bluuebunny/crossref_metadata_2025 huggingface dataset:
Occludin regulates macromolecule flux across the intestinal epithelial tight junction barrier
Authors: Al-Sadi Rana , Khatib Khaldun , Guo Shuhong , Ye Dongmei , Youssef Moustafa , Ma Thomas
Published: March 2011

Defective intestinal epithelial tight junction (TJ) barrier has been shown to be an important pathogenic factor contributing to the development of intestinal inflammation. The expression of occludin is markedly decreased in intestinal permeability disorders, including in Crohn's disease, ulcerative colitis, and celiac disease, suggesting that the decrease in occludin expression may play a role in the increase in intestinal permeability. The purpose of this study was to delineate the involvement of occludin in intestinal epithelial TJ barrier by selective knock down of occludin in in vitro (filter-grown Caco-2 monolayers) and in vivo (recycling perfusion of mouse intestine) intestinal epithelial models. Our results indicated that occludin small-interfering RNA (siRNA) transfection causes an increase in transepithelial flux of various-sized probes, including urea, mannitol, inulin, and dextran, across the Caco-2 monolayers, without affecting the transepithelial resistance. The increase in relative flux rate was progressively greater for larger-sized probes, indicating that occludin depletion has the greatest effect on the flux of large macromolecules. siRNA-induced knock down of occludin in mouse intestine in vivo also caused an increase in intestinal permeability to dextran but did not affect intestinal tissue transepithelial resistance. In conclusion, these results show for the first time that occludin depletion in intestinal epithelial cells in vitro and in vivo leads to a selective or preferential increase in macromolecule flux, suggesting that occludin plays a crucial role in the maintenance of TJ barrier through the large-channel TJ pathway, the pathway responsible for the macromolecule flux.
Early growth response (EGR)-1 is required for timely cell-cycle entry and progression in hepatocytes after acute carbon tetrachloride exposure in mice
Authors: Pritchard Michele T. , Malinak Robert N. , Nagy Laura E.
Published: March 2011

Cell-cycle induction in hepatocytes protects from prolonged tissue damage after toxic liver injury. Early growth response ( Egr) -1−/− mice exhibit increased liver injury after carbon tetrachloride (CCl4) exposure and reduced TNF-α production. Because TNF-α is required for prompt cell-cycle induction after liver injury, here, we tested the hypothesis that Egr-1 is required for timely hepatocyte entry into the cell cycle after CCl4-induced liver injury. Acute liver injury was induced by a single injection of CCl4. Assays were employed to assess indices of the cell cycle in liver after CCl4 exposure. Bromodeoxyuridine incorporation peaked in wild-type mice at 48 h after CCl4 but was reduced by 80% in Egr-1−/− mice. Proliferating-cell nuclear-antigen immunohistochemistry revealed blocks in cell-cycle entry and progression to DNA synthesis in Egr-1-deficient mice 48 h after CCl4. Cyclin D, important for G0/G1 progression, was reduced at baseline and 36 h after CCl4. Cyclin E1, required for G1/S-phase transition, was reduced in Egr-1−/− mice 24 and 48 h after CCl4 exposure and was associated with reduced phosphorylation of the retinoblastoma protein. Proliferation in Egr-1−/− mice was delayed, rather than blocked, because indices of cell-cycle progression were restored 72 h after CCl4 exposure. We concluded that Egr-1 was required for prompt cell-cycle entry (G0- to G1-phase) and G1/S-phase transition after toxic liver injury. These data support the hypothesis that Egr-1 provides hepatoprotection in the CCl4-injured liver, attributable, in part, to timely cell-cycle induction and progression.
Elevated oxidative stress and endothelial dysfunction in right coronary artery of right ventricular hypertrophy
Authors: Lu Xiao , Dang Charles Q. , Guo Xiaomei , Molloi Sabee , Wassall Cynthia D. , Kemple Marvin D. , Kassab Ghassan S.
Published: March 2011

Remodeling of right coronary artery (RCA) occurs during right ventricular hypertrophy (RVH) induced by banding of the pulmonary artery (PA). The effect of RVH on RCA endothelial function and reactive oxygen species (ROS) in vessel wall remains unclear. A swine RVH model ( n = 12 pigs) induced by PA banding was used to study RCA endothelial function and ROS level. To obtain longitudinal coronary hemodynamic and geometric data, digital subtraction angiography was used during the progression of RVH. Blood flow in the RCA increased by 82% and lumen diameter of RCA increased by 22% over a 4-wk period of RVH. The increase in blood flow and the commensurate increase in diameter resulted in a constant wall shear stress in RCA throughout the RVH period. ROS was elevated by ∼100% in RCA after 4 wk of PA banding. The expressions of p47phox, NADPH oxidase (NOX1, NOX2, and NOX4) were upregulated in the range of 20–300% in RCA of RVH. The endothelial function was compromised in RCA of RVH as attributed to insufficient endothelial nitric oxide synthase cofactor tetrahydrobiopterin. In vivo angiographic analysis suggests an increased basal tone in the RCA during RVH. In conclusion, stretch due to outward remodeling of RCA during RVH (at constant wall shear stress), similar to vessel stretch in hypertension, appears to induce ROS elevation, endothelial dysfunction, and an increase in basal tone.
Targeting Tumor Hypoxia: Suppression of Breast Tumor Growth and Metastasis by Novel Carbonic Anhydrase IX Inhibitors
Authors: Lou Yuanmei , McDonald Paul C. , Oloumi Arusha , Chia Stephen , Ostlund Christina , Ahmadi Ardalan , Kyle Alastair , auf dem Keller Ulrich , Leung Samuel , Huntsman David , Clarke Blaise , Sutherland Brent W. , Waterhouse Dawn , Bally Marcel , Roskelley Calvin , Overall Christopher M. , Minchinton Andrew , Pacchiano Fabio , Carta Fabrizio , Scozzafava Andrea , Touisni Nadia , Winum Jean-Yves , Supuran Claudiu T. , Dedhar Shoukat
Published: March 2011

Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1–inducible protein that regulates intra- and extracellular pH under hypoxic conditions and promotes tumor cell survival and invasion in hypoxic microenvironments. Interrogation of 3,630 human breast cancers provided definitive evidence of CAIX as an independent poor prognostic biomarker for distant metastases and survival. shRNA-mediated depletion of CAIX expression in 4T1 mouse metastatic breast cancer cells capable of inducing CAIX in hypoxia resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis formation. Stable depletion of CAIX in MDA-MB-231 human breast cancer xenografts also resulted in attenuation of primary tumor growth. CAIX depletion in the 4T1 cells led to caspase-independent cell death and reversal of extracellular acidosis under hypoxic conditions in vitro. Treatment of mice harboring CAIX-positive 4T1 mammary tumors with novel CAIX-specific small molecule inhibitors that mimicked the effects of CAIX depletion in vitro resulted in significant inhibition of tumor growth and metastasis formation in both spontaneous and experimental models of metastasis, without inhibitory effects on CAIX-negative tumors. Similar inhibitory effects on primary tumor growth were observed in mice harboring orthotopic tumors comprised of lung metatstatic MDA-MB-231 LM2-4Luc+ cells. Our findings show that CAIX is vital for growth and metastasis of hypoxic breast tumors and is a specific, targetable biomarker for breast cancer metastasis. Cancer Res; 71(9); 3364–76. ©2011 AACR.
Ribonucleotide Reductase Small Subunit M2B Prognoses Better Survival in Colorectal Cancer
Authors: Liu Xiyong , Lai Lily , Wang Xiaochen , Xue Lijun , Leora Sofia , Wu Jun , Hu Shuya , Zhang Keqiang , Kuo Mei-Ling , Zhou Lun , Zhang Hang , Wang Yafan , Wang Yan , Zhou Bingsen , Nelson Rebecca A. , Zheng Shu , Zhang Suzhan , Chu Peiguo , Yen Yun
Published: March 2011

Ribonucleotide reductase subunit RRM2B (p53R2) has been reported to suppress invasion and metastasis in colorectal cancer (CRC). Here, we report that high levels of RRM2B expression are correlated with markedly better survival in CRC patients. In a fluorescence-labeled orthotopic mouse xenograft model, we confirmed that overexpression of RRM2B in nonmetastatic CRC cells prevented lung and/or liver metastasis, relative to control cells that did metastasize. Clinical outcome studies were conducted on a training set with 103 CRCs and a validation set with 220 CRCs. All participants underwent surgery with periodic follow-up to determine survivability. A newly developed specific RRM2B antibody was employed to carry out immunohistochemistry for determining RRM2B expression levels on tissue arrays. In the training set, the Kaplan–Meier and multivariate Cox analysis revealed that RRM2B is associated with better survival of CRCs, especially in stage IV patients (HR = 0.40; 95% CI = 0.18–0.86, P = 0.016). In the validation set, RRM2B was negatively related to tumor invasion (OR = 0.45, 95% CI = 0.19–0.99, P = 0.040) and lymph node involvement (OR = 0.48, 95% CI = 0.25–0.92, P = 0.026). Furthermore, elevated expression of RRM2B was associated with better prognosis in this set as determined by multivariate analyses (HR = 0.48, 95% CI = 0.26–0.91, P = 0.030). Further investigations revealed that RRM2B was correlated with better survival of CRCs with advanced stage III and IV tumors rather than earlier stage I and II tumors. Taken together, our findings establish that RRM2B suppresses invasiveness of cancer cells and that its expression is associated with a better survival prognosis for CRC patients. Cancer Res; 71(9); 3202–13. ©2011 AACR.
Dual mTORC2/mTORC1 Targeting Results in Potent Suppressive Effects on Acute Myeloid Leukemia (AML) Progenitors
Authors: Altman Jessica K. , Sassano Antonella , Kaur Surinder , Glaser Heather , Kroczynska Barbara , Redig Amanda J. , Russo Suzanne , Barr Sharon , Platanias Leonidas C.
Published: March 2011

Purpose: To determine whether mTORC2 and rapamycin-insensitive (RI)-mTORC1 complexes are present in acute myeloid leukemia (AML) cells and to examine the effects of dual mTORC2/mTORC1 inhibition on primitive AML leukemic progenitors.

Experimental Design: Combinations of different experimental approaches were used, including immunoblotting to detect phosphorylated/activated forms of elements of the mTOR pathway in leukemic cell lines and primary AML blasts; cell-proliferation assays; direct assessment of mRNA translation in polysomal fractions of leukemic cells; and clonogenic assays in methylcellulose to evaluate leukemic progenitor-colony formation.

Results: mTORC2 complexes are active in AML cells and play critical roles in leukemogenesis. RI-mTORC1 complexes are also formed and regulate the activity of the translational repressor 4E-BP1 in AML cells. OSI-027 blocks mTORC1 and mTORC2 activities and suppresses mRNA translation of cyclin D1 and other genes that mediate proliferative responses in AML cells. Moreover, OSI-027 acts as a potent suppressor of primitive leukemic precursors from AML patients and is much more effective than rapamycin in eliciting antileukemic effects in vitro.

Conclusions: Dual targeting of mTORC2 and mTORC1 results in potent suppressive effects on primitive leukemic progenitors from AML patients. Inhibition of the mTOR catalytic site with OSI-027 results in suppression of both mTORC2 and RI-mTORC1 complexes and elicits much more potent antileukemic responses than selective mTORC1 targeting with rapamycin. Clin Cancer Res; 17(13); 4378–88. ©2011 AACR.
Persistence of Disseminated Tumor Cells in the Bone Marrow of Breast Cancer Patients Predicts Increased Risk for Relapse—A European Pooled Analysis
Authors: Janni Wolfgang , Vogl Florian D. , Wiedswang Gro , Synnestvedt Marit , Fehm Tanja , Jückstock Julia , Borgen Elin , Rack Brigitte , Braun Stephan , Sommer Harald , Solomayer Erich , Pantel Klaus , Nesland Jahn , Friese Klaus , Naume Bjørn
Published: March 2011

Background: The prognostic significance of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients at the time of primary diagnosis has been confirmed by a large pooled analysis. In view of the lack of early indicators for secondary adjuvant treatment, we here evaluated whether the persistence of DTCs after adjuvant therapy increases the risk of subsequent relapse and death.

Patients and Methods: Individual patient data from 676 women with primary diagnosis of early breast cancer stages I–III from 3 follow-up studies were pooled. During clinical follow-up, patients underwent BM aspiration (BMA) to determine the presence of DTC. Tumor cells were detected by the standardized immunoassays. Univariate and multivariable proportional hazards models were estimated to assess the prognostic significance of DTC for disease-free survival (DFS) and overall survival (OS).

Results: Patients were followed for a median of 89 months. BMA was performed at median 37 months after diagnosis of breast cancer. At follow-up BMA, 15.5% of patients had DTCs. The presence of DTC was an independent indicator of poor prognosis for DFS, distant DFS (DDFS), cancer-specific survival, and OS during the first 5 years following cancer diagnosis (log-rank test P < 0.001 values for all investigated endpoints).

Conclusion: Among breast cancer patients, persistent DTCs during follow-up significantly predicted the increased risk for subsequent relapse and death. Analysis of DTC might serve as a clinically useful monitoring tool and should be tested as an indicator for secondary adjuvant treatment intervention within clinical trials. Clin Cancer Res; 17(9); 2967–76. ©2011 AACR.
New Strategies in Muscle-Invasive Bladder Cancer: On the Road to Personalized Medicine
Authors: Shah Jay B. , McConkey David J. , Dinney Colin P.N.
Published: March 2011

Bladder cancer remains one of the most deadly and expensive diseases affecting modern society. The options currently available to patients with muscle-invasive bladder cancer have remained essentially unchanged for the last generation. As the roles for surgery and chemotherapy in the management of this lethal disease have become better defined, so too have the limitations of these two treatment modalities. Despite the lack of groundbreaking clinical advances over the past two decades, recent years have witnessed a notable increase in the amount of promising preclinical and early translational research that will greatly improve our understanding of the molecular underpinnings of bladder cancer. If this momentum in bladder cancer research continues to build, it is likely that in the next 5 to 10 years we will be able to achieve our goal of bringing bladder cancer treatment into the age of personalized medicine. Clin Cancer Res; 17(9); 2608–12. ©2011 AACR.
PRIMA-1Met/APR-246 Induces Apoptosis and Tumor Growth Delay in Small Cell Lung Cancer Expressing Mutant p53
Authors: Zandi Roza , Selivanova Galina , Christensen Camilla Laulund , Gerds Thomas Alexander , Willumsen Berthe Marie , Poulsen Hans Skovgaard
Published: March 2011

Purpose: Small cell lung cancer (SCLC) is a highly malignant disease with poor prognosis, necessitating the need to develop new and efficient treatment modalities. PRIMA-1Met (p53-dependent reactivation of massive apoptosis), also known as APR-246, is a small molecule, which restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Since p53 is mutated in more than 90% of SCLC, we investigated the ability of PRIMA-1Met to induce apoptosis and inhibit tumor growth in SCLC with different p53 mutations.

Experimental Design: The therapeutic effect of PRIMA-1Met/APR-246 was studied in SCLC cells in vitro using cell viability assay, fluorescence-activated cell-sorting analysis, p53 knockdown studies, and Western blot analyses. The antitumor potential of PRIMA-1Met/APR-246 was further evaluated in two different SCLC xenograft models.

Results: PRIMA-1Met/APR-246 efficiently inhibited the growth of the SCLC cell lines expressing mutant p53 in vitro and induced apoptosis, associated with increased fraction of cells with fragmented DNA, caspase-3 activation, PARP cleavage, Bax and Noxa upregulation and Bcl-2 downregulation in the cells. The growth suppressive effect of PRIMA-1Met/APR-246 was markedly reduced in SCLC cell lines transfected with p53 siRNA, supporting the role of mutant p53 in PRIMA-1Met/APR-246-induced cell death. Moreover, in vivo studies showed significant antitumor effects of PRIMA-1Met after i.v. injection in SCLC mouse models with no apparent toxicity.

Conclusion: This study is the first to show the potential use of p53-reactivating molecules such as PRIMA-1Met/APR-246 for the treatment of SCLC. Clin Cancer Res; 17(9); 2830–41. ©2011 AACR.
Mesenchymal Stem Cells Ameliorate Ischemia-Reperfusion-Induced Renal Dysfunction by Improving the Antioxidant/Oxidant Balance in the Ischemic Kidney
Authors: Zhuo Wenli , Liao Lianming , Xu Tingzhao , Wu Weizhen , Yang Shunliang , Tan Jianming
Published: March 2011

Background: Renal ischemia followed by reperfusion leads to acute renal failure in both native kidneys and renal allograft. This study aimed at investigating the effects ofmesenchymal stem cells (MSC) on ischemia/reperfusion (I/R) injury and the underlying mechanisms in a rat model. Methods: Renal ischemia was produced by clamping the right renal vessels for 60 min after the left kidney was removed. Immediately after visual confirmation of reflow, 1 × 106 MSC were administered by intravenous injection, followed by reperfusion for 24 h. The kidney functions, tissue malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels were evaluated. Histopathological examinations were also performed. Results: MSC infusion significantly improved kidney function as indicated by lower urea and creatinine levels in the MSC compared to the vehicle group (p < 0.05). I/R-induced reduction in renal tissue SOD enzyme activity and GSH-Px was significantly improved by MSC (p < 0.05). Treatment with MSC also resulted in significant reduction in renal tissue MDA levels that were increased by renal I/R injury (p < 0.05). At histological examination, the kidneys of MSC-treated rats showed a fairly normal morphology. Conclusions: MSC protects the kidneys against I/R injury at least via their antioxidant effects.
Does Finasteride Have a Preventive Effect on Chronic Bacterial Prostatitis? Pilot Study Using an Animal Model
Authors: Lee Choong Bum , Ha U-Syn , Yim Seung Hyuk , Lee Hyun Rim , Sohn Dong Wan , Han Chang Hee , Cho Yong-Hyun
Published: March 2011

Aim: To evaluate the preventive effect of finasteride on chronic bacterial prostatitis (CBP), Wistar rats were divided into four groups: control, ciprofloxacin, finasteride, and ciprofloxacin/finasteride. Methods: All drug pretreatments were conducted for 4 weeks, and then experimental CBP was induced by instillation of a bacterial suspension (Escherichia coli Z17 O2:K1;H–). Results: After 4 weeks, results of microbiological cultures of prostate and urine samples as well as histological findings of the prostate in each group were analyzed. Finasteride significantly reduced bacterial infection and decreased inflammatory cell infiltration in prostatic tissue compared with the control group. The group given both finasteride and antibiotic showed a greater inhibition of bacterial infection in the tissue than those given either finasteride or antibiotic alone. Conclusion: Our experiments suggest the possibility that finasteride has a preventive effect on development of CBP, although there is as yet no consensus on the mechanism of this effect.
Epidermal Growth Factor Receptor Mutations as a Prognostic Factor in Korean Patients with Advanced Lung Adenocarcinoma Who Had Not Been Treated with Received Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Authors: Kim Seung Tae , Choi Yoon Ji , Park Kyong Hwa , Oh Sang Cheul , Seo Jae Hong , Shin Sang Won , Kim Jun Suk , Kim Yeul Hong
Published: March 2011

Background: Epidermal growth factor receptor (EGFR) mutations as prognostic marker in patients with non-small cell lung cancers remain controversial. In particular, there is only a limited amount of data on the subject in Asian patients with advanced lung adenocarcinomas. Patients and Methods: We analyzed 50 patients with advanced lung adenocarcinoma, who received best supportive care with and without cytotoxic chemotherapy, between March 2006 and December 2008. The patients had never been treated with EGFR tyrosine kinase inhibitors. Tumor tissues of all 50 patients were analyzed for the status of EGFR gene mutations. Results: The median age of patients was 64 years (range 32–84) at diagnosis, and the male/female ratio was 2.6/1.0. Thirty-two patients were current or ever smokers. EGFR gene mutations were detected in 11 patients (22%). Seven of them had in-frame deletion within exon 19, resulting in the loss of codon 746 through 750 (delE746-A750), 2 patients had L858R in exon 21, and 2 patients had point mutation at codon 709 in exon 18, resulting in the substitution of glycine either with glutamic acid or alanine. The status of EGFR mutations was not significantly associated with gender, smoking status, ages, metastatic sites and number of metastasized sites. Seventeen patients received best supportive care without cytotoxic chemotherapy and 33 patients received the standard platinum-based doublet chemotherapy. The median overall survival was 8.90 months (95% CI 4.01–13.79). There were no significant differences in overall survival (p = 0.282) according to the status of EGFR mutations. Conclusion: These results suggest that EGFR mutation is not a prognostic marker in Korean patients with advanced lung adenocarcinoma who had not been treated with EGFR tyrosine kinase inhibitors.
Management of a New Isolated Metastasis during Sunitinib Treatment in Renal Cell Carcinoma Patients: A Lesson from Two Cases
Authors: Shablak Alaaeldin , O’Dwyer Jackie , Hawkins Robert , Board Ruth
Published: March 2011

Metastatic renal cell carcinoma (mRCC) is a difficult to treat malignancy and currently Sunitinib is a standard of care first-line therapy. A new metastasis during the treatment is considered a sign of drug failure and alternative therapeutic methods should be tried. Here, we report 2 cases of newly diagnosed isolated metastasis during Sunitinib treatment of mRCC patients. Our management plan included local palliative therapy to the lesion followed by recommencing of Sunitinib. This resulted in a good symptomatic relief locally as well as good overall control of the disease.
Pathological Features and Adverse Prognosis of a Contemporary Series of Neuroendocrine Bladder Tumours
Authors: Oderda Marco , Ruoppolo Michele , Marson Francesco , Pisano Francesca , Fragapane Giuseppe , Molinaro Luca , Pacchioni Donatella , Tizzani Alessandro , Gontero Paolo
Published: March 2011

Objective: Neuroendocrine bladder tumours are rare entities known for their aggressive behaviour. The aim of this study was to retrospectively evaluate the outcome of a contemporary series of 14 consecutive bladder neuroendocrine neoplasms observed at 2 institutional hospitals. Materials and Methods: The charts of patients with a pathological diagnosis of neuroendocrine bladder tumours observed at 2 institutions in the last 5 years were reviewed. Fourteen cases were retrieved. The main endpoint was to evaluate the pathological features and the cancer-specific survival (CSS) of the cohort. Subanalysis of survival based on the type of treatment received was attempted. Results: Mean age was 70.2 years. The rate of metastatic disease at diagnosis was 57.1%. Mean follow-up was 13.7 months (95% CI 5.1–22.3). The 6-month CSS rate was 57.1%, while the 2-year CSS rate was 21.4%. CSS and overall survival rates overlapped. The median survival for the cohort was 7 months. There was no statistically significant difference in survival between patients who underwent surgery and those who did not. Conclusion: Neuroendocrine bladder tumours remain a disease with an extremely unfavourable prognosis. The impact of radical surgery on survival remains questionable. Patients harbouring this rare bladder cancer should be referred for trials assessing neoadjuvant and adjuvant systemic treatment strategies.
Aqueductal Stenosis Presenting as Isolated Tremor: Case Report and Review of the Literature
Authors: Seiler F. Arran , Lew Sean M.
Published: March 2011

Essential tremor is rare in children, particularly in the absence of a significant family history. We report the case of a child with compensated hydrocephalus secondary to aqueductal stenosis whose sole presenting symptom was tremor. An otherwise healthy 6-year-old male developed a fine hand tremor, which over the course of 4 years both increased in intensity and spread to involve the lower limbs and head. After an MRI had confirmed hydrocephalus due to aqueductal stenosis, the patient underwent an endoscopic third ventriculostomy. His tremor improved markedly, but did not completely resolve. Occult hydrocephalus should be considered in the differential diagnosis of new-onset tremor. Progression of the tremor should halt with treatment of the hydrocephalus, and clinical improvement may be seen.
Transfer of Bilirubin Covalently Bound to 125l-Albumin from Blood to Brain in the Gunn Rat Newborn
Authors: Ohsugi Mami , Sato Hiroshi , Yamamura Hideki
Published: March 2011

Transfer of bilirubin covalently bound to albumin (Alb·B) from blood into brain was examined in Gunn rats at postnatal day 3, 7, 14,28 or 70. The ratio of the 125I-Alb·B concentration in the brain to that in the plasma 2 h after the injection (RAB) was used as a criterion for Alb·B transfer. RAB in brain decreased with age until day 28. Significant correlations were indicated between 125I-Alb·B plasma levels and those in the brain at days 7 and 14, but not at day 28. These results suggested that 125I-Alb·B could transfer from the blood to the brain until day 14. Comparison of the relative amount of radioactivity accumulated in the brain by a 125I-Alb·B injection with that of 125I-albumin alone revealed higher radioactivity in the former than the latter only at day 14, suggesting a transient appearance of particular cellular elements with high affinity to bilirubin in the developmental stage of the brain.
C-Reactive Protein Polarizes Human Macrophages to an M1 Phenotype and Inhibits Transformation to the M2 Phenotype
Authors: Devaraj Sridevi , Jialal Ishwarlal
Published: March 2011

Objective—

Inflammation is pivotal in atherosclerosis. Monocyte-macrophages are crucial in atherosclerosis. Monocytes can develop into subsets: classically (M1) or alternatively (M2) activated cells. Several studies point to a proinflammatory role for C-reactive protein (CRP). Because there is a paucity of data on the effects of CRP on macrophage phenotype, we tested effects of CRP on macrophage polarization.

Methods and Results—

Monocytes were incubated with CRP (0 to 50 μg/mL) and differentiated into macrophages for 7 days. Phenotypic characterization of M1 and M2 macrophages was performed using flow cytometry. CRP treatment resulted in increased population of M1 macrophages (tumor necrosis factor [TNF]/interleukin [IL]-12/C-C chemokine receptor 2, TNF/IL-12/monocyte chemotactic protein-1, or TNF/IL-1/IL-12). These effects were not abrogated by polymixin B or small interfering RNA to Toll-like receptor-4, but they were abrogated by boiled CRP. Administration of human CRP to rats in vivo increased polarization of macrophages to M1 phenotype compared with human serum albumin. When macrophages were primed to the M2 phenotype with IL-4, addition of CRP resulted in significantly increased secretion of TNF-α, MCP-1, and IL-1 and conversion of macrophages from the M2 to the M1 phenotype. CRP failed to prime macrophages to the M1 phenotype in presence of CD32/CD64 small interfering RNA or dominant-negative nuclear factor kappa B.

Conclusion—

Collectively, these results further support a role for CRP in promoting differentiation of human monocytes toward a proinflammatory M1 phenotype.
Late Gadolinium Enhancement Magnetic Resonance Imaging in the Diagnosis and Prognosis of Endomyocardial Fibrosis Patients
Authors: Salemi Vera M.C. , Rochitte Carlos E. , Shiozaki Afonso A. , Andrade Joalbo M. , Parga José R. , de Ávila Luiz F. , Benvenuti Luiz A. , Cestari Ismar N. , Picard Michael H. , Kim Raymond J. , Mady Charles
Published: March 2011

Background—

Endocardial fibrous tissue (FT) deposition is a hallmark of endomyocardial fibrosis (EMF). Echocardiography is a first-line and the standard technique for the diagnosis of this disease. Although late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) allows FT characterization, its role in the diagnosis and prognosis of EMF has not been investigated.

Methods and Results—

Thirty-six patients (29 women; age, 54±12 years) with EMF diagnosis after clinical evaluation and comprehensive 2-dimensional Doppler echocardiography underwent cine-CMR for assessing ventricular volumes, ejection fraction and mass, and LGE-CMR for FT characterization and quantification. Indexed FT volume (FT/body surface area) was calculated after planimetry of the 8 to 12 slices obtained in the short-axis view at end-diastole (mL/m
2
). Surgical resection of FT was performed in 16 patients. In all patients, areas of LGE were confined to the endocardium, frequently as a continuous streak from the inflow tract extending to the apex, where it was usually most prominent. There was a relation between increased FT/body surface area and worse New York Heart Association functional class and with increased probability of surgery (
P
<0.05). The histopathologic examination of resected FT showed typical features of EMF with extensive endocardial fibrous thickening, proliferation of small vessels, and scarce inflammatory infiltrate. In multivariate analysis, the patients with FT/body surface area >19 mL/m
2
had an increased mortality rate, with a relative risk of 10.8.

Conclusions—

Our study provides evidence that LGE-CMR is useful in the diagnosis and prognosis of EMF through quantification of the typical pattern of FT deposition.
Feasibility of Contrast-Enhanced and Nonenhanced MRI for Intraprocedural and Postprocedural Lesion Visualization in Interventional Electrophysiology
Authors: Nordbeck Peter , Hiller Karl-Heinz , Fidler Florian , Warmuth Marcus , Burkard Natalie , Nahrendorf Matthias , Jakob Peter M. , Quick Harald H. , Ertl Georg , Bauer Wolfgang R. , Ritter Oliver
Published: March 2011

Background—

Imaging of myocardial ablation lesions during electrophysiology procedures would enable superior guidance of interventions and immediate identification of potential complications. The aim of this study was to establish clinically suitable MRI-based imaging techniques for intraprocedural lesion visualization in interventional electrophysiology.

Methods and Results—

Interventional electrophysiology was performed under magnetic resonance guidance in an animal model, using a custom setup including magnetic resonance–conditional catheters. Various pulse sequences were explored for intraprocedural lesion visualization after radiofrequency ablation. The developed visualization techniques were then used to investigate lesion formation in patients immediately after ablation of atrial flutter. The animal studies in 9 minipigs showed that gadolinium-DTPA–enhanced T1-weighted and nonenhanced T2-weighted pulse sequences are particularly suitable for lesion visualization immediately after radiofrequency ablation. MRI-derived lesion size correlated well with autopsy (
R
2
=0.799/0.709 for contrast-enhanced/nonenhanced imaging). Non–contrast agent–enhanced techniques were suitable for repetitive lesion visualization during electrophysiological interventions, thus allowing for intraprocedural monitoring of ablation success. The patient studies in 24 patients with typical atrial flutter several minutes to hours after cavotricuspid isthmus ablation confirmed the results from the animal experiments. Therapeutic lesions could be visualized in all patients using contrast-enhanced and also nonenhanced MRI with high contrast-to-noise ratio (94.6±35.2/111.1±32.6 versus 48.0±29.0/68.0±37.3 for ventricular/atrial lesions and contrast-enhanced versus nonenhanced imaging).

Conclusions—

MRI allows for precise lesion visualization in electrophysiological interventions just minutes after radiofrequency ablation. Nonenhanced T2-weighted MRI is particularly feasible for intraprocedural delineation of lesion formation as lesions are detectable within minutes after radiofrequency delivery and imaging can be repeated during interventions.
Local Retention Versus Systemic Release of Soluble VEGF Receptor-1 Are Mediated by Heparin-Binding and Regulated by Heparanase
Authors: Sela Shay , Natanson-Yaron Shira , Zcharia Eyal , Vlodavsky Israel , Yagel Simcha , Keshet Eli
Published: March 2011

Rationale:

The vascular endothelial growth factor (VEGF) decoy receptor soluble VEGF-R1 (sVEGF-R1) is thought to protect the cells that produce it from adverse VEGF signaling. To accomplish this role, a mechanism for pericellular retention of sVEGF-R1 is required. Local retention may also prevent the accumulation of high circulating levels of sVEGF-R1 and resulting interference with homeostatic VEGF functions in remote organs.

Objective:

To reveal natural storage depots of sVEGF-R1 and determine mechanisms underlying its pericellular retention. To uncover natural mechanisms regulating its systemic release.

Methods and Results:

We show that both the canonical and human-specific isoforms of sVEGF-R1 are strongly bound to heparin. sVEGF-R1 produced by vascular smooth muscle cells is stored in the vessel wall and can be displaced from isolated mouse aorta by heparin. Another major reservoir of sVEGF-R1 is the placenta. Heparin increases the level of sVEGF-R1 released by cultured human placental villi, and pregnant women treated with low molecular weight heparin showed markedly elevated levels of sVEGF-R1 in the circulation. Heparanase is expressed in human placenta at the same locales as sVEGF-R1, and its transgenic overexpression in mice resulted in a marked increase in the levels of circulating sVEGF-R1. Conversely, heparanase inhibition, by either a neutralizing antibody or by inhibition of its maturation, reduced the amounts of sVEGF-R1 released from human placental villi, indicating a natural role of heparanase in sVEGF-R1 release.

Conclusions:

Together, the findings uncover a new level of regulation governing sVEGF-R1 retention versus release and suggest that manipulations of the heparin/heparanase system could be harnessed for reducing unwarranted release of sVEGF-R1 in pathologies such as preeclampsia.
Intramyocardial Stem Cell Injection in Patients With Ischemic Cardiomyopathy
Authors: Williams Adam R. , Trachtenberg Barry , Velazquez Darcy L. , McNiece Ian , Altman Peter , Rouy Didier , Mendizabal Adam M. , Pattany Pradip M. , Lopera Gustavo A. , Fishman Joel , Zambrano Juan P. , Heldman Alan W. , Hare Joshua M.
Published: March 2011

Rationale:

Transcatheter, intramyocardial injections of bone marrow–derived cell therapy produces reverse remodeling in large animal models of ischemic cardiomyopathy.

Objective:

We used cardiac MRI (CMR) in patients with left ventricular (LV) dysfunction related to remote myocardial infarction (MI) to test the hypothesis that bone marrow progenitor cell injection causes functional recovery of scarred myocardium and reverse remodeling.

Methods and Results:

Eight patients (aged 57.2±13.3 years) received transendocardial, intramyocardial injection of autologous bone marrow progenitor cells (mononuclear or mesenchymal stem cells) in LV scar and border zone. All patients tolerated the procedure with no serious adverse events. CMR at 1 year demonstrated a decrease in end diastolic volume (208.7±20.4 versus 167.4±7.32 mL;
P
=0.03), a trend toward decreased end systolic volume (142.4±16.5 versus 107.6±7.4 mL;
P
=0.06), decreased infarct size (
P
<0.05), and improved regional LV function by peak Eulerian circumferential strain in the treated infarct zone (−8.1±1.0 versus −11.4±1.3;
P
=0.04). Improvements in regional function were evident at 3 months, whereas the changes in chamber dimensions were not significant until 6 months. Improved regional function in the infarct zone strongly correlated with reduction of end diastolic volume (
r
2
=0.69,
P
=0.04) and end systolic volume (
r
2
=0.83,
P
=0.01).

Conclusions:

These data suggest that transcatheter, intramyocardial injections of autologous bone marrow progenitor cells improve regional contractility of a chronic myocardial scar, and these changes predict subsequent reverse remodeling. The findings support the potential clinical benefits of this new treatment strategy and ongoing randomized clinical trials.
Remote Ischemic Limb Preconditioning After Subarachnoid Hemorrhage
Authors: Koch Sebastian , Katsnelson Michael , Dong Chuanhui , Perez-Pinzon Miguel
Published: March 2011

Background and Purpose—

Making a limb transiently ischemic has been shown to induce ischemic tolerance in a distant organ. This phenomenon is known as remote ischemic limb preconditioning. We conducted a Phase IB study of remote ischemic limb preconditioning to determine the safety and feasibility of increasing durations of limb ischemia in patients with subarachnoid hemorrhage.

Methods—

Patients with aneurysmal subarachnoid hemorrhage underwent limb preconditioning every 24 to 48 hours for 14 days. Limb preconditioning consisted of 3 5-minute inflations of a blood pressure cuff to 200 mm Hg around a limb followed by 5 minutes of reperfusion. In the lead-in phase, we preconditioned the upper extremities, but this proved impractical and we began preconditioning the leg in a similar manner. Ischemia times were then escalated to 7.5 and 10 minutes. After each session, a visual analog scale was obtained and the extremity examined for neurovascular complications.

Results—

A total of 33 patients completed the study. Mean age was 53±12 years and mean Hunt Hess score was 2.4±0.9. In the lead-in phase, an average of 7.7±2.4 preconditioning sessions was completed with mean visual analog scale 3.6±3.4. In the dose escalation phase, an average of 8.6±2.1 preconditioning sessions was done with mean visual analog scale 1.8±2.2 and 2.5±2.9 for the 7.5- and 10-minute cohorts, respectively. No session was prematurely terminated due to subject discomfort. No objective signs of neurovascular injury were observed.

Conclusions—

We found limb preconditioning to be safe and well tolerated, even at ischemia times of 10 minutes, in critically ill patients with subarachnoid hemorrhage.
A Simple Empirical Model for Decadal Climate Prediction
Authors: Krueger Oliver , Von Storch Jin-Song
Published: March 2011

Decadal climate prediction is a challenging aspect of climate research. It has been and will be tackled by various modeling groups. This study proposes a simple empirical forecasting system for the near-surface temperature that can be used as a benchmark for climate predictions obtained from atmosphere–ocean GCMs (AOGCMs). It is assumed that the temperature time series can be decomposed into components related to external forcing and internal variability. The considered external forcing consists of the atmospheric CO2 concentration. Separation of the two components is achieved by using the Intergovernmental Panel on Climate Change Fourth Assessment Report (IPCC AR4) twentieth-century integrations. Temperature anomalies due to changing external forcing are described by a linear regression onto the forcing. The future evolution of the external forcing that is needed for predictions is approximated by a linear extrapolation of the forcing prior to the initial time. Temperature anomalies owing to the internal variability are described by an autoregressive model. An evaluation of hindcast experiments shows that the empirical model has a cross-validated correlation skill of 0.84 and a cross-validated rms error of 0.12 K in hindcasting global-mean temperature anomalies 10 years ahead.
Effects of Model Resolution and Statistical Postprocessing on Shelter Temperature and Wind Forecasts
Authors: Müller M. D.
Published: March 2011

Shelter temperature and wind forecasts from numerical weather prediction models are subject to large systematic errors. Kalman filtering and model output statistics (MOS) are commonly used postprocessing methods, but how effective are they in comparison with steadily increasing resolution of the forecast model? Observations from over 1100 stations in central Europe are used to compare the different postprocessing methods and the influence of model resolution in complex and simple terrain, respectively. A 1-yr period with hourly, or at least 3-hourly, data is used to achieve statistically meaningful results. Furthermore, the importance of real-time observations as MOS predictors and the effects of daily training of the MOS equations are studied.
Thermodynamics of the Madden–Julian Oscillation in a Regional Model with Constrained Moisture
Authors: Hagos Samson , Leung L. Ruby , Dudhia Jimy
Published: March 2011

To identify the main thermodynamic processes that sustain the Madden–Julian oscillation (MJO), an eddy available potential energy budget analysis is performed on a regional model simulation with moisture constrained by observations. The model realistically simulates the two MJO episodes observed during the winter of 2007/08. Analysis of these two cases shows that instabilities and damping associated with variations in diabatic heating and energy transport work in concert to provide the MJO with its observed characteristics. The results are used to construct a simplified paradigm of MJO thermodynamics.

Furthermore, the effect of moisture nudging on the simulation is analyzed to identify the limitations of the model cumulus parameterization. Without moisture nudging, the parameterization fails to provide adequate low-level (upper level) moistening during the early (late) stage of the MJO active phase. The moistening plays a critical role in providing stratiform heating variability that is an important source of eddy available potential energy for the model MJO.
Temperature and Water Vapor Variance Scaling in Global Models: Comparisons to Satellite and Aircraft Data
Authors: Kahn B. H. , Teixeira J. , Fetzer E. J. , Gettelman A. , Hristova-Veleva S. M. , Huang X. , Kochanski A. K. , Köhler M. , Krueger S. K. , Wood R. , Zhao M.
Published: March 2011

Observations of the scale dependence of height-resolved temperature T and water vapor q variability are valuable for improved subgrid-scale climate model parameterizations and model evaluation. Variance spectral benchmarks for T and q obtained from the Atmospheric Infrared Sounder (AIRS) are compared to those generated by state-of-the-art numerical weather prediction “analyses” and “free-running” climate model simulations with spatial resolution comparable to AIRS. The T and q spectra from both types of models are generally too steep, with small-scale variance up to several factors smaller than AIRS. However, the two model analyses more closely resemble AIRS than the two free-running model simulations. Scaling exponents obtained for AIRS column water vapor (CWV) and height-resolved layers of q are also compared to the superparameterized Community Atmospheric Model (SP-CAM), highlighting large differences in the magnitude of CWV variance and the relative flatness of height-resolved q scaling in SP-CAM. Height-resolved q spectra obtained from aircraft observations during the Variability of the American Monsoon Systems Ocean–Cloud–Atmosphere–Land Study Regional Experiment (VOCALS-REx) demonstrate changes in scaling exponents that depend on the observations’ proximity to the base of the subsidence inversion with scale breaks that occur at approximately the dominant cloud scale (~10–30 km). This suggests that finer spatial resolution requirements must be considered for future satellite observations of T and q than those currently planned for infrared and microwave satellite sounders.
Analysis of a Warm-Season Surface-Influenced Mesoscale Convective Boundary in Northwest Mississippi
Authors: Dyer Jamie
Published: March 2011

The lower Mississippi River alluvial valley in southeastern Arkansas, northeastern Louisiana, and northwestern Mississippi is characterized by widespread agriculture with few urban areas. Land use is predominantly cultivated cropland with minimal topographic variation; the eastern edge of the alluvial valley is defined by a rapid, although small, change in elevation into a heavily forested landscape, however. This change in land use/land cover has been shown to potentially enhance precipitation through generation of a weak mesoscale convective boundary. This project defines the influence of the land surface on associated precipitation processes by simulating a convective rainfall event that was influenced by regional surface features. Analysis was conducted using a high-resolution simulated dataset generated by the Weather Research and Forecasting Model (WRF). Results show that the strongest uplift coincides with an abrupt low-level thermal boundary, developed primarily by a rapid change from sensible to latent heat flux relative to the agricultural and forested areas, respectively. In addition, surface heating over the cultivated landscape appears to destabilize the boundary layer, with precipitation occurring as air is advected across the land cover boundary and the associated thermal gradient. This information can be used to define and predict surface-influenced convective precipitation along agricultural boundaries in other regions where the synoptic environment is weak.
Kalman Filter and Analog Schemes to Postprocess Numerical Weather Predictions
Authors: Delle Monache Luca , Nipen Thomas , Liu Yubao , Roux Gregory , Stull Roland
Published: March 2011

Two new postprocessing methods are proposed to reduce numerical weather prediction’s systematic and random errors. The first method consists of running a postprocessing algorithm inspired by the Kalman filter (KF) through an ordered set of analog forecasts rather than a sequence of forecasts in time (ANKF). The analog of a forecast for a given location and time is defined as a past prediction that matches selected features of the current forecast. The second method is the weighted average of the observations that verified when the 10 best analogs were valid (AN). ANKF and AN are tested for 10-m wind speed predictions from the Weather Research and Forecasting (WRF) model, with observations from 400 surface stations over the western United States for a 6-month period. Both AN and ANKF predict drastic changes in forecast error (e.g., associated with rapid weather regime changes), a feature lacking in KF and a 7-day running-mean correction (7-Day). The AN almost eliminates the bias of the raw prediction (Raw), while ANKF drastically reduces it with values slightly worse than KF. Both analog-based methods are also able to reduce random errors, therefore improving the predictive skill of Raw. The AN is consistently the best, with average improvements of 10%, 20%, 25%, and 35% with respect to ANKF, KF, 7-Day, and Raw, as measured by centered root-mean-square error, and of 5%, 20%, 25%, and 40%, as measured by rank correlation. Moreover, being a prediction based solely on observations, AN results in an efficient downscaling procedure that eliminates representativeness discrepancies between observations and predictions.