Southwestern Medical School Research Articles

Editorial introductions

Editorial introductions

Editorial introductions

Editorial introductions

Commentary on “Effective testicular germ cell tumor therapy on renal function.” Cost NG, Adibi M, Lubahn JD et al, Department of Urology, University of Texas Southwestern Medical School, Dallas, TX: Urology 2012;80:641

ObjectiveTo assess the pre- and post-therapy glomerular filtration rate in patients with testicular germ cell tumors to determine its effect on the natural history of renal function. MethodsWe reviewed an institutional database of patients with testicular germ cell tumor, with pre- and post-therapy serum creatinine levels available. The renal function was estimated using a calculated glomerular filtration rate. We compared the patients treated without chemotherapy (orchiectomy with or without radiotherapy or retroperitoneal lymph node dissection) with those who received systemic chemotherapy. We analyzed the data for the outcome of new-onset chronic kidney disease (CKD) stage 3 between these groups. Kaplan-Meier curves were constructed and compared using a log-rank test. ResultsA total of 144 patients were reviewed. The testicular germ cell tumor stage distribution was stage I in 78 (54.2%), stage II in 28 (19.4%), and stage III in 38 (26.4%). Overall, the median creatinine and estimated glomerular filtration rate at diagnosis was 0.9mg/dL (range 0.5-1.5) and 104.0mL/min/1.73m2 (range 58.7-235), respectively. Of the 144 patients, 102 (70.8%) had CKD stage 0-1, 41 (28.5%) stage 2, and 1 (0.7%) stage 3. The median creatinine and estimated glomerular filtration rate at the last follow-up visit was 1.0mg/dL (range 0.6-2.6) and 95.5mL/min/1.73m2 (range 31.5-167.6), respectively. This difference between the pre- and post-therapy estimated glomerular filtration rate was significant (P<0.01). A total of 81 patients (56.3%) received chemotherapy (median 4 cycles, range 1-12), and 63 (43.7%) were treated without chemotherapy. Of the 81 patients who received chemotherapy, 8 (9.9%) developed new-onset CKD 3 compared with none in the nonchemotherapy group (P =0.01). ConclusionPatients with testicular germ cell tumor receiving chemotherapy experienced a significant decrease in the estimated glomerular filtration rate and had a significantly increased risk of developing CKD stage 3 compared with those treated without chemotherapy. These findings offer insight into the long-term risks of testicular germ cell tumor survivorship and will be useful in counseling patients.

Commentary on “Radiofrequency ablation of incidental benign small renal mass: Outcomes and follow-up protocol.” Tan YK, Best SL, Olweny E, Park S, Trimmer C, Cadeddu JA, Department of Urology, University of Texas Southwestern Medical School, Dallas, Texas, TX.

To review our 10-year experience with radiofrequency ablation, focusing on the outcomes for the incidental benign renal tumor. Tumor ablation is an alternative, minimally invasive approach for the treatment of small renal masses (SRMs), with published series appropriately emphasizing the outcomes for the renal cell carcinoma subset of treated tumors. However, similar to partial nephrectomy, approximately 20% of the SRMs are benign. The intermediate to long-term outcome of the incidentally ablated benign tumor and its appropriate follow-up protocol are unknown. All SRMs treated with temperature-based radiofrequency ablation from 2001 to 2011 were reviewed. Of a total of 280 enhancing SRMs biopsied at radiofrequency ablation, 47 were confirmed as benign tumors. Ablation success was defined as the lack of enhancement on the initial postablation axial imaging. Recurrence was defined as tumor growth and enhancement on follow-up axial imaging. Of the 47 benign tumors, 32 were treated percutaneously and 15 laparoscopically. The histologic biopsy finding was angiomyolipoma in 10 and oncocytoma in 37. The median tumor size was 2cm (range 1-3.6), and the mean follow-up was 45 months. No recurrences developed, and all lesions required only 1 treatment session. The median preoperative and postoperative glomerular filtration rate was 77ml/min/1.73m(2) (range 39-137) and 68ml/min/1.73m(2) (range 36-137). The present study was limited by its retrospective nature and small sample population. Radiofrequency ablation of SRMs<3.5cm, found to be benign on concurrent biopsy, can be efficaciously treated with a single treatment session. Long-term follow-up imaging might not be required if successful ablation is determined at the initial post-treatment cross-sectional imaging study.

A conversation with Jean Wilson

We are joined by a JCI favorite, Dr. Jean Wilson from the University of Texas Southwestern Medical School, who was the editor in chief of the JCI between 1972 and 1977 (Figure ​(Figure1).1). Dr. Wilson’s research centered on cholesterol metabolism and steroid hormone action, laid the groundwork for understanding male/female genital development, and led to the first medical therapy for benign prostatic hyperplasia (BPH). The full interview can be seen at http://www.jci.org/kiosk/cgm.

A conversation with Donald Seldin

Today we are joined by Donald Seldin from The University of Texas Southwestern Medical School (Figure ​(Figure1).1). Seldin served as the chairman of medicine at UT Southwestern for nearly four decades and transformed the department and the school from a grouping of ramshackle army barracks to a world-class medical center, host to Nobel Laureates and members of the national academies.

Editorial introductions

Editorial introductions

Translational Physiology: Understanding the WHI gap

“impact of aging vs. estrogen loss on cardiac gene expression: estrogen replacement and inflammation” by Pechenino et al. ([7][1]) is an exciting addition to the literature that helps explain the discrepancy between the observational studies and the randomized clinical trials with regard to

Superior calcium bioavailability of effervescent potassium calcium citrate over tablet formulation of calcium citrate after Roux-en-Y gastric bypass

BackgroundCalcium supplementation is commonly recommended for patients after Roux-en-Y gastric bypass to avert bone loss. To test the hypothesis that effervescent (liquid) potassium-calcium-citrate (PCC) might be more bioavailable than a tablet formulation of calcium citrate (Citracal Petite), the present study compared a single dose response of the 2 compounds. The present study was conducted at the University of Texas Southwestern Medical School at Dallas. MethodsA total of 15 patients who had undergone Roux-en-Y gastric bypass were included in a 2-phase, crossover, randomized study comparing the single-dose bioavailability of PCC versus Citracal Petite. After following a restricted diet for 1 week, the participants ingested either a single dose of 400 mg elemental calcium as PCC or Citracal Petite. Sequential serum and urine samples were collected for a 6-hour period after the dose and analyzed for calcium, parathyroid hormone, and acid-base parameters. ResultsCompared with citracal petite, PCC significantly increased the serum calcium concentrations at 2, 3, and 4 hours after the oral load. The peak to baseline variation and increment in serum calcium (area under the curve) were significantly greater after PCC (P = .015 and P = .002, respectively). Concurrently, the baseline to nadir variation and decrement in serum parathyroid hormone (area over the curve) were significantly greater after PCC (P = .004 and P = .005, respectively). Moreover, compared with Citracal Petite, PCC caused a significantly greater increment in urinary citrate (P < .0001) and potassium (P = .0004) and a significantly lower increase in urinary ammonium (P = .045). ConclusionIn patients who have undergone Roux-en-Y gastric bypass, PCC was superior to Citracal Petite in conferring bioavailable calcium and suppressing parathyroid hormone secretion. PCC also provided an alkali load.

Chlorthalidone Versus Hydrochlorothiazide

See related article, pp 1001–1007 Chlorthalidone (CTD) is the best diuretic for the treatment of hypertension, both in blood pressure–lowering efficacy and, most importantly, in prevention of hypertension-related morbidity and mortality. Despite this fact, hydrochlorothiazide (HCTZ) has been and continues to be by far the most frequently prescribed diuretic in the United States.1 Even among patients with resistant hypertension, where a more potent diuretic is especially needed, CTD is chosen in only 3% of patients.2 There are numerous possible reasons for this flagrant failure of evidence-based medicine. I will refer to the Aesop tale of “The Tortoise and the Hare” as my way of explaining the paradox. In this reference, physicians are the tortoises, whereas a pharmaceutical company is the hare; here, unlike in the original, the hare easily wins the race. The 2 diuretics were approved for the treatment of hypertension within a year of each other, HCTZ in 1959 and CTD in 1960. Soon thereafter, small trials documented the equal efficacy of CTD in much smaller doses in lowering blood pressure compared with HCTZ3 or other thiazides.4 A few years later, the Multiple Risk Factor Intervention Trial (MRFIT) was begun, and the designers offered the 15 participating clinics the choice of using either HCTZ or CTD; 9 chose HCTZ and 6 chose …

The case of a viable pregnancy post vaginal radical trachelectomy followed by combined chemo-radiation therapy

a Gynecologic Oncology Service, Centre Hospitalier Universitaire de Quebec (CHUQ), L'Hotel-Dieu de Quebec, Laval University, Quebec City, Canada b Gynecologic Oncology Division, Texas Oncology, Austin, TX, USA c Radiation Oncology Division, Austin Cancer Centers, Austin, TX, USA d Texas Fertility Center, Austin, Texas, University of Texas Southwestern Medical School, Dallas, TX, USA e Women Partners in Health, Austin, Texas, Seton Medical Center, University of Texas Southwestern Medical School, Dallas, TX, USA

PAUL A. GRAYBURN, MD, on Percutaneous Mitral Repair With the MitraClip™ Device: A Conversation With the Editor

Paul Grayburn did his general cardiology fellowship under the tutelage of Dr. Anthony N. DeMaria at the University of Kentucky from 1984 to 1986, followed by a year of interventional cardiology training with Dr. David C. Booth. In 1988, he was recruited to the University of Texas Southwestern Medical School by Dr. James T. Willerson, where he served on the faculty for 15 years. During that time, he was director of the echocardiography laboratories at the University of Texas Southwestern and chief of cardiology at the Dallas Veterans Affairs Medical Center, where he also practiced interventional cardiology. In 2002, Dr. Grayburn moved to Baylor University Medical Center to accept the Paul J. Thomas Chair in Cardiology Research and Education. He has published more than 260 articles, mainly in peer-reviewed medical journals. He has served as an associate editor of The American Journal of Cardiology since 1997. He is on the editorial boards of Circulation, the Journal of the American College of Cardiology: Cardiovascular Imaging, and Heart. Dr. Grayburn currently serves on the Publications Committee for the Endovascular Edge-toEdge Repair Study (EVEREST) II and the Core Lab Committee and Steering Committee of the Surgical Treatment for Ischemic Heart Failure (STICH) trial. He has held a National Institutes of Health K24 grant for mentoring junior faculty members and an R01 grant, “Functional Mitral Regurgitation in Ischemic Cardiomyopathy,” for 3-dimensional transesophageal echocardiographic evaluation of the mechanisms of functional mitral regurgitation (MR) in the STICH trial. He has served on multiple committees for the American Society of Echocardiography, including the Task Force for Quantitation of Valvular Regurgitation. He is currently the principal investigator for the MitraClip (Abbott Laboratories, Abbott Park, Illinois) studies at Baylor Health Care System and co-investigator for the Cardiothoracic Surgery Network Trials on MR. Dr. Grayburn’s background in interventional cardiology and echocardiography, including intraoperative transesophageal echocardiography during surgical mitral valve repair, give him a unique insight into percutaneous mitral valve therapies. William Clifford Roberts, MD (hereafter Roberts): Dr. Grayburn, I appreciate your coming to my house for our discussion. It is March 24, 2011. You have been involved with percutaneous mitral valve repair for a number of years?

Airway Obstruction Due to Endotracheal Tube's Lumen Collapse Secondary to Cuff

To the Editor An 11-year-old boy was admitted to the emergency room after falling 15 m. His trachea was intubated in the field with a 5.5-mm inner diameter (ID) cuffed Rusch® endotracheal tube (ETT, Teleflex Medical, Research Triangle Park, NC), pulse oximeter saturation was 100%, and the ETT position was confirmed by capnography and chest radiograph. Ventilation became increasingly difficult (peak airway pressures of 30–35 cm H2O), breath sounds were barely audible, chest movements were minimal, and the end-tidal carbon dioxide was in the high 40s. The patient was urgently transported to the computed tomography (CT) suite, where after the initial scan sequences, ventilation became more difficult and the patient's trachea was reintubated with a styletted 5.5-mm ID cuffed ETT with immediate improvement of all respiratory variables. Examination of the initial CT images revealed a grossly overinflated ETT cuff causing collapse of the ETT lumen with almost complete airway obstruction (Fig. 1).Figure 1: Computed tomography of the head and anterior neck (sagittal image) showing the large, overinflated cuff and the collapsed endotracheal tube.Despite the suggestive CT imaging, we remained uncertain about the mechanism of the ETT collapse and decided to try to reproduce it in vitro. We placed the cuff of five 5.5-mm ID ETTs (Hi-Lo®; Mallinckrodt Co., Juárez, Mexico, the type of ETT we use in our institution) within the barrel of a 20-mL syringe and inflated the tube's cuff. We were unable to produce an ETT collapse in any of the ETTs studied even after cuff inflation with 20 mL of air, which developed a cuff pressure well above the maximal pressure (120 cm H2O) measurable with a cuff manometer (Cufflator #8199; Posey Co., Arcadia, CA). We repeated the in vitro test with three 6.0 Rusch ETTs (the type used for the prehospital intubation in our patient) and the lumens of the ETTs collapsed at lower volumes (12.5, 14.3, and 15 mL, respectively) and pressure >120 cm H2O (Fig. 2).Figure 2: Cuffed Rusch® endotracheal tube, 6.0-mm inner diameter, filled with contrast fluid, showing the collapsed tube after inflation of the cuff with 15 mL of air.When ETT cuff pressures are not monitored, cuff pressures greater than the recommended 20 to 30 cm H2O may develop. In one study, ETT cuff pressures were within the recommended ranges in only 27% of the patients.1 In the prehospital setting, most cuff pressures exceeded 40 cm H2O and required correction.2 In our in vitro trial, only the Rusch but not the Mallinckrodt ETT collapsed upon extreme overinflation of the cuff. The difference may stem from the quality of the polyvinyl chloride tube and hence from different compliances of the ETT wall. Although the findings in our in vitro model might resemble those of the in vivo situation, there are some differences. First, the human trachea has a greater compliance than that of a syringe barrel. Second, we did not warm the ETT and the syringe to body temperature but we theorize that warming would have made the ETT even softer (less rigid), thus requiring even less volume for cuff inflation to collapse the ETT. The patient's clinical timeline suggests that the obstruction worsened over time, possibly because of the temperature effect on the ETT tube, resulting in almost complete obstruction. Practitioners should be aware of the differences among different ETTs and the possibility that certain tubes may have the propensity to collapse after cuff overinflation. Dan Davis, MD Joseph Murphy, MDRadu B. Pop, MS Department of Anesthesiology and Pain Management University of Texas Southwestern Medical School and Children's Medical Center at Dallas Dallas, Texas Peter Szmuk, MD Department of Anesthesiology and Pain Management University of Texas Southwestern Medical School and Children's Medical Center at Dallas Dallas, Texas Outcomes Research Consortium The Cleveland Clinic Cleveland, Ohio [email protected] or [email protected]

Richard G.W. Anderson (1940–2011) and the birth of receptor-mediated endocytosis

On March 19, 2011, the discipline of cell biology lost a creative force with the passing of Richard G.W. Anderson, Professor and Chairman of the Department of Cell Biology at the University of Texas Southwestern Medical School. An unabashed chauvinist for cell biology, Dick served for many years on the editorial board of The Journal of Cell Biology and the Council of the American Society for Cell Biology. He died of glioblastoma multiforme six days before his 71st birthday.

Extremity magnetic resonance imaging in rheumatoid arthritis: Updated literature review.

Introduction In April 2006, a white paper on extremity magnetic resonance imaging (MRI) in rheumatoid arthritis (RA) was published, based on a review of the literature by a task force commissioned by the American College of Rheumatology (ACR) (1). The document was well received for its scientific rigor and overview of the literature at that time. However, the report had unexpected consequences as certain insurers began to restrict coverage for extremity MRI, which was not the intent of the original scientific review. Over the last 4 years, research into the value of extremity MRI and its role compared with conventional radiography and high-field MRI has been ongoing. In May 2009, the International Society of Extremity MRI in Rheumatology (ISEMIR) forwarded to the ACR publications they believed to be important in the field, requesting that the ACR review these new data and update the white paper with inclusion of the new information. The ACR Executive Committee and ACR Board of Directors thought that it was important to respond to this group, but due to the many efforts the ACR had ongoing, it was decided not to reconvene the original formal task force. Three members of the initial task force were asked to participate in this literature review: Atul Deodhar (an academic clinical rheumatologist with research interest in imaging modalities), to provide clinical perspective; Hollis Potter (a musculoskeletal radiologist with extensive experience in MRI), to provide technical expertise; and Stanley Cohen (a clinical rheumatologist in private practice with research interests in RA treatment). Paul Emery, who was not a member of the original task force, was asked to participate due to his expertise in MRI in RA as well as his involvement in the ISEMIR. Subsequent to the initial development of the manuscript, Philip Conaghan and Mikkel Ostergaard were invited to contribute to the review based on their expertise in the field and the desire of the working group as well as the ACR Board of Directors to broaden the perspective on this subject. This group reviewed the publications forwarded, as well as conducted a literature review of additional articles in Medline and PubMed involving MRI in RA published since 2006. This was not a formal evidence-based review such as the nowpopular RAND-based methodology, but simply a literature review addressing the same questions raised in 2006 to determine if the conclusions reached at that time should be modified. These publications can be broadly divided into 3 groups. The first group of publications deals with technical aspects, such as comparing low-field extremity units to high-field units, comparing the reproducibility of results obtained with low-field units in different centers, or addressing the Outcome Measures in Rheumatology Clinical Trials (OMERACT) MRI scoring systems. The second group consists of publications that confirm previously recorded observations, e.g., MRI scanning is more sensitive in detecting erosions compared with conventional radiography and predicts future radiographic erosions. The third group consists of publications that advance our knowledge of peripheral MRI further by breaking new ground. Although there are now extremity MRI units that are higher field at 1.0–1.5T, there was no available literature to determine the role of high-field extremity MRI in the diagnosis and management of RA. Stanley B. Cohen, MD: Presbyterian Hospital and University of Texas Southwestern Medical School, Dallas; Hollis Potter, MD: Hospital for Special Surgery and Weill Medical College of Cornell University, New York, New York; Atul Deodhar, MD: Rheumatology Clinics, Oregon Health and Science University, Portland; Paul Emery, MA, MD, FRCP, Philip Conaghan, MBBS, PhD, FRACP, FRCP: University of Leeds and National Institute of Health Research Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK; Mikkel Ostergaard, MD: Copenhagen University Hospital at Glostrup and Hvidovre, Copenhagen, Denmark. Dr. Potter has received institutional research support from General Electric Healthcare. Dr. Deodhar has received consultant fees, speaking fees, and/or honoraria (less than $10,000) from Centocor. Dr. Emery has received consultant fees, speaking fees, and/or honoraria (less than $10,000 each) from MSD, Pfizer, Roche, BMS, and Abbott. Dr. Conaghan has received consultant fees, speaking fees, and/or honoraria (less than $10,000 each) from BMS, Centocor, MSD, Novartis, Roche, and Pfizer. Address correspondence to Stanley B. Cohen, MD, 8144 Walnut Hill, Suite 800, Dallas, TX 75231. E-mail: Arthdoc@aol.com. Submitted for publication August 25, 2010; accepted November 22, 2010. Arthritis Care & Research Vol. 63, No. 5, May 2011, pp 660–665 DOI 10.1002/acr.20413 © 2011, American College of Rheumatology

Garrett Gross: Probing the Processes of Protection

In keeping with the idea that a little bit of bad can sometimes be good, transient ischemic episodes in the heart can be protective against more serious future attacks. This protective process, called preconditioning, was identified in 1986.1 Just a few years later, Garrett Gross and his colleagues discovered that drugs that opened cardiac ATP-sensitive potassium channels mimicked the preconditioning process.2,–,4 The gateway to the molecular understanding of preconditioning was opened, and the field grew and grew. Gross was, and still is, a preeminent leader in that field. In the late 1990s, work by his team showed that opioids, just like potassium channel openers, could mimic preconditioning.5,6 This discovery spawned yet more excitement and research activity, partly because of the ready availability of opioid drugs, such as morphine. Today, Gross, who is Professor of Cardiovascular Pharmacology at the Medical College of Wisconsin, Milwaukee, is still hunting for cardioprotective compounds and deciphering how they work. He talked to Circulation Research recently about his persistent passion for preconditioning and cardioprotective drugs. ### Where Did You Grow Up? Why did I grow up? That's a good question. Oh, where? [Laughs] I grew up in South Dakota. It was in a small town with only about 1500 people, so everybody knew everybody else's business. It was a farming and dairy community. I used to go out and work on the farms in the summer and bale hay and things like that. It was good exercise. My father was the local pharmacist, so I also worked in the drug store during my younger years, on and off throughout high school and college. It was the family business. My mother helped out too, as well as being a housewife. ### Did the Family Business Stimulate Your Interest in Science? I definitely would agree with that statement, that and the fact that at school, …

Quantitative role of LAL, NPC2, and NPC1 in lysosomal cholesterol processing defined by genetic and pharmacological manipulations

Lipoprotein cholesterol taken up by cells is processed in the endosomal/lysosomal (E/L) compartment by the sequential action of lysosomal acid lipase (LAL), Niemann-Pick C2 (NPC2), and Niemann-Pick C1 (NPC1). Inactivation of NPC2 in mouse caused sequestration of unesterified cholesterol (UC) and expanded the whole animal sterol pool from 2,305 to 4,337 mg/kg. However, this pool increased to 5,408 and 9,480 mg/kg, respectively, when NPC1 or LAL function was absent. The transport defect in mutants lacking NPC2 or NPC1, but not in those lacking LAL, was reversed by cyclodextrin (CD), and the ED₅₀ values for this reversal varied from ~40 mg/kg in kidney to >20,000 mg/kg in brain in both groups. This reversal occurred only with a CD that could interact with UC. Further, a CD that could interact with, but not solubilize, UC still overcame the transport defect. These studies showed that processing and export of sterol from the late E/L compartment was quantitatively different in mice lacking LAL, NPC2, or NPC1 function. In both npc2(-/-) and npc1(-/-) mice, the transport defect was reversed by a CD that interacted with UC, likely at the membrane/bulk-water interface, allowing sterol to move rapidly to the export site of the E/L compartment.

Frank J. Murphy, M.D., C.M., 1900–1972

Frank J. Murphy, M.D., C.M., 1900–1972

Ethics for the Pediatrician: The Ethics of Complementary and Alternative Medicine

1. Brenda J. Mears, MD* 1. *Department of Pediatrics, University of Texas at Southwestern Medical School, Dallas, Tex. Complementary and alternative medicine (CAM) is being used by a significant segment of society. To aid families who are using or considering CAM, pediatricians need to educate themselves about the available modalities and make this information available to these families. (1)(2) The 2007 National Health Interview Survey from the Centers for Disease Control and Prevention's National Center for Health Statistics estimated that 38.2% of adults and 11.8% of children had used some type of CAM in the preceding 12 months. (3) The rates may range as high as 70% in some groups. (4) In one survey, 87% of pediatricians had been asked by patients or parents about CAM, although as many as 66% may not tell their physicians when they do use CAM. (4)(5) Some of the cost of this care may be covered by insurance or government programs, but much is paid directly by families. The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health defines CAM as “a group of diverse medical and health care systems, practices, and products that are not generally considered part of conventional medicine.” Everything from whole medical systems such as homeopathy or naturopathy; mind-body medicine such as meditation, prayer, yoga, biofeedback, hypnosis, guided imagery, and art or music therapy; biologically based practices such as herbs, vitamins, and nutritional therapy; manipulative and body-based practices such as chiropractic or massage; and energy medicine such as biofield and bioelectromagnetic therapies has been considered CAM by some people. (6) When families use alternative medicine, these therapies are used instead of conventional medicine. Complementary medicine uses these therapies as …

Warfare, Genocide, and Ethnic Conflict: A Darwinian Approach

As the 21st century dawns, I reflect on the history of humankind with growing concern about the need to understand the underlying biological and cultural roots of ethnic conflict and warfare. In the many studies of human conflict, innate biological predispositions have been neglected. This article is the third part of a series of seminars for medical residents at the University of Texas Southwestern Medical School at Dallas (see http://adarwinstudygroup.org/). The series starts with in-depth coverage of Darwinian natural and sexual selection, with examples from the domestication of animals and plants and the crisis of antibiotic resistance. The series strives to show how biology has been neglected in the study of the we-they orientation of human behavior, with its devastating consequences. The subject material is profoundly disturbing, as it looks at “human nature” and contrasts the “dark side” of human behavior with the opposite, profoundly caring and loving side.