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Biomedical subjects

K Gould

Publications and source records attributed to K Gould.

At least 19 recordsLinked to original sources
PubMed2004

Prevalence and clonality of Burkholderia cepacia complex genomovars in UK patients with cystic fibrosis referred for lung transplantation.

BACKGROUND: It has previously been reported that patients infected with Burkholderia cenocepacia (genomovar III) before lung transplantation have a poorer outcome than those with other B. cepacia complex infections. METHODS: An extensive study was conducted to determine the prevalence and clonality of B. cepacia complex genomovars isolated from patients referred for transplant assessment between 1989 to the present and, where appropriate, whether strain type was related to transplant outcome. RESULTS: Isolates from 29 patients were identified as B. cepacia complex organisms by molecular analysis. Thirteen patients (45%) were infected with the highly transmissible ET-12 strain of B. cenocepacia recA lineage III-A, while all remaining patients were infected with genetically unique B. cenocepacia, B. multivorans, and B. vietnamiensis strains. All previously reported deaths following transplantation were associated with ET-12 infection. CONCLUSIONS: The ET-12 strain is the predominant cause of B. cenocepacia infections in patients with cystic fibrosis referred to our pulmonary transplant centre and is associated with poor transplant outcomes using standard treatment regimens.

Burkholderia Infections↗
PubMed2001

Burkholderia cepacia complex genomovars and pulmonary transplantation outcomes in patients with cystic fibrosis.

Burkholderia cepacia is a group of organisms that comprises seven genotypically distinct species (B cepacia genomovars I-VII), which are collectively known as the B cepacia complex. Preoperative infection with B cepacia is associated with a poor prognosis in lung transplant recipients with cystic fibrosis. Many centres do not, therefore, offer transplants to these individuals. Our aim was to ascertain whether or not post-transplant mortality is affected by pretransplant genomovar status. We studied archived isolates with PCR-based methods, and recorded excessive mortality in patients infected with B cepacia genomovar III, but not in those infected with other genomovars.

Anti-Bacterial Agents↗
PubMed2001

Pig-tailed macaques infected with human immunodeficiency virus (HIV) type 2GB122 or simian/HIV89.6p express virus in semen during primary infection: new model for genital tract shedding and transmission.

Characterizing human immunodeficiency virus (HIV) expression in semen during primary infection remains essential to understanding the risk of sexual transmission. This investigation represents the first systematic evaluation of male genital tract shedding to use a nonhuman primate model, including the impact of exposure route and viral virulence. Male macaques were inoculated with either a chronic disease-causing virus (HIV-2(GB122); n=4 intravenous; n=4 intrarectal) or an acutely pathogenic simian/HIV strain (SHIV(89.6P); n=2 intravenous). All macaques were systemically infected, and seminal plasma virion-associated RNA (vRNA) levels were approximately 10-fold lower than those in blood. In HIV-2(GB122) infection, seminal virus was delayed by 1-2 weeks compared with that in blood. Intrarectal inoculation resulted in a shorter duration of seminal vRNA expression and intermittent seminal cell provirus. No delays, higher peaks ( approximately 50-fold), or longer durations in seminal virus expression were noted for SHIV(89.6P) infection. This novel model definitively establishes that virus dissemination results in early peak seminal levels and provides a basis for evaluating interventions targeting male genital tract expression.

Animals↗
PubMed2001

Lipoprotein access to MHC class I presentation during infection of murine macrophages with live mycobacteria.

Following uptake by macrophages, live mycobacteria initially reside within an immature phagosome that resists acidification and retains access to recycling endosomes. Glycolipids are exported from the mycobacterial phagosome and become available for immune recognition by CD1-restricted T cells. The aim of this study was to explore the possibility that lipoproteins might similarly escape from the phagosome and act as immune targets in cells infected with live mycobacteria. We have focused on a 19-kDa lipoprotein from Mycobacterium tuberculosis that was previously shown to be recognized by CD8(+) T cells. The 19-kDa Ag was found to traffic separately from live mycobacteria within infected macrophages by a pathway that was dependent on acylation of the protein. When expressed as a recombinant protein in rapid-growing mycobacteria, the 19-kDa Ag was able to deliver peptides for recognition by MHC class I-restricted T cells by a TAP-independent mechanism. Entry into the class I pathway was rapid, dependent on acylation, and could be blocked by killing the mycobacteria by heating before infection. Although the pattern of 19-kDa trafficking was similar with different mycobacterial species, preliminary experiments suggest that class I presentation is more efficient during infection with rapid-growing mycobacteria than with the slow-growing bacillus Calmette-Guérin vaccine strain.

Animals↗
PubMed2000

9:45-10:00. Superimposition of EBCT Determined Coronary Calcium Deposits onto Myocardial PET Perfusion Images by Rubidium-82 and Nitrogen-13 Ammonia for Assessment of Flow Limiting Defects.

Calcium localization by Electron Beam CT (EBCT) in the coronary arteries is becoming an important non-invasive method for screening asymptomatic patients for early coronary atherosclerosis. However, the relationship between coronary artery calcium deposits and myocardial perfusion abnormalities has not been established. We have developed software to superimpose location of coronary calcium by EBCT onto PET myocardial perfusion images, so that we can determine the role of location and amount of calcium in the arteries to flow-limiting perfusion defects by PET.EBCT and PET transaxial images are each first converted to three-dimensional arrays of 1 mm voxels. The resulting two image volumes sets are displayed so that a vertical line can be drawn from the clavicle to the spine for proper rotation of the body. The rotated images are then displayed superimposed and are shifted in the vertical, horizontal, and the long axis directions to co-register the EBCT and PET images. The EBCT images are windowed for calcium Houndsfield numbers and calcium location is added to the PET images as a maximum intensity value in the image. The modified PET image volume is then translated back to the PET data format and reprocessed using cardiac analysis software such that the calcium location is superimposed on the PET myocardial perfusion images.Preliminary results of the PET-EBCT superimposition program correlate with location of coronary calcium by EBCT and PET perfusion defects following stress. This technique may be useful for identifying flow-limiting calcium deposits in the coronary arteries.

Journal Article↗
PubMed2000

9:00-9:15. Antiangiogenic Treatment with Endostatin Results in Uncoupling of Blood Flow and Glucose Metabolism in Human Tumors.

Endostatin is a novel antiangiogenic agent currently in phase I trials. In the context of this trial, we are evaluating the use of non-invasive imaging with PET to determine the relationship between tumor blood flow and glucose metabolism in imaged tumors from treated patients.Ten patients have been treated with escalating daily iv Endostatin doses of 30 to 180 mg/m(2). PET images were obtained before the start of therapy and again after 28 days of treatment. Each patient was scanned with Oxygen-15 labeled water for estimation of tumor blood flow and Flourine-18 labeled FDG to estimate tumor metabolic activity. In most cases, two distinct tumor-bearing sites were analyzed in each patient. Thus, a total of 19 tumors were imaged. Regional blood flow and standard uptake values (SUV) were computed at baseline and 28 days post treatment and the percentage change in blood flow and SUV plotted as a function of Endostatin dose.Both blood flow and glucose metabolism in the imaged tumors were observed to increase in patients treated with </=60 mg/m(2)/d, but became uncoupled in the tumors imaged from patients treated at the 180 mg/m(2)/d dose level. Thus, in patients receiving Endostatin at a dose of 180 mg/m(2)/d, blood flow decreased but glucose metabolism increased. This relationship is displayed in Figure 1 below.

Journal Article↗
PubMed2000

9:30-9:45. First Pass FDG Measured Blood Flow in Tumors: A Comparison with O-15 Labeled Water Measured Blood Flow.

The purpose of this study was to determine if the first-pass of FDG can be used to measure regional blood flow in tumors in the absence of perfusion imaging with a known blood flow tracer.PET scans were obtained in patients being evaluated for tumor perfusion and metabolism in a Phase I dose escalating protocol for Endostatin, a novel antiangiogenic agent. A two minutes perfusion scan was done with a bolus injection of 60 mCi of O-15 labeled water followed by a 10 mCi dose of FDG and four sequential scans consisting of a first pass two minutes scan and three 15 minutes scans. Regions of interest were drawn on two tumor sites for each scan. Blood flow was computed using a one-compartment model previously published by the authors. Linear regression analysis was carried out between the first pass FDG measured blood flow and O-15 measured blood flow (Figure 1).Blood flow estimated from the first pass of FDG was linearly correlated with O-15 measured blood flow with an intercept of 0.01, slope of 0.86, and r squared regression coefficient of 0.74 (R = 0.86) for blood flow values of up to 0.6 ml/min/gm of tissue. These results suggests that in the absence of a perfusion tracer, the first pass of FDG provides an estimate of perfusion in a tumor within the limitations of incomplete extraction of FDG compared to O-15 water.

Journal Article↗
PubMed1999

Identification of cold-sensitive mutations in the Schizosaccharomyces pombe actin locus.

In recent years, the actin cytoskeleton in Schizosaccharomyces pombe has become the subject of intense scrutiny. However, to date, only a single actin mutation has been identified. Described here is the isolation and characterization of four new cold-sensitive actin mutations. Sequence analysis of the mutant actin genes indicated that each of these mutations caused alterations in single amino acids that are conserved in all actin sequences. These mutants differ in their phenotypes. One of these mutations (act1-48) was identified as an extragenic suppressor of a mutation in the cdc4 gene, which is required for actin ring formation and cytokinesis. Interestingly, when act1-48 mutant cells were shifted to the restrictive temperature, actin patches were not detected but the actin ring formation and stability was unaffected. The three other mutations, act1-16, act1-32 and act1-67, primarily affected the actin ring formation or stability while F-actin patches did not seem to be substantially different in appearance. Given that the ultrastructural architectures of F-actin patches and the F-actin ring are presently unclear, these mutations, which affect one structure or the other, should be useful for future studies on the role of actin itself in the function of these F-actin-containing structures in S. pombe.

Actins↗
PubMed1999

Pre-transplantation testing: who, when and why?

An ever-widening range of human organs and tissues is being transplanted, limited currently only by the ingenuity of surgeons and immunologists to overcome the physical and immune barriers. Microbiologists are in danger of being left behind. Although the major infective risks of human organ transplantation are now well understood, many details remain controversial, and the special risks associated with tissue banking have received little attention until recently. What should we do? Are we making mountains out of molehills? Are there any data on which to base a rational decision? Topics covered include: bacteriology of cadaveric heart valve transplantation (why are valves not cultured and only dunked in antibiotic solution for 24h, whereas endocarditis gets treated for 4 weeks?); screening for tissue-born viruses (why does everyone persist with serology when genomic methods are so much better?); screening organ donors for CMV (surely we should use the optimally sensitive combination of methods?); peripheral blood stem cell transplants (should we culture these, and what do the positive results mean if we do?); donor sputum screening before heart-lung transplantation (does this aid the post-operative management of the recipient?). With active participation from the floor some areas of consensus were identified and topics worthy of scientific investigation in the future were highlighted.

Heart Valves↗
PubMed1998

Empyema thoracis: a role for open thoracotomy and decortication.

BACKGROUND: Thoracentesis and antibiotics remain the cornerstones of treatment in stage I empyema. The management of disease progression or late presentation is controversial. Open thoracotomy and decortication is perceived to be synonymous with protracted recovery and prolonged hospitalisation. Advocates of thoracoscopic adhesiolysis cite earlier chest drain removal and hospital discharge. This paper challenges traditional prejudice towards open surgery. METHODS: A five year audit of empyema cases referred to a regional cardiothoracic surgical unit analysing previous clinical course, surgical management, and outcome. RESULTS: Between February 1992 and February 1997, the number of referrals to this centre increased dramatically. Twenty-two children were referred for surgery (15 boys, seven girls; age range, 0.5-16 years). Before referral, patients had been unwell for 6-50 days (median, 15), had been treated with several antibiotics, and had undergone chest ultrasound (15 patients), computed tomography (five patients), pleural aspiration attempts (13 patients), and intercostal drainage (seven patients). The organism responsible was identified in only two cases (Streptococcus pneumoniae). Three patients had intraparenchymal abscess formation. Eighteen patients underwent open thoracotomy and decortication. Drain removal was performed on the first or second day. Fever resolved within 48 hours. Median hospital stay was four days. All patients had complete clinical and radiological resolution. CONCLUSIONS: Treatment must be tailored to the disease stage. In stage II and III diseases, open decortication followed by early drain removal results in rapid symptomatic recovery, early hospital discharge, and complete resolution. In the early fibrinopurulent phase, alternative strategies should be considered. However, even in ideal cases, neither fibrinolysis nor thoracoscopic adhesiolysis can achieve more rapid resolution at lower risk.

Adolescent↗
PubMed1997

The proteasome-specific inhibitor lactacystin blocks presentation of cytotoxic T lymphocyte epitopes in human and murine cells.

We describe the effect of the proteasome specific inhibitor lactacystin on the metabolic stability of influenza nucleoprotein (NP) and on the generation of antigens presented by human and murine class I molecules of the major histocompatibility complex to cytotoxic T lymphocytes (CTL). We show that cells treated with lactacystin fail to present influenza antigens to influenza-specific CTL, but retain the capacity to present defined epitopes expressed as peptides intracellularly by recombinant vaccinia viruses. This block in antigen presentation can be overcome by expressing the viral protein within the lumen of the endoplasmic reticulum, confirming the specificity of lactacystin for cytosolic proteases. We also show that the effect of lactacystin on antigen presentation correlates with the block of breakdown of a rapidly degraded form of the influenza NP linked to ubiquitin. These results demonstrate that proteasome-dependent degradation plays an important role in the cytosolic generation of CTL epitopes.

Acetylcysteine↗
PubMed1997

Infection with HIV-1 group O.

The author presents the case history of the first patient with HIV-1 group O reported in the United States. The various human retroviruses and their clinical syndromes are described and the increasing diversity of HIV-1 strains and their spread are documented. The discovery of the divergent group O and its spread from endemic areas are discussed. The clinician is alerted to the pitfalls of laboratory diagnosis and is advised to seek special studies when clinical findings and epidemiologic history suggest the possibility of HIV infection.

Adult↗
PubMed1997

Prolonged inhibition of normal ovarian cycles in the rat and cynomolgus monkeys following a single s.c. injection of danazol.

In castrated male rats, a single s.c. injection of danazol has been shown to result in an inordinately prolonged inhibition of serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations. In the present study, we have examined whether the same and similar routes of administration suppresses ovarian function in normally cycling rats and cynomolgus monkeys. Normally cycling female rats received danazol as a single administration either orally, i.m. or s.c. and a separate group also received danazol in silastic capsules. The duration of the dioestrous interval until the next oestrous smear was followed daily and cycle lengths were compared with vehicle-treated groups. Six normally cycling cynomolgus monkeys were followed by daily observation and blood sampling at 2-3 day intervals. After one normal cycle, danazol (200 mg/kg) was administered as a single s.c. injection. Monkeys were followed until the next menses and one cycle thereafter and blood samples were assayed for oestradiol, progesterone and bioactive LH. Oestrous cycle length in vehicle-treated control rats was 4.7 days. A single administration of danazol s.c. at the higher dose prolonged the dioestrous interval to 31.3 days (P <0.001) and a similar prolongation was observed with this high dose when administered i.m. (27.7 days; P <0.001). In normally cycling monkeys, the menstrual cycle length was 30.2 days, but following a single danazol administration, the mean duration to the next menses was prolonged to 117.5 days (P <0.001). In five out of six monkeys, there was a decrease in LH and an absence of normal oestradiol and progesterone patterns. After this prolonged hiatus, a subsequent menstrual cycle was normal in length and endocrine pattern. A single s.c. administration of danazol resulted in a prolonged suppression of ovarian cyclicity in both normally cycling rats and cynomolgus monkeys.

Animals↗