Biomedical subjects

D Marshall

Publications and source records attributed to D Marshall.

At least 73 records · Page 4Linked to original sources

PubMed1997

A linkage map of chromosome 6 based on 2 large kindreds segregating bipolar affective disorder.

Twenty-eight markers, both simple sequence repeats (SSRs) and restriction fragment length polymorphisms (RFLPs), were genotyped on members of 2 large pedigrees (OOA, BIP167) segregating bipolar affective disorder. Using the multipoint program "build" of CRIMAP and odds of placement 1000:1, a unique sex-averaged map was generated that spans 227 cM and includes 26 markers. The two other markers were placed on the map with a lower likelihood. The female recombination map is larger than the male recombination map by about 80%. Linkage analysis between the polymorphisms and the disease in the OOA screening pedigree did not result in any significantly positive lod scores nor did a non-parametric, identity-by-descent, method generate any significant p-values. BIP167 was analyzed for allele sharing at the simple sequence repeat loci and significant associations were not found. At present we conclude, that the pedigrees under study do not have a major predisposition gene for bipolar affective disorder on chromosome 6 under the diagnostic and transmission models analyzed by the 2 different methods.

Bipolar Disorder↗

PubMed1997

Is the ultrastructural damage caused by subinhibitory concentrations of trimethoprim and sulphadiazine part of their normal mechanism of action?

The test organism was Escherichia coli 1810 which was highly resistant to trimethoprim (TMP). Electron microscopy (EM) of cells grown in the presence of subinhibitory concentrations of 300 micrograms/ml sulphadiazine (SD) and/or 300 micrograms/ml TMP indicated marked structural damage. No effect on the outer membrane (OM) or ultrastructure of E. coli 1810 was observed with 7.68 micrograms/ml TMP and/or 16.9 micrograms/ml SD. Concentrations of antibacterials affecting the ultrastructure of the bacterial cells of resistant and sensitive E. coli as determined by EM, were shown by a permeability probe (Triton X-100) to alter the OM permeability and to partially inhibit growth of E. coli 1810 cultures. It was concluded that, since the action of SD and TMP, singly and in combination, on the cell structure of E. coli 1810 took place only at concentrations approaching the respective MICs, then this was a part of their normal mechanisms of antibacterial action.

Anti-Bacterial Agents↗

PubMed1996

Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures.

OBJECTIVE: To determine the ability of measurements of bone density in women to predict later fractures. DESIGN: Meta-analysis of prospective cohort studies published between 1985 and end of 1994 with a baseline measurement of bone density in women and subsequent follow up for fractures. For comparative purposes, we also reviewed case control studies of hip fractures published between 1990 and 1994. SUBJECTS: Eleven separate study populations with about 90,000 person years of observation time and over 2000 fractures. MAIN OUTCOME MEASURES: Relative risk of fracture for a decrease in bone mineral density of one standard deviation below age adjusted mean. RESULTS: All measuring sites had similar predictive abilities (relative risk 1.5 (95% confidence interval 1.4 to 1.6)) for decrease in bone mineral density except for measurement at spine for predicting vertebral fractures (relative risk 2.3 (1.9 to 2.8)) and measurement at hip for hip fractures (2.6 (2.0 to 3.5)). These results are in accordance with results of case-control studies. Predictive ability of decrease in bone mass was roughly similar to (or, for hip or spine measurements, better than) that of a 1 SD increase in blood pressure for stroke and better than a 1 SD increase in serum cholesterol concentration for cardiovascular disease. CONCLUSIONS: Measurements of bone mineral density can predict fracture risk but cannot identify individuals who will have a fracture. We do not recommend a programme of screening menopausal women for osteoporosis by measuring bone density.

Aged↗

PubMed1996

Health policy on bone density measurement technology in Sweden and Australia.

The possible adverse consequences of osteoporosis, particularly hip fractures, are a considerable health concern that is particularly relevant for elderly women. Bone density measurement is a method to assess bone mineral that has grown rapidly in recent years in both Sweden and Australia. The types of technologies adopted, their location and their level of use reflect the characteristics of the different health care systems, health technology assessments and policies adopted by health authorities. The health policy issues related to use of these technologies are complex and include consideration of who should be examined and treated, potential risks and benefits, machine performance, patient compliance and evidence of benefit.

Absorptiometry, Photon↗

PubMed1996

Tetrodotoxin-sensitivity of nicotine-evoked dopamine release from rat striatum.

Recent observations from synaptosome preparations have questioned the tetrodotoxin (TTX) insensitivity of nicotine-evoked release in the striatum, a characteristic previously considered diagnostic of presynaptically located nicotinic acetylcholine receptors (nAChRs). Therefore, we have undertaken a comparison of nicotine-evoked dopamine release in the presence of TTX from the rat striatum in vitro, using synaptosomes and brain slices, and in vivo, using microdialysis. In P2 and Percoll-purified synaptosome preparations, 1.5 microM TTX partially inhibited nicotine-evoked [3H]dopamine release by 54% and 37%, respectively, whereas in more intact preparations (brain slices and microdialysis) TTX completely inhibited mecamylamine-sensitive nicotine-stimulated dopamine release. These results suggest that caution should be exercised in the interpretation of TTX sensitivity of nicotine-evoked responses with regard to the location of nAChRs.

Animals↗

PubMed1996

The internationalization of health technology assessment.

Health technology assessment as a formalized set of activities has a relatively short history. At its current stage of development, it is clear that it has global dimensions and impact. In this paper we review the history of health technology assessment, its development as a form of health services research, and its "institutionalization." We then identify the reasons for its internationalization, review current international initiatives, and propose actions to be taken to improve cooperation among countries.

Communication↗

PubMed1996

Polyethylene glycol modification of a galactosylated streptavidin clearing agent: effects on immunogenicity and clearance of a biotinylated anti-tumour antibody.

Effective radioimmunotherapy is limited by slow antibody clearance from the circulation, which results in low tumour to blood ratios and restricts the dose of radiolabelled anti-tumour antibody that can be safely administrated. Avidin and streptavidin clearing agents have been shown to effectively complex and clear radioactive biotinylated antibodies from the circulation, but their immunogenicity may limit their repeated use. We have investigated whether polyethylene glycol (PEG) modification can reduce the immunogenicity of our galactosylated streptavidin (gal-streptavidin) clearing agent without altering its effectiveness as a clearing agent. The immune response evoked in mice after intraperitoneal infection of 30 micrograms of gal-streptavidin was decreased after PEG modification, as shown by lower antibody titres and a reduction in the number of mice that elicited an anti-gal-streptavidin response. The effect of PEG-modified gal-streptavidin on the blood clearance and tumour localisation of a 125I-labelled biotinylated anti-CEA was investigated in the LS174T human colon carcinoma xenograft in nude mice. Although PEG modified gal-streptavidin bound the [125I]biotinylated antibody in vivo, effective clearance from the circulation was inhibited, resulting in very little reduction in the levels of circulation radioactivity, together with a decrease in the antibody localised to the tumour.

Animals↗

PubMed1996

Clinical evaluation of back optic radius and power determination by age in pediatric aphakia due to congenital cataract fitted with a Silicone Elaster contact lens.

The purpose of this study was to provide optometrists with suggested base curves and powers for initial lens choice based on the infant's age. A retrospective chart review of 16 congenital cataract patients fitted at U.C. Davis Eye Clinic between July 1987 and May 1993 was performed. Patients with associated ocular pathologies were excluded. All patients were fitted with a Bausch & Lomb Silsoft lens, a Silicone Elastomer, set at a 3.00 D myopic posture, which was decreased with the child's increasing age and activity. This study provides a graphical approach to pediatric aphakic silicone elastomer contact lens fitting. Best-fit regression lines for both graphs have an r squared value better than 0.9. Optometrists will now be able to reference the Base Curve vs. Age and Power vs. Age graphs to determine the initial lens choice when keratometry is unachievable. Furthermore, the data suggest a need for an increased range of powers provided by the Silicone elastomer lens in order to approximate normal visual development.

Aging↗

PubMed1996

Generation and characterization of variants of NWS/G70C influenza virus after in vitro passage in 4-amino-Neu5Ac2en and 4-guanidino-Neu5Ac2en.

The compounds 4-amino-Neu5Ac2en (5-acetylamino-2,6-anhydro-4-amino-3,4,5- trideoxy-D-glycerol-D-galacto-non-2-enoic acid) and 4-guanidino-Neu5Ac2en (5-acetylamino-2,6-anhydro-4-guanidino-3,4,5- trideoxy-D-glycerol-D-galacto-non-2-enoic acid), which selectively inhibit the influenza virus neuraminidase, have been tested in vitro for their ability to generate drug-resistant variants. NWS/G70C virus (H1N9) was cultured in each drug by limiting-dilution passaging. After five or six passages in either compound, there emerged viruses which had a reduced sensitivity to the inhibitors in cell culture. Variant viruses were up to 1,000-fold less sensitive in plaque assays, liquid culture, and a hemagglutination-elution assay. In addition, cross-resistance to both compounds was seen in all three assays. Some isolates demonstrated drug dependence with an increase in both size and number of plaques in a plaque assay and an increase in virus yield in liquid culture in the presence of inhibitors. No significant difference in neuraminidase enzyme activity was detected in vitro, and no sequence changes in the conserved sites of the neuraminidase were found. However, changes in conserved amino acids in the hemagglutinin were detected. These amino acids were associated with either the hemagglutinin receptor binding site, Thr-155, or the left edge of the receptor binding pocket, Val-223 and Arg-229. Hence, mutations at these sites could be expected to affect the affinity or specificity of the hemagglutinin binding. Compensating mutations resulting in a weakly binding hemagglutinin thus seem to be circumventing the inhibition of the neuraminidase by allowing the virus to be released from cells with less dependence on the neuraminidase.

Antiviral Agents↗

PubMed1996

A follow-up report of a genome search for affective disorder predisposition loci in the Old Order Amish.

Progress of a full-genome scan for predisposition loci for affective disorder in the Old Order Amish is reported. LOD-score results have been previously published for 51 loci on chromosomes 1 and 11, collectively. The present report contains results for an additional 367 loci throughout the genome with extensive coverage on chromosomes 1, 2, 3, 4, 6, 7, 9, 10, 13, 14, 18, 19, and 21 (average marker density for these chromosomes = 10.7 cM). Analyses were conducted in a four-stage process: (1) two-point LOD scores were calculated for all loci under a dominant model with reduced penetrance, consistent with results of segregation analyses of these pedigrees; (2) a screen for the sharing of alleles in similarly affected individuals was used to highlight areas potentially important for further analysis; (3) the preceding areas and markers on densely covered chromosomes were analyzed using the affected-pedigree-member (APM) method; and (4) the sharing of extended haplotypes in affected individuals was examined in areas showing apparent clustering of significant allele sharing as assessed by the APM method. Of the 367 markers analyzed, no statistically significant LOD scores resulted. Some degree (P < .05) of allele sharing was found at 74 loci, and 3.8% of all markers analyzed (N = 14) passed more stringent significance criteria suggestive of linkage (P < or = .001 for at least one of the weighting functions). Multilocus APM and detailed exploration of extended haplotype sharing in areas highlighted by the APM analyses provided methods for more informative exploration of potentially suggestive results but did not identify areas clearly involved in the etiology of affective disorder in this population.

Bipolar Disorder↗

PubMed1996

Turnaround time of in-patient discharge letters: a simple system of audit.

This user-friendly audit system, successfully developed and implemented in a district general hospital for use across all clinical specialties, is able to calculate the turnaround time of final discharge letters and as a consequence identify any areas of delay between patients' discharge and the letter being mailed. By serially monitoring both individual consultant and specialty performance, the system can provide valuable information on the discharge letter process to Purchaser and Provider alike. A copy of the audit system together with details of audit design and methodology is available to interested clinicians, managers and audit facilitators.

Communication↗

PubMed1996

Prodrugs of thymidylate synthase inhibitors: potential for antibody directed enzyme prodrug therapy (ADEPT).

Prodrugs of quinazoline antifolate thymidylate synthase (TS) inhibitors have been designed and synthesized for use in antibody-directed enzyme prodrug therapy (ADEPT). The syntheses of the alpha-linked dipeptides of two potent thymidylate synthase inhibitors, ZD1694 [N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6- ylmethyl)-N-methylamino]-2-thenoyl]-L-glutamic acid] and ICI198583 ¿N-[4-[N-[(2-methyl-3,4-dihydro-4-oxo-6-quinazolinyl) methyl]-N-prop-2-ynylamino]benzoyl]-L-glutamic acid¿ are described. The alpha-carboxyl of the glutamic acid has been linked through an amide bond to an L-alanine or an L-glutamic acid. The alpha-linked L-dipeptide prodrugs were designed to be activated to their corresponding thymidylate synthase inhibitors at a tumour site by prior administration of a monoclonal antibody conjugated to the enzyme carboxypeptidase A (CPA). The viability of a colorectal cell line was monitored with the potential prodrugs in the presence or absence of CPA or with the parent drugs alone. All the dipeptides had greatly decreased cytotoxicity, with a deactivation of approximately 100-fold for the ZD1694 prodrugs and approximately 20-200-fold for the ICI198583 prodrugs. Activation of the alpha-linked L-alanine dipeptides with CPA led to a cytotoxicity enhancement of approximately 10-100 fold.

Antineoplastic Agents↗

PubMed1995

The place of magnetic resonance imaging in health care.

Magnetic resonance imaging has been an important advance in diagnostic imaging technology and is now widely established in many countries. However, evidence of proven benefit in patient management and outcome remains limited. Health policy makers, professional groups and administrators are faced with a range of questions on the technical capabilities, costs and comparative advantage over other diagnostic methods. The challenge remains to use this expensive technology in an effective manner, with critical review of its cost effectiveness and its suitability for individual health care programs.

Australia↗

PubMed1995

How a three-campus heart service line improves clinical processes and outcomes.

BACKGROUND: In 1993, Intermountain Health Care's three Salt Lake Valley Hospitals formed service lines in four clinical areas, one of which was heart services. After experimenting with various organizational structures, the Salt Lake Valley Hospitals formed a cardiac executive council and three specialty work teams--the clinical process and outcome, satisfaction, and resource teams--to allow for unified planning and greater teamwork. CASE STUDY--OPEN HEART TEAM: The team mapped out the current process and identified areas for potential improvement in the care of patients undergoing coronary artery bypass graft (CABG) surgery. One of the key processes selected for study was extubation. Patients were extubated for an average of 20.41 hours (range, 6 to 120 hours). Analysis of practice patterns demonstrated that extubation was related to staffing patterns, not the patient's readiness. The team created a weaning path, which reduced extubation time to an average of 8.89 hours. LESSONS LEARNED: A common vision and an organized structure to support integrated services is essential. Cross-training of staff helps ensure that the same standards of care apply across the three campuses. Even when the medical staff and hospital departments each have their own structures for dealing with quality issues, cohesiveness among physicians treating a certain group of patients, such as cardiac patients, can be promoted. In conclusion, a "cardiac culture" that is evident throughout the three hospitals promotes performance improvement.

Angioplasty, Balloon, Coronary↗

PubMed1995

Galactosylated streptavidin for improved clearance of biotinylated intact and F(ab')2 fragments of an anti-tumour antibody.

Persistence of high levels of radiolabelled antibody in the circulation is a major limitation of radioimmunotherapy. Biotinylation of the radiolabelled anti-tumour antibody followed by administration of streptavidin is known to give much improved tumour to blood ratios as the radioantibody is complexed and subsequently cleared via the reticuloendothelial system, although prolonged splenic uptake is a problem. We have investigated the effect on the clearance pattern and tumour localisation of a 125I-labelled biotinylated anti-CEA antibody (A5B7) after administration of a galactosylated form of streptavidin (gal-streptavidin) in nude mice bearing a human colon carcinoma xenograft. Fifteen minutes to 1 h after gal-streptavidin administration the complexes were cleared via the liver alone (as opposed to liver and spleen after native streptavidin). Twenty-four hours after administration of gal-streptavidin, the tumour to blood ratio for biotinylated A5B7 IgG increased from 2.9 to 13.2 and for biotinylated F(ab')2 fragments an increase from 4.9 to 33.2 was achieved. The reduction in tumour accumulation of F(ab')2 24 h after injection of the clearing agent was less than that seen with intact antibody. Injection of asialofetuin inhibited clearance, confirming that removal of the gal-streptavidin-biotinylated antibody complexes from the blood was via the asialoglycoprotein receptor on liver hepatocytes. Therefore, galactosylation of the streptavidin clearing agent allows rapid removal of radiolabelled biotinylated antibodies via the liver asialoglycoprotein receptor, as opposed to the reticuloendothelial system.

Antibodies, Monoclonal↗

PubMed1995

Mechanism of sulphadiazine enhancement of trimethoprim activity against sulphadiazine-resistant Enterococcus faecalis.

Sulphadiazine had little or no antibacterial effect against three strains of Enterococcus faecalis (MICs of above 3600 mg/L) but it caused approximately six-fold increases in bacterial uptake of trimethoprim, increased release of bacterial ATP and produced ultrastructural damage to both the trimethoprim resistant E. faecalis 463 and the trimethoprim sensitive NCTC 5957. MICs of trimethoprim were 0.6, 0.8 and 76.8 mg/L for E. faecalis NCTC 775, NCTC 5957 and 463 respectively. When log phase E. faecalis 463 and NCTC 5957 were grown for 4 h in trimethoprim 56 and 0.6 mg/L plus sulphadiazine 320 and 100 mg/L respectively there was an approximate ten-fold and nine-fold increase in uptake of sulphadiazine and a two-fold increase in leakage of ATP. Trimethoprim caused more damage to the cell wall and cytoplasmic membrane than sulphadiazine but the combination of sulphadiazine plus trimethoprim caused the most cell damage. The increased activity observed with the combination seems very likely to have resulted from the increased uptakes of the antibacterials, which in turn had resulted from the cell wall damage and consequent increased cell permeability caused by each antibacterial. It is proposed that a markedly subinhibitory concentration of sulphadiazine enhanced the antibacterial activity of trimethoprim against all three strains of E. faecalis by this mechanism.

Adenosine Triphosphate↗

PubMed1995

Aging effects for opponent mechanisms in the central visual field.

Visual field sensitivity measures were obtained for normal observers between the ages of 20 and 83 years, using test conditions in which detection has been shown to be mediated by opponent (chromatic) mechanisms (Size V target, 620 nm stimulus, 31.5 asb [10 cd/m2] white background). Average visual field sensitivity for opponent mechanisms decreased by approximately 0.6 dB per decade. This age-related sensitivity loss was smallest for the central 10 degrees visual field (0.5 dB per decade) and increased as a function of stimulus eccentricity (0.66 dB per decade for 20 to 30 degrees eccentricity), although the differences in aging effects for various eccentricities were not statistically significant. There were negligible differences in age-related sensitivity losses for opponent mechanisms in various quadrants of the visual field. These findings are generally similar to those obtained for standard automated perimetry, which uses a small white target on a white background. By comparison, short wave-length-sensitive mechanisms exhibit age-related losses that are more than twice as large, even after lenticular transmission losses are taken into account. These data provide a basis for distinguishing early disease-related losses from those related to normal aging.

Adult↗

PubMed1995

Epstein-Barr virus nuclear antigen 3C is a transcriptional regulator.

Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA-3C) is one of five viral nuclear proteins that are essential for EBV-induced immortalization of primary human B lymphocytes in vitro. Previous studies have implied that EBNA-3C acts as a transcription factor. Using transient transfection assays, we demonstrate that EBNA-3C has two effects on reporter genes that are linked to the latent membrane protein 1 promoter, (i) low-level activation by EBNA-3C alone, as well as potentiation of EBNA-2-mediated transactivation, and (ii) inhibition of the normally strong activation mediated by EBNA-2. These two disparate effects seem to be mediated at different stages following cell feeding. The inhibitory effect of EBNA-3C was localized to a known EBNA-2 response element that had previously been shown to be recognized by the DNA-binding protein RBP-J kappa. In addition, direct interaction between RBP-J kappa and EBNA-3C was observed by coimmunoprecipitation. Activation by EBNA-3C, however, seems to be achieved via sequences that are distinct from RBP-J kappa sites, since activation remained even after these sites had been mutated. Consistent with its ability to activate transcription, a region of EBNA-3C which has homology to the glutamine-rich activation domain of Sp1 can function as a transcription activation domain when it is fused to the heterologous DNA-binding domain of Gal4 and can partially restore the activity of a mutant EBNA-2 protein with a deletion in the transactivation domain. Collectively, these data strongly support the role of EBNA-3C as a transcriptional regulator.

Antigens, Viral↗