Search PubMed⌕ Search

Biomedical subjects

R Williams

Publications and source records attributed to R Williams.

At least 91 records · Page 5Linked to original sources
PubMed2001

Trophoblast-specific expression and function of the integrin alpha 7 subunit in the peri-implantation mouse embryo.

For implantation and placentation to occur, mouse embryo trophoblast cells must penetrate the uterine stroma to make contact with maternal blood vessels. A major component of the uterine epithelial basement membrane and underlying stromal matrix with which they interact is the extracellular matrix protein laminin. We have identified integrin alpha 7 beta 1 as a major receptor for trophoblast-laminin interactions during implantation and yolk sac placenta formation. It is first expressed by trophectoderm cells of the late blastocyst and by all trophectoderm descendants in the early postimplantation embryo through E8.5, then disappears except in cells at the interface between the allantois and the ectoplacental plate. Integrin alpha 7 expression is a general characteristic of the early differentiation stages of rodent trophoblast, given that two different cultured trophoblast cell lines also express this integrin. Trophoblast cells interact with at least three different laminin isoforms (laminins 1, 2/4, and 10/11) in the blastocyst and in the uterus at the time of implantation. Outgrowth assays using function-blocking antibodies show that alpha 7 beta 1 is the major trophoblast receptor for laminin 1 and a functional receptor for laminins 2/4 and 10/11. When trophoblast cells are cultured on substrates of these three laminins, they attach and spread on all three, but show decreased proliferation on laminin 1. These results show that the alpha 7 beta 1 integrin is expressed by trophoblast cells and acts as receptor for several isoforms of laminin during implantation. These interactions are not only important for trophoblast adhesion and spreading but may also play a role in regulating trophectoderm proliferation and differentiation.

Alternative Splicing↗
PubMed2001

Comparative expressed sequence hybridization to chromosomes for tumor classification and identification of genomic regions of differential gene expression.

Altered expression of genes can have phenotypic consequences in cancer development and treatment, developmental abnormalities, and differentiation processes. Here we describe a rapid approach, termed comparative expressed sequence hybridization (CESH), which gives a genome-wide view of relative expression patterns within tissues according to chromosomal location. No prior knowledge of genes or cloning is required, and minimal amounts of tissue can be used. Expression profiles are achieved in a manner similar to the identification of chromosomal imbalances by comparative genomic hybridization analysis. The approach is demonstrated to indicate a chromosomal region that harbors overexpressed genes that may be associated with a drug-resistant phenotype. In addition, known and new regions of differential gene expression in both normal tissues and tumor samples from the soft tissue sarcoma group of rhabdomyosarcoma (RMS) are indicated. These regions included 2p24; overexpression of MYCN at 2p24 was confirmed by quantitative reverse transcription-PCR for all of the alveolar RMS cases and did not necessarily correspond to genomic amplification. Evidence including region specific microarray analysis indicated that overexpression of several genes from a region may be required for detection by CESH. This evidence is consistent with clusters of functionally related genes and mechanisms that affect the expression of a number of genes at a particular genomic location. The distinctive CESH profiles demonstrated in different subtypes of RMS show potential for tumor classification.

Chromosomes, Artificial, Yeast↗
PubMed2001

Hepatocyte Growth Factor/scatter factor-induces phosphorylation of cortactin in A431 cells in a Src kinase-independent manner.

The Hepatocyte Growth Factor receptor transduces proliferating and scattering signals in epithelial and endothelial cells. We have explored potential interactions of the HGF/SF receptor beta-subunit (p145(beta MET)) with F-actin binding partners aiming to identify novel downstream effectors implicated in HGF/SF pluripotent signalling. Cortactin, a p80/85 F-actin binding protein, was found phosphorylated on tyrosine in response to HGF-SF in A431 human epidermoid carcinoma cells, expressing the HGF/SF receptor (c-MET). The HGF/SF receptor was enriched in the detergent-insoluble fraction and was found to co-precipitate with cortactin and to associate in vitro with cortactin. The Grb2 small adapter protein known to associate via its Src homology 2 domain (SH2) with the MET C-terminus, was also associated with cortactin. Transient transfection of A431 cells with dominant-negative Grb2 constructs has revealed that the Grb2-C-SH3 domain possesses a central role in cortactin phosphorylation in response to HGF/SF. Finally, tyrosine phosphorylation of cortactin was found uncoupled of endogenous c-Src kinase activity, thus further supporting the hypothesis that cortactin is a direct target of the MET kinase. We propose that cortactin may constitute a docking site for MET-derived signals within the cytoskeleton.

Adaptor Proteins, Signal Transducing↗
PubMed2001

MUC 1: a genetic susceptibility to infertility?

In man and some animals regulation of embryo implantation by endometrial expression of the highly polymorphic MUC 1 mucin has been suggested. We assessed the polymorphism of MUC 1 in women known to be fertile and those with infertility due to suspected failure of embryo implantation. The median of the lower allele size in the infertile group was only 2.5 kb compared with 3.4 kb in the fertile group (p=0.0029, difference 0.9, [95% CI 0.1-1.3]). Women with unexplained infertility might have a genetic susceptibility to failure of embryo implantation due to small MUC 1 allele size.

Adult↗
PubMed2001

Global trends in resistance to antituberculosis drugs. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance.

BACKGROUND: Data on global trends in resistance to antituberculosis drugs are lacking. METHODS: We expanded the survey conducted by the World Health Organization and the International Union against Tuberculosis and Lung Disease to assess trends in resistance to antituberculosis drugs in countries on six continents. We obtained data using standard protocols from ongoing surveillance or from surveys of representative samples of all patients with tuberculosis. The standard sampling techniques distinguished between new and previously treated patients, and laboratory performance was checked by means of an international program of quality assurance. RESULTS: Between 1996 and 1999, patients in 58 geographic sites were surveyed; 28 sites provided data for at least two years. For patients with newly diagnosed tuberculosis, the frequency of resistance to at least one antituberculosis drug ranged from 1.7 percent in Uruguay to 36.9 percent in Estonia (median, 10.7 percent). The prevalence increased in Estonia, from 28.2 percent in 1994 to 36.9 percent in 1998 (P=0.01), and in Denmark, from 9.9 percent in 1995 to 13.1 percent in 1998 (P=0.04). The median prevalence of multidrug resistance among new cases of tuberculosis was only 1.0 percent, but the prevalence was much higherin Estonia (14.1 percent), Henan Province in China (10.8 percent), Latvia (9.0 percent), the Russian oblasts of Ivanovo (9.0 percent) and Tomsk (6.5 percent), Iran (5.0 percent), and Zhejiang Province in China (4.5 percent). There were significant decreases in multidrug resistance in France and the United States. In Estonia, the prevalence in all cases increased from 11.7 percent in 1994 to 18.1 percent in 1998 (P<0.001). CONCLUSIONS: Multidrug-resistant tuberculosis continues to be a serious problem, particularly among some countries of eastern Europe. Our survey also identified areas with a high prevalence of multidrug-resistant tuberculosis in such countries as China and Iran.

Antitubercular Agents↗
PubMed2001

Properties of microtubules assembled from mammalian tubulin synthesized in Escherichia coli.

When isolated from tissues, the alpha beta-dimeric protein tubulin consists of multiple isoforms which originate from the expression and subsequent posttranslational modification of multiple polypeptide sequences. Microtubules studied in vitro consist of mixtures of these isoforms. It is therefore not known whether dimers composed of single sequences of alpha- and beta-tubulin can polymerize to form microtubules, or whether posttranslational modifications may be necessary for microtubule assembly. To initiate investigation of these questions, rabbit reticulocyte lysate, which contains the cytoplasmic chaperonin CCT and its cofactors, was employed to prepare substantial quantities (tens of micrograms) of active tubulin by in vitro folding of mouse alpha- and beta-tubulins recombinantly synthesized in E. coli. This recombinant tubulin is composed of only a single alpha-chain and a single beta-chain. When analyzed after folding by isoelectric focusing, each chain yielded only one band, indicating that neither was detectably posttranslationally modified in the course of the folding reaction. When subjected to assembly-promoting conditions, this tubulin formed microtubules without the addition of any exogenous protein. Electron microscopy showed them to be of normal morphology. Analysis of their protein composition showed that they are composed nearly entirely of recombinant tubulin. These results demonstrate that the naturally occurring mixtures of isoforms are not strictly required for the formation of microtubules. They also open a route to other studies, both biomedical and structural, of fully defined tubulin in vitro.

Animals↗
PubMed2001

Novel immunoassay for the detection of hepatitis B surface 'escape' mutants and its application in liver transplant recipients.

Hepatitis B virus (HBV) strains with mutations in the surface gene are responsible for the failure of prophylaxis with hepatitis B immunoglobulin (HBIG) in a proportion of patients transplanted for HBsAg positive cirrhosis. So far, the emergence and evolution of these 'surface antibody escape' mutants have been studied by DNA sequencing. In this study the use of an immunoassay is described for diagnosis and characterisation of HBV recurrence after liver transplantation (OLT), based on a monoclonal antibody able to recognise both wild-type and mutant HBsAg. Pre- and post-transplant samples from 22 patients transplanted for HBsAg positive cirrhosis were studied: Group A: 12 patients who reinfected the graft despite receiving HBIG; Group B: 6 patients with no HBV recurrence with continuous HBIG; Group C: 4 patients with HBV recurrence without prophylaxis. By running the new assay in parallel with an immunoassay that is susceptible to HBsAg mutants, 4 of 12 cases were identified in Group A with HBV recurrence due to surface antibody escape mutants, whereas in 8 patients this was due to the wild-type HBV. The results from the immunoassays were confirmed in all cases by HBV DNA sequencing. The surface gene mutations in the 4 patients affected codons 144 and 145 and in one of these 4 patients HBV strains with mutations in both codons were detected before and after transplantation. The epitope recognised by the new monoclonal antibody that reacts with both wild-type and mutant HBsAg seems to remain stable in the HBIG-induced HBV mutants. This serological approach allows rapid and cost-effective screening for HBsAg escape mutants in the liver transplant setting and may be helpful in the selection of appropriate prophylaxis.

Antibodies, Monoclonal↗
PubMed2001

Pathological evaluation of intervertebral disc tissue specimens after routine cervical and lumbar decompression. A cost-benefit analysis retrospective study.

BACKGROUND: After decompression of cervical and lumbar nerve roots for radicular pain, pathological evaluation of the extracted disc material is commonly performed. Although histological examination rarely detects clinically significant unsuspected disease, it remains a common practice in most hospitals in the United States. To determine the cost-effectiveness of this routine practice, we conducted a retrospective study. The results are contained within this report. METHODS: Using the University Neurosurgery database, we retrospectively identified 1,387 patients who had spinal decompression surgery (laminectomy and/or discectomy). These cases were broadly classified into routine and non-routine cases depending on the preoperative diagnosis. Benign and noninfectious cases were classified as routine; malignant and all other cases were classified as nonroutine. We reviewed the medical records and pathology reports of these routine and nonroutine cases in an attempt to study the efficacy of the pathological evaluation of the disc material. The cost-benefit value of histopathology in these cases was analyzed, retrospectively. RESULTS: In all routine cases, the histopathology was consistent with benign disc disease and yielded no additional information that could have altered the treatment plan. In the nonroutine cases, however, histopathology was significant in the management of the patient. The cost factor for pathological study was the same for both case groups. CONCLUSIONS: Pathological study of intervertebral disc specimens is cost beneficial only in cases with significant preoperative clinical diagnoses. Pathological evaluation of routine herniated nucleus pulposus extracted during decompressive surgeries is not warranted.

Cervical Vertebrae↗
PubMed2001

Endoscopic-guided trephination dacryocystorhinostomy (Hesham DCR): technique and pilot trial.

OBJECTIVES: (1) Test the feasibility and the safety of guided transnasal trephination in creating a nasolacrimal fistula. (2) Develop an appropriate lacrimal maintainer and test its value in modulating healing at the fistula site. DESIGN: Prospective, noncomparative interventional case series. PARTICIPANTS: Five cadavers and 19 patients. METHOD: A transcanalicular lacrimal probe penetrated the lacrimal fossa to guide the passage of a flexible trephine up the nose, which created the nasolacrimal communication. A special wide-caliber lacrimal maintainer was inserted along lacrimal tubes within the created passage. OUTCOME MEASURES: For cadaveric study, direct inspection after dissection of the facial flap was performed. For the clinical trial, subjective improvement in watery eye, dye testing, lacrimal probing, lacrimal irrigation, and endoscopic nasal examination. RESULTS: The technique resulted in the creation of a regular fistula of reproducible diameter into which a standard-shaped wide caliber maintainer could be inserted. Three months after removal of the maintainer and 6 months after surgery, a patent ostium was achieved in 17 of 18 (94%) patients who had a completed procedure. Relief of symptoms was achieved in 83%. CONCLUSIONS: Guided endoscopic dacryocystorhinostomy provides a simple and safe option for the treatment of nasolacrimal duct obstruction. The lacrimal maintainer is a useful device to achieve a large patent nasolacrimal communication.

Adult↗
PubMed2001

Living related adult-to-adult liver transplantation: meeting the donor shortage.

Experience in the Cromwell Hospital London, Adult-to-Adult Living Donor Liver Transplantation programme is described with particular reference to the results obtained in the first five recipients. The first two of these received a left lobe graft and the remaining three a right lobe graft. Three sons/daughters, and two siblings were the donors. Four of the five recipients survived and did well. The one recipient who died was a complicated retransplant procedure. The donors showed rapid recovery of liver function with normal tests by the 10th day and with evidence of regeneration on follow-up CT volume evaluation. The value of the procedure for patients who have little chance of obtaining a cadaver organ is undoubted, but critical assessment of the recipient's clinical state is essential if success is to be obtained with a small graft and at all times the safety of the donor must remain of paramount concern, as reports to date indicate instances of donor death in adult programme.

Adolescent↗
PubMed2001

Diabetes healthcare strategies.

This article describes and contrasts two approaches to planning strategies for diabetes care. These are the 'epidemiologically based healthcare needs assessment' and 'marginal analysis'. Both have their advantages and disadvantages. The most effective way of planning services is likely to be a pragmatic combination of these two approaches.

Delivery of Health Care↗
PubMed2001

Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation.

BACKGROUND/AIMS: The long-term prophylaxis of hepatitis B after liver transplantation requires further optimization. In a randomized trial we investigated a regimen where the initially given hepatitis B immunoglobulin (HBIg) is replaced by long-term lamivudine treatment. METHODS: Twenty-four liver transplant recipients (all HBsAg-positive/HBV DNA-negative before transplantation), who had received HBIg for at least 6 months without HBV recurrence, were randomized to receive lamivudine (n = 12) or HBIg (n = 12) for 52 weeks. The efficacy criteria involved seronegativity for HBsAg and undetectable HBsAg/ HBcAg in the liver. RESULTS: Twenty-one of 24 patients completed the study without hepatitis B virus (HBV) recurrence (11 on HBIg, ten on lamivudine), while three patients became HBsAg-positive. Amongst those without HBV recurrence HBV DNA was detectable only by polymerase chain reaction, intermittently in serum and lymphocytes, and in liver specimens from six of eight patients receiving HBIg and five of seven receiving lamivudine. YMDD variant was found in four cases with no viral antigen expression. Eight patients continued lamivudine after the study and during an additional 6-22 months remained HBsAg-negative with normal graft function. CONCLUSIONS: Substitution of HBIg with lamivudine is effective for prevention of HBV recurrence in low-risk liver transplant recipients and offers a convenient and cost-effective alternative for long-term HBV prophylaxis.

Adult↗
PubMed2001

Non-cytolytic inhibition of hepatitis B virus replication in human hepatocytes.

BACKGROUND/AIMS: Interferon-gamma (IFN-gamma) has been shown to abolish hepatitis B virus (HBV) gene expression and replication in HBV transgenic mice without destroying infected hepatocytes. We investigated the characteristics of IFN-gamma induced non-cytolytic inhibition of viral replication in human HBV infection. METHODS: We used an in vitro model where lymphocytes from 15 HBsAg positive patients were co-cultured with transfected hepatocytes supporting HBV replication. The effector and target cells were separated by a membrane, which allowed transfer of soluble factors only, to determine whether IFN-gamma produced from antigen-specific CD4+ T cells or mitogen stimulated lymphocytes inhibits HBV replication. RESULTS: IFN-gamma produced following lymphocyte stimulation reduced cytoplasmic HBV DNA in the target cells. The degree of HBV DNA reduction correlated with the level of IFN-gamma in the supernatants. Further investigations using naturally infected human hepatocytes confirmed that recombinant IFN-gamma reduces HBV DNA and HBV RNA in these cells as well, in parallel with the induction of cellular interferon-responsive genes. This antiviral effect was without significant cytotoxicity and was more pronounced in hepatocytes from patients with low HBV replication. CONCLUSIONS: These results provide direct evidence that IFN-gamma can inhibit both HBV transcription and replication in human hepatocytes without cell lysis.

Adult↗
PubMed2001

Morbidity and Irish Catholic descent in Britain. Relating health disadvantage to socio-economic position.

In common with some other ethnic and religious minorities whose forebears migrated from their country of origin, Irish Catholics in Britain are less well off than the host population in terms of socio-economic position and health. Results are presented from a Scottish study, where Catholic religion of origin mainly indicates Irish ancestry, and it is estimated that about one-third of the population is of significant Irish descent. In this study, excess of physical and mental health problems and disability have previously been reported for those of Catholic background, particularly in the eldest cohort (aged 56 in 1988), and have not been fully explained by health-related behaviour. In this paper, we examine a number of key health measures, namely self-assessed health, number of symptoms in the month prior to interview, sadness or depression, disability and lung function, and various indicators of socio-economic position (head of household social class, main source of income, car ownership, housing tenure and school-leaving age), which all show Catholic disadvantage. Using longitudinal results from the 723 respondents who completed interviews both at sweeps one (1988) and three (1995), it is estimated that about half of the morbidity excess amongst middle-aged Catholics in Glasgow can be explained by socio-economic disadvantage. The health and socio-economic position of white minorities and disadvantaged religious minorities like Catholics in Scotland should be monitored by a co-ordinated information strategy.

Aged↗
PubMed2001

Developing and deploying a patient safety program in a large health care delivery system: you can't fix what you don't know about.

BACKGROUND: The Veterans Administration (VA) identified patient safety as a high-priority issue in 1997 and implemented the Patient Safety Improvement (PSI) initiative throughout its entire health care system. In spring 1998 the External Panel on Patient Safety System Design recommended alternative methods to enhance reporting and thereby improve patient safety. REDESIGNING THE PSI INITIATIVE: The VA began redesigning the PSI initiative in late 1998. The dedicated National Center for Patient Safety (NCPS) was established. Using the panel's recommendations as a jumping-off point, NCPS began to identify known and suspected obstacles to implementation (such as possible punitive consequences and additional workload). NCPS adopted a prioritization scoring method, the Safety Assessment Code (SAC) Matrix, for close calls and adverse events, which requires assessing the event's actual or potential severity and the probability of occurrence. The SAC Matrix specifies actions that must be taken for given scores. Use of the SAC score permits a consistent handling of reports throughout the VA system and a rational selection of cases to be considered. A system for performing a root cause analysis (RCA) was developed to guide caregivers at the frontline. This system includes a computer-aided tool, a flipbook containing a series of six questions, and reporting of the findings back to the reporter. The final step requires that the facility's chief executive officer "concur" or "nonconcur" on each recommended corrective action. The RCA team outlines how the effectiveness of the corrective action will be evaluated to verify that the action has had the intended effect, and it ascertains that there were no unintended negative consequences. IMPLEMENTATION: Based on successful implementation in two pilots, full-scale national rollout to the 173 facilities began in April 2000 and was concluded by the end of August 2000. NCPS supplied 3 days of training for individuals at each facility. The training included didactic components, an introduction to human factors engineering concepts, and small- and large-group simulation exercises. Facility leaders were reminded of the necessity to reinforce the point that assignment to an RCA team was considered an important duty. DISCUSSION: It is essential to design and implement a system that takes into account the concerns of the frontline personnel and is aimed at being a tool for learning and not accountability. The system must have as its primary focus the dissemination of positive actions that reduce or eliminate vulnerabilities that have been identified, not a counting exercise of the number of reports.

Databases, Factual↗