Publications

Prolonged exposure of human epidermis to excess endogenous or exogenous glucocorticoids can result in well-recognized cutaneous abnormalities. Here, we determined whether short-term glucocorticoid treatment would also display adverse effects, specifically on two key epidermal functions, permeability barrier homeostasis and stratum corneum integrity and cohesion, and the basis for such changes. In humans 3 d of treatment with a potent, commonly employed topical glucocorticoid (clobetasol), applied topically, produced a deterioration in barrier homeostasis, characterized by delayed barrier recovery and abnormal stratum corneum integrity (rate of barrier disruption with tape strippings) and stratum corneum cohesion (microg protein removed per stripping). Short-term systemic and topical glucocorticoid produced similar functional defects in mice, where the basis for these abnormalities was explored further. Both the production and secretion of lamellar bodies were profoundly decreased in topical glucocorticoid-treated mice resulting in decreased extracellular lamellar bilayers. These structural changes, in turn, were attributable to a profound global inhibition of lipid synthesis, demonstrated both in epidermis and in cultured human keratinocytes. The basis for the abnormality in stratum corneum integrity and cohesion was a diminution in the density of corneodesmosomes in the lower stratum corneum. We next performed topical replacement studies to determine whether lipid deficiency accounts for the glucocorticoid-induced functional abnormalities. The abnormalities in both permeability barrier homeostasis and stratum corneum integrity were corrected by topical applications of an equimolar distribution of free fatty acids, cholesterol, and ceramides, indicating that glucocorticoid-induced inhibition of epidermal lipid synthesis accounts for the derangements in both cutaneous barrier function and stratum corneum integrity/cohesion. These studies indicate that even short-term exposure to potent glucocorticosteroids can exert profound negative effects on cutaneous structure and function. Finally, topical replenishment with epidermal physiologic lipids could represent a potential method to reduce the adverse cutaneous effects of both topical glucocorticoid treatment and Cushing's syndrome.

Conventional risk factors of cardiovascular disease and mortality in the general population such as body mass, serum cholesterol, and blood pressure are also found to relate to outcome in maintenance dialysis patients, but often in an opposite direction. Obesity, hypercholesterolemia, and hypertension appear to be protective features that are associated with a greater survival among dialysis patients. A similar protective role has been described for high serum creatinine and possibly homocysteine levels in end-stage renal disease (ESRD) patients. These findings are in contrast to the well-known association between over-nutrition and poor outcome in the general population. The association between under-nutrition and adverse cardiovascular outcome in dialysis patients, which stands in contrast to that seen in non-ESRD individuals, has been referred to as "reverse epidemiology." Publication bias may have handicapped or delayed additional reports with such paradoxical findings in ESRD patients. The etiology of this inverse association between conventional risk factors and clinical outcome in dialysis patients is not clear. Several possible causes are hypothesized. First, survival bias may play a role since only a small number of patients with chronic kidney disease (CKD) survive long enough to reach ESRD. Hence, the dialysis patients are probably a distinctively selected population out of CKD patients and may not represent the risk factor constellations of their CKD predecessors. Second, the time discrepancy between competitive risk factors may play a role. For example, the survival disadvantages of under-nutrition, which is frequently present in dialysis patients, may have a major impact on mortality in a shorter period of time, and this overwhelms the long-term negative effects of over-nutrition on survival. Third, the presence of the "malnutrition-inflammation complex syndrome" (MICS) in dialysis patients may also explain the existence of reverse epidemiology in dialysis patients. Both protein-energy malnutrition and inflammation or the combination of the two are much more common in dialysis patients than in the general population and many elements of MICS, such as low weight-for-height, hypocholesterolemia, or hypocreatininemia, are known risk factors of poor outcome in dialysis patients. The existence of reverse epidemiology may have a bearing on the management of dialysis patients. It is possible that new standards or goals for such traditional risk factors as body mass, serum cholesterol, and blood pressure should be considered for these individuals.

PURPOSE

The typical leg bypass surveillance program begins with a duplex scan evaluation of the vein graft 3 months after surgery; studies are repeated every 3 months during the first year of follow-up and are fully reimbursed by our Medicare carrier. Some authors have recommended early (before discharge or first postoperative visit) duplex scanning to identify high-risk grafts. However, the natural history of velocity disturbances detected with early scans is unclear, and furthermore, such studies are not reimbursed by Medicare.

METHODS

We reviewed all infrainguinal vein bypass grafts prospectively entered into a surveillance protocol that included an early (<6 weeks) duplex scan study. Routine completion angiography was performed at the initial operation in all patients. Early duplex scan results, the need for graft revision, and detailed follow-up of these bypass grafts were analyzed.

RESULTS

Early duplex scans were performed in 224 bypass grafts placed in 204 patients. Early scans were abnormal (peak systolic velocity [PSV], >200 cm/s) in 58 grafts (26%). Six grafts of the 58 (10.3%; 2.7%) with an early abnormal duplex scan and unrepaired defects occluded during the follow-up period. Thirty grafts were revised on the basis of the initial early scan; 23 of these revisions were performed for critical or rapidly progressive lesions in the first 3 postoperative months. Seven lesions progressed more slowly and were repaired at a mean of 8 months after surgery. Interestingly, 22 flow abnormalities (37%) resolved or stabilized despite a PSV of more than 300 cm/s in six cases (27%). Clear duplex scan evidence of regression or progression of these early flow abnormalities occurred within 3 months in 51/58 cases (88%). A total of 68 grafts (30%) were revised during the entire study period; 30 of these (44%) were on the basis of the early abnormal scan.

CONCLUSION

Despite normal completion arteriography, early graft velocity abnormalities are strikingly common and were detected in 26% of the 224 infrainguinal vein grafts in this series. These lesions were clinically important because 52% necessitated revision. Surprisingly, however, 38% of these early flow disturbances resolved, despite a PSV of more than 300 cm/s in 27% of cases. Early duplex scan surveillance singularly detects a clinically significant subgroup of grafts that need revision. The possible origin of these early lesions deserves further inquiry, but on the basis of its clinical yield, we recommend that early duplex scan surveillance of infrainguinal bypass grafts should be routine and should be considered for Medicare reimbursement.

The study of distal lung morphogenesis and vascular development would be greatly facilitated by an in vitro or ex vivo experimental model. In this study we show that the growth of mouse embryonic day 12.5 lung rudiments implanted underneath the kidney capsules of syngeneic or immunodeficient hosts follows closely lung development in utero. The epithelium develops extensively with both proximal and distal differentiation to the saccular stage. The vasculature also develops extensively. Large blood vessels accompany large airways and capillaries develop within the saccular walls. Interestingly, vessels in the lung grafts develop from endothelial progenitor cells endogenous to the explants and host vessels do not vascularize the grafts independently. This suggests that embryonic lungs possess mechanisms to prevent the inappropriate ingrowth of surrounding vessels. However, vessels in the lung grafts do connect to host vessels, showing that embryonic lungs have the ability to stimulate host angiogenesis and recruit host vessel connections. These data support the hypothesis that the lung vasculature develops by both vasculogenic and angiogenic processes: a vascular network develops in situ in lung mesenchyme, which is then connected to angiogenic processes from central vessels. The lung renal capsule allograft is thus an excellent model to study the development of the pulmonary vasculature and of late fetal lung development that requires a functional blood supply.

2,4-Dichlorophenoxyacetic acid (2,4-D) is a widely used broadleaf herbicide that has been associated with acute liver toxicity in exposed humans or animals. Chemically reactive metabolites of 2,4-D are proposed as mediators of 2,4-D-induced hepatotoxicity. The aim of the present study was to investigate a novel reactive metabolite of 2,4-D, namely 2,4-dichlorophenoxyacetyl-S-acyl-CoA (2,4-D-CoA), and to determine its involvement in 2,4-D covalent adduct formation. Thus, incubations of synthetic 2,4-D-CoA (106 microM) with GSH (1 mM) in phosphate buffer (pH 7.4) showed 2,4-D-CoA to be able to transacylate the cysteine sulfhydryl of GSH, resulting in the formation of 2,4-D-S-acyl-glutathione (2,4-D-SG) thioester and reaching a concentration of 65 microM after 1 h of incubation. Under similar conditions, 2,4-D-CoA was shown to covalently bind to nucleophilic groups on human serum albumin (HSA, 30 mg/ml), resulting in time-dependent 2,4-D-HSA covalent adduct formation that reached a maximum of 440 pmol/mg HSA after 1 h of incubation. In addition to these studies, incubations of [1-(14)C]2,4-D (1 mM) with rat hepatocytes showed a time-dependent covalent binding of 2,4-D to hepatocyte protein. Inhibition of acyl-CoA formation by trimethylacetic acid (2 mM) decreased the amount of covalent binding to protein in rat hepatocytes by 50%. These results indicate that 2,4-D-CoA thioester is a reactive metabolite of 2,4-D that may contribute to 2,4-D-protein adduct formation in vivo and therefore the associated hepatotoxicity.

BACKGROUND

In addition to lower operative mortality, patients undergoing selected cancer operations at high volume centers have improved longterm survival. We sought to determine the overall effect of hospital volume on life expectancy after cancer surgery.

STUDY DESIGN

We used a Markov decision analysis model to estimate life expectancy for patients undergoing resection for pancreatic, lung, or colon cancer. Model inputs included probabilities of operative mortality and longterm survival. For input data, we examined operative mortality (in-hospital or within 30 days) stratified by volume in over 400,000 patients undergoing resection for these three cancers using the national Medicare database (1994-1999). Risks of late mortality were abstracted from published studies (MEDLINE, 1966 to present) to model the effect of hospital volume on longterm survival. In analysis, we first calculated life expectancy for patients undergoing surgery at very low, low, medium, high, and very high volume hospitals. We then explored the effects of various regionalization strategies.

RESULTS

Life expectancy increased steadily with hospital volume for all three cancers. Life expectancy after pancreatic cancer resection increased linearly with hospital volume: from 1.9 years at very low volume centers to 3.6 years at very high volume centers. For lung cancer, life expectancy ranged from 5.4 to 6.6 years. Increases in life expectancy for colon cancer were not as dramatic: from 6.8 at very low volume hospitals to 7.4 years at very high volume hospitals. Differences in life expectancy across volume strata were largely attributable to differences in longterm survival, not operative mortality. From a policy perspective, regionalizing surgery for colon cancer would produce the greatest overall life-expectancy gains, but it would require moving most patients.

CONCLUSIONS

Patients aged 65 and older with pancreatic, lung, and colon cancer have substantially greater life expectancy after cancer resection at higher volume hospitals. Further work is needed to understand the mechanisms underlying differences in performance across hospitals in cancer care.