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Biomedical subjects

G S Francis

Publications and source records attributed to G S Francis.

At least 19 recordsLinked to original sources
PubMed2006

Cardiac troponins and chronic kidney disease.

The prevalence of coronary artery disease in patients with chronic kidney disease (CKD) is high, and acute myocardial infarction contributes significantly to the steep mortality rate in this population. Diagnosing an acute coronary syndrome in these patients is often difficult though essential. Traditional diagnostic tools such as symptoms and electrocardiographic manifestations are not entirely helpful in patients with CKD, and physicians are often left to rely on laboratory analysis of biomarkers such as cardiac troponin. However, troponin levels are increased in patients with renal failure in the absence of clinical myocardial ischemia, making their interpretation problematic. Several theories have been proposed for the mechanism of elevated troponin levels in CKD. Irrespective of our uncertainty regarding mechanism, studies have shown that there is a strong prognostic implication of elevated troponin levels; and that it is predictive of increased risk of mortality and cardiovascular events. Troponin levels rise over 6-8 h in the setting of acute myocardial injury; hence, it is imperative to obtain these levels sequentially in patients with CKD in whom a clinical cardiac event is suspected. A distinct rise and fall in the levels over baseline strongly support the diagnosis of acute myocardial necrosis. Despite uncertainties regarding increased troponins in patients with CKD, their value remains clear.

Biomarkers↗
PubMed2005

Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis.

BACKGROUND: Although patients with multiple sclerosis (MS) are advised to stop interferon (IFN) beta-1a therapy before becoming pregnant, some patients become pregnant while on treatment. METHODS: We examined individual patient data from eight clinical trials with IFNbeta-1a. RESULTS: Of 3,361 women in the studies, 69 pregnancies were reported, of which 41 were patients receiving (or who had stopped receiving within 2 weeks prior to conception) IFNbeta-1a (in utero exposure group), 22 were patients who discontinued IFNbeta-1a treatment more than 2 weeks before conception (previous exposure group), and six were patients receiving placebo. The 41 in utero exposure pregnancies resulted in 20 healthy full-term infants, one healthy premature infant, nine induced abortions, eight spontaneous abortions, one fetal death, and one congenital anomaly (hydrocephalus). One patient was lost to follow-up. The 22 previous exposure pregnancies resulted in 20 full-term healthy infants, one healthy premature infant, and one birth-related congenital anomaly (Erb palsy). CONCLUSIONS: The majority (21/31) of pregnancies that had the potential to go to full term produced healthy infants. The rate of spontaneous abortion was higher, but not significantly so, in the in utero exposure group compared to general population estimates. Until more exposure data become available, patients remain advised to stop IFNbeta therapy before becoming pregnant.

Abnormalities, Drug-Induced↗
PubMed2005

Comparative tolerance of IFN beta-1a regimens in patients with relapsing multiple sclerosis. The EVIDENCE study.

The EVIDENCE study was a direct comparative study of two dose regimens of interferon (IFN) beta-1a used in the treatment of relapsing-remitting multiple sclerosis (RRMS): 30 mcg intramuscularly once weekly (qw; n=338) and 44 mcg subcutaneously three times weekly (tiw; n=339). The study continued for an average of 64 weeks. The safety population consisted of all patients receiving at least one dose of study drug. Clinical assessments occurred every 4 weeks for 24 weeks and then every 12 weeks. Blood tests for safety were taken at baseline and at weeks 4 and 12, and every 12 weeks thereafter. Overall adverse events were more common with the 44 mcg tiw regimen (p=0.007), and were due predominantly to differences in injection-site reactions. The majority of adverse events were rated mild by investigators. Hepatic and haematological adverse events and asymptomatic laboratory abnormalities were more common with 44 mcg tiw (p<0.001),with no difference seen for severe events. Flu-like symptoms were more common with 30 mcg qw (p=0.031), were more severe and persisted for longer. Serious adverse events were comparable for both groups, as were drug discontinuations. In conclusion, although adverse events were more common with high-dose, high-frequency IFN therapy, differences were primarily for mild events and did not affect treatment adherence. Based on superior clinical and magnetic resonance imaging outcomes over an average of 64 weeks, coupled with modest safety differences, the risk-benefit ratio for IFN therapy in RRMS favours the 44 mcg tiw regimen over this period of time.

Central Nervous System↗
PubMed2005

Randomized study of once-weekly interferon beta-1la therapy in relapsing multiple sclerosis: three-year data from the OWIMS study.

BACKGROUND: Once weekly interferon beta-1a for multiple sclerosis (OWIMS) demonstrated modest, but significant, magnetic resonance imaging (MRI) benefit of once-weekly (qw) interferon (IFN) beta-1a at 48 weeks, but no significant effect on relapses. OBJECTIVE: An OWIMS extension permitted assessment of longer-term efficacy/safety of qw IFN beta-1a in relapsing-remitting multiple sclerosis (RRMS). METHODS: Placebo patients were rerandomized to IFN beta-1a, 22 or 44 mcg qw, for two additional 48-week intervals. Primary outcome was MRI lesion activity. Relapse rate and other MRI measures were secondary outcomes. RESULTS: After three years, median (mean) T2 lesion count/patient/scan was 1.3 (2.6) for 44 mcg, 1.7 (3.3) for 22 mcg, 1.7 (3.4) for placebo/22 mcg, 2.0 (3.6) for placebo/44 mcg (all differences not significant). Annualized relapse rates were lowest for 44 mcg (0.77) versus other groups (0.83-0.86, not significant). Persistent neutralizing antibodies did not affect relapse rates, but MRI active lesions were increased in antibody-positive patients receiving 44 mcg compared to antibody negative patients. CONCLUSIONS: In RRMS, once weekly IFN beta-1a, particularly 44 mcg, can induce a significant MRI, but not relapse, effect, compared with placebo. No significant dose effect was seen. In contrast to the significant effect observed with three-times-weekly dosing of subcutaneous IFN beta-1a compared with placebo, this study confirms the lack of meaningful clinical benefit with once-weekly dosing.

Adjuvants, Immunologic↗
PubMed2004

Clinical outcomes of patients with impaired left ventricular ejection fraction undergoing autologous bone marrow transplantation: can we safely transplant patients with impaired ejection fraction?

Experience with autologous bone marrow transplantation (ABMT) in patients with impaired left ventricular ejection fraction (LVEF) or heart failure (HF) is limited. We identified 308 consecutive patients who underwent ABMT for Hodgkin's or non-Hodgkin's lymphoma at our institution (1996-2003). Patient characteristics, clinical course and overall survival were compared between patients with preserved ( > or = 50%) or impaired ( < 50%) LVEF. Of the 308 patients identified, 20 had baseline impaired LVEF (four with LVEF < or = 40%, all NYHA class I-II HF). None of the patients with post-ABMT echocardiogram had worsened LVEF (n = 7). Among the 20 patients with impaired LVEF, four patients had reversible cardiac complications post-ABMT (including worsening HF). The two deaths observed in the impaired LVEF group were both due to noncardiac causes. The 5-year survival was similar between patients with preserved and impaired LVEF (P = 0.43). Careful selection of patients with stable, mild-to-moderate HF and impaired LVEF for ABMT can achieve similar long-term survival. As medical care for HF and ABMT improves, the exclusion criteria for ABMT with regard to HF and impaired LVEF should be re-examined.

Adult↗
PubMed2001

ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America.

Explore the source record for details and available documents.

Adult↗
PubMed2001

Pathophysiology of chronic heart failure.

Heart failure is a changing paradigm. The hemodynamic model, which served our needs well from the 1950s through the early 1980s, has now been largely abandoned, except for the management of decompensated patients in the hospital. The pathophysiology is exceedingly complex and involves structural changes, such as loss of myofilaments, apoptosis and disorganization of the cytoskeleton, as well as disturbances in Ca(2+) homeostasis, alteration in receptor density, signal transduction, and collagen synthesis. A more contemporary working hypothesis is that heart failure is a progressive disorder of left ventricular remodeling, usually resulting from an index event, that culminates in a clinical syndrome characterized by impaired cardiac function and circulatory congestion. This change in the framework of our understanding of the pathophysiology of heart failure is predicated on the results of numerous clinical trials conducted during the past 20 years. New therapies are now evolving that are designed to inhibit neuroendocrine and cytokine activation, whereas drugs specifically designed to heighten cardiac contractility and "unload" the left ventricle have proven to be unhelpful in long-term management of patients with chronic heart failure. However, the hemodynamic model is still relevant for patients in the hospital with decompensated heart failure, where positive inotropic drugs and vasodilators are still widely used. The modern treatment of chronic heart failure is now largely based on the neurohormonal hypothesis, which states that neuroendocrine activation is important in the progression of heart failure and that inhibition of neurohormones is likely to have long-term benefit with regard to morbidity and mortality. Thus, the evolution of treatment for chronic heart failure as a result of clinical trials has provided much enlightenment for our understanding of the fundamental biology of the disorder, a reversal of the usual flow of information from basic science to clinical investigation.

Adrenergic beta-Antagonists↗
PubMed2001

Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability.

OBJECTIVE: To assess axonal damage and its contribution to disability at different stages of multiple sclerosis (MS). BACKGROUND: Recent in vivo imaging and in situ pathologic studies have demonstrated that substantial axonal damage accompanies the inflammatory lesions of MS. However, the relation of axonal damage to the duration of MS and its contribution to disability at different stages of the disease remain poorly defined. DESIGN: We performed proton magnetic resonance spectroscopic imaging in 88 patients with a wide range of clinical disability and disease duration to measure N-acetylaspartate (NAA, an index of axonal integrity) relative to creatine (Cr) in a large central brain volume that included mostly normal-appearing white matter on magnetic resonance imaging. RESULTS: We observed that the NAA/Cr values were abnormally low in the early stages of MS, even before significant disability (measured using the Expanded Disability Status Scale [EDSS]) was evident clinically, and declined more rapidly with respect to EDSS at lower than at higher EDSS scores (P<.001). The correlation of NAA/Cr values with EDSS score was significantly (P<.03) stronger in patients with mild disability (EDSS score <5, Spearman rank order correlation = -0.54, P<.001) than in patients with more severe disability (EDSS score >/=5, Spearman rank order correlation = -0.1, P<.9). When similar analyses were performed in patients with MS grouped for duration of disease, the subgroup with early disease duration (<5 years) also showed central brain NAA/Cr resonance intensity ratios significantly lower than healthy controls (P<.001). CONCLUSION: Cerebral axonal damage begins and contributes to disability from the earliest stages of the disease.

Adult↗
PubMed2001

Beta-adrenergic receptors and calcium cycling proteins in non-failing, hypertrophied and failing human hearts: transition from hypertrophy to failure.

Left ventricular hypertrophy may lead to heart failure. The transition between hypertrophy and heart failure is, however, incompletely understood. On the cellular level, human heart failure is characterized by alterations in Ca(2+)-cycling proteins and beta-adrenergic receptor density, but the hypertrophied human heart remains largely under studied. In this investigation, 21 donor hearts which could not be used for transplantation were studied. Ten of these hearts came from organ donors with documented left ventricular hypertrophy and normal cardiac function. Eleven of the hearts were non-failing, obtained from individuals with no evidence of cardiac disease. Nine failing hearts from transplant recipients were also studied. beta-adrenergic receptor density was determined by radioligand binding. mRNA for atrial natriuretic factor, calsequestrin, sarcoplasmic reticulum Ca(2+)-ATPase, and phospholamban was measured by Northern blot. Actin, calsequestrin, sarcoplasmic reticulum Ca(2+)-ATPase, and phospholamban proteins were quantified by Western blot. In both hypertrophied and failing ventricles, mRNA for atrial natriuretic factor was expressed, as compared to no expression in non-failing hearts. In failing hearts, beta -adrenergic receptor density and both mRNA and protein levels of the Ca(2+)-ATPase were significantly decreased v non-failing hearts. By comparison, hypertrophied hearts showed a reduction in mRNA expression for both the Ca(2+)-ATPase and phospholamban with no change in the corresponding protein levels, and no change in beta-receptors. These data suggest that the previously demonstrated reduction in beta-adrenergic receptors and Ca(2+)-cycling proteins in the failing human heart may be features of the decompensated state, but are not found in human hearts with left ventricular hypertrophy and preserved systolic function.

Aged↗
PubMed2001

Axonal metabolic recovery in multiple sclerosis patients treated with interferon beta-1b.

Patients with multiple sclerosis (MS) can benefit from treatment with interferon beta-1b. However, the mechanisms of action of this drug are incompletely understood and effects of interferon beta-lb on axonal injury are not known. A measure of axonal injury can be obtained in vivo using magnetic resonance spectroscopy to quantify the resonance intensity of the neuronal marker, N-acetylaspartate (NAA). In a small pilot study, we performed combined magnetic resonance imaging and magnetic resonance spectroscopic imaging on 10 patients with relapsing-remitting MS before and 1 year after starting treatment with subcutaneous interferon beta-lb. Resonance intensities of NAA relative to creatine (Cr) were measured in a large, central brain volume. These measurements were compared with those made in a group of 6 untreated patients selected to have a similar range of scores on the Expanded Disability Status Scale and mean NAA/Cr at baseline. NAA/Cr in the treated group [2.74 (0.16), mean (SD)] showed an increase of 5.5% 12 months after the start of therapy [2.89 (0.24),p = 0.05], while NAA/Cr in the untreated group decreased, but not significantly [2.76 (0.1) at baseline, 2.65 (0.14) at 12 months,p > 0.1]. NAA/Cr had become significantly higher in the treated group at 12 months than in the untreated group (p = 0.03). Our data suggest that, in addition to losing axons, patients with chronic multiple sclerosis suffer from chronic, sublethal axonal injury that is at least partially reversible with interferon beta-lb therapy.

Adjuvants, Immunologic↗
PubMed2001

The looming polypharmacy crisis in the management of patients with heart failure. Potential solutions.

Physicians may be on the road to a polypharmacy crisis in the development of new drugs for heart failure. They must somehow learn how to tailor the therapy to individual patients, rather than treating all patients with every potentially beneficial drug. This will not be an easy task, but the current model of rational drug development followed by a large megatrial is costly and not likely to be sustained indefinitely.

Forecasting↗
PubMed2001

Polypharmacy of heart failure. Creating a rational pharmacotherapeutic protocol.

In the management of chronic heart failure, polypharmacy is common, necessary, and often overlooked. The increasing costs of care, noncompliance, and frequent adverse drug interactions have led to diminishing benefits by simply adding additional drugs to the already complex regimen. This review outlines a rational pharmacotherapeutic protocol based on establishing overall therapeutic goals and confirming treatment targets, tailoring therapy to individual patients by balancing beneficial and adverse drug effects, and paying particular attention to patient education and other nonpharmacologic support.

Adrenergic beta-Antagonists↗
PubMed2000

Decreased SLIM1 expression and increased gelsolin expression in failing human hearts measured by high-density oligonucleotide arrays.

BACKGROUND: Failing human hearts are characterized by altered cytoskeletal and myofibrillar organization, impaired signal transduction, abnormal protein turnover, and impaired energy metabolism. Thus, expression of multiple classes of genes is likely to be altered in human heart failure. METHODS AND RESULTS: We used high-density oligonucleotide arrays to explore changes in expression of approximately 7000 genes in 2 nonfailing and 2 failing human hearts with diagnoses of end-stage ischemic and dilated cardiomyopathy, respectively. We report altered expression of (1) cytoskeletal and myofibrillar genes (striated muscle LIM protein-1 [SLIM1], myomesin, nonsarcomeric myosin regulatory light chain-2 [MLC(2)], and ss-actin); (2) genes responsible for degradation and disassembly of myocardial proteins (alpha(1)-antichymotrypsin, ubiquitin, and gelsolin); (3) genes involved in metabolism (ATP synthase alpha-subunit, succinate dehydrogenase flavoprotein [SDH Fp] subunit, aldose reductase, and TIM17 preprotein translocase); (4) genes responsible for protein synthesis (elongation factor-2 [EF-2], eukaryotic initiation factor-4AII, and transcription factor homologue-HBZ17); and (5) genes encoding stress proteins (alphaB-crystallin and mu-crystallin). In 5 additional failing hearts and 4 additional nonfailing controls, we then compared expression of proteins encoded by the differentially expressed genes, alphaB-crystallin, SLIM1, gelsolin, alpha(1)-antichymotrypsin, and ubiquitin. In each case, changes in protein expression were consistent with changes in transcript measured by microarray analysis. Gelsolin protein expression was also increased in cardiomyopathic hearts from tropomodulin-overexpressing (TOT) mice and rac1-expressing (racET) mice. CONCLUSIONS: Altered expression of the genes identified in this study may contribute to development of the heart failure phenotype and/or represent compensatory mechanisms to sustain cardiac function in failing human hearts.

Adolescent↗