Citations

Increasing evidence indicates that cerebrovascular dysfunction plays a pathogenic role in Alzheimer's dementia (AD). Amyloid-β (Aβ), a peptide central to the pathogenesis of AD, has profound vascular effects mediated, for the most part, by reactive oxygen species produced by the enzyme NADPH oxidase. The mechanisms linking Aβ to NADPH oxidase-dependent vascular oxidative stress have not been identified, however. We report that the scavenger receptor CD36, a membrane glycoprotein that binds Aβ, is essential for the vascular oxidative stress and neurovascular dysfunction induced by Aβ 1–40 . Thus, topical application of Aβ 1–40 onto the somatosensory cortex attenuates the increase in cerebral blood flow elicited by neural activity or by endothelium-dependent vasodilators in WT mice but not in CD36-null mice (CD36 0/0 ). The cerebrovascular effects of infusion of Aβ 1–40 into cerebral arteries are not observed in mice pretreated with CD36 blocking antibodies or in CD36 0/0 mice. Furthermore, CD36 deficiency prevents the neurovascular dysfunction observed in transgenic mice overexpressing the Swedish mutation of the amyloid precursor protein Tg2576 despite elevated levels of brain Aβ 1–40 . CD36 is also required for the vascular oxidative stress induced by exogenous Aβ 1–40 or observed in Tg2576 mice. These observations establish CD36 as a key link between Aβ 1–40 and the NADPH oxidase-dependent vascular oxidative stress underlying the neurovascular dysfunction and suggest that CD36 is a potential therapeutical target to counteract the cerebrovascular dysfunction associated with Aβ.

Abstract Human blood eosinophils exposed ex vivo to hematopoietic cytokines (e.g., IL-5 or GM-CSF) subsequently display enhanced responsiveness to numerous chemoattractants, such as chemokines, platelet-activating factor, or FMLP, through a process known as priming. Airway eosinophils, obtained by bronchoalveolar lavage after segmental Ag challenge, also exhibit enhanced responsiveness to selected chemoattractants, suggesting that they are primed during cell trafficking from the blood to the airway. Earlier work has shown that chemoattractants stimulate greater activation of ERK1 and ERK2 following IL-5 priming in vitro, thus revealing that ERK1/ERK2 activity can be a molecular readout of priming under these circumstances. Because few studies have examined the intracellular mechanisms regulating priming as it relates to human airway eosinophils, we evaluated the responsiveness of blood and airway eosinophils to chemoattractants (FMLP, platelet-activating factor, CCL11, CCL5, CXCL8) with respect to degranulation, adherence to fibronectin, or Ras–ERK signaling cascade activation. When compared with blood eosinophils, airway eosinophils exhibited greater FMLP-stimulated eosinophil-derived neurotoxin release as well as augmented FMLP- and CCL11-stimulated adherence to fibronectin. In airway eosinophils, FMLP, CCL11, and CCL5 stimulated greater activation of Ras or ERK1/ERK2 when compared with baseline. Ras activation by FMLP in blood eosinophils was also enhanced following IL-5 priming. These studies are consistent with a model of in vivo priming of eosinophils by IL-5 or related cytokines following allergen challenge, and further demonstrate the key role of priming in the chemoattractant-stimulated responses of eosinophils. These data also demonstrate the importance of the Ras–ERK signaling pathway in the regulation of eosinophil responses to chemoattractants in the airway. Human airway eosinophils respond to several chemoattractants with increased activation of the Ras–ERK cascade, eosinophil-derived neurotoxin release, and adherence to fibronectin relative to blood eosinophils.

Background Often in randomized controlled trials of cancer screening, cause of death is determined by a mortality review committee. However, little is known regarding how findings from mortality review compare to those from death certificates alone. Purpose To examine the results of four different U. S. trials of cancer screening when death certificate data only were used, as compared to results using all available mortality review information. Methods Trials included were the Health Insurance Plan of New York breast screening trial (HIP), the Minnesota trial of fecal occult blood testing, and the Johns Hopkins and Mayo Lung Projects, which each examined chest x-ray and sputum cytology. The sensitivity, specificity, positive and negative predictive values, and Cohen’s kappa for death certificates were calculated for all arms of all trials. Separate intention-to-screen analyses were conducted for each trial using cause of death information from either death certificates alone or full mortality review data. Results Generally there was excellent agreement between the death certificates and the mortality review committee as to the underlying cause of death (kappa >0.85 in all cases); death certificate agreement was similar between arms in all trials. Modest changes in the screening effectiveness estimates were observed when mortality review information was utilized, ranging from a 9% decrease to a 2% increase in the calculated mortality rate ratios. However, in one instance (HIP) a statistically significant benefit of screening was observed when mortality review committee data were used (rate ratio (RR) 0.77, 95% confidence interval (CI) 0.62— 0.95) but not when death certificate data were used (RR 0.82, 95% CI 0.65—1.03). Limitations Although considered to be the gold standard, even carefully conducted mortality review may result in errors in cause of death assignment. Conclusions For each trial, results were similar regardless of the source of cause of death information. Clinical Trials 2010; 7: 69—77. http://ctj.sagepub.com

To better understand the role of equilibrative nucleoside transporters (ENT) in purine nucleoside-dependent physiology of the cardiovascular system, we investigated whether the ENT1-null mouse heart was cardioprotected in response to ischemia (coronary occlusion for 30 min followed by reperfusion for 2 h). We observed that ENT1-null mouse hearts showed significantly less myocardial infarction compared with wild-type littermates. We confirmed that isolated wild-type adult mouse cardiomyocytes express predominantly ENT1, which is primarily responsible for purine nucleoside uptake in these cells. However, ENT1-null cardiomyocytes exhibit severely impaired nucleoside transport and lack ENT1 transcript and protein expression. Adenosine receptor expression profiles and expression levels of ENT2, ENT3, and ENT4 were similar in cardiomyocytes isolated from ENT1-null adult mice compared with cardiomyocytes isolated from wild-type littermates. Moreover, small interfering RNA knockdown of ENT1 in the cardiomyocyte cell line, HL-1, mimics findings in ENT1-null cardiomyocytes. Taken together, our data demonstrate that ENT1 plays an essential role in cardioprotection, most likely due to its effects in modulating purine nucleoside-dependent signaling and that the ENT1-null mouse is a powerful model system for the study of the role of ENTs in the physiology of the cardiomyocyte.

Purpose Single-fraction image-guided intensity-modulated radiation therapy (IG-IMRT) allows for tumoricidal treatment of traditionally radioresistant cancers while sparing critical adjacent structures. Risk of vertebral fracture after IG-IMRT for spinal metastases has not been defined. Patients and Methods We evaluated 62 consecutive patients undergoing single fraction IG-IMRT at 71 sites for solid organ metastases. A neuroradiologist and three spine surgeons evaluated prospectively obtained magnetic resonance/computed tomography (CT) imaging studies for post-treatment fracture development and tumor recurrence. Results Fracture progression was noted in 27 vertebrae (39%). Multivariate logistic regression analysis showed that CT appearance, lesion location, and percent vertebral body involvement independently predicted fracture progression. Lesions located between T10 and the sacrum were 4.6 times more likely to fracture than were lesions above T10 (95% CI, 1.1 to 19.7). Lytic lesions were 6.8 times more likely to fracture than were sclerotic and mixed lesions (95% CI, 1.4 to 33.3). As percent vertebral body involvement increased, odds of fracture also increased. Patients with fracture progression had significantly higher narcotic use, change in Karnofsky performance score, and a strong trend toward higher pain scores. Local tumor progression occurred in seven patients and contributed to one fracture. Obesity, posterior element involvement, bisphosphonate use, and local kyphosis did not confer increased risk. Conclusion Vertebral fracture is common after single fraction IG-IMRT for metastatic spine lesions. Lytic disease involving more than 40% of the vertebral body and location at or below T10 confer a high risk of fracture, the presence of which yields significantly poorer clinical outcomes. These results may help clinicians identify high-risk patients who would benefit from prophylactic vertebro- or kyphoplasty.

The objective of this study was to determine the impact of lupus nephritis disease activity on maternal and foetal outcomes in pregnant patients with systemic lupus erythematosus (SLE). Medical records of all pregnant patients with SLE treated at our institution between 1976 and 2007 were reviewed. All patients met American College of Rheumatology classification criteria for SLE. Demographic data, history of lupus nephritis, nephritis disease activity and maternal and foetal outcomes of pregnancy were abstracted. Active lupus nephritis was defined as the presence of proteinuria >0.5 g/day and/or active urinary sediment with or without an elevation in serum creatinine (Cr). Quiescent lupus nephritis was confirmed in the presence of proteinuria <0.5 mg/day and inactive urinary sediment. We identified 58 patients with 90 pregnancies. Compared with pregnancies in SLE patients without renal involvement ( n = 47), pregnancies in patients with active lupus nephritis ( n = 23) were associated with a higher incidence of maternal complications (57% vs 11%, P < 0.001), whereas those with quiescent lupus nephritis ( n = 20) were not (35% vs 11%, P = 0.10). Women with active lupus nephritis were more likely to deliver preterm than women without lupus nephritis, median of 34 weeks vs 40 gestational weeks, respectively ( P = 0.002) and were more likely to suffer foetal loss (35% vs 9%, P = 0.031). Active, but not quiescent, lupus nephritis during pregnancy is associated with a higher incidence of maternal and foetal complications compared with pregnancies in SLE patients without renal involvement.

Abstract The purpose of the workshop was to identify still obscure or novel cellular components of the lung, to determine cell function in lung development and in health that impacts on disease, and to decide promising avenues for future research to extract and phenotype these cells. Since robust technologies are now available to identify, sort, purify, culture, and phenotype cells, progress is now within sight to unravel the origins and functional capabilities of lung cells in developmental stages and in disease. The Workshop's agenda was to first discuss the lung's embryologic development, including progenitor and stem cells, and then assess the functional and structural cells in three main compartments of the lung: (1) airway cells in bronchial and bronchiolar epithelium and bronchial glands (basal, secretory, ciliated, Clara, and neuroendocrine cells); (2) alveolar unit cells (Type 1 cells, Type 2 cells, and fibroblasts in the interstitium); and (3) pulmonary vascular cells (endothelial cells from different vascular structures, smooth muscle cells, and adventitial fibroblasts). The main recommendations were to: (1) characterize with better cell markers, both surface and nonsurface, the various cells within the lung, including progenitor cells and stem cells; (2) obtain more knowledge about gene expression in specific cell types in health and disease, which will provide insights into biological and pathologic processes; (3) develop more methodologies for cell culture, isolation, sorting, co-culture, and immortalization; and (4) promote tissue banks to facilitate the procurement of tissue from normal and from diseased lung for analysis at all levels.

This study was undertaken to determine whether carotid intima-media thickness can predict complex aortic atherosclerosis. A retrospective review was conducted of 64 consecutive patients who underwent transesophageal echocardiography and carotid ultrasonography for evaluation of recent ischemic stroke at MCP Hahnemann University, Medical College of Pennsylvania Hospital between January 1, 1999, and December 31, 1999. The mean age was 65 ± 14 years and 59% of the patients were women. Thirty-nine patients (61 %) had carotid atherosclerosis (defined as an intima-media thickness ≥ 1 mm) and seven patients (11%) had complex aortic atherosclerosis (defined as the presence of protruding atheroma ≥4 mm thick, mobile atherosclerotic debris, or plaque ulceration in any aortic segment by transesophageal echocardiography). Compared to patients without complex aortic atherosclerosis, patients with complex aortic atherosclerosis were more likely to have hypercholesterolemia (19% vs 57%, p = 0.05) and a carotid intima-media thickness of 2 mm or greater (35% vs 86%, p = 0.02). A carotid intima-media thickness of 2 mm or more had 86% sensitivity, 65% specificity, 23% positive predictive value, 97% negative predictive value, 2.5 positive likelihood ratio, and 0.22 negative likelihood ratio for the diagnosis of complex aortic atherosclerosis. Carotid intima- media thickness measurement can be used to noninvasively estimate the probability of complex aortic atherosclerosis. A carotid intima-media thickness less than 2 mm makes complex aortic atherosclerosis very unlikely.