[Comparison between reference oncologic colpocytology and severity of intraepithelial cervical lesions]. / Comparação entre a colpocitologia oncológica de encaminhamento e a da gravidade das lesões cervicais intra-epiteliais.

OBJECTIVE: The study was designed to compare the Pap smear results, performed on the public health service, with: the results of Pap smear collected on the reference service; the colposcopy and punch biopsy results. METHODS: The total of 213 women assisted at the women's hospital from January 1989 to April 1991, and followed until July 1998 were selected. Ninety were referred because a Pap smears suggestive of Human Papillomavirus (HPV) induced lesion or cervical intraepithelial neoplasia (CIN) grade 1, and 123, CIN 2 or 3. RESULTS: Among the 90 women referred because of HPV/CIN 1.49% presented CIN 2 or 3 in the Pap smears performed at this service. At the colposcopy, 16/90 women did not present suspicious lesions, and in 10 women, the squamous columnar junction was not observed. At biopsy, 42 (46%) presented CIN 2 or 3. Out of the 123 women referred with Pap smear of CIN 2 or 3.54% presented CIN 2 or 3 at this service. At the colposcopy, 24 women did not present suspicious lesions and the squamous columnar junction was not observed in 12. About biopsy, 61 (49%) presented CIN 2 or 3. CONCLUSIONS: The expectant conduct in cases of Pap smear with HPV/CIN 1, should follow a criterion, involving qualified professionals to collect the Pap smear, and should provide people awareness as to control follow-up.

Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties.

We studied microvessel organization in five brain tumor models (ENU, MSV, RG-2, S635cl15, and D-54MG) and normal brain, including microvessel diameter (LMVD), intermicrovessel distance (IMVD), microvessel density (MVD), surface area (S(v)), and orientation. LMVD and IMVD were larger and MVD was lower in tumors than normal brain. S(v) in tumors overlapped normal brain values and orientation was random in both tumors and brain. ENU and RG-2 tumors and brain were studied by electron microscopy. Tumor microvessel wall was thicker than that of brain. ENU and normal brain microvessels were continuous and nonfenestrated. RG-2 microvessels contained fenestrations and endothelial gaps; the latter had a maximum major axis of 3.0 microm. Based on anatomic measurements, the pore area of RG-2 tumors was estimated at 7.4 x 10(-6) cm(2) g(-1) from fenestrations and 3.5 x 10(-5) cm(2) g(-1) from endothelial gaps. Increased permeability of RG-2 microvessels to macromolecules is most likely attributable to endothelial gaps. Three microvessel populations may occur in brain tumors: (1) continuous nonfenestrated, (2) continuous fenestrated, and (3) discontinuous (with or without fenestrations). The first group may be unique to brain tumors; the latter two are similar to microvessels found in systemic tumors. Since structure-function properties of brain tumor microvessels will affect drug delivery, studies of microvessel function should be incorporated into clinical trials of brain tumor therapy, especially those using macromolecules.

Absence of host-site influence on angiogenesis, blood flow, and permeability in transplanted RG-2 gliomas.

The host site is believed to regulate tumor angiogenesis, which could result in site-dependent drug delivery parameters, greatly affecting experimental tumor research. In RG-2 rat gliomas we measured cellular proliferation; cell cycle time was the same for RG-2 cells in brain and s.c. tumors (25 h), and was the same for endothelial cells in these tumors (46 h). We measured the transcapillary transfer constant (K) of alpha-aminoisobutyric acid and blood flow (F) with iodoantipyrine in RG-2 gliomas transplanted into brain, liver, kidney, muscle, s.c. tissue, and into the abdominal cavity. Data was evaluated by quantitative autoradiography and direct tissue sampling. The variation of F (12.6-84.0 ml/g/min) and K (26.1-49.2 microl/g/min) in RG-2 tumors in the different host sites was less than in surrounding tumor-free tissue (F = 20-1500 ml/g/min and K = 1.6-700 microl/g/min). In contrast to other models, RG-2 does not result in tumors with host site-dependent behavior. The RG-2 tumor cells appear to participate in, if not dominate, the angiogenesis process regardless of the host site. Values of F and K were more dependent on tumor topography (center versus periphery) and local histological features (necrosis versus viable tumor) than host site. We believe that the methods used for data acquisition may introduce as much variability in Results as the tumors themselves and that to better understand how tumor angiogenesis affects the vascular phenotype, comparative studies are needed to validate the results obtained with newer methodologies.

Blood-brain barrier integrity in Alzheimer's disease patients and elderly control subjects.

A defective blood-brain barrier (BBB) has been postulated to be present in Alzheimer's disease (AD), which would allow circulating beta-amyloid peptide to enter the brain. The authors tested this hypothesis by studying BBB function in 14 individuals with probable AD and 9 elderly control subjects. A computed tomographic method was used to measure blood-to-brain transport (K1), tissue-to-blood efflux (k2), tissue plasma space (Vp), and tissue extracellular space (Ve) of meglumine iothalamate. Repeated-measures analysis of variance indicated no significant differences between the groups for any of the measures. The authors conclude that there is no generalized abnormality of the blood-brain barrier in AD.

The effects of dexamethasone on experimental brain tumors: I. Transcapillary transport and blood flow in RG-2 rat gliomas.

Dexamethasone dramatically improves cerebral edema associated with malignant gliomas. Although the pathophysiology of this effect is not clearly understood, many investigators have postulated that tumor capillary permeability is reduced by dexamethasone. We studied blood-to-tissue transport and blood flow in 178 RG-2 transplanted gliomas in a control group and four groups given dexamethasone at doses of 3, 6, 9, and 12 mg/kg for four days. 14C-alpha aminoisobutyric acid (AIB) was used to study blood-to-tissue transport in 31 animals; in an additional 27 animals 14C-AIB and 131I-iodoantipyrine (IAP) were used in double label experiments to study blood-to-tissue transport and blood flow. Regional measurements of the transfer constant (K) of AIB and blood flow (F) were made with quantitative autoradiography. There were significant differences between the control and dexamethasone-treated groups with regard to weight loss and plasma glucose. However, there was no significant effect of dexamethasone on values of K or F, regardless of the tumor or brain region examined, and regardless of the dose of dexamethasone administered. Analysis of the profiles of the transfer constant of AIB in the brain around tumor showed that the K of AIB decreased within 0.5 mm of the tumor edge in direct relationship to the dexamethasone dose. These results do not support the hypothesis that dexamethasone reduces brain tumor capillary permeability, and suggest that dexamethasone may decrease tumor-associated cerebral edema by effects on bulk flow away from the tumor margin.

The effects of dexamethasone on transcapillary transport in experimental brain tumors: II. Canine brain tumors.

We studied the effect of dexamethasone on transcapillary transport in ten Avian Sarcoma Virus (ASV)-induced canine brain tumors, before and one week after administration of dexamethasone, 2.5 mg/kg/day. A computed tomographic (CT) method was used to measure regional values of K1 (blood-to-tissue transfer constant), k2 (tissue-to-blood efflux constant), and Vp (tissue plasma vascular space) of meglumine iothalamate (Conray-60); the values were reconstructed for each 0.8 x 0.8 x 5 mm volume element of the CT data. For all tumors considered together, there was a decrease in the whole tumor K1 value of meglumine iothalamate from 26 +/- 2.2 (SE) before dexamethasone to 24 +/- 2.9 microliters/g/min after dexamethasone. Vp decreased from 7.2 +/- 0.7 to 6.7 +/- 0.9 ml/100 g, and the size of the tumor extracellular space (Ve) decreased from 0.30 to 0.26 ml/g. These changes were not statistically significant. However, when each tumor was used as its own control, K1 significantly decreased after dexamethasone in four tumors, significantly increased in two and was unchanged in four. These results suggest that decreased blood-to-tissue transport may be one mechanism underlying resolution of tumor associated cerebral edema in some brain tumors and that the effects of dexamethasone on blood-to-tissue transport in brain tumors are variable from one tumor to the next. Decreased 'permeability' may not be the sole mechanism by which dexamethasone reduces tumor-associated cerebral edema.

Noninvasive measurement of arterial blood plasma concentration of iodinated contrast agents from CT scans of human brain.

OBJECTIVE: Our goal was to assess the accuracy of estimating the time course of the arterial plasma concentration of meglumine iothalamate from cranial CT images of different vascular structures in the brain. MATERIALS AND METHODS: Dynamic CT studies of transcapillary transport in various brain lesions were analyzed. Vascular structures in the brain were identified and classified in three categories: arteries, veins, and venous sinuses. Systemic venous blood samples were taken prior to the infusion of meglumine iothalamate and 10 min after completion of the infusion and used as a calibration for the volume averaging fraction of the image of each vascular structure. A time course of plasma meglumine iothalamate concentration for each of the vascular categories in the CT images was obtained and compared with a variety of methods. RESULTS: Significant differences were found for measurement of plasma meglumine iothalamate concentration from different vascular categories. There was also a disparity between the volume averaging fraction that we calculated and what would be expected due to the measured systemic hematocrit for all vascular structures. CONCLUSION: The use of images of veins and venous sinuses consistently underestimated the arterial concentration around the peak values. Correcting the imaged venous sinus values with the measured systemic hematocrit was even less reliable. The most accurate method of determining arterial plasma concentration of meglumine iothalamate from CT images of brain was to correct the identified arterial vessels for volume averaging.

A new head holder for reducing axial movement and repositioning errors during physiological CT imaging.

OBJECTIVE: We designed a new head holder for immobilization and repositioning in dynamic CT studies of the brain. MATERIALS AND METHODS: A customized thermoplastic face mask and foam head rest were made to restrict movement of the head in all directions, but particularly out of the axial plane (z-movement). RESULTS: This design provided a rigid, detailed mold of the face and back of the head that minimized motion during lengthy CT studies and enabled accurate repositioning of the head for follow-up studies. Markers applied directly to the skin were used to quantify z-movement. CONCLUSION: When tested on 12 subjects, immobilization was limited to < 2.0 mm under worst-case conditions when the subject was asked to attempt forced movements. Repositioning was accurate to < 1.5 mm when the subject was removed from the head holder and then placed back into it.

Noninvasive CT determination of arterial blood concentration of meglumine iothalamate.

A quantity that often must be determined in physiological imaging studies is the blood concentration of the tracer over time. This is usually performed by direct arterial or venous blood sampling. We studied the relationship between the concentration of meglumine iothalamate in arterial blood and values determined from voxels containing large blood vessels in a series of CT images at the same location over time. After correction for volume averaging based on a single venous blood sample, there was an excellent correlation between the two blood curves. Differences between the curves were shown to be inconsequential by a simulation of transcapillary transport determinations. We thus conclude that determination of plasma concentration from CT images is a reliable technique for CT transcapillary transport studies.

A method to quantitatively measure transcapillary transport of iodinated compounds in canine brain tumors with computed tomography.

We present a quantitative method for determining a blood-to-tissue influx constant (K1), a tissue-to-blood efflux constant (k2), and tissue plasma vascular space (Vp) that uses a computed tomographic (CT) scanner to make tissue and plasma measurements of the concentration of an iodinated compound. Meglumine iothalamate was infused intravenously over time periods of 0.5-5 min, up to 49 CT scans were obtained at one brain level, and arterial plasma was sampled over a 30- to 40-min period. K1, k2, and Vp were calculated for each voxel of the 320 x 320 matrix, using a two-compartment pharmacokinetic model and nonlinear least-squares regression. The method was used in dogs with avian sarcoma virus-induced brain tumors. As many as four studies on different days were done in the same animal. In tumor-free cortex, K1 of meglumine iothalamate was 2.4 +/- 1.7 microliter g-1 min-1 (mean +/- SD) and Vp was 3.4 +/- 0.5 ml 100 g-1. Mean whole-brain tumor K1 values ranged from 3.3 to 97.9 microliters g-1 min-1; k2 ranged from 0.032 to 0.27 min-1; and Vp ranged from 1.1 to 11.4 ml 100 g-1. These values were reproducible in serial experiments in single animals. Independent verification of K1 values was obtained with quantitative autoradiographic measurements of alpha-aminoisobutyric acid, which has similar physicochemical properties to meglumine iothalamate. The CT methodology is capable of demonstrating regional variation of transcapillary transport in brain tumors and may be of value in the study of human brain tumors.

Quantitative measurements of capillary transport in human brain tumors by computed tomography.

The rate at which water-soluble chemotherapeutic drugs enter brain tumors can be extremely variable. The ability to measure or predict the rate of drug entry may have an important role in treatment. We have developed a method that uses information from contrast-enhanced computed tomographic scans to measure quantitatively the rate of transcapillary transport of iodinated compounds in brain tumors. In a group of 10 patients with brain tumors, we obtained serial measurements of tissue (Am) and arterial plasma (Cp) iodine concentration from timed computed tomographic scans done over 30 minutes, after intravenous infusion of meglumine iothalamate (Conray-60). These measurements were analyzed with a two-compartment pharmacokinetic model and nonlinear least-squares regression methods to obtain K1, a blood-to-tissue transfer constant; k2, a tissue-to-blood rate constant; and Vp, tissue plasma vascular volume. Images of K1, k2, and Vp were reconstructed after calculating these values for each 0.8 x 0.8 x 5-mm volume element of the original data. Mean whole tumor K1 values varied from 2.0 mu 1 gm-1 min-1 in a thalamic astrocytoma to 33.9 mu 1 gm-1 min-1 in a glioblastoma multiforme. The value of k2 varied from 0.034 to 0.108 min-1, and Vp varied from 2.4 to 7.9 ml 100 gm-1. In tumor-free brain, the K1 of meglumine iothalamate was 2.9 mu 1 gm-1 min-1; k2 was 0.058 min-1; and Vp was 2.1 ml 100 gm-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential errors due to aliasing in digital video analysis of quantitative autoradiography.

Digital image analysis of quantitative autoradiographic (QAR) films is widely used in neuroscience applications. Unless proper precautions are taken when autoradiographic images are converted to digital form they can be inadvertently modified by improper application of the sampling process. This type of modification is termed aliasing error and can cause nonexistent structures to appear in the reconstructed digital image, changing the apparent optical density values of the data. The theoretical basis of aliasing error is presented, along with examples of aliasing from optical resolution test patterns and 2-deoxy[14C]glucose (2-DG) experimental QAR images. We show that aliasing can change the apparent shape of structures, as well as the derived values obtained from QAR experiments. In an example with experimental 2-DG images, aliasing in the cerebellar cortex consistently underestimates tissue radioactivity levels in gray matter (P less than 0.001) and overestimates levels in adjacent white matter (P less than 0.001). Additional data transformations, such as the equations used for blood flow or glucose utilization, can, somewhat unpredictably, accentuate the errors introduced by aliasing. We present a discussion of the autoradiographic image features and electronic design that play a role in introducing aliasing errors and means by which aliasing can be recognized and minimized.

Effect of hyperosmotic blood-brain barrier disruption on transcapillary transport in canine brain tumors.

Whether hyperosmotic blood-brain barrier (BBB) disruption is a technique that can be used to increase permeability of brain-tumor capillaries and thereby transiently increase drug delivery to the brain tumor is controversial. Nine virally induced brain tumors were studied in seven dogs, before and after hyperosmotic BBB disruption with 1.4 osmolar mannitol. Each dog was studied with computerized tomography (CT) after administration of the water-soluble tracer meglumine iothalamate. Each study lasted 30 minutes. A baseline CT scan and 35 to 40 additional CT scans were obtained to provide a time-related measurement of the amount of meglumine iothalamate in tissue (Am(t], and 30 plasma samples were collected to provide the time-related measurement of meglumine iothalamate in plasma (Cp(t]. The data were analyzed by three different methods: 1) a two-compartment model and nonlinear curve fitting were used to calculate K1 (blood-to-tissue or influx constant), k2 (tissue-to-blood or efflux constant), and Vp (plasma vascular space); 2) K1 values were calculated with a two-compartment model, assuming no efflux, at the time point for each CT scan; and 3) a "tissue advantage ratio" was calculated that expressed the ratio of tissue uptake of meglumine iothalamate at each time point, comparing values before and after BBB disruption. Regardless of which method of data analysis was used, there was a marked and significant increase in transcapillary transport of meglumine iothalamate to tumor-free brain regions, while there was only a small, transient, and insignificant increase to the brain tumors. Although there were often marked increases in delivery to cortex in the same hemisphere as the tumors, there was no significant increase to brain immediately surrounding the tumors, perhaps due to altered circulatory dynamics in this region. These data raise serious questions as to the wisdom of using this technique to increase drug delivery to brain tumors in patients and strongly support the continued study of this technique in experimental brain tumors before it is used in patients.

Neonatal and infancy time scale for extension into childhood and adulthood.

A logarithmic time scale is presented for exposition of clinical events and related data on a unified scale extending from neonatal time into childhood and adulthood. Such a scale preserves time scale proportions but has the advantage for certain applications of featuring early neonatal and infancy events. This type of time base avoids the disadvantages of a crowded and obscured linear scale or an arbitrary and non-unified split time scale. For clinical application all timed events are initially converted to a common unit such as days. A visually comprehensible logarithmic time scale can be derived by plotting the logarithmic scale (labeled in days, base 2) and then establishing conventional calendar interval marks (weeks, months, years) and the data plot points. A simple equation is presented for establishing the time scale graph markers and the plot data points for a logarithmic time scale of any scale axis length.

Quantification of scalp hair--a computer-aided methodology.

A method for obtaining a quantitative assessment of hair density is described. First, a photographic image of the scalp is digitized onto a high-resolution computer graphics screen. Second, the frequency of each of 256 gray levels (one for each of 500 vertical X 500 horizontal = 250,000 locations on the screen) is obtained and the frequency histogram of gray levels is displayed. Third, a statistical procedure, gaussian mixture analysis, is used to resolve the frequency distribution into two normally distributed component distributions. The first component distribution describes the range of gray levels that are typically associated with hair. The second component distribution describes shades of gray that are typically associated with scalp. The statistical model provides a precise measure of the proportion of the head that exhibits gray levels in each of the two component distributions (hair or scalp). The proportion of the first component distribution is a scale-independent measure of hair density. The difference in this quantity before and after treatment provides an accurate quantitative determination of the change in hair density and hence of the efficacy of treatment.

Measurement of mitral valve orifice area in infants and children by two-dimensional echocardiography.

Two-dimensional echocardiograms of the mitral valve orifice area were obtained in 50 normal pediatric subjects, 15 patients with congenital mitral stenosis and 7 patients with tricuspid atresia. The mitral area was measured near the tips of the mitral valve leaflets from a diastolic cross-sectional image of the left ventricle. The cardiac images were recorded on videotape and later transferred to video disc for high resolution contour tracing. Contour analysis was performed by a special purpose microcomputer system for calculation of the enclosed calibrated area. In normal patients, there was an excellent correlation (r = 0.95) between mitral valve area (MVA) (in cm2) and body surface area (BSA) (in m2) described by MVA = 4.83 X BSA - 0.07. Each patient with mitral stenosis had a mitral valve area that measured less than the third percentile predicted from the normal regression formula. In eight patients in whom the Gorlin formula could be applied, there was excellent correlation (r = 0.95) between echocardiographic and hemodynamic measurements of mitral valve area. Each patient with tricuspid atresia had a very large mitral valve area (greater than 99th percentile of normal). It is concluded that noninvasive measurement of mitral valve orifice area can be accurately achieved by two-dimensional echocardiography in pediatric patients with congenital mitral stenosis, allowing serial measurement of their mitral valve area.

Permeability of different experimental brain tumor models to horseradish peroxidase.

The permeability of different brain tumor models to horseradish peroxidase (HRP) was examined by determining the fraction of tumor that contained HRP after intravenous administration. The intracerebral tumor models studied were Avian Sarcoma Virus (ASV)-induced tumors and tumors from transplanted RG-2, S69-C1-5, and 9L cell lines. The average fraction of RG-2 tumors permeable to HRP was .95; of S69-C1-5 tumors, .699; of ASV-induced tumors. .63; and of 9L tumors, .52. Except for the RG-2 tumors, there was considerable regional variation in HRP permeability, which was most marked in the ASV-induced tumors. In ASV-induced tumors, HRP permeability did not correlate with tumor histological classification, size, or anatomic location within the brain. The subcutaneous tumor models studied were RG-2-, S69-C1-5, and 9L-transplanted tumors in rats, and human glioblastoma cell lines transplanted into nude mice. All were completely permeable to HRP. These results indicate that significant differences in permeability to HRP exist among brain tumor models when the tumors are intracerebral, and that all subcutaneous tumors from transplanted glial cell lines are completely permeable to HRP. These variables must be considered in future studies of permeability in experimental brain tumors. Care must be exercised in extrapolating results about permeability from one brain tumor model to another.