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Biomedical subjects

I R Williams

Publications and source records attributed to I R Williams.

At least 37 records · Page 2Linked to original sources
PubMed1996

Constitutive expression of B7-1 (CD80) on mouse keratinocytes does not prevent development of chemically induced skin papillomas and carcinomas.

Expression of the B7-1 (CD80) costimulatory molecule in a variety of tumor cell lines leads to an enhanced CD8+ T cell response to tumor Ags. We used transgenic mice constitutively expressing B7-1 on keratinocytes (K14/B7-1 line) to determine whether keratinocyte B7-1 expression would inhibit the development of papillomas and carcinomas following two-stage chemical carcinogenesis in skin. FVB inbred mice carrying the K14/B7-1 transgene and controls were initiated with 25 micrograms of 7,12-dimethylbenz[a]anthracene and promoted weekly with 5 micrograms of 12-O-tetradecanoylphorbol-13-acetate for 20 wk. Expression of the B7-1 transgene did not result in statistically significant decreases in the mean number of papillomas or carcinomas compared with controls. The incidence of carcinomas in both transgenic and control mice reached 90% or greater by 60 wk after initiation. Carcinoma cell lines established from the K14/B7-1 mice maintained expression of B7-1 and Kq. These B7-1 expressing carcinomas grew progressively following intradermal injection into syngeneic FVB mice, further demonstrating their inability to evoke protective tumor immunity. These same carcinoma cell lines were rapidly rejected by minor alloantigen-mismatched SWR mice, confirming their susceptibility to immune effector mechanisms. The failure of constitutive B7-1 expression on keratinocytes to prevent the growth of squamous cell papillomas and carcinomas may reflect the limited immunogenicity of tumors arising after initiation-promotion carcinogenesis. Our results in this transgenic model system are further evidence that B7-1 gene therapy alone may not be sufficient to induce protective immunity to some types of tumors.

Animals↗
PubMed1996

Immunity at the surface: homeostatic mechanisms of the skin immune system.

The coordinated function of multiple epidermal and dermal cell populations allows the skin immune system to respond rapidly and effectively to a wide variety of insults occurring at the interface of the organism and its environment. Keratinocytes are the first line of defense in the skin immune system, and keratinocyte-derived cytokines are pivotal in mobilizing leukocytes from blood and signaling other cutaneous cells. Cytokine-mediated cellular communication also enables dermal fibroblasts and endothelial cells lining the cutaneous vasculature to participate in immune and inflammatory responses. Skin is an important site for antigen presentation, and both epidermal Langerhans cells and dermal dendritic cells play pivotal roles in T cell-mediated immune responses to antigens encountered in skin. Proinflammatory signaling pathways are necessarily balanced by a variety of regulatory pathways that help maintain the homeostatic functioning of the skin immune system.

Animals↗
PubMed1996

Overview of polyethylene as a bearing material: comparison of sterilization methods.

Polyethylene has been used for more than 30 years as an orthopaedic bearing material; however, there has been recent concern regarding the early failure of a small percentage of the polyethylene bearings. The damage seen in some retrieved polyethylene components has been linked to gamma radiation sterilization in air, which was widely used by the industry for years. Gamma radiation in air has been documented to cause an increase in oxidation and degradation of mechanical properties with time. The degradation of polyethylene initiated by gamma sterilization in air has led the orthopaedic industry toward alternative sterilization methods, including gamma radiation in an inert gas or vacuum environment, ethylene oxide gas sterilization, and gas plasma sterilization. For many of these alternative techniques, little clinical performance data exist. This study is a comparative evaluation of sterilization methods using the same analytic techniques that have been used to document the effects of gamma sterilization in air on polyethylene. Fourier transform infrared spectroscopy, electron spin resonance, and uniaxial tensile testing are used to compare, respectively, the oxidation levels, free radical concentration, and mechanical properties of material sterilized by each method. The polyethylene is evaluated before sterilization, poststerilization, and postartificial aging. All examined alternative sterilization methods, when compared with gamma sterilization in air, caused less material degradation during a component's preimplantation shelf life.

Electron Spin Resonance Spectroscopy↗
PubMed1995

Disease progression and perceptions of health in patients with motor neurone disease.

Motor neurone disease (MND) is a useful paradigm for many progressive disabling neurological disorders and serves as a particularly opposite model for the study of patients' responses to progressive and irreversible disability. We studied the progression of disability and the patients' perception of their health in a group of MND patients (n = 14) for 6 months from diagnosis or soon after. A comparison group of similar age, gender ratio and initial disability on Barthel index were Parkinson's disease (PD) patients, admitted because of poor response to outpatient drug therapy and increasing disability (n = 22). MND patients showed rapid deterioration in all aspects of self care and mobility, as assessed by Barthel Index. 32% PD patients showed a significant improvement in disability during their admission. For both groups, perception of their physical health on the SF36 was very poor at recruitment compared to age- and sex-matched population norms. However for patients in both groups the SF36 could not be used to monitor changes in perception of health because of floor effects. In those in whom change could be assessed, there was a trend for MND patients to deteriorate and PD patients to improve. We conclude that loss of independence in self care and failing mobility may occur more rapidly than current medical and social services can accommodate. There is a need for planning and proactive intervention to support patients and careers. The patients' perception of their physical health is poor from time of diagnosis as assessed by the SF36, but this scale cannot be used to monitor patients with MND or late stage PD over time.

Aged↗
PubMed1995

Keratinocyte-derived monocyte chemoattractant protein 1 (MCP-1): analysis in a transgenic model demonstrates MCP-1 can recruit dendritic and Langerhans cells to skin.

Chemokines are thought to play a central role in the recruitment and activation of leukocytes during inflammatory responses. Monocyte chemoattractant protein 1 (MCP-1) is a chemokine of the C-C or beta family that is chemotactic in vitro for monocytes, T cells, and basophils. Its excessive production by keratinocytes has been implicated in psoriasis and other skin diseases. To test the in vivo role of MCP-1 in inflammatory skin disease, we undertook the generation of transgenic mice that express murine MCP-1 in the basal layer of epidermis. Despite production of high levels of functional MCP-1 by basal keratinocytes, documented in vivo and in vitro, these mice did not exhibit spontaneous cutaneous inflammation or any other discernible skin pathology. In contrast, elicited inflammation in the skin of these mice differed qualitatively and quantitatively from that observed in non-transgenic controls. Contact hypersensitivity challenge responses in transgenic animals were characterized by an exaggerated lichenoid infiltration of monocytes and T cells. Additional phenotypic characterization of the normal appearing skin in these mice showed that the only spontaneous change was a dramatic increase and redistribution of CD45+, I-A+ cells that assumed a dendritic morphology in situ, including a subset that expressed markers characteristic of Langerhans cells. Taken together, these data indicate that tissue-specific expression of MCP-1 alone is not sufficient to induce an inflammatory response, though its presence can modify inflammatory and immune events initiated by exogenous stimuli. The recruitment of dendritic and Langerhans cells in the absence of inflammation is a previously unknown consequence of cutaneous MCP-1 production in vivo.

Afferent Pathways↗
PubMed1995

The Otto Aufranc Award. Impact of gamma sterilization on clinical performance of polyethylene in the hip.

Despite studies to determine their causes, significant variations in polyethylene acetabular component wear rates, radial cracking of component rims, and occasional delamination cannot be explained. A subsurface white band frequently occurs in such damaged components. These damaged components often are gamma sterilized. To date, the origin of the band and its effect on polyethylene chemical and mechanical properties, and hence, clinical performance, have not been confirmed, and correlations between radiation sterilization and clinical wear have not been made. By developing techniques for polyethylene retrieval testing and rating, chemical analysis, and mechanical analysis, this research has determined that gamma sterilization in air alters the chemical and mechanical properties of polyethylene over time, resulting in high subsurface oxidation, reduced ductility, and reduced strength. Gamma sterilization-induced oxidation is found to be most severe in the subsurface region of components, and coincides with zones of significantly reduced strength and ductility. This chemical and mechanical property degradation is time dependent and is not typically visible until after 3 years' postirradiation. The presence of the subsurface white band significantly correlates with clinical cracking and delamination observed in retrieved components. Wear of the retrieved components often is observed to have progressed into this heavily oxidized, weakened, and embrittled zone. A method for accelerated aging shows that irradiating in air causes oxidation damage in polyethylene components that is not seen with other sterilization methods. Modifications of gamma sterilization techniques to minimize this damage are discussed.

Biomechanical Phenomena↗
PubMed1995

The tradeoffs associated with modular hip prostheses.

In an effort to gain greater insight into the tradeoffs associated with modular hip prostheses, 2 approaches were taken. A questionnaire was sent to each of the orthopaedic implant manufacturing companies asking specific questions regarding modular components, and a series of retrieved prostheses, both modular and nonmodular, were examined to determine the potential sources of problems associated with modular connections. The respondents to the questionnaire generally agreed that it was more expensive to produce modular prostheses due to the required tolerances at the modular connections, and that the increased flexibility provided by the modularity was important to surgical outcome. There was less consensus on whether inventories were reduced and little data to support any improvement in surgical outcome caused by modularity. The most frequent problems associated with modular connections were fretting and corrosion. Easily observable significant fretting occurred in 4% of 701 head/neck tapers. Corrosion was observed in > 30% of the mixed-alloy head/stem combinations, in < 10% of all-titanium-alloy modular components, and in < 6% of all-cobalt-alloy devices. In 1 series of retrieved modular femoral components (15 titanium alloy and 15 cobalt alloy) with both sets having approximately the same duration of implantation, 7% of the all-cobalt-alloy components had corrosion, whereas 33% of the mixed-alloy components had corrosion.

Alloys↗
PubMed1994

Keratinocyte expression of B7-1 in transgenic mice amplifies the primary immune response to cutaneous antigens.

Resting epidermal keratinocytes do not express B7-1 and other known CD28 counterligands with costimulatory activity. The absence of these costimulators on keratinocytes correlates with their ability to preferentially induce T-cell anergy instead of T-cell activation. To test the hypothesis that keratinocytes expressing a CD28 counterligand would be more effective inducers of T-cell-mediated immune responses in skin, we prepared transgenic mice in which expression of the B7-1 costimulator was targeted to basal keratinocytes by using the human K14 promoter. Keratinocytes from the K14/B7-1 transgenic line expressed high levels of surface B7-1. No spontaneous inflammatory changes were seen in transgenic skin, but epicutaneous application of contact sensitizers to these mice elicited a stronger primary ear swelling response than in controls. Sites of initial hapten application in transgenic mice also responded much more strongly to reapplication of hapten to a remote cutaneous site. Epidermal cell suspensions from transgenic mice contained normal numbers of Langerhans cells and dendritic epidermal T cells when analyzed by flow cytometry. Systemic treatment of the transgenic mice with interferon gamma induced high levels of class II major histocompatibility complex expression on keratinocytes but was not sufficient to initiate an inflammatory response. We conclude that the constitutive expression of the B7-1 molecule in vivo on a nonprofessional antigen-presenting cell is not by itself sufficient to trigger inflammatory changes, but B7-1 expression amplifies the host immune responses after exposure to nonself antigens presented by B7-1-expressing cells.

Animals↗
PubMed1994

Epidermal expression of intercellular adhesion molecule 1 is not a primary inducer of cutaneous inflammation in transgenic mice.

Keratinocytes at sites of cutaneous inflammation have increased expression of intercellular adhesion molecule 1 (ICAM-1), a cytokine-inducible adhesion molecule which binds the leukocyte integrins LFA-1 and Mac-1. Transgenic mice were prepared in which the expression of mouse ICAM-1 was targeted to basal keratinocytes by using the human K14 keratin promoter. The level of constitutive expression attained in the transgenic mice exceeded the peak level of ICAM-1 expression induced on nontransgenic mouse keratinocytes in vitro by optimal combinations of interferon gamma and tumor necrosis factor alpha or in vivo by proinflammatory stimuli such as phorbol 12-myristate 13-acetate. In vitro adhesion assays demonstrated that cultured transgenic keratinocytes were superior to normal keratinocytes as a substrate for the LFA-1-dependent binding of mouse T cells, confirming that the transgene-encoded ICAM-1 was expressed in a functional form. However, the high level of constitutive ICAM-1 expression achieved on keratinocytes in vivo in these transgenic mice did not result in additional recruitment of CD45+ leukocytes into transgenic epidermis, nor did it elicit dermal inflammation. Keratinocyte ICAM-1 expression also did not potentiate contact-hypersensitivity reactions to epicutaneous application of haptens. The absence of a spontaneous phenotype in these transgenic mice was not the result of increased levels of soluble ICAM-1, since serum levels of soluble ICAM-1 were equal in transgenic mice and controls. We conclude that elevated ICAM-1 expression on keratinocytes cannot act independently to influence leukocyte trafficking and elicit cutaneous inflammation.

Animals↗
PubMed1994

Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1-deficient mice.

Intercellular adhesion molecule 1 (ICAM-1) is one of three immunoglobulin superfamily members that bind to the integrins lymphocyte function associated 1 (LFA-1) and Mac-1 on leukocytes. We have generated mice that are genetically and functionally deficient in ICAM-1. These mice have elevated numbers of circulating neutrophils and lymphocytes, as well as diminished allogeneic T cell responses and delayed type hypersensitivity. Mutant mice are resistant to lethal effects of high doses of endotoxin (lipopolysaccharide [LPS]), and this correlates with a significant decrease in neutrophil infiltration in the liver. Production of inflammatory cytokines such as tumor necrosis factor alpha or interleukin 1 is normal in ICAM-1-deficient mice, and thus protection appears to be related to a diminution in critical leukocyte-endothelial interactions. After sensitization with D-galactosamine (D-Gal), ICAM-1-deficient mice are resistant to the lethal effect of low doses of exotoxin (Staphylococcus aureus enterotoxin B [SEB]), which has been shown to mediate its toxic effects via the activation of specific T cells. In this model, ICAM-1-mediated protection against SEB lethality correlates with a decrease in the systemic release of inflammatory cytokines, as well as with prevention of extensive hepatocyte necrosis and hemorrhage. ICAM-1-deficient mice sensitized with D-Gal, however, are not protected from lethality when challenged with low doses of endotoxin (LPS). These studies show that the different contribution of ICAM-1 in the activation of either T cells or macrophages is decisive for the fatal outcome of the shock in these two models. This work suggests that anti-ICAM-1 therapy may be beneficial in both gram-positive and -negative septic shock, either by reducing T cell activation or by diminishing neutrophil infiltration.

Animals↗
PubMed1993

Opsoclonus-myoclonus syndrome: an autopsy study of three cases.

Opsoclonus-myoclonus is a rare clinical syndrome. We report three patients who died with a pure opsoclonus-myoclonus syndrome. The presentation, management and associations of this distinctive condition are discussed, and the results of detailed pathological examination described. In each case the only abnormality was perivascular collections of lymphocytes widely distributed in the brain. This supports an immune-mediated rather than structural aetiology.

Aged↗
PubMed1992

Development of prognostic index for primary supratentorial intracerebral tumours.

The clinical course of intrinsic supratentorial tumours is variable. Prediction of outcome would be useful in defining patients for specific treatment policies. A retrospective analysis of 560 patients with intrinsic supratentorial tumours was performed. Proportional hazards models for survival were derived by using a stepwise selection procedure with only clinical and CT features as possible explanatory variables. The variables of prognostic importance were age, a first symptom of epilepsy, focal signs at presentation, a cystic lesion on CT scan, and duration of symptoms before presentation. The model defined a group with a good prognosis (score less than or equal to 9, n = 211) and a group with a poor prognosis (score greater than 9, n = 344). The median survival was 27 months for those with a score less than or equal to 9 or less and three months for those with score greater than 9. An alternative model, not including duration of symptoms, is also capable of defining groups with long (score less than or equal to 16, n = 234) and short (score greater than 16, n = 325) survival. The model may provide a means of classifying patients for inclusion in prospective randomised studies.

Actuarial Analysis↗
PubMed1992

Neurology in the market place.

The White Paper, "Working for Patients", led to a change in the way in which hospitals were funded from April 1991. The changes will have profound effects on the future shape of health care in the United Kingdom. Neurologists will need to understand the new National Health Service if their patients are to benefit from the changes. If neurology is to survive as a specialty separate from general medicine it will have to show that it can provide quality care which is accessible, relevant, efficient and effective, at a price which Districts can afford.

Contract Services↗
PubMed1991

Characterization of accessory cell costimulation of Th1 cytokine synthesis.

We studied the capacity of macrophage and B cell lines to provide a costimulatory signal that enhances synthesis of IFN-gamma and IL-2 by mouse Th1 clones stimulated with suboptimal doses of immobilized anti-CD3 antibody. The J774 macrophage line and the CH27 B lymphoma line had the greatest costimulatory activity and routinely increased IL-2 production by 10-fold to 100-fold. Other macrophage and B cell lines had less activity and T cell lines were unable to costimulate. The J774 and CH27 lines did not costimulate IL-4 production by a Th2 clone and had only a small effect on IL-2 production by T cell hybridomas. The process of costimulation was fixation-sensitive, contact-dependent and did not involve stable cytokines present in the T cell/accessory cell conditioned media. Neutralizing antibodies for IL-1, IL-6, and TNF failed to inhibit costimulation. Antibodies to the LFA-1/ICAM-1 pair of adhesion molecules also failed to inhibit. Costimulation of IL-2 production by accessory cells was found to have a unidirectional species restriction: mouse accessory cells costimulated mouse and human IL-2-producing T cells, but human U937 cells induced with PMA were effective only for human T cells. The results indicate that accessory cells can significantly regulate Th1 effector function at the level of cytokine production.

Animals↗
PubMed1991

The prognosis of primary intracerebral tumours presenting with epilepsy: the outcome of medical and surgical management.

It is not known whether conservative or early aggressive (resective surgery with or without radiotherapy) management is better for tumours presenting with epilepsy. The prognosis of 560 patients with a clinical and CT diagnosis of intrinsic supratentorial tumour was examined retrospectively. Epilepsy was the first symptom in 164 patients. Histological confirmation of diagnosis was available in 391 (70%) of cases. Median survival was 37 months in the group presenting with epilepsy and six months in those presenting with other symptoms (p less than 0.0001). Patients presenting with epilepsy were more likely to have a normal clinical examination, a non-enhancing low density lesion on CT scan and a low grade tumour. From Cox's stepwise proportional hazards model, significant independent variables adversely affecting prognosis were increasing age, focal neurological signs and enhancing CT lesions at diagnosis, non-resective surgery and male sex. Of those presenting with epilepsy 80 patients had surgical treatment within two months of CT diagnosis. The Cox's model failed to identify any beneficial effects for either early resective surgery or radiotherapy. In primary intracerebral tumours with presentations other than epilepsy, resective surgery and radiotherapy were amongst the important factors associated with prolonged survival. Primary intracerebral tumours presenting with epilepsy are relatively benign and their outcome appears to be chiefly determined by clinical factors.

Adolescent↗
PubMed1991

Unrecognised Cushing's syndrome and adrenal suppression due to topical clobetasol propionate.

A 53-year-old man with cushingoid appearance--obesity, osteoporosis causing lumbar and thoracic vertebral collapse and a past history of hypertension and depression presented with symptoms and signs of adrenocortical insufficiency. He denied the use of corticosteroid medication. However, it was eventually discovered that he had used clobetasol propionate (Dermovate), a potent topical steroid cream, for five years. The development of adrenal insufficiency symptoms coincided with the withdrawal of the cream.

Adrenal Insufficiency↗
PubMed1990

Costimulatory requirements of murine Th1 clones. The role of accessory cell-derived signals in responses to anti-CD3 antibody.

We examined the role of accessory cell-derived signals in promoting growth and lymphokine production by murine Th1 clones. Five of six Th1 clones failed to proliferate to immobilized anti-CD3 antibody despite producing IL-2 and IFN-gamma. These clones became unresponsive to Ag after exposure to anti-CD3. With the addition of irradiated splenic accessory cells (SAC), Th1 clones proliferated to anti-CD3 and produced greater amounts of IL-2 and IFN-gamma. High doses of plate-bound anti-CD3 completely inhibited responses of these clones to IL-2 and diminished the growth-promoting activity of SAC. The costimulatory effects of SAC on growth of Th1 clones were also seen in the presence of exogenous IL-2, indicating that enhanced IL-2 production alone was not responsible for the costimulatory effect. Delivery of the costimulatory signal from SAC required their close proximity to the T cells. The costimulatory activity of SAC was not reproduced by the addition of IL-1, IL-6, or IL-1 plus IL-6. IL-7 induced weak proliferation of Th1 clones, but did not synergize with plate-bound anti-CD3. Our results suggest a model in which SAC-derived costimulatory signals regulate growth of Th1 cells primarily at the level of cell cycle progression rather than at the level of IL-2 production.

Animals↗