Computational simulation of blood flow in human systemic circulation incorporating an external force field.

A quasi-one-dimensional non-linear mathematical model for the computation of the blood flow in the human systemic circulation is constructed. The morphology and physical modelling of the whole system (arteries, capillaries and veins) are completed by different methods for the different vessel generations. A hybrid method is used to solve the problem numerically, based on the governing equation (continuity, momentum and state equations), the input boundary conditions and the predetermined initial conditions. The two-step Lax-Wendroff finite-difference method is used to compute variables for each individual vessel, and the characteristic method is employed for the computation of internal boundary conditions of the vessel connection and the input and output system boundary conditions. Using this approach, blood flow, transmural pressure and blood velocity are computed at all vessel sites and for each time step. The pressure and flow waveforms obtained show reasonable agreement with clinical data and results reported in the literature. When an external conservative force field is applied to the system, the results computed from the model are intuitively correct. The term representing the external pressure added to the system by the muscle, which represents active control on the cardiovascular system, is also embodied in this model.

Hydrodynamic simulation of arterial networks which include compliant and rigid bypass grafts.

The conditions required to produce an ideal bypass graft have not yet been determined. In order to understand the hemodynamic impact of bypass grafts on cardiovascular function, a hydrodynamic model for the part of the human arterial network below the renal arteries has been constructed. The results from this physical model were used to validate a digital computer model of the arterial network developed by the authors, that incorporated loops which occur due to bypass grafts. The hydrodynamic model was designed to study the interaction between an arterial stenosis and bypass graft and, in particular, the effect of the compliance of the graft on their function. In the model, similarity laws have been maintained with regard to geometry, viscosity, peripheral resistance, wall elastic properties, pulse shape, and blood flow rate. Measured and predicted pressure and flow wave-forms showed an increase in their mean and peak values for the healthy leg when the bypass graft was closed. There was also a severe pressure drop across the stenosis and a marked decrease in mean and pulsatile flow in the stenotic leg. The stenosis in the hydrodynamic model produced similar behaviour to published results obtained on animals. When the graft was open, the agreement between our experimental and theoretical model was within 5% and both the pressure and flow waves were almost similar at the maxima and minima in both legs. Although the arterial system is non-linear, the non-linearities are shown to be of insignificant magnitude and therefore, we have concluded that the pressure flow relationship is essentially linear. The effect of the degree of compliance of the graft and the 'steal' phenomenon due to the graft have been investigated. It was found that there were no significant differences in the flow delivery between the compliant graft and stiff graft. Also, there was no 'steal'. Thus the compliance of the graft is not a significant factor in promoting its patency.

Haemodynamic model of a unilateral iliac stenosis with an aortoiliac bypass.

A hydrodynamic model for the part of the human arterial network below the renal arteries has been constructed using specially fabricated distensible tubes and a pulsatile pump to simulate an aortoiliac bypass. The experiments and the computer model indicated that no 'steal' occurred due to the insertion of the bypass graft. Also, the results showed that the length of the stenosis had a non-systematic apparent effect on the physiological significance of the obstruction and that the kinetic power represented only a small percentage of the total power. The total power efficiency of the bypass graft was unaffected by its elastic properties. The experimental investigation also indicated that the pressure drop across the stenosis was considerably larger than the drop calculated using the Poiseuille flow relationship when the stenosis was severe. Therefore, a critical arterial stenosis value cannot be defined as an obstruction of a constant percentage reduction of luminal area. It varies directly with the effective cross-sectional area and inversely with the flow rate. The value of angiography in assessing the functional significance of any arterial stenosis is therefore limited. A better method for evaluation requires quantitative measurements of local blood pressure and blood flow, not only at rest, but also under conditions creating augmented flows due to exercise.

Semi-automated cervical smear pre-screening systems: an evaluation of the Cytoscan-110.

This paper reports a test of a system for provision of machine assistance in cervical cytology screening. The hypothesis tested was that if the results of examination by a screener of a small number of high-ploidy cells on specially prepared monolayers, automatically selected and presented by the system, were combined with machine measurement of cell and cell population characteristics, it would be possible to distinguish conditions requiring further action on the part of a cytology service from those in which the patient could safely be signed out. The system appeared broadly capable of this discrimination, with a false-negative error not significantly different (for the numbers tested) on CIN1 and more severe cases to that obtaining for routine screening of the parallel PAP smears, and also to results obtained by a panel of three observers. The machine system appeared to do better than other systems in selecting borderline cases for review, but this may have been an artefact of the method of evaluation used: all results were compared with a 'reference diagnosis', which was computed using statistical techniques to integrate diagnostic information from all available sources. The false-negative error-rate of the system amounted to 5% of high-grade cases, 17% of CIN1's and 29% of borderlines, but were not substantially different from the FN rates for other reporting systems on the same material. The proportion of negative cases referred back for full cytological diagnosis was 34%. Despite this high false-positive rate, the system is potentially cost-effective in use.

Fish oil produces an atherogenic lipid profile in hypertensive men.

The effects of fish oil supplements on plasma and platelet membrane lipids, lipoproteins, sex steroid hormones, glucose, insulin, platelet aggregation, and blood pressure in normal subjects (n = 13) and patients with essential hypertension (n = 13) were studied in this randomized, double-blind, placebo-controlled, two-way crossover study. Treatments consisted of 30 days of 5 g of n-3 fatty acids (ten 1-g capsules of fish oil daily) or placebo capsules (ten wheat germ oil capsules daily) with a one-month washout in between each crossover. Serum lipids and lipoproteins were measured before dosing and every two weeks during the study. Sex steroid hormones, glucose, insulin, and fatty acid composition in platelet membrane phospholipids were measured before dosing and at the end of each crossover. During treatment with fish oil, only the hypertensive had increases in total cholesterol (8%, p less than 0.026), LDL cholesterol (19%, p less than 0.006) and apolipoprotein B (18%, p less than 0.026). Serum androgens (total and free testosterone) were 30% lower in hypertensives than normotensives before any dosing, but were unchanged with placebo or fish oil capsules in either group. Plasma glucose, insulin, platelet aggregation, and the incorporation of n-3 fatty acids into platelet membrane phospholipid subfractions were similar in both normotensive and hypertensive men. Blood pressure was not affected by fish oil treatment in either group of men. These results provide evidence that fish oil may adversely affect serum lipids to yield an atherogenic lipid profile in hypertensive men.

Theoretical model for assessing haemodynamics in arterial networks which include bypass grafts.

The paper presents a theoretical model which can be used to simulate a vascular network which includes loops and bypass grafts, a feature not possible with previous models. Using the linearised Navier-Stokes equations, the linearised equation of a uniform thick-walled viscoelastic tube, and the equation of continuity, the model is applied to a vascular network which includes a bypass graft. This method represents each segment of an artery or graft by a four-terminal-network whose A, B, C, D parameters are functions of the frequency and physical characteristics of the segment. The model predicts the flow and pressure waveforms at any point in the human arterial network very accurately when compared with data obtained from normal patients, patients with arterial stenoses and for hypertensive patients. The model also gives results which are in close agreement with hydraulic experimental data for the input impedance of systems with bypass loops.

The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil.

The effects of alteration of gastric pH and food on the pharmacokinetics of 200 mg doses of cefpodoxime proxetil tablets were studied in two separate randomized, open label, crossover studies in healthy subjects. In the pH study (n = 17 subjects), there was a lead-in period done under fasting conditions, followed by randomization to a four-way crossover of pentagastrin (6 micrograms/kg, subcutaneously), ranitidine (150 mg orally, 10 and 2 hours before dosing with the antibiotic), sodium bicarbonate (12.6 gm), or aluminum hydroxide (120 cc). Gastric pH was determined by nasogastric aspirates before and 10 minutes after the intervention, just before the antibiotic was given. Peak plasma concentrations (Cmax) and area under plasma concentration-time curve (AUC) were highest in fasting and pentagastrin periods and were 35% to 50% lower for all of the other periods (p less than 0.0001). Gastric pH and Cmax and AUC were inversely related (r = 0.66 and r = 0.62; p less than 0.0001 for both). In the food study (n = 16 subjects), there were two lead-in periods, one done while subjects were fasting and one while they were normal diet, followed by randomization to a four-way crossover of either high or low protein diets, or high or low fat diets. There were six meals in each diet. Dosing with the antibiotic was done at the midpoint of the fourth meal. Cmax and AUC were 22% to 34% higher for all diets than for the fasting period (p less than 0.0001), whereas the time to Cmax was unchanged. These studies demonstrated that absorption of cefpodoxime proxetil is best at low gastric pH or in the presence of food, which suggests that the role of gastrointestinal function on the pharmacokinetic profile is complex.

Quantitative DNA analysis of low grade cervical intraepithelial neoplasia and human papillomavirus infection by static and flow cytometry.

Quantitative deoxyribonucleic acid (DNA) analysis of cervical biopsy specimens from 26 women with cytological, colposcopic, and histological evidence of mild cervical atypia consistent with cervical intraepithelial neoplasia grade I, reactive atypia, or human papillomavirus infection alone or in combination was performed in a comparative evaluation of Feulgen microspectrophotometry, the fast interval processor image analysis system, and flow cytometry. The fast interval processor image analysis system showed a distinct advantage over the other methods, being faster and allowing the operator to see the cells that were selected for measurement. The three methods of measurement together showed that the DNA content of at least 2% of the cells measured exceeded 5C (C being the haploid amount of DNA in a normal cell and 2C representing the diploid complement of a normal cell) in all cases of cervical intraepithelial neoplasia grade I and reactive atypia and in 87% of those reported as showing human papillomavirus infection alone. In contrast, the DNA content of cervical biopsy specimens from the transformation zone of 11 normal controls did not exceed 4C. This study shows the value of using a DNA threshold--that is, the "5C exceeding rate"--to distinguish between normal and neoplastic appearances of the cervix. These results support the view that cervical infection by human papillomavirus is a true precursor of neoplasia.

Quantitative deoxyribonucleic acid analysis of patients with mild cervical atypia: a potentially malignant lesion?

Quantitative deoxyribonucleic acid (DNA) analysis of cervical biopsy material from 32 women with cytologic, colposcopic, and histologic evidence of mild cervical atypia consistent with cervical intraepithelial neoplasia I, reactive atypia, or human papillomavirus infection was carried out using flow cytometry and Feulgen microspectrophotometry. Evidence of aneuploidy, ie, neoplastic transformation, was demonstrated in all cases of cervical intraepithelial neoplasia I and 68% of cases with human papillomavirus-induced atypia. These results support the growing impression that human papillomavirus-induced cervical atypia should be regarded as a true precursor of cervical neoplasia, and emphasize the necessity to refer patients with mild atypia for definitive diagnosis and management.

Preparatory methods for DNA hydrolysis, cytochemistry, immunocytochemistry and ploidy analysis. Their application to automated and routine diagnostic cytopathology.

A review is presented of some methods used to prepare cytologic specimens for analytical and/or automated studies, with the steps of the procedures detailed in appendices. The preparation of the cell monolayers required for optimal automated cell image analysis and classification, e.g., by the Cytoscan 110, is discussed, as is the preparation of poly-L-lysine-coated slides used in the production of monolayered specimens. These monolayers, which can be prepared from a variety of specimens, are also useful for cytochemical and immunocytochemical studies and DNA ploidy analysis. For DNA analysis, a modified gallocyanin chrome alum staining procedure is described as a stoichiometric alternative to the time-consuming Feulgen reaction. The hydrolysis technique required by the latter method is also detailed. The freeze-fracturing technique for the enhancement of monoclonal antibody immunocytochemical staining of detectable antigens is described, along with an indirect immunoalkaline phosphatase staining method. The use of enzyme cytochemical reactions for glucose 6 phosphate dehydrogenase and lysosomal naphthylamidase is also presented.

Simulation of coronary artery revascularization.

Simulation of the commonly constructed geometries of aorto-coronary bypass anastomoses was carried out using especially fabricated distensible tubes and a pulsatile pump. The system pressure was maintained between 80 and 120 mmHg. The total mean flow was set at 250 ml min-1 (Reynolds number of 200) and the pulsatile frequency was varied from 0 to 2 Hz. A water-glycerine mixture having a density and viscosity similar to that of blood was used throughout. A 16 mm film of the front of black dye injected proximal to the anastomosis was made as the dye approached and passed through the anastomosis. Anastomotic geometries consisted of: end to side, parallel, 45 degree angle, and 90 degree angle. Stenoses, located in the tube representing the coronary artery, were simulated using a bevelled insert which represented an 80-85% area reduction. Flow visualization revealed that distensible tubes gave more realistic flow patterns than rigid tubes, a result particularly evident when a stenosis was present. Pulsatile flow demonstrated considerably more mixing than steady flow. The use of pulsatile flow in distensible tubing with a partial stenosis showed retrograde flow through the stenosis which was not evident for either steady flow or for flow in rigid tubing. The flow at the anastomatic site of the graft having an angle of 0 degrees showed a jetting action with a zone of recirculating fluid being present whereas for a 90 degree graft a distinct helical flow was formed distal to the anastomosis.

The use of cationic polyelectrolytes in the preparation of cell monolayers for automated cell scanning and diagnostic cytopathology.

The introduction of cationic polyelectrolytes as cellular adherents has significantly advanced the preparation of cervical scrape specimens for automated cell scanning and has also provided an efficient technique for the preparation of cell monolayers of other cytologic specimens, e.g., breast cyst fluids, urines and serous effusions, for diagnostic cytopathology. Variable thickness of cell preparation and cell overlap have both been resolved by laying cells onto glass slides coated with the cationic polyelectrolyte poly-L-lysine. We have determined the optimal conditions for pH, molecular weight, concentration and temperature for the application of poly-L-lysine as a cell-to-slide adhesive.

The value of immunohistochemical markers in the diagnosis of cervical neoplasia.

This study was designed to determine whether immunohistochemical stains for tumour-associated markers may be useful in the detection and differential diagnosis of premalignant and malignant lesions of the cervix. The expression of four markers detected by monoclonal antibodies, human milk fat globule 1 and 2 (HMFG-1 and 2), Ca1 and anti-carcinoembryonic antigen (anti-CEA) on conventional histological sections of various cervical lesions has been investigated. None of these markers was specific for neoplastic lesions of the cervix and all four markers were expressed by metaplastic as well as neoplastic cells, and it was concluded that their application in the histopathological examination of the cervix is limited.

Chromosome studies on cells cultured from serous effusions. Use in routine cytologic practice.

Cytogenetic analysis was used to supplement the cytologic diagnosis of malignancy in serous effusions. Current methods of analysis involve immediate preparation, but our study showed that prior culture of the cells is a more practical approach to the use of chromosome analysis in the routine cytology laboratory. This method permits the retrospective selection of specimens for chromosome analysis from patients in whom there is a strong clinical suspicion of malignant disease but who have negative or equivocal cytology reports. The preparative technique and the recognition of structural and numerical chromosome anomalies can be readily learned by the cytotechnologist and incorporated into the routine cytology laboratory.