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Biomedical subjects

J W Dobbie

Publications and source records attributed to J W Dobbie.

At least 19 recordsLinked to original sources
PubMed1998

Phenotypic mapping of human mesothelial cells.

In recent years it has become clear that the mesothelium plays a prominent homeostatic role in the peritoneum, and can be profoundly altered in disease and during peritoneal dialysis. The cell-surface phenotype of the mesothelial cell has not been thoroughly investigated. This study begins to identify cell surface molecules which may be important in mesothelial functions such as adhesion and interaction with cells of the immune system. The expression of adhesion structures on mesothelial cells such as CD44, the beta integrin chain CD29, the beta 3 integrin chain CD61 and alpha chains CD49 alpha (alpha 1), CD49b (alpha 2), CD49c (alpha 3), CD49e (alpha 5), and CD51 (alpha v) is described. In addition, a wide range of novel molecules including CD90, CD105, CD140b, CD142, CD147, CD151, CD157, CD165, and CD166 are identified. The role and function of such molecules in mesothelial biology and their significance for peritoneal dialysis is discussed.

Antigens, CD↗
PubMed1997

New principles, better practices, and clearer perceptions in intraperitoneal chemotherapy: clinical experience using icodextrin 20 as a carrier solution.

The rationale for using intraperitoneal chemotherapy is based on three phenomena: certain types of tumor are confined to the abdominal cavity for many years; the ability to deliver the drug directly to the surface of tumor deposits; the pharmacological advantage of attaining high local concentrations of the drug within the cavity. Current techniques of intraperitoneal chemotherapy do not use a specially designed carrier solution, which greatly restricts flexibility and does not permit continuous ambulatory intraperitoneal chemotherapy necessary for optimal use of cell cycle-specific antitumor agents. Using icodextrin 20 as a carrier solution containing 50% of the dose of 5-fluorouracil in a 24-hour dwell, simultaneously with a 24-hour elastomeric infusor device containing 50% of the dose, we have succeeded in carrying out continuous ambulatory intraperitoneal chemotherapy, 5 days out of 7 for up to 12 weeks, exposing the peritoneal contents to drug concentrations a thousand-fold greater than attained in the serum in a Phase I clinical trial. These studies have for the first time demonstrated that it is possible to expose continuously for long periods intraperitoneal tumor deposits to sustained high levels of cell cycle-specific cytotoxic agents.

Antineoplastic Agents↗
PubMed1996

Prolonged intraperitoneal infusion of 5-fluorouracil using a novel carrier solution.

A novel peritoneal carrier solution, Icodextrin 20 (7.5%), has allowed exploration of prolonged, intraperitoneal (i.p.) infusion of the cytotoxic drug 5-fluorouracil (5-FU). A phase I and pharmacokinetic study was performed to determine the toxicities and maximum tolerated dose of prolonged and continuous intraperitoneal 5-FU in patients with peritoneal carcinomatosis. Seventeen patients were entered into this study. Each patient had a Tenckhoff catheter placed into the peritoneal cavity under general anaesthetic. After initial flushing and gradual increase in exchange volumes with Icodextrin 20, 5-FU was administered daily from Monday to Friday, 50% as a bolus in the exchange bag and 50% in an elastomeric infusor device delivering continuous 5-FU to the peritoneal cavity at 2 ml h-1. Treatment was continued for 12 weeks or until intolerable toxicity developed. Abdominal pain and infective peritonitis proved to be the main dose-limiting toxicities. Initial problems with infective peritonitis were overcome by redesign of the delivery system, and it proved possible to deliver 300 mg m-2 5-FU daily (5 days per week) for 12 weeks. Pharmacokinetic studies showed i.p. steady-state 5-FU concentrations (mean 47 500 ng ml-1) that were > 1000-fold higher than systemic venous levels (mean 30 ng ml-1).

Adult↗
PubMed1995

Lamellar body secretion: ultrastructural analysis of an unexplored function of synoviocytes.

The intra- and extracellular distribution and relative density of lamellar bodies (LBs) were determined by electron microscopy in synovial biopsies from 20 non-rheumatoid arthritis (RA) patients. LBs were found on the synovial surface, in intimal cells, throughout intimal matrix, in blood vessel walls, in endothelial cytoplasm and within vascular lumena. Lamellar profiles were observed in type B synoviocytes within rough endoplasmic reticulum (RER), in association with the Golgi apparatus, and embedded in electron dense matrix (projection cores) in multivesicular bodies. Exocytotic release of mature LBs into intimal matrix was observed. In type A synoviocytes the outer lamellae of LBs were frequently found in contiguity with the limiting membrane of lysosomes. An in vitro investigation of the ultrastructural features of LB formation in cultured type B synoviocytes (from 3 non-RA patients) gave results similar to those obtained in biopsies. These studies provide ultrastructural evidence of synoviocyte activity in secreting and degrading phospholipid lubricant in a sophisticated system whose function and pathological derangements are largely unknown.

Humans↗
PubMed1995

Multiple drug classes and hyperosmolarity alter binding of muscarinic drugs to mesothelial cells in vitro.

Mesothelial cells in vitro exhibited binding sites for L-quinuclidinyl[phenyl-4-3H]-benzilate ([3H]-QNB), but not [3H]-N-methylscopolamine (NMS), a cell-impermeable ligand. [3H]-QNB binding demonstrated a biphasic pattern of binding in living cells: a maximum after 15 min at 37 degrees C was followed by a decrease out to 90 min. [3H]-QNB binding was blocked by increasing concentrations of atropine; WIN35428 and GBR12909, dopamine transport inhibitors also decreased binding. Pretreatment of cells for 18 hours with atropine, QNB, or WIN35428 resulted in enhanced [3H]-QNB binding, but coexposure to cycloheximide blocked this increase. Hyperosmolarity caused by NaCl or mannitol decreased binding of [3H]-QNB to living cells. Thus rabbit peritoneal mesothelial cells possess binding sites for [3H]-QNB that are influenced by other drugs and osmolarity.

Animals↗
PubMed1995

The biology of the mesothelium during peritoneal dialysis.

Substantial derangements of mesothelial biology are observed during experimental simulations of dialysis conditions, inferred from the content of human dialysis effluent and visualized by microscopy of human mesothelial biopsies. Can osmotically active solutions be made biocompatible with the osmoregulatory system of the mesothelium? Can the contributions of the mesothelium to host defenses against inflammation and/or infection be supported during CAPD? Do underlying metabolic derangements present in various kidney diseases and end-stage renal disease, regardless of cause, require customized CAPD protocols and solutions? Use of dialysis solutions less directly toxic to the mesothelium is a necessary step toward some day manipulating peritoneal biology by pharmacological and therapeutic modalities.

Cytotoxins↗
PubMed1994

Pharmacokinetic study of 5-fluorouracil in a novel dialysate solution: a long-term intraperitoneal treatment approach for advanced colorectal carcinoma.

Five patients with advanced colorectal and gastric carcinoma with peritoneal deposits were treated by continuous weekdays intraperitoneal (i.p.) instillation of 5-fluorouracil (5-FU) 200 mg m-2 day-1 in a novel dialysate solution that ensures maximal exposure of peritoneal areas liable to bear tumours for 24 h. A solution of icodextrin, a glucose polymer, in a 21 twin-bag delivery system allowed a single daily exchange and demonstrated the feasibility of long-term continuous ambulatory treatment with up to 17.4 g of 5-FU, delivered intraperitoneally, in this initial study. During the entire study, there were 235 fluid exchanges or 470 connections and disconnections and no bacterial peritonitis or exit site infection were observed. There was no treatment-associated toxicity worse than WHO grade 2. Drug concentrations in both peritoneal and plasma compartments followed a first-order model with similar half-life value of 1.3 h. 5-FU pharmacokinetic parameters (half-life values, total body clearance, peritoneal clearance and pharmacological advantage of the i.p. route) with this novel icodextrin carrier solution were similar to those obtained in other referenced pharmacokinetic studies with other carrier solutions (dextrose dialysate and lactated Ringer's solutions). This confirms that icodextrin solution is physiologically neutral, drug compatible and allows adequate dwell times with constant fluid balance for long-term continuous intraperitoneal chemotherapy. The pharmacokinetic parameters from this study will be used to design a loading dose infusion schedule in an attempt to maintain steady-state i.p. 5-FU levels in a new multicentre phase I trial.

Colorectal Neoplasms↗
PubMed1994

Lamellar bodies in synoviocytes, mesothelium and specific epithelia as possible site of auto-antigen in rheumatoid disease.

Intracytoplasmic lamellar organelles identical in ultrastructure to surfactant-containing lamellar bodies found in type II pneumocytes, have been demonstrated in other tissues, in synoviocytes and mesothelial cells, in a distribution pattern which reflects the systemic expression of rheumatoid disease. Antibodies raised against surfactant protein A (SP-A), exhibit a ranking of tissue reactivity in area, intensity and density of cells which also parallels the frequency and degree of pathological involvement characteristic of rheumatoid disease, showing in ascending order of immunopositivity, lacrymal and salivary epithelia, pulmonary parenchyma, mesothelium and synoviocytes. Maximal tissue reactivity to anti-SP-A antibodies was found in the synovium of 55 rheumatoid patients exhibiting classical histopathological appearances of RA, in a pattern of immunostaining identical to that obtained with ML30, an antibody to mycobacterial heat shock protein 65kDa which, in turn, cross-reacted with SP-A in dot blot testing.

Arthritis, Rheumatoid↗
PubMed1993

Evidence of muscarinic acetylcholine receptors and GTP-binding proteins in peritoneal mesothelial cells in vitro.

Preliminary evidence of muscarinic acetylcholine receptors (AchRs) in rabbit and human peritoneal mesothelial cells grown in tissue culture is reported. Atropine displaceable binding of L-quinuclidinyl[phenyl-4-3H]-benzilate (QNB), an antagonist that binds to all AchR subtypes, and [N-methyl-3H]-4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), an antagonist specific for AchR subtypes 1 and 3, to homogenates of mesothelial cells was approximately 400 and 120 fmol ligand bound/milligram cell protein, respectively. A similar value for specific [3H]-QNB binding was observed in living cells exposed to ligand and atropine for 1 hour at 37C. Guanosine 5'-triphosphate (GTP)-binding proteins measured as beta,gamma-imido[8-3H] guanosine 5'-triphosphate binding to mesothelial cell membranes was approximately 9 pmol/mg cell protein. Our finding of both muscarinic receptors and GTP-binding proteins in mesothelial cells suggests first, the presence of a functional muscarinic receptor system(s) in peritoneal mesothelial cells, and second, the potential susceptibility of these cells to direct pharmacological manipulation by muscarinic drugs.

Animals↗
PubMed1993

Serositis: comparative analysis of histological findings and pathogenetic mechanisms in nonbacterial serosal inflammation.

Peritonitis is the established term for infective inflammation of the peritoneum, while serositis generally refers to nonorganismal inflammation in any serous cavity, including the peritoneum. In continuous ambulatory peritoneal dialysis (CAPD) literature, however, culture-negative peritoneal inflammation is referred to as "sterile" or "chemical" peritonitis. These terms not only imply unwarranted etiologic assumptions, but may also deflect attention from the existence of medical conditions to which the peritoneum is subject. This is evident in CAPD literature where there is little recognition that the peritoneum, as a member of the serosa and a secretor of lamellar bodies, is prey to a wide range of disorders. Thus before, during, and after CAPD, the membrane is liable to fall victim to disease states unconnected with the process of dialysis. Significant peritoneal pathology occurs as part of a pan-serositis, which may be metabolic (uremia, cholesterolosis), autoimmune (systemic lupus erythematosus, rheumatoid disease, acute rheumatism, endocrinopathies), genetic (recurrent hereditary polyserositis), allergic (eosinophilic serositis), and granulomatous in nature. This paper presents a comparative analysis of histopathological presentation and pathogenetic mechanisms involved in all forms of peritoneal serositis. It incorporates recent advances in molecular biology of the membrane into a holistic reappraisal of peritoneal pathology, revealing hitherto unrecognized homologies in peritoneal reaction to diverse disorders.

Animals↗
PubMed1993

Choline incorporation into phospholipids in mesothelial cells in vitro.

OBJECTIVE: To determine the effect of extracellular choline concentration on phospholipid production and handling by peritoneal mesothelial cells in vitro. DESIGN AND MEASUREMENTS: Radiolabeled choline was used to monitor the formation of phosphatidylcholine (PC), sphingomyelin (SPH), and lysophosphatidylcholine (LPC) by rat and rabbit mesothelial cells as a function of concentration and time of exposure to choline. The subcellular location of the newly formed phospholipids was examined by ultracentrifugation in Percoll-sucrose gradients using analytical cell fractionation techniques. The fatty acid composition of the PC formed was determined by thin-layer chromatography (TLC) and gas chromatography. RESULTS: Choline incorporation into PC, SPH, and LPC increased with extracellular choline levels up to 640 mumol/L, which is 100 times greater than physiological levels of choline in plasma and 20 times higher than choline levels measured in peritoneal dialysis effluent. The newly formed, radiolabeled phospholipids were primarily found in a single subcellular compartment that exhibited a buoyant density of 1.05 g/mL in Percoll-sucrose gradients. Analysis of the fatty acyl groups of PC obtained from the mesothelial cells showed enrichment in palmitic [16:0], oleic [18:1], and linoleic [18:2] acids. CONCLUSION: The rate of phospholipid formation by mesothelial cells in vitro can be manipulated, in part, by choline concentration.

Animals↗