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Biomedical subjects

E C Smith

Publications and source records attributed to E C Smith.

At least 19 recordsLinked to original sources
PubMed1999

A dichotomous role for nitric oxide in protection against blood stage malaria infection.

Nitric oxide (NO) is cytotoxic and cytostatic to blood stage malaria parasites in vitro, but the precise mechanism(s) by which it mediates an effect in vivo is not known. In particular, whether or not control of acute parasitemia depends on the presence of NO is unclear. We have shown previously that blocking NO synthesis at the time of its induction may cause an increase in peak primary parasitemia during infection of mice with Plasmodium chabaudi, suggesting that NO may be parasiticidal in vivo. However, as recent data indicate that NO suppresses Th1 cell proliferation in vitro by downregulating IL-2 production, we have investigated whether this immunoregulatory function of NO affects its capacity for anti-malarial activity. Treatment of P. chabaudi-infected mice with the iNOS inhibitor aminoguanidine hemisulfate (AG) starting just prior to the peak of primary parasitemia caused a significant elevation and extension of the acute infection and led to a partial but significant abrogation of the suppression of spleen cell proliferation to both mitogen and specific antigen observed when NO synthesis was not blocked. In the absence of NO, levels of IL-2, but not of IFN-gamma, TNF-alpha, or of any Th2-regulated cytokines examined, increased significantly. However, when AG treatment was brought forward to the early ascending phase of primary parasitemia, significantly increased levels of IFN-gamma and TNF-alpha, as well as of IL-2, were observed over those for infected control mice similarly treated with phosphate-buffered saline. Moreover, despite the absence of NO, parasitemias of AG-treated mice were not significantly elevated. The effect of AG therefore appeared to be dependent upon the timing of its administration in vivo. We propose that during malaria infections, there is a dynamic balance between the regulatory and anti-parasitic roles of NO. While the immunosuppressive function of NO leads to a downregulation in vivo of production of IL-2, and indirectly of IFN-gamma and TNF-alpha, this perceived weakening of the host cell-mediated immune response is in part masked by the protective anti-malarial effects of NO itself.

Animals↗
PubMed1999

Modulation of experimental blood stage malaria through blockade of the B7/CD28 T-cell costimulatory pathway.

Recent studies have implicated cytokines associated with CD4+ T lymphocytes of both T helper (Th)1 and Th2 subsets in resistance to experimental blood stage malaria. As the B7/CD28 costimulatory pathway has been shown to influence the differentiation of Th cell subsets, we investigated the contribution of the B7 molecules CD80 and CD86 to Th1/Th2 cytokine and immunoglobulin isotype profiles and to the development of a protective immune response to malaria in NIH mice infected with Plasmodium chabaudi. Effective blockade of CD86/CD28 interaction was demonstrated by elimination of interleukin (IL)-4 and up-regulation of interferon (IFN)-gamma responses by P. chabaudi-specific T cells and by reduction of P. chabaudi-specific immunoglobulin G1 (IgG1). The shift towards a Th1 cytokine pattern corresponded with efficient control of acute parasitaemia but an inability to resolve chronic infection. Moreover, combined CD80/CD86 blockade by using anti-CD80 and anti-CD86 monoclonal antibodies raised IFN-gamma production over that seen with CD86 blockade alone, with augmentation of this Th1-associated cytokine reducing levels of peak primary parasitaemia. These results demonstrate that IL-4 production by T cells in P. chabaudi-infected NIH mice is dependent upon CD86/CD28 interaction and that IL-4 and IFN-gamma contribute significantly, at different times of infection, to host resistance to blood stage malaria. In addition, combined CD80/CD86 blockade resulted in preferential expansion of IFN-gamma-producing T cells during P. chabaudi infection, suggesting that costimulatory pathways other than B7/CD28 may contribute to T-cell activation during continuous antigen stimulation. This study indicates a role for B7/CD28 costimulation in modulating the CD4+ T-cell response during malaria, and further suggests involvement of this pathway in other infectious and autoimmune diseases in which the Th cell immune response is also skewed.

Animals↗
PubMed1999

A role for cytokines in potentiation of malaria vaccines through immunological modulation of blood stage infection.

Malaria is the world's major parasitic disease, for which effective control measures are urgently needed. One of the difficulties hindering successful vaccine design against Plasmodium is an incomplete knowledge of antigens eliciting protective immunity, the precise types of immune response for which to aim, and how these can be induced. A greater appreciation of the mechanisms of protective immunity, on the one hand, and of immunopathology, on the other, should provide critical clues to how manipulation of the immune system may best be achieved. We are studying the regulation of the balance between T helper 1 (Th1) and T helper 2 (Th2) CD4+ T lymphocytes in immunity to asexual blood stages of malaria responsible for the pathogenicity of the disease. Protective immunity to the experimental murine malarias Plasmodium chabaudi and Plasmodium yoelii involves both Th1 and Th2 cells, which provide protection by different mechanisms at different times of infection characterised by higher and lower parasite densities, respectively. This model therefore facilitates a clearer understanding of the Th1/Th2 equilibrium that appears central to immunoregulation of all host/pathogen relationships. It also permits a detailed dissection in vivo of the mechanisms of antimalarial immunity. Here, we discuss the present state of malaria vaccine development and our current research to understand the factors involved in the modulation of vaccine-potentiated immunity.

Animals↗
PubMed1998

Synthesis and 5 alpha-reductase inhibitory activity of 8-substituted benzo[f]quinolinones derived from palladium mediated coupling reactions.

Benzoquinolinones have been shown to be potent, selective inhibitors of the Type I 5 alpha-reductase enzyme, which is responsible for the production of dihydrotestosterone from testosterone localized in the scalp. In an effort to identify compounds that demonstrate inhibition of both 5 alpha-reductase isozymes, we have employed 8-bromobenzoquinolinone as an advanced intermediate for participation in a variety of palladium mediated carbon-carbon bond forming reactions. By varying the 8-substituent it is possible to alter the selectivity profile of the series.

Cholestenone 5 alpha-Reductase↗
PubMed1997

In vivo proton magnetic resonance spectroscopy in polymyositis and dermatomyositis: a preliminary study.

The aim of the study is to determine whether biochemical abnormalities, such as lipid, creatine and choline metabolites, are observed in the more distal muscles of polymyositis (PM) and dermatomyositis (DM) patients. 12 patients suffering from chronic active PM/DM and 9 controls underwent a combined proton magnetic resonance (MR) imaging and proton MR spectroscopy study of the calf muscle. From a combination of T1-weighted MR images and corresponding fat suppressed images, fat infiltration into the muscle of both PM and DM patients was consistently observed. Muscular atrophy with a variable distribution was also noted in all patients. The biochemical profile of the localised proton MR spectra of soleus muscle showed reduction of both 'choline' to lipid and 'creatine' to lipid ratios in chronic PM and DM patients when compared with controls.

Adipose Tissue↗
PubMed1997

Staff education.

Explore the source record for details and available documents.

Drug Delivery Systems↗
PubMed1996

Standardising joint assessment in rheumatoid arthritis.

Evaluating joint involvement in rheumatoid arthritis in a key clinical assessment. We investigated the extent of variation in measurement of joint swelling and tenderness and evaluated the impact of training to standardise methods. Eight observers (medical and nursing staff) examined eight rheumatoid patients for joint swelling and tenderness before and after training in clinical methods. The EULAR handbook for joint evaluation was used for training and assessments were based on the 28 joint count. There was extensive variability in both numbers of swollen and tender joints. Coefficients of variation for articular indices recorded by the 8 observers in individual patients were often high (up to a maximum of 204%), indicating considerable differences between observers. Training had an impact on the assessment of the numbers of swollen joints which increased by a mean of 32% (P < 0.05) and the number of tender joints which increased by 41% (p < 0.01). Training had only a limited impact on the variation among observers in determining the number of swollen and number of tender joints. After training, the mean coefficients of variation were still 59% for swollen joints and 65% for tender joints. These results highlight the extent of variation in clinical assessment of rheumatoid arthritis and show the advantages of training. It leads to increased sensitivity of measurement. Standardisation appears essential for clinical studies.

Analysis of Variance↗
PubMed1996

The clinical need for an acute rheumatology referral service.

Should rheumatologists provide an acute referral service for general practitioners (GPs) and other clinical units? Is it cost effective? We prospectively studied acute referrals to one unit over 10 months, recording their source, diagnosis, management and outcome. Current rheumatology patients and cases only needing telephone advice were excluded. There were 253 referrals: 82 from GPs, nine from Accident and Emergency, and 162 from other hospital units. Their diagnoses comprised connective tissue diseases (22), back pain (46), inflammatory arthritis (59), osteoarthritis (22), paediatric cases (11), soft tissue problems (41) and 52 other disorders. Thirty-two needed active treatment within 24 h (classified as emergencies); examples included cerebral lupus, vasculitic pulmonary haemorrhage, retroperitoneal lymphoma with sacral plexus compression, temporal arteritis with reduced visual acuity and acute monoarthritis. All needed immediate therapy; only one died. Most (176 cases) were less urgent and needed advice in 48 h. Examples included osteoporotic vertebral collapse and acute rheumatoid disease. Forty-five could have been seen routinely; examples included lateral epicondylitis and adhesive capsulitis. The service required 1 day per week of medical staff time at an average cost of 45 pounds per case. We concluded that an acute rheumatology service is needed; it can be provided within the working day and is cost effective.

Direct Service Costs↗
PubMed1996

Diagnosis and management of the dry mouth: Part 1.

Dry mouth is a relatively common problem, often neglected by patients and dentists alike. This article reviews the symptoms, causes and treatment of xerostomia and provides guidelines for recognizing the condition at an early stage.

Adult↗
PubMed1995

The efficacy of filters used in respiratory function apparatus.

The ability of two low resistance barrier filters (Collins DC-1 and Pall Pf 305) to remove bacteria from expired air was assessed. A specially designed coupling device was used to hold each filter or a disposable plain cardboard mouthpiece a fixed distance (4.5 cm) from a blood agar plate. Volunteers performed maximal forced vital capacity manoeuvres through the assembled apparatus and bacteria impinged on to the agar plate were enumerated. Both filters allowed the transmission of approximately one-third of expired colony forming units. The efficacy of these filters for reducing the likelihood of cross-infection during spirometry is not supported by this study.

Air Microbiology↗
PubMed1995

Role of cocaine in end-stage renal disease in some hypertensive African Americans.

During a period of 1 year we observed 12 African American patients who had smoked or sniffed cocaine for several years and presented to inner city hospitals with accelerated hypertension and renal insufficiency. Ten required maintenance dialysis; 1 recovered partially after a brief period of dialysis, and 1 had moderate renal insufficiency. In the absence of striking proteinuria, cardiomegaly or renal shrinkage, the probable diagnosis in most of the patients was primary accelerated hypertension. The clinical history suggested that the habitual use of cocaine had worsened the hypertension, made it more difficult to control or triggered an accelerated phase resulting in renal shutdown. At a time when billions of dollars are being spent on the treatment of end-stage renal disease, the harmful role of cocaine in susceptible individuals requires due attention.

Adult↗