Publications

Cytokines are involved in a number of physiologic and pathophysiologic processes in the liver. These small molecules impact hepatic growth and repair, regulate inflammation, and influence fibrogenesis. Cytokines acting within the liver derive from both resident and recruited cells; the pattern of cytokines produced in a given clinical situation depends upon the inciting stimulus and the background cellular milieu. Experimental animals display inherited differences in cytokine responses to environmental insults. If these differences are operative in human beings, they may account in part for variations in susceptibility among individuals or groups to certain types of liver disease.

Characterization of intramyocardial coronary artery flow may offer insight into the spectrum of coronary physiology. The purposes of this study were to test the feasibility of detection and measurement of intramyocardial coronary artery flow by using high-frequency transthoracic ultrasound and to evaluate the hemodynamic and morphologic differences in intramyocardial coronary arteries between patients with echocardiographically normal myocardium and patients with diseased myocardium. In 116 subjects (age 58 +/- 19 years; male:female 67:49; 58 normal [control subjects], 40 with left ventricular hypertrophy [LVH], 18 with systolic left ventricular dysfunction [cardiomyopathy, CM]), we examined the myocardium just beneath the apical impulse window at a depth of 3 to 5 cm by using a 6- or 7-MHz centerline frequency transducer. For color Doppler examination, a special preset coronary program with a low Nyquist limit (12 to 20 cm) was used. After obtaining linear color signals, the width and length, peak and mean diastolic pulsed Doppler flow velocities, diastolic velocity time integrals, and percent duration of diastolic Doppler flow were measured. The number of linear color flow signals per square centimeter was counted in 520 different cardiac cycles, and the angles formed by their inner curvature was measured with a graduated protractor. We identified color flow Doppler signals within the myocardium having a mean width of 1.1 +/- 0.4 mm and flow direction from epicardium to endocardium in 104 (89. 7%) subjects and spectral Doppler signals in 74 (63.8%) subjects. In 33 (45.8%) subjects, only diastolic flow was detected and in 39 (54. 2%) subjects, diastolic flow was predominant with systolic reversal. Peak and mean diastolic flow velocities and velocity time integrals of spectral Doppler signal in control subjects were 26.2 +/- 8.6 cm/s, 19.0 +/- 6.3 cm/s, and 9.5 +/- 2.7 cm, respectively. There were no significant differences in width and density of linear color flow signals among the 3 groups. The color flow signals in the LVH and CM groups had a narrower angle of inner curvature (P <.005 for LVH, P <.05 for CM, respectively), and their spectral Doppler signals showed significantly higher diastolic velocities and shorter diastolic flow duration (P <.005 for LVH, P <.05 for CM, respectively) than those of the control subjects. Detection and measurement of flow signals consistent with penetrating intramyocardial coronary arteries are feasible in a high percentage of subjects by use of high-frequency transthoracic ultrasound. The findings in patients with LVH and CM suggest that there are distinct hemodynamic and morphologic departures from those with normal left ventricles that may be a consequence of disordered myocardial perfusion in diseased myocardium.

Embryonic development and tumor progression both require the exquisite coordination of programs for extracellular matrix (ECM) formation and remodeling, and those for angiogenesis and vascular development. Without a vascular supply the normal tissue or tumor is limited in size and organization. Without ECM remodeling the alteration of tissue and tumor boundaries and cellular migrations are limited. Recent insights into the molecular mechanisms regulating the extracellular environment of the growing embryonic tissue or tumors have implicated proteases, the matrix metalloproteinases (MMPs) in particular, in both the process of ECM remodeling and angiogenesis, and in a potential causal relationship between these processes. This review focuses on the roles that MMPs play in regulating three processes in which both proteolysis and vascular development are tightly coordinated: embryo implantation, bone development and tumor progression.

This paper describes a method to construct a standardized health care resource use database. Billing and clinical data were analyzed for 916 patients who received liver transplantations at three medical centers over a 4-year period. Data were checked for completeness by assessing whether each patient's bill included charges covering specified dates and for specific services, and for accuracy by comparing a sample of bills to medical records. Detailed services were matched to a standardized service list from one of the centers, and a single price list was applied. For certain services, clinical data were used to estimate service use or, if a match was not possible, adjusted charges for the services were used. Twenty-three patients were eliminated from the database because of incomplete resource use data. There was very good correspondence between bills and medical records, except for blood products. Direct matches to the standardized service list accounted for 69.3% of services overall; 9.4% of services could not be matched to the standardized service list and were thus adjusted for center and/or time period. Clinical data were used to estimate resource use for blood products, operating room time, and medications; these estimations accounted for 21.3% of services overall. A database can be constructed that allows comparison of standardized resource use and avoids biases due to accounting, geographic, or temporal factors. Clinical data are essential for the creation of such a database. The methods described are particularly useful in studies of the cost-effectiveness of medical technologies.

The dysregulated expression of interleukin 4 (IL-4) can have deleterious effects on the outcome of infectious and allergic diseases. Despite this, the mechanisms by which naive T cells commit to IL-4 expression during differentiation into mature effector cells remain incompletely defined. As compared to cells from most strains of mice, activated CD4(+) T cells from BALB mice show a bias towards IL-4 production and T helper 2 commitment in vitro and in vivo. Here, we show that this bias arises not from an increase in the amount of IL-4 produced per cell, but rather from an increase in the proportion of CD4(+) T cells that commit to IL-4 expression. This strain-specific difference in commitment was independent of signals mediated via the IL-4 receptor and hence occurred upstream of potential autoregulatory effects of IL-4. Segregation analysis of the phenotype in an experimental backcross cohort implicated a polymorphic locus on chromosome 16. Consistent with a role in differentiation, expression of the phenotype was CD4(+) T cell intrinsic and was evident as early as 16 h after the activation of naive T cells. Probabilistic gene activation is proposed as a T cell-intrinsic mechanism capable of modulating the proportion of naive T cells that commit to IL-4 production.

The pathogenesis of asthma reflects, in part, the activity of T cell cytokines. Murine models support participation of interleukin-4 (IL-4) and the IL-4 receptor in asthma. Selective neutralization of IL-13, a cytokine related to IL-4 that also binds to the alpha chain of the IL-4 receptor, ameliorated the asthma phenotype, including airway hyperresponsiveness, eosinophil recruitment, and mucus overproduction. Administration of either IL-13 or IL-4 conferred an asthma-like phenotype to nonimmunized T cell-deficient mice by an IL-4 receptor alpha chain-dependent pathway. This pathway may underlie the genetic associations of asthma with both the human 5q31 locus and the IL-4 receptor.