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Biomedical subjects

A D Scott

Publications and source records attributed to A D Scott.

At least 19 recordsLinked to original sources
PubMed2006

Determination of genetic toxicity and potential carcinogenicity in vitro--challenges post the Seventh Amendment to the European Cosmetics Directive.

Genetic toxicology and its role in the detection of carcinogens is currently undergoing a period of reappraisal. There is an increasing interest in developing alternatives to animal testing and the three R's of reduction, refinement and replacement are the basis for EU and national animal protection laws the Seventh Amendment to the EU Cosmetics Directive will ban the marketing of cosmetic/personal care products that contain ingredients that have been tested in animal models. Thus in vivo tests such as the bone marrow micronucleus test, which has a key role in current testing strategies for genotoxicity, will not be available for this class of products. The attrition rate for new, valuable and safe chemicals tested in an in vitro-only testing battery, using the in vitro tests currently established for genotoxicity screening, will greatly increase once this legislation is in place. In addition there has been an explosion of knowledge concerning the cellular and molecular events leading to carcinogenesis. This knowledge has not yet been fully factored into screening chemicals for properties that are not directly linked to mutation induction. Thus there is a pressing need for new, more accurate approaches to determine genotoxicity and carcinogenicity. However, a considerable challenge is presented for these new approaches to be universally accepted and new tests sufficiently validated by March 2009 when the animal testing and marketing bans associated with the Seventh Amendment are due to come into force. This commentary brings together ideas and approaches from several international workshops and meetings to consider these issues.

Animal Experimentation↗
PubMed2001

The Medicago Genome Initiative: a model legume database.

The Medicago Genome Initiative (MGI) is a database of EST sequences of the model legume MEDICAGO: truncatula. The database is available to the public and has resulted from a collaborative research effort between the Samuel Roberts Noble Foundation and the National Center for Genome Resources to investigate the genome of M.truncatula. MGI is part of the greater integrated MEDICAGO: functional genomics program at the Noble Foundation (http://www.noble.org ), which is taking a global approach in studying the genetic and biochemical events associated with the growth, development and environmental interactions of this model legume. Our approach will include: large-scale EST sequencing, gene expression profiling, the generation of M.truncatula activation-tagged and promoter trap insertion mutants, high-throughput metabolic profiling, and proteome studies. These multidisciplinary information pools will be interfaced with one another to provide scientists with an integrated, holistic set of tools to address fundamental questions pertaining to legume biology. The public interface to the MGI database can be accessed at http://www.ncgr.org/research/mgi.

Computational Biology↗
PubMed2001

How to build a cardiac surgery program.

Follow one hospital's experience in opening a new heart center, including its philosophy, triaging of issues, and staff preparation to achieve successful patient outcomes.

Cardiology Service, Hospital↗
PubMed1999

Spontaneous mutation, oxidative DNA damage, and the roles of base and nucleotide excision repair in the yeast Saccharomyces cerevisiae.

The OGG1 gene of Saccharomyces cerevisiae encodes a DNA glycosylase that excises 7,8-dihydro-8-oxoguanine (8-OxoG). When compared to wild-type, ogg1 mutants show an increase in the frequency of GC to TA transversions, indicating a role for Ogg1 in the repair of 8-OxoG. Here we report an increased frequency of forward mutation to canavanine resistance in mutants defective in the nucleotide excision repair (NER) gene RAD14. This was not increased further in strains additionally defective in OGG1. However, when compared to strains solely defective in OGG1, ogg1radl4 mutants displayed an increase in spontaneous GC to TA transversions. Intriguingly, reversion of the lys1-1 ochre allele was not increased in rad14 mutants, suggesting that oxidative base damage may only represent a substrate for NER in certain regions of the genome. We also examined repair of oxidative DNA damage by transforming mutant strains with plasmid DNA treated with methylene blue plus visible light. Mutants defective in OGG1 showed no significant reduction in transformation efficiency compared with wild-type strains. In contrast, disruption of RAD14 reduced the efficiency of transformation, yet there was no further decrease in an ogg1rad14 mutant. This strongly supports a role for NER in the repair of oxidative base damage in yeast, and differs from similar experiments carried out in E. coli, where transformation efficiency is only reduced in mutants defective in both fpg and uvrA. Finally, the repair of Fpg-sensitive sites was examined at the MATalpha and HMLalpha mating type loci, and NER was found to play a role in their removal.

Canavanine↗
PubMed1998

Severe acute respiratory distress syndrome secondary to acute pancreatitis successfully treated with extracorporeal membrane oxygenation in three patients.

OBJECTIVE: To review three patients who underwent extracorporeal membrane oxygenation (ECMO) for acute respiratory failure secondary to pancreatitis. SUMMARY BACKGROUND DATA: Severe acute pancreatitis often causes the acute respiratory distress syndrome (ARDS), and if ventilation is required, the mortality rate is more than 50%. If the ratio of PaO2/FiO2 falls below 100 mm Hg or the Murray lung injury score exceeds 3.5, the mortality rate rises to more than 80%. Three patients who have severe ARDS secondary to pancreatitis, who were hypoxic despite ventilation with 100% oxygen and high airway pressures, and who were all successfully treated with ECMO are reported here. The consensus here is that all three patients would have died without ECMO. METHODS: Retrospective chart review and discussion of the literature. RESULTS: Pre-ECMO data: mean PaO2/FiO2 59.3 mm Hg, mean Murray lung injury score 3.7, one patient administered 20 ppm inhaled nitric oxide. ECMO data: mean extracorporeal flow at initiation of ECMO 56.3 mL/kg per minute, all patients administered veno-venous ECMO, mean duration of ECMO 104.7 hours. All patients were successfully weaned from ECMO and extubated. One patient had a protracted hospital stay because of a colo-cutaneous fistula. All patients are long-term survivors. CONCLUSIONS: Extracorporeal membrane oxygenation proved an effective therapy for severe ARDS complicating acute pancreatitis. Extracorporeal membrane oxygenation was conducted without bleeding complications in these three patients.

Acute Disease↗
PubMed1997

Inducible nucleotide excision repair (NER) of UV-induced cyclobutane pyrimidine dimers in the cell cycle of the budding yeast Saccharomyces cerevisiae: evidence that inducible NER is confined to the G1 phase of the mitotic cell cycle.

We previously reported on an inducible component of nucleotide excision repair in Saccharomyces cerevisiae that is controlled by the RAD16 gene. Here we describe a study of this event at the MAT alpha and HML alpha mating-type loci and on the transcribed (TS) and nontranscribed (NTS) strands of the RAD16 gene. Events were examined at various stages of the mitotic cycle in cells synchronised by centrifugal elutriation. Repair of cyclobutane pyrimidine dimers (CPDs) following a single UV dose does not vary significantly in different stages of the mitotic cell cycle. CPDs are removed more rapidly from the transcriptionally active MAT alpha locus than from the silent HML alpha locus, and the TS of RAD16 is repaired faster than the NTS in all stages of the cycle following a single UV irradiation. Enhanced excision of CPDs at MAT alpha and HML alpha can be induced only in the G1 and early S stages of the cell cycle. Here prior irradiation of cells with 25 J/m2 enhances the removal of CPDs following a second UV dose of 70 J/m2. The level of enhancement of repair does not differ significantly between MAT alpha and HML alpha in G1. Enhanced removal of CPDs is absent when cells receive the inducing dose in late S or G2/M. Repair of CPDs in both strands of RAD16 is similarly enhanced only if cells receive the initial irradiation in G1 and early S. The level of enhanced removal of CPDs is not significantly different in the TS and NTS of RAD16 either in asynchronous cells or in cells preirradiated in G1 and early S. It has been shown by others that UV-induced expression of RAD16 remains at high levels if cells are held in G1 by treatment with alpha factor. Therefore the increase in RAD16 transcript levels in G1 may be responsible for the ability to enhance NER solely in this stage of the cell cycle.

Adenosine Triphosphatases↗
PubMed1997

The Saccharomyces cerevisiae RAD7 and RAD16 genes are required for inducible excision of endonuclease III sensitive-sites, yet are not needed for the repair of these lesions following a single UV dose.

The RAD7 and RAD16 genes of Saccharomyces cerevisiae have roles in the repair of UV induced CPDs in nontranscribed genes [1], and in the repair of CPDs in the nontranscribed strand of transcribed genes [2]. Previously, we identified an inducible component to nucleotide excision repair (NER), which is absent in a rad16 delta strain [3]. We have examined the repair of UV induced endonuclease III sensitive-sites (EIIISS), and have shown repair of these lesions to proceed by NER but their removal from nontranscribed regions is independent of RAD7 and RAD16. Furthermore, EIIISS are repaired with equal efficiency from both transcribed and nontranscribed genes [4]. In order to dissect the roles of RAD7 and RAD16 in the above processes we examined the repair of EIIISS in the MAT alpha and HML alpha loci, which are, respectively, transcriptionally active and inactive in alpha haploid cells. These loci have elevated levels of these lesions after UV (in genomic DNA EIIISS constitute about 10% of total lesions, whereas CPDs are about 70% of total lesions). We have shown that excision of UV induced EIIISS is enhanced following a prior UV irradiation. No enhancement of repair was detected in either the rad7 delta or the rad16 delta mutant. The fact that RAD7 and RAD16 are not required for the repair of EIIISS per se yet are required for the enhanced excision of these lesions from MAT alpha and HML alpha suggests two possibilities. These genes have two roles in NER, namely in the repair of CPDs from nontranscribed sequences, and in enhancing NER itself regardless of whether these genes' products are required for the excision of the specific lesion being repaired. In the latter case, the induction of RAD7 and RAD16 may increase the turnover of complexes stalled in nontranscribed DNA so as to increase the availability of NER proteins for the repair of CPDs and EIIISS in all regions of the genome.

DNA Repair↗
PubMed1997

Medical causes of faecal incontinence.

Faecal incontinence can result from a disturbance in any one of the multiple factors which maintain continence. In practice, faecal incontinence is most commonly seen in women who have had children. This symptom can also be seen in other patient groups, who may in addition have had children, and this article will discuss the mechanisms involved in the loss of continence in diabetics and patients with multiple sclerosis.

Anal Canal↗
PubMed1997

Neutropenic colitis: a continuing surgical challenge.

BACKGROUND: Neutropenic colitis is a clinicopathological syndrome characteristically seen as a complication of chemotherapy for haematological malignancy. This review explores the pathogenesis of the condition and appraises the options for management. METHODS: A Medline search was carried out and all relevant papers were reviewed. RESULTS: There are many case reports but few published series, so experience is mainly anecdotal. Both medical and surgical management have been successful; it is not possible to compare treatment groups formally. CONCLUSION: The greater use of aggressive multiagent chemotherapy regimens may increase the frequency with which the condition is encountered. Heightened awareness of neutropenic colitis may prompt diagnosis and a better understanding of the pathophysiology may help guide clinical management.

Colitis↗
PubMed1995

Influence of soluble suture factors on in vitro macrophage function.

Suture materials may interact with immune competent cells and thereby affect localized immunity. Macrophages are central to the inflammatory response and coordinate wound healing. They are also involved in the clearance of foreign material, bacteria and malignant cells. We studied the influence of soluble factors associated with silk, steel, nylon, polyglactin, polydioxanone and chromic catgut sutures on macrophage adherence, phagocytosis and the production of lysozyme and tumour necrosis factor. Soluble factors from suture materials influenced macrophage behaviour in vitro causing cellular activation, functional impairment and alterations in secreted levels of the cytokine tumour necrosis factor and the bactericidal agent lysozyme. Of the six materials studied, polyglactin had the most extreme effect, causing significant inhibition of cell adherence and lysozyme production. Silk also exerted a considerable effect on macrophages, significantly inhibiting adherence. In contrast, steel and polydioxanone media caused minimal inhibition of macrophage function although, as with all materials, they did activate the cells. This study has demonstrated that sutures release immunotoxic factors which considerably influence macrophage behaviour in vitro. These effects may have important clinical implications.

Animals↗
PubMed1995

Comparison of the effects of propofol and isoflurane anaesthesia on right ventricular function and shunt fraction during thoracic surgery.

I.v. anaesthetic agents, including propofol, have not been shown to inhibit hypoxic pulmonary vasoconstriction (HPV). This may encourage the use of propofol in thoracic surgery where one lung ventilation (OLV) is required. We have compared the effects of maintaining anaesthesia with either isoflurane or propofol infusion on right ventricular function and shunt fraction. We studied 10 patients who received isoflurane and 12 who received propofol. When OLV commenced there was a greater reduction in both mean cardiac index (3.2 (SEM 0.2) to 2.4 (0.1) litre min-1 m-2 for propofol, and 3.4 (0.2) to 3.3 (0.4) litre min-1 m-2 for isoflurane) and right ventricular ejection fraction (0.45 (0.03) to 0.37 (0.02) for propofol, and 0.48 (0.02) to 0.42 (0.02) for isoflurane) in patients who received propofol. Furthermore, these reductions were sustained for longer in the propofol group. However, propofol was not associated with a significant increase in shunt fraction during OLV, which increased threefold in patients who received isoflurane.

Adult↗
PubMed1993

Suppression of macrophage function by suture materials and anastomotic recurrence of Crohn's disease.

After surgical excision of bowel, Crohn's disease is likely to recur around the anastomosis. It is suggested that this may indicate a biological effect of suture materials on gastrointestinal immunology. To investigate this, the influence of six suture materials on the function of macrophages obtained from the rat peritoneal cavity and human intestinal mucosa was assessed. All materials significantly impaired macrophage function.

Anastomosis, Surgical↗
PubMed1993

Nasal intermittent positive-pressure ventilation in weaning intubated patients with chronic respiratory disease from assisted intermittent, positive-pressure ventilation.

Nasal intermittent positive-pressure ventilation (NIPPV) has been used for domiciliary ventilatory support, and to avoid intubation for acute respiratory failure in patients with chronic airflow limitation (CAL). Its role in weaning patients from assisted ventilation in intensive care has not been defined. We have used NIPPV to wean 14 patients with respiratory disease who were referred either because of predicted difficulty in weaning or failure to wean using standard techniques. Twelve patients were ventilated for acute respiratory failure; eight patients had CAL and four had chest wall or neuromuscular disease. Two further patients with chest disease were difficult to wean following surgery. Weaning was successful in 13 patients. NIPPV corrected hypoxia, reduced hypercapnia and was well tolerated. Weaning from NIPPV was achieved in all patients with CAL, although three patients with chest wall disease later required domiciliary ventilatory support. All but one of the patients survived to leave hospital. NIPPV may have an important role in weaning from assisted ventilation, particularly in patients with underlying chronic respiratory disease. This preliminary report needs to be followed by a controlled study comparing NIPPV with established weaning methods.

Adult↗
PubMed1992

Preoperative laser therapy in a patient with resectable bronchogenic carcinoma and severe coronary artery disease.

A 67 year old man with severe coronary artery disease was found to have a resectable bronchogenic carcinoma. Myocardial revascularisation and lung resection were considered to be unduly hazardous as either separate or combined operations. Preoperative laser therapy, however, enabled the two procedures to be performed in greater safety in the most appropriate sequence.

Aged↗
PubMed1992

Laparoscopic laser cholecystectomy: results of the technique in 210 patients.

The results of laparoscopic laser cholecystectomy (LLC) in a consecutive series of 210 patients, operated on between May 1990 and August 1991, were assessed to analyse the advantages of the technique and to detail the causes of any technical problems, failures, or complications. The operations were performed by JMcKW and ADNS. A success rate of 98% (206/210) was achieved with a minor complication rate of 13% (26/210) and major complication rate of 3% (7/206), including three patients (3/206; 1.5%) who had a reactionary haemorrhage postoperatively, two requiring laparotomy. The length of hospital stay was 48 h or less in over 80% (148/184) of the patients. The period of absence from work was 2 weeks or less in over 90% (118/130) of the patients. Cholecystectomy can safely be performed laparoscopically and this procedure has significant advantages over open cholecystectomy.

Adolescent↗