Biomedical subjects

A Williams

Publications and source records attributed to A Williams.

At least 307 records · Page 17Linked to original sources

PubMed1996

Tin(IV)-functionalised polymer supports; non-toxic and practical reagents for regioselective acetylation of sucrose.

Polymer-supported butyltin(IV) reagents have been surveyed for regioselectivity in acetylation of sucrose. Polymer-supported butyltin(IV) dichloride 8 catalysed the acetylation of sucrose to give a 59% yield of 6-O-acetyl sucrose 3, the precursor of sucralose. The yield is close to that of a previously reported process involving dibutyltin(IV) oxide (Bu2SnO). The spent polymeric resin could readily be regenerated and can be subsequently used in further synthetic reactions.

Acetylation↗

PubMed1996

Phase I trial of extracellular adenosine 5'-triphosphate in patients with advanced cancer.

Adenosine 5'-triphosphate (ATP) has antineoplastic activity in vitro and in murine tumor systems, but there are no data in humans defining its potential use as an antineoplastic agent. We conducted a phase I study to determine the spectrum of toxicity, maximum safely tolerated dose (MTD), and pharmacokinetics of intravenous ATP. Fourteen men with advanced cancer received 96-hour infusions of ATP once monthly in doses ranging from 50 to 100 micrograms/kg/minute. Toxicity was assessed by standard National Cancer Institute (NCI) criteria, cardiac function was monitored serially by two-dimensional echocardiography, and whole blood ATP was measured serially in a subset of patients. ATP was generally well tolerated and no significant hematologic toxicity was noted. The dose-limiting toxicity was a cardiopulmonary reaction characterized by chest tightness and dyspnea that resolved within seconds of discontinuing ATP. Dose-limiting cardiopulmonary toxicity occurred in 3 of 3 patients at 100 micrograms/kg/minute, in 3 of 6 patients at 75 micrograms/kg/minute, and 4 of 11 patients at 50 micrograms/kg/minute. Whole blood ATP levels significantly increased with treatment, reaching a steady state by 24 hours and returning to or near baseline by 1 week after treatment. Plateau levels were 63%, 67%, and 116% above base-line at 50, 75, and 100 micrograms/kg/min, respectively. We conclude that prolonged infusions of ATP are feasible with acceptable toxicity and that 50 micrograms/kg/minute is both the MTD and the most appropriate dose rate for subsequent Phase II testing of 96-hour infusions of ATP in patients with advanced cancer.

Adenosine Triphosphate↗

PubMed1996

Metabolic changes associated with vacuolation in murine models of scrapie using in vitro 1H-NMR spectroscopy.

In this study, metabolic changes in the 79A/C3H, ME7/VM, ME7/C3H, 87V/VM and 22A/SV scrapie mouse models were investigated during the clinical phase of the disease, using in vitro proton nuclear magnetic resonance spectroscopy. N-acetyl-aspartate was found to be significantly reduced in infected mice of the ME7/ C3H (40% reduction), ME7/VM (26%) and 79A/C3H (17%) models when compared to control mice, but not in the 87V/VM and 22A/SV models. The concentration of choline containing compounds and creatine remain unchanged in all models when compared with control murine brains. The level of N-acetyl-aspartate reduction correlated with the extent of grey-matter brain vacuolation. The levels of myo-inositol were found to be significantly increased in the ME7/VM (143%) and 79A/C3H (132%) models only and no significant changes were observed in the ME7/C3H, 87V/VM and 22A/SV models. These changes did not correspond to the severity of gliosis.

Animals↗

PubMed1996

Expression of E-selectin and E-selectin ligands in human liver inflammation.

Lymphocyte recruitment to tissue is regulated by homing molecules expressed on subsets of leukocytes that bind to endothelial adhesion molecules termed addressins in target tissues. The addressins and homing molecules involved in recruiting lymphocytes to inflamed human liver are not known. E-selectin, which acts as an addressin for a subset of skin-infiltrating T cells that express a distinct E-selectin ligand called the cutaneous lymphocyte antigen (CLA), can be detected on endothelium in inflammatory liver diseases suggesting it might also act as an addressin for liver-infiltrating lymphocytes. To determine whether E-selectin does play such a role we looked for concomitant expression of E-selectin on hepatic endothelium and E-selectin ligands on infiltrating lymphocytes in liver sections from patients with primary biliary cirrhosis (PBC), acute allograft rejection, alcoholic liver disease, and normal liver. E-selectin was detected on vascular endothelium in association with lymphocytic infiltrates in all three liver diseases but not on normal endothelium. However, less that 10% of infiltrating lymphocytes expressed the only known lymphocyte E-selectin ligand, CLA. We used E-selectin chimeric fusion proteins to probe for novel E-selectin ligands on liver-infiltrating lymphocytes; however, less than 10% of lymphocytes had t he ability to bind the fusion proteins. Thus, E-selectin is unlikely to act as an addressin for liver-infiltrating lymphocytes, suggesting that other molecules are involved in lymphocyte recruitment to the liver. Despite the lack of binding to lymphocytes other structures in the liver expressed CLA and bound the E-selectin fusion proteins. Inflamed, but not normal, intrahepatic bile ducts expressed CLA and bound E-selectin, suggesting that they express activation dependent carbohydrate binding receptors. Furthermore, Kupffer cells did not express CLA but bound to both E-selectin fusion proteins, suggesting that they express potentially novel E-selectin ligands.

Antibodies, Monoclonal↗

PubMed1996

Surface adhesion-mediated regulation of chondrocyte-specific gene expression in the nontransformed RCJ 3.1C5.18 rat chondrocyte cell line.

Recent evidence suggests that decreased chondrocyte function in osteoarthritis and other articular disorders may be due to chondrocyte dedifferentiation produced by altered regulatory signals from the cartilage extracellular matrix (ECM). However, there are currently no mammalian chondrocytic cell line systems adapted to the study of this process. We therefore examined the effects of ECM growth conditions on markers of differentiated chondrocytic phenotype expression in the nontransformed rat RCJ 3.1C5.18 (RCJ) chondrocyte cell line, including type II collagen expression, aggrecan production, link protein gene expression, and parathyroid hormone (PTH) receptor number. RCJ cells grown in monolayer on plastic exhibited a dedifferentiated phenotype characterized by flattened cell morphology, with > 80% type I collagen and < 5% type II collagen production, as determined by two-dimensional gel mapping electrophoresis of collagen cyanogen bromide peptides. In addition, aggrecan production was low, and link protein mRNA was not expressed at detectable levels. After transfer to growth under minimal attachment conditions on the surface of a composite type I collagen/agarose (0.15%-0.8%) gel (CAG) for 7 days, RCJ cells developed a rounded, chondrocytic morphology and a pattern of differentiated, chondrocytic gene expression, with 79% type II and 8% type I collagen production. Steady-state type I and type II procollagen mRNA levels were altered in parallel with collagen protein expression. In cells grown on CAG, aggrecan production increased 6-fold, and there was a marked increase in both aggrecan core protein and link protein mRNA levels. In addition, maximal PTH-stimulated cAMP generation increased 15-fold in association with an increased PTH receptor number. Therefore, the RCJ chondrocyte cell line is highly sensitive to ECM regulation of chondrocyte-specific gene expression.

Animals↗

PubMed1996

Endogenous interleukin-11 (IL-11) expression is increased and prophylactic use of exogenous IL-11 enhances platelet recovery and improves survival during thrombocytopenia associated with experimental group B streptococcal sepsis in neonatal rats.

Future preventive and/or concurrent therapy of neonatal sepsis may require the use of adjuvant immunohematopoietic therapy. In the present study, using reverse transcription-polymerase chain reaction, we demonstrated a significant increase in IL-11 mRNA extracted from the femurs of group B streptococcus (GBS)-infected rats during acute thrombocytopenia (platelet count: 65.8 +/- 19.3 K/mm3, n = 5) compared to that of uninfected neonatal rats (NR) (635.2 +/- 89 K/mm3, n = 5) (174 +/- 17% vs. 100%, p < 0.001, n = 5). We next investigated the prophylactic effect of rhIL-11 on the PLT recovery as well as survival in NR during experimental GBS sepsis. NR received either rhIL-11 (250 micrograms/kg/d) intraperitoneally for 11 d or sham injections before the induction of experimental GBS sepsis. While experimental GBS sepsis resulted in severe thrombocytopenia in control NR, the rhIL-11 pre-treated group had significantly higher PLT counts (24 hr: 417 +/- 50 vs. 221 +/- 54 K/mm3, p < 0.01; 36 hr: 276 +/- 60 vs. 82 +/- 33 K/mm3, p < 0.01; 48 hr: 402 +/- 77 vs. 101 +/- 82 K/mm3, p < 0.05). Administration of rhIL-11 alone also significantly increased the survival rate at 36 and 48 hrs after GBS inoculation compared to the control group (36 hr: 83% vs. 58%, p < 0.05; 48 hr: 50% vs. 18%, p < 0.01, n > or = 30), as did the combination of rhIL-11 with ABS treatment at 36 hrs, compared to the control group (90% vs. 69%, p < 0.05, n > or = 30). These results suggest that endogenous IL-11 gene expression may be upregulated during acute thrombocytopenia and associated bacterial sepsis in NR. This increase in IL-11 gene expression, however, does not appear to prevent severe thrombocytopenia. Furthermore, prophylactic administration of pharmacological doses of rhIL-11 may be potentially beneficial in the management of neonatal GBS sepsis and its associated thrombocytopenia. Future studies are needed to determine the clinical implications of these findings.

Animals↗

PubMed1996

Health state valuations from the general public using the visual analogue scale.

In the clinical and economic evaluation of health care, the value of benefit gained should be determined from a public perspective. The objective of this study was to establish relative valuations attached to different health states to form the basis for a 'social tariff' for use in quantifying patient benefit from health care. Three thousand three hundred and ninety-five interviews were conducted with a representative sample of the adult British population. Using the EuroQol health state classification and a visual analogue scale (VAS), each respondent valued 15 health states producing, in total, direct valuations for 45 states. Two hundred and twenty-one re-interviews were conducted approximately 10 weeks later. A near complete, and logically consistent, VAS data set was generated with good test-retest reliability (mean ICC = 0.78). Both social class and education had a significant effect, where higher median valuations were given by respondents in social classes III-V and by those with intermediate or no educational qualifications. These effects were particularly noticeable for more severe states. The use of such valuations in a social tariff raises important issues regarding the use of the VAS method itself to elicit valuations for hypothetical health states, the production of separate tariffs according to social class and/or education and the appropriate measure of central tendency.

Activities of Daily Living↗

PubMed1996

An essential role for platelet-derived growth factor in neointima formation in human saphenous vein in vitro.

The role of platelet-derived growth factor (PDGF), a potent vascular smooth muscle cells (SMC) mitogen and chemoattractant, was investigated during neointima formation in human saphenous vein organ culture. PDGFA and B messenger ribonucleic acid (mRNA) expression was detected by RNase protection assay and in situ hybridisation and PDGF protein by immunocytochemistry. The expression of PDGFA and B mRNA was low in veins before culture while PDGF protein was detected in all cell types. A neointima consisting of densely packed SMC developed after 14 days of culture. The dense packing and high expression of PDGFA and B mRNA in neointimal SMC led to higher PDGF protein concentrations in the neointima, the role of which was examined by culturing with neutralising anti-(human PDGF) antibodies. The anti-PDGF antibodies significantly reduced neointimal thickness by approximately 66% and the number of neointimal cells by approximately 50%, without affecting neointimal or medial proliferation indices or cell viability. These results suggest that PDGF played an essential role in SMC migration into the neointima in human saphenous vein.

Adult↗

PubMed1996

Supertasting, earaches and head injury: genetics and pathology alter our taste worlds.

Family studies using thresholds showed that PROP (6-n-propylthiouracil) tasting is produced by a dominant allele, T. Nontasters have two recessive alleles and tasters have one or two dominant alleles. The bitterness of suprathreshold PROP and anatomical criteria subdivide tasters into medium and supertasters. Supertasters may be TT tasters, but this has yet to be demonstrated. Supertasters preceive the greatest bitterness and sweetness from many stimuli as well as the greatest oral burn from alcohol and capsaicin. Women are more likely than men to be supertasters. Otitis media and head trauma can alter taste and thus PROP classifications, complicating studies on PROP genetics. Some subjects with a history of otitis media show taste reductions, but others show enhanced tastes and appear to have more taste buds per fungiform papilla. Subjects with head trauma show reduced tastes on some oral loci, but there is evidence that severe reductions on the front of the tongue ameliorate reductions at the circumvallate papillae on the back of the tongue by a release of inhibition mechanism.

Brain Injuries↗

PubMed1996

Valuing health states: a comparison of methods.

In eliciting health state valuations, two widely used methods are the standard gamble (SG) and the time trade off (TTO). Both methods make assumptions about individual preferences that are too restrictive to allow them to act as perfect proxies for utility. Therefore, a choice between them might instead be made on empirical grounds. This paper reports on a study which compared a "props" (using specifically-designed boards) and a "no props" (using self-completion booklets) variant of each method. The results suggested that both non props variants might be susceptable to framing effects and that TTP props outperformed SG props.

Adolescent↗

PubMed1996

QALYS and ethics: a health economist's perspective.

Objectors on ethical grounds to the use of QALYs in priority-setting in public health care systems are here categorised as (1) those who reject all collective priority-setting as unethical; (2) those who accept the need for collective priority-setting but believe that it is contrary to medical ethics; (3) those who accept the need for collective priority-setting and do not believe that it is contrary to medical ethics, but reject the role of QALYs in it on other ethical grounds; and (4) those who accept the need for collective priority-setting in principle, but are unwilling to specify how it should be done in practice. It is argued that the first two groups of objectors are simply wrong, if distributive justice is a proper ethical concern in this context. The third group is of more interest, as this group appears to believe that QALYs are unethical because it is unethical to regard QALY maximisation as the sole objective of the health care system. This paper argues that QALYs are relevant to a much wider range of objectives than QALY maximisation, and that they can accommodate a wide variety of health dimensions and sources of valuation. They can also accommodate the differential weighting of benefits according to who gets them, so they do not commit their users to any particular notion of distributive justice. What they do commit their users to is the notion that the health of people is a central concept in priority-setting, and that it is desirable, for reasons of accountability, to have the bases for such priority-setting made as precise and explicit as possible. The fourth group of objectors needs to acknowledge that there is no perfect system on offer, and since priority-setting does and will proceed willy-nilly we cannot wait until there is. It would be more constructive to set up the desiderata that a priority-setting system should ideally fulfil, and then appraise all feasible alternatives (including the status quo) even-handedly by those criteria. None will be perfect, but this author predicts that QALYs would emerge from such an appraisal with a significant role to play.

Ethics, Medical↗

PubMed1996

In vitro selection of a high affinity antibody to oestradiol using a phage display human antibody library.

We have isolated a monoclonal antibody binding to oestradiol with high affinity (3.7 nM), and exhibiting a better than 1000-fold selectivity in binding to other steroids. A high affinity antibody with good specificity is essential for the accurate determination of circulating oestradiol levels. To date, conventional hybridoma technology has not yielded a reagent of sufficiently high affinity and specificity for this ligand. The aim of this study was to investigate whether such a reagent was accessible through the engineering of antibodies on the surface of filamentous phage. Antibodies were isolated from a large repertoire of single chain Fv fragments (scFv) derived from non-immunised human donors, with selection and screening procedures biased to favour those binding to free oestradiol. This resulted in an antibody with nanomolar affinity for oestradiol, while affinities for related steroids are in the micromolar range. The relative lack of reactivity for steroids substituted at either end of the molecule suggests that this antibody is unique among anti-steroid monoclonal antibodies in lacking a 'blind-spot'. Our results demonstrate that phage display can provide solutions to problems that have so far proved intractable using conventional hybridoma technology.

Antibodies, Monoclonal↗

PubMed1996

Isolates of Salmonella enterica Enteritidis PT4 with enhanced heat and acid tolerance are more virulent in mice and more invasive in chickens.

Two Enteritidis PT4 isolates which differed in inherent tolerance to heat, acid, H2O2 and the ability to survive on surfaces were used to infect mice, day-old chicks or laying hens. The acid-, heat-, H2O2- and surface-tolerant isolate was more virulent in mice and more invasive in laying hens, particularly in reproductive tissue. However, no significant differences were observed in behaviour in chicks. Both PT4 isolates were able to infect chicks housed in the same room as infected birds, although the heat-tolerant isolate survived significantly better than the heat-sensitive one in aerosols.

Acids↗

PubMed1996

Respiratory insufficiency in neuronopathic and neuropathic disorders.

Twenty-nine patients with a neuronopathic or neuropathic disorder were referred for assessment of respiratory insufficiency between 1978 and 1994. Diagnoses included spinal muscular atrophy (6), chronic idiopathic demyelinating neuropathy (4), Vialetto-van Laere syndrome (3), hereditary motor and sensory neuropathy (3) and a miscellaneous group (5). We also describe seven patients with Guillain-Barré syndrome (GBS) who required long-term ventilatory support for over 6 months to 7 years after the initial illness. Respiratory insufficiency occurred as a consequence of respiratory muscle weakness, impaired bulbar function and restrictive lung defects. In some groups presentation was with progressive nocturnal hypoventilation culminating in acute respiratory failure. Five patients with GBS or chronic idiopathic demyelinating neuropathy were weaned from ventilatory support up to 18 months after the initial illness. The remaining 24 patients required continuous or nocturnal ventilatory support using intermittent positive-pressure ventilation (13), negative pressure ventilation (4), nasal-mask-delivered intermittent positive-pressure ventilation (4), nasal-mask-delivered continuous positive-pressure ventilation (3), mouthpiece-assisted ventilation by day (2) and rocking bed (1). None have been weaned from support after a period of ventilation ranging from one month to 10 years. Eight patients have subsequently died.

Adolescent↗

PubMed1996

Paroxetine as a treatment for premenstrual dysphoric disorder.

Research into the psychobiology of premenstrual dysphoric disorder (PDD) finds alterations in markers associated with serotonergic neurotransmission. Supporting this is work showing that patients with PDD respond to some agents that block the reuptake of serotonin. In this open trial, patients were treated for one cycle with placebo and then for three consecutive cycles with the serotonin reuptake inhibitor paroxetine. The study population was composed of 14 participants who met DSM-IV criteria for PDD with moderate to severe symptomatology and specifically endorsed anger and irritability as a central premenstrual complaint. Patients showed modest improvement over the course of the pretreatment evaluation, with significant improvement occurring for feelings of worthlessness, decreased interest, and low energy. The effects of active treatment were marked by the first active cycle with luteal phase 17-item Hamilton Rating Scale for Depression scores decreasing from 14.9 (+/- 5.3) to 8.2 (+/- 4.9) in the first, 7.8 (+/- 5.1) in the second, and 7.8 (+/- 6.8) in the third active treatment cycles (F[1,13] = 17.6; p < 0.0001). A group of items from daily ratings indicative of anger and irritability (mood swings, anger and irritability, behavioral dyscontrol, and interpersonal conflicts) also showed improvement (F[1,13] = 5.94; p < 0.03). Various definitions of response were applied to treatment completers. The most conservative measure, the Clinical Global Impression (CGI), revealed that 7 of 14 patients had a complete response (CGI = 1 or 2) whereas 4 patients had a partial response (CGI = 3). These open trial findings are consistent with the notion that paroxetine is effective in the acute phase for the treatment of PDD.

Adult↗

PubMed1996

Replication of scrapie in spleens of SCID mice follows reconstitution with wild-type mouse bone marrow.

SCID mice are resistant to intraperitoneal infection with 10(3) and 10(4) intracerebral ID50 units of ME7 scrapie agent whereas they develop disease after intracerebral challenge. However, higher doses introduced, by intraperitoneal or subcutaneous routes, produce disease. Immunocompetent mice of the same strain (CB20) developed scrapie following either intracerebral or intraperitoneal infection. Bioassay of spleens from SCID mice infected with 10(-1) dilutions of ME7 scrapie by intraperitoneal, intracerebral or abdominal subcutaneous injection showed traces or low levels of infectivity in spleen. However, subcutaneous injection beneath the skin of the neck failed to infect the spleen. CB20 bone marrow reconstitution of SCID mice resulted in the regeneration of a normal lymphoid architecture in the spleen. Spleens from these reconstituted mice, infected intracerebrally with a 10(-1) dilution of ME7 contained high levels of infectivity. These results suggest that the ability to replicate scrapie agent in spleen or lymphoid tissue depends on the restoration of normal lymphoid structure and in particular the presence of differentiated follicular dendritic cells. The possibility that SCID mice can select minor strains of scrapie which are normally unrecognized in cloned ME7 is discussed.

Animals↗

PubMed1996

The learning career in the community setting: a phenomenological study of a Project 2000 placement.

The findings of one element of an English National Board-funded research study conducted in two phases between 1989 and 1992 are discussed. The study examined one aspect of the new Project 2000 courses introduced in 13 'demonstration districts' in England in the autumn of 1989. During Phase 2 of the study (1991-1992). 14 district nursing sisters and 12 of the students they supervised were interviewed. Data were re-transcribed and interpreted in 1993; the interpretation was based on a phenomenological paradigm which focused on the subjective perceptions of students and supervisors. Participants identified 'learning', as it took place in the community setting, as a sequential process, which is referred to here as the 'learning career'. Using terminology adopted by participants themselves; the authors identify the stages of the 'learning career' as:'encountering reality'; 'having a go' 'gaining confidence'; 'thinking through and understanding'; 'developing ideas'; 'being independent'; and 'being assessed'. Supervisors could ease their students' passage through this complex and anxiety-provoking sequence of events in a number of ways. They could demonstrate their practice and provide opportunities for students to gain experience for themselves; they could teach their students about nursing, and enable them to reflect on their own practice; and they could also monitor and assess their students' work.

Community Health Nursing↗

PubMed1996

Outcomes and process in genetic counselling.

Although it may be simple to evaluate some elements of clinical genetics, it is difficult to evaluate genetic counselling. We review previous studies of the outcomes of genetic counselling; although the methods used may be valid in research studies, there are practical and ethical difficulties in applying them to the measurement of clinical effectiveness in standard practice. No simple measures of outcomes would be suitable. Research evidence will be helpful in deciding what services it is appropriate to offer, and the quality of a service can then be assured by assessing the quality of the clinical process in three ways: 1) adherence to agreed protocols and standards of care; 2) peer review and audit of clinical activity; and 3) ongoing review of the satisfaction of clients and referring physicians with the service. The assessment of client satisfaction will need to be a sophisticated form of retrospective satisfaction with the service provided, and such a scheme has yet to be fully developed.

Attitude of Health Personnel↗