Search PubMed⌕ Search

Biomedical subjects

T C Wright

Publications and source records attributed to T C Wright.

At least 91 records · Page 5Linked to original sources
PubMed1991

Avascular necrosis and vascular anatomy of the metacarpals.

Aseptic necrosis of the metacarpal head is extremely rare and has been described in association with systemic lupus erythematosus, steroid use, trauma, and other sites of bone infarction. The long metacarpal is the most commonly involved. The extrinsic and intrinsic vascular anatomy of the metacarpal is described in fifty metacarpal specimens. No definite conclusions can be drawn about anatomic variations in blood supply between the different metacarpals. However, in 35% of the specimens, a main arteriole in the distal epiphysis was absent, making these metacarpal heads solely dependent on small circumferential pericapsular arterioles. This group of metacarpals, when associated with other risk factors, such as trauma, systemic lupus erythematosus, or steroid use, may be at increased risk for the development of aseptic necrosis.

Adolescent↗
PubMed1991

Pathology of the cervix.

Over the last year, the majority of research on the pathology of the cervix has been focused on the human papillomavirus (HPV) and its role in the pathogenesis of cervical neoplasia. Several major points emerged from these studies. First, the incidence of latent HPV infection in the general population is greater than previously thought. Up to 31% of a college-aged population has HPV DNA detected in cervical swabs. Second, in situ hybridization to detect HPV has been found to be a useful quality control measure for laboratories diagnosing cervical lesions. Finally, it is now recognized that many different HPV types can infect the cervix and be associated with cervical neoplasia. With regard to treatment, the introduction of loop electrosurgical excision procedures for treating cervical intraepithelial neoplasia lesions promises to have a significant impact on the management of cervical disease.

Female↗
PubMed1991

Pearly penile papules: absence of human papillomavirus DNA by the polymerase chain reaction.

Pearly penile papules clinically resemble the sexually transmitted papular variant of genital condylomata. Histologically, however, pearly penile papules consist of fibropapillomata that lack the characteristic morphologic features of human papillomavirus (HPV) infection. To study the possible association of HPV infections with pearly penile papules, we examined tissue specimens from 13 men with pearly penile papules with and without associated penile condylomata. Biopsy specimens were tested for the presence of HPV DNA by the polymerase chain reaction. None of the pearly penile papules contained HPV DNA sequences, whereas four of seven cases clinically suspected of being condylomata associated with pearly penile papules contained HPV DNA. These results confirm that pearly penile papule lesions do not contain HPV DNA; therefore, the distinction between pearly penile papules and penile condylomata is clinically significant.

Adult↗
PubMed1990

Role of human papillomavirus in the pathogenesis of genital tract warts and cancer.

During the last decade a large number of clinical, epidemiological, and experimental studies have elucidated the role of HPV in the pathogenesis of anogenital cancer. Although the clinical and epidemiological studies have been criticized for a variety of technical and design shortcomings, for the most part they have independently reached the same conclusion--there is a strong association between the presence of specific types of HPV and the development of anogenital cancer. Similarly, laboratory studies clearly indicate that specific types of HPV act in concert with other cellular changes to transform a variety of cell types in vitro, including human cervical epithelial cells. Over the next decade the challenge is twofold. First we need to define precisely the mechanisms by which HPV either by itself or in concert with other factors, acts to transform anogenital epithelial cells. These studies will, it is hoped, identify important cofactors in the transformation process and determine the role of host immunity. Second, we need to determine the clinical applicability of the association between HPV and anogenital cancer. Large clinical studies will determine whether HPV testing of asymptomatic patients facilitates the detection of patients at risk for developing cervical cancer and whether the presence of a specific type of HPV in a cervical cancer actually affects a patient's prognosis. As the answers to these and other questions become available, we will be in a better position to assess the clinical importance of the associations between HPV and anogenital cancer.

Female↗
PubMed1990

Heparin inhibits c-fos and c-myc mRNA expression in vascular smooth muscle cells.

Heparin is a potent inhibitor of vascular smooth muscle cell (VSMC) growth. In this paper we show that heparin suppressed the induction of c-fos and c-myc mRNA in rat and calf VSMC. This effect of heparin is closely associated with its growth-inhibitory activity, as shown by isolating and characterizing a strain of rat VSMC that was resistant to heparin's antiproliferative effect; heparin did not suppress c-fos mRNA induction in these cells. Moreover, neither a nonantiproliferative heparin fragment or other glycosaminoglycans that lack growth-inhibitory activity repressed c-fos or c-myc mRNA levels. The effect of heparin on c-fos mRNA induction was selective for specific mitogens, as heparin inhibited c-fos mRNA induction in phorbol 12-myristate 13-acetate (TPA) stimulated but not epidermal growth factor (EGF) stimulated VSMC. The effect of heparin on gene expression is independent of ongoing protein synthesis, and inhibition of c-fos mRNA is at the transcriptional level. These results suggest that heparin may selectively inhibit a protein kinase C-dependent pathway for protooncogene induction and that this may be one mechanism used by heparin to inhibit cell proliferation.

Animals↗
PubMed1989

Structural determinants of heparin's growth inhibitory activity. Interdependence of oligosaccharide size and charge.

The glycosaminoglycan heparin inhibits the growth of several cell types in vitro including smooth muscle cells and rat cervical epithelial cells. The commercially available heparin which has antiproliferative activity is a structurally heterogeneous polymer that undergoes extensive modifications during maturation. In this report we have performed structure-function studies on heparin's antiproliferative activity using three different cell types: both rat and calf vascular aortic smooth muscle cells and rat cervical epithelial cells. The minimal oligosaccharide size requirements for antiproliferative activity were determined for the three cell types by using oligosaccharide fragments of defined length prepared by nitrous acid cleavage and gel filtration and a synthetic pentasaccharide. The size requirements are similar but not identical for the different cell types. Hexasaccharide fragments are antiproliferative for all three cell types but the synthetic pentasaccharide inhibits the growth of only the rat and calf vascular aortic smooth muscle cells. The interdependence between size and charge for antiproliferative activity was investigated using chemically modified oligosaccharides as well as oligosaccharides prepared from heparin and separated into fractions of differing charge by ion-exchange chromatography. There is a strong interdependence between size and charge for antiproliferative activity. For example, increasing the charge of inactive tetrasaccharide fragments by O-oversulfation makes them antiproliferative whereas reducing the charge of active larger fragments causes them to loose their antiproliferative activity. Finally the importance of 2-O-sulfate glucuronic acid moieties for antiproliferative activity was investigated using heparin preparations that lack 2-O-sulfate glucuronic acid. These compounds possess antiproliferative activity indicating that 2-O-sulfate glucuronic acid is not required for antiproliferative activity.

Animals↗
PubMed1989

Heparin suppresses the induction of c-fos and c-myc mRNA in murine fibroblasts by selective inhibition of a protein kinase C-dependent pathway.

Heparin is a complex glycosaminoglycan that inhibits the proliferation of several cell types in culture and in vivo. To begin to define the mechanism(s) by which heparin exerts its antiproliferative effects, we asked whether heparin interferes with the expression of the growth factor-inducible protooncogenes c-fos and c-myc. We show that heparin suppressed the induction of c-fos and c-myc mRNA by serum in murine (BALB/c) 3T3 fibroblasts. Using purified mitogens, we further show that suppression was most marked when protooncogene expression was induced by phorbol 12-myristate 13-acetate, an activator of protein kinase C. By contrast, there was little or no suppression when the cells were stimulated by epidermal growth factor, which, in these cells, utilizes a protein kinase C-independent pathway for the induction of gene expression. Heparin also inhibited the change in cell morphology induced by the phorbol ester but had no effect on the morphological change induced by epidermal growth factor and agents that raise intracellular cAMP. Heparin did not inhibit intracellular protein kinase C activity, phorbol ester-induced down-regulation of protein kinase C, or phosphorylation of the 80-kDa intracellular protein kinase C substrate. These results suggest that heparin inhibits a protein kinase C-dependent pathway for cell proliferation and suppresses the induction of c-fos and c-myc mRNA at a site distal to activation of the kinase.

Animals↗
PubMed1989

Heparin selectively inhibits a protein kinase C-dependent mechanism of cell cycle progression in calf aortic smooth muscle cells.

The proliferation of arterial smooth muscle cells (SMCs) plays a critical role in the pathogenesis of arteriosclerosis. Previous studies have indicated that the glycosaminoglycan heparin specifically inhibited the growth of vascular SMCs in vivo and in culture, although the precise mechanism(s) of action have not been elucidated. In this study, we have examined the ability of specific mitogens (PDGF, EGF, heparin-binding growth factors, phorbol esters, and insulin) to stimulate SMC proliferation. Our results indicate that SMCs derived from different species and vascular sources respond differently to these growth factors. We next examined the ability of heparin to inhibit the proliferative responses to these mitogens. In calf aortic SMCs, heparin inhibits a protein kinase C-dependent pathway for mitogenesis. Detailed cell cycle analysis revealed several new features of the effects of heparin on SMCs. For example, heparin has two effects on the Go----S transition: it delays entry into S phase and also reduces the number of cells entering the cycle from Go. Using two separate experimental approaches, we found that heparin must be present during the last 4 h before S phase, suggesting a mid-to-late G1 heparin block. In addition, our data indicate that heparin-treated SMCs, while initially blocked in mid-to-late G1, slowly move back into a quiescent growth state in the continued presence of heparin. These results suggest that heparin may have multiple targets for its antiproliferative effect.

Animals↗
PubMed1987

Characterization of keratins from rat cervical epithelial cells in vivo and in vitro.

The keratins expressed in cultured rat cervical epithelial cells were analyzed by using two-dimensional gel electrophoresis and monoclonal antikeratin antibodies and were compared with those expressed in the rat cervix in vivo in the presence and absence of estrogen stimulation. The cervical epithelium in vivo responds to estrogen stimulation with alterations in keratin composition. In response to estrogen, the epithelium undergoes proliferation and stratification and begins expressing increased amounts of two basic Mr 57,000 and 58,000 keratins and two acidic Mr 51,000 and 52,000 keratins. Cultured rat cervical epithelial cells were found to express only small amounts of the basic Mr 57,000 and 58,000 keratins and the two acidic Mr 51,000 and 52,000 keratins characteristic of the estrogen-stimulated cervix. In addition to the keratins found in the cervical epithelium in vivo, rat cervical epithelial cells in vitro begin expressing two Mr 55,000 and 56,000 keratins of the basic keratin family (type II) and an acidic component with a molecular weight of 40,000. Although these components are not detected in the rat cervix in vivo, they migrate similarly on two-dimensional electrophoretic gels to proteins expressed by the rat endometrial epithelium in vivo. These findings indicate that alterations in keratin expression could serve as markers for studying the effects of steroid hormones on the differentiation of rat cervical epithelial cells in vitro and during the development of squamous metaplasia.

Animals↗
PubMed1987

Metabolic effects of heparin on rat cervical epithelial cells.

The glycosaminoglycan heparin inhibits the growth of a number of different cell types in vitro including smooth muscle cells, mesangial cells, fibroblasts, and rat cervical epithelial cells (RCEC). Studies investigating the antiproliferative effects of heparin on smooth muscle cells have demonstrated the site of the cell cycle block and revealed several metabolic alterations that could be causally associated with growth inhibition. We have investigated these metabolic parameters in RCEC to determine whether they are also associated with the antiproliferative effects of heparin in epithelial cells. Heparin acts rapidly to inhibit RCEC growth with inhibition detectable by autoradiography 7 h after the addition of heparin. Heparin treated RCEC begin to enter S-phase 12 h after the removal of heparin. These findings suggest that heparin blocks RCEC in the early-to-mid G1 phase of the cell cycle rather than late in G1 or early in S-phase as has previously been demonstrated for smooth muscle cells. Unlike smooth muscle cells, the uptake of thymidine and uridine is not inhibited by heparin in RCEC. Treatment of medium with heparin-Sepharose does not reduce the subsequent growth of RCEC; heparin inhibits the growth of RCEC in heparin-Sepharose treated medium in a manner identical to that in nontreated medium. Therefore the growth inhibitory effects of heparin cannot be explained by the inactivation of mitogens present in serum. In contrast to its effects on smooth muscle cells, heparin treatment of RCEC does not result in a reduction in the binding of epidermal growth factor (EGF) to the cells. These results indicate that although heparin inhibits the growth of a variety of cell types, significant differences exist in the responses of the different cells to heparin.

Animals↗
PubMed1986

Growth requirements and characterization of rat cervical epithelial cells in culture.

The extended culture of rat cervical epithelial cells can be achieved in the absence of a fibroblast feeder layer by utilizing collagen gels and a complex growth medium. The medium contains a 1:1 mixture of RPMI-1640 and Ham's F12 supplemented with 7.5% porcine serum and epidermal growth factor, cholera toxin, transferrin, insulin, and hydrocortisone. Under these culture conditions the cells show rapid log-phase growth and high saturation densities while retaining the ultrastructural characteristics of immature squamous metaplastic cells of the rat uterine cervix even after extended passage. In a manner similar to epithelial cells from a variety of sources, rat cervical epithelial cells form hemicysts at confluence in vitro when cultured on impermeable substrates. The development of these methods for culturing cervical epithelial cells provides an experimental system for the study of factors important in regulating the growth and differentiation of metaplastic squamous epithelial cells.

Animals↗
PubMed1985

Binding and internalization of heparin by vascular smooth muscle cells.

Previous work from our laboratory has demonstrated that heparin specifically inhibits the proliferation of vascular smooth muscle cells in vivo and in vitro. In this paper, we examine the binding and mode of internalization of heparin by smooth muscle cells. For these studies, radiolabeled and fluoresceinated (FITC) heparin probes were synthesized that retained their antiproliferative capacity. Binding of 3H-heparin to these cells occurs via specific, high-affinity binding sites (Kd = 10(-9) M, 100,000 binding sites per cell). Approximately 80% of the heparin bound to the cell surface was shed into the culture medium within 2 hr. The heparin that was left on the cell surface was internalized with biphasic kinetics. Approximately 50% of the bound material was internalized within 2 hr. After this initial rapid uptake, the rate slowed substantially, with the remaining heparin requiring 1-2 days to be internalized. Binding and uptake of FITC heparin was monitored using video image intensification fluorescence microscopy. When smooth muscle cells were exposed to FITC heparin at 4 degrees C, a diffuse surface staining pattern was observed. After warming the cells to 37 degrees C, intensely fluorescent vesicles were seen superimposed over the diffuse surface staining within 2 min. After 15 min at 37 degrees C, numerous large punctate vesicles were seen inside the cell. After 2 hr these vesicles had concentrated in the perinuclear region. This pattern of uptake, when considered along with the presence of specific, high-affinity binding sites and the initial rapid uptake of 3H-heparin, suggests that heparin enters smooth muscle cells by both receptor-mediated and other endocytic pathways.

Animals↗
PubMed1985

Inhibition of rat cervical epithelial cell growth by heparin and its reversal by EGF.

The effects of heparin on the in vitro growth of rat cervical epithelial cells were examined. Heparin was found to inhibit in a dose dependent fashion the log-phase growth of rat cervical epithelial cells (RCEC) grown in the absence of medium supplements. An inhibition of growth is observed at concentrations as low as 500 ng/ml and 50% inhibition of growth occurs at a concentration of 5 micrograms/ml. The growth inhibitory activity of heparin is independent of anticoagulant activity since three separate non-anticoagulant preparations of heparin all inhibit growth. Other glycosaminoglycans including chondroitin 4-sulfate, chondroitin 6-sulfate, dermatan sulfate, hyaluronic acid, and keratin sulfate do not inhibit the growth of rat cervical epithelial cells. The ability of heparin to inhibit the log-phase growth of rat cervical epithelial cells is dependent on the composition of the medium in which the cells are grown. The addition of greater than or equal to 7.5 ng/ml epidermal growth factor to epithelial cultures blocks the growth inhibitory activity of heparin. These results suggest that components of the extracellular matrix modulate the growth responses of epithelial cells and may be important in regulating cellular proliferation in normal and pathological states.

Animals↗
PubMed1984

Increased adhesiveness of Down syndrome fetal fibroblasts in vitro.

We compared the in vitro rate of divalent cation-independent aggregation of fibroblasts derived from abortuses with normal karyotypes and with trisomy 21 (Down syndrome). Fibroblasts from five lung and two of three cardiac cultures from subjects with Down syndrome aggregated more rapidly than matched fibroblasts from normal controls or lung fibroblasts from an abortus with trisomy 13. In contrast, skin fibroblasts derived from the trisomy 21 subjects had low rates of aggregation. The high rates of aggregation of trisomy 21 lung fibroblasts were not affected by hyaluronidase treatment. Lung fibroblasts from both normal and Down syndrome subjects had similar membrane polarization values in an assay using the fluorescent probe 1,6-diphenyl-1,3,5-hexatriene. Thus, the increased aggregation rate we observed for trisomy 21 fibroblasts was restricted to specific fibroblast cultures, was not mediated by hyaluronic acid or gross membrane lipid alterations, and was specific for trisomy of chromosome 21. As illustrated in computer simulations presented elsewhere, increased intercellular adhesiveness during organogenesis could explain the frequent occurrence of malformations, including pulmonary hypoplasia and congenital heart defects, in Down syndrome.

Cell Adhesion↗
PubMed1984

Localization of calmodulin in differentiating pulmonary type II epithelial cells.

Pulmonary surfactant is synthesized by alveolar type II pneumonocytes and stored in inclusions called lamellar bodies. In the present study we have investigated the role of the calcium-binding protein, calmodulin, in regulating surfactant secretion in differentiating rat fetal type II pneumonocytes. Lamellar body secretion is stimulated in differentiating type II cells in vitro by the calcium ionophore, A23187. A23187-induced secretion is blocked by the phenothiazine drugs, trifluoperazine and chlorpromazine, but is unaffected by the inactive analogs, trifluoperazine sulfoxide and chlorpromazine sulfoxide. Immunofluorescence studies on cultured type II pneumonocytes show that the percentage of Nomarski-dense intracellular granules, which stain positively with anticalmodulin antibody, increases when the cells are stimulated with the calcium ionophore, A23187. Since these Nomarski-dense granules are positively stained by phosphine-3R, these results indicate that increased amounts of immunoreactive calmodulin appear associated with lamellar body surfaces when the cells are stimulated for secretion. In addition, ultrastructural localization of calmodulin on isolated lamellar bodies using protein A-colloidal gold indicates that calmodulin is present on their outer surfaces. The endogenous calmodulin present on the isolated lamellar bodies is not removed by treatment of the lamellar bodies with ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid. Using the same localization technique, we found that isolated lamellar bodies are capable of binding exogenously added calmodulin in the presence of calcium. Taken together, these results implicate calmodulin in pulmonary surfactant secretion.

Animals↗