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Biomedical subjects

D Dudley

Publications and source records attributed to D Dudley.

At least 19 recordsLinked to original sources
PubMed2001

N-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility.

The Wiskott-Aldrich syndrome protein (WASP) family of molecules integrates upstream signalling events with changes in the actin cytoskeleton. N-WASP has been implicated both in the formation of cell-surface projections (filopodia) required for cell movement and in the actin-based motility of intracellular pathogens. To examine N-WASP function we have used homologous recombination to inactivate the gene encoding murine N-WASP. Whereas N-WASP-deficient embryos survive beyond gastrulation and initiate organogenesis, they have marked developmental delay and die before embryonic day 12. N-WASP is not required for the actin-based movement of the intracellular pathogen Listeria but is absolutely required for the motility of Shigella and vaccinia virus. Despite these distinct defects in bacterial and viral motility, N-WASP-deficient fibroblasts spread by using lamellipodia and can protrude filopodia. These results imply a crucial and non-redundant role for N-WASP in murine embryogenesis and in the actin-based motility of certain pathogens but not in the general formation of actin-containing structures.

Actins↗
PubMed2000

Outcome of trabeculectomy with mitomycin-C in the iridocorneal endothelial syndrome.

PURPOSE: Eyes with iridocorneal endothelial (ICE) syndrome have a high risk of failure in glaucoma filtering surgery failing. We investigated the efficacy of trabeculectomy with intraoperative mitomycin-C application in these patients. DESIGN: Retrospective nonrandomized comparative trial with historical controls. PARTICIPANTS AND CONTROLS: Ten patients with unilateral iridocorneal endothelial (ICE) syndrome were reviewed. Their intraocular pressures could not be controlled medically. In five eyes, this was the primary surgery performed. Five of the patients had undergone prior intraocular pressure-(IOP) lowering surgery that had failed at the time enrolled. Results were compared with previously published case series of similar patients treated with trabeculectomy alone or trabeculectomy and subconjunctival 5-fluorouracil injections. INTERVENTION: Intervention consisted of trabeculectomy with a limbus-based conjunctival flap and mitomycin-C application. The dosage of mitomycin-C was 0.4 mg/ml for 1 to 4 minutes (mean, 1.9 min). MAIN OUTCOME MEASURES: Adequate control of IOP (without medication lower than 21 mm Hg). RESULTS: In eight eyes the IOP remained well controlled (mean IOP, 12.1 mm Hg) over the entire length of available of follow-up (mean, 14.9 months). Two eyes required implantation of an aqueous tube shunt at 4 and 11 months, respectively, after trabeculectomy with mitomycin-C. One eye experienced visual loss of 3 Snellen lines because of hypotony maculopathy. CONCLUSIONS: Trabeculectomy with mitomycin-C application offers a reasonable intermediate-term success rate in ICE patients, who are otherwise at high risk for failure of filtering surgery.

Adult↗
PubMed1997

Hepatitis C virus-specific cytolytic T lymphocyte and T helper cell responses in seronegative persons.

Hepatitis C virus (HCV) is a common infection worldwide, and in most persons, it leads to persistent viremia and liver damage. Efforts to identify the correlates of protective immunity are hampered by this high rate of persistent infection in both infected humans and the only animal model, the chimpanzee. Peripheral blood mononuclear cells from seronegative persons were stimulated with synthetic peptides that represent epitopes recognized by HCV-specific cytotoxic T lymphocytes (CTL) after natural infection. In addition, CD4+ proliferative responses to recombinant HCV proteins were examined in these same persons. CTL responses directed against a peptide epitope of HCV and proliferative responses in 2 HCV-seronegative persons with possible occupational exposure to HCV were found. These otherwise healthy persons were not viremic, suggesting that they may have recovered from acute HCV infection. Characterization of virus-specific immune responses in exposed but seronegative persons may provide important clues as to the nature of protective immunity in HCV.

Candida↗
PubMed1996

Value of fetal fibronectin as a predictor of preterm delivery for a low-risk population.

OBJECTIVE: We examined clinical value of cervical fetal fibronectin detection by a quantitative enzyme-linked immunosorbent assay as a predictor of preterm delivery in a population (n = 111) of middle-class pregnant women considered to be at low risk for preterm delivery. STUDY DESIGN: In this prospective study, fetal fibronectin samples from cervicovaginal secretions were obtained biweekly from 24 to 34 weeks' gestation. RESULTS: Twenty-two (20%) patients had at least one positive fetal fibronectin test result. Eleven women (10%) were delivered spontaneously at < 37 weeks; seven of these had at least one positive fetal fibronectin test result (positive predictive value = 31.8%, sensitivity = 63.6). An additional three women were delivered prematurely because of other obstetric indications, and all had negative fetal fibronectin test results. The remaining 15 patients with at least one positive fetal fibronectin test result were delivered at term (> or = 37 weeks). Of the seven women with positive fetal fibronectin results who were delivered prematurely, five were delivered within 2 weeks of obtaining a positive result. However, there were no obvious clinical discriminators between true-positive and false-positive fetal fibronectin results. Eighty-nine women tested negative, and 85 of these women were delivered at term (specificity = 82.0%). The negative predictive value of fetal fibronectin as a predictor of term delivery in this low-risk population is 96.6%, with odds ratio = 8.8 (95% confidence interval 1.9 to 40.3), relative risk = 6.9 (95% confidence interval 1.8 to 26.6), and Fisher Exact Test p = 0.007. CONCLUSIONS: Although negative biweekly fetal fibronectin determinations for prediction of preterm delivery in this low-risk obstetric population correlate well with the absence of preterm delivery, they are of limited clinical value for the prediction of preterm birth.

Adult↗
PubMed1995

HLA class I-restricted cytotoxic T lymphocytes specific for hepatitis C virus. Identification of multiple epitopes and characterization of patterns of cytokine release.

Cytotoxic T lymphocytes (CTL) are important to the control of viral replication and their presence may be important to disease outcome. An understanding of the spectrum of proteins recognized by hepatitis C virus (HCV)-specific CTL and the functional properties of these cells is an important step in understanding the disease process and the mechanisms of persistent infection, which occurs in the majority of HCV-infected individuals. In this report we identify HCV-specific CTL responses restricted by the HLA class I molecules A2, A3, A11, A23, B7, B8, and B53. The epitopes recognized by these intrahepatic CTL conform to published motifs for binding to HLA class I molecules, although in some cases we have identified CTL epitopes for which no published motif exists. The use of vectors expressing two different strains of HCV, HCV-1 and HCV-H, revealed both strain-specific and cross-reactive CTL. These HCV-specific CTL were shown to produce cytokines including IFN-gamma, TNF-alpha, GM-CSF, IL-8, and IL-10 in an antigen- and HLA class I-specific manner. These studies indicate that the CTL response to HCV is broadly directed and that as many as five different epitopes may be targeted in a single individual. The identification of minimal epitopes may facilitate peptide-specific immunization strategies. In addition, the release of proinflammatory cytokines by these cells may contribute to the pathogenesis of HCV-induced liver damage.

Amino Acid Sequence↗
PubMed1993

Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes recognize epitopes in the core and envelope proteins of HCV.

Hepatitis C virus (HCV) is a major cause of posttransfusion and community-acquired hepatitis, and a majority of individuals infected with this virus will subsequently develop chronic hepatitis. Characterization of the host immune response to this infection is an important first step that should facilitate the development of immunomodulatory agents and vaccines. Cellular immune responses, especially those mediated by cytotoxic T lymphocytes (CTL), are important in the control of many viral diseases. In this study, liver-infiltrating lymphocytes from persons with chronic HCV hepatitis were examined for evidence of HCV-specific CTL by using target cells infected with recombinant vaccinia viruses expressing the HCV core, E1, E2, and part of the NS2 proteins. Bulk expansion of liver-derived CD8+ lymphocytes resulted in the detection of HCV-specific CTL activity, whereas activity could not be found in CD8+ lymphocytes expanded from peripheral blood. Epitopes recognized by these CTL were defined by using CTL clones obtained by limiting dilution and target cells sensitized with synthetic HCV peptides. Four distinct HLA class I-restricted epitopes were identified, including two epitopes in the amino-terminal portion of the core protein. These studies provide evidence that the highly conserved core protein is a target for HCV-specific CTL and identify CTL epitopes within the more highly variable E2 envelope protein. Our studies also suggest that HCV-specific CTL are localized at the site of tissue injury in infected persons with chronic hepatitis. Identification of the epitopes recognized by HCV-specific CTL will facilitate exploration of their role in disease pathogenesis and may provide information useful in development of therapeutic interventions or vaccines.

Amino Acid Sequence↗
PubMed1992

Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis.

Hepatitis C virus (HCV) is a major cause of post-transfusion and sporadic hepatitis worldwide, leading to chronic liver disease in at least 50% of infected individuals. The pathogenic mechanisms that result in chronic hepatitis are unknown. Lymphocytes are typically observed within the hepatic parenchyma, but the functional characteristics of these cells have not been defined. In this study, liver-infiltrating lymphocytes from two subjects with chronic HCV hepatitis were cloned at limiting dilution and tested for HCV-specific cytolytic activity using autologous target cells infected with vaccinia viruses expressing recombinant HCV Ag or sensitized with synthetic HCV peptides. In both subjects, HCV-specific, HLA class I-restricted CTL were identified that recognized epitopes in variable regions of either the envelope or nonstructural proteins. These results demonstrate the presence of HCV-specific CTL at the site of tissue damage in persons with chronic HCV hepatitis, and provide a means to evaluate the possible pathogenic role of these cells in HCV infection.

Amino Acid Sequence↗
PubMed1992

Serial thoracic versus abdominal circumference ratios for the prediction of pulmonary hypoplasia in premature rupture of the membranes remote from term.

OBJECTIVES: The purpose of this study was to evaluate the fetal thoracic versus abdominal circumference ratio in the prediction of pulmonary hypoplasia after preterm premature rupture of the membranes. STUDY DESIGN: A standard curve of thoracic versus abdominal circumference ratio versus gestational age was derived from 120 uncomplicated pregnancies. Thoracic versus abdominal circumference ratio and amniotic fluid estimations were obtained serially in 16 women with premature rupture of the membranes at less than 26 weeks' gestation. RESULTS: An abnormal thoracic versus abdominal circumference ratio predicted lethal pulmonary hypoplasia in six infants. A progressive decline in thoracic versus abdominal circumference ratio was identified in all of these patients. Six of eight women with persistent oligohydramnios had abnormal thoracic versus abdominal circumference ratios and lethal pulmonary hypoplasia. Two surviving infants had restriction deformities and pulmonary complications. CONCLUSIONS: In the setting of premature rupture of the fetal membranes at less than 26 weeks, serial thoracic versus abdominal circumference ratio measurement is a reliable predictor of pulmonary hypoplasia. Persistent oligohydramnios is ominous because of the risk of restriction deformities and pulmonary complications in the survivors.

Abdomen↗
PubMed1990

Regulation of murine lymphokine production in vivo. III. The lymphoid tissue microenvironment exerts regulatory influences over T helper cell function.

We investigated the capacity of murine T lymphocytes, isolated from various lymphoid organs of normal or antigen-primed donors, to produce IL-2 or IL-4 after activation with anti-CD3 or specific antigen. Our results established that T cells resident within lymphoid organs being drained by nonmucosal tissue sites (e.g., axillary, inguinal, brachial lymph nodes, or spleen) produced IL-2 as the predominant T cell growth factor (TCGF) after activation. Conversely, activated T cells from lymphoid organs being drained by mucosal tissues (Peyer's patches, and cervical, periaortic, and parathymic lymph nodes) produced IL-4 as the major species of TCGF. Analysis of the lymphoid tissues obtained from adoptive recipients of antigen-primed lymphocytes provided by syngeneic donors provided evidence that direct influences were being exerted on T cells during their residence within defined lymphoid compartments. These lymphoid tissue influences appeared to be responsible for altering the potential of resident T cells to produce distinct species of TCGF. Steroid hormones, known transcriptional enhancers and repressors of specific cellular genes, were implicated in the controlling mechanisms over TCGF production. Glucocorticoids (GCs) were found to exert a systemic effect on all recirculating T cells, evidenced by a marked dominance in IL-4 production by T cells obtained from all lymphoid organs of GC-treated mice, or after a direct exposure of normal lymphoid cells to GCs in vitro before cellular activation with T cell mitogens. Further, the androgen steroid DHEA appeared to be responsible for providing an epigenetic influence to T cells trafficking through peripheral lymphoid organs. This steroid influence resulted in an enhanced potential for IL-2 secretion after activation. Anatomic compartmentalization of the DHEA-facilitated influence appears to be mediated by differential levels of DHEA-sulfatase in lymphoid tissues. DHEA-sulfatase is an enzyme capable of converting DHEA-sulfate (inactive) to the active hormone DHEA. We find very high activities of this enzyme isolated in murine macrophages. The implications of our findings to immunobiology are very great, and indicate that T cells, while clonally restricted for antigen peptide recognition, also appear to exhibit an extreme flexibility with regards to the species of lymphokines they produce after activation. Regulation of this highly conservative mechanism appears to be partially, if not exclusively, controlled by cellular influences being exerted by distinct species of steroid hormones, supplied in an endocrine or a paracrine manner where they mediate either systemic or tissue-localized influences, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Expression of surface antigen and mRNA for the CD11c (alpha X, p150) subunit of the human leukocyte adherence receptor family in hematopoietic cells.

We characterized the surface antigen and mRNA expression for the CD11c (alpha X, p150) subunit of the human leukocyte adherence receptor family during hematopoietic cell differentiation. The CD11c subunit antigen and mRNA are constitutively expressed in undifferentiated HL-60 promyelocytic leukemia cells, and levels increase markedly with differentiation along the monocyte/macrophage pathway using phorbol myristate acetate. Human monocyte-derived macrophages and human alveolar macrophages express elevated levels of the CD11c subunit antigen and mRNA, indicating that the changes observed in vitro are present in vivo. Dot blot analysis of immature and mature lymphoid and myeloid cells and cell lines demonstrate equivalent levels of CD11c mRNA expression. We conclude that CD11c gene expression is selectively increased during hematopoietic cell differentiation along the monocyte/macrophage pathway.

Antigens, Differentiation↗
PubMed1989

Long-term tocolysis with intravenous magnesium sulfate.

Although the tocolytic effect of magnesium sulfate is well known, it has generally been used for this purpose for only brief periods. In this study, we administered intravenous magnesium sulfate tocolysis, either alone or in combination with other tocolytics, to 111 women as follows: 1) 60 (54%) received the drug for 3 or fewer days (short-term group); 2) 29 (26%) received the drug for 3-10 days (intermediate group); and 3) 22 (20%) received the drug for 10 days or longer (long-term group). Side effects (ileus and/or constipation, visual blurring, headache) were more common in the intermediate and long-term groups, but no life-threatening complications were seen. The drug was discontinued because of side effects in 7% of the patients in each group. We believe our data indicate that there need be no time limit and that magnesium sulfate tocolysis may be continued as clinically indicated.

Delivery, Obstetric↗
PubMed1982

Laboratory evaluation and assistance efforts: mailed, on-site and blind proficiency testing surveys conducted by the Centers for Disease Control.

During the last three years, the Centers for Disease Control (CDC) has conducted: 1) on-site surveys in which trained personnel visited laboratories that had experienced performance problems in the quarterly mailed proficiency testing (PT) program, reviewing the laboratories' analytical procedures by using carefully referenced samples to determine sources of errors and providing assistance in correcting them; 2) special assistance surveys in which carefully referenced samples were mailed to laboratories that had performed unsatisfactorily in routine mailed PT surveys and then telephone consultations were conducted to correct the problems; and 3) blind surveys in which carefully referenced samples were sent through normal patient sample acquisition routes to assess the actual day-to-day performance capability of the laboratories. Results suggest that on-site surveys by trained laboratory surveyors and special mailed assistance surveys can be very effective in identifying the source of analytical errors in laboratories previously found, through mailed PT surveys, to have performance problems. Blind-survey results indicate that good performance in mailed PT does not necessarily imply good laboratory performance with routine patient specimens. Although difficult to conduct, blind surveys should be conducted whenever the logistics can be worked out by contractors for laboratory services, clinicians using laboratory services, and the laboratories themselves to assure the continuation of quality service.

Blood Chemical Analysis↗
PubMed1966

The blue arcs of the retina.

Around a dim light viewed in a dark room can be seen faint blue-gray arcs which occupy that part of the visual field corresponding to the retina where the arcuate nerve fiber bundle passes from macular ganglion cell bodies to the optic nerve. These blue arcs of the retina are an entoptic phenomenon in which action potentials of the arcuate nerve fiber bundle presumably excite adjacent neurons. The experiments here described show that the light stimulus initially evoking the blue arcs excites cones and not rods as has been generally believed until now. Another commonly held idea is that the blue arcs are produced by bioluminescence or fluorescence associated with the action potentials in the arcuate nerve fiber bundle. The experiments described here disprove this hypothesis.

Adaptation, Ocular↗