Numerical Modeling of Fluid Flow in Solid Tumors

A mathematical model of interstitial fluid flow is developed, based on the application of the governing equations for fluid flow, i.e., the conservation laws for mass and momentum, to physiological systems containing solid tumors. The discretized form of the governing equations, with appropriate boundary conditions, is developed for a predefined tumor geometry. The interstitial fluid pressure and velocity are calculated using a numerical method, element based finite volume. Simulations of interstitial fluid transport in a homogeneous solid tumor demonstrate that, in a uniformly perfused tumor, i.e., one with no necrotic region, because of the interstitial pressure distribution, the distribution of drug particles is non-uniform. Pressure distribution for different values of necrotic radii is examined and two new parameters, the critical tumor radius and critical necrotic radius, are defined. Simulation results show that: 1) tumor radii have a critical size. Below this size, the maximum interstitial fluid pressure is less than what is generally considered to be effective pressure (a parameter determined by vascular pressure, plasma osmotic pressure, and interstitial osmotic pressure). Above this size, the maximum interstitial fluid pressure is equal to effective pressure. As a consequence, drugs transport to the center of smaller tumors is much easier than transport to the center of a tumor whose radius is greater than the critical tumor radius; 2) there is a critical necrotic radius, below which the interstitial fluid pressure at the tumor center is at its maximum value. If the tumor radius is greater than the critical tumor radius, this maximum pressure is equal to effective pressure. Above this critical necrotic radius, the interstitial fluid pressure at the tumor center is below effective pressure. In specific ranges of these critical sizes, drug amount and therefore therapeutic effects are higher because the opposing force, interstitial fluid pressure, is low in these ranges

In Silico Simulation of Corticosteroids Effect on an NFkB- Dependent Physicochemical Model of Systemic Inflammation

During the onset of an inflammatory response signaling pathways are activated for "translating" extracellular signals into intracellular responses converging to the activation of nuclear factor (NF)-kB, a central transcription factor in driving the inflammatory response. An inadequate control of its transcriptional activity is associated with the culmination of a hyper-inflammatory response making it a desired therapeutic target. Predicated upon the nature of the response, a systems level analysis might provide rational leads for the development of strategies that promote the resolution of the response.A physicochemical host response model is proposed to integrate biological information in the form of kinetic rules and signaling cascades with pharmacokinetic models of drug action for the modulation of the response. The unifying hypothesis is that the response is triggered by the activation of the NFkB signaling module and corticosteroids serve as a template for assessing anti-inflammatory strategies. The proposed in silico model is evaluated through its ability to predict and modulate uncontrolled responses. The pre-exposure of the system to hypercortisolemia, i.e. 6 hr before or simultaneously with the infectious challenge "reprograms" the dynamics of the host towards a balanced inflammatory response. However, if such an intervention occurs long before the inflammatory insult a symptomatic effect is observed instead of a protective relief while a steroid infusion after inducing inflammation requires much higher drug doses.We propose a reversed engineered inflammation model that seeks to describe how the system responds to a multitude of external signals. Timing of intervention and dosage regimes appears to be key determinants for the protective or symptomatic effect of exogenous corticosteroids. Such results lie in qualitative agreement with in vivo human studies exposed both to LPS and corticosteroids under various time intervals thus improving our understanding of how interacting modules generate a behavior

Effects of cardiac versus circulatory angiotensin-converting enzyme inhibition on left ventricular diastolic function and coronary blood flow in hypertrophic obstructive cardiomyopathy

Background-Left ventricular (LV) diastolic function and coronary flow are impaired in hypertrophic obstructive cardiomyopathy (HOCM). This study was designed to evaluate the impact of cardiac and circulatory ACE inhibition on such derangements. Methods and Results-Twenty patients with HOCM underwent cardiac ACE inhibition with intracoronary (IC) enalaprilat (0.05 mg/min infused into the left anterior descending coronary artery for 15 minutes) followed by circulatory ACE inhibition with 25 mg sublingual (SL) captopril. Contrast ventriculography, pressure, and coronary flow measurements were performed at baseline, after IC enalaprilat infusion, and 45 minutes after SL captopril. Heart rate was not affected by the respective interventions (75+/-11 versus 76+/-13 versus 75+/-10 bpm; P=NS), whereas mean aortic pressure dropped slightly after IC enalaprilat and significantly after SL captopril (90+/-8 versus 85+/-10 versus 74+/-9 mm Hg; P<.05). Compared with baseline, IC enalaprilat resulted in a decrease in LV end-diastolic pressure (17.6+/-5.9 versus 14.4+/-4.9 mm Hg; P<.05), time constant of isovolumic LV pressure relaxation (tau(G)) (69+/-9 versus 52+/-10 ms; P<.05), and outflow gradient (45.2+/-6.9 versus 24.4+/-3.7 mm Hg; P<.05) and in an increase in coronary blood flow (107+/-10 versus 127+/-12 mL/min; P<.05) and coronary flow reserve (2.2+/-0.4 versus 2.6+/-0.3; P<.05). After SL captopril, tau(G), was prolonged (60+/-13 ms; P<.05 versus IC enalaprilat), and LV outflow gradient, coronary blood flow, and coronary flow reserve values returned to baseline (45.5+/-5.3 mm Hg, 107+/-12 mL/min, and 2.2+/-0.5, respectively; P=NS versus baseline). Conclusions-Activation of the cardiac renin-angiotensin system contributes to LV diastolic dysfunction as well as to the decreased coronary blood flow and coronary flow reserve in HOCM. Cardiac ACE inhibition restores and circulatory ACE inhibition aggravates the above derangements

Relation of coronary artery ectasia to diabetes mellitus

An increased prevalence of coronary artery ectasia (CAE) and a low frequency of diabetes mellitus have been reported in patients with abdominal aortic aneurysm (AAA). The prevalence of diabetes was studied in 190 patients with CAE in comparison with 341 age- and gender-matched patients with coronary artery disease alone. Diabetes mellitus was found to be independently but inversely associated with CAE (relative risk 0.603, 95% confidence interval 0.375 to 0.960, p = 0.037), thus resembling the relation between diabetes and AAA. (C) 2004 by Excerpta Medica, Inc

Protein expression of bax, bcl-2, and p53 in patients with non-Hodgkin's gastric lymphoma: Prognostic significance

The biologic significance of bcl-2, bax, and p53 gene expression in patients with non-Hodgkin’s gastric lymphoma is unknown. We examined the prognostic value of these genes in 36 patients with gastric lymphoma treated in our clinic between 1990 and 1995. Paraffin-embedded specimens from 36 patients who underwent primary resection of the stomach for gastric lymphoma were analyzed immunohistochemically for p53, bax, and bcl-2 gene expression. Expression of bax was seen in 24 of 36 patients (66.7%), p53 expression was found in 8 of 36 tumors (22.2%), and bcl-2 cytoplasmic staining was detected in 6 of 36 patients (16.7%). We performed a univariate analysis to examine the possible correlation between the expression of these genes and the survival of our patients. Expression of bax protein proved to be a statistically significant prognostic factor (p = 0.049). Protein expression of p53 and bcl-2 did not statistically correlate with survival. In the bcl-2-negative (-) patient group (30 patients). those who were bax-positive had a statistically significant better survival than those who were bax-negative (63.3% vs. 36.7%, p = 0.03). There was also a statistically significant correlation between p53 expression and the grade of the tumor (p = 0.0014). P53 protein expression increased along with the grade. Expression of bax is a significant prognostic factor in patients with gastric lymphoma. Its prognostic value increases significantly when studied in bcl-2-negative patients: hut expression of bax failed to be an independent prognostic factor. Expression of bcl-2 and p53 has no prognostic significance. Expression of p53 seems to represent a marker for loss of differentiation

Varicose veins are common in patients with coronary artery ectasia. Just a coincidence or a systemic deficit of the vascular wall?

Objectives. Coronary artery ectasia (CAE), an uncommon finding during coronary arteriography, has been associated with the presence of aneurysm(s) in other parts of the arterial tree including the abdominal aorta. Varicose veins (VV) or phlebectasias are a common disorder of the superficial leg veins. Correlations between arterial and venous ectasias have not been established. We sought to examine whether there is an association between CAE and VV. Methods and results. CAE was diagnosed in 181 patients out of 7510 eligible patients undergoing coronary arteriography within 33 months. The prevalence of VV was significantly higher among patients with CAE (40%) compared to 200 aged-matched patients with coronary artery disease but without CAE (17%) and to 201 randomly selected subjects from the general population (23%). In multivariate analysis, CAE was found to be significantly and independently associated with VV (RR = 3.42, 95% confidence interval (CI) 2.24-5.59, p < 0.001). Conclusion. In this study population, VV were more common in patients with CAE than in those without. This association was valid in both univariate and multivariate analysis, suggesting the possible existence of a generalised defect of the entire vascular wall