Donald Regula, MD

All Publications

• Mortui vivos docent: a modern revival of temporal bone plug harvests. Frontiers in neuroscience Sagi, V., Kosaraju, N., Moore, L. S., Mulders, J. Y., Solyali, M., Ma, X., Regula, D. P., Hooper, J. E., Stankovic, K. M. 2023; 17: 1242831

  Abstract

  Human temporal bones (HTBs) are invaluable resources for the study of otologic disorders and for evaluating novel treatment approaches. Given the high costs and technical expertise required to collect and process HTBs, there has been a decline in the number of otopathology laboratories. Our objective is to encourage ongoing study of HTBs by outlining the necessary steps to establish a pipeline for collection and processing of HTBs. In this methods manuscript, we: (1) provide the design of a temporal bone plug sawblade that can be used to collect specimens from autopsy donors; (2) establish that decalcification time can be dramatically reduced from 9 to 3months if ethylenediaminetetraacetic acid is combined with microwave tissue processing and periodic bone trimming; (3) show that serial sections of relatively-rapidly decalcified HTBs can be successfully immunostained for key inner ear proteins; (4) demonstrate how to drill down a HTB to the otic capsule within a few hours so that subsequent decalcification time can be further reduced to only weeks. We include photographs and videos to facilitate rapid dissemination of the developed methods. Collected HTBs can be used for many purposes, including, but not limited to device testing, imaging studies, education, histopathology, and molecular studies. As new technology develops, it is imperative to continue studying HTBs to further our understanding of the cellular and molecular underpinnings of otologic disorders.

  View details for DOI 10.3389/fnins.2023.1242831

  View details for PubMedID 37886674

• Biochemical, biophysical, and immunological characterization of respiratory secretions in severe SARS-CoV-2 infections. JCI insight Kratochvil, M. J., Kaber, G., Demirdjian, S., Cai, P. C., Burgener, E. B., Nagy, N., Barlow, G. L., Popescu, M., Nicolls, M. R., Ozawa, M. G., Regula, D. P., Pacheco-Navarro, A. E., Yang, S., de Jesus Perez, V. A., Karmouty-Quintana, H., Peters, A. M., Zhao, B., Buja, M. L., Johnson, P. Y., Vernon, R. B., Wight, T. N., Stanford COVID-19 Biobank Study Group, Milla, C. E., Rogers, A. J., Spakowitz, A. J., Heilshorn, S. C., Bollyky, P. L. 2022; 7 (12)

  Abstract

  Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e., resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We found the percentages of solids and protein content were greatly elevated in COVID-19 compared with heathy control samples and closely resembled levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) were major components of respiratory secretions in COVID-19 and were likewise abundant in cadaveric lung tissues from these patients. COVID-19 secretions exhibited heterogeneous rheological behaviors, with thicker samples showing increased sensitivity to DNase and hyaluronidase treatment. In histologic sections from these same patients, we observed increased accumulation of HA and the hyaladherin versican but reduced tumor necrosis factor-stimulated gene-6 staining, consistent with the inflammatory nature of these secretions. Finally, we observed diminished type I interferon and enhanced inflammatory cytokines in these secretions. Overall, our studies indicated that increases in HA and DNA in COVID-19 respiratory secretion samples correlated with enhanced inflammatory burden and suggested that DNA and HA may be viable therapeutic targets in COVID-19 infection.

  View details for DOI 10.1172/jci.insight.152629

  View details for PubMedID 35730564

• Pathology Competencies for Medical Education and Educational Cases ACADEMIC PATHOLOGY Knollmann-Ritschel, B. C., Regula, D. P., Borowitz, M. J., Conran, R., Prystowsky, M. B. 2017; 4: 2374289517715040

  Abstract

  Current medical school curricula predominantly facilitate early integration of basic science principles into clinical practice to strengthen diagnostic skills and the ability to make treatment decisions. In addition, they promote life-long learning and understanding of the principles of medical practice. The Pathology Competencies for Medical Education (PCME) were developed in response to a call to action by pathology course directors nationwide to teach medical students pathology principles necessary for the practice of medicine. The PCME are divided into three competencies: 1) Disease Mechanisms and Processes, 2) Organ System Pathology, and 3) Diagnostic Medicine and Therapeutic Pathology. Each of these competencies is broad and contains multiple learning goals with more specific learning objectives. The original competencies were designed to be a living document, meaning that they will be revised and updated periodically, and have undergone their first revision with this publication. The development of teaching cases, which have a classic case-based design, for the learning objectives is the next step in providing educational content that is peer-reviewed and readily accessible for pathology course directors, medical educators, and medical students. Application of the PCME and cases promotes a minimum standard of exposure of the undifferentiated medical student to pathophysiologic principles. The publication of the PCME and the educational cases will create a current educational resource and repository published through Academic Pathology.

  View details for PubMedID 28815204

• Best Cases from the AFIP Fatal 2009 Influenza A (H1N1) Infection, Complicated by Acute Respiratory Distress Syndrome and Pulmonary Interstitial Emphysema RADIOGRAPHICS Guo, H. H., Sweeney, R. T., Regula, D., Leung, A. N. 2010; 30 (2): 327-333

  View details for DOI 10.1148/rg.302095213

  View details for Web of Science ID 000275622400003

  View details for PubMedID 20068001

• Features of hemolysis due to Clostridium perfringens infection INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY Boyd, S. D., Mobley, B. C., Regula, D. P., Arber, D. A. 2009; 31 (3): 364-367

  Abstract

  Infection by Clostridium perfringens can be an unsuspected cause of hemolysis in emergency room patients. Historically, this condition has been associated with wound contamination and other tissue infections. We report the case of an autistic patient who presented to our emergency department with a distended abdomen and hemolysis of unknown etiology. The patient had no history of recent surgery. Exploration of the abdomen revealed a hepatic abscess. Blood cultures tested culture positive for C. perfringens. We present images demonstrating the salient features of the peripheral blood smear in cases of this uncommon but deadly cause of hemolysis.

  View details for DOI 10.1111/j.1751-553X.2007.01018.x

  View details for Web of Science ID 000265407400013

  View details for PubMedID 18177433

• Using a statistical natural language Parser augmented with the UMLS specialist lexicon to assign SNOMED CT codes to anatomic sites and pathologic diagnoses in full text pathology reports. AMIA ... Annual Symposium proceedings / AMIA Symposium. AMIA Symposium Lowe, H. J., Huang, Y., Regula, D. P. 2009; 2009: 386-390

  Abstract

  To address the problem of extracting structured information from pathology reports for research purposes in the STRIDE Clinical Data Warehouse, we adapted the ChartIndex Medical Language Processing system to automatically identify and map anatomic and diagnostic noun phrases found in full-text pathology reports to SNOMED CT concept descriptors. An evaluation of the system's performance showed a positive predictive value for anatomic concepts of 92.3% and positive predictive value for diagnostic concepts of 84.4%. The experiment also suggested strategies for improving ChartIndex's performance coding pathology reports.

  View details for PubMedID 20351885

• Continuous Intramedullary Polymer Particle Infusion Using a Murine Femoral Explant Model JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS Ortiz, S. G., Ma, T., Regula, D., Smith, R. L., Goodman, S. B. 2008; 87B (2): 440-446

  Abstract

  In vitro models are important investigative tools in understanding the biological processes involved in wear-particle-induced chronic inflammation and periprosthetic osteolysis. In the clinical scenario, particles are produced and delivered continuously over extended periods of time. Previously, we quantified the delivery of both polystyrene and polyethylene particles over 2- and 4-week time periods using osmotic pumps and collection tubes. In the present study, we used explanted mice femora in organ culture and showed that continuous intramedullary delivery of submicron-sized polymer particles using osmotic pumps is feasible. Furthermore, infusion of 2.60 x 10(11) particles per mL (intermediate concentration) of ultrahigh molecular weight polyethylene (UHMWPE) for 2 weeks and 8.06 x 10(11) particles per mL (high concentration) UHMWPE for 4 weeks both yielded significantly higher scores for bone loss when compared with controls in which only mouse serum was infused.

  View details for DOI 10.1002/jbm.b.31122

  View details for Web of Science ID 000260355000017

• Specimen Photography for Canon Powershot http://specimenphoto.sourceforge.net Regula, D. 2006
• Multiresolution browsing of pathology images using wavelets Annual Symposium of the American-Medical-Informatics-Association Wang, J. Z., Nguyen, J., Lo, K. K., Law, C., Regula, D. BMJ PUBLISHING GROUP. 1999: 430–434

  Abstract

  Digitized pathology images typically have very high resolution, making it difficult to display in their entirety on the computer screen and inefficient to transmit over the network for educational purposes. Progressive zooming of pathology images is desirable despite the availability of inexpensive networking bandwidth. An efficient progressive image resolution refining system for on-line distribution of pathology image using wavelets has been developed and is discussed in this paper. The system is practical for real-world applications, pre-processing and coding each 24-bit image of size 2400 x 3600 within 40 seconds on a Pentium II PC. The transmission process is in real-time. Besides its exceptional speed, the algorithm has high flexibility. The server encodes the original pathology images without loss. Based on the image request from a client, the server dynamically generates and sends out the part of the image at the requested scale and quality requirement. The algorithm is expandable for medical image databases such as PACS.

  View details for Web of Science ID 000170207300089

  View details for PubMedID 10566395

• A pilot study of faculty development for basic science teachers ACADEMIC MEDICINE Skeff, K. M., Stratos, G. A., Bergen, M. R., Regula, D. P. 1998; 73 (6): 701-704

  Abstract

  Relatively little research has focused on faculty development methods that assist basic science teachers to improve their instructional skills. This study was designed to assess the effectiveness for basic science faculty of a faculty development seminar series that had been previously shown useful for clinical teachers.The Stanford Faculty Development Program's seminars on clinical teaching were adapted for basic science instruction. Eight pathology faculty participated in a series of nine small-group seminars designed to provide teachers with knowledge of a framework for analyzing teaching and identifying areas for improvement, and skill-based training in specific teaching behaviors. Each seminar included (1) brief lectures, (2) review of videotaped reenactments of teaching interactions, (3) role-play exercises with videotape review, and (4) formulation of personal and departmental teaching goals.Program evaluation included multiple measures: participant self-assessment, student ratings of the participants, and blinded ratings of pre- and post-seminar videotapes of participants' classroom teaching. All measures indicated a positive effect of the intervention.Faculty development programs have significant potential to enhance basic science instructors' teaching effectiveness.

  View details for Web of Science ID 000074383900028

  View details for PubMedID 9653410

• Targeted disruption of the mouse beta 1-adrenergic receptor gene: Developmental and cardiovascular effects PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Rohrer, D. K., Desai, K. H., Jasper, J. R., Stevens, M. E., Regula, D. P., Barsh, G. S., Bernstein, D., Kobilka, B. K. 1996; 93 (14): 7375-7380

  Abstract

  At least three distinct beta-adrenergic receptor (beta-AR) subtypes exist in mammals. These receptors modulate a wide variety of processes, from development and behavior, to cardiac function, metabolism, and smooth muscle tone. To understand the roles that individual beta-AR subtypes play in these processes, we have used the technique of gene targeting to create homozygous beta 1-AR null mutants (beta 1-AR -/-) in mice. The majority of beta 1-AR -/- mice die prenatally, and the penetrance of lethality shows strain dependence. Beta l-AR -/- mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered. Moreover, this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice. These findings occur despite persistent cardiac beta 2-AR expression, demonstrating the importance of beta 1-ARs for proper mouse development and cardiac function, while highlighting functional differences between beta-AR subtypes.

  View details for Web of Science ID A1996UW79200098

  View details for PubMedID 8693001

• TISSUE INGROWTH AND DIFFERENTIATION IN THE BONE-HARVEST CHAMBER IN THE PRESENCE OF COBALT-CHROMIUM-ALLOY AND HIGH-DENSITY-POLYETHYLENE PARTICLES JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME Goodman, S., Aspenberg, P., Song, Y., Knoblich, G., Huie, P., Regula, D., Lidgren, L. 1995; 77A (7): 1025-1035

  Abstract

  Particulate wear debris from joint replacements has been implicated in the etiology of periprosthetic bone resorption. However, the effect of high-density-polyethylene or cobalt-chromium-alloy particles on osteoclastic bone resorption in vivo has not been studied previously, to our knowledge. Therefore, we examined the effect of these particles on tissue ingrowth, net bone formation (per cent trabecular bone), and osteoclastic bone resorption (osteoclasts per unit of bone surface) with use of a bone-harvest chamber that had a transverse one-millimeter channel for tissue ingrowth. After an initial six-week period for incorporation of the chamber into the proximal part of the tibia of rabbits, the contents of the channel were harvested repeatedly at three-week intervals. The carrier solution, 1 per cent sodium hyaluronate, was implanted first. In subsequent implantations, the hyaluronate was mixed with high-density-polyethylene or cobalt-chromium particles at concentrations of 10(8) particles per milliliter. The tissue harvested from the chambers that contained no particles was composed of longitudinally oriented trabecular bone in a fibrovascular stroma. Particulate high-density polyethylene evoked a moderate foreign-body reaction and a chronic inflammatory response and decreased net bone formation. When cobalt-chromium particles had been implanted, the tissue exhibited a more florid foreign-body reaction and a chronic inflammatory response, often in a nodular arrangement, in a background of dense connective tissue. Bone was sparse, and areas of cell necrosis and hyaline degeneration were noted. Histomorphometric analyses were carried out to determine the amount of net bone formation and osteoclastic bone resorption in the presence or absence of high-density-polyethylene or cobalt-chromium particles. The amount of bone was greatest in the control specimens, moderately decreased in the presence of high-density-polyethylene particles, and greatly decreased in the presence of cobalt-chromium particles. The number of osteoclasts in Howship lacunae per unit of trabecular bone surface was increased in the presence of high-density polyethylene, indicating that these particles stimulate osteoclastic bone resorption.

  View details for Web of Science ID A1995RJ67100008

• EPSTEIN-BARR VIRUS-ASSOCIATED NATURAL-KILLER LARGE GRANULAR LYMPHOCYTE LEUKEMIA HUMAN PATHOLOGY Gelb, A. B., VANDERIJN, M., Regula, D. P., CORNBLEET, J. P., Kamel, O. W., Horoupian, D. S., Cleary, M. L., Warnke, R. A. 1994; 25 (9): 953-960

  Abstract

  We describe the first case of an Epstein-Barr virus (EBV)-associated natural killer-large granular lymphocyte (NK-LGL) leukemia in the United States to the best of our knowledge. A 29-year-old woman of Japanese descent developed EBV infection after a blood transfusion as indicated by a rise in serum antibody titers. Peripheral blood and bone marrow aspirate smears demonstrated increased LGLs. Flow cytometry showed that these cells expressed NK-associated surface antigens. Cytogenetic analysis of the bone marrow aspirate showed two distinct but related clones with multiple copies of a modified 7 marker chromosome. Death followed colonic perforation. Findings at necropsy included bone marrow lymphocytosis and erythrophagocytosis, a mononucleosis-like lymphadenitis, atypical hepatitis with a mixed, predominantly T-cell infiltrate, interstitial pneumonitis, and multiorgan system vasculitis with perforation of the transverse colon. Epstein-Barr virus transcripts were identified in lymphocytes infiltrating liver and peripheral nerve by in situ hybridization. In addition, Southern blot analyses showed monoclonal bands superimposed on oligoclonal ladders of EBV termini in liver and lymph node. The identical episomal form of EBV was found in the bone marrow, lymph node, and liver. No immunoglobulin (Ig), T-cell receptor beta, or T-cell receptor gamma chain gene rearrangements were identified. These studies support the hypothesis that the LGL population was a neoplastic EBV-related clonal proliferation of NK cells.

  View details for Web of Science ID A1994PG35800018

  View details for PubMedID 8088773

• Autopsy findings after coronary rotational atherectomy. The American journal of cardiovascular pathology van de Rijn, M., Regula, D. P., Billingham, M. 1990; 3 (4): 301-304

  Abstract

  We describe the findings at autopsy in a patient who underwent Rotablator atherectomy of the right coronary artery. During the procedure, the artery became occluded. Despite attempts to reopen the vessel with balloon angioplasty and emergency coronary artery bypass grafting, the patient developed irreversible cardiac failure and expired 2 days after the Rotablator procedure. At autopsy, the right coronary artery was found to be occluded by thrombus. No evidence of dissection or perforation of the vessel wall was seen. Small intramyocardial arteries and arterioles, downstream from the treated vessel, were embolized by pulverized atheroma.

  View details for PubMedID 2129571

• NODULAR AND DIFFUSE TYPES OF LYMPHOCYTE PREDOMINANCE HODGKINS-DISEASE NEW ENGLAND JOURNAL OF MEDICINE Regula, D. P., Hoppe, R. T., Weiss, L. M. 1988; 318 (4): 214-219

  Abstract

  The nodular form of lymphocyte predominance Hodgkin's disease has been shown to be immunophenotypically distinct from the histologically diffuse form and from other types of Hodgkin's disease. We undertook a clinicopathological study of 73 cases to determine whether any clinical differences between the nodular and diffuse subtypes could be discerned. Patients with the diffuse form (n = 41) tended to have a course similar to that of other types of Hodgkin's disease; there were few relapses and only two deaths due to Hodgkin's disease. In contrast, patients with the nodular form (n = 32) had significantly more relapses, which were independent of stage or treatment and equally distributed up to 10 years after initial therapy. Despite the frequent relapses, patients with the nodular form had an indolent course, and there was only one death due to Hodgkin's disease. There were seven fatal second cancers and two non-neoplastic treatment-related deaths, equally distributed between the nodular and diffuse groups. We conclude that nodular lymphocyte predominance Hodgkin's disease may have important clinical as well as immunophenotypic differences from other forms of Hodgkin's disease, and that patients with this condition should be followed carefully because of the possibility of late relapse.

  View details for Web of Science ID A1988L784400004

  View details for PubMedID 3336412