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Biomedical subjects

K M Fox

Publications and source records attributed to K M Fox.

At least 19 recordsLinked to original sources
PubMed2005

Vasculitis masquerading as aortic valve endocarditis.

Small vessel vasculitis and endocarditis can both present with multisystem involvement and may present a diagnostic dilemma. Renal and cardiac involvement is common in small vessel vasculitis and rarely small vessel vasculitis may cause heart block. When a patient presents with diffuse symptoms, deteriorating renal function, and heart block, endocarditis and vasculitis should be included in the differential diagnosis. The case is discussed of a man with a history of aortic valve endocarditis who presented again with similar symptoms, deteriorating renal function, and heart block. There was no evidence of aortic valve endocarditis with abscess formation. A renal biopsy confirmed small vessel vasculitis and the patient responded promptly to immunosuppressive treatment. Correct diagnosis is essential in such cases, as immunosuppression in true endocarditis can be catastrophic. In this case, with the correct diagnosis, immunosuppression proved life saving and prevented erroneous aortic valve surgery.

Acute Kidney Injury↗
PubMed2004

Preprocedural inflammatory markers do not predict restenosis after successful coronary stenting.

BACKGROUND: Levels of C-reactive protein (CRP), serum amyloid A protein (SAA), and interleukin-6 (IL-6) can predict coronary restenosis following angioplasty and stent deployment in patients with unstable angina. We investigated whether measurement of periprocedural inflammatory markers predicted the angiographic outcome at 6 months in stable angina patients undergoing coronary stenting. METHODS: We prospectively studied 182 patients; 152 patients underwent elective and successful stenting procedure for de novo lesions in native and nongrafted coronary arteries and 30 individuals in the control group underwent diagnostic angiography alone. CRP, SAA, and IL-6 were determined by high-sensitivity immunoassays. RESULTS: At 6 months, quantitative computer-assisted angiographic analysis in 133 patients with stents showed a binary restenosis rate of 33.8%. Statins were being taken by 80% of the patients. There were no significant differences between the pre- or postprocedure values of CRP, SAA, or IL-6 in patients with or without in-stent restenosis. CONCLUSIONS: Preprocedural inflammatory markers in stable angina subjects undergoing coronary artery stent deployment did not correlate with the development of in-stent restenosis. Differences in pathobiology between stable and unstable coronary syndromes, the widespread use of statins with anti-inflammatory activity in our cohort of patients, along with different mechanisms underlying the early angiographic appearances of restenosis as compared to clinical end points, most likely explain our findings.

Angina Pectoris↗
PubMed2003

Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).

BACKGROUND: Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces the rate of cardiovascular events among patients with left-ventricular dysfunction and those at high risk of such events. We assessed whether the ACE inhibitor perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease and no apparent heart failure. METHODS: We recruited patients from October, 1997, to June, 2000. 13655 patients were registered with previous myocardial infarction (64%), angiographic evidence of coronary artery disease (61%), coronary revascularisation (55%), or a positive stress test only (5%). After a run-in period of 4 weeks, in which all patients received perindopril, 12218 patients were randomly assigned perindopril 8 mg once daily (n=6110), or matching placebo (n=6108). The mean follow-up was 4.2 years, and the primary endpoint was cardiovascular death, myocardial infarction, or cardiac arrest. Analysis was by intention to treat. FINDINGS: Mean age of patients was 60 years (SD 9), 85% were male, 92% were taking platelet inhibitors, 62% beta blockers, and 58% lipid-lowering therapy. 603 (10%) placebo and 488 (8%) perindopril patients experienced the primary endpoint, which yields a 20% relative risk reduction (95% CI 9-29, p=0.0003) with perindopril. These benefits were consistent in all predefined subgroups and secondary endpoints. Perindopril was well tolerated. INTERPRETATION: Among patients with stable coronary heart disease without apparent heart failure, perindopril can significantly improve outcome. About 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event. Treatment with perindopril, on top of other preventive medications, should be considered in all patients with coronary heart disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

The endothelial nitric oxide synthase (Glu298Asp and -786T>C) gene polymorphisms are associated with coronary in-stent restenosis.

AIMS: Coronary stent deployment is a major advance in percutaneous treatment of ischaemic heart disease, but 10-40% of patients still develop angiographic restenosis by 6 months due to neointimal hyperplasia. Patient-specific factors, including genetic factors, can contribute to this process. We have conducted a prospective study to examine the involvement of genetic risk factors (eNOS, ACE, MMP-3, IL-6, and PECAM-1) in restenosis following coronary stent deployment. METHODS AND RESULTS: A total of 226 patients who underwent elective and successful coronary artery stenting to de novo lesions in native coronary arteries were studied. Two hundred and five (90.7%) patients were restudied by coronary angiogram at 6 months and the stented lesions were assessed using an automated quantitative angiography system. Genotype was determined by polymerase chain reaction (PCR) and restriction enzyme digestion. Restenosis rate, defined as >or=50% diameter stenosis, was 29.3%. The overall genotype frequency distributions were in Hardy-Weinberg equilibrium for all variants. Carriers of the 298Asp allele of the eNOS Glu298Asp polymorphism showed a higher frequency of restenosis with an odds ratio of 1.88 (95%CI: 1.01-3.51, P=0.043) compared to 298Glu homozygotes. Carriers of the -786C allele of the eNOS -786T>C polymorphism also showed a higher frequency of restenosis with odds ratio of 2.06 (95%CI: 1.08-3.94, P=0.028). These effects were essentially additive and were independent of other classical risk factors. Other studied genes did not show significant association with coronary in-stent restenosis. CONCLUSION: In patients with coronary artery disease, the possession of the 298Asp and -786C variants of the eNOS gene are a risk factor for coronary in-stent restenosis, demonstrating the importance of the nitric oxide system in restenosis.

Analysis of Variance↗
PubMed2001

Intertwined structure of the DNA-binding domain of intron endonuclease I-TevI with its substrate.

I-TevI is a site-specific, sequence-tolerant intron endonuclease. The crystal structure of the DNA-binding domain of I-TevI complexed with the 20 bp primary binding region of its DNA target reveals an unusually extended structure composed of three subdomains: a Zn finger, an elongated segment containing a minor groove-binding alpha-helix, and a helix-turn-helix. The protein wraps around the DNA, mostly following the minor groove, contacting the phosphate backbone along the full length of the duplex. Surprisingly, while the minor groove-binding helix and the helix-turn- helix subdomain make hydrophobic contacts, the few base-specific hydrogen bonds occur in segments that lack secondary structure and flank the intron insertion site. The multiple base-specific interactions over a long segment of the substrate are consistent with the observed high site specificity in spite of sequence tolerance, while the modular composition of the domain is pertinent to the evolution of homing endonucleases.

Base Sequence↗
PubMed2001

The EUROPA trial: design, baseline demography and status of the substudies.

BACKGROUND: Angiotensin-converting enzyme inhibitors do reduce both mortality and morbidity in patients with left ventricular dysfunction, recent myocardial infarction and hypertension. However, the long-term effects in patients with coronary artery disease have not been established. The EUROPA study is designed to assess the long-term (3-4 years) effects of perindopril on the reduction of cardiac events in patients with proven stable coronary artery disease but with no evidence of heart failure. STUDY DESIGN AND METHODS: EUROPA is a 12236 patient, randomised, double-blind, placebo-controlled and multicentre trial. EUROPA had an initial run-in period of 4 weeks during which patients received 4 and then 8 mg of perindopril daily to assess tolerance to maximum dose. This was followed by a double-blind randomisation to either perindopril or placebo. Patients were followed-up at 3 and 6 months and then 6 monthly until the last patient included in the main study completes the 3-year follow-up. EUROPA includes five sub-studies. Each of these sub-studies investigates the effects of perindopril on a different aspect of coronary artery disease: endothelial dysfunction, atherosclerosis progression regression, diabetes mellitus, inflammation, thrombosis, neurohormonal activation. Patients are characterised genetically to assess characteristics associated with improved or unfavourable outcome. The final results of EUROPA will be available in 2002.

Adult↗
PubMed2001

Serum and urine markers of bone metabolism during the year after hip fracture.

OBJECTIVE: As part of a larger study to describe indices of recovery during the year after hip fracture, the current prospective study investigated longitudinal changes in serum and urine markers of bone metabolism for the year after hip fracture and related them to bone mineral density (BMD). DESIGN: A representative subset of participants provided serum and urine samples and had bone density measured at 3, 10, 60, 180, and 365 days postfracture. SETTING: Two Baltimore hospitals. PARTICIPANTS: The subjects were 205 community-dwelling, white women age 65 and older with fresh proximal femur fractures. MEASUREMENTS: Samples were assayed for specific bone-related proteins and bone turnover markers, including serum osteocalcin (OC), procollagen type 1 carboxy-terminal extension peptide (PICP), bone-specific alkaline phosphatase (BAP), and urinary deoxypyridinoline (DPD) cross-links. Selected hormonal regulators of bone metabolism, including parathyroid hormone (PTH), calcitonin (CT), 1,25-dihydroxy vitamin D(3) (1,25 (OH)(2)D), and estrone (E(1)) were measured from serum samples. Repeated measures analyses were used to evaluate postfracture changes in each of the markers. RESULTS: BAP, OC, and PICP were most active during the early postfracture period (3-60 days). BAP and OC remained elevated at 365 days compared with 3 days. DPD rose 48% from 3 days to 60 days, but this difference was not statistically significant. PTH and 1,25 (OH)(2)D increased steadily and significantly from 3 to 365 days. E(1) was highest at baseline and decreased at each time point, whereas CT showed no significant changes. When subjects were stratified into high-, medium-, and low-BMD groups based on their measurement at 3 days, both osteoclastic and osteoblastic markers in the low-BMD group displayed exaggerated and different patterns over time compared with the other groups. CONCLUSION: Currently, the standard treatment of care for hip fractures still results in high morbidity and mortality and failure to regain prefracture quality of life. Gaining an understanding of bone cell activity in these patients after hip fracture, derived by measuring markers longitudinally during recovery, provides a baseline by which to measure the effectiveness of new interventions to improve recovery from hip fracture.

Absorptiometry, Photon↗
PubMed2001

Why is recurrent myocardial ischaemia a predictor of adverse outcome in unstable angina? An observational study of myocardial ischaemia and its relation to coronary anatomy.

OBJECTIVE: To establish why recurrent myocardial ischaemia predicts adverse outcome in patients with refractory unstable angina on maximal medical treatment. DESIGN: Prospective observational study in 101 patients with refractory unstable angina who underwent continuous ST-segment monitoring and kept detailed pain charts prior to cardiac catheterization. Setting Tertiary referral centre. RESULTS: Significant coronary disease was identified in 90 subjects with 74 (82%) having multivessel disease, 41 (46%) complex lesion morphology, and 10 (11%) subjects with definite features of intra-coronary thrombus. The frequency of complex lesions or intra-coronary thrombus did not differ in relation to the extent of coronary disease. Recurrent chest pain was present in 72 of the 90 (80%) subjects, while transient ischaemia was detected in 26 (29%). The presence of transient ischaemia was a powerful predictor of complex lesions or thrombus (odds ratio 7.1;P<0.001). Subjects with severe recurrent chest pain had a greater frequency of intracoronary thrombus (odds ratio 9.5;P<0.05). CONCLUSIONS: In unstable angina once the normal mechanisms causing myocardial ischaemia (i.e. increased myocardial demand and coronary vasoconstriction) have been treated using maximal antianginal treatment, the continued development of transient myocardial ischaemia is strongly associated with complex coronary lesion morphology and intracoronary thrombus. It is already known that patients with complex lesion morphology and intracoronary thrombus have an adverse outcome in unstable angina and therefore it is this association that explains why transient ischaemia is a predictor of poor outcome in unstable angina.

Adult↗
PubMed2001

Three-dimensional structure of human follicle-stimulating hormone.

The crystal structure of a betaThr26Ala mutant of human follicle-stimulating hormone (hFSH) has been determined to 3.0 A resolution. The hFSH mutant was expressed in baculovirus-infected Hi5 insect cells and purified by affinity chromatography, using a betahFSH-specific monoclonal antibody. The betaThr26Ala mutation results in elimination of the betaAsn24 glycosylation site, yielding protein more suitable for crystallization without affecting the receptor binding and signal transduction activity of the glycohormone. The crystal structure has two independent hFSH molecules in the asymmetric unit and a solvent content of about 80%. The alpha- and betasubunits of hFSH have similar folds, consisting of central cystine-knot motifs from which three beta-hairpins extend. The two subunits associate very tightly in a head-to-tail arrangement, forming an elongated, slightly curved structure, similar to that of human chorionic gonadotropin (hCG). The hFSH heterodimers differ only in the conformations of the amino and carboxy termini and the second loop of the beta-subunit (L2beta). Detailed comparison of the structures of hFSH and hCG reveals several differences in the beta-subunits that may be important with respect to receptor binding specificity or signal transduction. These differences include conformational changes and/or differential distributions of polar or charged residues in loops L3beta (hFSH residues 62-73), the cystine noose, or determinant loop (residues 87-94), and the carboxy-terminal loop (residues 94-104). An additional interesting feature of the hFSH structure is an extensive hydrophobic patch in the area formed by loops alphaL1, alphaL3, and betaL2. Glycosylation at alphaAsn52 is well known to be required for full signal transduction activity and heterodimer stability. The structure reveals an intersubunit hydrogen bonding interaction between this carbohydrate and betaTyr58, an indication of a mechanism by which the carbohydrate may stabilize the heterodimer.

Alanine↗
PubMed2001

Potassium channel openers in myocardial ischaemia: therapeutic potential of nicorandil.

Potassium channel openers or agonists represent a novel new class of compounds in the treatment of a range of cardiovascular disorders, particularly angina pectoris and hypertension. Nicorandil is the only clinically available potassium channel opener with antianginal effects, and with comparable efficacy and tolerability to existing antianginal therapy. It confers benefits through a dual action: opening the mitochondrial KATP channels leading to preconditioning of the myocardium and a nitrate-like effect. Myocardial preconditioning is important in reducing infarct size, severity of stunning and cardiac arrhythmias. These effects make nicorandil a unique antianginal compound that reduces both pre- and after-load and improves coronary blood flow. Comparative and noncomparative studies support the use of nicorandil as monotherapy or in combination with other antianginal therapy for stable angina pectoris. However, large studies are required to confirm its role in the treatment of acute coronary syndromes despite the favourable results from small studies.

ATP-Binding Cassette Transporters↗
PubMed2000

Diltiazem in acute myocardial infarction treated with thrombolytic agents: a randomised placebo-controlled trial. Incomplete Infarction Trial of European Research Collaborators Evaluating Prognosis post-Thrombolysis (INTERCEPT)

BACKGROUND: Diltiazem reduces non-fatal reinfarction and refractory ischaemia after non-Q-wave myocardial infarction, an acute coronary syndrome similar to the incomplete infarction that occurs after successful reperfusion. We postulated that this agent would reduce cardiac events in patients after acute myocardial infarction treated initially with thrombolytic agents-a clinical application previously unexplored with heart-rate-lowering calcium antagonists. METHODS: A prospective, randomised, double-blind, sequential trial was done in 874 patients with acute myocardial infarction, but without congestive heart failure, who first received thrombolytic agents. Patients received either 300 mg oral diltiazem once daily, or placebo, initiated within 36-96 h of infarct onset, and given for up to 6 months. The trial primary endpoint was the cumulative first event rate of cardiac death, non-fatal reinfarction, or refractory ischaemia. Additional prespecified endpoints included several composites of non-fatal cardiac events (non-fatal reinfarction combined with refractory ischaemia, all recurrent ischaemia, or the need for myocardial revascularisation). The diagnosis of ischaemia, whether refractory or recurrent, and the need for myocardial revascularisation, was always based on objective electrocardiographical evidence of ischaemia, either at rest or on exertion. RESULTS: For the trial primary endpoint, 131 events occurred in the 444 placebo patients and 97 events in the 430 diltiazem patients (hazard ratio 0.79; 95% CI, 0.61-1.02; p=0.07). For non-fatal cardiac events, diltiazem treatment was associated with a relative decrease (0.76; 0.58-1.00) in the combined event rate of non-fatal reinfarction and refractory ischaemia. There was a similar decrease in the composite non-fatal endpoints of non-fatal reinfarction combined with all recurrent ischaemia (0.80; 0.64-1.00) and non-fatal reinfarction combined with the need for myocardial revascularisation (0.67; 0.46-0.96). The need for myocardial revascularisation alone was significantly reduced by 42% (0.61; 0.39-0.96). No major safety issues were encountered. CONCLUSIONS: Diltiazem did not reduce the cumulative occurrence of cardiac death, non-fatal reinfarction, or refractory ischaemia during a 6-month follow-up, but did reduce all composite endpoints of non-fatal cardiac events, especially the need for myocardial revascularisation.

Calcium Channel Blockers↗
PubMed2000

Are there gender differences in patients presenting with unstable angina?

BACKGROUND: There are limited studies on gender differences in patients with unstable angina. We investigated the influence of gender in these patients in a tertiary referral centre. METHODS AND RESULTS: Three hundred and thirteen consecutive patients (210 men and 103 women) with unstable angina were studied over a 42-month period. Patient characteristics, cardiovascular risk factors and subsequent management including coronary artery bypass graft (CABG) operation and percutaneous transluminal coronary angioplasty (PTCA) were investigated. There was no difference in age [61.6 (11.0) (S.D.) years for men vs. 63.5 (10.5) years for women]. Diabetes mellitus and hypertension were more common in women (diabetes, 11% vs. 23%, P = 0.007; hypertension, 32% vs. 52%; P = 0.001). The number of smokers was greater in men (73% vs. 46%, P = 0.00001). There was no difference in the prevalence of hypercholesterolaemia or in the incidence of previous myocardial infarction, previous history of angina and family history of ischaemic heart disease. The duration of unstable angina before presentation to the referring hospital was similar in both sexes. The use of aspirin, intravenous heparin and antianginal drugs was also comparable in the two genders. The number of coronary arteries involved in men and women appeared similar (one vessel, 22% vs. 27%; two vessels, 26% vs. 21%; three vessels, 52% vs. 52% in men and women, respectively). The proportion of men and women who underwent subsequent revascularisation was also similar (CABG, 31% vs. 33%; PTCA, 42% vs. 40%). The overall in-hospital mortality was higher in women (6.8% vs. 2.8%), but was not statistically significant (P = 0.18). CONCLUSIONS: Gender differences in unstable angina manifest in the preponderance of selected risk factors including diabetes mellitus and hypertension in women and smoking in men. There is no difference in age, the degree of coronary artery involvement and the subsequent management in a tertiary referral centre.

Angina, Unstable↗
PubMed2000

Loss of bone density and lean body mass after hip fracture.

Few studies of bone loss have assessed the amount of loss directly after a hip fracture. The present prospective study was conducted to determine changes in bone mineral density (BMD) and muscle mass shortly after fracture and through 1 year to assess short-term loss and related factors. The setting was two acute care teaching hospitals in Baltimore, Maryland, and subjects were 205 community-dwelling women with a new fracture of the proximal femur between 1992 and 1995. Bone density of the nonfractured hip and whole-body and body composition were measured by dual-energy X-ray absorptiometry at 3 and 10 days and 2, 6 and 12 months after admission. Mean BMD of the femoral neck was 0.546 +/- 0.007 g/cm(2) at baseline. Average loss of femoral neck BMD from baseline was 2.1% at 2 months, 2.5% at 6 months and 4.6% at 12 months. The average loss of BMD in the intertrochanteric region was 2.1% at 12 months. Total lean body mass decreased by 6% while fat mass increased by 3. 6% by 1 year after the fracture. These findings indicate that significant loss in BMD and lean body mass occur shortly after hip fracture while body fat increases. Continued loss was evident throughout the 1 year of follow-up. This loss of both bone density and muscle mass may lead to new fractures.

Absorptiometry, Photon↗
PubMed2000

Femoral neck and intertrochanteric fractures have different risk factors: a prospective study.

The aim of this study was to determine whether both types of hip fracture, femoral neck and intertrochanteric, have similar risk factors. A prospective cohort study was carried out on community-dwelling elderly women in four areas of the United States: Baltimore, MD; Pittsburgh, PA; Minneapolis, MN and Portland, OR. The participants were 9704 Caucasian women, 65 years and older, of whom 279 had fractured their femoral neck and 222 had fractured their trochanteric region of the proximal femur. The predictors used were the bone mass of the calcaneus and proximal femur, anthropometry, history of fracture (family and personal), medication use, functional status, physical activity and visual function. The main outcome measures were femoral neck and intertrochanteric fractures occurring during an average of 8 years of follow-up. In multivariate proportional hazards models, several risk factors increased the risk of both types of hip fracture; including femoral neck bone density and increased functional difficulty. In hazard regression models that directly compared risk factors for the two types of hip fracture, calcaneal bone mineral density (BMD) predicted femoral neck fractures more strongly than intertrochanteric fractures (OR = 1.16; 95% CI = 1.02-1.31). Steroid use and impaired functional status also predicted femoral neck fractures instead of intertrochanteric fractures. Poor health status (OR = 0.74; 95% CI = 0.55-1.00) predicted intertrochanteric fractures more strongly than femoral neck fractures. We conclude that femoral neck fractures are largely predicted by BMD and poor functional ability while aging and poor health status predispose to intertrochanteric fractures.

Age Factors↗
PubMed2000

Guidelines for the diagnosis and management of unstable angina and non-Q-wave myocardial infarction: proposed revisions. International Cardiology Forum.

BACKGROUND: In 1994, the United States Agency for Health Care Policy and Research issued clinical practice guidelines for the diagnosis and management of unstable angina and non-Q-wave myocardial infarction. In the past 5 years, rapid progress has been made in the management of patients with unstable coronary syndromes, yet current guidelines do not necessarily reflect these advances. METHODS AND RESULTS: An international forum of cardiology investigators reviewed existing guidelines and discussed areas in which the diagnosis and treatment of unstable angina and non-Q-wave myocardial infarction should be modified. It was agreed that there is sufficient evidence to recommend the following changes: (1) use of serum cardiac markers should be expanded to include troponin I and T levels as diagnostic and prognostic tools; (2) low-molecular-weight heparins should replace unfractionated heparin as antithrombotic agents; (3) new classes of antiplatelet agents are recommended in addition to aspirin; and (4) the use of cholesterol-lowering drugs is appropriate in the long-term management of these patients. CONCLUSIONS: Evidence from clinical trials within the last 5 years requires that significant changes be made to existing guidelines for the diagnosis and management of unstable angina and non-Q-wave myocardial infarction. The recommendations detailed should be considered in the creation and implementation of updated guidelines.

Adrenergic beta-Antagonists↗