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The U.S. auto outlook--a global perspective

Automobile industry and trade

Intercellular adhesion molecule-1 induction: A sensitive and quantitative marker for cardiac allograft rejection

ObjectivesRats with abdominal heterotopic heart transplants were studied to determine whether cardiac allograft rejection could be assessed by immunoscintigraphy targeting intercellular adhesion molecule-1 (ICAM-1), which was induced on allografted organ cells in association with rejection.BackgroundIt is important to detect early rejection before development of myocyte necrosis. Although a variety of methods for the detection of cardiac rejection have been investigated, histologic inspection of biopsied samples is still used routinely for clinical diagnosis of rejection.MethodsDA rat (RT-1a) hearts were transplanted into PVG rats (RT-1c). Immunohistologic examination of the allografts demonstrated that ICAM-1 induction on vascular endothelial cells was observed as early as 4 days after transplantation in this combination. Thirty-nine allografted rats and seven isografted rats were studied. One day after injection of 100 μCi of 111Inlabeled anti—ICAM-1 monoclonal antibody (1A29), planar images were obtained.ResultsRejecting allografts showed increased radiotracer uptake and could be identified on the images as early as 5 days after transplantation. In contrast, nonrejecting cardiac allografts and isografts did not show specific uptake. Mildly rejecting allografts, with mononuclear cell infiltration but without significant myocyte necrosis, could be scintigraphically identified, and the level of radiotracer uptake reflected the histologic severity of rejection. Accumulation of 111In-labeled monoclonal antibody of isotypematched irrelevant specificity was not detected in the rejecting allografts.ConclusionsThese data indicate that ICAM-1 induction can be assessed quantitatively by radioimmunoscintigraphy. Radioimmunoscintigraphy is a sensitive method for early detection and assessment of cardiac allograft rejection

Time Course of Paclitaxel-Induced Apoptosis in an Experimental Model of Virus-Induced Breast Cancer

Early assessment of the efficacy of treatment is important in patients with breast cancer, whose routine adjuvant regimen frequently includes chemotherapy. Irrespective of the exact mechanisms involved in induction, the common early phenotypic marker of apoptosis is the expression on the outer cell membrane surface of phosphatidylserine, which avidly binds annexin V. 99mTc-labeled annexin V has been proposed for in vivo scintigraphic detection of apoptosis, albeit with contradicting results. This study was performed to define the time course of apoptosis induced by the chemotherapeutic agent paclitaxel in a model of virus-induced murine breast cancer. Methods: The RIII virus induces an estrogen-dependent, slow-growing breast cancer; BALB-c/cRIII female mice with breast tumors averaging 10 mm were studied, both in baseline conditions and at various times after the intravenous administration of paclitaxel (equivalent to a human dose of 20 mg/70 kg of body weight). The biodistribution of 99mTc-annexin V was evaluated at baseline and then at 1, 3, 6, and 24 h after paclitaxel administration. Apoptotic and antiapoptotic markers were also evaluated in tumor samples obtained at the same time points: DNA breaks (terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling [TUNEL]), active caspase-3, apoptosis-inducing factor, and Bcl-2 protein. Results: Baseline uptake of 99mTc-annexin V in breast tumors was about 2-fold higher than the uptake in normal breast tissue (demonstrating some ongoing apoptosis); tracer uptake increased at 1 and 3 h after paclitaxel administration (to almost double the baseline value) and then declined to levels even lower than baseline. Although no activation of the apoptosis-inducing factor mechanism was detected, a peak in TUNEL-positive tumor cells was reached 3 h after paclitaxel administration (to more than 6-fold the baseline level). The antiapoptotic marker Bcl-2 exhibited a biphasic pattern, with a maximum drop at 3 h, followed by return toward baseline levels at 6 h. Conclusion: These results define the time course of various biologic events taking place in this model of murine breast cancer after a proapoptotic insult (single-dose paclitaxel). Although confirming that in vivo uptake of 99mTc-annexin V reflects the degree of apoptosis, the study also suggests that the apoptotic response to antitumor therapy may differ from tumor type to tumor type. Therefore, contradicting results previously reported may depend on an inadequate time window chosen for imaging with 99mTc-annexin V

Quantitative analysis of dipyridamole-thallium images for the detection of coronary artery disease

To determine if the detection of coronary artery disease by dipyridamole-thallium imaging is improved by 1) quantitative versus qualitative analysis, and 2) combining quantitative variables, 80 patients with chest pain (53 with and 27 without coronary artery disease) who underwent cardiac catheterization were studied. Segmental thallium initial uptake, linear clearance, mono-exponential clearance and redistribution were measured from early, intermediate and delayed images acquired in three projections. Normal values were determined from 13 other clinically normal subjects.When five segments per view were used for quantitative analysis, sensitivity and specificity were 87 and 63%, respectively, for uptake, 77 and 67% for linear clearance, 60 and 60% for monoexponential clearance and 62 and 56% for redistribution. Of the four variables, uptake and linear clearance were the most sensitive (p < 0.01) and specificity did not differ significantly. Using three segments per view, the specificity of uptake increased (p < 0.05) to 78% without a significant change in sensitivity (85%). With this approach, sensitivity and specificity did not differ from those of qualitative analysis (85 and 78%, respectively).Stepwise logistic regression analysis demonstrated that the best quantitative thallium correlate of the presence of coronary artery disease was a combination variable of “either abnormal uptake or abnormal linear clearance, or both.” Using five segments per view, the model's specificity (85%) was greater than that of uptake alone (p < 0.02), with similar sensitivity (92%). Using three segments per view, the model's specificity (93%) was greater than that of uptake alone (p < 0.05) and of qualitative analysis (p < 0.05), with similar sensitivity (85%). Compared with qualitative analysis, the diagnostic accuracy of the model was greater using either five segments (90 versus 82%, p < 0.01) or three segments (88 versus 82%, p < 0.05) per view.Quantitative analysis of dipyridamole-thallium images using single individual variables provides results comparable with those of qualitative analysis and this can be further optimized when a combination of quantitative variables is used

Effects of gender and race on prognosis after myocardial infarction: Adverse prognosis for women, particularly black women

Controversy has arisen concerning whether gender influences the prognosis after myocardial infarction. Although some studies have shown there to be no difference between the sexes, most have indicated a worse prognosis for women, attributing this to differences in baseline characteristics. It has been further suggested that black women have a particularly poor prognosis after infarction. To determine the contribution of gender and race to the course of infarction, 816 patients with confirmed myocardial infarction who were enrolled in the Multi-center Investigation of the Limitation of Infarct Size (MILIS) were analyzed. Of those patients, 226 were women and 590 were men, 142 were black and 674 were white.The cumulative mortality rate at 48 months was 36% for women versus 21% for men (p < 0.001, mean follow-up 32 months). The cumulative mortality rate by race was 34% for blacks versus 24% for whites (p < 0.005). Both women and blacks exhibited more baseline characteristics predictive of mortality than did their male or white counterparts. It was possible to account for the greater mortality rate of blacks by identifiable baseline variables; however, even after adjustment, the mortality rate for women remained significantly higher (p < 0.002). The poorer prognosis for women was influenced by a particularly high mortality rate among black women (48%); the mortality rate for white women was 32%, for black men 23% and for white men 21%. The mortality for black women was significantly greater than that of the other subgroups. Thus, findings in the MILIS population indicate that the prognosis after myocardial infarction is worse for women, particularly black women

18F-Fluoride Positron Emission Tomographic Imaging of Penile Arteries and Erectile Dysfunction.

BACKGROUND: Fluorine-18 sodium fluoride (NaF), a bone-seeking radiopharmaceutical used to detect osseous metastases, localizes in regions of microcalcification in atherosclerosis. OBJECTIVES: To determine if atherosclerosis of penile arteries plays a role in erectile dysfunction (ED), this study analyzed NaF images in prostate cancer patients. METHODS: NaF positron emission tomography-computed tomography bone scans were evaluated in 437 prostate cancer patients (age 66.6 ± 8.7 years). Their urologic histories were reviewed for prevalent ED (diagnosed before the scan date) or incident ED (no ED at first scan, but developed during 1-year follow-up); patients with no ED (neither before the scan nor during follow-up) were included as a control group. A semicircular region of interest was set on the dorsal one-half of the penis (to avoid residual excreted activity in the urethra) on 5 contiguous slices at the base of the penis on positron emission tomography-computed tomography coronal reconstructions, and the average standardized uptake value (SUVmax) was described as NaF uptake. RESULTS: Of 437 patients, 336 (76.9%) had prevalent ED, 60 incident ED (13.7%), and 41 had no ED (9.4%). SUVmax in patients with prevalent (median 1.88; interquartile range [IQR]: 1.67 to 2.16) or incident (median 1.86; IQR: 1.72 to 2.08) ED was significantly higher than no ED (median 1.42; IQR: 1.25 to 1.54) patients (p < 0.001). After adjustment for other risk factors, the odds ratio of prevalent or incident ED was 25.2 (95% confidence interval: 9.5 to 67.0) for every 0.5-U increment in SUVmax with receptor operating characteristic area of 0.91 (95% confidence interval: 0.88 to 0.94). CONCLUSIONS: NaF uptake in penile vessels suggests that atherosclerosis is associated with ED in prostate cancer patients. The importance of NaF uptake needs to be tested in noncancer subjects and cause-effect relationship needs to be established

Stenting of venous bypass grafts: A new treatment modality for patients who are poor candidates for reintervention

Abstract During a 2-year period, 136 self-expanding Wall-stents were implanted in saphenous vein bypass grafts in 69 patients with end-stage coronary artery disease. All patients had severe symptoms and the majority were poor candidates for either repeat surgery or conventional bypass coronary angioplasty because of unfavorable native anatomy, impaired left ventricular function, or a high-risk bypass lesion anatomy for coronary angioplasty. All procedures were technically successful without major complications and a need for emergency bypass surgery. However, during the hospital stay acute thrombotic complications occurred in seven patients (10%) resulting in one death and acute myocardial infarction in five patients and necessitating emergency repeat PTCA in two patients and repeat CABG in four. Twenty-three patients had serious hemorrhagic complications directly related to the rigorous anticoagulation schedule. Two patients died of fatal cerebral bleeding. During follow-up, another five patients died accounting for a total mortality rate of 12%. At late angiographic follow-up (4.9 ± 3.4 months, n = 53), 25 patients (47%) had a restenosis (≥50% DS) within or immediately adjacent to the stent, necessitating reintervention in 19 patients (PTCA, n = 12; repeat CABG, n = 7). In the group without stent-related restenosis (n = 28), 15 patients had progression of disease in either the native or bypass vessels leading to recurrence of major anginal symptoms within 1 to 24 months. Ten of these patients required further intervention (stent, n = 6; PTCA, n = 3; repeat CABG, n = 1). Stenting in saphenous coronary bypass grafts can be performed safely with excellent immediate angiographic and clinical results. Early occlusion, late restenosis, and bleeding complications associated with the aggressive anticoagulant treatment remain significant limitations. Reintervention as a result of restenosis or progression of disease in other lesions is common. Stenting of diseased bypass grafts in symptomatic patients with end-stage coronary artery disease (who are at high risk for conventional angioplasty or surgical reintervention) may be useful as palliative therapy

Gene-Expression Signature Predicts Postoperative Recurrence in Stage I Non-Small Cell Lung Cancer Patients

About 30% stage I non-small cell lung cancer (NSCLC) patients undergoing resection will recur. Robust prognostic markers are required to better manage therapy options. The purpose of this study is to develop and validate a novel gene-expression signature that can predict tumor recurrence of stage I NSCLC patients. Cox proportional hazards regression analysis was performed to identify recurrence-related genes and a partial Cox regression model was used to generate a gene signature of recurrence in the training dataset −142 stage I lung adenocarcinomas without adjunctive therapy from the Director's Challenge Consortium. Four independent validation datasets, including GSE5843, GSE8894, and two other datasets provided by Mayo Clinic and Washington University, were used to assess the prediction accuracy by calculating the correlation between risk score estimated from gene expression and real recurrence-free survival time and AUC of time-dependent ROC analysis. Pathway-based survival analyses were also performed. 104 probesets correlated with recurrence in the training dataset. They are enriched in cell adhesion, apoptosis and regulation of cell proliferation. A 51-gene expression signature was identified to distinguish patients likely to develop tumor recurrence (Dxy = −0.83, P<1e-16) and this signature was validated in four independent datasets with AUC >85%. Multiple pathways including leukocyte transendothelial migration and cell adhesion were highly correlated with recurrence-free survival. The gene signature is highly predictive of recurrence in stage I NSCLC patients, which has important prognostic and therapeutic implications for the future management of these patients