Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin.

The human immunodeficiency virus type 1 (HIV-1) viral protein R (vpr) gene is an evolutionarily conserved gene among the primate lentiviruses. Several functions are attributed to Vpr including the ability to cause cell death, cell cycle arrest, apoptosis and DNA damage. The Vpr domain responsible for DNA damage as well as the mechanism(s) through which Vpr induces this damage is unknown. Using site-directed mutagenesis, we identified the helical domain II within Vpr (aa 37-50) as the region responsible for causing DNA damage. Interestingly, Vpr Delta(37-50) failed to cause cell cycle arrest or apoptosis, to induce Ku70 or Ku80 and to suppress tumor growth, but maintained its capability to activate the HIV-1 LTR, to localize to the nucleus and to promote nonhomologous end-joining. In addition, our cytogenetic data indicated that helical domain II induced chromosomal aberrations, which mimicked those induced by cisplatin, an anticancer agent. This novel molecular mimicry function of Vpr might lead to its potential therapeutic use as a tumor suppressor.

Differences in ICAM-1 and TNF-alpha expression between large single fraction and fractionated irradiation in mouse brain.

PURPOSE: To elucidate the brain molecular response to irradiation. The expression of the intercellular adhesion molecule (ICAM-1) and tumour necrosis factor-alpha (TNF-alpha) in the mouse brain was compared after single-dose and fractionated whole-brain irradiation. MATERIALS AND METHODS: Mice received a single dose of 2, 10 or 20 Gy or a fractionated dose (2 Gy day(-1)) of 10, 20 or 40 Gy. ICAM-1, and TNF-alpha mRNA expression were quantified by the highly sensitive real-time polymerase chain reaction technique. Expression of ICAM-1 protein was quantified by dual-labelled monoclonal antibody assay. RESULTS: After a 20-Gy single dose, there was an increase in ICAM-1 and TNF-alpha mRNA levels (14- and 11-fold, respectively) as well as a significant increase in the level of ICAM-1 protein (p=0.0243). The expression of ICAM-1 and TNF-alpha mRNA increased at the end of the 40-Gy fractionated regimen (3.55- and 2.30-fold, respectively). CONCLUSIONS: The molecular response of the brain to single-dose irradiation was rapid, while its response to fractionated irradiation was slow. This finding is consistent with clinical observations and could be of use when designing strategies to mitigate radiation sequelae.

Expression and functional significance of adhesion molecules on cultured endothelial cells in response to ionizing radiation.

OBJECTIVE: Upregulation of adhesion molecules on endothelial cells following irradiation has been shown, but the functional significance of this upregulation in various endothelial cell lines is not clear. We have developed an in vitro flow model to study the functional consequences of the radiation-induced upregulation of E-selectin and intercellular adhesion molecule (ICAM-1). METHODS: Human dermal microvascular endothelial cells (HDMEC), human umbilical vein endothelial cells (HUVEC), or transformed human microvascular endothelial cells (HMEC-1) were grown in 35-mm dishes and irradiated with a single dose of 10 Gy. HL-60 (human promyelocytic leukemia) cells were perfused over the irradiated endothelial cells in a parallel plate flow chamber at shear stress ranging from 0.5 to 2.0 dynes/cm2. Flow cytometry was used to quantify the expression of E-selectin and ICAM-1 on the various endothelial cells. RESULTS: Flow cytomeric analysis revealed an upregulation of ICAM-1 expression on all three cell types postirradiation (post-IR), and an upregulation of E-selectin expression only on HDMEC post-IR. E-selectin expression was detected on control HDMEC, but at a lower level than that detected on post-IR HDMEC. Flow assays revealed a significant increase in the number of rolling and firmly adherent HL-60 cells on post-IR HDMEC at shear stress < or =1.5 dynes/cm2; pretreatment of control and irradiated HDMEC with antibodies to E-selectin and ICAM-1 significantly diminished the number of rolling and firmly adherent HL-60 cells, respectively. No rolling or firm adhesion of HL-60 cells was observed on HUVEC or HMEC-1 monolayers post-IR. CONCLUSION: These findings suggest that ICAM-1 is upregulated on irradiated HDMEC, HUVEC, and HMEC-1. E-selectin is upregulated to a functional level only on irradiated HDMEC, and not on irradiated HUVEC or HMEC-1.

Extravasation of poly(amidoamine) (PAMAM) dendrimers across microvascular network endothelium.

PURPOSE: To study the influence of a controlled incremental increase in size and molecular weight of a series of poly(amidoamine) (PAMAM) dendrimers on their extravasation across the microvascular network endothelium. METHODS: A series of PAMAM dendrimers (generations 0-4) were fluorescently labeled using fluorescein isothiocyanate (FITC). Purification and fractionation of the fluorescently labeled polymers were done using size exclusion chromatography. The hamster cremaster muscle preparation was used as an in vivo model to study the extravasation process of the fluorescently labeled polymers. The extravasation process was visualized and recorded using intravital microscopy techniques. Analysis of the recorded experiments was done using Metamorph Imaging System. Extravasation of the fluorescently labeled polymers is reported in terms of their extravasation time (tau), i.e., the time needed for the fluorescence intensity in the interstitial tissue to reach 90% of the fluorescence intensity in the neighboring microvessels. RESULTS: Extravasation time (tau) describes the rate of microvascular extravasation of polymeric drug carriers across the microvascular endothelium into the interstitial tissue. Extravasation time (tau) of the studied PAMAM dendrimers showed size and molecular weight dependence. An increase in size and/or molecular weight of PAMAM dendrimers resulted in a corresponding exponential increase in the extravasation time (tau). CONCLUSIONS: Extravasation of PAMAM dendrimers across the microvascular endothelium showed size and molecular weight dependence. Results suggest that in addition to size and molecular weight, other physicochemical properties of polymeric drug carriers such as molecular geometry and charge may influence their microvascular extravasation. Systematic studies of the influence of the physico-chemical properties of polymeric drug carriers on their microvascular extravasation will aid in the design of novel macromolecular drug carriers with controlled extravasation profiles.

Late effects of ionizing radiation on the microvascular networks in normal tissue.

Damage to the microvascular networks constitutes one of the most important components of ionizing radiation damage to normal tissue. Previously, we have reported the early (3, 7 and 30 days postirradiation) effects of ionizing radiation on the structure and function of normal tissue microvascular networks. Here we report on the late effects of ionizing radiation on the structural and functional changes in microvascular networks in locally irradiated (single 10-Gy dose) hamster cremaster muscles observed 60, 120 and 180 days postirradiation; age-matched animals were used as controls. As in the previous study, intravital microscopy was used to measure structural and functional parameters in complete microvascular networks in vivo. A factorial design was used to examine the effects of radiation status, time postirradiation, and network vessel type on the structure and function of microvascular networks. Our results indicate that the progression of radiation-induced microvascular damage continues during the late times but that there is partial recovery from radiation damage within 6 months postirradiation. Red blood cell flux, red blood cell velocity, and capillary blood flow in irradiated networks at 180 days postirradiation were significantly greater than control levels. As at the early times, all vessel types were not damaged equally by radiation at every time.

Early effects of ionizing radiation on the microvascular networks in normal tissue.

Microvascular networks, which control the delivery of oxygen and nutrients and the removal of metabolic waste, are the most sensitive part of the vascular system to ionizing radiation. Structural and functional changes in microvascular networks were studied in locally irradiated (single 10-Gy dose) hamster cremaster muscles observed 3, 7 and 30 days post-irradiation. Networks were selected in reference to a well-defined location in the tissue to reduce heterogeneity due to spatial variations. Intravital microscopy was used to measure structural and functional parameters in vivo. A factorial design was used to examine the effects of radiation status, time postirradiation, and network vessel type on the structure and function of microvascular networks. While the diameter of microvessels in control animals increased significantly with age, vessel diameter in irradiated vessels decreased significantly with age. Red blood cell velocity in irradiated networks at 3 and 30 days postirradiation was significantly lower than in control networks. There was a significant decrease in capillary surface area and a significant increase in vessel hematocrit in irradiated animals. Blood flow in irradiated vessels was significantly lower than in control vessels. Changes in functional parameters were evident at 3 days postirradiation while changes in structural parameters occurred later. All vessel types were not damaged equally by radiation at every time examined.

A "geographic information systems" based technique for the study of microvascular networks.

An automated system (ANET) has been developed to construct interactive maps of microvascular networks, calculate blood flow parameters, and simulate microvascular network blood flow using the geographic information systems (GIS) technology. ANET enables us to automatically collect and display topological, structural, and functional parameters and simulate blood flow in microvascular networks. The user-definable programming interface was used for the manipulation of drawings and data. Visual enhancement techniques such as color can be used to display useful information within a network. In ANET the network map becomes a graphical interface through which network information is stored and retrieved and simulations of microvascular network blood flow are carried out. We have used ANET to study the effects of ionizing radiation on normal tissue microvascular networks. Our results indicate that while vessel diameters significantly increased with age in control animals they decreased in irradiated animals. The tortuosity of irradiated vessels (16.3+/-1.1 mean+/-standard error of the mean) was significantly different from control vessels (10.0+/-1.3) only at 7 days postirradiation. Average red blood cell transit time was significantly different between control (1.6+/-0.6s) and irradiated (10.7+/-5.7s) microvascular networks at 30 days postirradiation. ANET provides an effective tool for handling the large volume of complex data that is usually obtained in microvascular network studies and for simulating blood flow in microvascular networks.

Observations on the accuracy of photometric techniques used to measure some in vivo microvascular blood flow parameters.

OBJECTIVE: The accuracy of optical methods used to measure in vivo microvascular blood flow parameters is investigated using measurements made in all vessels of microvascular networks of the rat mesentery. METHODS: The principle of mass conservation was applied to in vivo blood flow rate and discharge hematocrit data, which were determined by photometric methods. One of the several implied assumptions of most interpretations of in vivo optical data is that the vessels are circular in cross-section: to see the impact of vessel lumen shape on one of these measurements, the average velocity of blood flowing through a D-shaped glass capillary tube was measured by the dual-slit method. RESULTS: For in vivo data, significant imbalance exists in a large number of bifurcations, and the correlation between the blood flow imbalance and the red cell flux imbalance is very small (r2 = 0.39), indicating multiple sources of error. Furthermore, the measured discharge hematocrits were consistent with the observed flow directions at bifurcations in only 39% to 46% of the bifurcations in a network. The imbalance at these bifurcations is not simply caused by the inaccuracy of measurements in only a few microvessels that join such bifurcations, i.e., the inaccuracies are evenly distributed among the vessels. The results of the in vitro study of blood velocity measurement in D-shaped tubes indicates that the ratio of dual-slit velocity to the actual average blood velocity is sensitive to the shape of the vessel lumen, and is a function of blood flow rate, hematocrit, vessel lumen shape, and orientation. CONCLUSIONS: Significant inaccuracies exist in the flow and hematocrit data obtained by current methods of interpretation of in vivo photometric measurements. These inaccuracies must be considered when making vessel to-vessel comparisons, or vessel-by-vessel comparisons between in vivo observations and model predictions, even though the inaccuracies are greatly reduced when comparing averaged data.

Diameter variability and microvascular flow resistance.

Microvessels are known to exhibit irregular shapes, deviating substantially from an idealized cylindrical tube geometry. Such irregularities must be taken into account in calculating microvascular flow resistance and may add to the observation that flow resistance in living microvessels in vivo is about twice that predicted on the basis of tube flow studies in vitro. The present study was aimed at providing a comprehensive database describing the apparent diameter variability for all segments of a complete microvascular network in the rat mesentery and assessing the impact of this variability on segmental flow resistance and the pressure drop across the network. Diameters were estimated by intravital microscopy at axial intervals of 20 microns along the 546 vessel segments of a mesenteric microvessel network, resulting in 6,319 separate diameter measurements. The amplitude of diameter variations in individual vessel segments decreased from approximately 15% of the mean vessel diameter in the smallest segments (approximately 5 microns diam) to approximately 5% in the largest segments (approximately 60 microns diam). Segmental hindrance was estimated to be 10-23% higher than calculated from arithmetic mean diameter, depending on the model used to estimate the hydrodynamically effective segment diameter. The overall pressure drop across the network calculated using a mathematical flow simulation was increased by 7-13.5%. This increase in flow resistance can explain approximately 10% of the observed discrepancy between flow resistance in vivo and in vitro.

Effects of ionizing radiation on the adhesive interaction of human tumor and endothelial cells in vitro.

A centrifugation assay was used to determine the effects of ionizing radiation on the adhesive interaction of A549 human lung adenocarcinoma tumor cells and human umbilical vein endothelial cells (HUVEC). The tumor cells were fluorescently labeled and divided into control (sham-irradiated) and irradiated groups. The irradiated groups were exposed to irradiation levels ranging from 5 to 20 Gy using a 137Cs source. A specified number of these A549 tumor cells were then delivered into each well of 96-well cell culture plates containing confluent monolayers of human umbilical cord vein endothelial cells (HUVEC), and were given time to adhere to the endothelial cells. The wells were then sealed and were exposed to an acceleration field varying from 1 to 42 g (0-500 rpm) for 10 min. Finally, the wells were drained, and the number of tumor cells adhering to the endothelial monolayer were counted using a fluorescent microscope system. Our results indicate that the irradiation of A549 tumor cells significantly increased their adhesive interaction with endothelial cells (number of adhering irradiated cells/number of adhering control cells = 1.0, 1.3, 1.9, 2.2 for 0, 5, 10, 20 Gy respectively). In contrast, when endothelial cells were irradiated, rather than tumor cells, adhesive interaction decreased with an increase in the radiation dose (irradiated/control = 1.0, 0.9, 0. 8, 0.5 for 0, 5, 10, 20 Gy respectively). Simultaneous irradiation of both the tumor cells and the endothelial cells did not alter their adhesive interaction significantly. These findings may have important implications for the metastatic ability of irradiated tumor cells.

Should direct measurements of tumor oxygenation relate to the radiobiological hypoxic fraction of a tumor?

PURPOSE: Numerous previous studies have attempted to relate the radiobiological hypoxic fraction (HF) to direct measures of tumor oxygenation such as HbO2 saturations, tumor pO2 levels, or hypoxic cell labeling. Although correlations have been found within tumor lines, no overall relationships were seen across tumor lines. The current objective was to examine the effect on HF of changes in the fractions of the oxygenated and anoxic tumor cells that remain clonogenic. METHODS AND MATERIALS: A mathematical model was developed that relates the HF to direct measures of tumor oxygenation. The primary assumptions were that: (a) the tumor is divided into distinct compartments of either fully oxygenated or fully anoxic cells, and (b) the survival of the oxygenated cells is negligible compared to that of the anoxic cells. Based on these assumptions, the HF is plotted as a function of the fractions of clonogenic or nonclonogenic, and oxygenated or anoxic cells. RESULTS: If all cells are clonogenic, then the HF equals the fraction of anoxic cells. If a higher fraction of anoxic than oxygenated cells are nonclonogenic, then the HF will be overestimated by the fraction of the tumor measured to be anoxic using direct measuring techniques. If a higher fraction of the oxygenated than anoxic cells are nonclonogenic, the HF will be underestimated by the fraction of anoxic cells. CONCLUSION: Correlations between the HF and direct measures of tumor oxygenation have been described within tumor lines evaluated under different physiological condition. However, such relationships can be totally unpredictable between different tumors if the fraction of the anoxic cells that is clonogenic varies substantially. Clearly, if tumor anoxia cannot be detected using direct measures, this is an accurate indication that the tumor is well oxygenated. When tumor anoxia is present, however, the conclusions are ambiguous. Even when a small fraction of the tumor is measured as anoxic, direct measures of tumor oxygenation may not be representative of the HF if a substantial proportion of nonclonogenic cells is present.

Inherent cellular differences may explain the dissimilar survival of RIF-1 and KHT tumour cells under aerobic and hypoxic conditions.

Although previous work has shown striking differences in radiobiological hypoxic fraction between KHT and RIF-1 murine sarcomas, intravascular oxyhaemoglobin (HbO2 saturations have revealed less substantial variations. Using quantitative histological techniques, we have also found minor differences in the distributions of distances between tumour cells and the nearest bloods vessel for KHT versus RIF-1 sarcomas. We report here, the results of an investigation of the inherent ability of these tumour cells to withstand conditions of hypoxia by in vitro culturing under aerobic and anoxic conditions. Tumours were dissociated, seeded into culture dishes, and placed in air-tight aluminium chambers. These chambers were repeatedly evacuated and refilled with a mixture of 95% N2 and 5% CO2 over a 2.5-h period. Following anoxic exposure, cells were removed and replated, and the in vitro plating efficiency (PE) was determined using a colony survival assay. After normalizing to aerobic controls, KHT tumour cells had a significantly lower PE, following a 16-hour exposure to anoxic conditions (0.4), than RIF-1 (0.6). Increasing the hypoxic exposure to 40 h resulted in normalized PEs of 0.07 for KHT versus 0.4 for RIF-1. Although these results support the hypothesis that the two tumour lines have different inherent abilities to withstand hypoxia, they do not explain the failure of direct measures of tumour oxygenation to correlate with the radiobiological hypoxic fraction. Additional factors such as differences in oxygen diffusivity or oxygen consumption rates between tumour lines may also be involved.

Mean ages at parities: an indirect estimation.

"The objective of this paper is to describe an indirect approach for estimating the age patterns of occurrence of birth by parity. The main concern here is not of estimating the frequency of occurrence of births (in a period of time) in relation to the population (birth rate) or in relation to the number of females (fertility). Rather, the focus here is on the ages of first, second, and subsequent births, and on their shifts over time. Essentially, the approach is an extension of Hajnal's method for using proportions single to estimate singulate mean age at marriage...." The approach is illustrated using data from the 1975 Pakistan Fertility Survey and the 1990-1991 Pakistan Demographic and Health Survey. A comment by Sultan S. Hashmi is included (pp. 560-1).

Additional pressure drop at a bifurcation due to the passage of flexible disks in a large scale model.

The flow of red blood cells (RBC) through a microvascular capillary bifurcation was modeled in a large scale system in which rigid circular tubes and bifurcations (diameter = .95 cm) simulated capillaries and capillary bifurcations, flexible disks (undeformed diameter = 0.75 cm) simulated RBC and glycerol simulated plasma. At low Reynolds numbers (0.01 to 0.1), pressure drop was measured in the tubes upstream and downstream from the bifurcation as well as across the bifurcation itself, for various flow splits at the bifurcation while the inflow in the upstream tube was held constant. Pressure gradient across the bifurcation is taken to be the average of the upstream and downstream pressure gradients if the additional pressure drop at the bifurcation due to the partitioning of flow and disks is negligible. For the case of glycerol alone, the ratio of pressure gradient (G) at the bifurcation to the one at the upstream region was always greater than expected and reached 1.14 when the flow in the side branch was zero. With introduction of flexible disks into the system, G at the bifurcation was as much as 10 times the G at the upstream region as disks came in contact with, or close to, the dividing line of the bifurcation and paused momentarily before they entered one or the other side of the bifurcation. The largest G was for even flow split at the bifurcation and the smallest G was for the case where the flow in the side branch was smallest. Therefore, for the range of tube hematocrits (0-30 percent) and flow splits tested here, a significant additional pressure drop at the bifurcation is observed.

Fluctuations in microvascular blood flow parameters caused by hemodynamic mechanisms.

We have developed a mathematical model of microvascular network blood flow in which the nonlinear flow properties of blood and the nonuniform axial distribution of red blood cells in each vessel, as well as disproportionate cell partitioning at bifurcations, are all accounted for. The movements of red blood cells in the network are tracked; hence, the model is able to simulate temporal variations in local flow parameters in the network due to hemodynamic mechanisms. The model was applied to four rat mesenteric networks for which the topology, boundary conditions, blood velocity, and discharge hematocrit (Hctd) had been measured for each branch. Temporal variations in Hctd and blood velocity after simulation convergence were predicted. In some cases of the three vessels connected to a node, Hctd of one vessel fluctuates in a simple periodic form, Hctd of the second one oscillates in a more complex periodic form, whereas the Hctd of the third one does not oscillate at all. These variations were obtained with constant flow boundary conditions and, therefore, are due to hemodynamic factors alone. The temporal variations in flow parameters predicted by the model simulations are caused by hemorheological mechanisms and would be superimposed on variations caused by other mechanisms (e.g., vasomotion). The frequencies of the predicted fluctuations in blood velocity are in qualitative agreement with observed in vivo variations in dual-slit velocity in the arterioles of the cremaster muscle of anesthetized Golden hamster.

Health care determinants of child survival in Pakistan.

PIP: The authors examined the relationships between selected individual and household level factors and the survival of children under five years old based upon data in the Pakistan Demographic and Health Survey of 1990-91. Analysis found that maternal age greater than 35 years enhances child survival. Mother's secondary and higher education have a net positive and significant influence upon child survival in urban areas only, with only a weak effect in rural areas; father's education is not a powerful net predictor of child mortality. Among health care factors, breastfeeding and having the child ever immunized are the most beneficial factors for both urban and rural children. Furthermore, household sanitary and living conditions do not appear to significantly influence the survival probability of children under five years old in both urban and rural areas.^ieng

Effect of diameter variability along a microvessel segment on pressure drop.

In most microcirculatory studies, the diameter of a blood vessel is characterized by a single, average value, obtained from a projected two-dimensional microscopic view of the vessel. Such diameter values are often used to calculate microvascular hemodynamic variables (e.g., pressure drop along vessels). The validity, and some possible consequences, of the assumption that vessel diameter is constant along vessels were examined for (a) single capillaries of the hamster cremaster muscle and (b) a network model of blood flow in a rat mesenteric network. Vessel diameter was measured in cremaster microvessels of anesthetized golden hamsters (Nembutal, 70 mg/kg ip) at regular intervals along the lengths of individual vessels. The standard deviation of the diameter measurements (ranging from 0.2 to 4.0 microns) in each vessel increased with the average diameter (ranging from 4 to 27 microns, 132 vessels, 12 animals). The coefficient of variation (CV = SD/Mean) was close to 0.1 for vessels larger than 15 microns and up to 0.4 for smaller vessels. In individual isolated vessels, the ratio of calculated pressure drop using the actual diameter measurements (delta P) to pressure drop assuming an average diameter (delta Po) was between 1.05 and 3.0 (at constant volume flow rate); this ratio correlated significantly with the CV for that vessel. Using an iterative mathematical model of network blood flow in a mesenteric network, we investigated the effects on single-vessel delta P/delta P0 of using a single average estimate of diameter for each microvessel segment, compared to the inclusion of variations in each vessel diameter expected from the single-vessel data. The results from the model indicated that single vessel delta P/delta Po values obtained with expected diameter variations in each vessel varied between 0.01 and 100. This implies that the axial variations in vessel diameter that exist in vivo may affect the calculations of vessel pressure drop both in single vessels and in microvascular networks.

The role of wall shear stress in microvascular network adaptation.

The possible role of wall shear stress in microvascular network adaptation was investigated by computer simulation in planar polygonal model networks. Adaptation of vessel diameter to local wall shear stress resulted in false geometry and excessive rarefaction of the networks. Adaptation to mean wall shear stress decreased the range of shear stress, decreased the total power dissipation, and prevented network rarefaction. A measure of mean wall shear stress may serve as a control signal for the adaptation of vessel diameter to blood flow in microvascular networks.

Differentials in child mortality and health care in Pakistan.

PIP: Differentials in child mortality are analyzed by parent's education, health care, and rural-urban residence with data on 7405 currently married women, obtained from the Pakistan Contraceptive Prevalence Survey, 1984-85. The assumption is that educated parents and fathers working in the formal sector have less risks of child mortality than illiterates and those working in the traditional sector; the findings support this assumption. Educated mothers have a greater impact on child mortality risk than educated fathers. Child mortality is highest in families where both parents are illiterates. Mothers, who are housewives or who are working in a family business, have higher child mortality risk than working mothers. Child mortality risk was reduced with a hospital delivery. Father's education and a hospital delivery only reduced risk when women were aged 35 years or less. Urban educated mothers with a hospital delivery had a lower risk of child mortality than mothers with no education. Residence was not a significant factor, when hospital delivery was controlled for younger mothers. Older mothers with a hospital delivery had lower child mortality. Educated mothers with an immunized child had lower child mortality than mothers aged over 25 years. Father's education and immunization showed even lower mortality. Younger educated urban mothers, who immunized their child or infant, had lower child mortality than educated mothers. Rural educated mothers had lower child mortality than rural uneducated mothers, but including immunization as a factor, did not improve child survival. The use of oral rehydration therapy among urban educated mothers also reduced child mortality risk compared with other drug use. The majority of the population was rural (70%) and had the highest child mortality. Not only is child survival reflected in the maldistribution of health facilities, but in lack of access to these facilities, and low levels of literacy, poor sanitation, and low income. Improvement in living conditions in rural areas is recommended; development programs should emphasize access to health and education.^ieng

Computer simulation of growth of anastomosing microvascular networks.

Stochastic growth of polygonal microvascular networks was simulated on computer by dichotomous terminal branching and bridging (anastomosing with an existing segment). The model was applied to describe microvascular growth into a rectangular plane from the sides when vessels bifurcate in a probabilistic manner. The angle of bifurcation was drawn from a normal distribution, the mean of which was varied between 40 degrees and 80 degrees. The resulting networks contained an average of 88-104 nodes of which 30-38% were due to bridging. Number of nodes, number of branches, number of vascular polygons and a fractal dimension representing the density of nodes were calculated for each simulated network. Capillary density increased when mean angle of bifurcation was increased between 40 degrees and 80 degrees. Distributions of normalized vessel lengths and polygon shapes were compared with those of a mesenteric vascular network. The distributions were not found to be significantly different (p less than 0.05) for most values of the mean angle of bifurcation, matching best for the mean bifurcation angle of 50 degrees. Vascular polygons had an average shape between pentagonal and hexagonal for the mesenteric network as well as for all values of the mean bifurcation angle used in this study.