Ciliary beat frequency and structure of recipient and donor epithelia following lung transplantation

To investigate possible changes following lung transplantation, the structure and in vitro ciliary beat frequency (CBF) of airway epithelium from the cytology brushings of 9 heart-lung (HLT) and 5 single-lung (SLT) transplant recipients were examined. The CBF of brushings taken proximal and distal to the anastomosis was measured 2-10 months following transplant. There was no difference between the measured mean CBF at the two sites or between the two groups; HLT CBF: distal 11.0 +/- 0.5 Hz (standard error of mean), proximal 10.5 +/- 0.4 Hz, SLT CBF: distal 11.7 +/- 0.9 Hz, proximal 12.0 +/- 0.6 Hz. Mean CBF of bronchial brushings (except distal brushings from SLT patients) was significantly lower than that from controls: 13.6 +/- 0.3 Hz (n = 7) (p less than 0.05). Transmission electron microscopy of epithelial brushings from 4 patients (3 HLT, 1 SLT) revealed epithelial abnormalities both proximal and distal to the anastomosis, particularly ciliary depletion, mitochondrial abnormalities and death of cells. No significant ciliary ultrastructural abnormalities were seen in any tissue. We conclude that epithelial abnormalities were observed both proximal and distal to the anastomosis following lung transplantation. These may contribute to impairment of mucociliary clearance.     

Advances in radiotherapy for lung cancer

The past decade has seen steady advances in the field of radiation therapy, impacting definitive treatment options for early and advanced tumors, as well as identifying further roles for adjuvant and palliative therapy. The widespread availability of (18)F-fluoro-2-deoxy-D-glucose positron emission tomographic (FDG PET) imaging has improved staging, and better defines a population that will benefit from aggressive local therapy. Technological advances in radiation treatment planning allow for less normal lung irradiation, allowing increasing dose and decreasing normal tissue toxicity. Ongoing clinical investigations in the role of radiosurgery for early lung tumors, postoperative radiation of locally advanced non-small-cell lung cancer (NSCLC), and prophylactic cranial irradiation in small-cell lung cancer (SCLC) help to identify patients who may benefit from treatment.     

Identification of somatic JAK1 mutations in patients with acute myeloid leukemia

Somatic mutations in JAK2 are frequently found in myeloproliferative diseases, and gain-of-function JAK3 alleles have been identified in M7 acute myeloid leukemia (AML), but a role for JAK1 in AML has not been described. We screened the entire coding region of JAK1 by total exonic resequencing of bone marrow DNA samples from 94 patients with de novo AML. We identified 2 novel somatic mutations in highly conserved residues of the JAK1 gene (T478S, V623A), in 2 separate patients and confirmed these by resequencing germ line DNA samples from the same patients. Overexpression of mutant JAK1 did not transform primary murine cells in standard assays, but compared with wild-type JAK1, JAK1^T478S, and JAK1^V623A expression was associated with increased STAT1 activation in response to type I interferon and activation of multiple downstream signaling pathways. This is the first report to demonstrate somatic JAK1 mutations in AML and suggests that JAK1 mutations may function as disease-modifying mutations in AML pathogenesis.     

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.