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The COVID-19 crisis has seriously affected academic medical centers (AMCs) on multiple levels. Combined with many trends that were already under way pre pandemic, the current situation has generated significant disruption and underscored the need for change within and across AMCs. In this article, the authors explore some of the major issues and propose actionable solutions in 3 areas of concentration. First, the impact on medical students is considered, particularly the trade-offs associated with online learning and the need to place greater pedagogical emphasis on virtual care delivery and other skills that will be increasingly in demand. Solutions described include greater utilization of technology, building more public health knowledge into the curriculum, and partnering with a wide range of academic disciplines. Second, leadership recruiting, vital to long-term success for AMCs, has been complicated by the crisis. Pressures discussed include adapting to the dynamics of competitive physician labor markets as well as attracting candidates with the skill sets to meet the requirements of a shifting AMC leadership landscape. Solutions proposed in this domain include making search processes more focused and streamlined, prioritizing creativity and flexibility as core management capabilities to be sought, and enhancing efforts with assistance from outside advisors. Finally, attention is devoted to the severe financial impact wrought by the pandemic, creating challenges whose resolution is central to planning future AMC directions. Specific challenges include recovery of lost clinical revenue and cash flow, determining how to deal with research funding, and the precarious economic balancing act engendered by the need to continue distance education. A full embrace of telehealth, collaborative policy-making among the many AMC constituencies, and committing fully to being in the vanguard of the transition to value-based care form the solution set offered.

BACKGROUND Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6 (IL-6) blockade–refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6 blockade–refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype.

Summary Geographically dispersed patients, inconsistent treatment tracking, and limited infrastructure slow research for many orphan diseases. We assess the feasibility of a patient-powered study design to overcome these challenges for Castleman disease, a rare hematologic disorder. Here, we report initial results from the ACCELERATE natural history registry. ACCELERATE includes a traditional physician-reported arm and a patient-powered arm, which enables patients to directly contribute medical data and biospecimens. This study design enables successful enrollment, with the 5-year minimum enrollment goal being met in 2 years. A median of 683 clinical, laboratory, and imaging data elements are captured per patient in the patient-powered arm compared with 37 in the physician-reported arm. These data reveal subgrouping characteristics, identify off-label treatments, support treatment guidelines, and are used in 17 clinical and translational studies. This feasibility study demonstrates that the direct-to-patient design is effective for collecting natural history data and biospecimens, tracking therapies, and providing critical research infrastructure., Graphical Abstract, Highlights Partnership with the patient community supports recruitment and results dissemination A patient-powered design enables high enrollment from a rare disease population Extensive clinical data reveal >40 off-label treatments used in Castleman disease De-identified linkage with a biobank supports translational research discoveries, Pierson et al. describe the feasibility of a patient-powered natural history registry for studying Castleman disease. They pair a traditional registry with a patient-powered approach, in which patients self-enroll and data collection is centralized. Clinical insights support treatment guidelines, and de-identified linkage to a biobank enables translational discoveries.

Background: Given the persistent disparity in the advancement of women compared with men faculty in academic medicine, it is critical to develop effective interventions to enhance women's careers. We carried out a cluster-randomized, multifaceted intervention to improve the success of women assistant professors at a research-intensive medical school. Materials and Methods: Twenty-seven departments/divisions were randomly assigned to intervention or control groups. The three-tiered intervention included components that were aimed at (1) the professional development of women assistant professors, (2) changes at the department/division level through faculty-led task forces, and (3) engagement of institutional leaders. Generalized linear models were used to test associations between assignment and outcomes, adjusting for correlations induced by the clustered design. Results: Academic productivity and work self-efficacy improved significantly over the 3-year trial in both intervention and control groups, but the improvements did not differ between the groups. Average hours worked per week declined significantly more for faculty in the intervention group as compared with the control group (−3.82 vs. −1.39 hours, respectively, p = 0.006). The PhD faculty in the intervention group published significantly more than PhD controls; however, no differences were observed between MDs in the intervention group and MDs in the control group. Conclusions: Significant improvements in academic productivity and work self-efficacy occurred in both intervention and control groups, potentially due to school-wide intervention effects. A greater decline in work hours in the intervention group despite similar increases in academic productivity may reflect learning to “work smarter” or reveal efficiencies brought about as a result of the multifaceted intervention. The intervention appeared to benefit the academic productivity of faculty with PhDs, but not MDs, suggesting that interventions should be more intense or tailored to specific faculty groups.

Individuals with type 1 diabetes are at increased risk for depression, anxiety disorder, and eating disorder diagnoses. People with type 1 diabetes are also at risk for subclinical levels of diabetes distress and anxiety. These mental/behavioral health comorbidities of diabetes are associated with poor adherence to treatment and poor glycemic control, thus increasing the risk for serious short- and long-term physical complications, which can result in blindness, amputations, stroke, cognitive decline, decreased quality of life, as well as premature death. When mental health comorbidities of diabetes are not diagnosed and treated, the financial cost to society and health care systems is catastrophic, and the human suffering that results is profound. This review summarizes state-of-the-art presentations and working group scholarly reports from the Mental Health Issues of Diabetes Conference(7–8 October 2013, Philadelphia, PA), which included stakeholders from the National Institutes of Health, people living with type 1 diabetes and their families, diabetes consumer advocacy groups, the insurance industry, as well as psychologists, psychiatrists, endocrinologists, and nurse practitioners who are all nationally and internationally recognized experts in type 1 diabetes research and care. At this landmark conference current evidence for the incidence and the consequences of mental health problems in type 1 diabetes was presented, supporting the integration of mental health screening and mental health care into routine diabetes medical care. Future research directions were recommended to establish the efficacy and cost-effectiveness of paradigms of diabetes care in which physical and mental health care are both priorities.

After a period of financial losses in the University of Pennsylvania Health System stemming from a combination of internal decision making and negative external market forces, the university set out to make substantial changes in the governance and administrative organization overseeing its health system and medical school. The changes were designed to assure the university and its trustees that financial controls were strengthened and that the missions of research, education, and patient care were balanced. The governance changes included creating a structure whereby a single administrative leader was responsible for all three missions— education, research, and clinical care— and reported directly to the president of the university. Further, existing governing boards responsible for various entities within the school of medicine and health system were disbanded, and a new single board was created to oversee PENN Medicine, the overarching organization established in 2001 and now responsible for oversight of the University of Pennsylvania School of Medicine and the University of Pennsylvania Health System. The realignment initiated by these major changes spawned additional refinements in leadership responsibilities and process controls that, together with the new governance model, are credited with financial recovery and stronger performance in all aspects of the enterprise. These structural changes led to greater emphasis on integrating and coordinating programs to take advantage of PENN Medicine’s home in a leading university. Acad Med. 2008; 83:861–866. More than 250 years after its founding, the University of Pennsylvania (Penn), home to the nation’s first medical school, continues to embrace tradition as a springboard for developing new approaches for facing current challenges and for preparing for those yet to come. We suspect that Penn is no different from other large universities in that having a strong medical school and a large health system engenders a mixture of significant pride, some angst, and everything in between. The pride obviously is generated by the tremendous potential to improve the human condition, spanning basic science through translational research and new treatments for patients; the angst arises over how to best manage such a complex, highreward, high-risk organization.

One of the most important questions in diabetes management is whether long-term glycemic control can reduce the risk for micro- and macrovascular complications in diabetes. Dr. Hadler in this issue of the Clinical Journal of the American Society of Nephrology raises his concerns about the use of glycosylated hemoglobin (HbA1c) as a surrogate marker of diabetes control and questions whether lowering HbA1c with the currently available oral hypoglycemic agents makes a clinically important long-term outcome difference for patients with type 2 diabetes. He is particularly concerned about the lack of evidence of cardiovascular risk reduction with HbA1c reduction in patients with type 2 diabetes. He further comments that “we were blinded” by the results of Diabetes Control and Complications Trial (DCCT) that showed reduction in microvascular complications after meticulous blood glucose control. However, it took 17 yr before any discernible advantage in terms of macrovascular disease was documented and the results are “far from a dramatic advance” in patients with type 1 diabetes; hence, one should not expect any more benefit in the middle-aged population with insulin resistance. He further cited the United Kingdom Prospective Diabetes Study (UKPDS), in which, after several years of intervention, there was no significant improvement in macrovascular complications. He questions the validity of UKPDS secondary analysis and challenges the new screening guidelines for detection and treatment of diabetes. Dr. Hadler supports his argument of lack of beneficial effects of effectiveness of oral hypoglycemic agents by reviewing A Diabetes Outcomes Progression Trial (ADOPT) results that showed relatively modest overall beneficial effects and an unexpected finding of higher fracture rates in women. Finally, he admonishes that in our focus of bringing down HbA1c, we are exposing our patients to higher risk for adverse effects such as weight gain, hypoglycemia, and fractures: “…talk …

Fostering professionalism requires institutional leadership and faculty buy-in. At the University of Pennsylvania School of Medicine, policies and educational programs were developed to enhance professionalism in three areas: conduct of clinical trials, relations with pharmaceutical manufacturers, and the clinical and teaching environment. Responsible conduct of clinical trials has been addressed with mandatory online education and certification for clinical investigators, but some still fail to recognize conflicts of interest. Activity of pharmaceutical representatives has been strictly regulated, meals and gifts from pharmaceutical companies prohibited, and the role of the pharmaceutical industry in the formulary process and in continuing medical education curtailed. Some faculty members have resented such restrictions, particularly in regard to their opportunity to give paid lectures. Professionalism in the clinical and teaching environment has been addressed with interdisciplinary rounding, experiential learning for medical students and residents in small groups, increased recognition of role models of professionalism, and active management of disruptive physicians. Leadership has been exerted through policy development, open communications, and moral suasion and example. Faculty members have expressed both their support and their reservations. Development of communication strategies continues, including town hall meetings, small groups and critical incident narratives, and individual feedback. The understanding and endorsement of faculty, staff, and trainees are an essential element of the professionalism effort.

Summary Background Multicentric Castleman's disease describes a group of poorly understood lymphoproliferative disorders driven by proinflammatory hypercytokinaemia. Patients have heterogeneous clinical features, characteristic lymph node histopathology, and often deadly multiple organ dysfunction. Human herpesvirus 8 (HHV8) causes multicentric Castleman's disease in immunosuppressed patients. The cause of HHV8-negative multicentric Castleman's disease is idiopathic; such cases are called idiopathic multicentric Castleman's disease. An absence of centralised information about idiopathic multicentric Castleman's disease represents a major challenge for clinicians and researchers. We aimed to characterise clinical features of, treatments for, and outcomes of idiopathic multicentric Castleman's disease. Methods We did a systematic literature review and searched PubMed, the Cochrane database, and ClinicalTrials.gov from January, 1995, with keywords including "Castleman's disease" and "giant lymph node hyperplasia". Inclusion criteria were pathology-confirmed Castleman's disease in multiple nodes and minimum clinical and treatment information on individual patients. Patients with HHV8 or HIV infection or diseases known to cause Castleman-like histopathology were excluded. Findings Our search identified 626 (33%) patients with HHV8-negative multicentric Castleman's disease from 1923 cases of multicentric Castleman's disease. 128 patients with idiopathic multicentric Castleman's disease met all inclusion criteria for the systematic review. Furthermore, aggregated data for 127 patients with idiopathic multicentric Castleman's disease were presented from clinical trials, which were excluded from primary analyses because patient-level data were not available. Clinical features of idiopathic multicentric Castleman's disease included multicentric lymphadenopathy (128/128), anaemia (79/91), elevated C-reactive protein (65/79), hypergammaglobulinaemia (63/82), hypoalbuminaemia (57/63), elevated interleukin 6 (57/63), hepatomegaly or splenomegaly (52/67), fever (33/64), oedema, ascites, anasarca, or a combination (29/37), elevated soluble interleukin 2 receptor (20/21), and elevated VEGF (16/20). First-line treatments for idiopathic multicentric Castleman's disease included corticosteroids (47/128 [37%]), cytotoxic chemotherapy (47/128 [37%]), and anti-interleukin 6 therapy (11/128 [9%]). 49 (42%) of 116 patients failed first-line therapy, 2-year survival was 88% (95% CI 81–95; 114 total patients, 12 events, 36 censored), and 27 (22%) of 121 patients died by the end of their observed follow-up (median 29 months [IQR 12–50]). 24 (19%) of 128 patients with idiopathic multicentric Castleman's disease had a diagnosis of a separate malignant disease, significantly higher than the frequency expected in age-matched controls (6%). Interpretation Our systematic review provides comprehensive information about clinical features, treatment, and outcomes of idiopathic multicentric Castleman's disease, which accounts for at least 33% of all cases of multicentric Castleman's disease. Our findings will assist with prompt recognition, diagnostic criteria development, and effective management of the disease. Funding None.

Background Guidelines exist for chronic kidney disease (CKD) but are not well implemented in clinical practice. We evaluated the impact of a guideline-based clinical decision support system (CDSS) on laboratory monitoring and achievement of laboratory targets in stage 3–4 CKD patients. Methods We performed a matched cohort study of 12,353 stage 3–4 CKD patients whose physicians opted to receive an automated guideline-based CDSS with CKD-related lab results, and 42,996 matched controls whose physicians did not receive the CDSS. Physicians were from US community-based physician practices utilizing a large, commercial laboratory (LabCorp®). We compared the percentage of laboratory tests obtained within guideline-recommended intervals and the percentage of results within guideline target ranges between CDSS and non-CDSS patients. Laboratory tests analyzed included estimated glomerular filtration rate, plasma parathyroid hormone, serum calcium, phosphorus, 25-hydroxy vitamin D (25-D), total carbon dioxide, transferrin saturation (TSAT), LDL cholesterol (LDL-C), blood hemoglobin, and urine protein measurements. Results Physicians who used the CDSS ordered all CKD-relevant testing more in accord with guidelines than those who did not use the system. Odds ratios favoring CDSS ranged from 1.29 (TSAT) to 1.88 (serum phosphorus) [CI, 1.20 to 2.01], p

New medical-education models in which research plays a modest role could engender a two-tiered educational system, cause a reduction in the physician-scientist pipeline, and diminish the translation of biomedical advances.

The AAMC's Increasing Women's Leadership Project Implementation Committee examined four years of data on the advancement of women in academic medicine. With women comprising only 14% of tenured faculty and 12% of full professors, the committee concludes that the progress achieved is inadequate. Because academic medicine needs all the leaders it can develop to address accelerating institutional and societal needs, the waste of most women's potential is of growing importance. Only institutions able to recruit and retain women will be likely to maintain the best housestaff and faculty. The long-term success of academic health centers is thus inextricably linked to the development of women leaders. The committee therefore recommends that medical schools, teaching hospitals, and academic societies (1) emphasize faculty diversity in departmental reviews, evaluating department chairs on their development of women faculty; (2) target women's professional development needs within the context of helping all faculty maximize their faculty appointments, including helping men become more effective mentors of women; (3) assess which institutional practices tend to favor men's over women's professional development, such as defining “academic success” as largely an independent act and rewarding unrestricted availability to work (i.e., neglect of personal life); (4) enhance the effectiveness of search committees to attract women candidates, including assessment of group process and of how candidates' qualifications are defined and evaluated; and (5) financially support institutional Women in Medicine programs and the AAMC Women Liaison Officer and regularly monitor the representation of women at senior ranks.

Over at least the past 20 years, putative and real conflicts of interest (COI) at academic medical centers have been featured prominently in the lay press, often with reputational damage to individuals and institutions.1 The heightened focus of concern about alleged financial payments to physicians and academic institutions by pharmaceutical and device companies, coupled with increasing concern by medical students (most notably in the American Medical Student Association scorecard, which gave grades to medical schools ranging from A to F based on how well they performed in avoiding conflicts of interest with the pharmaceutical industry) shone a bright light on individual and institutional integrity.

The sections in this article are: 1 Insulin: Properties and Structure 2 Biosynthesis of Insulin 2.1 Structure and Functions of Precursor Forms 2.2 Cell Biology 2.3 Mechanism of Proteolytic Conversion of Proinsulin to Insulin 2.4 Insulin Storage Vesicles 2.5 C Peptide, a Co-secretory Product of the β Cell 3 Regulation of Insulin Biosynthesis 4 The Insulin Gene and its Defects 4.1 Mutations in the Insulin Gene 5 Defects in Insulin Biosynthesis 5.1 Prohormone Convertase Defects 6 Conclusion

During the last decade academic medical centers (AMCs) have hired large numbers of clinician-educators to teach and provide clinical care. However, these clinician-educators often do not advance in academic rank, since excellence in clinical care and teaching alone is not adequate justification for advancement. The authors articulate the problems with the present system of recognition for clinician-educators-i.e., the requirement for regional and national reputation, the lack of reliable measures of clinical and teaching excellence, and the lack of training opportunities for young clinician-educators. They call for solutions, including fundamental changes in promotion criteria (e.g., focus criteria for promotion on clinician-educators' accomplishments within their institutions) and the development of valid and feasible methods to measure outcomes of teaching programs. Further, they recommend the development of a new faculty position, a "clinician-educator researcher," to foster the scholarship of discovery in medical education and clinical practice. Investments in clinician-educator researchers will ultimately help AMCs to achieve their threefold mission-excellence in patient care, teaching, and research.

Objective To identify the circulating species of insulin after separation by high-performance liquid chromatography (HPLC) in patients with factitious hypoglycemia. Research Design and Methods In three of four patients presented, the diagnosis of surreptitious insulin injection was made by documenting the presence of animal insulin in the circulation after separation of the circulating insulin forms by HPLC. Results Animal insulin was identified. Conclusions Thus, the identification of the circulating form of insulin in the circulation by HPLC may be a useful adjunct in the diagnosis of factitious hypoglycemia if animal insulin has been injected and if the simultaneously measured concentrations of insulin and C-peptide are inconclusive.

It is now well established that insulin biosynthesis proceeds through a precursor molecule, proinsulin. This single polypeptide chain form has been identified as a ribosomal product in the microsomal fraction from islet tissues. The newly synthesized peptide chain, after folding and thiol oxidation, is transferred to the Golgi apparatus where it begins to undergo proteolytic processing to insulin and packaging into secretory granules. The secretion from the cells of significant amounts of newly synthesized material by exocytosis begins only one hour or more after biosynthesis and this process is regulated by several factors, including glucose. Foci of current attention discussed in this paper include (1) the possible existence of larger precursor forms than proinsulin, especially short-lived biosynthetic transients with extended NH2-termini analogous to the recently described immunoglobulin L chain and proparathyroid hormone precursors; (2) the large-scale production of insulin by chemical or genetic engineering approaches; (3) isolation of beta-cell plasma membranes; (4) regulatory mechanisms for the biosynthesis and secretion of insulin, the possible role of mRNA modification in this process, and effects of somatostatin on insulin biosynthesis and secretion; (5) studies on the secretion, metabolism and clinical usefulness of the proinsulin C-peptide; (6) finally, the biosynthesis of glucagon and other peptide hormones and the general significance of precursor forms.

Since circulating proinsulin has been suggested to be important in the pathogenesis of noninsulin-dependent diabetes, and biosynthetic human proinsulin (HPI) may have a therapeutic role in patients with diabetes mellitus, the biological activity of proinsulin metabolites is of potential significance. Moreover, recent studies have suggested that the majority of circulating proinsulin immunoreactivity consists of metabolites. We, therefore, compared the blood glucose-lowering ability and MCR of the two proinsulin metabolites des-(31,32)HPI and des-(64,65)HPI with intact HPI in seven anesthetized dogs after an overnight fast. Intravenous bolus injections of 12.5 micrograms HPI/kg BW and equimolar amounts of des-(31,32)HPI and des-(64,65)HPI were given on three separate occasions. In addition to blood glucose, des-(31,33)HPI, des-(64,65)HPI, and HPI were measured using an insulin RIA and peptide-specific standard curves. Kinetic parameters were derived by fitting two exponentials to the respective decay curves. The MCR of HPI (3.3 +/- 0.1 ml/kg.min) was significantly lower (P less than 0.05) than that of des-(64,65)HPI (6.4 +/- 0.6 ml/kg.min), but was not significantly different from that of des-(31,32)HPI (3.8 +/- 0.4 ml/kg.min). The MCR of biosynthetic insulin (17.2 +/- 1.8 ml/kg.min), as measured in three of the dogs, was higher than that of HPI or the two metabolites. The blood glucose-lowering ability (defined as nadir glucose/fasting glucose, expressed as a percentage) of des-(64,65)HPI (49.3 +/- 5.0%) was significantly greater (P less than 0.05) than that of intact HPI (87 +/- 2.2%), and the glucose-lowering ability of des-(31,32)HPI (75.2 +/- 3.8%) was intermediate. In conclusion, HPI metabolites are more biologically active than intact HPI. The extent of in vivo conversion of proinsulin to metabolites may enhance the biological activity of proinsulin and, thus, have physiological, pathophysiological, and therapeutic significance.

The effect of different temporal patterns of calorie intake on plasma glucose, serum insulin, and insulin secretion rates was examined in six patients with moderately well controlled non-insulin-dependent diabetes mellitus (NIDDM). Patients were studied on three separate occasions over 26 h. Total calories and food composition (50% carbohydrate, 15% protein, and 35% fat) were kept constant, but the pattern of calorie intake was varied. In study A (similar meal size), calories were distributed as 30, 40, and 30% at breakfast, lunch, and dinner, respectively. In study B (3 snacks, 3 meals), each subject ate three meals of 20, 20, and 30% of calories for breakfast, lunch, and dinner, respectively, and three snacks, each comprising 10% of calories, presented 2.5 h after the meal. In study C (large dinner), 10% of calories were consumed at breakfast, 20% at lunch, and 70% at dinner. Glucose, insulin, and Cpeptide concentrations were measured at 15- to 30-min intervals. Insulin secretion rates were calculated from C-peptide levels with individually derived C-peptide clearance parameters. The different eating patterns were associated with only modest differences in overall levels of glucose and insulin secretion. Daytime insulin secretion was lowest when most of the daily calorie intake occurred in the form of a large dinner. Overnight levels of glucose and insulin secretion rates did not differ for the three eating patterns, and the morning glucose levels were also unaffected by the pattern of calorie intake on the previous day. A morning rise of glucose of >0.28 mM occurred consistently only when dinner was of moderate size (30% of total calories). We conclude that if total calorie content and food composition are kept constant, overall blood glucose control is only modestly affected by the temporal pattern of food intake. The partition of food intake into meals and snacks does not improve glucose control, and a large dinner does not result in significantly higher overnight or next-morning glucose levels.

Studies on naturally occurring and man-made mutations in the insulin gene have provided new insights into insulin biosynthesis, action, and metabolism. Ten families have been identified in which one or more members have single-point mutations in their insulin genes that result in amino acid substitutions within the proinsulin molecule. Six of these cause the secretion of biologically defective insulin molecules due to changes within the A or B chains. Replacing A3-Val with Leu, B24-Phe with Ser, or B25-Phe with Leu results in molecules that have essentially normal immunoreactivity but greatly reduced insulin-receptor-binding potency. Individuals with these mutations have a syndrome of mild diabetes or glucose intolerance, which is inherited in an autosomal-dominant mode and is associated with hyperinsulinemia and altered insulin-C-peptide ratios. Although affected individuals are heterozygous and coexpress both normal and abnormal molecules, the elevated circulating insulin consists mainly of the biologically defective form, which accumulates because it fails to be rapidly metabolized via receptor-mediated endocytosis. Four additional families have mutations that are associated with relatively asymptomatic hyperproinsulinemia. A point mutation affecting proinsulin occurs in 3 of the 4 families, leading to replacement of Arg-65 by His, which prevents recognition of the C-peptide-A-chain dibasic cleavage site by the appropriate (β-cell processing protease and results in the circulation of a type II proinsulin intermediate form (des 64, 65 HPI). Members of a fourth family with hyperproinsulinemia have a substitution of B10-His with Asp, resulting in a proinsulin that exhibitsmarkedly altered subcellular sorting behavior. A significant proportion of the newly synthesized Asp-10 proinsulin is secreted in an unprocessed form via an unregulated or constitutive secretory pathway. This syndrome has been modeled in transgenic mice by introduction of this abnormal gene into the germ line, resulting in its expression at high levels along with the normal mouse insulin genes in the β-cells. These animals have not only reproduced the hyperproinsulinemia syndrome, thus allowing us to examine its mechanism in considerable detail, but have also provided opportunities to examine other aspects of insulin-gene expression. Various molecular expression techniques are now available that allow normal or mutated insulin genes to be expressed via transfection of DNA in cultured cells, injections of in vitro-generated mRNA into Xenopus oocytes, or translation of mRNA in reticulocyte cell-free systems so that their altered properties can be assessed. Application of these and other molecular biological techniques to the expression of naturally occurring mutant proinsulins and others made in the laboratory has provided new forms of insulin for therapy of diabetes and a deeper understanding of the mechanisms of biosynthesis, intracellular sorting, processing, and secretion of insulin under normal and abnormal conditions.

The mechanism of tumor-associated hypoglycemia was examined in 11 patients with hepatocellular carcinoma, 6 of whom presented with severe hypoglycemia and 5 in whom plasma glucose was persistently normal. Serum insulin levels in the hypoglycemic patients were low. Although total serum insulin-like growth factor II (IGF-II) levels in both groups of tumor patients were lower than normal, tumor tissue from hypoglycemic patients contained levels of IGF-II mRNA that were 10-20-fold higher than those present in normal liver. IGF-II immunoreactivity consisted in all cases of a mixture of both higher molecular weight forms and material having the character of IGF-II itself. The former comprised a greater proportion of total IGF-II, in patients with hypoglycemia. Studies to characterize the interactions of IGF-II with serum proteins showed that (a) the radiolabeled peptide bound to an approximately 40,000-D protein in sera from both hypoglycemic patients and normal subjects, (b) sera from hypoglycemic patients and normal subjects had similar capacity to bind the radiolabeled peptide, and (c) the apparent affinities of serum binding proteins for IGF-II were the same for both hypoglycemic patients and normal subjects. Whereas, acid extracted, tumor-derived IGF-II immunoreactive peptides with low or intermediate molecular weights bound to serum proteins in a manner indistinguishable from that of IGF-II itself, the highest molecular weight IGF-II immunoreactive peptide exhibited negligible ability to compete for radiolabeled ligand binding to serum proteins. The low affinity of serum binding proteins for this component suggests that high molecular weight IGF-II immunoreactivity might circulate free and be available for interaction with cell-surface receptors.

Increasing an academic health system's research productivity is an institutional challenge that requires multiple complex actions over a sustained period of time. In this Commentary, we describe how 2 academic health systems with different organizational structures used similar models of investment of clinical income in the research enterprise to enhance their success. This strategy assumes enhanced urgency in the current climate of flat National Institutes of Health (NIH) budgets. In 2006, NIH experienced its first budget cut since 1970, resulting in a 13% loss of research purchasing power since 2003, while grant applications have doubled since 1998.1 The level of NIH support remains one of the few objective benchmarks by which an academic health system can evaluate its academic and research success. Unlike reputational rankings, the NIH process is the only nationally competitive, peer-reviewed metric available.

It has recently become obvious that the prevalence of obesity has been rapidly increasing in the United States, as well as other countries, over the past two decades. This change has involved both sexes, all age ranges and various ethnic groups. The rising prevalence in children and adolescents is of particular concern because of the implications for negative effects on their morbidity and mortality in young adulthood. Obesity is definitely associated with a relative increase in diabetes, cardiovascular disease, various cancers, respiratory disorders in sleep, gallbladder disease and osteoarthritis. It also has negative effects on a variety of other conditions such as pregnancy complications, menstrual disorders, psychological disorders, and urinary stress incontinence. It is an integral component of the metabolic syndrome, which is emerging as a key constellation of risk factors for cardiovascular disease. Dealing with this epidemic will require the mobilization of multiple constituencies and allocation of adequate resources. These approaches should be instituted with urgency.

Background: Multicentric Castleman disease (MCD) describes a heterogeneous group of poorly-understood diseases involving proinflammatory hypercytokinemia that ultimately results in systemic inflammatory symptoms, generalized lymphadenopathy, multiple organ system dysfunction, and even death. HHV-8 is responsible for driving MCD in immunosuppressed patients (HHV-8-associated MCD). There is also a cohort of HHV-8-negative MCD cases, referred to as idiopathic MCD (iMCD), in which the etiology remains unknown. No formal diagnostic criteria exist for iMCD, and knowledge is limited to small case series and case reports. Objectives: We conducted a systematic literature review to describe demographic, clinical, and laboratory features of iMCD as well as the treatments currently used in practice. Methods: PubMed was queried using a comprehensive list of terms to identify all published cases of HHV-8-negative MCD. Criteria for study inclusion were as follows: (1) Pathology-confirmed Castleman disease in multiple lymph nodes; (2) Exclusion of another cause of Castleman-like histopathology, such as SLE or POEMS syndrome; (3) Negative testing for HHV-8 via PCR of blood, PCR of lymph node tissue, serum serologies, and/or IHC for LANA-1; (4) Written in English and published from January 1995 to July 2013; and (5) Availability of specified minimum data elements. HIV-positive cases were excluded. Inclusion criteria were confirmed by three independent investigators, who also extracted data into a standardized database. Case report authors were contacted to gather additional data in a standardized case report form. Results: 3,428 articles were identified on PubMed. Initial evaluation for exclusion criteria yielded 1,951 MCD cases; 629 patients were HIV-positive (32%). Of the 999 HIV-negative and 323 HIV-unknown MCD cases, 626 were HHV-8 negative (32% of total MCD), 517 were HHV-8-unknown (26%), and 179 were HHV-8-positive (9%).129 cases of HHV-8-negative MCD met all inclusion criteria and were included in the final analysis. 58% were male and median age was 50 years (range: 2-80). Frequently reported clinical features included: fever (51/64), enlarged liver and/or spleen (45/60), pleural effusion (29/38), edema (26/36), and weight loss (21/29). There were 43 plasmacytic, 26 mixed, and 23 hyaline vascular cases out of 108 cases that reported histopathological subtype. The most commonly reported laboratory abnormalities included elevated CRP (70/79), anemia (76/90), hypergammaglobulinemia (63/82), hypoalbuminemia (57/63), elevated IL-6 (57/63), and positive ANA (14/38). Of cases with abnormal platelet levels, 28 had thrombocytopenia and 14 had thrombocytosis. There were 19 reported cases with elevated soluble IL-2R levels and 15 with elevated VEGF. 27 patients were diagnosed with a malignancy before (5), concurrently with (12), or after (10) diagnosis. Most commonly employed first line therapies included corticosteroid monotherapy (36%), combinations of cytotoxic chemotherapies (36%) that included regimens with cytoxan (17%) and rituxan (12%), and anti-IL-6 therapies, such as siltuximab and tocilizumab, without a cytotoxic agent (10%). Thalidomide, bortezomib, anakinra, and IVIG were used less frequently. Patients experienced no response (21%), partial response (42%), and complete response (37%) to first-line therapies. Failure (relapse, death, additional treatment) of first line therapy occurred in 41% of patients, and median time to treatment failure was 6 months. Overall, 22% of patients died by the time of most recent follow up (median: 28 months) with median length of survival among fatal cases being 26 months (range: 1-120). The most common causes of death were septic shock, multi-organ failure, including renal and cardiac, pulmonary complications, and malignancy. Conclusion: This study identified a significant proportion of MCD patients who are HIV-negative and HHV-8-negative (iMCD). 45% of patients did not demonstrate the plasmacytic variant alone, which has been classically associated with MCD. It is striking that 22% of patients died by the time of most recent follow up, which had a median length of 26 months. Despite the many limitations of analyzing case reports, this study provides the most comprehensive data on HHV-8-negative MCD to date. A global natural history study and Castleman disease registry are urgently needed to gather more extensive data on MCD. Disclosures Fajgenbaum: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Cyclophosphamide, rituximab, tocilizumab, thalidomide, bortezomib, anakinra, and intravenous immunoglobulin will be presented as drugs used in HHV-8-negative MCD. It is very important to inventory the treatments that a physician has available when conventional therapies do not work, which is frequent in MCD. At the time that this data set was assembled, there were no FDA approved therapies for this orphan disease. van Rhee:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Despite changes in the structure of the U.S. health care system, patients continue to need and seek out generalist physicians. However, the proportion of U.S. graduates of medical schools who choose to enter generalist residency training decreased from 50% in 1998 to less than 40% in the 2004 match. Unless we act now to reverse this trend, we may face a shortage of primary care physicians to care for the complex medical needs of an aging population. This article reviews the history of and trends in career choice and proposes 4 evidence-based recommendations to rekindle student interest in generalist careers: 1) We must improve satisfaction and enthusiasm among generalist physician role models. 2) Schools of medicine should redouble their efforts to produce primary care physicians. 3) We must facilitate the pathway from medical school to generalist residency. 4) The U.S. government should increase funding for primary care research and research training. In the absence of a major overhaul of economic incentives in favor of generalist careers, we will need to work at these multiple levels to restore balance to the generalist physician workforce and align with the desires and expectations of patients for continuing healing relationships with generalist physicians.

The mission of academic medical centers typically includes three distinct goals: providing patient care, educating future doctors, and acquiring new medical knowledge.1 Academic medical centers see...

As representatives of 50 leading academic medical centers focusing on clinical research and many of academic medicine’s scientific leaders, the Clinical Research Forum and Association of American Physicians disagree with the JCI’s recent editorials on the NIH Roadmap, Elias Zerhouni’s leadership, and the future directions of biomedical research.

Patients with diabetes can lead relatively normal lives when treated with the hormone insulin, although they eventually exhibit vascular and neural complications. Now a report in this week9s issue by Ido et al. (p. 563) suggests that these complications might be alleviated by the simultaneous administration of C-peptide, a protein fragment cleaved from insulin during its synthesis. In his Perspective, Steiner describes how C-peptide, previously thought to be biologically inactive, may correct the vascular and neural dysfunctions of diabetes.

We studied insulin secretion rates (ISR) during low-intensity exercise (40% peak aerobic capacity [VO2]) in 12 normal subjects to assess the contribution of altered insulin secretion to the reduction in peripheral insulin concentrations associated with exercise. ISR were calculated by a previously validated method of two-compartment analysis of peripheral C-peptide concentrations using individual parameters derived following a bolus injection of biosynthetic human C-peptide. In addition, the effect of low-intensity exercise on kinetic parameters of C-peptide was evaluated. The results showed that low-intensity exercise did not significantly affect C-peptide kinetics. Peripheral insulin concentrations and ISR decreased to a similar degree throughout exercise. There was a mean maximum decrease in serum insulin concentrations from 42 +/- 5.4 pmol/L basally to 24 +/- 2.6 pmol/L, constituting a 51% +/- 5.9% decrease (P.001), and ISR decreased from 85.7 +/- 11.9 pmol/min to a nadir of 45.6 +/- 10.6 pmol/min (P.001), a 48% +/- 8.4% decline. Plasma glucose and glucagon concentrations did not change significantly either during or after exercise, although there was a matched twofold increase in glucose utilization and disposal rates. We suggest that the reduction in peripheral insulin concentrations during exercise is due to reduced insulin secretion.

Excerpt Although it has been recognized for several years that insulin-dependent diabetes mellitus is a chronic autoimmune disease (1), it has only recently been possible to identify antigens invol...

Excerpt In a past issue of this journal, the Association of Professors of Medicine (APM) was identified as an organization with "the power to effect change because it has the authority, responsibil...

Dr Delbanco: Mr D is a 64-year-old married man who is now a media announcer after a career as a salesman. He has long-standing diabetes mellitus, first diagnosed when he was 38 years old. He has private health insurance through a managed care plan and receives ongoing care from Dr S, a general internist in a suburban community near Boston. A man who has enjoyed competitive tennis all his life, Mr D is 6 ft (180 cm) tall and has maintained a steady weight of about 178 lb (80 kg). There is a distant smoking history of about 20 pack-years; he has not smoked since 1970. He has 1 or 2 alcoholic beverages daily; there is no history of alcohol or drug abuse. He has no family history of diabetes mellitus. He continues to play tennis at least 3 times a week for 2 to 3 hours and enjoys horseback

Estimation of the insulin secretory rate from peripheral C-peptide concentrations depends upon the following characteristics of C-peptide kinetics: (a) equimolar secretion of insulin and C-peptide by pancreatic beta cells; (b) negligible hepatic extraction of C-peptide; (c) constant metabolic clearance rate (MCR) of C-peptide over a physiological and pathophysiological range of plasma levels; and (d) proportional changes in the secretion rate of C-peptide and its peripheral concentrations under varying physiological conditions. In the present experiments, the relationship between a variable intraportal infusion of C-peptide and its concentration in the femoral artery was explored in 12 pancreatectomized dogs. As the infusion of C-peptide was rapidly increased, the magnitude of its peripheral concentration initially increased less than the infusion rate by 20-30%. After an equilibration period of approximately 30 min, however, further increases and decreases in the intraportal infusion were accompanied by nearly proportional changes in its peripheral concentration. Estimates of the amount of C-peptide infused during the experiment based on the steady state C-peptide MCR and its peripheral concentration were within 20% of the amount of C-peptide actually infused. These experiments demonstrate that the portal delivery rate of C-peptide can be calculated from its MCR and peripheral concentration in the dog. They also provide a basis for testing the validity of more complicated models of insulin secretion based on peripheral C-peptide concentrations in the dog as well as other species, including man. Finally, we have shown that the hepatic extraction of endogenously secreted C-peptide is negligible in the basal state (3.1 +/- 6.1%), and does not change after oral glucose ingestion. The MCR of exogenous dog C-peptide was similar whether measured by constant peripheral intravenous infusion (12.3 +/- 0.7 ml/kg per min), constant intraportal infusion (13.4 +/- 0.6 ml/kg per min), or analysis of the decay curve after a bolus injection (13.5 +/- 0.7 ml/kg per min).

A simple and precise equilibrium binding assay has been developed for the quantitation of circulating insulin antibodies. This procedure differs from previously reported methods in that (1) serum samples were deinsulinized in order to avoid endogenous insulin's interfering with the binding assay, (2) l25I-monoiodoinsulin was used to prevent artifacts resulting from variability in ligand binding due to excessive iodination, and (3) separation of free and bound insulin was accomplished by rapid precipitation of the hormone-antibody complexes without disturbing the binding equilibrium. This approach prevented dissociation and underestimation of the bound species. In agreement with previous reports, two classes of antibody sites (high-affinity-low-capacity and low-affinity-high-capacity) were demonstrated in the sera of insulin-treated diabetic patients. No consistent differences existed in the association constants and/or binding capacities for insulins of bovine, porcine, and human origin, even though the immunogenic stimulus for antibody formation in these patients was treatment with commercial preparations of bovine and porcine insulins. Thus, higher affinities and/or binding capacities for human versus bovine and porcine insulins does not provide evidence for an autoimmune origin of insulin antibodies, as has been previously proposed. Significant differences in the antibody-binding capacities for all three species of insulin were found in individual serum samples, and underestimation of antibody titers may occur if only one species of the hormone is used. Kinetic studies on the dissociation of the insulin-antibody complexes revealed two classes of dissociating sites, in agreement with the equilibrium binding data. The corresponding dissociation rate constants were large enough to implicate the release of insulin from the pool of antibody-bound hormone as a possible hypoglycemic mechanism in some diabetic patients.

A sensitive and specific double antibody radioimmunoassay for the major apolipoprotein (apo A-I) of human serum high density lipoprotein (HDL) was developed. Initial studies indicated that direct measurements of apo A-I concentration in whole untreated sera or isolated high density lipoprotein fractions yielded variable results, which were lower than those obtained in the corresponding samples which had been subjected to delipidation. Subsequently, it was observed that heating diluted sera or HDL for 3 hr at 52 °C prior to assay resulted in maximal increases in apo A-I immunoreactivity to levels comparable to those found in the delipidated specimens. This simple procedure permitted multiple sera to be assayed efficiently with full recovery of apo A-I.Serum apo A-I in healthy normolipemic males was 130 ± 3 mg/dl (range 95–165), while the values in females were significantly higher 154 ± 6 mg/dl (range 107–199) (P < 0.005). The apo A-I levels correlated with the total serum cholesterol (males r = 0.46, P < 0.005; females r = 0.58, P < 0.001).Preliminary results with sera from patients with abetalipoproteinemia, hypercholeskrdemia and Tangier disease indicated that alterations in the low density lipoprotein concentration and changes in the physical chemical properties of the high density lipoproteins did not affect the optimal conditions for mnwuring serum apo A-I. The apo A-I concentrations were abnormally low in each of the above disorders.

To assess the effects of pregnancy on the relationships between plasma insulin and proinsulin, studies were performed during late gestation in women with normal carbohydrate metabolism or diabetes mellitus. Plasma was secured after overnight fast and 1, 2, and 3 hours following oral glucose (100 g). Samples were analyzed directly for total immunoreactive insulin (TIR) and for insulin and proinsulin following plasma fractionation by gel filtration. Fractionation disclosed that most of the normal gestational increase in basal and glucose-stimulated TIR can be ascribed to insulin rather than disproportionate increments in proinsulin-like components. Normal proinsulin/insulin relationships were also preserved in mild diabetics despite greater variability in their TIR response to glucose. Thus, mild carbohydrate intolerance during pregnancy is not attended by abnormalities in plasma proinsulin. In contrast basal proinsulin levels were elevated in 4 of 9 pregnant subjects with diabetes sufficiently severe to necessitate subsequent insulin therapy. Following glucose administration in the severe diabetics, the relative contribution from proinsulin to TIR was altered so that ratios of circulating proinsulin/insulin were increased at all levels of blood sugar. Postpartum tests of glucose tolerance in some of the normal and mildly diabetic subjects confirmed that pregnancy per se does not modify appreciably the relationships between plasma insulin and proinsulin although there may be some tendency for proinsulin to account for a smaller proportion of TIR.

We describe a family from Japan displaying the mutant insulin syndrome with hyperinsulinaemia and an increased insulin: C-peptide molar ratio. Serum insulin isolated from several family members showed reduced in vitro biological activity, and analysis by high performance liquid chromatography revealed a peak co-eluting with human insulin and a second species of increased hydrophobicity co-migrating with the previously reported Insulin Wakayama. The insulin genes from the propositus were cloned and sequenced, revealing one normal allele; the second allele, encoding a leucine for valine amino acid substitution at position 3 of the insulin A chain, was similar to that previously described for Insulin Wakayama. Synthesized [LeuA3] insulin showed 0.14% of receptor binding activity on rat adipocytes and a 10-fold prolonged half-life in a somatostatin-infused dog compared with human insulin. The finding of the same mutant gene in two unrelated Japanese families suggests that Insulin Wakayama may be discovered in additional Japanese families with hyperinsulinaemia and/or diabetes.

Basal values for C-peptide and the responses to intravenous glucose have been examined 2—4 h after birth in nine infants from normal and nine infants from diabetic mothers (IDM) (including eight who were being treated with insulin antepartum). Potentially cross-reacting antibody-bound proinsulin was removed prior to C-peptide estimations. Values for basal plasma glucose and fractional rates of glucose disposition (Kt) were inversely correlated in normal and IDM. Mean basal plasma glucose levels were significantly lower in the IDM. Although basal Cpeptide values did not differ significantly in the two groups,C-peptide/glucose ratios were significantly higher in IDM. After glucose administration, C-peptide and immunoreactive insulin increased in parallel in the normal infants, with peak values for both peptides being observed in the late plasma specimens. In contrast, in five IDM, maximal increments in C-peptide occurred in the earliest plasma specimen secured after glucose administration,i.e., at +2 or +10...

Two new radioimmunoassays for human proinsulin (hPI) have been developed and used to study patients with islet cell tumors and familial hyperproinsulinemia. Both antisera were adsorbed against human C-peptide conjugated to Sepharose, following which cross-reactivity to insulin and C-peptide was less than 0.001%. Antiserum 18D recognized the junction between the insulin B-chain and C-peptide and provided fivefold greater sensitivity than our previously reported hPI assay. Antiserum 11E recognized a determinant which includes or is adjacent to the A-chain-C-peptide junction or which is specified by the tertiary structure. In all 20 patients studied with surgically confirmed islet cell tumors, fasting plasma proinsulinlike material (PLM) was abnormal (greater than 3 SD from the mean measured in either lean or obese subjects) in both assays. This provided better discrimination than has been reported for PLM measured by gel filtration (abnormal in 13 of 14 of the present samples) with a considerably less laborious procedure. Samples from two families in which a mutant proinsulin is present in the circulation have immunoreactivity in the two assays consistent with previous identification of the molecule as an A-chain-C-peptide-linked intermediate of proinsulin conversion. The immunoreactivity of a sample from another family in which large amounts of proinsulin circulate are consistent with an intact molecule being the predominant form. This assay will be useful for confirming the diagnosis of insulin-secreting tumor in patients suspected of recurrent fasting hypoglycemia and in physiologic studies of proinsulin secretion.

Five patients with glucagonomas had elevated plasma levels of total glucagon immunoreactivity. Gel filtrations of these plasma samples on Bio-Gel P30 columns showed that most of the immunoreactivity eluted in the 3,500-(true glucagon) and 9,000-dalton fractions. After the administration of alpha cell effectors, changes in total glucagon immunoreactivity were seen which were accounted for primarily by the 3,500-dalton species, but there were also changes in the 9,000-dalton moiety. Venous effluent plasma from tumors of two subjects contained elevated concentrations of glucagon immunoreactivity in both fractions. When material from both the 3,500- and 9,000-dalton peaks were serially diluted in a glucagon immunoassay, parallel displacement curves were found, suggesting that both have similar or identical antigenic determinants. Thus, with conversion to a neoplastic state, alpha cells of glucagonomas, much like beta cells of insulinomas, may secrete an increased amount of a larger, 9,000-mol wt glucagon species which may be a prohormone.

Insulin isolated from the pancreas of a diabetic patient with fasting hyperinsulinaemia showed decreased activity in binding to cell membrane insulin receptors and in stimulating cellular 2-deoxyglucose transport and glucose oxidation. Chemical studies suggest that the isolated hormone is a mixture of normal insulin and an abnormal variant which contains a leucine for phenylalanine substitution at position 24 or 25 of the insulin B-chain.