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Biomedical subjects

I Drummond

Publications and source records attributed to I Drummond.

At least 19 recordsLinked to original sources
PubMed2003

Randomized clinical trial comparing consultant-led or open access investigation for large bowel symptoms.

BACKGROUND: Referral of patients with large bowel symptoms is common and increasing. Currently most of these referrals are assessed at an outpatient clinic to determine the need and priority for investigation. METHODS: Over 21 months, 1131 patients referred by the general practitioner with large bowel symptoms were randomized. Patients in the consultant-led group were assessed by surgeons with a colorectal interest while those in the open access group underwent colonoscopy if they were 55 years or older and flexible sigmoidoscopy if younger. RESULTS: The most common symptom among referred patients was rectal bleeding (69.1 per cent) followed by change in bowel habit (48.8 per cent) and abdominal pain (32.3 per cent). There was a significant trend (P < 0.001) for patients in the consultant-led to have more investigations, and more patients in this group had no investigations (P < 0.001). Despite this, the percentage of patients with colonic or other pathology diagnosed was the same in both groups, 63.6 per cent in the consultant-led group compared with 61.8 per cent in the open access group (P = 0.558). Likewise the percentage of patients with cancer or other significant pathology was similar in both groups (13.9 versus 15.4 per cent; P = 0.532). The mean(s.d.) time to diagnose cancer or other significant pathology was 55.1(39.2) days in the consultant-led group compared with 57.4(33.6) days in the open access group (P = 0.514). The cost per patient was almost pound 105 more for patients in the consultant-led group. CONCLUSION: Patients referred by the general practitioner with large bowel symptoms should go directly to a properly managed and staffed open access large bowel investigation unit. This would enable most patients to have their investigations completed at one hospital attendance.

Ambulatory Care↗
PubMed2003

Mortality and cancer morbidity in a cohort of Canadian petroleum workers.

AIMS: To assess mortality and cancer morbidity in Canadian petroleum workers and explore exposure-response relations for specific petroleum agents. METHODS: A total of 25 292 employees hired between 1964 and 1994 were linked to the Canadian tumour registry and national mortality database. Exposure-response trends were assessed for hydrocarbon solvents/fuels, hydrocarbon lubricants, petroleum coke/spent catalyst, and hydrogen sulphide (H2S). RESULTS: External comparison analyses (mortality and incidence) showed deficits for all causes and all malignant neoplasms combined and were consistent with expectation for most malignant and non-malignant sites analysed. Gall bladder cancer mortality was increased among males based on four deaths, but cases had no common job assignments and the increase was focused in workers employed <10 years. Mesothelioma incidence was increased. Most exposure-specific analyses were compromised by small numbers. Statistically significant increases were observed for H2S exposure and a subgroup of accidental deaths as well as for petroleum coke/spent catalyst exposure and lung cancer. While both findings have a degree of biologic plausibility, the H2S association, which exhibited a clearer exposure-response pattern, could be subject to unmeasured confounders. Additionally, interpretation was complicated by the high correlation between hydrocarbon and H2S exposures. With regard to lung cancer, the analysis could not adequately control for smoking, was based on small numbers, and exhibited a tenuous exposure-response pattern. CONCLUSION: The findings for mesothelioma suggest the need for continued attention to asbestos in the petroleum industry. The relation between accidental deaths and H2S exposure deserves closer scrutiny in similarly exposed populations. Further analyses of lung cancer are underway and will be reported separately.

Adult↗
PubMed2001

Polycystin-1 interacts with intermediate filaments.

Polycystin-1, the protein defective in a majority of patients with autosomal dominant polycystic kidney disease, is a ubiquitously expressed multi-span transmembrane protein of unknown function. Subcellular localization studies found this protein to be a component of various cell junctional complexes and to be associated with the cytoskeleton, but the specificity and nature of such associations are not known. To identify proteins that interact with the polycystin-1 C-tail (P1CT), this segment was used as bait in a yeast two-hybrid screening of a kidney epithelial cell library. The intermediate filament (IF) protein vimentin was identified as a strong polycystin-1-interacting partner. Cytokeratins K8 and K18 and desmin were also found to interact with P1CT. These interactions were mediated by coiled-coil motifs in polycystin-1 and IF proteins. Vimentin, cytokeratins K8 and K18, and desmin also bound directly to P1CT in GST pull-down and in in vitro filament assembly assays. Two observations confirmed these interactions in vivo: (i) a cell membrane-anchored form of recombinant P1CT decorated the IF network and was found to associate with the cytoskeleton in detergent-solubilized cells and (ii) endogenous polycystin-1 distributed with IF at desmosomal junctions. Polycystin-1 may utilize this association for structural, storage, or signaling functions.

Amino Acid Sequence↗
PubMed2001

Induction of ureter branching as a response to Wnt-2b signaling during early kidney organogenesis.

Epithelial-mesenchymal tissue interactions play a central role in vertebrate organogenesis, but the molecular mediators and mechanisms of these morphogenetic interactions are still not well characterized. We report here on the expression pattern of Wnt-2b during mouse organogenesis and on tests of its function in epithelial- mesenchymal interactions during kidney development. Wnt-2b is expressed in numerous developing organs in the mouse embryo, including the kidney, lung, salivary gland, gut, pancreas, adrenal gland, and genital tubercle. Additional sites of expression include the branchial arches and craniofacial placodes such as the eye and ear. The data suggest that the expression of Wnt-2b is associated with organs regulated by epithelial-mesenchymal interactions. It is typically localized in the capsular epithelium or peripheral mesenchymal cells of organ rudiments, e.g., the perinephric mesenchymal cells in the region of the presumptive renal stroma in the developing kidney at E11.5. Functional studies of the kidney demonstrate that cells expressing Wnt-2b are not capable of inducing tubule formation but instead stimulate ureter development. Incubation of isolated ureteric buds on such cells supports bud growth and branching. In addition, recombination of Wnt-2b-pretreated ureteric bud tissue with isolated nephrogenic mesenchyme results in a recovery of organogenesis and the expression of epithelial genes within the reconstituted organ explant. Lithium, a known activator of Wnt signaling (Hedgepeth et al. [1997] Dev Biol 185:82-91), is also sufficient to promote ureter branching in the reconstituted kidney in a comparable manner to Wnt-2b signaling, whereas Wnt-4, which induces tubules, neither supports the growth of a ureteric bud nor leads to reconstitution of the ureteric bud with the kidney mesenchyme. We conclude that Wnt-2b may act in the mouse kidney as an early mesenchymal signal controlling morphogenesis of epithelial tissue, and that the Wnt pathway may regulate ureter branching directly. In addition, Wnt signals in the kidney differ qualitatively and are specific to either the epithelial ureteric bud or the kidney mesenchyme.

3T3 Cells↗
PubMed2000

Polycystin 1 is required for the structural integrity of blood vessels.

Autosomal dominant polycystic kidney disease (ADPKD), often caused by mutations in the PKD1 gene, is associated with life-threatening vascular abnormalities that are commonly attributed to the frequent occurrence of hypertension. A previously reported targeted mutation of the mouse homologue of PKD1 was not associated with vascular fragility, leading to the suggestion that the vascular lesion may be of a secondary nature. Here we demonstrate a primary role of PKD1 mutations in vascular fragility. Mouse embryos homozygous for the mutant allele (Pkd1(L)) exhibit s.c. edema, vascular leaks, and rupture of blood vessels, culminating in embryonic lethality at embryonic day 15.5. Kidney and pancreatic ductal cysts are present. The Pkd1-encoded protein, mouse polycystin 1, was detected in normal endothelium and the surrounding vascular smooth muscle cells. These data reveal a requisite role for polycystin 1 in maintaining the structural integrity of the vasculature as well as epithelium and suggest that the nature of the PKD1 mutation contributes to the phenotypic variance in ADPKD.

Animals↗
PubMed1999

The polycystic kidney disease 1 gene product modulates Wnt signaling.

Two distinct signaling pathways, involving Wnt signaling and polycystin, have been found to be critical for normal kidney development. Renal tubulogenesis requires the presence of certain Wnt proteins, whereas mutations in polycystin impede the terminal differentiation of renal tubular epithelial cells, causing the development of large cystic kidneys that characterize autosomal dominant polycystic kidney disease. Polycystin is an integral membrane protein, consisting of several extracellular motifs indicative of cell-cell and cell-matrix interactions, coupled through multiple transmembrane domains to a functionally active cytoplasmic domain. We report here that expression of the C-terminal cytoplasmic domain of polycystin stabilizes soluble endogenous beta-catenin and stimulates TCF-dependent gene transcription in human embryonic kidney cells. Microinjection of the polycystin C-terminal cytoplasmic domain induces dorsalization in zebrafish. Our findings suggest that polycystin has the capacity to modulate Wnt signaling during renal development.

Animals↗
PubMed1997

Met -/- kidneys express epithelial cells that chemotax and form tubules in response to EGF receptor ligands.

The growth factor/receptor combination of hepatocyte growth factor (HGF)/c-met has been postulated to be critical for mesenchymal-to-epithelial conversion and tubule formation in the developing kidney. We therefore isolated and immortalized cells from embryonic kidneys of met -/- transgenic mice to determine whether these cells were epithelial and able to chemotax and form tubules in vitro. The cells were immortalized with retrovirus expressing human papillomavirus 16 (HPV 16) E6/E7 genes. Two rapidly dividing clones were isolated and found to express the epithelial cell markers cytokeratin, zonula occludens-1, and E-cadherin but not to express the fibroblast marker vimentin. The met -/- cells were able to chemotax in response to epidermal growth factor and transforming growth factor-alpha (TGF-alpha) and form tubules in vitro in response to TGF-alpha but not HGF. These experiments suggest that the HGF/c-met axis is not essential for epithelial cell development in the embryonic kidney and demonstrate that other growth factors are capable of supporting early tubulogenesis.

Animals↗
PubMed1990

Occurrence of 222Rn and progeny in natural gas processing plants in western Canada.

In Western Canada, there are many plants that process natural gas to remove impurities (CO2, H2S, H2O) and recover natural gas liquids (propane, butane, etc.). Trace quantities of 222Rn present in the inlet stream are concentrated in streams rich with propane. Potential hazards to plant operators include direct inhalation of 222Rn and progeny; exposure to gamma radiation from short-lived progeny deposited inside equipment; or inhalation of 210Pb when contaminated equipment is opened for repair. Twenty-four plants operated by seven companies cooperated to assess these potential hazards. The findings indicate a substantial flux of 222Rn and progeny passing through the plants, but little accumulation of radionuclides. In no case was there evidence of significant exposure of plant operators or maintenance personnel to ionizing radiation. Further investigation of pipeline operations, and chemical operations using natural gas liquids as feed stock, is recommended.

Bismuth↗
PubMed1989

Expression and organization of BP74, a cyclic AMP-regulated gene expressed during Dictyostelium discoideum development.

We have characterized a cDNA and the corresponding gene for a cyclic AMP-inducible gene expressed during Dictyostelium development. This gene, BP74, was found to be first expressed about the time of aggregate formation, approximately 6 h after starvation. Accumulation of BP74 mRNA did not occur in Dictyostelium cells that had been starved in fast-shaken suspension cultures but was induced in similar cultures to which cyclic AMP pulses had been added. The BP74 cDNA and gene were characterized by DNA sequence analysis and transcriptional mapping. When the BP74 promoter region was fused with a chloramphenicol acetyltransferase reporter gene and reintroduced into Dictyostelium cells, the transfected chloramphenicol acetyltransferase gene displayed the same developmentally regulated pattern of expression as did the endogenous BP74 gene, suggesting that all of the cis-acting elements required for regulated expression were carried by a 2-kilobase cloned genomic fragment. On the basis of sequence analysis, the gene appeared to encode a protein containing a 20-residue hydrophobic sequence at the amino-terminal end and 26 copies of a 20-amino-acid repeat.

Amino Acid Sequence↗
PubMed1982

The cellular uptake of horseradish peroxidase and its poly(lysine) conjugate by cultured fibroblasts is qualitatively similar despite a 900-fold difference in rate.

When horseradish peroxidase (HRP) is conjugated to poly(L-lysine) of molecular weight (MW) 13,000, its transport into cultured L929 fibroblasts in 1 hour at 37 degrees C is increased 918-fold. The kinetics of uptake are linear with time and concentration, reflecting a process of nonreceptor-mediated adsorptive endocytosis. Neither HRP-poly(Lys) conjugate nor free poly(Lys) of any size cause any increase in fluid phase endocytosis. All evidence indicates that the covalently bound poly(Lys) increases the binding of HRP to the cell surface and that this adequately accounts for an increased internalization occurring at a steady rate. In the absence of Ca++, both surface binding and uptake of the conjugate, but not of free HRP, are decreased. Cytochalasin B does not significantly inhibit the transport of either form of HRP. The half-lives of HRP and HRP-poly(Lys) are 7.6 and 5.6 hours, respectively, when measured over a period of 12 hours. Electron microscopic analysis of cells that have ingested comparable amounts of HRP shows that the intracellular localization of free and conjugated HRP are comparable and that both are found inside the same array of structures. Thus HRP, which binds very poorly to the cell surface and is considered a fluid-phase marker for the "contents" of pinocytotic vesicles, and HRP-poly(Lys), which binds very strongly to the cell surface and is considered a membrane marker for adsorptive endocytosis, are taken up along the same endocytotic pathway. Moreover, despite the fact that neither markers are transported by receptor-mediated endocytosis, both are seen in structures that were described as receptosomes. It appears, therefore, that the pathways utilized in receptor-mediated transport are available to all other forms of pinocytosis.

Animals↗
PubMed1982

Determination of total pentachlorophenol in the urine of workers. A method incorporating hydrolysis, an internal standard and measurement by liquid chromatography.

Free pentachlorophenol (PCP) represents a small and variable fraction of total PCP excreted in the urine of exposed workers. A method incorporating hydrolysis is essential to be able to relate PCP excretion to absorbed dose. 3,5-Dichloro-2,4,6-tribromophenol (DTP) is added as an internal standard to a urine sample which is then acidified and steam-distilled. The distillate is made alkaline and extracted with methylene chloride to remove interferences. The distillate is then acidified and the phenols extracted into methylene chloride. The extract is evaporated, redissolved in acetonitrile and the PCP is measured using high pressure liquid chromatography (HPLC) using a 15 X 0.46 cm Spherisob-ODS 5 microns column with isocratic elution (H2O:CH3CN:CH3CO2H, 45:55:0.3 v/v). Detection is by fixed wavelength detector at 313 nm and calculation by the method of internal standardization. The biological threshold value used to trigger action to reduce exposure is 7 mg/l (corrected to a specific gravity of 1.024).

Chlorophenols↗