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Biomedical subjects

G F Pierce

Publications and source records attributed to G F Pierce.

At least 91 records · Page 5Linked to original sources
PubMed1989

Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms.

Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) markedly potentiate tissue repair in vivo. In the present experiments, both in vitro and in vivo responses to PDGF and TGF-beta were tested to identify mechanisms whereby these growth factors might each enhance the wound-healing response. Recombinant human PDGF B-chain homodimers (PDGF-BB) and TGF-beta 1 had identical dose-response curves in chemotactic assays with monocytes and fibroblasts as the natural proteins from platelets. Single applications of PDGF-BB (2 micrograms, 80 pmol) and TGF-beta 1 (20 micrograms, 600 pmol) were next applied to linear incisions in rats and each enhanced the strength required to disrupt the wounds at 5 d up to 212% of paired control wounds. Histological analysis of treated wounds demonstrated an in vivo chemotactic response of macrophages and fibroblasts to both PDGF-BB and to TGF-beta 1 but the response to TGF-beta 1 was significantly less than that observed with PDGF-BB. Marked increases of procollagen type I were observed by immunohistochemical staining in fibroblasts in treated wounds during the first week. The augmented breaking strength of TGF-beta 1 was not observed 2 and 3 wk after wounding. However, the positive influence of PDGF-BB on wound breaking strength persisted through the 7 wk of testing. Furthermore, PDGF-BB-treated wounds had persistently increased numbers of fibroblasts and granulation tissue through day 21, whereas the enhanced cellular influx in TGF-beta 1-treated wounds was not detectable beyond day 7. Wound macrophages and fibroblasts from PDGF-BB-treated wounds contained sharply increased levels of immunohistochemically detectable intracellular TGF-beta. Furthermore, PDGF-BB in vitro induced a marked, time-dependent stimulation of TGF-beta mRNA levels in cultured normal rat kidney fibroblasts. The results suggest that TGF-beta transiently attracts fibroblasts into the wound and may stimulate collagen synthesis directly. In contrast, PDGF is a more potent chemoattractant for wound macrophages and fibroblasts and may stimulate these cells to express endogenous growth factors, including TGF-beta, which, in turn, directly stimulate new collagen synthesis and sustained enhancement of wound healing over a more prolonged period of time.

Animals↗
PubMed1988

In vivo incisional wound healing augmented by platelet-derived growth factor and recombinant c-sis gene homodimeric proteins.

Human platelet-derived growth factor (hPDGF) is likely to be important in stimulating tissue repair, based upon its in vivo chemotactic and stimulatory activities for inflammatory cells and fibroblasts and upon the presence of PDGF and related proteins in platelets, macrophages, and activated fibroblasts, cell types that make up the milieu of the healing wound. Recombinant human c-sis (rPDGF-B), homodimers of the B chain of PDGF, were compared with hPDGF in vitro. rPDGF-B was immunologically similar to hPDGF and, at identical concentrations, similar to hPDGF in stimulating fibroblast mitogenesis and chemotaxis of polymorphonuclear leukocytes, monocytes, and fibroblasts. Purified hPDGF and rPDGF-B were also tested in vivo for potency in a model of tissue repair using a linear incision wound through rat dermis. A single application of hPDGF or rPDGF-B (2-20 micrograms/wound) in a slow release vehicle at the time of wounding resulted in a dose-dependent, statistically highly significant increase of breaking strength of treated wounds. Wound healing in animals treated with rPDGF-B was 170% stronger and accelerated by 2 d during the first week over control wounds and by 4-6 d over the next 2 wk. Histologic evaluation of growth factor-treated wounds correlated the in vitro chemotactic activity and the accelerated healing of wounds with a striking inflammatory cell infiltrate early after wounding, markedly increased formation of granulation tissue by 4-d, and increased fibrosis by 14 d in comparison to control wounds. The results thus demonstrate that rPDGF-B is fully active in in vitro tests of mitogenesis and chemotaxis and, for the first time, demonstrate directly that PDGF significantly advances wound healing in incisional wounds of experimental animals.

Animals↗
PubMed1988

Identification and purification of PDGF/sis-like proteins from nuclei of simian sarcoma virus-transformed fibroblasts.

The platelet-derived growth factor (PDGF) is a potent mitogen for cells derived from mesenchyme and is highly related to the transforming protein of the simian sarcoma virus (SSV), p28v-sis. Both PDGF and p28v-sis appear to initiate DNA synthesis and cell proliferation through an interaction with PDGF cell surface receptors but the identity of the PDGF induced signals which are recognized within the nucleus is unknown. It has been suggested that PDGF is directly transported to the nucleus although conflicting data have been obtained when nuclear fractions have been analysed for PDGF-like proteins. Specific antisera recognizing PDGF and p28v-sis were used to isolate and partially characterize proteins from nuclei of SSV-transformed NRK fibroblasts. Nuclear proteins of 66, 65, and 44 kD were identified in immunoprecipitates. These proteins were displaced competitively from binding to anti-PDGF antisera by either PDGF or by mitogenically active recombinant v-sis protein homodimers and the proteins were not recognized by non-immune sera. Proteins of 66, 65, and 44 kD also were partially purified from nuclear extracts with anti-PDGF immunoaffinity chromatography and were identified in silver stained PAGE gels. The data establish the presence of proteins antigenically related to PDGF within the nuclei of SSV-transformed cells and suggest possible roles of nuclear proteins related antigenically to PDGF and p28v-sis in cell growth and transformation.

Animals↗
PubMed1987

Accelerated healing of incisional wounds in rats induced by transforming growth factor-beta.

The role of polypeptide growth factors in the processes of inflammation and repair was investigated by analyzing the influence of transforming growth factor-beta (TGF-beta), applied directly to linear incisions made through rat dorsal skin. A dose-dependent, direct stimulatory effect of a single application of TGF-beta on the breaking strength of healing incisional wounds was demonstrated. An increase in maximum wound strength of 220 percent of control was observed at 5 days; the healing rate was accelerated by approximately 3 days for at least 14 days after production of the wound and application of TGF-beta. These increases in wound strength were accompanied by an increased influx of mononuclear cells and fibroblasts and by marked increases in collagen deposition at the site of application of TGF-beta. TGF-beta is thus a potent pharmacologic agent that can accelerate wound healing in rats.

Animals↗
PubMed1987

Platelet-derived growth factor/sis in normal and neoplastic cell growth.

Platelet-derived growth factor (PDGF) is the major growth factor in serum and a potent mitogen for cells mesenchymal origin. It is a highly basic heterodimeric protein with a molecular mass of approximately 30 kDa and binds to a cell surface receptor with high affinity. The amino acid sequence of PDGF revealed sequence homology to the v-sis gene product of simian sarcoma virus (SSV), a transforming retrovirus. Characterization of cells transformed by SSV has revealed PDGF-related proteins in subcellular organelles and in conditioned media consistent with the autocrine stimulation of cell growth through cell surface receptors and perhaps through an internal autocrine mechanism as the growth factor and its receptor are processed. PDGF is also a potent chemotactic agent for inflammatory and other mesenchymal cells and has been implicated in normal tissue repair processes such as wound healing, as well as in aberrant proliferative processes like atherogenesis.

Animals↗
PubMed1987

The risk of AIDS: psychologic impact on the hemophilic population.

The psychologic impact of the risk of the acquired immune deficiency syndrome (AIDS) was evaluated by questionnaire survey of 116 hemophiliacs, age 16 or older, and 40 mates and 94 parents of hemophiliacs. Although the mean group distress ratings indicate a lessening of emotional discomfort over time, ongoing distress as well as interference with life activities are reported. Parents indicate more distress than either hemophiliacs or mates. Health preoccupation, the fear of being contagious, interference with parent-child intimacy and sexual intimacy between hemophiliac and mate are noted. A significant decrease in the use of clotting factor concentrates for the treatment of bleeding episodes is reported because these products have been linked to the transmission of AIDS. Although the overall hemophilic population is coping effectively with the AIDS risk, some hemophiliacs are at increased risk for psychiatric morbidity, social isolation, hypochondriasis, and medical noncompliance. Increased parental anxiety is likely to lead to over-protective child-rearing practices. Although it examines only the hemophilic population, this study describes stress responses likely to be present in other at risk groups and suggests that specific psychosocial interventions are urgently needed.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Ultrastructural localization of a platelet-derived growth factor/v-sis-related protein(s) in cytoplasm and nucleus of simian sarcoma virus-transformed cells.

The subcellular distribution of v-sis-related protein(s) was analyzed in three simian sarcoma virus (SSV)-transformed cell lines with immunofluorescence and protein A-gold labeling techniques using rabbit polyclonal anti-platelet-derived-growth factor (PDGF) antisera. Antigenically reactive proteins were recognized in subcellular organelles related to protein synthesis and processing, including polyribosomes, endoplasmic reticulum, and the Golgi apparatus, as well as on the cytoplasmic surface of plasma membranes. Prominent immunoreactive proteins were also shown in association with nuclear chromatin in intact cells and in isolated nuclei using Lowicryl K4M resin embedding techniques. Protein A-gold labeling was markedly reduced in sections of non-SSV-transformed fibroblasts incubated with anti-PDGF and absent from SSV-transformed cells if Epon resin was substituted for Lowicryl in the embedding process or if sections were with irrelevant antisera. Nuclear localization of v-sis-related antigens was confirmed in a nitrocellulose-based immunoassay using nuclei isolated from SSV-transformed fibroblasts. Thus, polypeptides recognized antigenically as related to the v-sis gene product not only may be found in subcellular organelles associated with protein synthesis and packaging but also may be found in the nucleus of SSV-transformed cells. These results raise the possibility that v-sis- or PDGF-like proteins may function within the nucleus of SSV-transformed cells.

Animals↗
PubMed1986

Cartilage hair hypoplasia: immunological aspects and their clinical implications.

Cartilage hair hypoplasia (CHH) is an autosomal recessive form of short-limbed dwarfism prevalent among the Old Order Amish. Mild to moderately severe cellular immunodeficiency is associated with this disorder. Antibody synthesis is, however, normal in CHH. Individuals affected with CHH were found to have marked impairment of T-lymphocyte function due to an intrinsic defect in cell proliferation. Defective proliferation was also found in B cells and fibroblasts from CHH individuals suggesting that impaired T-cell function reflects a generalized defect in cell proliferation in this syndrome. Studies of cytotoxic mechanisms in CHH patients revealed that proliferation-dependent mechanisms (e.g., cell-mediated cytotoxicity and natural killer [NK]-like activity) were markedly impaired while proliferation-independent NK activity was normal. In spite of impairment of T-cell function, an increased incidence of malignancy was not observed in CHH patients. These observations suggest that NK activity is vital in host defense against malignancies and that marked impairment of T-cell-mediated immunity need not be associated with an increased susceptibility to malignancy if NK function is preserved.

Adenosine Deaminase↗
PubMed1986

Natural cytotoxicity in immunodeficiency diseases: preservation of natural killer activity and the in vivo appearance of radioresistant killing.

We studied spontaneous natural killer (NK) cell activity and radiation-resistant NK mediated cytotoxicity in four patients with clinically documented severe combined immune deficiency disease (SCID), and in one subject each with intestinal lymphangiectasia and cartilage-hair hypoplasia. We observed the preservation of spontaneous NK activity in all patients despite the presence of profound B- and T-lymphocytopenia and clinical immunodeficiency. NK activity was associated with relatively normal circulating numbers of OKM1+ lymphocytes, a population known to contain NK effectors. Spontaneous NK activity resistant to 3000 rad was increased in all patients, indicating the presence of activated natural killer cells in vivo. The concept of a chronically activated immune system in these patients was further supported by the presence of increased Ia positive T cells in all subjects tested, suggesting that radioresistant NK activity may be a useful parameter to measure when assessing in vivo immune activation. Our data, as well as that of others, supports the hypothesis that at least one population of NK cells is a distinct lineage arising at the differentiation level of myeloid and lymphoid stem cells in the bone marrow.

Antigens, Surface↗
PubMed1986

Increased creatine kinase MB in the absence of acute myocardial infarction.

Although measurement of CK-MB is a very sensitive, specific, and cost-effective test for use in diagnosis or exclusion of acute myocardial infarction, it should not be used as the sole diagnostic indicator, and all positive values must be critically analyzed to exclude other causes of increased values in serum. This is particularly important when the population being tested consists of patients with multiple medical problems, with low to medium probability of myocardial infarction, and without clinical or other biochemical (i.e., LDH 1) evidence of acute myocardial infarction. When the temporal pattern and absolute CK-MB values are considered together with the patient's clinical status, the diagnostic specificity is dramatically increased. In addition, one must be familiar with the limitations of individual assay systems in order to exclude method-related artifactual values.

Adult↗
PubMed1985

Effects of dextran on five biuret-based procedures for total protein in serum.

We evaluated the effect of dextran on values for total protein in serum as measured by the biuret method with five widely used automated instruments: the American Monitor Parallel; the Du Pont aca II; the Roche Cobas-Bio; the Kodak Ektachem 400; and the Beckman Astra 8. Dextran concentrations as great as 25 or 30 g/L had relatively little or no influence on total protein measurements by the latter three instruments. Dextran concentrations exceeding 6 g/L caused falsely low results with the aca, whereas the Parallel gave falsely high results when the dextran concentration exceeded 2 g/L. The aca total protein procedure could be protected from the interference by dextran concentrations up to 30 g/L by injecting 0.4-0.8 mL of ethylene glycol directly into the reagent pack before sampling. However, we could not eliminate the interference with the Parallel procedure by any simple means; we thus recommend that it not be used for measuring total protein in serum samples from patients who are being treated with dextran.

Adult↗
PubMed1983

Impaired culture generated cytotoxicity with preservation of spontaneous natural killer-cell activity in cartilage-hair hypoplasia.

Recent studies of cartilage-hair hypoplasia (CHH), a form of short-limbed dwarfism, have shown that all affected individuals have a cellular proliferation defect that results in a cellular immunodeficiency. However, only a minority of CHH individuals suffer from severe, life-threatening infections. For this reason, relevant immune defense mechanisms that may be responsible for maintaining intact host defenses in the majority of CHH individuals were studied. Spontaneous and allogeneic culture-induced (mixed lymphocyte response-MLR) specific and nonspecific (NK-like) cytotoxic mechanisms were analyzed and correlated with lymphocyte subpopulations present in CHH and normal individuals. Spontaneous natural-killer (NK) activity was present at or above normal levels, but culture-induced specific cytotoxicity and NK-like cytotoxicity as well as NK-like activity by T cell lines were significantly reduced in CHH individuals. The generation of radiation-resistant cytotoxicity, which normally occurs during allogeneic MLR, was markedly diminished in CHH, and was correlated with the decreased proliferation observed in CHH cultures. Preservation of spontaneous NK activity and loss of all forms of culture-induced cytotoxicity was associated with an increase in the proportion of lymphocytes bearing a thymic independent NK phenotype (OKM1+ OKT3- Fc gamma + low-affinity E+), and a significant decrease in thymic derived OKT3+ cytolytic T cell sub-populations in CHH individuals. Therefore, an intact cellular cytotoxic effector mechanism has been identified in CHH (i.e., NK activity). Natural cytotoxicity may be of importance in maintaining host resistance to viral infections despite diminished thymic-derived effector mechanisms in cartilage-hair hypoplasia.

Adolescent↗
PubMed1982

Lymphocyte dysfunction in cartilage-hair hypoplasia: evidence for an intrinsic defect in cellular proliferation.

Individuals with cartilage-hair hypoplasia (CHH), an autosomal recessive form of short-limbed dwarfism, have markedly reduced lymphocyte proliferative responses and cutaneous delayed hypersensitivity reactions, but normal humoral immunity. In the present study we investigated the cellular basis of the immunodeficiency in CHH. Defective lymphocyte proliferation could be due to a) an imbalance of immunoregulatory lymphocyte subpopulations, b) defective accessory cell function, or c) an intrinsic cellular defect in lymphocytes from CHH individuals. The absolute numbers of B cells and immunoregulatory (OKT4+, OKT8+) T cells were markedly diminished, but the proportions of these populations were the same as in the normal controls. OKM1+ lymphocytes were increased in proportion, and OKM1+ macrophages had normal adherence, helper, and phagocytic properties. Co-culture experiments failed to reveal any evidence of suppression by CHH mononuclear cells. CHH lymphocytes could not be stimulated to proliferate normally with B and T cell activators, mitogenic monoclonal antibody (OKT3), allogeneic cells, or chemical activators (Ca++ ionophore A23187 and phorbol myristate acetate). Fibroblasts from three CHH individuals also proliferated at a significantly decreased rate, compared to two normal lines. These results demonstrate a selective loss of B and T lymphocytes in CHH, as well as an intrinsic proliferative defect in CHH lymphocytes distal to the initial events in the lymphocyte activation sequence. These findings in CHH fibroblasts and lymphocytes may reflect a generalized defect present in multiple cell types in CHH.

Adult↗
PubMed1981

Immunologic studies of cartilage-hair hypoplasia in the Amish.

The immunologic status of 18 Old Order Amish persons with cartilage-hair hypoplasia and 9 unaffected sibs was studied. Although none of the subjects had a history suggestive of persistent immune dysfunction, the subjects with cartilage-hair hypoplasia had significantly lower lymphocyte mitogenic and allogeneic cell stimulation responses when compared to unaffected sibs and unrelated control subjects. The abnormalities of cellular immune function found in the 18 affected subjects were similar to those reported in Finnish subjects with cartilage-hair hypoplasia.

Adolescent↗