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Biomedical subjects

S B Freedman

Publications and source records attributed to S B Freedman.

At least 19 recordsLinked to original sources
PubMed2006

Modular prevention of heart disease following acute coronary syndrome (ACS) [ISRCTN42984084].

BACKGROUND: Coronary heart disease (CHD) is a major cause of morbidity and mortality in Australia and it is recommended that all persons with unstable angina (UA) or myocardial infarction (MI) participate in secondary prevention as offered in cardiac rehabilitation (CR) programs. However, the majority of patients do not access standard CR and have higher baseline coronary risk and poorer knowledge of CHD than those persons due to commence CR. The objective of this study is to investigate whether a modular guided self-choice approach to secondary prevention improves coronary risk profile and knowledge in patients who do not access standard CR. METHODS/DESIGN: This randomised controlled trial with one year follow-up will be conducted at a tertiary referral hospital. Participants eligible for but not accessing standard CR will be randomly allocated to either a modular or conventional care group. Modular care will involve participation in individualised modules that involve choice, goal-setting and coaching. Conventional care will involve ongoing heart disease management as directed by the participant's doctors. Both modular and conventional groups will be compared with a contemporary reference group of patients attending CR. Outcomes include measured modifiable risk factors, relative heart disease risk and knowledge of risk factors. DISCUSSION: We present the rationale and design of a randomised controlled trial testing a modular approach for the secondary prevention of coronary heart disease following acute coronary syndrome.

Angina Pectoris↗
PubMed2006

C-reactive protein contributes to the hypercoagulable state in coronary artery disease.

OBJECTIVES: Elevated plasma C-reactive protein (CRP) levels predict coronary events, but it is unclear whether CRP plays a role in thrombosis associated with these events. We investigated tissue factor (TF) induction by CRP on peripheral blood mononuclear cells (PBMC) from patients with coronary disease. PATIENTS AND METHODS: PBMC from 35 patients with stable angina (SA) in study 1, 10 male patients with SA, 10 with unstable angina (UA) and 10 matched controls in study 2, and 25 patients with inflammatory disorders (ID) and 24 normal controls in study 3 were stimulated with CRP, interferon-gamma (IFN) or lipopolysaccharide (LPS), or their combination. PBMC from additional normal donors were also stimulated with CRP in adherent and non-adherent conditions, and TF activity, antigen and mRNA expression detected. RESULTS: CRP (5-25 microg mL(-1)) dose dependently induced more TF on PBMC from SA patients than 42 contemporary controls (P = 0.001, study 1). Compared with controls, patients with SA or UA had higher basal, and much higher CRP- or CRP/LPS-induced monocyte TF activity although serum CRP levels were similar (study 2). IFN induced monocyte TF activity in patients with angina, but not in controls. Basal or CRP-induced TF levels did not differ between controls and ID, even though ID patients had much higher serum CRP levels (study 3). CRP-induced monocyte TF activity correlated with serum CRP levels in controls (P = 0.005) and ID (P = 0.007) in study 3, but not in patients with angina (P =0.84) in study 2. CRP induced more TF activity, protein and mRNA under adherent than non-adherent conditions implying that it may mainly target macrophages in lymphocyte-rich lesions. CONCLUSIONS: Our results indicate that monocytes from patients with angina are preactivated and express TF but CRP is unlikely to be a major priming factor in vivo. IFN and CRP further increase TF levels that may contribute to the hypercoagulable state in coronary disease.

Adult↗
PubMed2005

Spontaneous remyelination following prolonged inhibition of alpha4 integrin in chronic EAE.

Inhibition of alpha(4)beta(1) integrin blocks immune cell influx into the CNS providing benefit to patients with multiple sclerosis and in animal model systems. We have used this mechanism to examine whether the presence of inflammatory cells suppresses spontaneous myelin repair in experimental autoimmune encephalomyelitis. We observed (1) 87% of plaques showed remyelination after 40 days of treatment; (2) myelin repair occurred in half of the total lesion area; (3) half of the animals regained motor function. There was no significant repair or gain of motor function in vehicle-treated animals. Therefore, prolonged inhibition of CNS inflammation, in the absence of targeted myelin repair, facilitates mechanisms of spontaneous remyelination.

Animals↗
PubMed2005

Elevated circulating levels of matrix metalloproteinase-9 and -2 in patients with symptomatic coronary artery disease.

BACKGROUND: Matrix metalloproteinases (MMP-9 and MMP-2) have been implicated in development of atherosclerosis and plaque rupture in acute coronary syndromes (ACS). AIM: To determine the relationship between circulating MMPs and symptomatic coronary artery disease. METHODS: Plasma levels of MMP-9 and MMP-2 were measured in patients with ACS, stable angina (SA) and in controls, using a quantitative gelatin zymography. These measurements were correlated with markers of systemic inflammation (hs-CRP) in all subjects and myocardial injury (troponin T) in patients with ACS. RESULTS: Plasma MMP-9 in ACS was greater than in SA, and was greater in SA than in controls (P < 0.01 ACS vs SA and controls, P < 0.01 SA vs control). Plasma MMP-2 was significantly greater in ACS than SA or controls (P < 0.01 vs SA and controls). There was strong overall relationship between hs-CRP and MMP-9 (r = 0.65, P < 0.0001) driven by a significant relationship in ACS patients (r = 0.58, P = 0.02), as there was no significant association in SA or controls. A weaker overall correlation was found between hs-CRP and MMP-2 (r = 0.39, P = 0.02), but no significant relationship was present for either of the two patient subgroups or controls. There was no correlation between levels of troponin T and MMP-9, MMP-2 or hs-CRP in ACS patients. CONCLUSION: Quantitative gelatin zymography identifies increased circulating levels of MMP-9 and MMP-2 in patients with symptomatic coronary disease. MMP-9 and MMP-2 are higher in ACS than SA patients and might have use as markers of plaque rupture or instability. The strong relationship between MMP-9 and hs-CRP in ACS patients suggests MMP-9 might be an additional marker and/or consequence of the inflammatory component in ACS.

Aged↗
PubMed2005

Suppression of acute experimental allergic encephalomyelitis with a small molecule inhibitor of alpha4 integrin.

PURPOSE: To determine the efficacy of a small molecule inhibitor of alpha4 integrin (CT301) at reversing the clinical, pathological and MR-detectable deficits associated with the acute phase of experimental allergic encephalomyelitis (EAE). MATERIALS AND METHODS: EAE was induced in 36 female Hartley guinea pigs, and the treatment period was from day 11 to day 17 post-immunization. Animals received either saline (n = 12), anti-alpha4 integrin antibody (AN100226m; n = 12) or CT301 (n = 12). T2-weighted fast spin echo and T1-weighted pre- and post-contrast scans were performed at the beginning (day 11) and end (day 18) of the treatment period, and scored for cerebral inflammation and gadolinium enhancement. T1-weighted images were further analyzed to quantify this enhancement as a measure of blood-brain barrier integrity. Dissected CNS was evaluated for inflammation and demyelination. RESULTS: CT301 successfully reversed two clinical indicators of disease over the course of the treatment period. These animals showed decreased T2-weighted abnormalities, as well as a reduction in gadolinium leakage on T1-weighted images. Meningeal and perivascular inflammation was decreased by anti-alpha4 integrin treatments. CONCLUSION: CT301 effectively reverses the clinical, pathological and MR-detectable deficits of acute EAE, and may therefore be a promising therapeutic agent in multiple sclerosis (MS).

Acute Disease↗
PubMed2002

Prolonged reversal of chronic experimental allergic encephalomyelitis using a small molecule inhibitor of alpha4 integrin.

CNS leukocytic invasion in experimental allergic encephalomyelitis (EAE) depends on alpha4beta1 integrin/vascular cell adhesion molecule-1 (VCAM-1) interactions. A small molecule inhibitor of alpha4beta1 integrin (CT301) was administered to guinea pigs in the chronic phase (>d40) of EAE for 10, 20, 30 or 40 days. CT301 elicited a rapid, significant improvement in the clinical and pathological scores that was maintained throughout the treatment period. A progressive loss of cells in the spinal cord of treated animals confirmed the resolution of inflammation associated with clinical recovery. Therefore, prolonged inhibition of alpha4beta1 integrin caused a sustained reversal of disease pathology in chronic EAE and may be similarly useful in MS.

Animals↗
PubMed2001

BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major components of plaque, beta-amyloid peptides (Abetas), are produced from amyloid precursor protein (APP) by the activity of beta- and gamma-secretases. beta-secretase activity cleaves APP to define the N-terminus of the Abeta1-x peptides and, therefore, has been a long- sought therapeutic target for treatment of AD. The gene encoding a beta-secretase for beta-site APP cleaving enzyme (BACE) was identified recently. However, it was not known whether BACE was the primary beta-secretase in mammalian brain nor whether inhibition of beta-secretase might have effects in mammals that would preclude its utility as a therapeutic target. In the work described herein, we generated two lines of BACE knockout mice and characterized them for pathology, beta-secretase activity and Abeta production. These mice appeared to develop normally and showed no consistent phenotypic differences from their wild-type littermates, including overall normal tissue morphology and brain histochemistry, normal blood and urine chemistries, normal blood-cell composition, and no overt behavioral and neuromuscular effects. Brain and primary cortical cultures from BACE knockout mice showed no detectable beta-secretase activity, and primary cortical cultures from BACE knockout mice produced much less Abeta from APP. The findings that BACE is the primary beta-secretase activity in brain and that loss of beta-secretase activity produces no profound phenotypic defects with a concomitant reduction in beta-amyloid peptide clearly indicate that BACE is an excellent therapeutic target for treatment of AD.

Alzheimer Disease↗
PubMed2001

Predictors of bacterial meningitis in the era after Haemophilus influenzae.

OBJECTIVE: To determine if, in the era after Haemophilus influenzae type b, the cerebrospinal fluid (CSF) white blood cell (WBC) count can be safely used to stratify children suspected of having bacterial meningitis into low- and high-risk groups. DESIGN: Retrospective analysis of CSF samples. SETTING: Tertiary care pediatric center in Toronto, Ontario, between January 1, 1992, and October 1, 1996. PATIENTS: All CSF samples collected on children aged 2 months to 17 years were included. The final database consisted of 1617 atraumatic samples from children without prior neurologic or immunologic disease who underwent a lumbar puncture to assess the possibility of community-acquired bacterial meningitis. MAIN OUTCOME MEASURES: The predictive values of CSF WBC count, differential, protein, and glucose. RESULTS: There were 44 cases of bacterial meningitis. Five had 3 CSF WBCs per microliter or less, and 6 had 4 to 30 CSF WBCs per microliter. The negative predictive value of CSF specimens with 30 WBCs per microliter or less for bacterial meningitis was 99.3%. Cerebrospinal fluid samples with greater than 30 WBCs per microliter had a likelihood ratio for bacterial meningitis of 10.3 (95% confidence interval, 8.0-13.1) and a positive predictive value of 22.3%. Other significant predictors of bacterial meningitis included age, CSF glucose, protein, gram stain, CSF-serum glucose ratio, and peripheral blood band count. CONCLUSIONS: Given the occurrence of bacterial meningitis in children in the absence of CSF pleocytosis, other factors should be considered when managing children with suspected bacterial meningitis. Children older than 6 months with 30 CSF WBCs per microliter or less are at low risk for bacterial meningitis. If clinically stable and without other laboratory markers of bacterial meningitis, hospital admission and empiric antibiotic therapy may be unwarranted.

Adolescent↗
PubMed2001

Therapeutic angiogenesis for ischemic cardiovascular disease.

In animal models of ischemia, a large body of evidence indicates that administration of angiogenic growth factors, either as recombinant protein or by gene transfer, can augment nutrient perfusion through neovascularization. While many cytokines have angiogenic activity, the best studied both in animal models and clinical trials are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Clinical trials of therapeutic angiogenesis in patients with end-stage coronary artery disease have shown large increases in exercise time and marked reductions in symptoms of angina, as well as objective evidence of improved perfusion and left ventricular function. Larger scale placebo-controlled trials have been limited to intracoronary and intravenous administration of recombinant protein, and have not yet shown significant improvement in either exercise time or angina when compared to placebo. Larger scale placebo-controlled studies of gene transfer are in progress. Future clinical studies will be required to determine the optimal dose, formulation, route of administration and combinations of growth factors, as well as the requirement for endothelial progenitor cell or stem cell supplementation, to provide effective and safe therapeutic myocardial angiogenesis.

Animals↗
PubMed2001

Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.

Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's disease.

Administration, Oral↗
PubMed2000

Interferon-gamma and lipopolysaccharide potentiate monocyte tissue factor induction by C-reactive protein: relationship with age, sex, and hormone replacement treatment.

BACKGROUND: Elevated plasma levels of C-reactive protein (CRP) in population studies and in patients with unstable coronary syndromes are predictive of future adverse events, including cardiac death and myocardial infarction, implicating inflammation in pathogenesis. Although CRP is considered a marker of inflammation, it induces monocyte tissue factor (TF) and may play a prothrombotic role in atherosclerosis and its complications. METHODS AND RESULTS: Peripheral blood mononuclear cells (PBMCs) from 79 healthy men and women aged 26 to 83 years and 21 healthy postmenopausal women taking hormone replacement therapy (HRT) were stimulated with CRP, lipopolysaccharide (LPS), interferon-gamma (IFN), or their combination. Levels of CRP in the normal range (1 to 5 microg/mL) increased basal monocyte TF 4- to 6-fold and 40-fold at higher concentrations (25 microg/mL). Coincubation of LPS with CRP produced a greater-than-additive response. IFN did not induce TF but synergized with CRP to approximately double activity. There was a striking positive correlation between age and monocyte TF induction, with a dramatic rise on monocytes from postmenopausal women that was not apparent on cells from women taking HRT. CONCLUSIONS: Synergy between CRP and inflammatory mediators may play a direct prothrombotic role in the pathogenesis of coronary atherosclerosis and its acute complications by increasing monocyte/macrophage TF. This may contribute to age and sex differences in coronary events and to the protective effects of HRT.

Adult↗
PubMed1999

Attenuation of anti-ischemic efficacy during chronic therapy with nicorandil in patients with stable angina pectoris.

After 2 weeks of nicorandil therapy, time to ischemia on stress testing was significantly less than on day 1 and not different from placebo. These data are consistent with attenuation of the anti-ischemic effects of this drug and suggest that the potassium channel-opening properties do not compensate for development of attenuation to the nitrate component of nicorandil.

Adrenergic beta-Antagonists↗
PubMed1998

Triggers of daily life ischaemia.

OBJECTIVE: To determine the usual triggers of silent and symptomatic ischaemia. DESIGN: Patients wore an ambulatory recorder for 48 hours. The device emitted a tone on detection of ischaemia and patients noted activities, feelings, and symptoms so that ischaemia could be attributed to one of four triggers: physical stress, mental stress, combined physical/mental stress, or no stressor. SETTING: Home environment. PATIENTS: Patients (n = 38) with stable coronary disease, positive exercise electrocardiography, and ischaemic episodes on ambulatory electrocardiography. MAIN OUTCOME MEASURE: Matching ischaemic episodes with perceived triggers. RESULTS: Altogether 257 ischaemic episodes (53% silent) were documented. Triggers were: physical stress, 56%; mental stress, 5%; combined physical/mental stress, 8%; no identifiable trigger, 31%. Episodes associated with mental or no stress were more often silent (69% and 75%, respectively) than those associated with physical stress (45%, p < 0.01), while combined physical/mental stress episodes were usually symptomatic (10% silent, p < 0.01 v other stressors). Although physical stress was less commonly a trigger of silent ischaemia than angina (47% v 65%, p < 0.01), it was still the predominant trigger of silent ischaemia. There was no identifiable trigger in 45% of silent and only 17% of anginal episodes (p < 0.01). Only nine silent episodes involved mental stress alone as a trigger. CONCLUSIONS: Daily life ischaemia is usually triggered by physical activity. Mental stress alone is an uncommon trigger of either silent or symptomatic ischaemia, while combined physical/mental stress is a significant but minor trigger of angina. Patients can identify a trigger in 83% of anginal episodes, compared with only half of silent ischaemic episodes.

Aged↗