Cardiovascular Medicine at the University of Minnesota: Lost and then Found in Translation

Translational research requires basic innovation and development, an infrastructure for deployment to the experimental clinical arena and a distribution system to connect patients to innovation. The University of Minnesota cardiovascular program led the way in translational medicine after World War II. Subsequently, it briefly lost its way. Learning from the lessons of the past, cardiovascular medicine at Minnesota is being reborn as a twenty-first century organization developing medical innovation from ideas and translating the product to patients in a complex healthcare system.     

Ileitis in Ulcerative Colitis: Is It a Backwash?

PURPOSE This study aims to determine the incidence, demography, pathologic nature, and clinical significance of ileitis in ulcerative colitis patients who underwent restorative proctocolectomy. METHODS A prospectively collected pouch database and the case notes of 100 consecutive patients who underwent restorative proctocolectomy for ulcerative colitis, under the care of a single surgeon, between 1988 and 2003 were reviewed. The original proctocolectomy specimens and pouch biopsies were reexamined and regraded blind, using the current diagnostic criteria. Patients were divided into two groups, those who had ileitis and those who had not. The demographic, clinical, and pathologic characteristics and the incidence of pouchitis of both groups were compared. RESULTS Twenty-two patients had ileitis (22 percent). Compared with those with noninflamed ileum, patients with ileitis had a significantly shorter disease duration (P < 0.005), many of them presented or progressed to a fulminant state requiring acute surgical intervention (P < 0.01), had strong association with pancolitis and primary sclerosing cholangitis (P < 0.001), and had a higher incidence of subsequent development of pouchitis (P < 0.001). There was no correlation between the presence of ileitis and colitis severity. CONCLUSIONS Ileitis in ulcerative colitis is not rare and does influence the prognosis, and the term “backwash” is a misnomer. Ulcerative colitis with ileitis represents a distinct disease-specific subset of patients. Its true incidence and clinical significance can be determined only if detailed microscopic characterization of the terminal ileum is performed routinely in every patient with ulcerative colitis and the clinical outcome of these patients is audited prospectively. Presented in part at the meetings of the British Society of Academic and Research Surgery (SARS), Newcastle, United Kingdom, January 12 to 14, 2005, the American Gastroenterological Association (DDW), New Orleans, Louisiana, May 15 to 20, 2004, and the Association of Surgeons of Great Britain and Ireland, Harrogate, United Kingdom, April 28 to 30, 2004. Reprints are not available.     

Specific molecular recognition of mixed nucleic acid sequences: an aromatic dication that binds in the DNA minor groove as a dimer

Phenylamidine cationic groups linked by a furan ring (furamidine) and related compounds bind as monomers to AT sequences of DNA. An unsymmetric derivative (DB293) with one of the phenyl rings of furamidine replaced with a benzimidazole has been found by quantitative footprinting analyses to bind to GC-containing sites on DNA more strongly than to pure AT sequences. NMR structural analysis and surface plasmon resonance binding results clearly demonstrate that DB293 binds in the minor groove at specific GC-containing sequences of DNA in a highly cooperative manner as a stacked dimer. Neither the symmetric bisphenyl nor bisbenzimidazole analogs of DB293 bind significantly to the GC containing sequences. DB293 provides a paradigm for design of compounds for specific recognition of mixed DNA sequences and extends the boundaries for small molecule-DNA recognition.     

Differences in end-of-life preferences between congestive heart failure and dementia in a medical house calls program

OBJECTIVES: To compare end-of-life preferences in elderly individuals with dementia and congestive heart failure (CHF). DESIGN: Retrospective case-control study. SETTING: Geriatrician-led interdisciplinary house-call program using an electronic medical record. PARTICIPANTS: Homebound individuals who died while under the care of the house-call program from October 1996 to April 2001. MEASUREMENTS: Medical records review for demographics, functional status, advance medical planning, hospice use, and place of death. RESULTS: Of 172 patients who died in the program, 29 had CHF, 79 had dementia, 34 had both, and 30 had neither. Patients with CHF were younger (82.6 vs 87.0, P=.011) and less functionally dependent (activities of daily living score 9.1 vs 11.5, P=.001). Time from enrollment to death was not significantly different (mean+/-standard deviation=444+/-375 days for CHF vs 325+/-330 days for dementia, P=.113). A do-not-resuscitate (DNR) directive was given in 62% of patients with CHF and 91% with dementia (P<.001). Advance medical planning discussions were not significantly different (2.10 in CHF vs 1.65 in dementia, P=.100). More patients with CHF participated in their advance medical planning than those with dementia (86% vs 17%, P<.001). Hospice was used in 24% of CHF and 61% of dementia cases (P<.001). Finally, 45% of patients with CHF and 18% of patients with dementia died in the acute hospital (P=.006). Multivariate analysis showed that the fact that more patients with CHF were involved in their medical planning was not significant in predicting end-of-life preferences. Alternatively, Caucasian ethnicity was an independent predictor of having a documented DNR and death outside of the acute hospital. CONCLUSION: In the months before death, patients with CHF were more likely to have care plans directed at disease modification and treatment, whereas dementia patients were more likely to have care plans that focused on symptom relief and anticipation of dying. Several factors may contribute to this difference.     

Effect of the sympathetic nervous system on limb circulation and metabolism during exercise in patients with heart failure

During exercise in patients with heart failure, activation of sympathetic vasoconstrictor nerves may impair vasodilation in active skeletal muscle and thereby interfere with skeletal muscle blood flow. To investigate this hypothesis, we examined the effect of acute alpha-adrenergic blockade with systemic administration of prazosin (10 patients) or regional administration of phentolamine (eight patients) on blood flow, vascular resistance, oxygen consumption (VO2), and lactate release in the leg during maximal bicycle exercise in patients with heart failure. During control exercise, systemic VO2 increased to 12.6 +/- 4.3 ml/min/kg (normal greater than 20 to 25 ml/min/kg), leg blood flow to 2.8 +/- 1.8 liters/min, and leg lactate release to 362 +/- 256 mg/min. Prazosin decreased systemic vascular resistance (12.5 +/- 3.2 to 9.7 +/- 2.5 units; p less than .003) and mean arterial pressure (101 +/- 20 to 87 +/- 22 mm Hg; p less than .002) at maximal exercise, supporting the presence of substantial sympathetic vasoconstrictor nerve activity. Prazosin also decreased leg resistance during exercise. However, the magnitude of leg blood flow, leg oxygen extraction, and leg VO2 during exercise were unchanged, suggesting that vasodilation in the leg was produced by an autoregulatory response to the drop in blood pressure rather than by blockade of sympathetic vasoconstriction. Maximal systemic VO2 and leg lactate release were also not improved. Regional blockade with phentolamine did not substantially drop the arterial blood pressure and had no effect on vasodilation, blood flow, VO2, and lactate release in the leg during exercise. These data suggest that during exercise in patients with heart failure, the sympathetic nervous system helps to sustain arterial blood pressure and that this beneficial effect is not associated with adverse effects on blood flow to working skeletal muscle.     

Preparing generalist physicians The organizational and policy context

A combination of financial, regulatory, and professional factors have led to a gradual but pronounced decline in generalist training and practice in the United States. This trend is likely to undergo dramatic reversal, however, as reflected by the diverse range of health care reform proposals incorporating incentives to promote generalist education and primary care practice. Considerable consensus has been reached by a number of professional organizations and public policy groups regarding the broad details of reform of generalist physician training, but key areas of controversy remain with important implications for academic medical centers. In addition, the generalist professional organizations, particularly those of family practice, general internal medicine, and general pediatrics, are being challenged to reconcile historic differences in the definitions and training of generalist competence. In this, the call for “retraining subspecialists” will both offer an opportunity and entail a risk. Finally, academic medical centers will need new organizational structures that can combine the distinctive intellectual traditions and the expertise of the generalist medical disciplines to develop new approaches to the education and practice of primary care.     

Studies of glucose turnover and renal function in an unusual case of hereditary fructose intolerance.

Examination of glucose kinetics, pancreatic alpha and beta cell function, plasma lipids, urinary acidification and calcium excretion has been undertaken in a patient with hereditary fructose intolerance. This case was unusual as it was associated with insulin-requiring diabetes, type IV hyperlipemia, hypercalciuria and renal calculi. He also demonstrated the previously described fructose-induced defect of urine acidification. Glucagon and C-peptide assays showed that the pancreatic alpha cells were stimulated by fructose and that the beta cells did not respond to fructose. It is not known whether the latter was due to his diabetes or to the lack of a beta cell response to this sugar. Primed 14C-glucose infusions were used for the first time to study nonsteady state glucose kinetics in man. They showed that, 24 hours after the last insulin injection and under basal conditions, the glucose concentrations increased because glucose production exceeded glucose utilization. However, after the administration of sorbitol the plasma glucose concentration decreased because glucose production decreased. After the administration of sorbitol there was no change in the metabolic clearance of glucose. This reflects the lack of a peripheral insulin effect and is consistent with the lack of any measurable C-peptide. Glucose utilization also decreased, but this decrease was less than the decrease in glucose production. Because the metabolic clearance of glucose remained unchanged, it was concluded that the change in glucose utilization was solely due to the decrease in glucose concentration. The absence of C-peptide in the plasma indicated that changes in glucose turnover were not related to any changes in endogenous plasma insulin. Furthermore, the plasma glucagon concentration increased and, hence, changes in this hormone could not account for the decrease in glucose production. Therefore, it was concluded that the sorbitol-induced decline in glucose production was due to a direct effect on hepatic metabolism.     

Beta-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway

Stimulation of beta-adrenergic receptors (betaARs) causes apoptosis in adult rat ventricular myocytes (ARVMs). The role of reactive oxygen species (ROS) in mediating betaAR-stimulated apoptosis is not known. Stimulation of betaARs with norepinephrine (10 micromol/L) in the presence of prazosin (100 nmol/L) for 24 hours increased the number of apoptotic myocytes as determined by TUNEL staining by 3.6- fold. The superoxide dismutase/catalase mimetics Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 10 micromol/L) and Euk-134 decreased betaAR-stimulated apoptosis by 89+/-6% and 76+/-10%, respectively. Infection with an adenovirus expressing catalase decreased betaAR-stimulated apoptosis by 82+/-15%. The mitochondrial permeability transition pore inhibitor bongkrekic acid (50 micromol/L) decreased betaAR-stimulated apoptosis by 76+/-8%, and the caspase inhibitor zVAD-fmk (25 micromol/L) decreased betaAR-stimulated apoptosis by 62+/-11%. betaAR-stimulated cytochrome c release was inhibited by MnTMPyP. betaAR stimulation caused c-Jun NH2-terminal kinase (JNK) activation, which was abolished by MnTMPyP. Transfection with an adenovirus expressing dominant-negative JNK inhibited betaAR-stimulated apoptosis by 81+/-12%, and the JNK inhibitor SP600125 inhibited both betaAR-stimulated apoptosis and cytochrome c release. Thus, betaAR-stimulated apoptosis in ARVMs involves ROS/JNK-dependent activation of the mitochondrial death pathway.     

Abnormal exercise hemodynamics in cardiac allograft recipients 1 year after cardiac transplantation. Relation to preload reserve

The well-established elevation in left ventricular filling pressures during exercise in patients after transplantation may contribute to decreased exercise tolerance. A proposed mechanism for this increase in filling pressures is an abnormal pressure-volume homeostasis of the transplanted heart. Twenty-three patients undergoing routine 1-year evaluations performed supine bicycle exercise during right heart catheterization. Within 24 hours, these patients underwent supine bicycle exercise to the identical work load during radionuclide ventriculography. For the group, resting hemodynamics and resting left and right ventricular ejection fractions were normal. With exercise, right atrial and pulmonary wedge pressure rose markedly (from 6 +/- 2 to 14 +/- 7 mm Hg, p less than 0.0001, and from 10 +/- 3 to 20 +/- 6 mm Hg, p less than 0.0001, respectively). Left ventricular ejection fraction increased appropriately with exercise (from 0.58 +/- 0.08 to 0.63 +/- 0.07, p = 0.004). End-diastolic volume also increased mildly (from 100 +/- 31 to 117 +/- 39 ml, p = 0.001), but change in end-diastolic volume was highly variable. Patients with little or no change in end-diastolic volume with exercise had the greatest resting and exercise left ventricular filling pressures resulting in significant negative correlations between filling pressures and change in end-diastolic volume (r = -0.64, p = 0.002 and r = -0.50, p = 0.025, respectively). Negative linear relations between exercise left ventricular filling pressures or resting heart rates and donor to recipient body weight ratio (r = -0.35, p = 0.10, and r = -0.37, p = 0.06, respectively) suggested that initial donor heart size influenced subsequent cardiac function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased serum levels of eotaxin in patients with inflammatory bowel disease

BACKGROUND: The CC-chemokines eotaxin and eotaxin-2, produced by epithelial and phagocytic cells, are potent and selective chemoattractants for eosinophils and basophils. The eosinophil is a potent inflammatory cell thought to play an important role in the pathogenesis of inflammatory bowel disease (IBD). In this study we investigated the serum concentrations of eotaxin and eotaxin-2 in patients with Crohn disease and ulcerative colitis. METHODS: Thirty-one patients with Crohn disease, 35 patients with ulcerative colitis and 41 control patients were studied. Eotaxin and eotaxin-2 serum levels were measured with solid phase sandwich enzyme-linked immunosorbent assays. RESULTS: Significantly increased serum eotaxin levels were observed in both patients with Crohn disease (289.4+/-591.5 pg/ml) and ulcerative colitis (207.0+/-243.4 pg/ml) when compared with controls (138.0+/-107.8 pg/ml) (P < 0.01). Moreover, patients with active Crohn disease and ulcerative colitis showed significantly higher serum eotaxin levels than patients with quiescent disease (434.0+/-776.8 pg/ml versus 113.8+/-65.4 pg/ml in Crohn disease and 295.7+/-337.1 versus 121.2+/-91.9 pg/ml in ulcerative colitis, P < 0.05). In contrast, there was no significant difference in eotaxin-2 serum levels among patients with Crohn disease (863.5+/-448.2 pg/ml), ulcerative colitis (1028.3+/-431.4 pg/ml) and controls (981.4+/-539.4 pg/ml). CONCLUSIONS: Eotaxin is significantly increased in serum of patients with active Crohn disease and ulcerative colitis, suggesting that this cytokine may play a role in the pathogenesis of IBD.