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Biomedical subjects

D G Lowe

Publications and source records attributed to D G Lowe.

At least 91 records · Page 5Linked to original sources
PubMed1992

Comparative evaluation of fresh, fixed, and cryopreserved solid tumor cells for reliable flow cytometry of DNA and tumor associated antigen.

Five different protocols for the short-term preservation of cells used for multiparameter flow cytometric assay of tumour associated antigens (TAA) and DNA were assessed in cell suspensions prepared by mechanical disaggregation of 15 gynecological tumors. The protocols at 4 degrees C were 1) storage in buffer, 2) storage in 50% methanol, and 3) storage in buffer after formalin fixation. Tissues were also cryopreserved as cell suspensions and tissue blocks. When the TAA expression and DNA histograms of the preserved cells were compared with those in fresh cell suspensions, cryopreservation was found to be the best method: TAA expression was well preserved and there was a good correlation between TAA expression and the quality of the DNA histograms, respectively, in fresh and cryopreserved cells (RS: 0.82-0.91, P less than 0.001 for all TAAs). The cell suspensions preserved at 4 degrees C all showed a significant increase in background fluorescence (P less than 0.05) and a reduction in the TAA specific fluorescence (P less than 0.011). Methanol fixation was better than buffered formalin for the proteins studied, though both gave significantly worse results than cryopreservation. The quality of these cell suspensions and the correlation with TAA measurements in fresh cell suspensions deteriorated progressively with time, particularly if they were stored more than a week.

Antigens, Neoplasm↗
PubMed1992

Oat cell carcinoma of urinary bladder.

Oat cell carcinoma of the urinary bladder is extremely uncommon. There have been 52 reported cases in world literature to date. On light microscopic, histochemical, and ultrastructural grounds, these tumors are similar to oat cell carcinoma of the bronchus and other extrapulmonary oat cell carcinomas. Furthermore, they may be grouped together as a clinical entity characterized by an aggressive clinical course with early and extensive metastases, and partial remission with certain chemotherapeutic agents. We report a case of primary small cell carcinoma of the urinary bladder in a forty-two-year-old man and review previous reports with similar histology. The importance of establishing this diagnosis and the optimum forms of therapy are discussed.

Adult↗
PubMed1992

Carcinoma in episiotomy scars.

The finding of primary or metastatic carcinoma in an episiotomy scar is a rare event; we report three cases. The first patient presented with an abnormal cervical smear and was found to have a primary squamous cell carcinoma of the vulva in an old, healed episiotomy scar. A second patient, diagnosed as having cervical carcinoma 6 months postpartum, was found to have a metastatic deposit in the episiotomy scar during the staging of her disease. The third patient developed adenocarcinoma metastatic from an endocervical primary in an episiotomy scar that presented as a small nodule at the introitus. These cases exemplify the need for careful inspection and biopsy of any nodular lesions in episiotomy scars as part of the initial assessment and follow-up of patients with premalignant or malignant lesions of the lower genital tract.

Adult↗
PubMed1992

Molecular cloning of a retina-specific membrane guanylyl cyclase.

We have isolated and characterized cDNA clones encoding the human retinal guanylyl cyclase (retGC), a novel member of the membrane guanylyl cyclase gene family. Like other membrane guanylyl cyclases, the 1101 aa retGC is predicted to have a hydrophobic amino-terminal signal sequence followed by a large extracellular domain, a single membrane spanning domain, a kinase homology domain, and a guanylyl cyclase catalytic domain. In contrast to other membrane guanylyl cyclases, such as natriuretic peptide receptors, retGC has a relatively high basal level of activity when expressed in human 293 cells. cGMP production by retGC is unaffected by any of the known natriuretic peptides. In situ hybridization analysis of a variety of rhesus monkey tissues showed retGC transcripts to be localized exclusively along the retinal outer nuclear layer, corresponding to the nuclei of the rod and cone photoreceptor cells. Our results suggest that retGC may synthesize cGMP required for recovery of the dark state after phototransduction.

Amino Acid Sequence↗
PubMed1992

Prevalence of gastritis in patients with acromegaly: untreated and during treatment with octreotide.

OBJECTIVE: It has previously been suggested that acromegalic patients treated with the somatostatin analogue octreotide invariably have chronic gastritis. We have examined the prevalence of gastritis in a large group of acromegalic patients, untreated and during treatment with octreotide. DESIGN: We studied three groups of acromegalic patients: (A) untreated; (B) octreotide-treated; (C) a subgroup of these studied both before and during octreotide therapy. PATIENTS: Forty-eight patients, grouped as above, with active acromegaly were examined for the presence of gastritis. MEASUREMENTS: Gastroscopy and histological examination of gastric biopsies for the presence of gastritis and Helicobacter organisms were undertaken. The principal outcome was quantification of the prevalence of gastritis in the various study groups. RESULTS: Group A: 10 of the 33 patients (30%) had gastritis before any therapy with octreotide. Group B: 17 of 36 patients (47%) on octreotide treatment for 6-59 months (mean 20.5) had gastritis, and this was present in five out of the sub-group of eight patients (62%) treated for over 3 years. Group C: three of 21 patients (14%) developed gastritis during treatment with octreotide for between 6 and 23 months (mean 12.4). There was a highly significant association between the presence of gastritis and the presence of Helicobacter pylori organisms. CONCLUSIONS: Octreotide therapy of acromegaly may predispose to the development of gastritis, but this remains statistically unproven. Certainly, gastritis is not an invariable consequence of octreotide therapy, even after prolonged periods of treatment. The presence of gastritis is associated with H. pylori infection.

Acromegaly↗
PubMed1992

Immunochemical investigation of insulinomas for islet amyloid polypeptide and insulin: evidence for differential synthesis and storage.

An affinity purified antibody to fragment 14-29 of islet amyloid polypeptide (IAPP) has been prepared. This antibody, which does not cross-react with the related molecule calcitonin gene-related peptide, was used to investigate immunochemically the presence of IAPP in normal and neoplastic human pancreatic endocrine tissue. The pattern of IAPP staining in normal pancreas mirrors that of insulin, although slight differences were observed. In neoplastic tissue, IAPP was found in 16 out of 19 tumours that were positive for insulin, and was absent from one tumour negative for insulin. In some cases there were differences in the staining patterns of IAPP and insulin. These results suggest that the synthesis and secretion of IAPP and insulin are not inter-dependent and support the concept that IAPP has a discrete biological function. Islet amyloid polypeptide was found in six out of six insulinoma amyloid deposits, suggesting that the peptide is an invariable component of these deposits. Over-expression of IAPP, with aberrant processing and/or secretion, may be the causative factor for amyloid deposition in insulinomas and in the islets of type 2 (non-insulin dependent) diabetic patients. Investigation of patients with insulinomas and of insulin cells in culture and tissue sections may help to clarify the biological function of IAPP.

Adenoma, Islet Cell↗
PubMed1992

The role of partial colpectomy in the management of persistent vaginal neoplasia after primary treatment.

OBJECTIVE: To describe and assess the technique of partial colpectomy for the treatment of persistent vaginal neoplasia. SETTING: Gynaecological oncology unit of a London teaching hospital. SUBJECTS: 12 women with persistent vaginal intraepithelial neoplasia (VAIN) following hysterectomy for cervical intraepithelial neoplasia (CIN) or for benign disease. TECHNIQUE: Partial colpectomy using a vaginal approach assisted by a Schuhardt incision to improve access. RESULTS: Assessment of patients between 9 and 99 (mean 55) months after partial colpectomy for VAIN showed no recurrence of disease in ten patients (83%). CONCLUSION: This technique of partial colpectomy is an effective procedure, associated with minimal morbidity which should be considered as primary treatment for patients suffering from persistent vaginal disease after hysterectomy or other procedures.

Adult↗
PubMed1992

Conservation of the kinaselike regulatory domain is essential for activation of the natriuretic peptide receptor guanylyl cyclases.

The natriuretic peptide receptors, NPR-A and NPR-B, are two members of the newly described class of receptor guanylyl cyclases. The kinaselike domain of these proteins is an important regulator of the guanylyl cyclase activity. To begin to understand the molecular nature of this type of regulation, we made complete and partial deletions of the kinase domain in NPR-A and NPR-B. We also made chimeric proteins in which the kinase domains of NPR-A and NPR-B were exchanged or replaced with kinase domains from structurally similar proteins. Complete deletion of the kinase homology domain in NPR-A and NPR-B resulted in constitutive activation of the guanylyl cyclase. Various partial deletions of this region produced proteins that had no ability to activate the enzyme with or without hormone stimulation. The kinase homology domain can be exchanged between the two subtypes with no effect on regulation. However, structurally similar kinaselike domains, such as from the epidermal growth factor receptor or from the heat-stable enterotoxin receptor, another member of the receptor guanylyl cyclase family, were not able to regulate the guanylyl cyclase activity correctly. These findings suggest that the kinaselike domain of NPR-A and NPR-B requires strict sequence conservation to maintain proper regulation of their guanylyl cyclase activity.

Amino Acid Sequence↗
PubMed1992

Dyspepsia, Helicobacter pylori, and peptic ulcer in a randomly selected population in India.

There seems to be a worldwide geographic variation in the prevalence of peptic ulcer disease, although there are few reliable population based studies. This study aimed to determine the prevalence of peptic ulcer disease in a community in southern India and to evaluate the relationship between dyspeptic symptoms, Helicobacter pylori infection, gastritis, and peptic ulcer disease. A sample population was selected randomly from a rural monastic settlement in southern India. Subjects were interviewed using a standardised symptom and demography questionnaire then underwent upper endoscopy and antral biopsy for histology and CLO rapid urease test. Altogether 197 subjects from a population of 1499 (13.1%) were studied. All were male monks and ethnically Tibetan. The median age was 28 years (range: 21-81). None smoked or took NSAIDs. The six month period prevalence of dyspeptic symptoms was 68.5%. Current symptoms were present in 58.9% of subjects. Dyspepsia was more common in subjects aged 40 years or younger (p < 0.0001). H pylori was detected in 77.2% subjects. There was no association between dyspepsia and the presence of H pylori or histological gastritis, although there was a strong correlation between symptoms and ulcer (p < 0.003). The point prevalence of active peptic ulcer was 6.6% (13/197). All ulcers detected were either prepyloric or pyloroduodenal in location. A further 6.6% of subjects had definite evidence of scarring or deformity indicative of ulceration in the past. Subjects with past or present ulcers comprised 17.8% of dyspeptic subjects. H pylori was present in all subjects with active ulcers and in 12/13 of those with scarring. Dyspepsia, H pylori infection, gastritis, and peptic ulcer are all more common in this population than in those from developed countries. Ulcer disease, however, accounts for only a small proportion of subjects with symptoms and neither H pylori infection nor gastritis are significantly associated with the presence of dyspepsia.

Adult↗
PubMed1992

Flow cytometric measurement of cell components other than DNA: virtues, limitations, and applications in gynecologic oncology.

Flow cytometry is a high-precision technique for rapid analysis and sorting of cells and particles. In theory, it can be used to measure any cell constituent, provided that a fluorescent tracer is available that reacts specifically and stoichiometrically with that constituent. The technique provides statistical accuracy, reproducibility, and sensitivity and allows simultaneous measurement of several constituents on a cell-to-cell basis. The main drawback of flow cytometry is the lack of visual control and structural information in solid tissues. Careful sample preparation, quality control of all staining and instrumentation procedures, and the use of immunohistologic or cytologic controls are essential for high-quality flow cytometric analysis. The technique has been used successfully for simultaneous measurement of DNA and tumor-associated antigens, oncogene products, proliferation markers, and markers for multidrug resistance in cultured cell lines and in cell suspensions prepared from solid tumors and cervical smears. Flow cytometry has the potential to play an important role in the study of carcinogenesis. With an appropriate panel of monoclonal antibodies, the technique can be used for screening, "biochemical" diagnosis of neoplasia, and rapid drug, hormone, and radiotherapy sensitivity tests.

Biomarkers, Tumor↗
PubMed1991

Extracellular domain-IgG fusion proteins for three human natriuretic peptide receptors. Hormone pharmacology and application to solid phase screening of synthetic peptide antisera.

The natriuretic peptide receptors (NPRs) are a family of three cell surface glycoproteins, each with a single transmembrane domain. Two of these receptors, designated NPR-A and NPR-B, are membrane guanylyl cyclases that synthesize cGMP in response to hormone stimulation. The third receptor, NPR-C, has been reported to function in the metabolic clearance of ligand and in guanylyl cyclase-independent signal transduction. We engineered three chimeric proteins consisting of the natriuretic peptide receptor extracellular domains fused to the Fc portion of human IgG-gamma 1. These molecules provide material for detailed studies of the human receptor's extracellular domain structure and interaction with the three human natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and type-C natriuretic peptide (CNP). The homodimeric fusion proteins, designated A-IgG, B-IgG, and C-IgG, were secreted from Chinese hamster ovary cells and purified by protein-A affinity chromatography. We present here the primary characterization of these fusion proteins as represented by the intrinsic hormone affinities measured by saturation binding and competition assays. The dissociation constant of 125I-ANP for A-IgG was 1.6 pM and for C-IgG, 1.2 pM. The dissociation constant of 125I-Y0-CNP (CNP with addition of tyrosine at the amino terminus) for B-IgG was 23 pM. The rank order of potency in competitive binding for A-IgG was ANP greater than BNP much greater than CNP, whereas for B-IgG the ranking was CNP much greater than ANP greater than BNP. For C-IgG, we observed ANP greater than CNP greater than or equal to BNP. These data demonstrate that the receptor-IgG fusion proteins discriminate among the natriuretic peptides in the same manner as the native receptors and provide a basis for future structural studies with these molecules. The purified fusion proteins have a variety of potential applications, one of which we illustrate by a solid phase screening assay in which rabbit sera from a series of synthetic-peptide immunizations were titered for receptor reactivity and selectivity.

Amino Acid Sequence↗
PubMed1991

Alteration in bone marrow adherent layer growth factor expression: a novel mechanism of chronic myelogenous leukemia progression.

Philadelphia chromosome1 positive (Ph1) chronic myelogenous leukemia (CML) is characterized by metamorphosis of the chronic phase to blastic crisis. However, cellular events associated with this transition are poorly understood. To examine the possible participation of hematopoietic growth factors in this process, we studied growth factor expression in adherent layers of bone marrows derived from CML Ph1 patients in various stages of the disease. Interleukin-1 beta (IL-1 beta) and IL-6 mRNA were expressed in five of six patients, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in one of six patients with myeloid/undifferentiated blast crisis. In addition, leukemia inhibitory factor (LIF) expression was increased in four of six patients with myeloid/undifferentiated blast crisis phase of the disease. IL-1 beta was also detected in bone marrow adherent layer conditioned medium from two of these patients. These results were in sharp contrast to the lack of detectable levels of uninduced IL-1 beta, IL-6, and GM-CSF mRNA, in samples derived from 4 patients in lymphoid blastic crisis, 3 in accelerated, and 11 in chronic phases of the disease, or from normal controls. The possibility of a paracrine loop formation, whereby the adherent layers representing the bone marrow stroma are induced to express hematopoietic growth factors, was supported by our finding IL-1 beta mRNA expression in the leukemic blast cells in three of four studied patients in blast crisis and IL-1 beta protein production in seven of eight patients studied. Finally, coculturing CML blast crisis cells onto pre-established adherent layers induced the expression of both IL-1 beta and IL-6 genes. From this preliminary study, it appears that abnormal expression of growth factors is a common event with CML Ph1 progression. We hypothesize that IL-1 beta generated by the transformed malignant clone stimulates the marrow stroma to produce various growth factors, and that this process may play a role in disease progression.

Blast Crisis↗
PubMed1991

Multi-parameter flow cytometric quantitation of the expression of the tumor-associated antigen SM3 in normal and neoplastic ovarian tissues. A comparison with HMFG1 and HMFG2.

SM3 is a monoclonal antibody that reacts with a peptide epitope in the core protein of polymorphic epithelial mucin. Multi-parameter flow cytometry was used to characterize the expression of SM3 and compare it with two related tumor-associated antigens, HMFG1 and HMFG2, in cell suspensions of 44 malignant ovarian tumors, 15 benign ovarian tumors, and 16 normal ovaries. Tumor-associated antigen expression was significantly higher in malignant ovarian neoplasms than in benign neoplasms (P less than 0.001 for all three antigens). SM3 was expressed more specifically in malignant than benign tumors but had a lower affinity than HMFG1 and HMFG2. Multi-parameter flow cytometric evaluation of a panel of monoclonal antibodies can be used to help in choosing the best antibody for immunohistochemistry, imaging, and eventually treatment of ovarian tumors.

Antibodies, Monoclonal↗
PubMed1991

Sonographic depiction of postmenopausal endometrium with transabdominal and transvaginal scanning.

The thickness of the endometrium was measured in postmenopausal women by both the transvaginal and transabdominal ultrasound approaches in two separate groups of patients. The first group consisted of 90 women who received a transabdominal scan of the endometrium before dilatation and curettage or hysterectomy for either postmenopausal bleeding or uterine prolapse. The second group consisted of 111 women who underwent a transvaginal scan of the endometrium for similar postmenopausal conditions. Both methods suggested that an endometrial thickness of 5 mm may be used as a cut-off level in the conservative management of patients with postmenopausal bleeding or in a screening program for endometrial carcinoma. Patient acceptance and image quality were better in the group examined transvaginally. The proximity of the transvaginal probe to the endometrium, in the absence of a full bladder compressing the endometrium, revealed a unique group of patients with atrophic endometrium but thick endometrial cavity caused by intracavity fluid. In the presence of uterine fibroids distorting the uterine cavity, transvaginal scanning was better than transabdominal scanning for visualizing the endometrium. The transabdominal full-bladder technique can be of value in detecting asymptomatic bladder pathology.

Journal Article↗
PubMed1991

Selective activation of the B natriuretic peptide receptor by C-type natriuretic peptide (CNP).

The natriuretic peptides are hormones that can stimulate natriuretic, diuretic, and vasorelaxant activity in vivo, presumably through the activation of two known cell surface receptor guanylyl cyclases (ANPR-A and ANPR-B). Although atrial natriuretic peptide (ANP) and, to a lesser extent, brain natriuretic peptide (BNP) are efficient activators of the ANPR-A guanylyl cyclase, neither hormone can significantly stimulate ANPR-B. A member of this hormone family, C-type natriuretic peptide (CNP), potently and selectively activated the human ANPR-B guanylyl cyclase. CNP does not increase guanosine 3',5'-monophosphate accumulation in cells expressing human ANPR-A. The affinity of CNP for ANPR-B is 50- or 500-fold higher than ANP or BNP, respectively. This ligand-receptor pair may be involved in the regulation of fluid homeostasis by the central nervous system.

Animals↗
PubMed1991

Multiparameter flow-cytometric quantitation of epidermal growth factor receptor and c-erbB-2 oncoprotein in normal and neoplastic tissues of the female genital tract.

A novel multiparameter flow-cytometric method was used to quantify the expression of epidermal growth factor receptor (EGFR) and c-erbB-2 oncoprotein on 85 cryopreserved normal tissues (30 ovary, 29 endometrium, 16 cervix) and 67 carcinomas (31 ovarian, 18 cervical, 15 endometrial, 3 vulvar). Overexpression of the EGFR and c-erbB-2 oncoproteins was found in respectively 3/31 (9%) and 10/31 (32%) ovarian carcinomas, 13/18 (72%) and 7/18 (38%) cervical carcinomas, and 2/15 (13%) and 2/15 (13%) endometrial carcinomas. Oncoprotein expression was significantly higher in the malignant tumors (for all tumor sites) than in the corresponding normal tissues (P less than 0.034 for all combinations). Aneuploid tumors expressed levels of EGFR and c-erbB-2 oncoprotein significantly higher than those of DNA diploid tumors (P = 0.042 and P = 0.048, respectively). Oncoprotein could be detected in nearly all normal tissues: expression was higher in premenopausal than in postmenopausal patients (EGFR, P = 0.07; c-erbB-2, P less than 0.001). The present study supports the idea that EGFR and c-erbB-2 may play an important role in the autocrine, paracrine, and/or endocrine growth control and differentiation of normal tissues. Alteration in the expression of these oncoproteins is probably involved in malignant transformation and tumorigenesis.

Carcinoma↗
PubMed1991

Familial mastocytosis: a clinical, immunophenotypic, light and electron microscopic study.

A women and her daughter both developed diffuse cutaneous mastocytosis in early infancy. The immunophenotypes of the cutaneous mast cells in the two cases were shown to be identical: leucocyte common antigen (CD45) and macrophage/monocyte marker EBM11 were both strongly positive, HLA-DR was positive and CD25 was weakly positive. The peripheral lymphocytes of the patients were analysed by flow cytometry and this revealed that there was no increase in the activation markers HLA-DR and CD25, contrary to recent claims that lymphocytes have a contributory role in driving mast-cell proliferation. Mast-cell granules in both cases were found on electron microscopy to have an abnormal ultrastructure. The close similarity between the two cases at clinical, immunophenotypic and ultrastructural levels strongly suggests that genetic factors are important in the development of this type of mastocytosis.

Adult↗