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Biomedical subjects

N Coleman

Publications and source records attributed to N Coleman.

At least 19 recordsLinked to original sources
PubMed1996

Altered muscle insulin sensitivity in the male offspring of protein-malnourished rats.

Insulin sensitivity of skeletal muscle was studied in male offspring of rat dams fed either a 20% (control) or 8% (low-protein) diet during pregnancy and lactation. Freshly isolated muscle strips took up more [3H]methylglucose from low-protein animals than from controls (19.2 +/- 2.5 and 4.26 +/- 0.45 nmol.min-1.mg muscle-1, respectively, P < 0.001). However, after a 60-min preincubation there was no significant difference in basal glucose transport (4.02 +/- 0.42 and 4.23 +/- 0.35 nmol.min-1.mg-1 for control and low-protein animals, respectively). Insulin (300 pM) had a significantly greater (P < 0.001) effect on stimulation of glucose transport into preincubated low-protein muscle strips than into controls (to 14.14 +/- 1.25 and 9.61 +/- 0.71 nmol.min-1.mg-1, respectively). There were no differences in total GLUT-4 protein content. However, subcellular fractionation revealed significantly (P < 0.001) more GLUT-4 in muscle plasma membranes of low-protein animals compared with controls. Insulin increased (P < 0.001) the GLUT-4 content of control plasma membranes but had no effect in low-protein animals. There were twofold more insulin receptors in low-protein muscle membranes compared with controls (2.35 +/- 0.17 x 10(11) and 1.28 +/- 0.10 x 10(11) and insulin receptors/mg muscle membrane protein, respectively, P < 0.01). These results suggest that programming of muscle insulin sensitivity can occur during fetal life.

Animals↗
PubMed1995

Somatic genetic changes in lung cancer and precancerous lesions.

BACKGROUND: Morphological abnormalities of the bronchial epithelium are associated with lung cancer development and are considered likely to represent the preneoplastic stage of the disease. The association of these lesions with different histological types of lung cancer was reviewed in a series of 97 samples. Lesions associated with squamous cell carcinomas provided the best samples for further study. The objective of this study was to describe the somatic genetic changes which occur in these preinvasive lesions. Among the various candidate somatic genetic changes, loss of heterozygosity on chromosome 3 and changes to the p53 gene were selected as being the most informative. It was demonstrated that these genetic changes, characteristic of fully invasive lung tumours, also occur at the premalignant stage of the disease. In an attempt to take a less directed approach to the comparison of invasive and preinvasive lesions, karyotype analysis was performed on short-term cultures of bronchial cells adjacent to the bronchial margin obtained from patients undergoing lung tumour resection. One such karyotype had a deletion to chromosome 3 (del 3p13-14) as the single abnormality. CONCLUSION: It was concluded that genetic damage to p53 and chromosome 3 is involved in the preinvasive stage of lung cancer, and that damage to chromosome 3 is a particularly early event.

Bronchi↗
PubMed1994

Characterization and functional analysis of the expression of vascular adhesion molecules in human papillomavirus-related disease of the cervix.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) is associated with changes in local immune cell populations, although the role of vascular adhesion molecules in mediating such changes by controlling the traffic of mononuclear cells to the cervix has not been investigated previously. METHODS: The authors used immunohistochemistry to examine the expression of three vascular adhesion molecules--ICAM-1, VCAM-1 and E-selectin--in the normal cervix and in biopsies of CIN Grade 1 (CIN-1) (low grade squamous intraepithelial lesions [LG-SIL]) and CIN-2/3 (high grade squamous intraepithelial lesions[HG-SIL]). In addition, the authors examined the functional role of these molecules by adapting the frozen section adhesion assay of Stamper and Woodruff to investigate in vitro the molecular basis of the interaction between cervical endothelial cells and activated T-lymphocytes. RESULTS: Whereas there was no difference in adhesion molecule expression between normal cervix and CIN-1 (LG-SIL), all three molecules investigated were significantly up-regulated in CIN-2/3 (HG-SIL), an observation that correlated with an enhanced ability of stromal endothelial cells in CIN-2/3 (HG-SIL) biopsies to bind activated peripheral blood lymphocytes in vitro. Monoclonal antibodies blocking ICAM-1 function were able to reduce such adhesion significantly in three of three experiments, and antibodies blocking VCAM-1 produced a significant reduction in one of three experiments. No inhibition was seen with antibodies against E-selectin. CONCLUSIONS: The enhanced expression of vascular adhesion molecules in CIN-2/3 (HG-SIL) appears to be functionally important in enabling the local recruitment of immunocompetent cells and supports the notion of a local antineoplastic immune response in high grade cervical intraepithelial lesions.

Carcinoma, Squamous Cell↗
PubMed1994

Analysis of HLA-DR expression on keratinocytes in cervical neoplasia.

We have investigated the expression in vivo and in vitro of HLA-DR in pre-invasive squamous-cell neoplasia of the uterine cervix. Immunohistochemistry of cervical biopsies demonstrated HLA-DR expression by cervical keratinocytes in 50% of cases of high-grade squamous intra-epithelial neoplasia, although the molecule was rarely expressed in low-grade squamous intra-epithelial neoplasia and was absent from normal ectocervical cells. HLA-DR-positive high-grade lesions were associated with significantly greater numbers of T lymphocytes in the immediately sub-epithelial stroma than were the HLA-DR-negative high-grade lesions. In vitro HLA-DR expression was absent from normal ectocervical epithelium, and from the HPV type 16 containing cell lines W12 (representing low-grade squamous intra-epithelial neoplasia) and CaSki and SiHa (each representing high-grade squamous intra-epithelial neoplasia), both in monolayer and in organotypic raft culture. HLA-DR expression was induced in all cell types following recombinant interferon gamma treatment. Our data suggest that the expression of HLA-DR by keratinocytes in some high-grade cervical lesions in vivo may be due to local induction of the molecule by pro-inflammatory cytokines released by immunocompetent cells. The functional significance of HLA-DR positivity in enabling an effective host immune response to neoplastic cervical keratinocytes remains unclear.

Carcinoma, Squamous Cell↗
PubMed1994

"Natural" presentation of human papillomavirus type-16 E7 protein to immunocompetent mice results in antigen-specific sensitization or sustained unresponsiveness.

We have used a mouse model that utilizes the exclusively epithelial nature of human papillomavirus (HPV) infections to investigate the in vivo immune response to the E7 protein of human papillomavirus type-16. A keratinocyte cell line expressing E7 protein has been established and grafted onto syngeneic mice using a transplantation technique that permits the reformation of a differentiated epithelium on a granulation tissue bed. In this way viral antigens may be presented to the immune system in a way comparable to natural infection. A delayed-type hypersensitivity (DTH) response was studied post grafting by intradermal challenge with recombinant E7 protein. A significant response to E7 has been demonstrated in this way; however, priming with a low amount of HPV-16 E7 antigen induces immunological unresponsiveness, as measured by a loss of DTH reactivity to the protein, and persistence of keratinocytes expressing E7. Lymphocytes from mice exhibiting DTH reactivity have been shown to proliferate when stimulated with purified recombinant E7 protein in vitro, while immunoperoxidase staining of tissue from the sites of immunologically-induced inflammation has defined the cell infiltrate to be phenotypically characteristic of DTH. The observations reported here have important implications for vaccine strategy.

Animals↗
PubMed1994

Expression of the myelomonocytic antigens CD36 and L1 by keratinocytes in squamous intraepithelial lesions of the cervix.

The keratinocytes in squamous intraepithelial lesions (SILs) of the cervix show altered expression of a number of molecules involved both in the control of growth and differentiation and in cell surface interactions, particularly with components of the immune system. We have used tissue biopsies and in vitro model systems to investigate the expression in SILs of the molecules CD36 and L1, which are predominantly expressed by myelomonocytic cells but which also have functional roles in keratinocyte biology. Whereas the L1 protein (defined by the monoclonal antibody Mac387) was expressed by suprabasal and superficial cells in 12 of 12 cases of normal cervix (NCx) and in 14 of 14 cases of low-grade SILs (LG-SILs), in two of 16 cases of high-grade SILs (HG-SILs) it was entirely absent and in the remainder it was restricted to the most superficial layers. When an arbitrary grading scale was applied, L1 expression in HG-SILs proved to be significantly lower than in LG-SILs (P < .01) or in cases of NCx (P < .01). CD36 was expressed by superficial cells in four of 12 cases of NCx, in six of 14 LG-SILs, and none of 16 cases of HG-SILs (when graded, LG-SILs v HG-SILs = P < .05). The mechanisms underlying the expression of both molecules were investigated by growth in organotypic tissue culture of normal ectocervical epithelium and the cervical keratinocyte cell lines W12 (a model for LG-SILs) and CaSki and SiHa (models for HG-SILs). L1 was diffusely expressed by NCx cells and the W12 cell line, although its expression in the CaSki and SiHa cell lines was much more irregular and restricted. CD36 was occasionally present on the surface of superficial NCx and W12 cells, but was absent from CaSki and SiHa cells. Neither molecule could be induced by treatment of the cells with interferon-gamma. These data suggest that the expression of CD36 and L1 by cervical keratinocytes is related to their differentiation status rather than representing an effect of exogenous factors, such as those released by the immune cell infiltrate associated with SILs. CD36 may function as an immunoregulatory molecule on cervical keratinocytes in SILs, while L1 is more likely to be involved in the intracellular regulation of cell proliferation and maturation.

Antigens, CD↗
PubMed1994

Immunological events in regressing genital warts.

Little is known of the in vivo role of the immune system in controlling human papillomavirus infection in the genital tract. The authors have studied 125 closely monitored patients with genital warts. Of these 125 patients, wart regression was seen in 28 patients. This study provides evidence that clearance of human papillomavirus from the genital tract is characterized by an active cell-mediated immune response. Regressing warts (n = 14) contained significantly more T lymphocytes (P < .05, Wilcoxon rank sum test) and macrophages (P < .01) than did nonregressing controls (n = 14). CD4-positive lymphocytes predominated in regression, both within the wart stroma and the surface epithelium, where there was a significant change in the ratio of CD4+ to CD8+ cells (P < .01). Lymphocytes in regression also showed greater expression of activation markers, and the majority were of the "antigen-experienced" phenotype. There was no difference in Langerhans cell numbers, although there was significant induction of the immune accessory molecules HLA-DR and ICAM1 (P < .05) on keratinocytes, and E-selectin and VCAM1 (P < .05) on endothelial cells in regressing warts. The changes in regression are consistent with a delayed-type hypersensitivity reaction to foreign antigen, and the ability to induce and mount such a response may be a critical determinant of effective natural immunity to the genital HPVs. Specific targeting of delayed-type hypersensitivity responsiveness may increase the efficacy of strategies for immuno-intervention against HPV infection in the genital tract.

Adult↗
PubMed1994

The role of swarm cell differentiation and multicellular migration in the uropathogenicity of Proteus mirabilis.

The uropathogenic bacterium Proteus mirabilis displays a form of multicellular behavior called swarming, in which typical vegetative rods differentiate into long hyperflagellate swarm cells that undergo rapid and coordinated population migration across surfaces. Such behavior might inherently assist ascending colonization of the urinary tract, and it has also been shown that swarming differentiation in vitro is central to the expression of conventional virulence factors. This study provides support for a role of swarming in vivo. Mortality rates of mice inoculated intravenously with 2.5 x 10(8) vegetative cells were lower than rates for those inoculated with wild type strains in the case of motile transposon mutants either completely unable to swarm (< 1%) or able to undergo only aberrant swarming migration (< 40%, P < .001). Histologic analysis of renal tissues from mice infected by wild type Proteus strains showed that long differentiated cells were the major cell type, whereas the extracellular inflammatory exudate contained primarily short vegetative cells. Following intravesical (bladder) inoculation with 2.0 x 10(7) vegetative cells, kidney infection was not established by any of the three motile swarm-defective mutants; indeed, the nonswarming mutant was not retained in the bladder. In contrast, the wild type strain and a normally swarming but nonhemolytic mutant achieved a high incidence of ascending infection to the kidney.

Animals↗
PubMed1994

Mid-dermal elastolysis.

We report a case of mid-dermal elastolysis in which dermal inflammation was a mild but definite feature. The aetiology of this condition remains unknown, although inflammatory destruction of elastic fibres appears to be the final result. In this study, areas of inflammation exhibited features of a specific immune response, with induction of a number of immune accessory molecules.

Cell Adhesion Molecules↗
PubMed1994

Prognostic value of c-erbB-2 and epidermal growth factor receptor in stage A1 (T1a) prostatic adenocarcinoma.

OBJECTIVE: To determine whether the presence or absence of the oncoproteins epidermal growth factor receptor (EGFR) and c-erbB-2 could predict tumour behaviour. PATIENTS AND METHODS: Tissue from 45 stage A1 (T1a) prostatic adenocarcinomas from patients with a mean age of 65 years were immunostained for EGFR (12E) and c-erbB-2 (NCL-CB11). Their expression in the tumour and surrounding benign hyperplastic epithelium was correlated with each other and with survival. RESULTS: Forty percent (18 of 45) and 36% (16 of 45) of patients respectively were EGFR and c-erbB-2 positive in the tumour. Expression of these tyrosine kinase oncogenes was not confined to the tumour and the surrounding hyperplastic prostate was also positive for EGFR in 76% (34/45) of patients and for c-erbB-2 in 16% (11 of 45). EGFR and c-erbB-2 expression was weakly associated in both benign and malignant epithelium. Statistical analysis of survival showed that tumour c-erbB-2 expression was associated with a significantly worse prognosis (exact two tailed P = 0.0316), whereas no significant association was observed between EGFR expression and survival (P = 0.737). CONCLUSION: As c-erbB-2 expression increases the rate of dying by 4.2 times, recording its expression by these tumours may be useful in selecting patients who would benefit from treatment in stage A1 (T1a) disease.

Adenocarcinoma↗
PubMed1994

The host response to lesions induced by human papillomavirus.

Human papillomaviruses (HPVs) are strictly intraepithelial pathogens: in the natural productive infection they induce benign epithelial proliferations of mucocutaneous surfaces, some of which may progress to malignancy. Benign HPV-induced lesions are chronic persistent growths; high levels of viral antigen are expressed in the apparent absence of a host immune response suggesting that these viruses have evolved efficient mechanisms of immune evasion. Cell-mediated responses are central in the pathogenesis of HPV and regression of both cutaneous and genital warts histologically resembles a delayed-type hypersensitivity response (DTH). The antigen(s) in the wart against which this response is initiated are not known but in an experimental murine model DTH responses to the E6 and E7 proteins of HPV-16 can be elicited when viral antigen is presented via the epithelial route. Priming with low levels of viral antigen in this model induces non-responsiveness and the loss of DTH. In HPV-associated cancers the E6/E7 genes are expressed and an antibody response to the proteins is found in at least 50% of cases indicating that these oncoproteins are potential targets for immunotherapy.

Animals↗
PubMed1993

Radiologically-guided cutting needle biopsy for suspected malignancy in childhood.

Twenty-seven cutting needle biopsies were performed on 25 children with suspected malignancy using computed tomographic (CT, 22) or ultrasound (US, 5) guidance. Anatomical sites were: retroperitoneum 6, liver 4, kidney 4, abdomen/pelvis 4, thorax 4, bowel 2, neck 1. Sixteen patients (64%) underwent subsequent open biopsy (5), marrow biopsy (2) or resection (9). There was complete concordance between the histological findings from the open or marrow biopsy and the previous needle biopsy in 12 of these 16 patients; in two patients the needle biopsy was misleading, causing inappropriate initial treatment in one. In two other patients needle biopsy was correct but lacked specific diagnostic features. Needle biopsies were performed under general, local or Ketamine anaesthesia. There were no apparent complications related to these procedures. We believe that radiologically-guided cutting needle biopsy should replace open biopsy in most children with solid malignant lesions. It can easily be performed during a single anaesthetic episode which allows radiological evaluation, biopsy, bone marrow and cerebrospinal fluid sampling. However, the potential for sampling error and histological variation within these tumours needs to be borne in mind.

Adolescent↗
PubMed1993

Neutropenic enterocolitis associated with Clostridium tertium.

A 15 year old boy being treated for relapsed acute lymphoblastic leukaemia developed severe diarrhoea and abdominal pain which worsened despite empirical antibiotic treatment. A right hemicolectomy was performed. The caecum and ascending colon showed changes typical of neutropenic enterocolitis. Clostridium tertium was isolated from faeces, blood cultures, and from the resected gut wall, with no evidence of other organisms capable of causing such a condition. As far as is known, this is the first reported case in which neutropenic enterocolitis has been associated with well documented C tertium infection, an organism previously described as a cause of bacteraemia in neutropenic patients.

Adolescent↗
PubMed1993

Characterization and functional analysis of the expression of intercellular adhesion molecule-1 in human papillomavirus-related disease of cervical keratinocytes.

We have investigated the expression of intercellular adhesion molecule-1 (ICAM-1) in squamous neoplasia of the cervix and have noted a significant induction of the molecule in high-grade intra-epithelial lesions. Using monolayer and organotypic in vitro tissue culture systems, we have shown that there is no constitutive ICAM-1 expression on cervical keratinocytes immortalized but not transformed by human papillomavirus type 16, whereas two human papillomaviruses type 16 containing and fully transformed cervical keratinocyte lines do constitutively express the molecule. All cell types, including human papillomavirus-negative normal cervical keratinocytes, can be induced to up-regulate their expression of ICAM-1 by pro-inflammatory cytokines such as interferon-gamma. In addition, we have used an in vitro adhesion assay to show that ICAM-1:lymphocyte function antigen-1 interaction is functionally important in lymphocyte binding to cervical keratinocytes, suggesting a role for ICAM-1 in retaining and enabling functional activity of lymphocytes in the cervix in intraepithelial neoplasia.

Carcinoma in Situ↗
PubMed1992

Epitope-mapped monoclonal antibodies against the HPV16E1--E4 protein.

The human papillomavirus (HPV) E1--E4 protein is the only nonstructural late protein encoded by the virus. We have isolated three hybridomas producing monoclonal antibodies to the E1--E4 protein of HPV16, which is the HPV type most frequently associated with cervical cancer. The three antibodies (TVG 401, 402, and 403) detect adjacent epitopes within the major seroreactive region of the molecule and show no reactivity against the E4 proteins of HPV1, HPV2, HPV4, or HPV6. The E1--E4 protein migrates as a 10K species on SDS-gel electrophoresis and forms cytoplasmic inclusion granules in infected cells in vitro similar in appearance to those produced by HPV1 in benign warts. In naturally occurring HPV16-induced tumors the E1--E4 protein was detected in the cytoplasm of cells in the upper layers of the lesion in areas in which HPV16 DNA replication was occurring, as determined by in situ hybridization. Although the epitopes recognized by these monoclonal antibodies survive brief fixation in 5% formaldehyde, reactivity was destroyed by prolonged fixation. These monoclonal antibodies represent the first against HPV16 E1--E4 and should complement those already available to E7 and L1 for the screening of frozen sections of clinical biopsies and will be of value in monitoring the progression of HPV infection from benign lesions to invasive cancer.

Amino Acid Sequence↗
PubMed1992

Ability of Proteus mirabilis to invade human urothelial cells is coupled to motility and swarming differentiation.

Proteus mirabilis causes serious kidney infections which can involve invasion of host urothelial cells. We present data showing that the ability to invade host urothelial cells is closely coupled to swarming, a form of cyclical multicellular behavior in which vegetative bacteria differentiate into hyperflagellated, filamentous swarm cells capable of coordinated and rapid population migration. Entry into the human urothelial cell line EJ/28 by P. mirabilis U6450 isolated at different stages throughout the swarming cycle was measured by the antibiotic protection assay method and confirmed by electron microscopy. Differentiated filaments entered urothelial cells within 30 min and were 15-fold more invasive (ca. 0.18% entry in 2 h) than an equivalent dry weight of vegetative cells isolated before differentiation, which attained only ca. 0.012% entry in the 2-h assay. The invasive ability of P. mirabilis was modulated in parallel with flagellin levels throughout two cycles of swarming. Septation and division of intracellular swarm cells produced between 50 and 300 vegetative bacteria per human cell, compared with 4 to 12 intracellular bacteria after incubation with vegetative cells. Transposon (Tn5) mutants of P. mirabilis with specific defects in motility and multicellular behavior were compared with the wild-type for the ability to invade. Mutants which lacked flagella (nonmotile nonswarming) were entirely noninvasive, and those which were motile but defective in swarm cell formation (motile nonswarming) were 25-fold less invasive than wild-type vegetative cells. Mutants with defects in the coordination of multicellular migration and the temporal control of consolidation (cyclical reversion of swarm cells to vegetative cells) were reduced ca. 3- to 12-fold in the ability to enter urothelial cells. In contrast, a nonhemolytic transposon mutant which swarmed normally retained over 80% of wild-type invasive ability. Swarm cells and early consolidation cells were at least 10-fold more cytolytic than vegetative cells as a result of their high-level production of hemolysin.

Animals↗
PubMed1992

Nuclear entry and nucleolar localization of the Newcastle disease virus (NDV) matrix protein occur early in infection and do not require other NDV proteins.

A large proportion of the Newcastle disease virus (NDV) matrix (M) protein is found in the nuclei of infected chicken embryo cells. Kinetic analysis indicated that much of the M protein enters the nucleus early in infection, concentrating in discrete regions of the nucleus and remaining there throughout infection. The M protein was found in localized regions of the nuclei of a variety of cell lines infected with NDV. Immunostaining for both M protein and nucleolar antigens indicated that most of these regions represent nucleoli. Moreover, this nucleolar localization of the M protein was observed in chicken embryo cells infected with 11 different strains of NDV. Only the M protein of strain HP displayed a modified pattern, concentrating in the nucleolus early in infection but in the cytoplasm late in infection. M protein transiently expressed in COS-1 cells also localized to the nucleus and nucleolus, indicating that the M protein does not require other NDV proteins for this localization.

Animals↗