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Biomedical subjects

I Williams

Publications and source records attributed to I Williams.

At least 19 recordsLinked to original sources
PubMed2003

Impaired ability of the Na+/Ca2+ exchanger from the Dahl/Rapp salt-sensitive rat to regulate cytosolic calcium.

We previously cloned Na(+)/Ca(2+) exchanger (NCX1) from mesangial cells of salt-sensitive (SNCX = NCX1.7) and salt-resistant (RNCX = NCX1.3) Dahl/Rapp rats. The abilities of these isoforms to regulate cytosolic Ca(2+) concentration ([Ca(2+)](i)) were assessed in fura 2-loaded OK cells expressing the vector (VOK), RNCX (ROK), and SNCX (SOK). Baseline [Ca(2+)](i) was 98 +/- 20 nM (n = 12) in VOK and was significantly lower in ROK (44 +/- 5 nM; n = 12) and SOK (47 +/- 13 nM; n = 12) cells. ATP at 100 microM increased [Ca(2+)](i) by 189 +/- 55 nM (n = 12), 21 +/- 9 nM (n = 12), and 69 +/- 18 nM (n = 12) in VOK, ROK, and SOK cells, respectively. ATP (1 mM) or bradykinin (0.1 mM) caused large increases in [Ca(2+)](i) and ROK but not SOK cells were much more efficient in reducing [Ca(2+)](i) back to baseline levels. Parental Sprague-Dawley rat mesangial cells express both RNCX (SDRNCX) and SNCX (SDSNCX). SDRNCX and RNCX are identical at every amino acid residue, but SDSNCX and SNCX differ at amino acid 218 where it is isoleucine in SDSNCX and not phenylalanine. OK cells expressing SDSNCX (SDSOK) reduced ATP (1 mM)-induced [Ca(2+)](i) increase back to baseline at a rate equivalent to that for ROK cells. PKC downregulation significantly attenuated the rate at which ROK and SDSOK cells reduced ATP-induced [Ca(2+)](i) increase but had no effect in SOK cells. The reduced efficiency of SNCX to regulate [Ca(2+)](i) is attributed, in part, to the isoleucine-to-phenylalanine mutation at amino acid 218.

Amino Acid Sequence↗
PubMed2002

Evidence for an atypical receptor mediating the augmented bronchoconstrictor response to adenosine induced by allergen challenge in actively sensitized Brown Norway rats.

The bronchoconstrictor response to adenosine is markedly and selectively increased following ovalbumin (OA) challenge in actively sensitized, Brown Norway rats. We present a pharmacological analysis of the receptor mediating this response. Like adenosine, the broad-spectrum adenosine receptor agonist, NECA, induced dose-related bronchoconstriction in actively sensitized, OA-challenged animals. In contrast, CPA, CGS 21680 and 2-Cl-IB-MECA, agonists selective for A(1) A(2A) and A(3) receptors, respectively, induced no, or minimal, bronchoconstriction. Neither the selective A(1) receptor antagonist, DPCPX, nor the selective A(2A) receptor antagonist, ZM 241385, blocked the bronchoconstrictor response to adenosine. MRS 1754, which has similar affinity for rat A(2B) and A(1) receptors, failed to block the bronchoconstrictor response to adenosine despite blockade of the A(1) receptor-mediated bradycardia induced by NECA. 8-SPT and CGS 15943, antagonists at A(1), A(2A), and A(2B) but not A(3) receptors, inhibited the bronchoconstrictor response to adenosine. However, the degree of blockade (approximately 3 fold) did not reflect the plasma concentrations, which were 139 and 21 times greater than the K(B) value at the rat A(2B) receptor, respectively. Adenosine and NECA, but not CPA, CGS 21680 or 2-Cl-IB-MECA, induced contraction of parenchymal strip preparations from actively sensitized OA-challenged animals. Responses to adenosine could not be antagonized by 8-SPT or MRS 1754 at concentrations >50 times their affinities at the rat A(2B) receptor. The receptor mediating the bronchoconstrictor response to adenosine augmented following allergen challenge in actively sensitized BN rats cannot be categorized as one of the four recognized adenosine receptor subtypes.

Adenosine↗
PubMed2002

T cell receptor usage in patients with non-progressing HIV infection.

It is still unclear why some patients with HIV progress more slowly than others to developing full blown AIDS. In this study using flow cytometry we have investigated the TCRBV repertoire of peripheral blood T lymphocytes in 17 long-term non-progressing HIV patients (LTNP) to determine if there is a biased usage of T cell receptor V gene products. Patients were identified from hospital records and entered into the study. Three colour flow cytometry was used to determine the expression of the TCRBV3S5, BV5S1, BV5S2, BV5S3, BV6S1, BV7S1, BV9, BV11, BV12, BV13, BV14, BV16, BV17, BV18, BV20, BV21S3, BV22, and BV23 by CD8 and CD4 positive cells isolated from the peripheral blood of patients and controls. Increases in the absolute numbers of CD8+ T cells expressing TCRBV2 and 8 were observed in the HIV-LTNP population (P < 0.05 in both cases). No differences were seen in numbers of CD8+ T cells expressing other TCRBV or in any TCRBV within the CD4+ T cell popu-lation. At follow up (1-2 years later), those patients in which CD4 levels were below 500 x 106/l were those initially found to have lower levels of TCRBV8 +ve CD8 cells. A significant increase in the absolute numbers of T cells coexpressing the gamma delta (gammadelta) T cell receptor and CD8 were also seen in the HIV-LTNP patients compared with controls (P = 0.002). The increase in CD8+ T cells in the HIV-LTNP patients may be interpreted as either an antigen specific, or group of antigen specific responses to viral antigen, or less likely a viral superantigen. A low level of TCRBV8, CD8+ T cells might be predictive of a more rapid disease progression and might indicate a protective role for this population in HIV infected patients. The increase in gammadeltaT cells bearing the CD8 coreceptor suggests a role for this cell type in the response to HIV infection.

Adult↗
PubMed2002

P-glycoprotein and MRP1 expression and reduced ritonavir and saquinavir accumulation in HIV-infected individuals.

OBJECTIVES: Efflux transporters may play a role in lowering intracellular drug concentrations. As the HIV protease inhibitors are substrates for the efflux transporters P-glycoprotein and MRP, we wished to investigate whether differences in expression of these transporters on human lymphocytes correlated with intracellular concentrations of ritonavir and saquinavir. PATIENTS AND METHODS: Drug efflux transporter expression (P-glycoprotein and MRP1) on peripheral blood mononuclear cells isolated from HIV-positive patients was investigated using flow cytometry. In addition, plasma and intracellular ritonavir and saquinavir concentrations were measured by HPLC/mass spectrometry. The ratio of intracellular:plasma drug concentration was used to quantify intracellular drug accumulation. RESULTS: Patients with lower MRP1 expression (<median) had a significantly higher accumulation of both ritonavir and saquinavir than those with higher MRP1 expression (P = 0.035, CI = -1.70 to -0.06 and P = 0.043, CI = -12.79 to -0.11, respectively). Ritonavir accumulation was significantly greater in patients with lower P-glycoprotein expression (<median) than in patients with higher expression (P = 0.014, CI = -1.56 to -0.14). There was no relationship between saquinavir accumulation in patients and P-glycoprotein expression (P = 0.219, CI = -5.02 to 2.40). Combining expression of P-glycoprotein and MRP1 (expression index, EI = [(P-glycoprotein - 1) + (MRP1 - 1) x 100]) resulted in a statistically significant relationship between transporter expression and intracellular accumulation of both saquinavir (r(2) = 0.195, P = 0.035) and ritonavir (r(2) = 0.220, P = 0.049). CONCLUSION: Increased expression of P-glycoprotein and MRP1 on lymphocytes is associated with lower intracellular accumulation of saquinavir and ritonavir. These two transporters may play a role in the efflux of ritonavir and saquinavir from lymphocytes in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Long-term follow-up of antiretroviral-naive HIV-positive patients treated with nevirapine.

This article reports on the extended follow-up of 125 antiretroviral (ARV)-naive patients treated with nevirapine (NVP) in the United Kingdom. The patients have been observed for a median of 1.8 years after starting NVP (range, 4 days-2.7 years). Baseline CD4 counts and HIV RNA levels were 210 (interquartile range, 130 - 335) cells/mm3 and 4.86 (range, 4.52-5.26) log10 copies/ml, respectively. Eleven patients (9.0%) developed a rash thought to be related to NVP, of whom 4 permanently discontinued NVP. Twenty-four months after starting NVP, RNA levels had dropped by a median of 2.32 log10 copies/ml and CD4 counts increased by a median of 143 cells/mm3. In all, 96 patients had at least one viral load measured <500 copies/ml, a median of 2.8 months after starting NVP. RNA levels rebounded >500 copies/ml in 37 of these patients, on average 2 years after initial response. In conclusion, in ARV-naive patients, NVP is generally well tolerated and long-term response rates are good.

Adult↗
PubMed2001

Antidepressant drugs and generic counselling for treatment of major depression in primary care: randomised trial with patient preference arms.

OBJECTIVES: To compare the efficacy of antidepressant drugs and generic counselling for treating mild to moderate depression in general practice. To determine whether the outcomes were similar for patients with randomly allocated treatment and those expressing a treatment preference. DESIGN: Randomised controlled trial, with patient preference arms. Follow up at 8 weeks and 12 months and abstraction of GP case notes. SETTING: 31 general practices in Trent region. PARTICIPANTS: Patients aged 18-70 who met research diagnostic criteria for major depression; 103 patients were randomised and 220 patients were recruited to the preference arms. MAIN OUTCOME MEASURES: Difference in mean Beck depression inventory score; time to remission; global outcome assessed by a psychiatrist using all data sources; and research diagnostic criteria. RESULTS: At 12 months there was no difference between the mean Beck scores in the randomised arms. Combining the randomised and patient preference groups, the difference in Beck scores was 0.4 (95% confidence interval -2.7 to 3.5). Patients choosing counselling did better than those randomised to it (mean difference in Beck score 4.6, 0.0 to 9.2). There was no difference in the psychiatrist's overall assessment of outcome between any of the groups. 221/265 (83%) of participants with a known outcome had a remission. Median time to remission was shorter in the group randomised to antidepressants than the other three groups (2 months v 3 months). 33/221 (15%) patients had a relapse. CONCLUSIONS: Generic counselling seems to be as effective as antidepressant treatment for mild to moderate depressive illness, although patients receiving antidepressants may recover more quickly. General practitioners should allow patients to have their preferred treatment.

Adult↗
PubMed2001

Comparative detection of measles and rubella IgM and IgG derived from filter paper blood and serum samples.

We compared the use of serum and filter paper blood spots as specimen sources for the detection of measles- and rubella-specific IgM and IgG. We collected capillary blood into microtainer tubes and onto filter paper spots from 60 children and 60 healthy adults. The blood was collected from 12-15-month-old children approximately 3 weeks after primary vaccination with measles, mumps, rubella vaccine, and the sample-pairs were tested for measles-specific IgM and IgG antibodies by using a capture antibody EIA and an indirect EIA, respectively. We tested sample-pairs from a subset of participants for rubella- specific IgM and IgG antibodies by using commercially available capture IgM (Captia) and indirect IgG (Wampole) assays. The concordance of results from serum and filter paper blood spots was high for all assays: 98% for measles IgM, 93% for measles IgG, 94% for rubella IgM, and 93% for rubella IgG, and increased to between 96-100% for all four assays when indeterminate samples were excluded. The correlation coefficients for EIA signals were 0.99 and 0.77 for measles IgM and IgG, respectively, and 0.92 and 0.94 for rubella IgM and IgG, respectively. The cut-off values used for filter paper samples were the same as those used for serum samples for all tests except for the rubella IgM assay. The use of filter paper blood spots is a promising future option for the detection of measles- and rubella-specific antibodies.

Adult↗
PubMed2001

Mechanism of airway hyperresponsiveness to adenosine induced by allergen challenge in actively sensitized Brown Norway rats.

1. We have explored the role of allergen sensitization and challenge in defining the response of the airways of the Brown Norway (BN) rat to adenosine. 2. In naïve animals or in rats sensitized to ovalbumin (OA) adenosine induced only weak bronchoconstrictor responses. Challenge of sensitized animals with OA induced a marked airway hyperresponsiveness to adenosine which was not seen with methacholine or bradykinin. 3. The augmented bronchoconstrictor response to adenosine was not affected by acute bivagotomy or atropine nor mimicked by an i.v. injection of capsaicin. It was, however, blocked selectively by disodium cromoglycate methysergide or ketanserin and reduced in animals treated sub-chronically with compound 48/80. 4. The augmented response to adenosine was associated with increases in the plasma concentrations of both histamine and 5-hydroxytryptamine (5-HT), which were attenuated by pretreatment with disodium cromoglycate, and degranulation of mast cells in the lung. 5. Parenchymal strips from lungs removed from sensitized rats challenged with OA gave augmented bronchoconstrictor responses to adenosine relative to strips from sensitized animals challenged with saline. Responses were inhibited by methysergide and disodium cromoglycate. 6. These data demonstrate a marked augmentation of the bronchoconstrictor response to adenosine in actively sensitized BN rats challenged with OA. The augmented response is primarily a consequence of mast cell activation, leading to the release of 5-HT, which in turn induces bronchoconstriction. Our data further suggest the involvement of a discrete lung-based population of mast cells containing and releasing mainly 5-HT and brought into play by prior exposure to allergen.

Adenosine↗
PubMed2001

Colonic epithelial hPepT1 expression occurs in inflammatory bowel disease: transport of bacterial peptides influences expression of MHC class 1 molecules.

BACKGROUND & AIMS: hPepT1 is an intestinal epithelial apical membrane transporter responsible for uptake of di/tripeptides (including bacterial derived proinflammatory n-formyl peptides). hPepT1 expression normally has a strict axial gradient-highest in the proximal small intestine with no expression in the colon. METHODS: Small intestinal-like cells (Caco2-BBE), and colonic-like cells (HT29-Cl.19A), and colonic mucosa from diseased and control patients were used in the present study. RESULTS: hPepT1 expression occurs aberrantly in the colon with chronic ulcerative colitis (6 patients) and Crohn's disease (4 patients), but not in normal colon (4 patients) or colon with microscopic colitis (4 patients). To model expression of hPepT1 by colonic-like cells in inflamed states, we stably transfected HT29-Cl.19A cells with a modified hPepT1 tagged on the N-terminus with green fluorescence protein. Analysis of transfected cells revealed that: GFP-hPepT1 protein, like the natural protein, is targeted to the apical plasma membrane. In addition, the tagged protein retains the capability of di/tripeptide absorption, and the expression of the tagged protein by HT29-Cl.19A cells permits absorption of N-formyl-methionyl-leucyl-phenylalanine (fMLP), as occurs in hPepT1 expressing Caco2-BBE cells. fMLP uptake by colonic cells expressing GFP-hPepT1 specifically enhances major histocompatibility complex class I surface expression. CONCLUSIONS: These data collectively indicate that, in some states of chronic inflammation, hPepT1 may be anomolously expressed in the colon. Further, transport of fMLP by hPepT1 potentially stimulates expression of key accessory immune molecule, MHC-1.

Amino Acid Sequence↗
PubMed2001

Decision aids: are they worth it? A systematic review.

OBJECTIVES: The field of consumer decision support interventions has grown rapidly in the last 20 years, particularly since the increased formalization of evidence-based decision-making in health care. However, little is known as yet about the effect these decision aids have on relevant outcomes. To identify outcomes influenced by consumer decision aids (CDAs) and the particular effects of CDAs on those outcomes. METHOD: Published reports of randomized controlled trials and other designs in English identified from searches of Medline, Cancerlit, CINAHL, PsycINFO, Social Science Abstracts, the Cochrane Library and Current Contents, and from ancestry searches, hand searches and consultation with key informants. Studies were included if consumers were the decision-makers, decisions were real and not hypothetical, the intervention met a strict definition of a CDA and decisions involved treatment or screening. Data on setting, subjects, decision types, decision aid features and outcomes were extracted. The validity of each study included was evaluated by two team members. Summative ratings were calculated and categorized as high, medium and low. RESULTS: Over 500 titles were initially assessed; 96 study reports were obtained and screened for inclusion. Twenty-two reports representing 20 studies met the inclusion criteria. Eight studies with a low rating were excluded. Results were synthesized from the remaining 12 studies. Published studies of CDAs are increasing although still few in number. Outcomes such as knowledge and decision-making processes are influenced by CDAs but effects on treatment preferences, the actual decision or other outcomes have yet to be clearly established. CONCLUSIONS: Improved outcomes result from the use of CDA in some categories of outcome but insufficient evidence exists yet to support improved outcomes in all categories or to evaluate whether, given the considerable costs of many CDAs, funding for extensive ongoing development and testing can be sustained.

Canada↗
PubMed2000

The multiperson use of non-syringe injection equipment and risk of hepatitis c infection in a cohort of young adult injection drug users, chicago 1997-1999.

PURPOSE: The possibility that hepatitis C virus (HCV) is transmitted via the multiperson use of injection paraphernalia other than syringes has been suggested, but epidemiologic studies to examine the association are difficult to design due to saturation levels of infection in most samples of injection drug users (IDUs). This study (1) assembled a sample of young adult IDUs, among whom hepatitis C infection prevalence was still moderate, (2) measured incident HCV infection, and (3) determined the risk for seroconversion associated with specific forms of sharing injection paraphernalia.METHODS: Between 1997 and 1999, 702 IDUs, 18-30 years old, were interviewed and screened for antibodies to HCV at baseline and at 6 and 12 months post-baseline. Participants were recruited through street outreach, advertising and chain-referral from ethnically diverse neighborhoods in metropolitan Chicago. Data were analyzed using standard survival statistical methods.RESULTS: HCV prevalence was 27% at enrollment. During 296.5 person-years of observation, we observed 37 HCV seroconversions (incidence: 12.5/100 person-years). The adjusted relative hazard (RH) of seroconversion, after controlling for demographic and drug use covariates, was highest for sharing cookers (RH, 3.58; 95% CI 1.47-8.70), followed by sharing rinse water (RH, 2.16; 95% CI 1.03-4.52), and cottons (RH, 1.84; 95% CI 0.95-3.56). Risk associated with syringe sharing was marginally significant, and backloading was unassociated with hepatitis C seroconversion. Adjusting for syringe sharing, the independent effects of sharing cookers and cottons remained significant, and a final model that included each sharing practice demonstrated that sharing cookers had at the strongest association with seroconversion (RH, 3.03; 95% CI 1.05-8.72).CONCLUSIONS: This study suggests that sharing non-syringe paraphernalia may be an important cause of hepatitis C virus transmission between IDUs.

Journal Article↗
PubMed2000

Protein phosphatase 1beta is required for the maintenance of muscle attachments.

Type 1 serine/threonine protein phosphatases (PP1) are important regulators of many cellular and developmental processes, including glycogen metabolism, muscle contraction, and the cell cycle [1] [2] [3] [4] [5]. Drosophila and humans both have multiple genes encoding PP1 isoforms [3] [6] [7]; each has one beta and several alpha isoform genes (alpha(1), alpha(2), alpha(3) in flies, alpha and gamma in humans; mammalian PP1beta is also known as PP1delta). The alpha/beta subtype differences are highly conserved between flies and mammals [6]. Though all these proteins are >85% identical to each other and have indistinguishable activities in vitro, we show here that the Drosophila beta isoform has a distinct biological role. We show that PP1beta9C corresponds to flapwing (flw), previously identified mutants of which are viable but flightless because of defects in indirect flight muscles (IFMs) [8]. We have isolated a new, semi-lethal flw allele that shows a range of defects, especially in muscles, which break away from their attachment sites and degenerate.

Alleles↗
PubMed2000

What help do GPs want from specialist services in managing patients with dementia?

The views of GPs about psychiatric services for dementia were obtained by questionnaire survey. Provision of adequate long term care, together with support for both family carers and healthcare workers were strongly stated needs. Other needs were rapid access to care, clear diagnosis, special needs of young patients with Alzheimer's disease, joint guidelines, and an increased role for CPNs. GPs valued the role of voluntary organisations and help given to them by Consultant Psycho-geriatricians.

Adult↗
PubMed2000

Sequence heterogeneity of TT virus and closely related viruses.

TT virus (TTV) is a recently discovered infectious agent originally obtained from transfusion-related hepatitis. However, the causative link between the TTV infection and liver disease remains uncertain. Recent studies demonstrated that genome sequences of different TTV strains are significantly divergent. To assess genetic heterogeneity of the TTV genome in more detail, a sequence analysis of PCR fragments (271 bp) amplified from open reading frame 1 (ORF1) was performed. PCR fragments were amplified from 5 to 40% of serum specimens obtained from patients with different forms of hepatitis who reside in different countries (e.g., China, Egypt, Vietnam, and the United States) and from normal human specimens obtained from U.S. residents. A total of 170 PCR fragments were sequenced and compared to sequences derived from the corresponding TTV genome region deposited in GenBank. Genotypes 2 and 3 were found to be significantly more genetically related than any other TTV genotype. Moreover, three sequences were shown to be almost equally related to both genotypes 2 and 3. These observations suggest a merger of genotypes 2 and 3 into one genotype, 2/3. Additionally, five new groups of TTV sequences were identified. One group represents a new genotype, whereas the other four groups were shown to be more evolutionary distant from all known TTV sequences. The evolutionary distances between these four groups were also shown to be greater than between TTV genotypes. The phylogenetic analysis suggested that these four new genetic groups represent closely related yet different viral species. Thus, TTV exists as a "swarm" of at least five closely related but different viruses. These observations suggest a high degree of genetic complexity within the TTV population. The finding of the additional TTV-related species should be taken into consideration when the association between TTV infections and human diseases of unknown etiology is studied.

Base Sequence↗
PubMed2000

HIV associated culture proved tuberculosis has increased in north central London from 1990 to 1996.

OBJECTIVES: To examine rates of culture proved tuberculosis in HIV infected patients in three specialist centres in north central London. METHODS: Cases of tuberculosis in patients with previously documented HIV infection from 1990 to 1996 were identified retrospectively from microbiological/clinical records at Chelsea and Westminster, St Mary's, and University College London Hospitals. RESULTS: Between 1990 and 1996 202 cases of culture proved tuberculosis were identified at the three centres. Of these, 132/202 (65.3%) occurred in homosexual/bisexual men, 41/202 (20.3%) were in patients with heterosexual contact in sub-Saharan Africa, and 29/202 (14.4%) were in "others." Overall 148/202 (73.3%) had pulmonary tuberculosis. The total number of HIV infected individuals seen at the three centres increased from 4298 in 1990 to 5048 in 1996. Rates of tuberculosis in the three centres increased from 0.46% in 1990 to 0.83% in 1996. Part of this increase was due to an increase in tuberculosis among Africans from 1993 to 1996. CONCLUSIONS: Rates of HIV associated tuberculosis increased in these three centres in north central London between 1990 and 1996. In part this was due to an increase in the number of African patients with HIV infection attending the three centres. In addition, there was circumstantial evidence of recent transmission among homosexual men with HIV infection. Prospective "real time" surveillance of tuberculosis in HIV infected patients is needed in order to detect case clustering and to improve tuberculosis control.

Africa↗