Wiley W. Souba

Glutamine Metabolism in Sepsis and Infection

Severe infection causes marked derangements in the flow of glutamine among organs, and these changes are accompanied by significant alterations in regional cell membrane transport and intracellular glutamine metabolism. Skeletal muscle, the major repository of glutamine, exhibits a twofold increase in glutamine release during infection, which is associated with a significant increase in endogenous glutamine biosynthesis. Despite an increase in glutamine synthetase activity in skeletal muscle, the intracellular glutamine pool becomes depleted, indicating that release rates exceed rates of synthesis. Simultaneously, the circulating pool of glutamine does not increase, indicating accelerated uptake by other organs. The liver appears to be the major organ of glutamine uptake in severe infection; studies in endotoxemic rodents have shown net hepatic glutamine uptake to increase by as much as 8- to 10-fold. This increase is due partially to increases in liver blood flow, but also to a three- to fourfold increase in hepatocyte System N activity in the liver. Cytokines and glucocorticoids mediate the increased uptake of glutamine by the liver in septic states as well as other compounds. Sepsis does not appear to induce an increase in System N gene expression, indicating that the increase in hepatic glutamine transport observed during severe infection is probably regulated at the protein level. The bowel displays a decrease in glutamine utilization during sepsis, a response that may be related to the decrease in circulating insulin-like growth factor-1 (IGF-1) levels that is characteristic of sepsis. Recent studies suggest that IGF-1 has a direct effect on stimulating glutamine transport across the gut lumen and thus may represent a therapeutic avenue for improving gut nutrition during severe infection. The cells of the immune system (lymphocytes, macrophages) are also major glutamine consumers during inflammatory states in which cell proliferation is increased. Under these conditions, glutamine availability can become rate limiting for key cell functions, such as phagocytosis and antibody production.

Branched-Chain Amino Acid-Enriched Nutritional Support in Surgical and Cancer Patients

Prolonged surgical stress and advanced malignant disease lead to systemic catabolism characterized by depletion of muscle protein and oxidation of skeletal muscle BCAA. BCAA oxidation provides energy for muscle and other organs and is the precursor for amino acid synthesis to replenish alanine and glutamine depleted in catabolic states. Persistent excessive catabolism leads to skeletal muscle wasting, negative nitrogen balance, and immune compromise. BCAAs, especially leucine, stimulate protein synthesis, inhibit proteolysis (in cell culture models and in animals), and promote glutamine synthesis. A number of small and diverse clinical trials studied the effects of BCAA-enriched nutritional support in moderately to severely stressed surgical and cancer patients. The findings of these clinical trials have been inconsistent; some show improved nitrogen balance, increased skeletal muscle protein synthesis, and reduced skeletal muscle catabolism whereas others show no significant improvement. The value of these trials is compromised by small sample size, heterogeneous patients, poor study design, varying degrees of metabolic stress, and inappropriate endpoints. More recent trials that evaluate clinical outcomes in hepatocellular carcinoma patients show promising results; in addition to improving metabolic parameters, BCAA-enriched oral supplementation improved morbidity and quality of life in patients undergoing major liver resection and chemo-embolization. In summary, the role of BCAAs in the nutritional support of stressed surgical and cancer patients remains to be clearly defined, despite their potential beneficial biological properties.

Developing the young academic surgeon

In the past, the process of developing the young academic surgeon was arguably less strategic, one that was often not deliberately managed and monitored, leading in some cases to academic drift and disillusionment. Once upon a time it was assumed that greatness was genetic and that the next triple threat would emerge when a pre-programmed set of genes was turned on. Today, as the complexities and vicissitudes of our work increase, it is practically impossible for even the most gifted young person to be successful without careful attention to career development. Faculty development must be deliberate and strategic--every junior faculty member is unique and will require a customized career development plan that is well thought out, linked to measurable goals, monitored routinely and buttressed by effective mentoring. This approach will require time and commitment--precious commodities that are in short supply as the demands on our time are only escalating. By recruiting the right people (those who fit with the organizations values and goals) and providing the right environment, we can optimize the growth and satisfaction of our young faculty and, in so doing, create departments that are leaders in carrying out our missions of research, education and patient care. We cannot afford to have our young people fail--it is simply too costly, both from a financial and a human perspective.

Building Our Future: A Plea for Leadership

In recent years the spastic nature of the health care marketplace has continued to increase, which has greatly escalated the demands of leadership in academic medical centers. The expectations of leaders, including surgery chairs, have increased considerably, whereas their capacity for independent action has undeniably diminished. In such a predicament, it is useful to revisit fundamentals, using them as a guide to build a sound future. Five leadership principles are critical to building a better future: (1) recognizing that the work of leadership involves an inward journey of self-discovery and self-development; (2) establishing clarity around a set of core values that guide the organization as it pursues its goals; (3) communicating a clear sense of purpose and vision that inspires widespread commitment to a shared sense of destiny; (4) building a culture of excellence and accountability throughout the entire organization; and (5) creating a culture that emphasizes the development of leaders and leadership as an organizational capacity. Leadership and learning are inextricably linked. We must change the perception that learning in academic surgery is about correcting a deficit rather than a natural part of human growth and development. Our ability to learn, grow, and contribute to an organization is what provides each of us with meaning and identity. This feeling of being part of something special that is larger than ourselves is a powerful force and an important dividend of great leadership.

Marketing strategy: An essential component of business development for academic health centers

BACKGROUNDnHistorically, academic health centers (AHCs) have detached themselves from commercialism and entrepreneurism, viewing these activities as being inconsistent with many of their core academic values. Word-of-mouth promotion was their primary, if not sole, marketing strategy. Less emphasis was placed on preparing, pricing, distributing, and promoting these services to targeted audiences. Understanding customers needs was not a top priority.nnnMETHODSnThe marketing strategies and tools currently being developed and utilized by AHCs were reviewed.nnnRESULTSnIn an effort to attract customers and win contracts, AHCs are aggressively marketing themselves by designing new services, promoting those services much more intensely, restructuring the entire distribution system that delivers those services, and crafting pricing strategies that build in flexibility. With growing frequency, these marketing tactics are part and parcel of a carefully crafted data-driven strategic plan designed to meet the business-development goals of the institution.nnnCONCLUSIONSnIn order to carry out their missions, AHCs have recognized that they can no longer rest on their ivory tower laurels. They must learn how to market themselves in a market economy.

Epidermal growth factor regulation of system L alanine transport in undifferentiated and differentiated intestinal Caco-2 cells

Epidermal growth factor (EGF) in intestinal lumen regulates many gut epithelial cell functions. Influenced by growth factors at various differentiation stages, enterocytes execute the major task of absorbing nutrient amino acids. The purpose of this study was to investigate the effects of EGF on Na+-independent L-alanine transport in intestinal epithelial cells. Na+-independent [3H]-L-alanine transport was measured in the differentiating Caco-2 cells. In both the undifferentiated and differentiated states, L-alanine uptake occurred via a single saturable Na+-independent system L plus simple passive diffusion. System L activity decreased as the cells progressed from the undifferentiated to the differentiated state. Prolonged incubation with EGF (>30 hours) resulted in a 70% increase in system L activity in both undifferentiated and differentiated cells. EGF stimulated the system L Vmax without affecting Km. System L activity stimulation was inhibited by chelerythrine chloride, cycloheximide, or actinomycin D. These data suggest that intestinal epithelial cell differentiation is associated with a decrease in system L transport capacity. EGF activates system L transport activity through a signaling mechanism involving protein kinase C, independent of cell differentiation state. Both cell differentiation and EGF regulation of system L activity occur via alteration of functional copies of the system L transporter.

Specific Reversible Stimulation of System y+ l-Arginine Transport Activity in Human Intestinal Cells

Abstractl-Arginine, which is intimately involved in cellular immune functions and nitric oxide biology, is transported by intestinal cells largely via transport System y+. The gut epithelium is exposed to various luminal amino acids at any given time, and therefore the purpose of this study was to study the regulation of luminal arginine transport by other amino acids. System y+l-arginine transport activity was measured in Caco-2 monolayers exposed to various amino acids. l-arginine and/or other System y+ substrates specifically upregulated System y+ transport activity twofold after 1 hour, with a response noted as early as 5 minutes. Non-System y+ substrates did not affect l-arginine absorption. Kinetic analysis indicated that l-arginine exposure increased both System y+ Km and Vmax. Neither cycloheximide nor actinomycin affected this stimulation, indicating that the regulation did not involve transcription or translation. The System y+ substrate activation effect was reversible. l-arginine transport activity returned to baseline within 3 hours when cells were reincubated in amino acid-free media. These data indicate that System y+ arginine transport activity is rapidly and reversibly activated by System y+ substrates via a mechanism consistent with transmembrane stimulation. These findings identify a mechanism by which luminal nutrients regulate arginine uptake by the gut.

Equipping Physicians to Lead: Principles for Innovation

The healthcare system in the United States has evolved rapidly in recent years, mainly in response to the economic pressures of the healthcare marketplace. The unparalleled American third-party payer system, the largest service economy in the world, is, for the first time, truly subject to classic forces of laissez faire economics (ie, capitalism). Outgrowths of this revolution include entities such as utilization review, contracting based on provider performance, and myriad cost-containment initiatives. Until recently as providers, we had the best of both worlds: the ability to set fee-for-service unencumbered by the laws of the marketplace; and a virtual guarantee of reimbursement, without regard to the necessity or quality of service. Clearly, the provider has historically dominated the system. In fact, during the 50 years after World War II, both providers and patients were almost entirely insulated from financial risk. Now, however, the advent of a true market economy has caused a major shift in power among the classic healthcare system entities: providers, patients, and third-party payers. Although some third-party payers, primarily the federal government and types of insurers, continue to compensate providers for their services, the underlying payers (large employers) are demanding that providers and patients also share the financial burden. Rather suddenly, it is these third parties that are positioned to assume a major degree of control over the delivery of healthcare. They will no longer tolerate unbridled growth in healthcare expense. The immediate consequence of these rapid changes is that physicians and patients alike are often disenchanted with the medical care delivered and received. The noble profession of medicine has been diminished as physicians have come to be viewed as “providers” in an industry where healthcare is in danger of becoming simply a commodity. The profession is finally subject to one of the major market forces set loose during the Industrial Revolution, that of the standardization of processes. The current emphasis on reduction in medical “errors,” which both the federal government and private industry believe can be achieved through a standardization approach (ie, a decrease in product variance), is but one manifestation of this market force. Most Americans still believe that the United States has the premier healthcare system in the world, but they also believe it doesn’t serve them as well as it should. Many people believe that physicians are greedy, that all hospitals are for-profits, and that the healthcare system is more interested in the bottom line than in patient care. Only through physician leadership that integrates our traditional core values with newer market values in such a way that the physician-patient relationship is our number one priority, can trust and confidence in our health system be restored. “In essence,” said James O’Toole, “the leadership challenge is to provide the glue to cohere independent units in a world characterized by forces of entropy and fragmentation. Only one element has been identified as powerful enough to overcome those centripetal forces, and that is trust. And recent experience shows that such trust emanates from leadership based on shared purpose, shared vision, and especially, shared values.” Obviously, the medical profession is at a crossroads. The overriding mission of most physicians is, and should be, to compassionately care for the ill. However, in order to succeed in this mission, we must now align ourselves with the realities of a radically changing healthcare system that is driven by financial considerations. When cost becomes the dominant outcome measure in patient care, our mission is in jeopardy. As in any service economy, eventually, value will become the dominant measure for both patients and payers; value is simply quality divided by cost. Increases in quality and decreases in cost both lead to increases in value (and vice versa). Only the physician, the focal point of the healthcare delivery system, can truly influence the value equation. Henry Kissinger once commented that, “History has no resting places; what does not advance, must sooner or later decline.” Rather than abdicate our traditional roles as leaders in healthcare provision, we, the physicians, need to acquire another vocabulary and its accompanying skill set, that of leadership and management competencies. With the advent of the healthcare delivery system as a market entity, patient care is a far more complex task than it was 50 years ago. For the concept of “managed” care (versus managed cost) to be truly operative, physicians must be able to integrate cost-containment principles and high standards of patient care (the quality component of value). Knowledge of managerial and financial strategies is needed to complement clinical training if superior patient care is Am J Surg. 2000;180:185–186. From the Department of Surgery (RWS), College of Medicine and Chancellor’s Office University of Kentucky Chandler Medical Center, and Clinical Operations, Veterans Administration Medical Center, Lexington, Kentucky, and the Department of Surgery (WWS), Penn State College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania. Requests for reprints should be addressed to Richard W. Schwartz, MD, Department of Surgery, Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536. Manuscript submitted May 15, 2000, and accepted in revised form July 15, 2000. PHYSICIAN LEADERSHIP

Stimulation of Expression of the Intestinal Glutamine Transporter ATB0 in Tumor-Bearing Rats

BackgroundGlutamine supplementation ameliorates host catabolic response in tumor bearing states. The purpose of this in vivo study was to investigate intestinal glutamine transport and expression of glutamine transporter ATB0 in methyl-cholanthrene (MCA)-sarcoma bearing rats.MethodsFisher-344 rats underwent subcutaneous flank implantation of MCA-sarcoma cells (saline as control) and were pair-fed an equal quantity of chow as controls, to account for tumor-induced anorexia, until tumors reached 10 or 20% body weight. Intestinal mucosal brush border membrane [3H]-Glutamine transport was measured. Glutamine transporter ATB0 mRNA and protein levels were measured by real-time PCR and western blot techniques, respectively.ResultsGlutamine transport activity across the intestinal brush border membrane (BBM) was 3.7-fold higher in tumor-bearing rats (TBR) than in controls (TBR 153xa0±xa022.6 vs. Control 41.9xa0±xa09.7xa0pmol/mg protein/10s, Pxa0<xa0.01). Transporter ATB0 mRNA levels were 1.4-fold higher in tumor-bearing rats (Relative value TBR .61xa0±xa0.12 vs. Control .43xa0±xa0.1, Pxa0<xa0.05). A 1.4-fold increase in transporter ATB0 protein levels was observed in the tumor-bearing rats (Relative value TBR .52xa0±xa0.07 vs. Control .37xa0±xa0.04, Pxa0<xa0.05). Circulating aortic plasma glutamine levels were 1.3-fold higher in tumor bearing rats ([Glutamine]xa0=xa0.63xa0±xa0.02 Control vs. [Glutamine]xa0=xa0.74xa0±xa0.01xa0mmol/l TBR, Pxa0<xa0.0001). Portal venous plasma glutamine levels were also higher in tumor bearing rats ([Glutamine]xa0=xa0.47xa0±xa0.01 Control vs. [Glutamine]xa0=xa0.60xa0±xa0.02xa0mmol/l TBR, Pxa0<xa0.0001).ConclusionIntestinal brush border membrane glutamine transport activity, transporter ATB0 mRNA and protein levels are up-regulate in tumor-bearing rats.

97 – Measuring the Performance of Surgical Research1

The creation of new knowledge through basic research or clinical trials is one of the social missions of academic medical centers. Indeed, research has been responsible for many of the improvements in the care of the surgical patient that have occurred over the years. In the past, departments of surgery were able to use overages from clinical revenues to support research, but this approach is no longer a viable strategy. Mounting pressures to reduce costs together with major reductions in reimbursement have made cross-subsidization of the research program more and more difficult. These challenges have placed the research enterprise in most departments of surgery in jeopardy—achieving the goals of research are inherently more difficult because of these new constraints. In order to meet these challenges and preserve research in academic departments of surgery, several aspects of the research enterprise will have to change. The department will have to develop expertise in strategic research management.