Citations

Background and Purpose — Contrast-enhanced magnetic resonance angiography (CEMRA) permits acquisition of high-spatial-resolution, venous-suppressed, 3D MR angiograms of the cervical carotid and vertebral arteries. In this study, an elliptic centric-view ordering with either MR fluoroscopic triggering or test bolus timing was used. The use of CEMRA of the cervical vessels has changed our clinical practice and is replacing conventional angiography for the evaluation of most carotid and vertebral artery diseases. Methods — We retrospectively reviewed our experience with the use of CEMRA performed in 422 patients from January through December 1999. Results — CEMRA was performed to evaluate transient ischemic attack and ischemic stroke in 239 patients, asymptomatic carotid bruit in 88 patients, and other neurological symptoms in 95 patients. Carotid endarterectomies were performed in 97 patients (103 procedures), and conventional angiography was performed in 12 of these patients. CEMRA was used to evaluate for the presence of an arterial dissection in 85 of the 239 patients with transient ischemic attack and ischemic stroke. Of this group, 32 patients had cervical arterial dissection, and pseudoaneurysm was detected in 11 of these patients. Compared with ultrasonography of the cervical vessels, CEMRA provided additional information in 43 of 422 patients and led to changes in the decision as to whether to perform carotid endarterectomy in 5 patients. Conclusions — Use of CEMRA permits noninvasive evaluation of patients suspected of having carotid or vertebral disease and avoids the potential complications of conventional angiography.

Purpose To report a multicenter experience treating anal canal cancer patients with concurrent chemotherapy and intensity-modulated radiation therapy (IMRT). Patients and Methods From October 2000 to June 2006, 53 patients were treated with concurrent chemotherapy and IMRT for anal squamous cell carcinoma at three tertiary-care academic medical centers. Sixty-two percent were T1-2, and 67% were N0; eight patients were HIV positive. Forty-eight patients received fluorouracil (FU)/mitomycin, one received FU/cisplatin, and four received FU alone. All patients underwent computed tomography–based treatment planning with pelvic regions and inguinal nodes receiving a median of 45 Gy. Primary sites and involved nodes were boosted to a median dose of 51.5 Gy. All acute toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 3.0. All late toxicity was scored using Radiation Therapy Oncology Group criteria. Results Median follow-up was 14.5 months (range, 5.2 to 102.8 months). Acute grade 3+ toxicity included 15.1% GI and 37.7% dermatologic toxicity; all acute grade 4 toxicities were hematologic; and acute grade 4 leukopenia and neutropenia occurred in 30.2% and 34.0% of patients, respectively. Treatment breaks occurred in 41.5% of patients, lasting a median of 4 days. Forty-nine patients (92.5%) had a complete response, one patient had a partial response, and three had stable disease. All HIV-positive patients achieved a complete response. Eighteen-month colostomy-free survival, overall survival, freedom from local failure, and freedom from distant failure were 83.7%, 93.4%, 83.9%, and 92.9%, respectively. Conclusion Preliminary outcomes suggest that concurrent chemotherapy and IMRT for anal canal cancers is effective and tolerated favorably compared with historical standards.

For many years, β-adrenergic receptor antagonists (β-blockers or βAR antagonists) have provided significant morbidity and mortality benefits in patients who have sustained acute myocardial infarction. More recently, β-adrenergic receptor antagonists have been found to provide survival benefits in patients suffering from heart failure, although the efficacy of different β-blockers varies widely in this condition. One drug, carvedilol, a nonsubtype-selective βAR antagonist, has proven particularly effective in the treatment of heart failure, although the mechanism(s) responsible for this are controversial. Here, we report that among 16 clinically relevant βAR antagonists, carvedilol displays a unique profile of in vitro signaling characteristics. We observed that in β2 adrenergic receptor (β2AR)-expressing HEK-293 cells, carvedilol has inverse efficacy for stimulating G s -dependent adenylyl cyclase but, nonetheless, stimulates ( i ) phosphorylation of the receptor's cytoplasmic tail on previously documented G protein-coupled receptor kinase sites; ( ii ) recruitment of β-arrestin to the β2AR; ( iii ) receptor internalization; and ( iv ) activation of extracellular regulated kinase 1/2 (ERK 1/2), which is maintained in the G protein-uncoupled mutant β2AR T68F,Y132G,Y219A (β2AR TYY ) and abolished by β-arrestin2 siRNA. Taken together, these data indicate that carvedilol is able to stabilize a receptor conformation which, although uncoupled from G s , is nonetheless able to stimulate β-arrestin-mediated signaling. We hypothesize that such signaling may contribute to the special efficacy of carvedilol in the treatment of heart failure and may serve as a prototype for a new generation of therapeutic β2AR ligands.

Abstract Rationale Transforming growth factor (TGF)-β has a central role in driving many of the pathological processes that characterize pulmonary fibrosis. Inhibition of the integrin αvβ6, a key activator of TGF-β in lung, is an attractive therapeutic strategy, as it may be possible to inhibit TGF-β at sites of αvβ6 up-regulation without affecting other homeostatic roles of TGF-β. Objectives To analyze the expression of αvβ6 in human pulmonary fibrosis, and to functionally test the efficacy of therapeutic inhibition of αvβ6-mediated TGF-β activation in murine bleomycin–induced pulmonary fibrosis. Methods Lung biopsies from patients with a diagnosis of systemic sclerosis or idiopathic pulmonary fibrosis were stained for αvβ6 expression. A range of concentrations of a monoclonal antibody that blocks αvβ6-mediated TGF-β activation was evaluated in murine bleomycin–induced lung fibrosis. Measurements and Main Results αvβ6 is overexpressed in human lung fibrosis within pneumocytes lining the alveolar ducts and alveoli. In the bleomycin model, αvβ6 antibody was effective in blocking pulmonary fibrosis. At high doses, there was increased expression of markers of inflammation and macrophage activation, consistent with the effects of TGF-β inhibition in the lung. Low doses of antibody attenuated collagen expression without increasing alveolar inflammatory cell populations or macrophage activation markers. Conclusions Partial inhibition of TGF-β using αvβ6 integrin antibodies is effective in blocking murine pulmonary fibrosis without exacerbating inflammation. In addition, the elevated expression of αvβ6, an activator of the fibrogenic cytokine, TGF-β, in human pulmonary fibrosis suggests that αvβ6 monoclonal antibodies could represent a promising new therapeutic strategy for treating pulmonary fibrosis.

OBJECTIVE—To determine mechanisms by which pioglitazone and metformin effect hepatic and extra-hepatic insulin action. RESEARCH DESIGN AND METHODS—Thirty-one subjects with type 2 diabetes were randomly assigned to pioglitazone (45 mg) or metformin (2,000 mg) for 4 months. RESULTS—Glucose was clamped before and after therapy at ∼5 mmol/l, insulin raised to ∼180 pmol/l, C-peptide suppressed with somatostatin, glucagon replaced at ∼75 pg/ml, and glycerol maintained at ∼200 mmol/l to ensure comparable and equal portal concentrations on all occasions. Insulin-induced stimulation of glucose disappearance did not differ before and after treatment with either pioglitazone (23 ± 3 vs. 24 ± 2 μmol · kg−1 · min−1) or metformin (22 ± 2 vs. 24 ± 3 μmol · kg−1 · min−1). In contrast, pioglitazone enhanced (P < 0.01) insulin-induced suppression of both glucose production (6.0 ± 1.0 vs. 0.2 ± 1.6 μmol · kg−1 · min−1) and gluconeogenesis (n = 11; 4.5 ± 0.9 vs. 0.8 ± 1.2 μmol · kg−1 · min−1). Metformin did not alter either suppression of glucose production (5.8 ± 1.0 vs. 5.0 ± 0.8 μmol · kg−1 · min−1) or gluconeogenesis (n = 9; 3.7 ± 0.8 vs. 2.6 ± 0.7 μmol · kg−1 · min−1). Insulin-induced suppression of free fatty acids was greater (P < 0.05) after treatment with pioglitazone (0.14 ± 0.03 vs. 0.06 ± 0.01 mmol/l) but unchanged with metformin (0.12 ± 0.03 vs. 0.15 ± 0.07 mmol/l). CONCLUSIONS—Thus, relative to metformin, pioglitazone improves hepatic insulin action in people with type 2 diabetes, partly by enhancing insulin-induced suppression of gluconeogenesis. On the other hand, both drugs have comparable effects on insulin-induced stimulation of glucose uptake.

In childhood acute lymphoblastic leukemia (ALL), a rapid decline of circulating leukemic blasts in response to induction chemotherapy or prednisone is one of the most important prognostic factors, not only for achieving remission but also for relapse-free survival (RFS). However, in acute myeloid leukemia (AML) parameters of chemosensitivity have been restricted mainly to the rapidity of achievement of complete remission (CR) or the assessment of residual leukemic bone marrow blasts during aplasia. We hypothesized that the time to circulating peripheral blood blast clearance, as a potential surrogate for in vivo chemosensitivity, would have prognostic relevance in AML also. In a retrospective analysis of a cohort of 86 adult patients with AML receiving uniform induction and consolidation chemotherapy, we demonstrate that the time to clearance of circulating blasts during induction chemotherapy is an independent prognostic marker of RFS, superseding other known or established risk factors, including karyotype and number of inductions to achieve CR.

Inhibition of proliferative neointima formed by vascular smooth muscle cells is a potential target in preventing angioplasty-induced restenosis. We have created a potent antiproliferative by fusing the active regions of the p27 and p16 cell cycle inhibitors. Intravascular delivery of a replication-deficient adenoviral vector (AV) encoding this p27-p16 fusion protein, named W9, inhibited balloon injury–induced neointimal hyperplasia in rabbit carotid arteries. In a therapeutically more relevant model, AV-W9 was delivered to balloon-injured porcine coronary arteries in vivo using an infusion catheter. Of the three coronary arteries, two were injured with a 15-mm balloon catheter and either were left untreated or were treated with 10 12 viral particles of either AV-W9 or a control null virus. AV-W9 treatment significantly inhibited neointimal hyperplasia in this porcine arterial balloon injury model compared with untreated or control virus–treated vessels. The average intimal area of the AV-W9–treated group 10 days after balloon injury and treatment was 0.42±0.36 mm 2 , whereas the AV-null group demonstrated an intimal area of 0.70±0.52 mm 2 . At day 10 the average intimal thickness of the AV-W9–treated vessels was 9.1 μm (n=5, ×20 magnification) compared with 21.2 μm (n=5, ×20 magnification) in control virus–treated vessels. This trend was also observed at 28 days after balloon injury and gene transfer during which AV-W9–treated vessels demonstrated an average intimal thickness of 4.7 μm (n=8, ×20 magnification) compared with 13.3 μm (n=3, ×20 magnification) in control virus–treated vessels and 7.3 μm (n=5, ×20 magnification) in the sham-treated vessels. The AV-W9 treatment was safe and well tolerated. These data suggest that AV-W9 gene therapy may be useful in preventing angioplasty–induced intimal hyperplasia in the coronary artery.

Abstract —Tissue factor (TF) is a low-molecular-weight glycoprotein that initiates the extrinsic clotting cascade and is considered a major regulator of arterial thrombogenicity. TF pathway inhibitor (TFPI) is a major physiological inhibitor of TF-initiated coagulation. The aim of this study was to define the complex interplay between TF and TFPI and the regulation of vascular thrombogenicity in a model of vascular remodeling. To determine the levels and pattern of vascular expression of TF and TFPI associated with vascular remodeling, a murine model of flow cessation was studied. TF activity of the arteries increased after ligation ( P <0.05). Quantitative analysis of homogenates of remodeled carotid arteries revealed increased TF expression but unchanged TFPI expression compared with normal carotid arteries, resulting in enhanced TF activity. To determine the potential therapeutic role of TFPI in this thrombogenic state, mice were treated with intravascular adenoviral delivery of either murine TFPI (Ad-mTFPImyc) or a control adenovirus (Ad-ΔE1). Overexpression of TFPI decreased vascular TF activity compared with viral control ( P <0.01). Overexpression of TFPI inhibited neointimal formation ( P =0.038), resulting in enhanced luminal area ( P =0.001) 4 weeks after flow cessation. In this murine model of vascular remodeling, an imbalance between TF and TFPI expression is generated, resulting in increased TF activity. Overexpression of TFPI in this model inhibits vascular TF activity and results in attenuation of vascular remodeling associated with flow interruption.

Background Electron-beam CT (EBCT) quantification of coronary artery calcification (CAC) allows noninvasive assessment of coronary atherosclerosis. We undertook a follow-up study to determine whether CAC extent, measured at the time of angiography by EBCT, predicted future hard cardiac events, comprising cardiac death and nonfatal myocardial infarction (MI). We also assessed the potential of selected coronary artery disease (CAD) risk factors, prior CAD event history (MI or revascularization), and angiographic findings (number of diseased vessels and overall disease burden) to predict subsequent hard events. Methods and Results Two hundred eighty-eight patients who underwent contemporaneous coronary angiography and EBCT scanning were contacted after a mean of 6.9 years. Vital status and history of MI during follow-up were determined. Cox proportional hazards models were used to compare the predictive ability of CAC extent with selected CAD risk factors, CAD event history, and angiographic findings. Median CAC score was 160 (range 0 to 7633). The 22 patients who experienced hard events during follow-up were older and had more extensive CAC and angiographic disease ( P <0.05). Only 1 of 87 patients with CAC score <20 experienced a subsequent hard event during follow-up. Event-free survival was significantly higher for patients with CAC scores <100 than for those with scores ≥100 (relative risk 3.20; 95% CI 1.17 to 8.71). When a stepwise multivariable model was used, only age and CAC extent predicted hard events (risk ratios 1.72 and 1.88, respectively; P <0.05). Conclusions In patients undergoing angiography, CAC extent on EBCT is highly predictive of future hard cardiac events and adds valuable prognostic information.