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Biomedical subjects

I Scott

Publications and source records attributed to I Scott.

At least 37 records · Page 2Linked to original sources
PubMed2000

HLA-A*6817, identified in the Kolla Amerindians of North-West Argentina possesses a novel nucleotide substitution.

Analysis of HLA polymorphism of the indigenous populations of Central and South America has identified many alleles not seen previously in other populations. We have described a novel allele, B*5113, previously in a Kolla Amerindian individual from North-West Argentina. Here we present a second novel allele from this population: A*6817, which differs from its closest neighbour A*68012 by a single substitution at nucleotide 419. This substitution of adenosine 419 A*68012 for thymidine in A*6817 results in a novel amino acid change (aspartate to valine) at residue 116.

Argentina↗
PubMed2000

WESTCOP: a disease management approach to coronary artery disease.

Disease management is a systematic approach to improving care of populations of patients with specific clinical conditions. Critical to success are the formation of collaborative teams of health care stakeholders, development and promulgation of clinical practice guidelines, and performance measurement and feedback to providers as a process of continuous practice improvement. This article describes a disease management program for patients with coronary artery disease in a provincial health district with a population of 180,000. It discusses the rationale and methods behind the operationalisation of the main program elements, benefits achieved to date and challenges confronted.

Acute Disease↗
PubMed2000

The use of evidence-based medicine in the practice of consultant physicians. Results of a questionnaire survey.

BACKGROUND: Information is lacking about the extent to which Australasian physicians apply methods of evidence-based medicine (EBM) in routine practice. AIMS: To assess the frequency and predictors of use of EBM methods in a sample of consultant physicians in adult medicine. METHODS: Self-administered questionnaires were distributed to a convenience sample of 545 physicians from October 1998 to January 1999. RESULTS: One hundred and eleven questionnaires were returned (20% response rate). Ninety-eight (88%) respondents formulated five or less clinical questions per week; 69 (62%) undertook five or more evidence searches per week, the majority as MEDLINE searches involving therapeutic topics. Respondents identified insufficient time (74%), limited search skills (41%), and limited access to evidence (43%) as search impediments. In determining evidence quality, 37% frequently relied on global impressions, while 22% frequently applied explicit critical appraisal (p=0.008). Efficiency of literature searches was rated on average as good/very good by 18%, fair by 52% and poor by 30%. As a result of EBM, 47% frequently had confidence in pre-existing decisions increased, 39% gained improved knowledge, and 5% altered clinical decisions. Frequently encountered inhibitors to changing practice were personal conservatism (40%), organisational constraints (40%), and interdisciplinary tensions (39%). Perceived weaknesses of EBM included: limited applicability to individual patients (26%); evidence deficiencies (25%); and too time consuming (13%). In making EBM more attractive, one third requested reliable evidence sources at the point of care. CONCLUSIONS: The application of EBM to routine practice by physicians is constrained by deficient EBM skills, limited access to evidence, lack of time, and cognitive and environmental factors. Targeted education in EBM and systems that quickly deliver high-quality evidence at the point of care are needed in realising the full potential of EBM to improve care.

Australia↗
PubMed2000

Cytotoxic T lymphocyte responses and CTL epitope escape mutation in HBsAg, anti-HBe positive individuals.

BACKGROUND/AIMS: Clearance of hepatitis B virus (HBV) is characterised by a strong cytotoxic T cell response. Persistence of HBV in chronic hepatitis B carriers may be related to failure of this response. The aim of this study was to determine whether HLA class I restricted cytotoxic T lymphocyte (CTL) responses persist in anti-hepatitis B e (HBe) positive / HBV DNA negative individuals, and to correlate the presence of viral CTL epitope mutation with clinical outcome. METHODS: An HLA/HBV dual transfectant model was used to demonstrate these CTL responses in individuals chronically infected with HBV. Subsequently, a known hepatitis B core (HBc) CTL epitope was sequenced in a family of five chronically infected individuals all sharing a HLA allele (HLA-A68.1). RESULTS: Low level HLA class I restricted cytotoxic T cell responses were detected in the peripheral blood of five of eight anti-HBe positive individuals. In the family of HLA-A68.1 positive chronically infected individuals, mutation of the HLA-A68.1 restricted hepatitis B core antigen (HBcAg) CTL epitope STLPETTVVRR was found in all four anti-HBe positive individuals but not in the sole hepatitis B e antigen (HBeAg) positive patient. CONCLUSION: These data are consistent with a continued immune selection pressure on HBV in anti-HBe positive chronically infected individuals with low replicating HBV infection and suggest that mutation of a CTL epitope may be a consequence of the immune response, as opposed to the cause of viral persistence.

Adult↗
PubMed1999

Identification of three HLA-A*0201-restricted cytotoxic T cell epitopes in the cytomegalovirus protein pp65 that are conserved between eight strains of the virus.

The Ag specificity of the CTL response against CMV is directed almost entirely to a single CMV tegument protein, the phosphoprotein pp65. We report the identification of three peptides derived from the protein pp65 that displayed a high or intermediate binding to HLA-A*0201 molecules, which were also able to induce an in vitro CTL response in peripheral blood lymphocytes from CMV seropositive individuals. The peptide-specific CTLs generated were capable of recognizing the naturally processed pp65 either presented by CMV-infected cells or by cells infected with an adenovirus construct expressing pp65 in an HLA-A*0201-restricted manner. Thus, we were able to demonstrate responses to subdominant CTL epitopes in CMV-pp65 that were not detected in polyclonal cultures obtained by conventional stimulations. We also found that the amino acid sequences of the three peptides identified as HLA-A*0201-restricted CTL epitopes were conserved among different wild-type strains of CMV obtained from renal transplant patients, an AIDS patient, and a congenitally infected infant, as well as three laboratory strains of the virus (AD169, Towne and Davis). These observations suggest that these pp65 CTL peptide epitopes could potentially be used as synthetic peptide vaccines or for other therapeutic strategies aimed at HLA-A*0201-positive individuals, who represent approximately 40% of the European Caucasoid population. However, strain variation must be taken in consideration when the search for CTL epitopes is extended to other HLA class I alleles, because these mutations may span potential CTL epitopes for other HLA molecules, as it is described in this study.

Antigen Presentation↗
PubMed1999

The distribution of pepsinogen within the abomasa of cattle and sheep infected with Ostertagia spp. and sheep infected with Haemonchus contortus.

The effect of nematode infections on the production of pepsinogen by ruminants was investigated immunohistochemically and biochemically. Abomasal tissues were collected from parasite-naive cattle and sheep, from sheep infected with predominantly Ostertagia circumcincta, sheep infected experimentally with Haemonchus contortus and cattle infected with Ostertagia ostertagi. Pepsinogen was also assayed biochemically in homogenates of fundic mucosae from sheep infected with predominantly O. circumcincta. Infection with Ostertagia spp. parasites was associated mainly with nodular hyperplasia, resulting in increased numbers of cells that produce both pepsinogen and mucus. Measured biochemically, nodules contained more pepsinogen than adjacent more normal mucosa (p < 0.05), and this effect was largely attributable to the greater mass of nodules. Infection of sheep with H. contortus was associated with generalised hyperplasia, characterised by increased numbers of mucopeptic cells and in at least one animal with reductions in parietal cell numbers. At the same time, the zymogen granule content of chief cells was reduced. Similar changes were occasionally seen in sheep infected predominantly with O. circumcincta. Generalised hyperplasia is likely to be indicative of the presence of ambulatory parasitic stages as opposed to those confined to nodules. The potential for the enhanced production of pepsinogen by increased numbers of cells with a joint mucous cell and zymogenic cell phenotype may offset decreases in the numbers of chief cells or reductions in chief cell activity.

Abomasum↗
PubMed1999

Hypergastrinaemia, abomasal bacterial population densities and pH in sheep infected with Ostertagia circumcincta.

Serum gastrin and pepsinogen concentrations, food intake, abomasal pH and abomasal aerotolerant and anaerobic bacterial populations were measured in sheep infected with Ostertagia circumcincta to search for links between hypergastrinaemia, food intake and changes in the abomasal environment. Abomasal pH and serum gastrin and pepsinogen concentrations were elevated in each of five sheep infected via abomasal cannulae with 150000 exsheathed larval stage three, followed 11 days later by 100000 sheathed larvae given intraruminally. Unparasitised abomasa contained aerotolerant bacterial population densities of between 10(3) and 10(6) cells ml(-1) and these did not change significantly following parasitism. In contrast, anaerobic bacterial population densities increased markedly by about 10(4)-fold following parasitism. Anaerobic numbers changed rapidly when abomasal pH increased from 2.5 to 3.5. At pH 4 and above, anaerobic bacterial numbers approached levels expected in rumen contents but parameters other than pH did not relate to bacterial numbers. Brief periods when serum gastrin was lower than expected, coinciding with raised abomasal pH, were not explicable by increased bacterial numbers. Food intake, which decreased for a variable period from around Day 5 p.i., correlated poorly with serum gastrin concentration, suggesting hypergastrinaemia is not the sole cause of anorexia in parasitised animals. The survival of substantial numbers of rumen bacteria in the abomasum at only slightly raised pH may significantly lower the bacterial protein available to the sheep.

Abomasum↗
PubMed1999

HLA-A, -B, -C polymorphism in a UK Ashkenazi Jewish potential bone marrow donor population.

To further our knowledge of HLA polymorphism in different ethnic populations and to increase the number of full HLA class I typed potential bone marrow donors on the Anthony Nolan Bone Marrow Trust register, HLA-A, -B and -C polymorphism was characterised in 412 Ashkenazi Jewish potential donors. Serological typings and limited molecular analysis was performed for HLA-A and -B, and molecular typings were performed for HLA-C. Gene and haplotype frequencies were calculated using the maximum likelihood method and compared with UK Caucasoid and other Jewish populations. While the specificities identified were in general overlapping with the UK Caucasoid data, a difference in the frequencies of individual specificities was observed. For example, HLA-B62, a common serotype found in the UK Caucasoid population, is almost absent in the Ashkenazim. HLA-A, -C, -B haplotype frequencies also differ between the two populations with A26-Cw*1203-B38 and A24-Cw*04-B35 significant in the Ashkenazim, whilst A1-Cw*07-B8, a common Caucasoid haplotype, was found to be less frequent. Overall the results for the UK Ashkenazi population were most similar to previous reports on Polish/Russian Jews.

Adolescent↗
PubMed1999

A novel HLA allele, HLA-B*5113, identified in the Kolla Amerindians of North-West Argentina.

A novel HLA-B51 allele, B*5113, was identified in a Kolla Amerindian individual from North-West Argentina. HLA-B*5113 differs from B*51011 by two nucleotide substitutions, one synonymous, the other nonsynonymous. The resulting amino acid difference at residue 116 in the HLA-B molecule's peptide binding site is likely to affect the nature of the peptides which bind to this molecule. The finding of this novel allele supports previous findings of increased diversity at HLA-B in Amerindian groups.

Alleles↗
PubMed1999

The relationship between the number and size of nematodes in the abomasum and the concentration of pepsinogen in ovine plasma.

Six-month-old lambs that had been naturally infected with predominantly Teladorsagia (Ostertagia) circumcincta were tested for plasma pepsinogen concentrations because pepsinogen concentrations may reflect the extent of damage to the abomasum. The distribution of pepsinogen concentrations among these lambs was positively skewed with most individuals having relatively low concentrations. Pepsinogen concentrations were more strongly associated with variation in the mean length of the adult female worms than with variation in the number of nematodes present. Previous trials have suggested that genetic variation in the growth of lambs is strongly influenced by genetic variation in worm length. Together these results imply that variation among lambs in the pathogenic effects of T. circumcincta depends upon the mean size of the worms as well as the number of worms present.

Abomasum↗
PubMed1999

The genetic epidemiology of early-onset epithelial ovarian cancer: a population-based study.

We conducted a population-based study to determine the contribution of germline mutations in known candidate genes to ovarian cancer diagnosed at age <30 years. Women with epithelial ovarian cancer were identified through cancer registries. DNA samples were analyzed for mutations in BRCA1, the "ovarian cancer-cluster region" (nucleotides 3139-7069) of BRCA2, and the mismatch-repair genes hMSH2 and hMLH1. Probable germline mutations in hMLH1 were identified in 2 (2%; 95% confidence interval 1%-8%) of 101 women with invasive ovarian cancer diagnosed at age <30 years. No germline mutations were identified in any of the other genes analyzed. There were no striking pedigrees suggestive of families with either breast/ovarian cancer or hereditary nonpolyposis colorectal cancer (HNPCC). There was a significantly increased incidence of all cancers in first-degree relatives of women with invasive disease (relative risk [RR] = 1.6, P=.01) but not in second-degree relatives or in relatives of women with borderline cases. First-degree relatives of women with invasive disease had increased risks of ovarian cancer (RR = 4.8, P=.03), myeloma (RR = 10, P=.01), and non-Hodgkin lymphoma (RR = 7, P=.004). Germline mutations in BRCA1, BRCA2, msh2, and mlh1 contribute to only a minority of cases of early-onset epithelial ovarian cancer. Our data suggest that early-onset ovarian cancer is not associated with a greatly increased risk of cancer in close relatives.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Molecular typing shows a high level of HLA class I incompatibility in serologically well matched donor/patient pairs: implications for unrelated bone marrow donor selection.

In comparison with HLA-matched sibling bone marrow transplants, unrelated donor transplants are associated with increased graft-versus-host disease and graft failure. This is likely in part due to HLA incompatibilities not identified by current matching strategies. High resolution DNA-based typing methods for HLA class II loci have improved donor selection and treatment outcome in unrelated donor bone marrow transplantation. By using DNA-based typing methods for HLA-A and -B on a cohort of 100 potential bone marrow donor/patient pairs, we find that serological typing for HLA class I is limited in its ability to identify incompatibilities in unrelated pairs. Furthermore, the incompatibilities identified are associated with the presence at high frequency of alloreactive cytotoxic T-lymphocyte precursors. DNA typing also indicates that HLA-C mismatches are common in HLA-A and -B serologically matched pairs. Such mismatches appear to be significantly less immunogenic with respect to cytotoxic T-lymphocyte recognition, but are expected to influence natural killer cell activity. Thus, improved resolution of HLA class I shows many previously undisclosed mismatches that appear to be immunologically functional. Use of high resolution typing methods in routine matching is expected to improve unrelated donor selection and transplant outcome.

Base Pair Mismatch↗
PubMed1998

The effects of excretions/secretions of Ostertagia circumcincta on ovine abomasal tissues in vitro.

Products excreted/secreted by Ostertagia circumcincta stimulated the in vitro release of pepsinogen from intact abomasal mucosal sheets and caused the contraction of strips of abomasal smooth muscle, also in vitro. However, responses occurred only when tissues had been derived from animals that were assumed to have experienced prior exposure to the parasite. The overall median responses for pepsinogen secretion in response to ES, expressed as the ratio of stimulated secretion to basal secretion, were 1.8 for previously exposed animals and 0.9 for parasite-naive animals. For the smooth muscle from the previously exposed animals, the overall median response to ES, expressed as a percentage of the maximal response to carbachol in the same tissues, was 27.0. No responses were seen in muscle from any parasite-naive animal. These results suggest that the responses obtained were hypersensitivity reactions to antigens released by the worms during in vitro culture, and occurring in tissues from animals sensitised by exposure to O. circumcincta in the natural environment.

Abomasum↗
PubMed1998

Infection of sheep with adult and larval Ostertagia circumcincta: abomasal morphology.

The infection of parasite-naive sheep with approximately 15,000 adult Ostertagia circumcincta via abomasal cannulae resulted in marked changes in the structure and function of the abomasum. The functional changes, which have been characterised previously, included elevated abomasal pH and increased serum concentrations of pepsinogen and gastrin. Eight days after the transplant of adult worms, the abomasa of recipient animals were significantly heavier than those of controls (P < 0.001), the thickness of the fundic mucosa was greater (P < 0.01), there were fewer parietal cells (P < 0.01) and increases in the numbers of mitotic figures and mucus-producing cells. Mucous cell hyperplasia was also evident in the fundic mucosae of sheep receiving a trickle infection of infective, third-stage O. circumcincta larvae and was prominent within nodules associated with larval development. In non-nodular mucosa, there was hyperplasia of mucous cells and changes in the distribution of parietal cells. Decreases in the number of parietal cells at the gland base were offset by increases at a mid-gland level, probably due to chronic hypergastrinaemia, so that, overall, total parietal cell number was unaffected. Mucous cell hyperplasia and the diminution of parietal cell number are seen in a diverse range of disease states and may be mediated by host growth factors such as Transforming growth factor-alpha. Alternatively, the cellular and/or the secretory changes in response to the presence of adult worms are mediated by chemicals that are cytotoxic/inhibitory for parietal cells, and released by the parasites themselves.

Abomasum↗
PubMed1998

Infection of sheep with adult and larval Ostertagia circumcincta: gastrin.

Gastric endocrine cell populations and serum and tissue gastrin have been examined in sheep which were infected either intraruminally by tube with 150,000 Ostertagia circumcincta larvae followed by a trickle infection of 10,000 larvae thrice weekly for 8 weeks or by the transfer of 15,000 adult worms directly into the abomasum and killed 8 days later. Depletion of both antral gastrin and somatostatin was evident in both groups: tissue gastrin concentrations were reduced by 85% in the trickle infection and both G cells (gastrin-containing) and D cells (somatostatin-containing) were pale and fewer after adult worm transfer. The concurrent depletion of antral gastrin and somatostatin supports the contention that the hypergastrinaemia in parasitised sheep is largely secondary to the increase in abomasal pH. Although there was no change in the proportions of G34 and G17 in the tissues, there was an increase in the longer form of gastrin in the circulation of the larval-infected sheep, suggesting that there may be differential secretion of G17 and G34 which may be exaggerated as the rate of secretion increases. Although the fundic mucosa was thicker following trickle infection, there was no evidence of enterochromaffin-like cell hyperplasia in either infected group. It is suggested that hyper-gastrinaemia may be beneficial to the host, as it may allow the abomasum to regain the ability to acidify its contents during continued exposure to the parasites.

Abomasum↗
PubMed1998

Changes in the zymogenic cell populations of the abomasa of sheep infected with Haemonchus contortus.

The effects of dietary urea supplementation and of a 10-week trickle infection regime, simulating chronic exposure to Haemonchus contortus, on the zymogenic population of the abomasa of Hampshire Down lambs was examined. At necropsy a variety of parameters including plasma pepsinogen concentration, the wet weights of abomasal fundic mucosal pieces and the amounts of pepsinogen contained in them, were assessed. Tissue pepsinogen concentration was measured as the total, acid-stable proteolytic activity present in mucosal homogenates, as well as immunohistochemically. The immunohistochemical findings were quantified using computer-aided image analysis. Elevation of plasma pepsinogen concentrations in infected animals was of borderline significance (P = 0.06). The fundic mucosae of infected animals were heavier (P < 0.02) than those of control animals, but there was no overall change in the pepsinogen content of tissues. Immunohistochemistry revealed that infected animals had increased numbers of zymogenic cells, due to mucous cell hyperplasia and the adaptation of cells to produce both mucins and pepsinogen. The pepsinogen content of chief cells, the major source of pepsinogen in uninfected animals, was reduced in infected lambs. Image analysis confirmed that at a mid-point of the mucosa of infected animals there was increased pepsinogen-specific immunoreactivity that corresponded with areas of mucosal hyperplasia. Mucous cell hyperplasia might therefore allow the maintenance of pepsinogen secretion in infected animals even if chief cell output is reduced.

Abomasum↗