Portal de Periódicos da CAPES

In the memory of our following colleagues, and friends

2022; Wiley; Volume: 34; Issue: 6 Linguagem: Inglês

10.1111/nmo.14393

1365-2982

Satish Rattan, Weibiao Cao, Philip O. Katz, Raj K. Goyal,

Eosinophilic Esophagitis

“People around the world will remember the year 2021 during which pandemic occupied our thoughts and actions and millions around the world lost their family members and friends to COVID. People interested in the science and discipline of gastrointestinal motility also lost several giants of the field during 2021, all of them not necessarily to COVID. Their work dazzled us for many decades and will continue to occupy our thoughts as long as we live. Future generations will have to go through and quote their work if they want to advance the field further. Some of the concepts that we take for granted were revealed to us by these people. These were exceptional people, passionate about their work, and we stand taller today because of them. It is with these emotions that the authors of this article write briefly about them and their contributions to science.” Ravinder K. Mittal, Division of Gastroenterology, University of California, San Diego, CA. Jaswant Singh Gidda (Jas), Ph.D. (1946–2021) Dr. Jaswant Gidda was born on October 1, 1946, and passed away in his hometown Carmel, IN, on September 8, 2021. He is survived by his wife, Raj Gidda, 2 sisters, son and daughter-in-law (Vipul and Amisha Gidda), daughter and son-in-law (Archana and Tim Bailey), and 6 grandchildren. In 1972, after receiving Ph. D. from Panjab University, India, he moved to Dallas, TX, where he received extensive research experience in neurophysiology in Southern Methodist University and University of Texas. I (SR) first met Jas in 1973, the year Dr. Raj Goyal and I had moved from Baylor College of Medicine, Houston, to UT Southwestern Medical School, Dallas. Over the years, Jas and I became close family friends. In 1977, Jas joined our group in UTSMS. Over the next 8 years, he made major contributions to our present understanding of primary peristalsis in the esophageal smooth muscle (SM) pathophysiology evident by a number of landmark papers, as highlighted below. From 1985 to 2021, in the pharmaceutical industry (Bristol Myers Squibb, Eli Lilly, and a founding member of multiple Biotech companies), he was responsible for significant publications in the gastrointestinal motility disorders and therapy, 14 U.S. patents, and 2 drugs that are currently in the market. Jas will be remembered as a great-family man, scientist, educator, philanthropist, innovator, a great friend, social worker, and a golfer. Jas dedicated his entire professional life working on the pathophysiology and therapeutic targeting of gastrointestinal motility disorders. However, he will be long remembered for his major contributions in understanding esophageal peristalsis as follows. Jas's earlier studies1, 2 revealed the following: (1). An increase in the duration and the strength of initial inhibition and refractoriness distally along the esophagus. Above observations are the basis of latency gradient along the length of the esophagus, which is the basis of esophageal peristalsis. (Initial inhibition occurs immediately following the vagal stimulation (VS), which increases with the higher frequencies.) Refractoriness, an inhibition of an evoked contraction, occurs by a previous stimulus (at low frequencies of VS), when the initial inhibition is less marked); (2) peristalsis in the esophageal SM can be explained entirely on the basis of peripheral mechanisms; and (3) the central nervous system via vagus nerve activates peripheral enteric nervous system, for the regulation of occurrence, polarity, and speed of propagation by modulating the intensity and frequency of VS. His later studies3 revealed that swallowing and VS produced similar peristaltic contraction in the esophageal SM. His recordings of neural activity from different vagal efferent fibers in response to swallowing identified two types of fibers: early discharging with a short latency (A type) and late discharging with a long latency (B type). He concluded that the A type are pre-ganglionic vagal fibers responsible for the initial inhibition by the activation of myenteric inhibitory neurons, while B type mediate the contractile wave by the activation of myenteric cholinergic excitatory neurons. His studies provided direct evidence of active inhibition in the esophageal SM, where otherwise it is difficult to demonstrate inhibition because of lack of any ongoing activity.4 His simultaneous recordings of electrical and mechanical events in the esophageal SM showed that swallowing leads to a prompt fall in the membrane potential, followed by overshoot depolarization, and the esophageal contraction. Additionally, these are strikingly similar to those with VS. His in vivo examination of esophageal SM responses to multiple successive revealed that during VS at a rate >15/min, contractions to all stimuli were inhibited and the contraction response occurred only at the end of the last stimulus.5 This is similar to the deglutitive inhibition, in response to multiple rapid swallows (MRS) observed in human studies by other investigators, showing no activity in the esophagus until the last swallow leading to the peristaltic contraction. These studies have significant implications in the pathophysiology and therapeutic targeting of a number of esophageal motility disorders. Collectively, Jas's studies show that swallowing activates the inhibitory neurons in the caudal dorsal motor neurons (cDMN) first, causing simultaneous inhibition of all parts of the esophagus; this inhibition lasts longer in the lower than in the upper part of the esophagus. (As we know now, this inhibition is mediated primarily via the release of nitric oxide.) As the inhibition ends, sequential activation of excitatory neurons (e.g., cholinergic) in the rostral DMN elicits a peristaltic contraction wave. The excitatory innervation in the esophagus is most marked proximally decreasing distally, and reverse is the case for the inhibitory innervation. Consequently, upon swallowing, the latency of contraction increases gradually distally, resulting in peristaltic esophageal contraction. His studies further revealed that both the inhibitory and excitatory mechanisms are entirely located in the wall of esophagus. Piero Biancani (Peter), Ph.D. (1941 – 2021) Jose Behar, M.D. (1934 – 2020) Dr. Piero Biancani (September 3, 1941-November 12, 2021) was an excellent mentor, scientist, mechanical engineer, and boat builder. He obtained his master's degree in mechanical engineering at Pisa University in 1964, his master's degree in applied mathematics at Yale University in 1966, and his Ph.D. degree in biomechanics at Yale University in 1971. He worked as a research associate and a senior research associate in the Department of Internal Medicine at Yale University School of Medicine from 1971 to 1980. He was an associate professor and professor of medicine at Rhode Island Hospital and Brown University from 1980 to 2013, respectively, when he retired. He was a past president of the American Motility Society from 1986 to 1988, a member of NIH study sections from 1989 to 1992 and 1994, and a member of VA study section from 2002 to 2005. Piero Biancani's PhD work6, 7 made two fundamental contributions to the understanding of biomechanics of the esophagus and the lower esophageal sphincter (LES). (1) He defined the contributions of the mucosa and the muscle layers to the strength of the esophagus. He showed that the pressure diameter curves during loading and unloading exhibited hysteresis. The mucosa and the whole esophagus showed increasing stiffness with increasing pressure, represented by a simple exponential relationship. The compliance was influenced by the rate of pressure change and history loading cycles. These observations had a major impact on the relationship between the rate of dilation and the material used for dilating the esophagus on the perforation rate. (2) He defined how intraluminal sphincter pressure is maintained during its closure in the basal state. He showed that only a small fraction of the tension, and hence energy, was required to maintain same intraluminal pressure at small diameters than at larger diameters. He also showed that mucosal plug plays an important role in the lower esophageal sphincter closure in the resting state. Dr. Jose Behar (August 11, 1934-July 20, 2020) was an excellent educator, gastroenterologist, and scientist. He obtained his bachelor's degree in sciences at San Marcos University in 1957 and his MD degree at San Fernado Medical School in Peru in 1961. He worked at Yale University and later moved to Rhode Island hospital until he retired. He was an assistant professor, associate professor, and professor at Brown University from 1976 to 2012. He was the chief of the Division of Gastroenterology, Rhode Island Hospital from 1995 to 1998, a councilor of the American Motility Society from 1994 to 1998, and a member of international liaison committee, American Gastroenterological Association from 1998 to 2001. Dr. Biancani and Dr. Behar made significant contributions to esophageal and gallbladder motility.8-10 They found that secretory phospholipase A2 (group I PLA2) contributes to the LES tone via the production of prostaglandins and thromboxanes. Prostaglandin F2aα (PGF2α) and thromboxane A2 (TXA2) activate small G protein RhoA and a PKC-dependent signaling pathway. This finding was supported by the result that the cyclooxygenase inhibitor indomethacin abolishes LES tone. During the initial contraction, PGF2a, TXA2, and high-dose acetylcholine release the calcium from the stores and activate Ca2+-calmodulin-myosin light chain kinase-dependent pathway. In esophagitis, esophageal mucosa releases inflammatory mediators (e.g., interleukin-6 (IL-6) and platelet-activating factor (PAF)), which diffuse into the circular muscle layer and cause production of H2O2 which in turn induces the production of IL-1b that further enhances H2O2 production in the circular smooth muscle as positive feedback. High levels of H2O2 may deplete the releasable Ca2+ stores by the inhibition of Ca2+ ATPase and impair activation of the Ca2+-dependent PKCb, thus decreasing the LES tone. LES muscle contractility was further decreased by muscle relaxants PAF and PGE2 and the endogenous PGF2α antagonist 8-iso-PGF2α. In chronic cholecystitis, high concentrations of hydrophobic bile salts damage the epithelial and smooth muscle cells by increasing production of H2O2 and lipid peroxidation. High levels of H2O2 may inhibit catalase activity and further increase free radical levels. PGE2’s cytoprotective functions are impaired by the presence of the high levels of cholesterol in plasma membrane. The increase in free radicals causes inflammatory reaction and impairs gallbladder motility. Gallbladder motility is also impaired during pregnancy. High levels of progesterone present during pregnancy downregulate G-protein Gi3, thereby inhibiting gallbladder smooth muscle contraction induced by cholecystokinin-8. In summary, Dr. Biancani's and Dr. Behar's research help us understand the mechanisms of hypomotility of LES and gallbladder during inflammation. Free radicals are the major players in the impairment of LES tone and gallbladder contractility during inflammation. Donald Overton Castell (DO), M.D. (1935–2021) A giant among giants, scientist, mentor, teacher, promoter, and friend, Donald Overton Castell (DO) was born on September 19, 1935. On a path to take over a three-generation family business, he instead became the first to go to college. His musical talents were a forerunner of his prolific academic career. He was a concert master trumpet player in his high school band and lead trumpet player in the Maryland State Orchestra. He started college as a music major and was a member of the wrestling team at George Washington University. He graduated Alpha Omega Alpha from George Washington University School of Medicine in 1960, followed by residency at Bethesda Naval Hospital. He began his GI career as a fellow in Boston with Tom Chalmers, moved to Bethesda where he spent 20 years at the Naval Hospital, where he was Chief of Medicine (at age 40), achieving the Navy rank of Captain. He moved to civilian life to become Chief of GI at Bowman Gray School of Medicine (now Wake Forest) in 1982. He was recruited by Willis Maddrey to become the Chief of GI at Jefferson in Philadelphia in 1989, moving to the Graduate Hospital as the Kimbel Professor and Chair of Medicine until 2001 when he moved to the Medical University of South Carolina where he remained for the next 19 years, becoming Emeritus Professor in 2020. DO was a devoted father of four (daughters Debbie, Karen, and Cynthia, and son Dan) as well as stepdaughters Marianna and Celine, stepsons Geoffrey and Colton. He was an avid tennis player, devoted Boston Red Sox, Washington Redskins (now Commanders), college basketball and later Alabama Crimson Tide football fan. He loved chocolate, red wine, and (Ledo's) pizza and had an aversion to sport coats and ties (the picture above not withstanding). His academic career spanned almost 55 years with over 600 peer-reviewed publications beginning in 1965, the last posthumously in 2021. I would bet few gave more invited lectures and visiting professorships all over the world than DO. His career was replete with academic honors including the AGA Distinguished Teacher Award, the AGA Kirschner Award for Clinical Research and the AGA’s highest honor the Julius Friedenwald Medal. He was AGA president in 1999. He was honored with two named lectures at the ACG annual meeting, and he was the first Director of the ACG Institute for Clinical Research among many honors bestowed throughout his career. He was elected by his peers as the “Pope of Esophagology” at OESO. His academic legacy is without parallel. Five of his direct trainees have been presidents of national societies (Joel Richter, Dave Johnson, Sarkis Chobanian, Ken DeVault, and Philip Katz). The number of us he has mentored in some way (the US and international) who are leaders in research and clinical esophagology are too numerous to count but include David Katzka (Penn, Mayo, Columbia), Braden Kuo (Mass General), Marcelo Vela (Mayo), and Radu Tutuian (University of Bern, Switzerland). Felice Schnoll-Sussman is president elect of the American Foregut Society. His decades long collaboration with Tom DeMeester and the annual six-day “Hawaii course” the combined GI and surgical esophageal course, a sought after invitation to be faculty is the forerunner of the new American Foregut Society the first combined Surgical and GI society solely devoted to foregut disease. His early interest was in liver disease. A first author publication in Gastroenterology on ammonia levels in liver disease while a resident in medicine, a study on liver scanning for portosystemic hypertension in the New England Journal, an article in the Annals of Internal Medicine in which he described what today is known as Castell's sign) the most sensitive and specific percussion sign for bedside assessment of spleen size), while a fellow was foreshadowing of a prolific academic career. He began his unparalled career as an esophageal investigator while with Lauren Harris in Boston, studying the role of hormonal control of the lower esophageal sphincter (LES), another New England Journal publication. While at Bethesda he developed in earnest the field of esophageal clinical investigation, studying the effect of vasoactive intestinal peptide, vagotomy, and histamine on the LES, beginning his study of non-cardiac chest pain with a publication linking high amplitude prolonged esophageal contractions (Nutcracker) with non-cardiac chest pain. I (POK) met him while Chief Resident in Medicine and began my GI career as his first fellow in Winston Salem. While at Wake, his laboratory studied the effect of Zollinger Ellison syndrome on the esophagus, calcium channel blockers, edrophonium provocation, and the relationship of motility disorders and non-cardiac chest pain. The laboratory lead the development of hypopharyngeal pH monitoring for extraesophageal GERD, developed the symptom index, described the finding of “normal” LES relaxation in achalasia, and began to study UES function with solid-state manometry. While in Philadelphia as GI Chief at Jefferson, he recruited Satish Rattan and established a basic research laboratory. While at Graduate with Dave Katzka, myself and an army of young students and residents his laboratory published new data on the acid pocket, tricyclic agents, and esophageal sensitivity, and described nocturnal gastric acid breakthrough, intragastric pharmacodynamics of proton pump inhibitors and the effect of nocturnal histamine blockers on nocturnal gastric pH. He introduced the esophageal world to IEM in 1997 and published his first studies of impedance detected non-acid reflux while at Graduate. At MUSC, his laboratory fully developed combined impedance/pH monitoring and impedance/manometry solidifying the contribution of weakly acidic and non-acidic reflux and its potential for causing reflux symptoms, especially in refractory GERD. DO will be remembered as a caring father, a great friend, promoter, and mentor, and for his infectious enthusiasm for discovery, his perpetual smile, and his desire to support the lives and careers of others. The many who have been touched by him in some ways are lucky. We can only hope we can come close to giving others what he gave us. David J. Sugarbaker, M.D. (1953−2018) Dr. David Sugarbaker was born in Jefferson City, Missouri, on August 5, 1953. He graduated from Cornell Medical School in 1979 and received Residency in Surgery at the Brigham & Women's Hospital (BWH) in Boston, research training at the Beth Israel Hospital (BIH) in Boston, and advanced training in esophageal surgery at the Toronto General Hospital. He was recruited back to BWH as chief of the newly formed Division of Thoracic Surgery. He became the Richard E. Wilson Professor of Surgical Oncology at Harvard Medical School. In 2012, he won the Pioneer Award from the Mesothelioma Applied Research Foundation. In 2014, Dr. Sugarbaker moved to Baylor to establish a mesothelioma center at the Baylor College of Medicine. He served as a Councilor, Treasurer, and the 94th president of the American Association for Thoracic Surgery (AATS). He passed away in 2018 at the young age of 65. He is survived by his wife, Linda, and his 6 children and 4 grandchildren. David Sugarbaker has made lasting contributions to the understanding of physiology, pathophysiology, and surgical treatment of esophageal motility disorders. I (RKG) was fortunate to have David join me for his Research Fellowship at the BIH. He started by identifying gaps in our knowledge of the pathophysiology of gastroesophageal reflux and hiatal hernia. He was struck by the fact that almost all the investigations were focused on the function of the circular muscle, and there was a glaring lack of information on the function of the longitudinal muscle of the esophagus. Therefore, he wanted to study how longitudinal muscle functioned during swallowing. I told him that the mechanism of the functional role of the esophageal longitudinal muscle was technically difficult. It will require specialized mechanical recording of isolated segments of the longitudinal muscle, extracellular recording of the electrical activity of the longitudinal muscle, and intracellular electrical recordings to record membrane potentials of the smooth muscles. Our laboratory was not set up to do those techniques. Moreover, to do all this required to study responses to swallowing in anesthetized opossums. I suggested that it was a difficult project. However, he proceeded to construct a vibration-free recording system by constructing a sandbox that he placed on tires, using miniature strain gauges to record contractions at various sites on the longitudinal muscle, and smooth muscle membrane potentials from the viable flaps of the longitudinal muscle. Parallel recordings were made from the circular muscle. Swallows were induced by pharyngeal stimulation and monitored by the mylohyoid muscle activity. He found that in response to a swallow, the longitudinal muscle contraction started earlier and lasted longer than circular muscle contraction. Circular muscle but not longitudinal muscle showed initial hyperpolarization, suggesting that while the circular smooth muscle of the esophagus received inhibitory nitrergic and cholinergic innervation, the longitudinal muscle received predominantly cholinergic innervation.1-3 He also showed that in response to a swallow the circular muscle showed prompt hyperpolarization throughout the length of the esophagus followed by sequential activation of excitation that is responsible for the latency gradient, which is responsible for peristalsis. Moreover, the longitudinal muscle showed sequential cholinergic excitation without preceding inhibition. He also showed the presence of nitrergic and cholinergic nerves in the human esophagus. His study formed the basis of all subsequent studies on the distinctive roles of the circular and longitudinal muscles of the esophagus. As the chief of thoracic surgery at the BWH, he put together a team of outstanding esophageal surgeons. In 1992, David developed the first general thoracic surgical residency track in the United States, and he eventually trained more than 80 residents; a large number of them are now leaders in the profession throughout the United States. He also authored a now-famous textbook on Adult Thoracic Surgery. During his practice, Dr. Sugarbaker met a patient who had mesothelioma. At that time, there was no accepted treatment of mesothelioma. He redesigned the operation, known as extrapleural pneumonectomy, and reported improved outcomes in 1992. He dedicated 25 years to establishing the International Mesothelioma Program at BWH, earning the nickname “Mr. Mesothelioma.” He leaves an enduring legacy through his discoveries and knowledge gained about the disease, the research, and treatment centers that he established.4, 5 As the President of the AATS Foundation, he transformed the Foundation into an international philanthropic organization. As an academic scholar, David discussed the role of perseverance in the life of an academic surgeon. He always emphasized the importance of focus and of eschewing modern distractions in achieving excellence described these as “the essence of excellence.” Dr. Coselli has aptly stated, “No one else in our lifetime had more impact on the field of thoracic surgery” than Dr. Sugarbaker.6 As a supplement, please see the following link for the video recording in honor of these colleagues, on January 24, 2022 zoom meeting, organized by Ravi Mittal, M.D. https://www.dropbox.com/s/svk03bfsdbgi6iw/ZEMM%20Jan24.mp4?dl=0. http://ZEMMJan24.mp4 All authors declare no conflict of interest.