Biomedical subjects

D Whitaker

Publications and source records attributed to D Whitaker.

At least 19 recordsLinked to original sources

PubMed1992

Establishment of a murine model of malignant mesothelioma.

Malignant mesothelioma (MM) is an aggressive tumour of the serosal cavities which is associated with previous asbestos exposure and is generally found to be resistant to conventional forms of therapy. Adequate scientific and clinical assessment of this disease has been severely limited by the relatively low incidence of mesothelioma and the lack of representative cell lines and animal models. The purpose of this study was to develop an asbestos-induced murine model of MM both as an in vivo-passaged malignancy and as in vitro-established cell lines. Such a model system would be invaluable for use in the study of various cellular, molecular and genetic aspects of the disease, and for the pre-clinical evaluation of potential therapeutic agents. BALB/c and CBA mice were injected intraperitoneally with crocidolite asbestos. Seven to 25 months after exposure, 35% of the mice developed mesothelioma (5 BALB/c, 9 CBA), as determined by standard cytological and histological parameters. From these primary tumours, 12 continuously growing cell lines (5 BALB/c, 7 CBA) were established in culture. All have been confirmed as mesothelioma by cytological and ultrastructural (electron microscopy) analyses. These lines have been in culture for 7 to 24 months and have achieved passages above 32 (range 32 to 106). As in the human disease, the murine mesothelioma lines vary in their morphology and growth rates (doubling times ranging from 14 to 30 hr). All cell lines produced tumours when injected into syngeneic mice.

Animals↗

PubMed1992

Simulating age-related optical changes in the human eye.

The decline in visual function observed in older adults has been attributed to a deterioration in optical quality, decreased neural function, or a combination of both of these factors. One way of separating their contribution is to design a simulation of the optics of the elderly eye and examine its effect on the visual performance of younger observers. The age-related reduction in pupil size was simulated by the administration of an ophthalmic miotic drug, whilst a neutral density filter was included to account for the increased absorption of the ocular media. An optical cell containing a critical concentration of 500 nm diameter polystyrene microspheres in suspension was used to simulate light scatter. The spatiotemporal contrast sensitivity of an older group of observers was then compared with that of a younger group with and without the optical simulation. The contrast sensitivity of the younger group was consistently better than that of the older, and the presence of the optical simulation produced no significant effect on performance. This suggests that, under normal viewing conditions, it is primarily neural factors which underlie the deterioration in visual quality experienced by older observers.

Adult↗

PubMed1992

The influence of eccentricity on position and movement acuities as revealed by spatial scaling.

The rate of decline with increasing eccentricity of several position and movement acuities was measured using a method of spatial scaling. In this method all stimuli at each visual field location are simply magnified versions of each other. The influence of separation and eccentricity were dissociated by presenting stimuli on an iso-eccentric arc. For each task, the rate of decline in performance was quantified by the parameter E2 which represents the eccentricity at which stimulus size must double in order to maintain performance equivalent to that at the fovea. All tasks were found to obey the concept of spatial scaling in that performance at a given field location could be equated with performance at any other location simply by a change of scale. However, the rate at which performance deteriorated with eccentricity varied over an enormous range (over 100-fold) depending on the task itself. The advantage of such diverse peripheral gradients is clear; the goal is to establish the physiological mechanisms which underlie this phenomenon.

Discrimination, Psychological↗

PubMed1992

Spatial scaling of vernier acuity tasks.

Vernier acuity thresholds for two abutting lines and for a two-dot stimulus were measured as a function of stimulus magnification at eccentricities of 0, 5, 10 and 15 deg using a spatial scaling technique in which all stimuli are simply magnified versions of each other. The advantage of such a technique is that no prior knowledge of a suitable magnification factor with which to increase the size of peripheral stimuli is required. Thresholds for the line stimulus could be successfully scaled by the application of a magnification factor with an E2 value of 1.23-1.78 deg. Further, provided that the effects of dot separation and eccentricity were dissociated, spatial scaling with an E2 value of 1.06-1.96 deg was also successful in removing eccentricity dependence for two-dot vernier thresholds.

Fovea Centralis↗

PubMed1992

An ultrastructural study of the developing urogenital tract in early human fetuses.

OBJECTIVES: This study examines the gonoducts during the ambisexual stage of human fetal development to define their ultrastructural characteristics, including the origin and antomic relationship of the mesonephric and paramesonephric ducts during gonoductal development. STUDY DESIGN: The reproductive tracts from five fetuses ranging in gestational age from 35 to 45 days were processed for ultrastructural examination. The developing mesonephric ducts, paramesonephric ducts, and their surrounding mesenchyme were studied with a Phillips 300 transmission electron microscope. RESULTS: The mesonephric ducts and paramesonephric ducts have distinctive cytoplasmic and cell surface ultrastructural characteristics, as well as different morphologic patterns of epithelial-mesenchymal interaction. Cephalad portions of mesonephric ducts and paramesonephric ducts are separated by mesenchyme, but more caudal aspects move progressively closer until they are juxtaposed but separate. CONCLUSIONS: Early mesonephric ducts and paramesonephric ducts may be distinguished because of their distinctive ultrastructural features; epithelial-mesenchymal interaction may be important in their differentiation and maintenance; both gonoducts retain their morphologic identity throughout, supporting their separate origins.

Cell Nucleolus↗

PubMed1992

How useful are contrast sensitivity charts in optometric practice? Case reports.

There are now a number of commercially available contrast sensitivity (CS) charts for clinical use. Although a great deal has been written about CS, there is little information regarding its usefulness in optometric practice. In this study 3 commercially available charts (the Vistech system, Pelli-Robson, and Cambridge charts) were used by 6 optometrists in clinical practice over a 14-month period. This report includes a review of the research literature on clinical CS testing, and contains case records from the in-practice study which indicate situations in which the measurement of CS proved useful.

Adult↗

PubMed1992

Mesothelioma in horses.

Pleural mesothelioma and pericardial mesothelioma with spread to the pleural cavity were diagnosed in 2 horses. Clinical signs included respiratory distress, depression and pleural pain. The affected body cavities contained copious, serous effusions containing very large neoplastic mesothelial cells with densely-staining cytoplasm, hyperchromic nuclei and prominent, often multiple, nucleoli. Ultrastructurally, the neoplastic cells appeared as solid aggregates, with profuse microvillous borders and neolumen formation. Cytological examination, together with confirmative ancillary diagnostic tests, including electron microscopy and immunocytochemistry, may be used to obtain an ante-mortem diagnosis of mesothelioma.

Animals↗

PubMed1992

Sequential mapping of weighting functions for visual location.

The effect upon perceived location of adding an extra dot offset from the centre of a cluster of pseudorandom dots was investigated using a vernier acuity task. With this technique, weighting functions showing the extent to which the added dot pulls the apparent location of the entire cluster can be defined as a function of distance from the centre of the cluster. When dot density within the cluster is high, the weighting functions approximate to what would be expected on the basis of centroid alignment. With low dot densities, it appears that performance is determined by aligning the outermost dots within each cluster. The peak amplitudes of these weighting functions are proportional to the square root of dot density within the clusters. The results are consistent with the view that each vernier element is localised in an orthoaxial direction prior to discrimination of the vernier offset.

Humans↗

PubMed1992

Clinical contrast sensitivity chart evaluation.

Three different types of contrast sensitivity chart were used on normal patients by six optometrists in clinical practice. The charts were the Vistech, the Pelli-Robson and the Cambridge low-contrast gratings test. We examine the data in terms of the differences between optometrists and the variation of contrast sensitivity with the age of the patient. There was a highly significant difference between the scores from different optometrists for all three charts. We attribute this to variability in measurement technique. There was also a highly significant effect of age for all three charts, with older observers tending to exhibit lower contrast sensitivity. On the Vistech chart, this sensitivity deficit was most pronounced at higher spatial frequencies. The level of redundant information in the tests is discussed.

Adolescent↗

PubMed1992

Variations in hyperacuity performance with age.

The term hyperacuity has been applied to a group of stimuli which produce spatial thresholds smaller than those expected given the relatively large receptor spacing and the retinal image quality of the human eye. It is not yet firmly established whether hyperacuity performance declines with increasing age in the same way as most other measures of visual ability. This is perhaps due to the use of varying task configurations and criterion-dependent psychophysical techniques. The present study examines age-related performance in three different hyperacuity tasks using a criterion independent forced-choice method. Both displacement and bisection thresholds were found to increase with age, but there was no significant change in vernier acuity. This indicates that age has a differential effect on thresholds for various hyperacuities depending upon the task requirements. No significant age-related trend was observed in hyperacuity bias, which represents the difference between subjective and true physical alignment.

Adolescent↗

PubMed1992

The concept of mesothelioma in situ: implications for diagnosis and histogenesis.

The concept of mesothelioma in situ is explored by a detailed examination of seven patients, subsequently proven to have pleural malignant mesothelioma, who initially had no evidence of gross tumor and for whom biopsy material was available at this early presentation. The tissue was assessed by routine microscopy, the immunoperoxidase technique for epithelial membrane antigen and silver staining for nucleolar organizer regions. Tiny lesions of the pleura that merged with or were adjacent to microscopically flat monolayered or folded mesothelium with cytological atypia were observed. The atypical cells reacted positively to epithelial membrane antigen, and the nucleolar organizer region counts were elevated. These observations are considered to support the possibility of the presence of mesothelioma in situ. These findings are discussed in the light of the proposed concept of mesothelioma in situ, its histogenesis, and its possible clinical relevance.

Adult↗

PubMed1991

Induction of local inflammation by recombinant human platelet factor 4 in the mouse.

Platelet factor 4 (PF-4) has been shown to be chemotactic for neutrophils and monocytes in vitro. To assess whether these observations have in vivo relevance, we tested the ability of recombinant human PF-4 (rPF-4) to induce acute and chronic dermal inflammation in the mouse. When injected as a single dose intradermally, rPF-4 induced an acute inflammatory response that peaked at 6 to 12 hr and which resolved by 36 hr. Injection of an equivalent amount of cytochrome c, buffer alone, or an amino-terminal PF-4 peptide failed to elicit a significant inflammatory response; however, the carboxy-terminal PF-4 peptide retained proinflammatory properties. The inflammatory infiltrate induced by a single injection of either rPF-4 or the 41 amino acid carboxy-terminal peptide was composed of neutrophils and smaller numbers of mononuclear cells. Repeated injection of rPF-4 resulted in nearly equal numbers of neutrophils and mononuclear cells. Moreover, marked dermal fibrosis developed after only 5 days of daily injection of rPF-4. Although relatively high concentrations of rPF-4 were required to elicit an inflammatory response, these concentrations may be locally attainable during platelet aggregation. Our findings thus support the hypothesis that PF-4 may contribute to the development of inflammatory responses at sites of platelet aggregation.

Animals↗

PubMed1991

Interaction between dactinomycin and tumor necrosis factor in mesothelioma. Cachexia without oncolysis.

There is no effective therapy for human malignant mesothelioma, and its susceptibility to recombinant cytokines has not been studied extensively. Recombinant human tumor necrosis factor alpha (rHuTNF alpha) was evaluated for its in vitro and in vivo antitumor activity using a human malignant mesothelioma cell line [DeH128(m)], both in culture and heterotransplanted in nude mice. In vitro, rHuTNF alone had no direct antimesothelioma activity assessed using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide assay, but in combination with the transcription inhibitor, dactinomycin (AD), mesothelioma cell metabolic activity was inhibited (80% of control). The effects of this combination of agents were studied on DeH128(m) cells heterotransplanted as subcutaneous tumors in nude mice. In vivo there was no significant inhibition of tumor growth by combined rHuTNF alpha and AD therapy, but the combination produced marked cachexia in doses at which each component (rHuTNF alone or AD alone) was well tolerated. The authors conclude that the well-described in vitro interaction between AD and rHuTNF also operates in vivo to produce cachexia and that the combination of these two agents is likely to have a low therapeutic index in malignant mesothelioma.

Animals↗

PubMed1991

Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1.

Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that mediates endothelial leukocyte interactions by inducing expression of adhesion molecules. In this report, we demonstrate that human dermal mast cells contain sizeable stores of immunoreactive and biologically active TNF-alpha within granules, which can be released rapidly into the extracellular space upon degranulation. Among normal human dermal cells, mast cells are the predominant cell type that expresses both TNF-alpha protein and TNF-alpha mRNA. Moreover, induction of endothelial leukocyte adhesion molecule 1 expression is a direct consequence of release of mast cell-derived TNF-alpha. These findings establish a role for human mast cells as "gatekeepers" of the dermal microvasculature and indicate that mast cell products other than vasoactive amines influence endothelium in a proinflammatory fashion.

Cell Adhesion↗

PubMed1991

Origins of BSE.

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Animal Feed↗

PubMed1991

Establishment and characterization of five human malignant mesothelioma cell lines derived from pleural effusions.

Malignant mesothelioma (MM) is an aggressive tumour of the serosal cavities which is associated with exposure to asbestos. Studies of this tumour have been limited by a paucity of well-characterized human MM cell lines. In this study, 5 human MM cell lines were established from pleural effusions of patients with this malignancy. All 5 patients were males with known crocidolite asbestos exposure, who had received no treatment for their disease and in whom the diagnosis was confirmed by cytology, histology and electron microscopy (EM). These lines have been in culture from 11 to 25 months, and all of them for more than 18 passages. The appearance of the cells in culture was extremely varied; in 3 of the lines they were spindle-shaped with few vacuoles (JU77, LO68 and ONE58); in 1 line they had a thick, stellate shape with vacuoles (NO36) and in 1 they were very pleomorphic in both shape and size with irregular membranes and numerous vacuoles [DeH128 (M)]. Upon reaching confluence, cells in 3 of the 5 lines assumed the cobblestone-like pattern characteristic of epithelial-type cells, whereas in the other 2 (LO68 and ONE58) they remained spindle-shaped. All 5 lines demonstrated a loss of contact inhibition (i.e., piling) at confluence. Minimum doubling times varied significantly from 18 hr (JU77) to more than 30 hr [DeH128 (M)]. Cytological examination showed characteristic mesothelial/mesothelioma morphology, and epithelial membrane antigen (EMA) and cytokeratin were demonstrated in cells from all 5 lines. These cells lacked CEA and epithelial mucin. The presence of cell junctions, glycogen and numerous long, thin, branching microvilli was readily demonstrable by EM. All lines had abnormal karyotypes, with the modal chromosome number varying from 40 to 80. Variable chromosome numbers, numerous structural rearrangements and unrecognizable marker chromosomes were readily observed; however, the only consistent change seen was del 6q21 in 4 of the 5 lines. The establishment of these 5 cultured human MM cell lines now provides an opportunity for comparative study of several aspects of the biology of MM in vitro as well as screening new treatment modalities.

Adult↗

PubMed1991

Interaction of spatial frequency and separation in vernier acuity.

There are two general theories which attempt to explain the ability to judge the relative positions of objects in the visual field. The first is the "local-sign" model which assigns location to individual features of the stimulus. The other is the "channel" model involving pooling of responses of overlapping filters having different spatial frequency and orientation tuning. We set out to investigate these using vernier stimuli whose frequency content could be controlled. The stimuli consisted of vertically orientated sinusoidal gratings placed one above the other with a variable separation between them. Thresholds for high frequency gratings increased rapidly with separation while low frequencies were little affected. In addition the cycle width of gratings which could just be distinguished as being in or out of phase and of gratings which gave optimum vernier acuity both increased linearly with separation. Results are discussed in terms of a model based on spatial frequency filters and we suggest that our findings place significant constraints upon a local-sign model.

Contrast Sensitivity↗

PubMed1991

The use of monoclonal antibody 44-3A6 in cell blocks in the diagnosis of lung carcinoma, carcinomas metastatic to lung and pleura, and pleural malignant mesothelioma.

Monoclonal antibody (MoAb) 44-3A6 recognizes a glandular differentiation-associated antigen and has been used to identify exocrine differentiation in pulmonary carcinomas. The authors assessed its value in the diagnosis of lung carcinomas metastatic to lung/pleura and pleural malignant mesothelioma (MM), using cell blocks derived from cytologic specimens. Sixty-three primary lung carcinomas, 31 metastatic adenocarcinomas (ACs) (from breast, gastrointestinal tract, or genitourinary tract), and 36 MMs were immunostained with 44-3A6, Leu-M1, and anti-carcinoembryonic antigen (CEA). The results confirm the value of 44-3A6 in identifying ACs but do not allow distinction between those of pulmonary, breast, GIT, or ovarian mucinous derivation. Endometrial, ovarian serous, and renal ACs are essentially nonreactive, as are almost all MMs. The occurrence of one positive MM predicates caution in interpreting 44-3A6 positivity in isolation, but, judiciously used with other discriminating antibodies such as Leu-M1 and anti-CEA, 44-3A6 is of value in the differential diagnosis of ACs and MMs. Further, its applicability to cytologic specimens may obviate the need for more invasive diagnostic procedures and lead to rapid, accurate diagnosis.

Antibodies, Monoclonal↗