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Biomedical subjects

S Cole

Publications and source records attributed to S Cole.

At least 19 recordsLinked to original sources
PubMed2001

A measurement of the cosmological mass density from clustering in the 2dF Galaxy Redshift Survey.

The large-scale structure in the distribution of galaxies is thought to arise from the gravitational instability of small fluctuations in the initial density field of the Universe. A key test of this hypothesis is that forming superclusters of galaxies should generate a systematic infall of other galaxies. This would be evident in the pattern of recessional velocities, causing an anisotropy in the inferred spatial clustering of galaxies. Here we report a precise measurement of this clustering, using the redshifts of more than 141,000 galaxies from the two-degree-field (2dF) galaxy redshift survey. We determine the parameter beta = Omega0.6/b = 0.43 +/- 0.07, where Omega is the total mass-density parameter of the Universe and b is a measure of the 'bias' of the luminous galaxies in the survey. (Bias is the difference between the clustering of visible galaxies and of the total mass, most of which is dark.) Combined with the anisotropy of the cosmic microwave background, our results favour a low-density Universe with Omega approximately 0.3.

Journal Article↗
PubMed2001

Hypersensitivity pneumonitis in a metal-working environment.

BACKGROUND: An outbreak of lung disease among workers in a metal-working plant included 16 biopsy-confirmed cases of hypersensitivity pneumonitis and additional patients with asthma, bronchiolitis and emphysema, usual interstitial pneumonitis, and sarcoidosis. Study design Clinical examination of patients; cross-sectional questionnaire survey of the outbreak plant and two control plant areas, one with and one without MWF exposures, in a separate facility; industrial hygiene survey with laboratory characterization of microbial flora; and immunological investigation. METHODS: Patients with suspected hypersensitivity pneumonitis underwent a clinical examination including detailed lung function, imaging, and tissue studies. A plant walk-through identified metal-working processes, microbial aerosols, and work practices. Microbial characteristics of the three microbial aerosol-producing processes were characterized. Antibodies to those agents were determined in patient sera. A questionnaire survey was conducted in the case plant and in two areas of a control plant, one with and one without metal-working fluids exposure. RESULTS: Thirty-nine (79.6%) patients described symptoms consistent with work-related lung disease, eight received other diagnoses, and two did not complete their examinations. Sixteen patients had hypersensitivity pneumonitis confirmed on biopsy. Mean decrements in lung forced expiratory volume in 1 s and force vital capacity from before to after work were similar in the 16 biopsy-confirmed cases of hypersensitivity pneumonitis ( - 6.3%; - 7.2%) and the 19 symptomatic patients without biopsies ( - 11.2%, - 10.1%). Symptoms were more common in the case plant than in a non-MWF control plant area. Three sources of water-based aerosols were identified that grew similar microbial flora. Although machining increased airborne bacterial levels, the increase was not related to the concentration of viable bacteria in the sumps. Antibody testing did not identify a specific single organisms. Endotoxin levels were similar in case and MWF control plant. CONCLUSIONS: Lung disease in environments with water-based aerosols may be more common than usually recognized. Patients with HP often present with only subtle abnormalities and may be missed if multiple clinical abnormalities are required to document disease.

Adult↗
PubMed2001

Intracellular P-gp contributes to functional drug efflux and resistance in acute myeloid leukaemia.

Drug compartmentalization as well as drug efflux can contribute to drug resistance. We demonstrate the presence of P-gp in intracellular vesicles in certain AML cell lines and show localization of DNR to a similar subcellular compartment(s) that can be altered in the presence of P-gp inhibitors. Analysis of leukaemic cell lines and 50 AML patient samples showed that the level of P-gp mRNA or total P-gp protein correlated better with drug efflux than surface P-gp protein, suggesting that intracellular P-gp may contribute to MDR in AML. Therefore, the level of total P-gp protein or mRNA may be a better indicator of MDR than surface P-gp protein. In addition, we provide evidence for a novel mechanism of drug sequestration in K562 myeloid leukaemic cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Ease of laryngeal passage during fibreoptic intubation: a comparison of three endotracheal tubes.

BACKGROUND: The use of a fibreoptic bronchoscope to facilitate endotracheal intubation is well established in modern anaesthetic practice. Difficulty may be encountered when inserting an endotracheal tube over the fibrescope as the bevelled tip can impinge on the vocal cords or epiglottis and impede advancement through the laryngeal inlet. Intavent have recently developed a tapered tip tube for use with their Intubating Laryngeal Mask Airway. A randomised, double-blind study was performed to compare the ease of railroading three different tubes over a fibrescope placed in the trachea. METHODS: We studied 54 patients presenting for elective dental surgery. General anaesthesia was induced with propofol 2-3 mg/kg, fentanyl 1-1.5 microg/kg, and atracurium 0.5 mg/kg and maintained with oxygen (5 l/min) and isoflurane 1-2%. Nasotracheal fibreoptic intubation was attempted in all patients. In each case the ease of tube advancement over the fibrescope and into the trachea was evaluated by the blinded observer, using the classification system (Grade 0-2) described by Jones et al. RESULTS/CONCLUSION: The Intavent tube was found to be superior for nasotracheal fibreoptic intubation to either the Mallinckrodt reinforced tube (P<0.034) or the Portex Blue Line tube (P<0.004).

Adolescent↗
PubMed2000

Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent.

AQ4 (1,4-Bis-[[2-(dimethylamino-N-oxide)ethyl]amino]5,8-dihydroxyanthrace ne-9, 10-dione) is a prodrug designed to be excluded from cell nuclei until bioreduced in hypoxic cells to AQ4, a DNA intercalator and topoisomerase II poison. Thus, AQ4N is a highly selective bioreductive drug that is activated in, and is preferentially toxic to, hypoxic cells in tumours. Five murine tumours (MAC16, MAC26, NT, SCCVII and RIF-1) have been used to investigate the anti-tumour effects of AQ4N. In only one tumour (MAC16) was AQ4N shown to be active as a single agent. However, when combined with methods to increase the hypoxic tumour fraction in RIF-1 (by physical clamping) and MAC26 tumours (using hydralazine) there was a substantial enhancement in anti-tumour effect. Notably, RIF-1 tumours treated with AQ4N (250 mg kg(-1)) followed 15 min later by physically occluding the blood supply to the tumour for 90 min, resulted in a 13-fold increase in growth delay. When combined with radiation or chemotherapy, AQ4N substantially increased the effectiveness of these modalities in a range of in vivo model systems. AQ4N potentiates the action of radiation in both a drug and radiation dose-dependent manner. Further the enhancement observed is schedule-independent with AQ4N giving similar effects when given at any time within 16 h before or after the radiation treatment. In combination with chemotherapy it is shown that AQ4N potentiates the activity of cyclophosphamide, cisplatin and thiotepa. Both the chemotherapeutic drugs and AQ4N are given at doses which individually are close to their estimated maximum tolerated dose (data not included) which provides indirect evidence that in the combination chemotherapy experiments there is some tumour selectivity in the enhanced action of the drugs.

Animals↗
PubMed1999

Retrovirus-mediated gene transfer of the human multidrug resistance-associated protein into hematopoietic cells protects mice from chemotherapy-induced leukopenia.

Utilization of chemotherapy for the treatment of tumors is mainly limited by its hematological toxicity. Because of the low-level expression of drug resistance genes, transduction of hematopoietic progenitors with multidrug resistance 1 (MDR1) or multidrug resistance-associated protein (MRP) genes should provide protection from chemotherapeutic agent toxicity. Successful transfer of drug resistance genes into hematopoietic cells may allow the administration of higher doses of chemotherapy and, thus, increase regression of chemosensitive tumors. The interest in the use of MRP as an alternative to MDR1 for bone marrow protection lies in its different modulation. This would allow, in the same patient, the use of MDR1 reversal agents to decrease MDR1 tumor resistance without reversing bone marrow (BM) protection of the MRP-transduced hematopoietic cells, since MRP expression is not reversed by these agents. We have constructed MRP-containing retroviral vectors using the phosphoglycerate kinase promoter and generated ecotropic producer cells. Lethally irradiated mice were engrafted with BM cells transduced by coculture with MRP producer cells. Evidence of long-term (9 months) gene transfer was provided by PCR of peripheral blood from MRP-transduced mice. Southern blot analysis confirmed the integrity of the provirus in the MRP-transduced mice. Long-term MRP expression (>5 months) was detected by RT-PCR and fluorescence-activated cell sorting of blood from living mice. High-level expression of MRP in murine hematopoietic cells reduces doxorubicin-induced leukopenia and mortality. Furthermore, we show in vivo selection of MRP-transduced cells following doxorubicin administration, with better and more significant chemoprotection after the second chemotherapy cycle. These data indicate that MRP retroviral gene transfer may be useful for chemoprotection and selection.

ATP-Binding Cassette Transporters↗
PubMed1999

Human pedigree-based quantitative-trait-locus mapping: localization of two genes influencing HDL-cholesterol metabolism.

Common disorders with genetic susceptibilities involve the action of multiple genes interacting with each other and with environmental factors, making it difficult to localize the specific genetic loci responsible. An important route to the disentangling of this complex inheritance is through the study of normal physiological variation in quantitative risk factors that may underlie liability to disease. We present an analysis of HDL-cholesterol (HDL-C), which is inversely correlated with risk of heart disease. A variety of HDL subphenotypes were analyzed, including HDL particle-size classes and the concentrations and proportions of esterified and unesterified HDL-C. Results of a complete genomic screen in large, randomly ascertained pedigrees implicated two loci, one on chromosome 8 and the other on chromosome 15, that influence a component of HDL-C-namely, unesterified HDL2a-C. Multivariate analyses of multiple HDL phenotypes and simultaneous multilocus analysis of the quantitative-trait loci identified permit further characterization of the genetic effects on HDL-C. These analyses suggest that the action of the chromosome 8 locus is specific to unesterified cholesterol levels, whereas the chromosome 15 locus appears to influence both HDL-C concentration and distribution of cholesterol among HDL particle sizes.

Adult↗
PubMed1999

Mutations affecting the ability of the Escherichia coli UmuD' protein to participate in SOS mutagenesis.

The products of the SOS-regulated umuDC operon are required for most UV and chemical mutagenesis in Escherichia coli, a process that results from a translesion synthesis mechanism. The UmuD protein is activated for its role in mutagenesis by a RecA-facilitated autodigestion that removes the N-terminal 24 amino acids. A previous genetic screen for nonmutable umuD mutants had resulted in the isolation of a set of missense mutants that produced UmuD proteins that were deficient in RecA-mediated cleavage (J. R. Battista, T. Ohta, T. Nohmi, W. Sun, and G. C. Walker, Proc. Natl. Acad. Sci. USA 87:7190-7194, 1990). To identify elements of the UmuD' protein necessary for its role in translesion synthesis, we began with umuD', a modified form of the umuD gene that directly encodes the UmuD' protein, and obtained missense umuD' mutants deficient in UV and methyl methanesulfonate mutagenesis. The D39G, L40R, and T51I mutations affect residues located at the UmuD'2 homodimer interface and interfere with homodimer formation in vivo. The D75A mutation affects a highly conserved residue located at one end of the central strand in a three-stranded beta-sheet and appears to interfere with UmuD'2 homodimer formation indirectly by affecting the structure of the UmuD' monomer. When expressed from a multicopy plasmid, the L40R umuD' mutant gene exhibited a dominant negative effect on a chromosomal umuD+ gene with respect to UV mutagenesis, suggesting that the mutation has an effect on UmuD' function that goes beyond its impairment of homodimer formation. The G129D mutation affects a highly conserved residue that lies at the end of the long C-terminal beta-strand and results in a mutant UmuD' protein that exhibits a strongly dominant negative effect on UV mutagenesis in a umuD+ strain. The A30V and E35K mutations alter residues in the N-terminal arms of the UmuD'2 homodimer, which are mobile in solution.

Bacterial Proteins↗
PubMed1999

Normal variation in leptin levels in associated with polymorphisms in the proopiomelanocortin gene, POMC.

We previously reported that our genome-scanning initiative had detected a highly significant linkage (log odds ratio = 4.95; P = 9 x 10(-7)) between a quantitative trait locus (QTL) on chromosome 2 and leptin levels in Mexican American families. We now have typed additional microsatellite markers in this region, increasing this log odds ratio score to 7.46 (P = 2 x 10(-9)). This region of chromosome 2 contains a strong positional candidate gene, POMC. The POMC gene codes for POMC, the prohormone from which alphaMSH, ACTH, and beta-endorphin are derived. Studies by others have shown that POMC-derived products are involved in the regulation of appetite and obesity. We have used polymorphisms in POMC to map its location within the 95% confidence interval of the peak for the linkage signal for the QTL. We also constructed POMC haplotypes using these polymorphisms and have found a significant association with normal variation in leptin levels (P = 0.001). We conclude that variation in POMC is associated with normal variation in serum leptin levels, providing further evidence that POMC may be the leptin QTL previously identified in Mexican American families.

Chromosome Mapping↗
PubMed1998

UDP-glucose deficiency causes hypersensitivity to the cytotoxic effect of Clostridium perfringens phospholipase C.

A Chinese hamster cell line with a mutation in the UDP-glucose pyrophosphorylase (UDPG:PP) gene leading to UDP-glucose deficiency as well as a revertant cell were previously isolated. We now show that the mutant cell is 10(5) times more sensitive to the cytotoxic effect of Clostridium perfringens phospholipase C (PLC) than the revertant cell. To clarify whether there is a connection between the UDP-glucose deficiency and the hypersensitivity to C. perfringens PLC, stable transfectant cells were prepared using a wild type UDPG:PP cDNA. Clones of the mutant transfected with a construct having the insert in the sense orientation had increased their UDP-glucose level, whereas those of the revertant transfected with a UDPG:PP antisense had reduced their level of UDP-glucose compared with control clones transfected with the vector. Exposure of these two types of transfectant clones to C. perfringens PLC demonstrated that a cellular UDP-glucose deficiency causes hypersensitivity to the cytotoxic effect of this phospholipase. Further experiments with genetically engineered C. perfringens PLC variants showed that the sphingomyelinase activity and the C-domain are required for its cytotoxic effect in UDP-glucose-deficient cells.

Animals↗
PubMed1998

Visual search for features and conjunctions in development.

Visual search performance was examined in three groups of children 7 to 12 years of age and in young adults. Colour and orientation feature searches and a conjunction search were conducted. Reaction time (RT) showed expected improvements in processing speed with age. Comparisons of RT's on target-present and target-absent trials were consistent with parallel search on the two feature conditions and with serial search in the conjunction condition. The RT results indicated searches for feature and conjunctions were treated similarly for children and adults. However, the youngest children missed more targets at the largest array sizes, most strikingly in conjunction search. Based on an analysis of speed/accuracy trade-offs, we suggest that low target-distractor discriminability leads to an undersampling of array elements, and is responsible for the high number of misses in the youngest children.

Adult↗
PubMed1998

Is a rising caesarean section rate inevitable?

OBJECTIVE: To determine the indications for singleton caesarean sections in Scotland in 1994. DESIGN: Prospective survey of singleton caesarean sections using information provided by clinicians entering data onto a computer in labour wards. SETTING: Twenty-three consultant-led obstetric units in Scotland. POPULATION: Women undergoing caesarean section in participating Scottish maternity units during 1994. RESULTS: Using routinely collected data it was found that the caesarean section rate varied by maternal age, parity, gestation, history of previous section and hospital of delivery, but there was no difference by area of deprivation. 87.4% (8369/9573) of Scottish caesarean sections were included in the survey of which 8098 were in women with singleton pregnancies. Most singleton caesarean sections were undertaken in primiparae (50.5%), 31.2% were in women with a history of previous section and 18.3% were in multiparous women who had not had a previous section; 38.9% of the operations were elective, 13.9% were emergencies before labour and 47.2% were emergencies during labour. Four main indications--elective section for breech presentation (10.7% of all sections); emergency caesarean section before labour because of fetal problems (2.8%); emergency caesarean section during labour for fetal distress and/or failure to progress (30.3%); repeat section for reasons other than above (16.2%) accounted for 60% of all caesarean sections in women with no other recorded complications. 7.7% of all singleton caesarean sections (19.8% of elective operations) were associated with maternal request for the operation. DISCUSSION: The survey has identified why caesarean sections are performed by Scottish obstetricians and highlighted some areas where there would be scope to increase the vaginal delivery rate. Before this can be attempted, agreement must be reached by clinicians about effective management of particular problems. Women also need to have ready access to evidenced-based information about caesarean section.

Algorithms↗
PubMed1998

The impact of molecular diagnosis on familial colorectal cancer.

We have shown the impact of molecular diagnostics related to mutation detection in an extensive family with a strong history of colorectal cancer. The nature and presentation of the cancers suggested that hereditary nonpolyposis colorectal cancer was the most likely cause. The strategies employed have enabled the detection and characterisation of the causative mutation in the proband and predictive testing in the remaining relatives where requested. Using the chemical cleavage of mismatches technique and direct sequencing, the MSH2 and MLH1 genes of the proband were investigated. A single base substitution, C-->T at nucleotide 350, codon 117, of the MLH1 gene was identified. Across the family pedigree at specific points, 22 other relatives have been tested for the mutation by direct DNA sequencing from genomic DNA. Of the total of 23 patients tested to date, 11 have the mutation. In conjunction with appropriate genetic counselling, this service has clarified the genetic status of many individuals within this family. Predictive information provided prior to the development of symptoms enables individuals to make informed choices regarding disease management and the future, removing the anxiety associated with the unknown.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Increasing consumer satisfaction. One social service and public health initiative shows how social marketing can increase consumer satisfaction.

The key to a successful social marketing approach to health care is continually listening to consumers' feedback and being willing to change the health product or service according to their needs and preferences. This approach can increase the likelihood of consumers being satisfied with, and continuing to utilize or provide the particular health service.

Consumer Behavior↗