unexposed birds (T. cupido virulome: 14.2 ± 13.5, 4.5 ± 4.2; T. cupido resistome: 31.6 ± 20.2 and 13.1 ± 12.0; T. phasianellus virulome: 5.2 ± 4.7 and 1.4 ± 1.5; T. phasianellus resistome: 13.7 ± 16.1 and 4.0 ± 6.4). [Display omitted] • Cropland grouse exhibit dysbiosis and elevated virulence and antibiotic resistance. • Crop production similarly affects microbiota in both study species. • Crop production affects microbiota to a greater extent than host species. • Naturally distinct microbiotas of study species converge in croplands. • Sex or age of grouse do not affect cecal microbiota, virulome, or resistome. [ABSTRACT FROM AUTHOR]- Published
- 2022
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