Isolated left ventricular non-compaction, not hypertrophic cardiomyopathy.
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Adult↗
Biomedical subjects
A Bridges
Publications and source records attributed to A Bridges.
Screening of silent myocardial ischaemia in type 2 diabetic patients with additional atherogenic risk factors: applicability and accuracy of the exercise stress test.
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Coronary Artery Disease↗
The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation.
BACKGROUND: Glycogen synthase kinase-3 (GSK-3) sequentially phosphorylates four serine residues on glycogen synthase (GS), in the sequence SxxxSxxxSxxx-SxxxS(p), by recognizing and phosphorylating the first serine in the sequence motif SxxxS(P) (where S(p) represents a phosphoserine). FRATtide (a peptide derived from a GSK-3 binding protein) binds to GSK-3 and blocks GSK-3 from interacting with Axin. This inhibits the Axin-dependent phosphorylation of beta-catenin by GSK-3. RESULTS: Structures of uncomplexed Tyr216 phosphorylated GSK-3beta and of its complex with a peptide and a sulfate ion both show the activation loop adopting a conformation similar to that in the phosphorylated and active forms of the related kinases CDK2 and ERK2. The sulfate ion, adjacent to Val214 on the activation loop, represents the binding site for the phosphoserine residue on 'primed' substrates. The peptide FRATtide forms a helix-turn-helix motif in binding to the C-terminal lobe of the kinase domain; the FRATtide binding site is close to, but does not obstruct, the substrate binding channel of GSK-3. FRATtide (and FRAT1) does not inhibit the activity of GSK-3 toward GS. CONCLUSIONS: The Axin binding site on GSK-3 presumably overlaps with that for FRATtide; its proximity to the active site explains how Axin may act as a scaffold protein promoting beta-catenin phosphorylation. Tyrosine 216 phosphorylation can induce an active conformation in the activation loop. Pre-phosphorylated substrate peptides can be modeled into the active site of the enzyme, with the P1 residue occupying a pocket partially formed by phosphotyrosine 216 and the P4 phosphoserine occupying the 'primed' binding site.
Amino Acid Motifs↗
Mutation of histidine 286 of the human P2X4 purinoceptor removes extracellular pH sensitivity.
1. Effects of external pH on the human P2X4 purinoceptor, an ATP-activated ion channel, were studied using the Xenopus oocyte expression system. 2. Changing the external pH from 7.4 to 6.5 significantly reduced, whilst an increase to pH 8 enhanced, maximum ATP-activated current amplitude, without changing the current- voltage relationship of the ATP-activated current. 3. Diethyl pyrocarbonate (DEPC; 10 mM) treatment of P2X4-injected oocytes had no effect on the pH sensitivity of the ATP-activated current. 4. Site-directed mutagenesis of histidine 286 (H286) to alanine completely abolished the pH sensitivity of the P2X4 receptor at all agonist concentrations. ATP potency showed a small (fourfold) leftward shift. Mutagenesis of the other three histidines present in the P2X4 sequence had no effect on pH sensitivity. 5. The results show that pH modulation of P2X4 in the pathophysiological range is mediated by protonation of H286. This provides direct confirmation that pH sensitivity resides in the P2X4 channel protein rather than the agonist species.
Adenosine Triphosphate↗
Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.
The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.
Animals↗
Identification of the binding site on cytochrome P450 2B4 for cytochrome b5 and cytochrome P450 reductase.
A model of cytochrome P450 2B4, which was constructed by homology modeling with the four known crystal structures of the cytochromes P450 (Chang, T.-T., Stiffelman, O. B., Vakser, I. A., Loew, G. H., Bridges, A., and Waskell, L. (1997) Protein Eng. 10, 119-129), was used to select amino acids predicted, by computer docking studies and numerous previous biochemical and site-directed mutagenesis studies, to be involved in binding the heme domain of cytochrome b5. Twenty-four amino acid residues located on both the distal and the proximal surface of the molecule were chosen for mutagenesis. These 24 mutant proteins were expressed in Escherichia coli, purified, and characterized with respect to their ability to bind cytochrome b5 and support substrate oxidation. Seven mutants, R122A, R126A, R133A, F135A, M137A, K139A, and K433A, all on the proximal surface of cytochrome P450 2B4 near the heme ligand, were identified that exhibited decreased ability to bind cytochrome b5. All of the mutants except K433A are located in either the C or C* helices or their termini. In addition, these seven mutants and two additional mutants on the proximal surface of cytochrome P450, R422A and R443A, were shown to exhibit decreased binding to cytochrome P450 reductase. These studies indicate that the binding sites for cytochrome b5 and cytochrome P450 reductase are, as predicted, located on the proximal surface of cytochrome P450 2B4 and are partially overlapping but not identical.
Aryl Hydrocarbon Hydroxylases↗
Neutralizing epitopes on the extracellular interferon gamma receptor (IFNgammaR) alpha-chain characterized by homolog scanning mutagenesis and X-ray crystal structure of the A6 fab-IFNgammaR1-108 complex.
The extracellular interferon gamma receptor alpha-chain comprises two immunoglobulin-like domains, each with fibronectin type-III topology, which are responsible for binding interferon gamma at the cell surface. The epitopes on the human receptor recognized by three neutralizing antibodies, A6, gammaR38 and gammaR99, have been mapped by homolog scanning mutagenesis. In this way, a loop connecting beta-strands C and C' in the N-terminal domain was identified as a key component of the epitopes bound by A6 and gammaR38, whereas gammaR99 binds to the C-terminal domain in a region including strands A and B and part of the large C'E loop. The epitope for A6 was confirmed in a crystal structure of a complex between a recombinant N-terminal receptor domain and the Fab fragment from A6, determined by X-ray diffraction to 2.8 A resolution. The antibody-antigen interface buries 1662 A2 of protein surface, including 22 antibody residues from five complementarity determining regions, primarily through interactions with the CC' surface loop of the receptor. The floor of the antigen binding cavity is formed mainly by residues from CDR L3 and CDR H3 while a surrounding ridge is formed by residues from all other CDRs except L2. Many potential polar interactions, as well as 13 aromatic side-chains, four in VL, six in VH and three in the receptor, are situated at the interface. The surface of the receptor contacted by A6 overlaps to a large extent with that contacted by interferon-gamma, in the ligand-receptor complex. However, the conformation of this epitope is very different in the two complexes, demonstrating that conformational mobility in a surface loop on this cytokine receptor permits steric and electrostatic complementarity to two quite differently shaped binding sites.
Amino Acid Sequence↗
Construction of a 3D model of cytochrome P450 2B4.
A three-dimensional structural model of rabbit phenobarbital-inducible cytochrome P450 2B4 (LM2) was constructed by homology modeling techniques previously developed for building and evaluating a 3D model of the cytochrome P450choP isozyme. Four templates with known crystal structures including cytochrome P450cam, terp, BM-3 and eryF were used in multiple sequence alignments and construction of the cytochrome P450 2B4 coordinates. The model was evaluated for its overall quality using available protein analysis programs and found to be satisfactory. The model structure was stable at room temperature during a 140 ps unconstrained full protein molecular dynamics simulation. A putative substrate access channel and binding site were identified. Two different substrates, benzphetamine and androstenedione, that are metabolized by cytochrome P450 2B4 with pronounced product specificity were docked into the putative binding site. Two orientations were found for each substrate that could lead to the observed preferred products. Using a geometric fit method three regions on the surface of the model cytochrome P450 structure were identified as possible sites for interaction with cytochrome b5, a redox partner of P450 2B4. Residues that may interact with the substrates and with cytochrome b5 have been identified and mutagenesis studies are currently in progress.
Amino Acid Sequence↗
A "list" is not for groceries ... a guide to electronic discussion groups in nursing.
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Computer Communication Networks↗
Production and characterization of anti-human interferon gamma receptor antibody fragments that inhibit cytokine binding to the receptor.
Three single-chain antibody fragments that recognize the extracellular human interferon gamma receptor alpha-chain (IFN gamma R), and inhibit the binding of human IFN gamma, have been produced in Escherichia coli. These fragments are derived from murine anti-receptor monoclonal antibodies, and comprise the variable heavy (VH) domain linked to the variable light (VL) chain through a 15 amino acid linker [(GGGGS)3]. Using surface plasmon resonance technology (BIAcore), the soluble proteins were shown to retain a high affinity for recombinant IFN gamma R, and by radioimmunoassay to possess a high inhibitory activity towards IFN gamma-binding to human Raji cells. The antibody fragments most likely recognize epitopes that overlap the cytokine binding site on the receptor surface. Attempts to dissect further the antibodies to isolated VH- and VL-chains and to synthetic linear and cyclic peptides derived from the individual complementarity determining regions failed to afford fragments with significant IFN gamma R binding affinity. Nevertheless, these native-like variable region fragments and petidomimetics derived from them are of interest in the design of novel IFN gamma R antagonists.
Amino Acid Sequence↗
Variable region cDNA sequences and characterization of murine anti-human interferon gamma receptor monoclonal antibodies that inhibit receptor binding by interferon gamma.
Murine monoclonal antibodies (mAbs) are described that recognize the extracellular human interferon gamma receptor alpha-chain (IFN gamma R) and inhibit the binding to it of interferon gamma. The inhibitory activities (IC50s) of these mAbs, quantified by radioimmunoassay using native receptor on human Raji cells, lie in the range 0.5-24 nM, whereas their relative affinities for the immobilised recombinant extracellular receptor, determined using surface plasmon resonance technology, are in the range 0.6-40.9 nM. Nine mAbs derived from one immunization, were shown by variable region cDNA sequencing to be clonally related, with mAb A6 from this group showing the highest affinity for the receptor. Another two mAbs, gamma R38 and gamma R99, derived from a separate immunization, are clonally unrelated to each other and to those in the A6 family. From the V-region sequences, the L-chains of mAbs A6, gamma R38 and gamma R99 were shown to belong to the V kappa 34C, V kappa 34C and V kappa 1 families, whereas the H-chains belong to the 3069, J606 and J558 families, respectively. The mAbs A6 and gamma R38 recognize overlapping epitopes on the N-terminal Ig-like domain of the IFN gamma R, whereas the gamma R99 epitope is located largely in the membrane proximal Ig-like domain. Sequence comparisons with Ig structures solved by X-ray diffraction allowed deductions concerning likely CDR canonical conformations. These studies provide essential information for crystallographic and mutagenesis experiments aimed at understanding the molecular basis of the interactions of these mAbs with the extracellular IFN gamma R.
Amino Acid Sequence↗
Family history of severe cardiovascular disease in Marfan syndrome is associated with increased aortic diameter and decreased survival.
OBJECTIVES: We attempted to determine whether a family history of severe cardiovascular disease in patients with the Marfan syndrome is associated with increased aortic dilation or decreased survival, or both. BACKGROUND: The prognostic importance of a family history of severe cardiovascular disease in patients with the Marfan syndrome has been incompletely examined. We hypothesized that such a family history would correlate with increased aortic dilation and would be associated with decreased survival. METHODS: One hundred eight affected patients and 48 unaffected family members from 33 multigenerational families with the Marfan syndrome underwent echocardiographic measurement of the aortic root, arch and mid-abdominal aorta. Date of birth and age at death ascertained from family pedigrees were used to perform life table analysis and estimate survival. RESULTS: Aortic root and arch diameters were significantly greater in patients with a family history of severe cardiovascular disease than in patients without such a family history. Of subjects in the highest quartile for aortic size, > 80% had such a family history in contrast to < 10% of those in the lowest quartile (chi-square 57.37, p < 0.00001). Mean age at death and cumulative probability of survival were significantly lower in patients with such a family history. CONCLUSIONS: Among patients with the Marfan syndrome, aortic dilation is greater and life expectancy shorter in those with a family history of severe cardiovascular manifestations. These data suggest that such a family history is an important risk factor for cardiovascular events in patients with the Marfan syndrome.
Adult↗
Effects of captopril and enalapril on renal function in elderly patients with chronic heart failure.
OBJECTIVE: To compare the effects on renal function of captopril and enalapril in elderly patients with chronic heart failure. DESIGN: A multi-centre double-blind parallel-group comparison of the two angiotensin-converting enzyme (ACE) inhibitors, captopril (12.5 mg bid) and enalapril (2.5 mg bid). SUBJECTS: 80 elderly patients with chronic heart failure (41 in the captopril group, 39 in the enalapril group). MAIN OUTCOME MEASURES: The blood pressure and pulse rate response to the first dose of ACE inhibitor was assessed in all patients. Glomerular filtration rate (GFR) was measured radioisotopically by 99mTcDTPA or 51CrEDTA clearance after three and six months of each treatment. Subgroups were assessed for effective renal plasma flow (33 patients), exercise tolerance (25 patients) and by a symptom-oriented questionnaire (45 patients). RESULTS: No serious adverse effect on GFR was noticed. There was no significant difference between the two treatments in the mean baseline GFR or in changes from baseline at three and six months (captopril mean baseline GFR 49.6 ml min-1 1.76 m-2, enalapril 54.7 ml min-1 1.76 m-2; mean change (95% confidence interval) at three months captopril 12 ml min-1 (+3.0, +21.0), enalapril -2 ml min-1 (-13.0; +9.0); mean change at six months, captopril 3.7 ml min-1 (-6.7; +14.2), enalapril -6.0 ml min-1 (-21.0; +9.4). Significantly more patients given captopril had an improvement in GFR during the study period (26/31 compared with 20/31 enalapril-treated patients at three months, p = 0.0096, and 23/30 compared with 15/27 at six months, p = 0.021). There were no significant changes in effective renal plasma flow. Three patients treated with enalapril developed symptomatic hypotension within three days of starting treatment. Quality of life questionnaires revealed more gastrointestinal symptoms in the enalapril group (p = 0.039). CONCLUSIONS: Captopril seems marginally preferable to enalapril in the treatment of chronic heart failure in elderly patients.
Aged↗
Hearing impairment and ear pathology in Nepal.
A stratified random cluster sample of 15,845 subjects was performed in two regions of Nepal to determine the prevalence and main causes of hearing impairment (the most common disability) and the prevalence of ear disease. Subjects reporting current ear pain, or ear discharge, or hearing impairment on direct questioning by a Nepali health worker (primary screening failed), had otoscopy and audiometry (using the Liverpool Field Audiometer) performed, and a questionnaire administered relating to past history. In every fifth house subjects who passed the primary screening (1,716 subjects) were examined to assess the false negative rate of screening. An estimated 16.6 per cent of the study population have hearing impairment (either ear worse than 30 dB hearing threshold level (HTL) 1.0-4.0 kHz, or 50 dB HTL 0.5 kHz), and 7.4 per cent ear drum pathology, equivalent to respectively 2.71 and 1.48 million people extrapolated to the whole of Nepal. Most hearing impairment in the school age group (55.2 per cent) is associated with otitis media or its sequelae. Probably at least 14 per cent of sensorineural deafness is preventable (7 per cent infectious disease, 3.9 per cent trauma, 0.8 per cent noise exposure, 1 per cent cretinism, and 1 per cent abnormal pregnancy or labour). Most individuals reporting current ear pathology (61 per cent) had never attended a health post, and of those receiving ear drop treatment, 84 per cent still had serious pathology. Of subjects who reported ear drop treatment at any time, 31 per cent still had serious pathology. The use of traditional remedies was prevalent.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Oxygen free radicals and platelet and granulocyte aggregability in renal transplant patients.
Oxygen free radical reaction products (plasma malondialdehyde), the free radical scavengers plasma thiol and red cell superoxide dismutase (SOD), and whole blood platelet and granulocyte aggregation were measured in 23 renal transplant patients and 23 age-matched controls. Malondialdehyde-like material (MDA) was significantly increased in transplant patients compared with controls (transplants MDA [median, range], 7.7 [5.3-11.5] nmol/ml; controls MDA, 6.3 [5.4-8.7] nmol/ml; P < 0.001). The patients also had increased red cell superoxide dismutase (transplants SOD, 128.1 [89.4-93.8] U/0.5 ml red cells; controls SOD, 95.9 [62.0-132.6] U/0.5 ml red cells; P < 0.001) and reduced plasma thiol (transplants thiol, 428 [266-496] mumol/L; controls thiol, 445 [358-501] mumol/L; P < 0.05). These factors were not influenced by immunosuppressive therapy, duration of transplantation, or creatinine concentration. Transplant patients had significantly higher levels of collagen-induced and spontaneous whole blood platelet aggregation compared with controls (collagen: transplants, 72 [4-93%]; controls 43 [6-94]%; P < 0.001; spontaneous: transplants 46 [11-93]%; controls 37 [10-75]%; P < 0.05). Spontaneous platelet aggregation, however, was significantly correlated with creatinine concentration (r = 0.525, P < 0.02, Spearman's correlation), and was raised only in those patients with a degree of renal impairment. Granulocyte aggregation was increased in patients receiving cyclosporine (CsA [n = 15], 57 [36-66]%; no cyclosporine [n = 8], 45 [37-62]%; controls [n = 23]; 39 [31-61]%; P = 0.004). Renal transplant patients are subject to oxidative cell damage, and may be at increased risk of vascular thrombosis. Possible contributory factors include an immunological reaction to the graft and/or the effects of immunosuppressive therapy.
Adolescent↗
Dipyridamole increases human red blood cell deformability.
An automated filtration technique has been used to investigate the effect of dipyridamole (DP) on red blood cell deformability in patients identified as having rigid red cells. They were patients on haemodialysis (HD) for chronic renal failure (n = 18), patients with peripheral vascular disease (PVD, n = 23) and controls (hospital outpatients, n = 33). Leucocytes and platelets were removed from heparinised blood by filtration through Imugard wool. Washed red cell suspensions in buffer at 5% haematocrit, without or with 5 microM DP, were filtered through Nuclepore Hemafil Membranes with 4.7 microns pores. The initial steady state relative filtration pressure (iRFP) was used to assess cell deformability. A low iRFP value reflects increased deformability and vice versa. The mean iRFP values were 0.33, 0.393 and 0.403 for controls, PVD and HD patients respectively, indicating that the red cells in the two groups of patients were significantly more rigid. DP reduced the iRFP to 0.266, 0.278 and 0.263 for controls, PVD and HD patients respectively. The results suggest that DP may be beneficial when red cell rigidity contributes to impaired microvascular perfusion.
Adult↗
Practical issues when initiating captopril therapy in chronic heart failure. What is the appropriate dose and how long should patients be observed?
To assess the feasibility of introducing captopril in patients with chronic heart failure on an outpatient rather than an inpatient basis a double-blind placebo-controlled study was carried out to compare either 6.25 mg or 25.0 mg of captopril as a starting dose; followed by either incremental doses of 6.25, 12.5, and 25.0 mg (low dose group), or 25.0 mg 8 hourly (high dose group) respectively. Forty-one patients in a general medical ward within a large teaching hospital with moderate to severe, stable, diuretic-controlled chronic heart failure, who were not hyponatraemic, hypokalaemic or on a dose of diuretic greater than 120 mg of frusemide took part. No patient experienced symptomatic hypotension. Both doses of captopril produced a significant drop in blood pressure (BP), the magnitude of which was similar in both groups. The first dose-induced fall correlated significantly with subsequent dose-related reductions in BP. Therefore if a patient did not have a hypotensive response to the first dose of captopril he/she would be unlikely to have one with subsequent doses. In the group as a whole, the magnitude of the fall in BP after the first dose correlated significantly with starting plasma levels of angiotensin II, atrial natriuretic peptide (ANP), aldosterone, and renin. However, on an individual basis, the two patients with the greatest fall in blood pressure did not have the most activated renin-angiotensin-aldosterone (RAA) system. This serves to emphasise the unpredictability of this response and the need to initiate therapy under clinical observation.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
A linkage map of 10 loci flanking the Marfan syndrome locus on 15q: results of an International Consortium study.
Members of an International Consortium for Linkage Analysis of the Marfan Syndrome (MFS1) have pooled data for joint analysis in an attempt to determine the precise location of the MFS1 gene and the order of 10 DNA markers on 15q. Five laboratories performed a total of 2111 genotypes in 22 families consisting of 225 affected and 248 normal subjects. For each marker a mean of 98 meioses was informative. D15S48 and D15S1 were identified as the closest linked markers with 99% upper confidence intervals of 12% and 13% respectively. We have used the CRI-MAP program to construct the most likely order as: D15S24-D15S25-D15S1-MFS1-D15S48-D15S49+ ++-(D15S45/S51)-(D15S29/S38). Placement of D15S2 in relation to -D15S1-D15S48- cannot be determined with certainty. The genetic map of these markers extends 53.6 cM in males and 65.0 cM in females with a sex averaged map of 60.7 cM. The sex difference was statistically significant (p = 0.005). Linkage heterogeneity between 22 MFS1 families was documented (p = 0.009) necessitating the exclusion of one family from the analysis. However, comparison of the remaining 21 families for two point and multipoint lod scores showed no evidence for linkage heterogeneity of the MFS1 locus.
Chromosome Mapping↗