Marlys H Witte

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Chapters

• Witte, M. H., Bernas, M. J., & Pires, P. (2023). Lymphatic pathophysiology. In Rutherford's Vascular Surgery and Endovascular Therapy(pp 108-126). Chapter 10: Elsevier.
• Witte, M. H., Bernas, M., Pires, P., Sidaway, A. N., & Perler, B. A. (2022). Lymphatic pathophysiology, Chapter 10. In Rutherford’s Vascular Surgery, Tenth Edition(pp 108-126). Philadelphia: Elsevier.
• Leong, S. P., & Witte, M. H. (2022). Lymphangiogenesis: Lymphatic system and lymph nodes; cancer lymphangiogenesis and metastasis. In Cancer Metastasis Through the Lymphovascular System(pp 209-229). Springer Nature, Switzerland AG.
• Witte, M. H. (2022). Lymphatic system and cancer metastasis. In Cancer Metastasis Through the Lymphovascular System(pp 185-186). Springer Nature, Switzerland AG.
• Witte, M. H., & Daley, S. K. (2022). Lymphatic system biology, pathobiology, and relation to cancer metastasis. In Cancer Metastasis Through the Lymphovascular System.
• Leong, S. P., & Witte, M. H. (2009). Future Perspectives for Cancer Metastasis: Unanswered Questions and Unquestioned Answers. In Cancer Metastasis: From Local Proliferation to Distant Sites Through the Lymphovascular System(pp 613-616). Chapter 52: Humana Press, Totowa, NJ. doi:10.1007/978-1-60327-087-8_52
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  In this sentinel lymph node (SLN) era, two new paradigms of cancer metastasis have emerged. First, in general, cancer spreads in a progressive fashion from the primary site to the SLNs and beyond to distant sites. Second, cancer heterogeneity may have a genetic basis. Gene profiling of cancer could identify subgroups of cancer patients for tailored, personalized therapy. With this knowledge and new insights, ever more unanswered questions and unquestioned answers on cancer metastasis have arisen. These will be the focus of the upcoming 3rd International Symposium on Cancer Metastasis and the Lymphovascular System: Basis for Rational Therapy, May 7–9, 2009, in San Francisco.
• Farrell, K. J., Witte, C. L., & Witte, M. H. (1981). A THEORETICAL METHOD OF ANALYSIS OF THE DYNAMICS OF OXYGEN EXCHANGE IN THE MICROCIRCULATION OF THE INTESTINAL TRACT IN THE DOG THAT IS APPLICABLE IN THE SHOCK STATE. In Adv. Physiol. Sci. 25: Oxygen Transport to Tissue(pp 33-34). Pergamon. doi:10.1016/B978-0-08-027346-4.50013-9
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  Publisher Summary This chapter describes a theoretical method of analysis of the dynamics of oxygen exchange in the microcirculation of the intestinal tract in the dog that is applicable in the shock state. The use of on-line measurement of mesenteric lymph PO2 in conjunction with the measurements of mesenteric oxygen delivery and mesenteric oxygen consumption potentially allow a detailed analysis of the dynamics of oxygen exchange in the microcirculation of the intestinal tract. This analysis includes the problem of shunted or nonnutrient blood flow. It has previously been shown that PmlO2 can be expressed quantitatively as a function of DO2/VO2 and the arterial PO2. For a constant PO2, if PmlO2 is plotted versus DO2/VO2, then a linear relationship in physiologic ranges is obtained.

Journals/Publications

• Bartlett, M. J., Erickson, R. P., Hutchinson, E. B., Witte, R. S., & Witte, M. H. (2024). Brain Lymphatics: Rediscovery and New Insights into Lymphatic Involvement in Diseases of Human Brains. Lymphology, 57(1), 27-33.
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  The brain's lymphatic system is comprised of a glymphatic-meningeal-cervical lymphatic vessel pathway. The study of its mechanism and pathophysiology in neurodegenerative disease has been one of the most exciting topics in basic and translational neuroscience of the last decade. However, while there has been some debate about when the meningeal lymphatics were discovered, it cannot be denied that studies in preclinical models and humans in this century represent a monumental step forward in our understanding of how the brain removes metabolic waste, the role this system plays in neurodegenerative disease, and, most importantly, its potential as a novel therapeutic target. This is a summary of the history, functional anatomy, and role of the brain's lymphatics in neurodegenerative disease.
• Granoski, M. B., Fischer, K. S., Hahn, W. W., Sivaraj, D., Kussie, H. C., Quintero, F., Alsharif, A. M., McKenna, E., Yasmeh, J. P., Hostler, A. C., Mora Pinos, M. G., Erickson, R. P., Witte, M. H., Chen, K., & Gurtner, G. C. (2024). Cancer and lymphatic marker FOXC2 drives wound healing and fibrotic tissue formation. Frontiers in physiology, 15, 1427113.
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  The FOXC2 transcription factor has been tied to a wide range of disease states, serving as a promising prognostic biomarker associated with aggressive basal-like human breast cancers (increased cancer invasion and metastasis). Dysregulation of FOXC2 expression has also been found to promote defects in lymphatic remodeling and hyperplastic lymphedema-distichiasis (LD). Since chronic lymphedema is a forerunner of several malignancies and cancers have been known to arise from poorly healing chronic wounds (e.g., Marjolin ulcers), we examined the effect of Foxc2 dysfunction on skin wound healing.
• Leong, S. P., & Witte, M. H. (2024). Cancer metastasis through the lymphatic versus blood vessels. Clinical & experimental metastasis, 41(4), 387-402.
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  Whether cancer cells metastasize from the primary site to the distant sites via the lymphatic vessels or the blood vessels directly into the circulation is still under intense study. In this review article, we follow the journey of cancer cells metastasizing to the sentinel lymph nodes and beyond to the distant sites. We emphasize cancer heterogeneity and microenvironment as major determinants of cancer metastasis. Multiple molecules have been found to be associated with the complicated process of metastasis. Based on the large sentinel lymph node data, it is reasonable to conclude that cancer cells may metastasize through the blood vessels in some cases but in most cases, they use the sentinel lymph nodes as the major gateway to enter the circulation to distant sites.
• Leong, S., & Witte, M. H. (2023). Cancer metastasis through the lymphatic versus blood vessels. Clinical and Experimental Metastasis.
• Witte, M. H. (2024). Looking Backward and Looking Forward: Revisiting "Clinical Usefulness of Thoracic Duct Cannulation". Lymphology, 57(1), 34-57.
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  Over the past decade, there has been a resurgence of interest in the thoracic duct and central lymphatic system and its disorders, stimulated by advances in interventional magnetic resonance imaging techniques and urgent challenges in the clinical management of lymphatic malformations and lymphatic complications from congenital heart disease. The following chapter reprinted here written shortly after the formal founding of the discipline of lymphology and the International Society of Lymphology, describes early efforts, and also suggests future directions now being revisited and others yet to be explored (1).
• Witte, M. H. (2024). Returning the Central Lymphatic System to the Center of Lymphology. Lymphology, 57(1), 1-3.
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  After the introduction of conventional oil contrast lymphography and the founding of the discipline of lymphology, great impetus was given to investigating central lymphatic system and its disorders along with lymphatic involvement and specifically lymphostasis in common diseases of major organs such as the liver (cirrhosis) and heart (heart failure). Gradually interest shifted to more peripheral disorders such as limb lymphedema and its treatment by physical and surgical measures. At the same time, basic lymphology turned to the study of isolate-ed ex vivo and in vitro, including lymphatic endothelial models and more recently, molecular lymphology focusing on lymphatic growth and modulating factors, genes and proteins under-lying primary lymphedema, and more potential biomarkers of lymphatic disease have gained prominence. However, it has been advances in lymphatic imaging, namely lymphoscintigraphy with SPECT-CT high resolution 3-D pictures and magnetic resonance imaging (contrast and non-contrast) of the peripheral and particularly central lymphatic system by more invasive means combined with endovascular interventional techniques to treat complex and life-threatening lymphatic disorders that has returned the central lymphatic system to the center of lymphology, where the journey began.
• Cox, T. P., Vance, C. J., Daley, S. K., Papendieck, C., McGregor, H., Kuo, P., & Witte, M. H. (2022). Systematic literature review of lymphatic imaging-guided procedural management of Noonan syndrome. Journal of vascular surgery. Venous and lymphatic disorders, 10(5), 1192-1196.e3. doi:10.1016
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  To assess through literature case analysis how advances in lymphatic imaging, interventional radiology, and lymphatic vascular microsurgery illuminate and improve the lymphatic-flow status in select patients with Noonan syndrome (NS) who have undergone surgical intervention as a part of their comprehensive and individualized treatment plan. Also, we sought to illustrate the spectrum of lymphatic complications that can occur in this patient population when lymphatic flow through abnormal vasculature is surgically disrupted.
• Witte, M. H. (2020). Overview of principles of basic lymphology and relation to cancer metastasis. Clinical & Experimental Metastasis.
• Witte, M. H., & Erickson, R. P. (2022). Centrifugal Versus Centripetal Origin(s) of the Lymphatic System: Controversy (Mostly) Resolved?. Lymphology, 55(4), 141-143.
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  New findings reopen the controversy about centrifugal vs. centripetal origin of the lymphatic system and support that the latter may be the predominant source of lymphatic endothelial cells from mesenchymal lymphangioblasts.
• Witte, M. H., Srinicasan, S., Geng, X., Detmar, M., Jackson, D. G., Erickson, R. P., Dellinger, M. T., Witte, R. S., Szuba, A., Boccardo, F. M., & Piller, N. (2020). Lymphatic system and cancer metastasis. Clinical & Experimental Metastasis.
• Witz, I. P., Witte, M. H., Vaske, O. M., Sleeman, J. P., Sanders, L., Sagi-assif, O., Piening, B. D., Newman, L. A., Martini, R., Leong, S. P., Izraely, S., Haussler, D., Fox, B. A., Davis, M. B., & Bifulco, C. (2022). Cancer microenvironment and genomics: evolution in process.. Clinical & Experimental Metastasis, 39(1), 85-99. doi:10.1007/s10585-021-10097-9
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  Cancer heterogeneity is a result of genetic mutations within the cancer cells. Their proliferation is not only driven by autocrine functions but also under the influence of cancer microenvironment, which consists of normal stromal cells such as infiltrating immune cells, cancer-associated fibroblasts, endothelial cells, pericytes, vascular and lymphatic channels. The relationship between cancer cells and cancer microenvironment is a critical one and we are just on the verge to understand it on a molecular level. Cancer microenvironment may serve as a selective force to modulate cancer cells to allow them to evolve into more aggressive clones with ability to invade the lymphatic or vascular channels to spread to regional lymph nodes and distant sites. It is important to understand these steps of cancer evolution within the cancer microenvironment towards invasion so that therapeutic strategies can be developed to control or stop these processes.
• Brouillard, P., Witte, M. H., Erickson, R. P., Damstra, R. J., Becker, C., Quéré, I., & Vikkula, M. (2021). Primary lymphoedema. Nature Reviews. Disease Primers, 7(1), 77.
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  Lymphoedema is the swelling of one or several parts of the body owing to lymph accumulation in the extracellular space. It is often chronic, worsens if untreated, predisposes to infections and causes an important reduction in quality of life. Primary lymphoedema (PLE) is thought to result from abnormal development and/or functioning of the lymphatic system, can present in isolation or as part of a syndrome, and can be present at birth or develop later in life. Mutations in numerous genes involved in the initial formation of lymphatic vessels (including valves) as well as in the growth and expansion of the lymphatic system and associated pathways have been identified in syndromic and non-syndromic forms of PLE. Thus, the current hypothesis is that most cases of PLE have a genetic origin, although a causative mutation is identified in only about one-third of affected individuals. Diagnosis relies on clinical presentation, imaging of the structure and functionality of the lymphatics, and in genetic analyses. Management aims at reducing or preventing swelling by compression therapy (with manual drainage, exercise and compressive garments) and, in carefully selected cases, by various surgical techniques. Individuals with PLE often have a reduced quality of life owing to the psychosocial and lifelong management burden associated with their chronic condition. Improved understanding of the underlying genetic origins of PLE will translate into more accurate diagnosis and prognosis and personalized treatment.
• Cox, T., Vance, C., Daley, S., Papendieck, C., McGregor, H., Kuo, P. H., & Witte, M. H. (2021). Imaging of lymphatic dysplasia in Noonan syndrome: Case studies and historical atlas. Lymphology, 54(1), 23-40.
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  To determine the historical use and utility of various lymphatic imaging modalities in Noonan syndrome (NS) patients, we performed a comprehensive literature review by collecting the published medical imaging of NS lymphatic dysplasias. We correlated imaging findings with clinical phenotypes and treatment. Our analysis of lymphatic imaging modalities provides an algorithmic approach to imaging and patient care across the spectrum of NS developmental defects. A total of 54 NS cases have been published since 1975. Using the observations reported in 15 reviewed publications, an association was made between disruptions in central lymphatic flow and poor clinical presentations/outcomes in NS patients.
• Itkin, M., Rockson, S. G., Witte, M. H., Burkhoff, D., Phillips, A., Windsor, J. A., Hur, S., Nadolski, G., Pabon-Ramos, W. M., Rabinowitz, D., & White, S. B. (2021). Research priorities in lymphatic imaging and interventions: Recommendations from a Multidisciplinary Research Consensus Panel. J. Vasc. Interv. Radiol, 32(5), 762. doi:doi: 10.1016/j.jvir.2021.01.269
• Leong, S. P., Naxerova, K., Keller, L., Pantel, K., & Witte, M. H. (2021). Molecular mechanisms of cancer metastasis via the lymphatic versus the vascular channels. Clin. & Exp. Metastasis. doi:https://doi.org/10.1007/s10585-021-10120-z
• Mustacich, D. M., Kylathu, R., Bernas, M. J., Myles, R. J., Jones, J. A., Kanady, J. D., Simon, A., Georgieva, T. G., Witte, M. H., Erickson, R. P., & Pires, P. (2020). Abnormal lymphatic phenotype in a CRISPR mouse model of the human lymphedema-causing Connexin 47 R260C point mutation. Physiological Genomics.
• Mustacich, D. M., Kylathu, R., Bernas, M. J., Myles, R. J., Jones, J. A., Kanady, J. D., Simon, A., Georgieva, T. G., Witte, M. H., Erickson, R. P., & Pires, P. (2021). Abnormal lymphatic phenotype in a CRISPR mouse model of the human lymphedema-causing Connexin 47 R260C point mutation. Lymphology, 54(1), 78-91.
• Mustacich, D. M., Kylathu, R., Bernas, M. J., Myles, R. J., Jones, J. A., Kanady, J. D., Simon, A., Georgieva, T. G., Witte, M. H., Erickson, R. P., & Pires, P. (2021). Abnormal lymphatic phenotype in a CRISPR mouse model of the human lymphedema-causing Connexin 47 R260C point mutation. Lymphology, 54(2), 78-91.
• Mustacich, D. M., Kylathu, R., Bernas, M. J., Myles, R. J., Jones, J. A., Kanady, J. D., Simon, A., Georgieva, T. G., Witte, M. H., Erickson, R. P., & Pires, P. (2021). Abnormal lymphatic phenotype in a CRISPR mouse model of the human lymphedema-causing Connexin47 R260C point mutation.. Lymphology, 54(2), 78-91.
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  Connexin proteins form gap junctions controlling exchange of ions and small molecules between cells and play an important role in movement of lymph within lymphatic vessels. Connexin47 (CX47) is highly expressed in lymphatic endothelial cells and CX47 missense mutations, i.e., R260C, cosegregate with primary lymphedema in humans. However, studies utilizing CX47 knockout mice have failed to demonstrate any lymphatic anomalies. To unravel the lymphatic consequences of expressing a mutant CX47 protein, we used CRISPR technology to create a mouse carrying a Cx47 missense mutation (Cx47R259C) equivalent to the human CX47R260C missense mutation associated with human primary lymphedema. Intradermal Evans Blue dye injection identified a 2-fold increase in regional lymph nodes in homozygous Cx47R259C mice compared to wildtype, particularly in the jugular region (4.8 ± 0.4 and 2.0 ± 0.0, respectively, p
• Mustacich, D. M., Lai, L., Bernas, M. J., Jones, J. A., Myles, R. J., Kuo, P. H., Williams, W., Witte, C., Erickson, R. P., & Witte, M. H. (2021). Digenic inheritance of a FOXC2 mutation and two biallelic PIEZ01 mutations underlies congenital lymphedema in a multi-generation family. American Journal of Medicine. doi:https://doi.org/10.1016/j.amjmed.2021.09.007
• Witte, M. H. (2021). Summary and future perspectives. Clin. & Exp. Metastasis. doi:https://doi.org/10.1007/s10585-021-10120-z
• Witte, M. H., & Erickson, R. P. (2020). Primary lymphedema. Nature Reviews Primer.
• Witte, M. H., Erickson, R. P., Luy, L., Brouillard, P., & Vikkula, M. (2021). Human chromosome map of lymphedema-lymphangiogenesis genes: Template for current and future discovery. Lymphology, 54(4), 167-169.
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  We have created a human chromosomal map of the location of known and candidate genes involved in primary lymphedema (PLE). This should facilitate further discovery and provide a basis for understanding microdeletions which cause lymphedema.
• Witte, M. H., Villa, G., Tacchella, M., Sukkar, S. G., Rossi, U. G., Risso, R., Petrocelli, F., Molinari, L., Marenco, R., Fulcheri, E., Demoro, A., Caro, G. D., Campisi, C., Campisi, C., & Campisi, C. (2021). Matching primary with secondary lymphedemas across lymphatic surgery in Genoa (Italy) from 1973 until time of COVID-19. Italian Journal of Vascular and Endovascular Surgery, 28(1). doi:10.23736/s1824-4777.21.01495-9
• Witte, M. H., Windsor, J. A., White, S. B., Rockson, S. G., Rabinowitz, D., Phillips, A. R., Pabon-ramos, W. M., Nadolski, G. J., Kassab, G. S., Itkin, M., Hur, S., & Burkhoff, D. (2021). Research Priorities in Lymphatic Interventions: Recommendations from a Multidisciplinary Research Consensus Panel.. Journal of vascular and interventional radiology : JVIR, 32(5), 762.e1-762.e7. doi:10.1016/j.jvir.2021.01.269
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  Recognizing the increasing importance of lymphatic interventions, the Society of Interventional Radiology Foundation brought together a multidisciplinary group of key opinion leaders in lymphatic medicine to define the priorities in lymphatic research. On February 21, 2020, SIRF convened a multidisciplinary Research Consensus Panel (RCP) of experts in the lymphatic field. During the meeting, the panel and audience discussed potential future research priorities. The panelists ranked the discussed research priorities based on clinical relevance, overall impact, and technical feasibility. The following research topics were prioritized by RCP: lymphatic decompression in patients with congestive heart failure, detoxification of thoracic duct lymph in acute illness, development of newer agents for lymphatic imaging, characterization of organ-based lymph composition, and development of lymphatic interventions to treat ascites in liver cirrhosis. The RCP priorities underscored that the lymphatic system plays an important role not only in the intrinsic lymphatic diseases but in conditions that traditionally are not considered to be lymphatic such as congestive heart failure, liver cirrhosis, and critical illness. The advancement of the research in these areas will lead the field of lymphatic interventions to the next level.
• Bernardi, A., Moses, S., Barber, B. J., Witte, M. H., & Seckeler, M. (2020). Higher Incidence of Protein-Losing Enteropathy in Patients with Single Systemic Right Ventricle. American Journal of Cardiology. doi:10.1007/s00246-020-02468-y
• Schwartz, F. R., James, O., Kuo, P. H., Witte, M. H., Koweek, L. M., & Pabon-Ramos, W. (2020). Lymphatic imaging: Current noninvasive and invasive techniques. Seminars in Interventional Radiology, 37(3), 1-13.
• Seckeler, M., Moedano, L., Mustacich, D., Kalb, B. T., Saranathan, M., Galons, J., & Witte, M. H. (2020). Non contrast MR lymphography of rare lymphatic abnormalities. Lymphology, 53(3), 133-137.
• Szuba, A., Witte, M. H., Thiadens, S. R., Szuba, A., Papendieck, C. M., Ohkuma, M., Nf, L., Manokaran, G., Liu, N., & Dimakakos, E. (2020). In memoriam: Professor Waldemar Lech Olszewski, PhD, MD. September 3, 1931 - November 8, 2020.. Lymphology, 53(4), 212-215.
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  In Memoriam: Professor Waldemar Lech Olszewski passed away on November 8th. He was born on September 3, 1931 In Poland. Graduated in 1954, he passed Board in Surgery exams in 1962, received degrees of Doctor of Philosophy in 1962 and Doctor of Science in 1968. Since 1970 Olszewski has been an associate professor at the Department of Surgery of the Warsaw Medical Academy, and the Medical Research Center at Polish Academy of Sciences in Warsaw. In 1978 he received a full professor degree at the same centers, and became chairman of the Clinical Department of Surgery, Ministry of Internal Affaires/Polish Academy of Science Hospital, Warsaw. For over 50 years Professor Olszewski carried out research on the lymphatic system. He has made many important discoveries related to lymphatic system functioning. However, Professor Olszewski's clinical and research activities were not limited to the lymphatic system and included vascular surgery, transplantation, physiology and surgery of the lymphatic system and immunology. His most important scientific contributions include designing and introducing into clinical practice the surgical lympho-venous shunts (1966), discovery of spontaneous rhythmic lymphatic contractility in humans (1980), proving that bacterial factors are responsible for development of human limb lymphedema (1994), introducing low-dose, long-term penicillin administration for prevention of chronic dermatitis and lymphangitis in Asian countries (1996), detecting the phenomenon of nonspecific elimination of cell grafts (1990), preservation of tissues for transplantation in dehydrating sodium chloride (2003). His last years encompassed substantial work on fluid hydromechanics in tissue edema. Recently, he developed a new method for treating lymphedema with the aid of subcutaneously implanted silicone drains. He authored and coauthored five scientific books and over 600 research papers.
• Witte, M. H. (2020). Thoracic duct decompression: An idea whose time has come - again.. Lymphology, 53(2), 51-54.
• Witte, M. H., & Bernas, M. J. (2020). EVOLUTION OF THE 2020 INTERNATIONAL SOCIETY OF LYMPHOLOGY CONSENSUS DOCUMENT PARALLELS ADVANCES IN LYMPHOLOGY: AN HISTORICAL PERSPECTIVE.. Lymphology, 53(1), 1-2.
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  [Editorial] Evolution of the 2020 international society of lymphology consensus document parallels advances in lymphology: An historical perspective.
• Witte, M. H., & Daley, S. K. (2020). SARS-CoV-2/COVID-19, lymphatic vessels, lymph and lymphology. Lymphology, 53(3), 97-98.
• DeAngelis, L. C., Bellini, T., Witte, M. H., Kylathu, R., Bernas, M. J., Boccardo, F., Paladini, D., Magnano, G. M., Ramenghi, L. A., & Bellini, C. (2019). Congenital chylothorax: Current evidence-based prenatal and post-natal diagnosis and management. Lymphology, 52(3), 108-125.
• Erickson, R. P., Lai, L. W., Mustacich, D. J., Bernas, M. J., Kuo, P. H., & Witte, M. H. (2019). Sex-limited penetrance of lymphedema to females with CELSR1 haploinsufficiency: A second family. Clinical genetics, 96(5), 478-482.
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  A second multigeneration family with hereditary lymphedema (LE) secondary to a variant in the planar polarity gene, CELSR1, is described. Dominant inheritance of the variant was discovered using whole-exome sequencing and confirmed by Sanger sequencing. In contrast to heterozygous males, all heterozygous females showed LE during physical examination albeit variable in severity and age of onset. Lymphscintigraphy in affected females showed previously undescribed lymphatic abnormalities consistent with lymphangiectasia, valve dysfunction, and thoracic duct reflux.
• Erickson, R. P., Lai, L., Mustacich, D., Bernas, M. J., Kuo, P. H., & Witte, M. H. (2019). Sex-limited penetrance of lymphedema to females with CELSR1 haploinsufficiency: A second family.. Clin Genet., 96(5), 478-482. doi:10.1111
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  A second multigeneration family with hereditary lymphedema (LE) secondary to a variant in the planar polarity gene, CELSR1, is described. Dominant inheritance of the variant was discovered using whole-exome sequencing and confirmed by Sanger sequencing. In contrast to heterozygous males, all heterozygous females showed LE during physical examination albeit variable in severity and age of onset. Lymphscintigraphy in affected females showed previously undescribed lymphatic abnormalities consistent with lymphangiectasia, valve dysfunction, and thoracic duct reflux.
• Erickson, R. P., Lai, L., Mustacich, D., Bernas, M. J., Kuo, P. H., & Witte, M. H. (2019). Sex-limited penetrance of lymphedema to females with CELSR1 haploinsufficiency: A second family.. Clinical Genetics, 96(5), 478-482. doi:10.1111
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  A second multigeneration family with hereditary lymphedema (LE) secondary to a variant in the planar polarity gene, CELSR1, is described. Dominant inheritance of the variant was discovered using whole-exome sequencing and confirmed by Sanger sequencing. In contrast to heterozygous males, all heterozygous females showed LE during physical examination albeit variable in severity and age of onset. Lymphscintigraphy in affected females showed previously undescribed lymphatic abnormalities consistent with lymphangiectasia, valve dysfunction, and thoracic duct reflux.
• Kuo, P. H., Barber, B. J., Kylathu, R., Sean, B., Sara, L., Bernas, M. J., Moedano, L., Bedrick, A. D., & Witte, M. H. (2019). Whole body lymphangioscintigraphy and SPECT-CT in children with lymphatic complications after surgery for complex congenital heart disease. Lymphology.
• Kylat, R., Witte, M. H., Barber, B. J., Dori, Y., & Ghishan, F. K. (2019). Resolution of protein-losing enteropathy after congenital heart disease repair by selective lymphatic embolization. Pediatr Gastroenterol Hepatol Nutr, 22(6), 1-7.
• Kylathu, R., Kuo, P. H., Barber, B. J., Klewer, S. E., Bernas, M. J., Behan, S., Moedano, L., Mustacich, D., & Witte, M. H. (2019). Whole Body Lymphangioscintigraphy and SPECT-CT in Infants and Children with Lymphatic Congestion after Surgical Repair of Complex Congenital Heart Disease. 27th World Congress of Lymphology Abstract Booklet.
• Kylathu, R., Mustacich, D., Bernas, M. J., Myles, R., Kanady, J. D., Simon, A. M., Georgieva, T., Erickson, R. P., & Witte, M. H. (2019). Lymphatic Anomalies in Mice Expressing a Connexin47 Point Mutation. 27th World Congress of Lymphology Abstract Booklet.
• Mahamud, M. R., Geng, X., Ho, Y. C., Cha, B., Kim, Y., Ma, J., Chen, L., Myers, G., Camper, S., Mustacich, D., Witte, M., Choi, D., Hong, Y. K., Chen, H., Varshney, G., Engel, J. D., Wang, S., Kim, T. H., Lim, K. C., & Srinivasan, R. S. (2019). GATA2 controls lymphatic endothelial cell junctional integrity and lymphovenous valve morphogenesis through. Development (Cambridge, England).
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  Mutations in the transcription factor GATA2 cause lymphedema. GATA2 is necessary for the development of lymphatic valves (LVs) and lymphovenous valves (LVVs), and for the patterning of lymphatic vessels. Here, we report that GATA2 is not necessary for valvular endothelial cell (VEC) differentiation. Instead, GATA2 is required for VEC maintenance and morphogenesis. GATA2 is also necessary for the expression of cell junction molecules VE-Cadherin and Claudin5 in lymphatic vessels. We identified as a target of GATA2, and embryos recapitulate the phenotypes of mice lacking GATA2. Primary human lymphatic endothelial cells (HLECs) lacking GATA2 (GATA2 ) have altered expression of Claudin5 and VE-Cadherin, and blocking activity in HLECs phenocopies these changes in expression. Importantly, overexpression of in GATA2 significantly rescues the cell junction defects. Thus, our work defines a new mechanism of GATA2 and uncovers as a novel regulator of mammalian lymphatic vascular development.
• Myles, R., Kylathu, R., Witte, M. H., Seckeler, M., & Klewer, S. E. (2019). The "Failing Fontan" Challenge to the Cardiolymphologist: Case Analysis. 27th World Congress of Lymphology Abstract Booklet.
• Paladini, D., Donarini, G., Conti, A., Constanza De Angelis, L., Witte, M. H., Genesio, R., Bernas, M., Bellini, T., Boccardo, F., Ramenghi, L. A., & Bellini, C. (2019). Early fetal hydropic changes are associated with moderate dilatation of the brain ventricular system: A clue to a possible link between cervical lymphatic engorgement and ventricular dilatation?. Lymphology, 52(1), 11-17.
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  The aim of this study is to assess whether early cervical lymphatic obstruction is associated with a sonographically detectable dilatation of the ventricular system in the 1st trimester of pregnancy. In particular, the objective is to assess whether fetuses with non-immune hydrops fetalis (NIHF), cystic hygroma, or enlarged nuchal translucency (NT) have a greater atrial width/biparietal diameter (AW/BPD) ratio than normal at time of the combined first trimester screening scan. This retrospective study included 96 first trimester fetuses (33 normal and 63 with various degree of cervical lymphatic engorgement). Inclusion criteria were CRL in the 45-84 mm range and availability of one or more three-dimensional volume datasets of the fetal head, acquired from the BPD plane. Each three-dimensional volume dataset was opened and multiplanar correlation employed to align the three orthogonal planes. The ratio between the atrial width and the BPD (AW/BPD ratio) was used to evaluate the possible presence of increased amount of cerebrospinal fluid. Abnormal cases were placed into 4 categories: 1) enlarged non-septated NT 2.5-3.9 mm, no hydrops; 2) grossly enlarged non-septated NT / edema >3.9 mm; 3) cystic hygroma and/ or NIHF; 4) major anomalies with NT
• Sprissler, R., Bina, R., Kasoff, W., Witte, M. H., Bernas, M. J., Walter, C. M., Labiner, D. M., Lau, B., Hammer, M., & Weinand, M. E. (2019). Leukocyte expression profiles reveal gene sets with prognostic value for seizure-free outcome following stereotactic laser amygdalohippocampotomy. Nature Scientific Reports.
• Witte, M. H. (2019). Manuel Viamonte, Jr., MD: "Lymphographer-Lymphologist-Radiologist Extraordinaire – Co-Founder of the International Society of Lymphology" 1930 - 2019. Lymphology, 52(4), 202-204.
• Witte, M. H., Bedrick, A. D., Moedano, L., Bernas, M. J., Sara, L., Sean, B., Kylathu, R., Barber, B. J., & Kuo, P. H. (2019). Whole body lymphangioscintigraphy and SPECT-CT in children with lymphatic complications after surgery for complex congenital heart disease. Lymphology, 52(4), 157-165.
• Witte, M. H., Bernas, M. J., Paniagua, I., Vergara, R., Roman, R., Romero, C., Bernard-Valle, M., Calderon, A., Jimenez, L., Boyer, L. V., & Alagon, A. (2019). Antivenom effect on lymphatic absorption and pharmacokinetics of Coral snake venom using large animal model. Clinical Toxicology, 57, 727-734. doi:10.1080/15563650.2018.1550199
• DeAngelis, L. C., Witte, M. H., Bellini, T., Bernas, M., Boccardo, F., Ramenghi, L. A., & Bellini, C. (2018). Brain Lymphatic Drainage System in Fetus and Newborn: Birth of a New Era of Exploration. Lymphology, 51(4), 140-147.
• Dellinger, M. T., & Witte, M. H. (2018). Lymphangiogenesis, lymphatic systemomics, and cancer: Context, advances and unanswered questions. Clin. & Exp. Metastasis, 35(5-6), 419–424. doi:doi.org/10.1007/s10585-018-9907-9
• Lai, L., Erickson, R. P., Bernas, M., & Witte, M. H. (2018). From childhood onset lymphedema to fatal fetal hydrops: Possible modifying genes for a FOXC2 Mutation. Lymphology, 51(3), 85-88.
• Tanoue, N., Moedano, L., Witte, M. H., Montague, M., Lukefahr, A., & Bernas, M. (2018). Primary vs. trauma-induced Gorham Stout disease. Lymphology, 51(1), 18-27.
• Weinand, M. E., Hammer, M., Labiner, D. M., Walter, C. M., Bernas, M. J., Witte, M. H., Sprissler, R. S., Kasoff, W., & Bina, R. W. (2018). Leukocyte RNA expression: Prognostic value for seizure-free outcome following stereotactic laser amygdalohippocampotomy. Neurosurgery, 65(1), 94.
• Witte, M. H. (2018). Allan E. Dumont, MD, 1924-2017, Revered surgeon, teacher, and pioneering lymphologist. Lymphology. Lymphology, 51(2), 44-45.
• Witte, M. H. (2016). Mechanisms of Ascites Development.. JAMA, 316(17), 1828-1829. doi:10.1001/jama.2016.15069
• Woolfenden, J. M., Pak, K. Y., Witte, M. H., Gmitro, A. F., Liang, R., Banerjee, B., Patel, C., Rouse, A. R., Furenlid, L. R., Bernas, M., Cai, M., Barber, C., Gray, B. D., & Liu, Z. (2016). Characterization of TCP-1 molecular imaging probes in mouse models with xenografted human colon cancer.. J Control Release, 239, 223-230.
• Boccardo, F., Witte, M. H., Pissas, A., Pecking, A., Olszewski, W., Liu, N., Brorson, H., Boccardo, F., Bernas, M., & Andrade, M. (2014). IN MEMORIAM: Robert Victor Cluzan. Lymphology, 47(4), 198-199.
• Witte, M. H., Wang, Y., Mathis, J. M., Jordan, P., Jennings, M. H., Daley, S. K., Bernas, M., & Alexander, J. S. (2009). Roles of Ang-2 KO in Experimental IBD. The FASEB Journal, 23.
• Erickson, R. P., Witte, M. H., Thome, K., Erickson, R. P., Dellinger, M. T., & Bernas, M. J. (2008). Novel FOXC2 missense mutation identified in patient with lymphedema-distichiasis syndrome and review.. Lymphology, 41(3), 98-102.
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  Lymphedema-distichiasis (OMIM 153400) is a dominantly inherited disorder typically presenting with lymphedema at puberty and distichiasis at birth. The condition has been decisively linked to mutations in the forkhead transcription factor FOXC2 which have been primarily frameshift mutations truncating the protein. We report here a novel missense mutation along with a literature review summarizing reported mutations.
• Witte, M. H. (2008). Joshua Lederberg's interest in ignorance.. Science (New York, N.Y.), 320(5880), 1159. doi:10.1126/science.320.5880.1159a
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  In October 2000, to my surprise and delight, I received a request from Joshua Lederberg to “be kind enough to favor me with a copy” of an article I had written on “Ignorance in infectious diseases” ([1][2]) and to “please tell me more about the Ignorance Agenda.” Thus began my own “continuing conversation” with Joshua Lederberg, the subject of the Retrospective by S. S. Morse in the 7 March issue (p. [1351][3]). We exchanged letters, reflections, and references about how to use ignorance—unanswered questions and unquestioned answers—rather than knowledge as the terrain for learning and discovery. Along the way, he completed the handwritten homework assignment that I assigned to our summer high school student researchers. Note that Dr. Lederberg's favorite question (“Are not bacteria ‘cells'…?”), in its elegant paradigm-shattering simplicity, would probably not score well in higher-order complexity according to Bloom's taxonomy. And curiously, he left the space under Human Genome Project blank! I never had the opportunity to meet Dr. Lederberg in person, but I came to know firsthand the grace, humility, uncanny intellect, and childlike wonder that endured through his latter years. 1. 1.[↵][4] 1. M.H. Witte, 2. C.L. Witte , Lymphology 33, 95 (2000). [OpenUrl][5][PubMed][6][Web of Science][7] [1]: pending:yes [2]: #ref-1 [3]: /lookup/doi/10.1126/science.1156612 [4]: #xref-ref-1-1 "View reference 1. in text" [5]: {openurl}?query=rft.jtitle%253DLymphology%26rft.stitle%253DLymphology%26rft.aulast%253DWitte%26rft.auinit1%253DM.%2BH.%26rft.volume%253D33%26rft.issue%253D3%26rft.spage%253D95%26rft.epage%253D121%26rft.atitle%253DIgnorance%2Bin%2Binfectious%2Bdiseases%253A%2Bthe%2Bcase%2Bof%2BAIDS%252C%2BKaposi%2Bsarcoma%252C%2Band%2Blymphology.%26rft_id%253Dinfo%253Apmid%252F11019399%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [6]: /lookup/external-ref?access_num=11019399&link_type=MED&atom=%2Fsci%2F320%2F5880%2F1159.1.atom [7]: /lookup/external-ref?access_num=000089428800003&link_type=ISI
• Witte, M. H. (2008). Lymphology, medical ignorance/ignoramics and the Nobel connection: Howard Florey, Joshua Lederberg, and Françoise Barre-Sinoussi.. Lymphology, 41(4), 149-52.
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  Intriguing interludes with Nobel laureates have marked the history of Lymphology. Bounded (or rather unbounded) by a mutual fascination with ignorance and the unknown, their curiosity converged around microbes, infections, and host responses mediated by the lymphatic system. These studies transcended a simple "molecular model of life".
• Witte, M. H., & Bernas, M. J. (2008). Unanswered Questions and Unquestioned Answers: Teaching Biomedical (and Other) Ignorance Live and on the Internet to Promote Curiosity; Learning; and Discovery. Thirteenth International Thinking Conference, Norrköping, Sweden, 6/15-22/07, Abstract Booklet, p. 91.
• Witte, M. H., Weinand, M. E., Verin, A. D., Ugen, K. E., Singer, E. J., Mirzapoiazova, T., Lossinsky, A. S., Fiala, M., Espinosa, A., Commins, D., & Bernas, M. (2008). HIV-1 Antigens in Neurons of Cocaine-Abusing Patients.. The open virology journal, 2(1), 24-31. doi:10.2174/1874357900802010024
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  Cocaine opens the blood-brain barrier by deregulating transcription of target genes. Here we show that cocaine at blood concentrations in drug abusers disrupts endothelial cell junctions in parallel with signaling by phosphorylation of extracellular signal-regulated kinase, myristoylated alanine-rich C kinase and myosin light chain. Cocaine effects may be important in vivo since the neurons of drug abusing patients with HIV-1 associated dementia displayed gp120, p24 and Nef.
• Stamer, W. D., Witte, M. H., Stamer, W. D., Ramos, R. F., & Hoying, J. B. (2007). Schlemm's canal endothelia, lymphatic, or blood vasculature?. Journal of Glaucoma, 16(4), 391-405. doi:10.1097/ijg.0b013e3180654ac6
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  In the human eye, the final barrier for aqueous humor to cross before returning to systemic circulation is the inner wall of Schlemm's canal. Unfortunately, the specific contribution of the inner wall to total outflow resistance in the conventional pathway is unknown in both normal and glaucomatous eyes. To better understand inner wall physiology, we contrasted it with 2 specialized continuous endothelia, initial lymphatic, and blood capillary endothelia. Specifically, we compare their developmental origin, morphology, junctional complexes, microenvironment, and physiologic responses to different biomechanical factors. Our evaluation concludes that the inner wall of Schlemm's canal is unique, sharing extraordinary characteristics with both types of specialized endothelia in addition to having distinctive features of its own.
• Witte, M. H., & Bernas, M. (2007). Silver bullets and shotguns in lymphedema therapy.. Lymphology, 40(1), 1-2.
• Witte, M. H., & Leong, S. P. (2007). Future perspectives and unanswered questions on cancer metastasis and the lymphovascular system.. Cancer treatment and research, 135, 293-6. doi:10.1007/978-0-387-69219-7_21
• Witte, M. H., Jensen, V., Garrafa, E., & Bernas, M. (2007). LYMPHOLOGISTS AT ELEPHANT FEET, NAVAJO NATION, ARIZONA. Lymphology, 40(4).
• Witte, M. H., Witte, C. L., Jones, K. A., & Bernas, M. (2007). Landmarks and advances in translational lymphology.. Cancer treatment and research, 135, 1-16. doi:10.1007/978-0-387-69219-7_1
• Yancopoulos, G. D., Witte, M. H., Shimoda, H., Kato, S., Gale, N. W., & Bernas, M. J. (2007). Abnormal recruitment of periendothelial cells to lymphatic capillaries in digestive organs of angiopoietin-2-deficient mice.. Cell and tissue research, 328(2), 329-37. doi:10.1007/s00441-006-0360-8
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  The fine structure of lymphatic capillaries in the digestive organs of angiopoietin-2 (Ang2) knockout mice was studied by using both immunohistochemistry and electron microscopy. The genetic deletion of Ang2 yielded hypoplasia and disorganization of the lymphatic capillaries, with their shapes being irregular, and an aberrant recruitment of vascular periendothelial cells immunopositive for smooth muscle actin to the lymphatic capillaries. The abnormal lymphatic periendothelial cells were considered to be a type of pericyte for the lymphatic capillaries after the deletion of Ang2, because they were ultrastructurally characterized by abundant thin myofilaments in their cytoplasm and long cytoplasmic extensions similar to those shown by blood vascular pericytes. The genetic replacement of Ang2 with Ang1 rescued the defects, viz., the disorganization and disordered structure of the lymphatic capillaries. The present findings suggest that Ang2 serves the morphogenesis of lymphatic capillaries as an agonist for the receptor, Tie2, and that Ang1 can replace Ang2 in guiding lymphatic formation and development.
• Witte, M. H., Erickson, R. P., Rennels, M. A., Witte, M. H., Rennels, M. A., Percy, D., Noon, A., Kriederman, B., Hunter, R. J., Erickson, R. P., Enerback, S., & Bernas, M. (2006). Comparative lymphatic, ocular, and metabolic phenotypes of Foxc2 haploinsufficient and aP2-FOXC2 transgenic mice.. Lymphology, 39(2), 84-94.
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  FOXC2 mutations cause the lymphatic/ocular disorder Lymphedema-Distichiasis (LD), and Foxc2 haploinsufficient mice mimic this disorder. To determine if FOXC2 overexpression might also cause lymphatic and/or ocular abnormalities, we performed dynamic lymphatic imaging (Evans blue dye), ocular tissue examination, and metabolic profiles in mice: transgenic for FOXC2 with an adipocyte (aP2) promoter (aP2-FOXC2 Tg), heterozygous for targeted disruption of Foxc2 (Foxc2+/-), or compound heterozygous and transgenic (Foxc2+/-, Tg) compared to wild-type controls (WT). Foxc2+/-; aP2-FOXC2 Tg; and Foxc2+/-, Tg, exhibited LD's distinctive hyperplastic lymphatic phenotype characterized by increased number of lymphatic channels and lymph nodes as well as retrograde lymph reflux. Foxc2+/-, and Foxc2+/-, Tg but not aP2-FOXC2 Tg or WT showed an abnormal ocular phenotype. Previously described alterations in brown/ white fat distribution and lean phenotype in aP2-FOXC2 transgenics were confirmed. AP2-FOXC2 Tg immunohistochemistry disclosed aberrant FOXC2 expression in ectopic sites, especially embryonic heart. Lymphatic system links with fat metabolism are discussed.
• Witte, M. H., Witte, C. L., & Bernas, M. (2006). Lymphangiogenesis reviews, lymphology, and medical ignorance. Lymphology, 39(2), 59-61.
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  Lymphology is launching aLymphangiogenesis Reviews series focusingon unanswered, unasked, and perhaps wronglyanswered questions (medical ignorance).The Journal’s historic role, along with ISLCongresses and many ISL lymphologists –past and present – in bringing thephenomenon of lymphangiogenesis to lightis emphasized.
• Witte, M. H. (2005). A celebration of ignorance.. Science (New York, N.Y.), 309(5738), 1185. doi:10.1126/science.309.5738.1185a
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  Congratulations to Science for shifting paradigms in the 125th Anniversary issue ([125 questions: what don't we know?, 1 July][1]), not only by focusing on what leading contemporary scientists “don't know,” but also by unabashedly labeling this collection of 125 important unanswered questions as a “survey of scientific ignorance.” Back in 1984, based on my mentor Lewis Thomas' whimsical suggestion ([1][2]), my late husband and I brought ignorance out of the closet by creating the University of Arizona's “Curriculum on Medical Ignorance” (featuring a Summer Institute, distinguished visiting “ignorami,” and ignorance logs and exercises) to teach medical and later undergraduate and K-12 students and science teachers how to recognize and deal with ignorance—“what we know we don't know, don't know we don't know, and think we know but don't”—about a wide range of medical and scientific topics ([2][3]). Our curriculum has resulted in various ignorance-based publications, presentations, media coverage, and products, earning me the dubious title of “Ignorama Mama,” mother of the global ignorance movement. Indeed, all learning and discovery do take place in the terrain of ignorance, not knowledge, and it is questions, questioning, and questioners that impel scientific advances. These mysteries and puzzles, not dry facts and pat answers, should also drive science education as well as the research enterprise. A Wall Street Journal editorial ([3][4]) paradoxically hailed our evolution from the Information Age to the “Age of Ignorance,” where we can recuse ourselves from excessive information, admit we don't know, and humbly “google” or grope our way through what we need to know. And newly minted Nobel physicist David Gross lauded “ignorance—the most important product of knowledge” as “lucky for science, scientists, and the Nobel Foundation” ([4][5]). 1. 1.[↵][6] 1. J. B. Wyngaarden, 2. L. H. Smith 1. L. Thomas , in Cecil Textbook of Medicine, J. B. Wyngaarden, L. H. Smith, Eds. (W.B. Saunders, Philadelphia, PA, 1982), 16. p. xli, xliii. 2. 2.[↵][7] See [www.medicine.arizona.edu/ignorance][8] and . 3. 3.[↵][9] 1. H. Stein , “The age of ignorance,” Wall Street J. A10 (11 June 1993). 4. 4.[↵][10] 1. D. Gross , Science News 167((no. 4)), 59 (2005). [OpenUrl][11] [1]: /lookup/doi/10.1126/science.309.5731.75 [2]: #ref-1 [3]: #ref-2 [4]: #ref-3 [5]: #ref-4 [6]: #xref-ref-1-1 "View reference 1. in text" [7]: #xref-ref-2-1 "View reference 2. in text" [8]: http://www.medicine.arizona.edu/ignorance [9]: #xref-ref-3-1 "View reference 3. in text" [10]: #xref-ref-4-1 "View reference 4. in text" [11]: {openurl}?query=rft.jtitle%253DScience%2BNews%26rft.volume%253D167%26rft.issue%253D%2528no.%2B4%2529%26rft.spage%253D59%26rft.atitle%253DSCIENCE%2BNEWS%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
• Witte, M. H., Ohkuma, M., Campisi, C., Boccardo, F., & Andrade, M. (2005). Nature's historic gap: the 20th century of lymphology.. Lymphology, 38(4), 157-8.
• Witte, M. H., Srinivasan, R. S., Sleeman, M. W., Oliver, G., Johnson, N. C., Harvey, N. L., Dillard, M. E., & Boyd, K. (2005). Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity.. Nature genetics, 37(10), 1072-81. doi:10.1038/ng1642
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  Multiple organs cooperate to regulate appetite, metabolism, and glucose and fatty acid homeostasis. Here, we identified and characterized lymphatic vasculature dysfunction as a cause of adult-onset obesity. We found that functional inactivation of a single allele of the homeobox gene Prox1 led to adult-onset obesity due to abnormal lymph leakage from mispatterned and ruptured lymphatic vessels. Prox1 heterozygous mice are a new model for adult-onset obesity and lymphatic vascular disease.
• Erickson, R. P., Witte, M. H., Hartsough, R. L., Glover, T. W., Erickson, R. P., Dagenais, S. L., & Butler, M. G. (2004). Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome.. Gene expression patterns : GEP, 4(6), 611-9. doi:10.1016/j.modgep.2004.07.004
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  The molecular events involved in lymphatic development are poorly understood. Hence, the genes responsible for hereditary lymphedema are of great interest due to the potential for providing insights into the mechanisms of lymphatic development, the diagnosis, prevention and treatment of lymphedema, and lymphangiogenesis during tumor growth. Mutations in the FOXC2 transcription factor cause a major form of hereditary lymphedema, the lymphedema-distichiasis syndrome. We have conducted a study of Foxc2 expression during mouse development using immunohistochemistry, and examined its expression in lymphatics compared to its paralog Foxc1 and to Vegfr-3, Prox1 and other lymphatic and blood vascular proteins. We have found that Foxc2 is expressed in lymphatic primordia, jugular lymph sacs, lymphatic collectors and capillaries, as well as in podocytes, developing eyelids and other tissues associated with abnormalities in lymphedema-distichiasis syndrome.
• Witte, M. H., & Bernas, M. (2004). Alternative/complementary treatment in lymphology: trying the untried and testing the untested.. Lymphology, 37(2), 43-4.
• Erickson, R. P., Rennels, M. A., Jackson, D. A., Witte, M. H., Witte, C. L., Rennels, M. A., Myloyde, T. L., Miura, N., Lynch, M. T., Kriederman, B. M., Jackson, D. G., Glover, T. W., Erickson, R. P., Dagenais, S. L., Caulder, M. S., Brooks, B. P., & Bernas, M. J. (2003). FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome.. Human molecular genetics, 12(10), 1179-85. doi:10.1093/hmg/ddg123
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  Lymphedema-distichiasis (LD) (OMIM 153400) is a rare autosomal-dominant condition characterized by pubertal onset of lower limb lymphedema and an aberrant second row of eyelashes arising from the meibomian glands. In some patients cardiac, skeletal and other defects coexist. We previously identified inactivating, nonsense and frameshift mutations in the forkhead transcription factor FOXC2 in affected members of LD families. To further delineate the relationship of FOXC2 deficiency to the clinical (and lymphangiodysplastic) phenotype in this syndrome, we performed dynamic lymphatic imaging and immunohistochemical examination of lymphatic tissues in mice heterozygous (+/-) for a targeted disruption of Foxc2. Adult heterozygote mice characteristically exhibited a generalized lymphatic vessel and lymph node hyper plasia and rarely exhibited hindlimb swelling. Retrograde lymph flow through apparently incompetent interlymphangion valves into the mesenteric nodes, intestinal wall and liver was also observed. In addition, Foxc2 +/- mice uniformly displayed distichiasis. We conclude that Foxc2 haploinsufficient mice mimic closely the distinctive lymphatic and ocular phenotype of LD patients. Furthermore, the craniofacial, cardiovascular and skeletal abnormalities sometimes associated with LD have previously been shown to be fully penetrant in homozygous Foxc2 null mice. This Foxc2 mutant mouse thus provides an ideal model for exploring molecular mechanisms and physiologic events in mesenchymal differentiation associated with lymphatic growth and development and the clinical abnormalities seen in human LD syndrome.
• Erickson, R. P., Witte, M. H., Witte, C. L., & Erickson, R. P. (2003). Cardio(blood-lymph)vascular genomics: need for a terminology adjustment.. Lymphology, 36(4), 159-61.
• Witte, M. H., Witte, C. L., & Northup, K. A. (2003). Syndromic classification of hereditary lymphedema.. Lymphology, 36(4), 162-89.
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  Since the late 1800's, the familial occurrence of peripheral lymphedema has been well-documented in Milroy and Meige syndromes. However, the presence of lymphedema in many other hereditary dysmorphic syndromes has not been fully appreciated. In order to establish more standardized and detailed clinical phenotypic criteria as the basis for rational classification and for greater precision in screening and genetic linkage studies, we conducted a comprehensive literature search and review of OMIM-identified and non-identified hereditary syndromes in which lymphedema was reported as a feature. Modes of inheritance, associated clinical features and images, and specific organ involvement were inventoried and suggested pathophysiologic mechanisms noted. The findings support the recommendation that when peripheral lymphedema of undetermined etiology is found, further careful, comprehensive clinical, including detailed dysmorphic, evaluation along with lymphatic imaging with subsequent syndromic classification is warranted. This information can provide clues to underlying pathogenesis and form the basis for genetic counseling and prognostication as well as offer guidance to the clinical investigator translating research at the molecular level into new approaches for evaluation and therapy.
• Witte, M. H., Witte, M. H., Witte, C. L., Summers, P., Stea, B., Preciado, S., Myloyde, T., Lynch, M., Lee-donaldson, L., Kriederman, B., & Bernas, M. (2002). Limb volume reduction after physical treatment by compression and/or massage in a rodent model of peripheral lymphedema.. Lymphology, 35(1), 23-7.
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  Lack of a standardized experimental counterpart of peripheral lymphedema (LE) in a small animal has hampered research into treatment of this debilitating condition. We recently refined a rodent model consisting of radical unilateral lymphatic/nodal groin excision in conjunction with a circumferential integumental gap, followed by regional irradiation of the groin to reproduce stable unilateral hindlimb LE (1). In the current study, Wistar-Fuzzy rats with established right hindlimb LE, were subdivided into five groups and subjected to one of the following daily physical regimens over a 5-day period: pneumatic compression pumping at 30 torr (PCP); low-stretch multi-layered compressive bandaging using Coban (CB); manual lymphedema drainage (MLD) or a light massage consisting of stationary circular motions using the fingertips; combined physiotherapy (CPT consisting of MLD + CB); and a no treatment or control group (CTRL). Hindlimb and LE volumes were serially measured before and after treatment. Whereas CTRL showed progressive worsening of hindlimb swelling, PCP, CB, CPT and MLD each produced similar and substantial edema reduction over the 5 day interval, PCP, CB and CPT induced vacillating edema reduction which, however, exceeded rebound swelling on a daily basis. MLD, on the other hand, showed a steady gradual daily decline in LE volume.
• Erickson, R. P., Jones, M. C., Witte, M. H., Nelson, C. C., Mcdonald, M., Lidral, A. C., Kerstjens-frederikse, W. S., Jones, M. C., Herman, G. E., Glover, T. W., Erickson, R. P., Downs, C. A., Dagenais, S. L., & Caulder, M. S. (2001). Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations.. Journal of medical genetics, 38(11), 761-6. doi:10.1136/jmg.38.11.761
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  Hereditary lymphoedema-distichiasis (LD) is an autosomal dominant disorder that classically presents as lymphoedema of the limbs, with variable age of onset, and extra aberrant growth of eyelashes from the Meibomian gland (distichiasis). Other major reported complications include cardiac defects, cleft palate, and extradural cysts. Photophobia, exotropia, ptosis, congenital ectropion, and congenital cataracts are additional eye findings. Recently, we reported that truncating mutations in the forkhead transcription family member FOXC2 resulted in LD in two families..The clinical findings in seven additional families with LD, including the original family described by Falls and Kertesz, were determined and mutational analyses were performed..Distichiasis was the most common clinical feature followed by age dependent lymphoedema. There is a wide variation of associated secondary features including tetralogy of Fallot and cleft palate. The mutational analyses identified truncating mutations in all of the families studied (two nonsense, one deletion, three insertion, and one insertion-deletion), which most likely result in haploinsufficiency of FOXC2..FOXC2 mutations are highly penetrant with variable expressivity which is not explicable by the pattern of mutations.
• Erickson, R. P., Witte, M. H., Witte, C. L., Holberg, C. J., Fultz, K. E., Erickson, R. P., Bernas, M. J., & Andrade, M. (2001). Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenital primary lymphedema families.. American journal of medical genetics, 98(4), 303-12. doi:10.1002/1096-8628(20010201)98:4<303::aid-ajmg1113>3.0.co;2-9
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  We previously described six families with Milroy congenital lymphedema, only one of which showed possible linkage to a candidate locus on chromosome 5 [Witte et al., 1998]. We have now performed a complex segregation analysis of these families, and performed linkage analyses with the other 387 markers used in our genome-wide search. Our results confirm that Milroy lymphedema is generally inherited as a dominant condition. However, this mode of inheritance, as elucidated from the segregation analyses, did not account for all observed familial correlations. The segregation analysis also suggested that shared environmental or additional genetic factors are important in explaining the observed familial aggregation. The finding of linkage to multiple locations in the largest family studied by multipoint parametric mapping (one of which was confirmed by sib-pair non-parametric mapping), suggests that Milroy congenital lymphedema may be oligogenic in this family.
• Witte, C. L., Witte, M. H., Witte, M. H., Witte, C. L., Cl, W., & Bernas, M. J. (2001). The diagnosis and treatment of peripheral lymphedema: draft revision of the 1995 Consensus Document of the International Society of Lymphology Executive Committee for discussion at the September 3-7, 2001, XVIII International Congress of Lymphology in Genoa, Italy.. Lymphology, 34(2), 84-91.
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  This proposed revision of the 1995 ISLConsensus Document in the evaluation andmanagement ofperipheral lymphedema (1) isbased upon modifications suggested andpublished following the 1997 XVI InternationalCongress of Lymphology (ICL) inMadrid, Spain (2), discussed at the 1999 XVIIICL in Chennai, India (3), and considered atthe most recent International Society ofLymphology (ISL) Executive Committeemeeting in Hinterzarten, Germany (4). It isdesigned to stimulate and frame debate at theupcoming XVIII ICL (September 2001,Genoa, Italy) and thereby help shape the nextofficial version of the Consensus Document tobe published early next year in the Journaland on the ISL Web site.The document attempts to amalgamatethe broad spectrum ofprotocols advocatedworldwide for the diagnosis and treatment ofperipheral lymphedema into a coordinatedproclamation representing a "Consensus" ofthe international community. The document isnot meant to override individual clinicalconsiderations for problematic patients nor tostifle progress. It is also not meant to be alegal formulation from which variations definemedical malpractice. The Society understandsthat in some clinics the method of treatmentderives from national standards while inothers access to medical equipment andsupplies is limited and therefore the suggestedtreatments are impractical. We continue tostruggle to keep the document concise whilebalancing the need for depth and details. Withthese considerations in mind, we believe thatthe next version of the Consensus shouldrepresent the best judgment of the ISLmembership on how to approach patients withperipheral lymphedema as of2001. Weanticipate that the document will and shouldbe challenged, debated in· the pages ofLymphology (e.g., as Letters to the Editor),and ideally become a continued focal point forrobust discussion at local, national andinternational conferences in lymphology andrelated disciplines. We further anticipate asexperience evolves and new ideas and technologiesemerge that this "living document"will undergo periodic revision and refinement.
• Witte, M. H., Witte, C. L., Summers, P., Myloyde, T., & Bernas, M. (2001). Design and use of a model database registry for lymphedema-angiodysplasia patients. Journal of Investigative Medicine, 49(1).
• Witte, M. H., & Witte, C. L. (2000). Ignorance in infectious diseases: the case of AIDS, Kaposi sarcoma, and lymphology.. Lymphology, 33(3), 95-121.
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  From the perspective of The University of Arizona's innovative Curriculum on Medical (and Other) Ignorance focusing on "what we know we don't know, don't know we don't know, and think we know but don't," the shifting terrain of information-knowledge-ignorance of AIDS (a disorder involving, to various incompletely understood degrees, the four components of the lymphatic system-lymph, lymphatics, lymphocytes, and lymph nodes) and Kaposi sarcoma (a lymphedemogenic lesion thought to arise from trans-differentiated lymphatic endothelium) is surveyed by pinpointing some key unanswered questions that have been raised over the course of the epidemic and pointedly in past International Congresses of Lymphology. These questions are placed in the context of general ignorance about infectious diseases and the relationship of "germ" to "terrain" through the "blood-tissue-lymph loop." A framework is suggested for an "ignorance agenda" encompassing basic biology, clinical management, and societal issues.
• Witte, M. H., Witte, C. L., Williams, W. H., & Mcneill, G. C. (2000). Radionuclide lymphangioscintigraphy in the evaluation of peripheral lymphedema.. Clinical nuclear medicine, 25(6), 451-64. doi:10.1097/00003072-200006000-00013
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  The primary difficulty in evaluating and treating peripheral lymphedema is visualization of the lymphatics. Functional lymphatic studies have been performed on patients with peripheral edema to diagnose lymphedema, to determine its severity, and to understand the varied drainage patterns..After intradermal injection in the hands or feet, initial flow and whole-body images were taken using Tc-99m human serum albumin in more than 700 patients with possible lymphedema..Clear images of truncal lymph transport and draining lymph nodes were obtained, and pattern differences between primary and secondary lymphedema were seen. Follow-up studies showed any functional change in lymphatic dynamics..Peripheral lymphatics can now be easily visualized. Because lymphangioscintigraphy can be performed before and after medical treatment, follow-up evaluation of patients with lymphedema is possible. The procedure is noninvasive, repeatable, easy to perform, and harmless to the lymphatic endothelium.
• Witte, C. L., Witte, M. H., Witte, M. H., Way, D., Stea, B., Lee-donaldson, L., Cl, W., & Bernas, M. (1999). Erratum: Refinement of a rodent model of peripheral lymphedema (Lymphology (1999) 32 (111-117)). Lymphology, 32(4).
• Witte, M. H., & Witte, C. L. (1999). Epilogue: what we don't know about cancer.. Anticancer research, 19(6A), 4919-33.
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  Despite billions of dollars expended since the "war on cancer" was declared more than 25 years ago, cancer continues to be a leading cause of death worldwide, and its precise pathogenesis remains elusive. Moreover, current treatments, even when successful, are grounded in extensive operations, high energy irradiation, and toxic chemotherapy, which carry substantial short- and long-term sequelae. It is, therefore, appropriate to reconsider current concepts of cancer biology in terms of the vast ignorance that surrounds this ancient scourge. From the perspective of a Curriculum on Medical Ignorance, this epilogue surveys questions raised by authors of this monograph, other experts, and patients afflicted with cancer and related disorders. Further, the focus is on basic biological, clinical, and societal implications of carcinogenesis theories as well as the nature and process of scientific inquiry in the context of the general phenomenon of ignorance in medicine.
• Witte, M. H., Way, D., & Meade-tollin, L. C. (1999). Expression of multiple matrix metalloproteinases and urokinase type plasminogen activator in cultured Kaposi sarcoma cells.. Acta histochemica, 101(3), 305-16. doi:10.1016/s0065-1281(99)80031-2
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  Kaposi's sarcoma (KS) cells are considered to be of endothelial origin. KS lesions are characterized by hyperproliferation and an invasive phenotype. We have determined that KS cell cultures constitutively secrete multiple forms of several matrix metalloproteinases (MMPs) and an altered form of urokinase plasminogen activator (uPA) by zymogram and Western analysis of the culture media. MMPs are a family of secreted endoproteinases which degrade components of the extracellular matrix. Their enhanced expression and activity are strongly correlated with cellular processes involving tissue remodeling and invasion. The KS cells secrete increased levels of gelatinase A and B and a high molecular weight uPA in vitro when compared with non-KS endothelial or epithelial cells. Multiple forms of gelatinases A and B were observed on gelatin zymograms. Caseinolytic bands observed were confirmed by Western blot analysis to be due to stromelysin activity, whereas matrilysin was not detected by casein zymography. Western blot analysis also detected secretion of interstitial collagenase and high molecular weight uPA. Gelatinolytic activity with the mobility of gelatinase B was detected on gelatin zymograms, but not by Western analysis. This unusual constitutive expression pattern of MMPs and uPA by KS cells in vitro is characterized by elevated levels of gelatinase A, gelatinase B, interstitial collagenase, stromelysin and a high molecular weight form of uPA, and the lack of expression of matrilysin. These secreted MMPs, taken together, are capable of digesting a broad range of components of the extracellular matrix. This unusual pattern is likely to contribute to the characteristic hyperproliferative and invasive phenotype of KS lesions.
• Witte, M. H., Witte, C. L., Stea, D., Ortiz, L., Lee-donaldson, L., & Bernas, M. (1999). Effects of pneumatic compression therapy on secondary lymphedema in a rodent model. Journal of Investigative Medicine, 47(2).
• Witte, M. H., Witte, C. L., Way, D., Martin, C. P., Lee-donaldson, L., & Bemas, M. (1999). Effect of Vascular Endothelial Growth Factor (VEGF) on microcirculatory water and protein flux in the rat intestine. Journal of Investigative Medicine, 47(2).
• Witte, M. H., Witte, C. L., Way, D., Stea, B., Lee-donaldson, L., & Bernas, M. (1999). Refinement of a rodent model of peripheral lymphedema.. Lymphology, 32(3), 111-7.
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  A reliable, inexpensive experimental counterpart of peripheral lymphedema has been notoriously difficult to reproduce thereby stifling basic and clinical research into this frustrating clinical condition. Accordingly, in 45 adult Wistar-Fuzzy rats, we attempted to produce sustained hindlimb lymphedema by either groin nodal/lymphatic microsurgical ablation (S) (guided by visual blue dye lymphography) or limited field-groin irradiation (R) alone (4500 rads) or combined S followed by R or R followed by S with an additional non-manipulated group serving as controls. Observations were made for 30-100 days thereafter. Hindlimb volumes were determined serially using the truncated cone formula based on multiple circumferential measurements at standardized intervals along the affected hindlimb and the findings compared with similar measurements in the contralateral non-manipulated hindlimb. In randomly selected rats from each group, lymphatic drainage was assessed by lymphangioscintigraphy (LAS), soft tissue swelling by magnetic resonance imaging (MRI), and edema fluid total protein content by refractometry. Whereas S or R alone produced only transient or mild hindlimb edema without associated morbidity or mortality, S-R or R-S induced moderate to severe sustained protein-rich hindlimb lymphedema associated with 9-13% early mortality and notable late local limb morbidity. Lymphatic obstruction was documented by sustained maintenance of increased hindlimb volume, subcutaneous fluid accumulation (MRI), and impaired lymphatic drainage (LAS). This reproducible rodent model of secondary lymphedema reliably simulates a stable clinical condition for a window of up to 100 days and should thereby facilitate standardized testing of therapeutic/preventive protocols and basic research into lymphatic dynamics in secondary lymphedema.
• Witte, M. H., Witte, C. L., Way, D., Stea, D., Lee-donaldson, L., & Bemas, M. (1999). A rodent method of peripheral lymphedema. Journal of Investigative Medicine, 47(2).
• Schmelz, M., Witte, M. H., Witte, C. L., Way, D. L., Schmidt, H., Schmelz, M., Peitsch, W. K., Moll, R., Franke, W. W., & Borgs, P. (1998). A novel type of adhering junction in an epithelioid tumorigenic rat cell culture line.. Cell and tissue research, 294(1), 11-25. doi:10.1007/s004410051152
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  Two major types of plaque-bearing adhering junctions are commonly distinguished: the actin microfilament-anchoring adhaerens junctions (AJs) and the desmosomes anchoring intermediate-sized filaments (IFs). Both types of junction usually possess the common plaque protein, plakoglobin, whereas the other plaque proteins and the transmembrane cadherins are mutually exclusive. For example, AJs contain E-, N-, or P-cadherin in combination with alpha- and beta-catenin, vinculin and alpha-actinin, whereas in desmosomes, desmogleins and desmocollins are associated with desmoplakin and one or several of the plakophilins (PP1-3). Here we describe a novel type of adhering junction comprising proteins of both AJs and desmosomes and the tight junction (TJ) plaque protein, ZO-1, in a newly established, liver-derived tumorigenic rat cell line (RMEC-1). By immunofluorescence microscopy, cell-cell contacts are characterized by mostly continuous-appearing lines which are usually resolved by electron microscopy as extended arrays of closely spaced small plaque subunits. These plaque-covered regions are positive for plakoglobin, alpha- and beta-catenin, the arm-repeat protein p120, vinculin, desmoplakin and protein ZO-1. They are positive for E-cadherin in cultures early on in passaging, but tend to turn negative for all known cadherins in densely grown cultures. On immunoblotting SDS-PAGE-separated proteins from dense-grown cell monolayers, "pan-cadherin" antibodies have reacted with a band at approximately 140 kDa, identified as N-cadherin by peptide fingerprinting of the immunoprecipitated protein, which for reasons not yet clear is modified or masked in immunolocalization experiments. The exact histological derivation of RMEC-1 cells is not known. However, the observations of several endothelial markers and the fact that all cells are rich in IFs containing vimentin and/or desmin, while only subpopulations also reveal IFs containing CKs 8 and 18, is suggestive of a mesenchymal, probably endothelial origin. We discuss the molecular relationship of this novel type of extended junction with other types of adhering junctions.
• Stazzone, A. M., Witte, C. L., Witte, M. H., Witte, M. H., Williams, W., Summers, P., Stazzone, A. M., Mcneill, G. C., Fiala, M., Escobar, G., Cl, W., & Bernas, M. (1998). Evolution of lymphangioscintigraphic findings and value of combined physiotherapy in peripheral edema from aids-associated Kaposi sarcoma. Lymphology, 31, 353-356.
• Witte, M. H., Witte, C. L., & Bernas, M. (1998). ISL Consensus Document revisited: suggested modifications (summarized from discussions at the 16th ICL, Madrid, Spain, September 1997 and the Interim ISL Executive Committee meeting).. Lymphology, 31(3), 138-40.
• Witte, M. H., Weinand, M. E., Way, D., Stins, M. F., Persidsky, Y., Kim, K. S., Gendelman, H. E., Fiala, M., & Bock, P. J. (1997). A model for monocyte migration through the blood-brain barrier during HIV-1 encephalitis.. Journal of immunology (Baltimore, Md. : 1950), 158(7), 3499-510.
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  HIV-1 invades the central nervous system early during viral infection, but neurologic impairment usually occurs years later. The strongest predictor for clinical dementia is the absolute numbers of immunocompetent brain macrophages. Thus, how monocytes penetrate the brain during disease remains critical for understanding the neuropathogenic mechanisms of HIV-1 encephalitis. To these ends, we constructed an artificial blood-brain barrier (BBB) consisting of a matrix-coated membrane with brain microvascular endothelial cells (BMVEC) on one side and astrocytes on the other. Astrocyte endfeet contacted the monolayer of BMVEC that formed tight junctions. To determine the role of viral and immune factors in monocyte penetration across the BBB, HIV-infected or uninfected monocytes with or without immune stimulation were placed onto the upper chamber of the BBB model system. Placement of immune-stimulated (LPS-treated) cells onto the BBB construct elicited gaps between BMVEC, with bulging of nuclear zones and increased numbers of vesicular Golgi complexes and endoplasmic reticulum. This correlated with a profound increase (up to 20-fold) in the number of migrating cells. Viral infection did not enhance monocyte migration. The activated monocytes showed increased numbers of philopodia, lysosomes, and vesicular Golgi complexes and expressed large levels of proinflammatory cytokines (TNF-alpha, IL-6, and IL-10). These data suggest that a major mechanism for the transendothelial migration of monocytes during HIV encephalitis is the immune activation that accompanies viral infection of the central nervous system.
• Witte, M. H., Witte, C. L., Stazzone, A. M., & Borgs, P. (1996). Acute lymphangitis and persistent lymphedema after topical application of cantharidin. Lymphology, 29, 341-342.
• Witte, M. H., Witte, C. L., Williams, W., & Mcneill, G. C. (1996). A simplified standardized technique for isotope lymphatic imaging of the extremities. Lymphology, 29, 130-133.
• Watson, R. R., Witte, M. H., Watson, R. R., Mufti, S. I., Mccuskey, R. S., Lantz, C., Johnson, M. I., Earnest, D. L., & Borgs, P. (1994). ALCOHOL, IMMUNOMODULATION, AND DISEASE. Alcohol and Alcoholism, 29(2), 131-139. doi:10.1093/oxfordjournals.alcalc.a045499
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  Recent research findings point to a spectrum of alcohol-induced immune dysfunctions in animal models and humans. Use of alcohol in vivo causes abnormalities in the function and/or structure of a broad array of cells involved in humoral and cellular immunity, including lymphocytes, Kupffer cells and other macrophages, as well as the endothelium of blood vessels and lymphatics. Regulatory cytokines and neuroendocrine factors can mediate some of these immunomodulatory effects which may be further re-phased, exaggerated or unbalanced by other drugs of misuse. A variety of animal models is available to study acute and chronic alcoholism, non-alcohol drug misuse, AIDS as well as other opportunistic infections, and neoplasias, which hold promise of clarifying the role of alcohol as an immunomodulator.
• Witte, M. H., Witte, C. L., Way, D. L., Ramirez, G., Borgs, P., & Bernas, M. J. (1994). AIDS, alcohol, endothelium, and immunity.. Alcohol (Fayetteville, N.Y.), 11(2), 91-7. doi:10.1016/0741-8329(94)90049-3
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  Analogies are drawn between important unknowns in AIDS and alcohol research, related to underlying common pathogenetic mechanisms, immunodysregulation, cofactors, and prominent vascular manifestations. The central role of the blood and lymphatic vasculatures and specifically their endothelial lining in many facets of the immune response is reviewed. Evidence is presented that both alcohol and HIV (as well as other coinfecting viruses in AIDS) target and alter endothelial cells and the angiogenic process. These concepts are further illustrated by a serendipitous viral epidemic among rats on continuous long-term alcoholic and control nonalcoholic diets, where synergism between alcohol and virus appeared to underlie multiple vascular proliferative lesions in the liver. In AIDS and alcoholism/alcoholic liver disease (ALD), the prominent features of dysregulated angiogenesis point to the endothelium as a key player in pathogenesis of these seemingly disparate disorders and potentially in immunomodulation.
• Witte, M. H., Witte, C. L., Way, D. L., Ramirez, G., Borgs, P., & Bernas, M. J. (1992). Alcohol, hepatic sinusoidal microcirculation, and chronic liver disease.. Alcohol (Fayetteville, N.Y.), 9(6), 473-80. doi:10.1016/0741-8329(92)90083-m
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  According to the "intact cell hypothesis," ethanol (EtOH) primarily targets nonparenchymal hepatic sinusoidal and perisinusoidal cells, thereby promoting sinusoidal capillarization, which impairs microcirculatory exchange of nutrients and wastes, promotes tissue fibrosis, and only indirectly damages hepatic parenchyma. To test this hypothesis, sinusoidal ultrastructure and hepatic lymph flow and protein composition were examined in rats up to 16 weeks after intragastric EtOH (36% calories)-high fat infusion (Tsukamoto-French model) (TF). The findings were compared to dietary controls and interpreted in light of restricted transsinusoidal protein movement observed in patients with alcoholic cirrhosis. In vitro, alterations in rat hepatic sinusoidal endothelial cell (RSE) morphology, proliferative index, and transendothelial macromolecular permeability (Evans blue-albumin uptake into microcarrier beads) were determined after acute and more chronic exposure to 0.1%-5 vol% EtOH. TF displayed 75% increased liver size, perisinusoidal collagenosis, and basal lamina deposition, ascitic fluid, and doubling of hepatic lymph liquid and protein flux. In vitro, 1% EtOH retracted RSE cell margins, enhanced transendothelial Evans blue-albumin flux and suppressed proliferative index. Thus, high EtOH concentration, clinically attainable in the portal blood during an alcoholic binge, both in vivo and in vitro, promotes early structural and functional alterations in sinusoidal endothelium, which over time may be responsible for progressive restriction of free intrahepatic exchange of liquid, macromolecules, and migrating immune cells.
• Witte, M. H., Witte, C. L., Way, D. L., & Fiala, M. (1990). AIDS, Kaposi sarcoma, and the lymphatic system: update and reflections.. Lymphology, 23(2), 73-80.
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  Based on ongoing basic and clinical investigations, further evidence is presented that the AIDS-Kaposi sarcoma (AIDS-KS) complex involves a progressive disturbance of the blood-lymph circulatory loop of fluid, macromolecules, and migrating cells. We first surveyed the spectrum of vascular abnormalities including Kaposi sarcoma (KS) found in the AIDS/ARC population, then non-invasively imaged lymphatic system abnormalities in AIDS-KS by whole body lymphangioscintigraphy, and finally examined the biologic behavior of AIDS-KS cells in long-term tissue culture. These observations are viewed in terms of the lymphatic and blood vascular route of entry and transport of free and cell-associated virus and other opportunistic pathogens as well as poorly understood host endothelial-immune system interactions.
• Witte, M. H., Witte, C. L., Scadron, A., & Kerwin, A. (1989). A curriculum on medical ignorance.. Medical education, 23(1), 24-9. doi:10.1111/j.1365-2923.1989.tb00808.x
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  The information and technology explosions in medicine have exposed the vast realm of ignorance in human biology as well as the transiency of accepted knowledge and shortcomings of instructional methods which foster rote memorization, excessive reliance on conflicting data bases, and short-answer testing. To circumvent this serious deficiency in medical education, we have initiated a multifaceted Curriculum on Medical Ignorance consisting of 'questioning' seminars and hands-on clinical and laboratory experiences. This teaching programme not only emphasizes medicine's current deficiencies and limited insight into disease processes (i.e. ignorance) but also assists students in developing attitudes and behaviours to investigate basic biologic and clinical unknowns while rendering sound everyday clinical decisions in the face of fragmentary understanding. Based on evaluative feedback over the past 3 years, participants have made substantial progress towards recognizing and dealing constructively with medical ignorance and the limitations of 'knowledge of the day', thereby preparing them for the certain uncertainty of future medical practice.
• Witte, M. H., Witte, C. L., Way, D., & Stuntz, M. (1989). AIDS, Kaposi's sarcoma, and the gay population. The germ or the terrain?. International journal of dermatology, 28(9), 585-6. doi:10.1111/j.1365-4362.1989.tb02532.x
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  This article explores the link between acquired immunodeficiency syndrome (AIDS) and an aggressive form of Kaposis sarcoma that appears almost exclusively in the gay male population
• Witte, M. H., & Witte, C. L. (1988). AIDS-Kaposi's sarcoma complex: evolution of a full-blown lymphologic syndrome.. Lymphology, 21(1), 4-10.
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  An hypothesis is presented to explain the link between acquired immunodeficiency syndrome (AIDS) and Kaposi's sarcoma (KS). According to this hypothesis, AIDS involves all four components of the integrated lymphatic system--lymphatics, lymph nodes, lymphocytes, and lymph--and thereby resembles various congenital and acquired lymphologic syndromes characterized by one or more of the following features: lymphostasis, angiogenesis, and fibrosis; depletion of immunocompetent cells and immunosuppression; opportunistic infections; and vascular neoplasms. A better understanding of the steps in the evolution of these processes and their interrelationships to the four components of the lymphatic system should provide insight into the immunopathogenesis of AIDS-KS as well as its detection and treatment.
• Witte, M. H., Witte, C. L., Minnich, L. L., Finley, P. R., & Drake, W. L. (1984). AIDS in 1968.. JAMA, 251(20), 2657. doi:10.1001/jama.1984.03340440017005
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  To the Editor.— The recent epidemic of acquired immune deficiency syndrome (AIDS), first reported in 1981,1has greatly alarmed the general public. Back in 1973, however, we described in detail2a curious clinical syndrome in a native-born American first seen by us in 1968 who in retrospect fulfilled the diagnostic criteria for AIDS. Report of a Case.— A 15-year-old black male, born and raised in St Louis and who to our knowledge had never left that area, had brawny penile and scrotal edema of one year's duration followed later by bilateral leg edema. He had not previously been seriously ill and specifically had never received a blood transfusion. While he admitted to heterosexual relations for several years, a homosexual history was not specifically elicited. Bilateral pedal lymphangiography revealed complete lymphatic obstruction at the inguinal ligaments with dermal backflow, and an excised inguinal lymph node showed marked fibrosis. Lymphedema
• Witte, M. H. (1982). Advancement of Men and Women in Medical Academia-Reply. JAMA, 247(24), 3311-3311. doi:10.1001/jama.1982.03320490015011
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  In Reply.— The letters of Drs Ruane and Barton focusing on specific variables such as "having a 'wife' " or the morbidity of "promotion with loss of tenure-track" indicate that they too recognize the differential survival of men and women in medicine as an epidemiologic problem worthy of pursuit. After computing the more basic survival curves suggested originally, these and other lines of inquiry can be more productively examined and placed in proper perspective.

Proceedings Publications

• Myles, R., Kylathu, R., Witte, M. H., Seckeler, M., & Klewer, S. E. (2019, September). The "Failing Fontan" Challenge to the Cardiolymphologist: Case Analysis. In 27th World Congress of Lymphology Abstract Booklet.
• Witte, M. H., Mustacich, D., Moedano, L., Behan, S., Bernas, M. J., Klewer, S. E., Barber, B. J., Kuo, P. H., & Kylathu, R. (2019, September). Whole Body Lymphangioscintigraphy and SPECT-CT in Infants and Children with Lymphatic Congestion after Surgical Repair of Complex Congenital Heart Disease. In 27th World Congress of Lymphology Abstract Booklet.

Presentations

• Granoski, M. B., Hahn, W. W., Fischer, K. S., Sivaraj, D., Kussie, H. C., Hostler, A. C., Witte, M. H., Chen, K., & Gurtner, G. C. (2023, Spring).

  FOXC2 dysregulation is associated with delayed wound healing in a standardized mouse model

  . 9th International Conference on Cancer Metastasis through the Lymphovascular System.
• Witte, M. H. (2023, Fall). History and Background of the International Society of Lymphology and Future Perspectives. 29th World Congress of Lymphology. Genoa, Italy: International Society of Lymphology.
• Witte, M. H. (2023, Fall). ISL - Lymphology Research Then and Now. 29th International Congress of Lymphology. Genova, Italy: International Society of Lymphology.
• Witte, M. H. (2023, Fall). Pan-American Lymphology and the ISL. 29th International Congress of Lymphology. Genova, Italy.
• Witte, M. H. (2023, Fall). The Role of Lymphatics in Systemic Disease - The Inaugural Marlys Witte Central and Regional Lymphatic System in Health and Disease Session presented by the Jill and Mark Fishman Center for Lymphatic Disorders at the Children's Hospital of Philadelphia. 29th International Congress of Lymphology. Genova, Italy: International Society of Lymphology.
• Witte, M. H. (2023, Spring). Landmarks and progress in Lymphatic Systemomics (Keynote Speaker). 3rd Annual Lymphatic Conference. Philadelphia, PA: Children's Hospital of Philadelphia.
• Witte, M. H. (2023, Spring). Lymphatic systemomics and cancer. 9th International Conference on Cancer Metastasis through the Lymphovascular System. San Francisco, CA.
• Witte, M. H., Erickson, R. P., & Barnes, T. (2023, Fall). Non-Invasive Peripheral and Central Lymphatic Imaging in Neonates and Young Children with Lymphatic Disorders. 29th World Congress of Lymphology. Genoa, Italy: International Society of Lymphology.
• Witte, M. H. (2022, Fall). Lymphedema and Lymphology: Historic and Scientific Aspects. Innovations in Wound Healing Meeting. Islamorada, Florida Keys.
• Witte, M. H. (2022, November). Brain lymphatic systems - bench to bedside. 1st Pan American Congress of Lymphology. Bucaramanga, Colombia: Escuela Colombiana de Linfologia/International Society of Lymphology.
• Witte, M. H. (2022, November). Lymphatic imaging for diagnosis and intervention. 1st Pan American Congress of Lymphology. Bucaramanga, Colombia: Escuela Colombiana de Linfologia/International Society of Lymphology.
• Witte, M. H. (2022, November). Lymphology, past, present and future. 1st Pan American Congress of Lymphology. Bucaramanga, Colombia: Escuela Colombiana de Linfologia/International Society of Lymphology.
• Witte, M. H. (2022, November). Lymphovascular/Lymphedema Genomics. 1st Pan American Congress of Lymphology. Bucaramanga, Colombia: Escuela Colombiana de Linfologia/International Society of Lymphology.
• Witte, M. H. (2022, November). Sars CoV2 and lymphatic system. 1st Pan American Congress of Lymphology. Bucaramanga, Colombia: Escuela Colombiana de Linfologia/International Society of Lymphology.
• Witte, M. H. (2022, Summer). Curriculum on Medical (and all other) Ignorance; Adventures in Curiosity. Teacher Masterclass. Oxfordshire, UK: Cokethorpe School.
• Witte, M. H. (2022, Summer). Ignorance, Failure, and Chaos; Reflections on the Past and Prepared for an Uncertain Future. Commencement/Prize Giving Ceremony. Oxfordshire, UK: Cokethorpe School.
• Cox, T., Vance, C., Daley, S. K., Papendieck, C., Mcgregor, H., Kuo, P. H., & Witte, M. H. (2021, September). Review and case-based recommendations for the imaging and image-guided treatment of central lymphatic dysplasia in Noonan syndrome. 28th World Congress of Lymphology. Athens, Greece: International Society of Lymphology.
• Cox, T., Vance, C., Daley, S. K., Papendieck, C., Mcgregor, H., Kuo, P. H., & Witte, M. H. (2021, September). Surgical outcomes analysis of Noonan syndrome patients evaluated with lymphatic imaging. 28th World Congress of Lymphology. Athens, Greece: International Society of Lymphology.
• Dimakakos, E., Witte, M. H., Szuba, A., Foeldi, E., Boccardo, F., & Moffat, C. (2021, September). Conservative Lymphedema Treatment Course: From Theory to Hands-On Practice Q & A. 28th World Congress of Lymphology. Athens, Greece: International Society of Lymphology.
• Vance, C., Kath, A. M., Williams, C., Witte, M. H., & Pires, P. (2021, September). Amyloid-β reduces contraction frequency of superficial cervical lymphatic in mice. 28th World Congress of Lymphology. Athens, Greece: International Society of Lymphology.
• Witte, M. H. (2021, January). Curriculum on Medical (and other) Ignorance: An Adventure in Curiosity. CORT Conference. UT Southwestern Medical Center; Dallas, Texas: Center for Organogenesis and Trauma Research (CORT).
• Witte, M. H. (2021, September). Expanding frontiers of Lymphology and the ISL: From Lymphedema to COVID-19. 28th World Congress of Lymphology. Athens, Greece: International Society of Lymphology.
• Witte, M. H. (2021, September). Lymphvascular genetics and lymphedema: From zero to genomewide. 28th World Congress of Lymphology. Athens, Greece: International Society of Lymphology.
• Bernardi, A., Moses, S., Barber, B. J., Witte, M. H., & Seckeler, M. (2019, October). Higher incidence of protein-losing enteropathy in patients with single systemic right ventricle. Finalist, Young Investigator Award, 2019 American Academy of Pediatrics National Conference & Exhibition. New Orleans, LA.
• Kylathu, R., Kuo, P. H., Barber, B. J., Klewer, S. E., Bernas, M. J., Behan, S., Moedano, L., Mustacich, D., & Witte, M. H. (2019, September). Whole Body Lymphangioscintigraphy and SPECT-CT in Infants and Children with Lymphatic Congestion after Surgical Repair of Complex Congenital Heart Disease. 27th World Congress of Lymphology. Buenos Aires and Iguazu, Argentina: International Society of Lymphology.
• Kylathu, R., Mustacich, D., Bernas, M. J., Myles, R., Kanady, J. D., Simon, A. M., Georgieva, T., Erickson, R. P., & Witte, M. H. (2019, September). Lymphatic Anomalies in Mice Expressing a Connexin47 Point Mutation. 27th World Congress of Lymphology. Buenos Aires and Iguazu, Argentina: International Society of Lymphology.
• Mustacich, D. J., Lai, L. W., Erickson, R. P., Bernas, M. J., Kuo, P. H., & Witte, M. H. (2019, Fall). Sex-limited penetrance of lymphedema in a family with a novel CELSR1 variant. 27th World Congress of Lymphology 2019. Buenos Aires, Argentina: International Society of Lymphology.
• Myles, R., Kylathu, R., Witte, M. H., Seckeler, M., & Klewer, S. E. (2019, September). The "Failing Fontan" Challenge to the Cardiolymphologist: Case Analysis. 27th World Congress of Lymphology. Buenos Aires and Iguazu, Argentina: International Society of Lymphology.
• Seckeler, M., Moedano, L., Kalb, B. T., Saranathan, M., Galons, J., & Witte, M. H. (2019, September). Non-Contrast MR Lymphology of Rare Central Lymphatic Abnormalities. 27th World Congress of Lymphology 2019. Buenos Aires, Argentina.
• Witte, M. H. (2019, October). Cancer microenvironment and the lymphatic system; old ideas, new ideas, and old ideas revisited. 8th International Conference on Cancer Metastases. San Francisco, CA.
• Witte, M. H. (2019, October). New Ideas Replace the Old ... But the Old Comes Back Again - Comments on Cancer, the Microenvironment and the Lymphatic System: A Lymphologist's Perspective. 8th International Conference on Cancer Metastases. San Francisco, CA.
• Witte, M. H. (2019, September). In Memorium: Charles L. Witte, MD, reluctant surgeon 1935-2003. 27th World Congress of Lymphology 2019. Buenos Aires, Argentina: International Society of Lymphology.
• Witte, M. H. (2019, September). Making the Invisible Visible; Discovery, Rediscovery, and Translation in Lymphology (Opening Lecture). 27th World Congress of Lymphology 2019. Buenos Aires, Argentina: International Society of Lymphology.

Poster Presentations

• Erickson, R. P., Kylat, R., Mustacich, D. J., Bernas, M., & Witte, M. H. (2018, Fall). The phenotype of a CRISPR mouse model of a human GapJunction C2 (connexin 47) mutant causing lymphedema. ASHG 2018. San Diego, CA: American Society of Human Genetics.

Creative Productions

• Witte, M. H. (2018. TedX Bloomington Update: Marlys Witte MD. TedX BloomingtonTedX.
• Witte, M. H., Ruiz, J., Gaxiola, D., & Crown, P. (2016. Zika epidemic: Knowns! and Unknowns!. VideoNIAID.

Others

• Witte, M. H. (2021, February). Child’s Play as Science and Vice Versa. Science.