bluuebunny/crossref_metadata_2025 huggingface dataset:
Simultaneous assessment of gastric emptying and secretion in rats by a novel computed tomography-based method
Authors: Jordi Josua , Verrey François , Lutz Thomas A.
Published: November 2013

Gastric emptying and gastric secretion are two major physiological functions of the stomach. The assessment of these functions in particular in small animals is challenging; no method currently available allows the simultaneous measurement of both functions, and methods used are lethal or invasive and often limited by spatial, temporal, or quantitative resolution. Here, we report the establishment and validation of a quantitative noninvasive high-throughput computed tomography-based method to measure simultaneously gastric emptying and secretion in rats in vivo. The imaging strategy enables one to visualize stomach anatomy and to quantify stomach volume and stomach contrast agent content. The method was validated by comparing the results to classical lethal methods (stomach phenol red content and stomach wet weight). Additionally, we showed that the use of a mild anesthetic does not interfere with normal gastric function, thereby enabling high-resolution temporal studies within single animals. These combined advantages were applied to reevaluate the impact of cholecystokinin (CCK), histamine, and oral glucose solutions on gastric function with high temporal resolution. CCK inhibited gastric emptying completely for 20 min, leading to the accumulation of gastric juice in the stomach. The CCK antagonist devazepide blocked this effect. Histamine stimulated both gastric secretion and delayed emptying. Oral glucose solution emptied at a fixed rate of 24–31 cal/min and stimulated gastric secretion. These results confirm previous observations and add volumetric changes as a new dimension. As computed tomography scanners become broadly available, this method is an excellent approach to measure the combined gastric functional readout and to reduce the number of animals used.
Upregulation of mitochondrial Nox4 mediates TGF-β-induced apoptosis in cultured mouse podocytes
Authors: Das Ranjan , Xu Shanhua , Quan Xianglan , Nguyen Tuyet Thi , Kong In Deok , Chung Choon Hee , Lee Eun Young , Cha Seung-Kuy , Park Kyu-Sang
Published: November 2013

Injury to podocytes leads to the onset of chronic renal diseases characterized by proteinuria. Elevated transforming growth factor (TGF)-β in kidney tissue is associated with podocyte damage that ultimately results in apoptosis and detachment. We investigated the proapoptotic mechanism of TGF-β in immortalized mouse podocytes. Exogenous TGF-β1-induced podocyte apoptosis through caspase-3 activation, which was related to elevated ROS levels generated by selective upregulation of NADPH oxidase 4 (Nox4). In mouse podocytes, Nox4 was predominantly localized to mitochondria, and Nox4 upregulation by TGF-β1 markedly depolarized mitochondrial membrane potential. TGF-β1-induced ROS production and caspase activation were mitigated by an antioxidant, the Nox inhibitor diphenyleneiodonium, or small interfering RNA for Nox4. A TGF-β receptor I blocker, SB-431542, completely reversed the changes triggered by TGF-β1. Knockdown of either Smad2 or Smad3 prevented the increase of Nox4 expression, ROS generation, loss of mitochondrial membrane potential, and caspase-3 activation by TGF-β1. These results suggest that TGF-β1-induced mitochondrial Nox4 upregulation via the TGF-β receptor-Smad2/3 pathway is responsible for ROS production, mitochondrial dysfunction, and apoptosis, which may at least in part contribute to the development and progression of proteinuric glomerular diseases such as diabetic nephropathy.
Transient transcriptional events in human skeletal muscle at the outset of concentric resistance exercise training
Authors: Murton A. J. , Billeter R. , Stephens F. B. , Des Etages S. G. , Graber F. , Hill R. J. , Marimuthu K. , Greenhaff P. L.
Published: November 2013

We sought to ascertain the time course of transcriptional events that occur in human skeletal muscle at the outset of resistance exercise (RE) training in RE naive individuals and determine whether the magnitude of response was associated with exercise-induced muscle damage. Sixteen RE naive men were recruited; eight underwent two sessions of 5 × 30 maximum isokinetic knee extensions (180°/s) separated by 48 h. Muscle biopsies of the vastus lateralis, obtained from different sites, were taken at baseline and 24 h after each exercise bout. Eight individuals acted as nonexercise controls with biopsies obtained at the same time intervals. Transcriptional changes were assessed by microarray and protein levels of heat shock protein (HSP) 27 and αB-crystallin in muscle cross sections by immunohistochemistry as a proxy measure of muscle damage. In control subjects, no probe sets were significantly altered (false discovery rate < 0.05), and HSP27 and αB-crystallin protein remained unchanged throughout the study. In exercised subjects, significant intersubject variability following the initial RE bout was observed in the muscle transcriptome, with greatest changes occurring in subjects with elevated HSP27 and αB-crystallin protein. Following the second bout, the transcriptome response was more consistent, revealing a cohort of probe sets associated with immune activation, the suppression of oxidative metabolism, and ubiquitination, as differentially regulated. The results reveal that the initial transcriptional response to RE is variable in RE naive volunteers, potentially associated with muscle damage and unlikely to reflect longer term adaptations to RE training. These results highlight the importance of considering multiple time points when determining the transcriptional response to RE and associated physiological adaptation.
Hyperventilation, cerebral perfusion, and syncope
Authors: Immink R. V. , Pott F. C. , Secher N. H. , van Lieshout J. J.
Published: November 2013

This review summarizes evidence in humans for an association between hyperventilation (HV)-induced hypocapnia and a reduction in cerebral perfusion leading to syncope defined as transient loss of consciousness (TLOC). The cerebral vasculature is sensitive to changes in both the arterial carbon dioxide (PaCO2) and oxygen (PaO2) partial pressures so that hypercapnia/hypoxia increases and hypocapnia/hyperoxia reduces global cerebral blood flow. Cerebral hypoperfusion and TLOC have been associated with hypocapnia related to HV. Notwithstanding pronounced cerebrovascular effects of PaCO2the contribution of a low PaCO2to the early postural reduction in middle cerebral artery blood velocity is transient. HV together with postural stress does not reduce cerebral perfusion to such an extent that TLOC develops. However when HV is combined with cardiovascular stressors like cold immersion or reduced cardiac output brain perfusion becomes jeopardized. Whether, in patients with cardiovascular disease and/or defect, cerebral blood flow cerebral control HV-induced hypocapnia elicits cerebral hypoperfusion, leading to TLOC, remains to be established.
Computational fluid dynamics endpoints to characterize obstructive sleep apnea syndrome in children
Authors: Wootton David M. , Luo Haiyan , Persak Steven C. , Sin Sanghun , McDonough Joseph M. , Isasi Carmen R. , Arens Raanan
Published: November 2013

Computational fluid dynamics (CFD) analysis may quantify the severity of anatomical airway restriction in obstructive sleep apnea syndrome (OSAS) better than anatomical measurements alone. However, optimal CFD model endpoints to characterize or assess OSAS have not been determined. To model upper airway fluid dynamics using CFD and investigate the strength of correlation between various CFD endpoints, anatomical endpoints, and OSAS severity, in obese children with OSAS and controls. CFD models derived from magnetic resonance images were solved at subject-specific peak tidal inspiratory flow; pressure at the choanae was set by nasal resistance. Model endpoints included airway wall minimum pressure (Pmin), flow resistance in the pharynx (Rpharynx), and pressure drop from choanae to a minimum cross section where tonsils and adenoids constrict the pharynx ( dP TAmax). Significance of endpoints was analyzed using paired comparisons ( t-test or Wilcoxon signed rank test) and Spearman correlation. Fifteen subject pairs were analyzed. Rpharynx and dP TAmax were higher in OSAS than control and most significantly correlated to obstructive apnea-hypopnea index (oAHI), r = 0.48 and r = 0.49, respectively ( P < 0.01). Airway minimum cross-sectional correlation to oAHI was weaker ( r = −0.39); Pmin was not significantly correlated. CFD model endpoints based on pressure drops in the pharynx were more closely associated with the presence and severity of OSAS than pressures including nasal resistance, or anatomical endpoints. This study supports the usefulness of CFD to characterize anatomical restriction of the pharynx and as an additional tool to evaluate subjects with OSAS.
On Solutions of Linear Fractional Differential Equations with Uncertainty
Authors: Allahviranloo T. , Abbasbandy S. , Shahryari M. R. Balooch , Salahshour S. , Baleanu D.
Published: November 2013

The solutions of linear fuzzy fractional differential equations (FFDEs) under the Caputo differentiability have been investigated. To this end, the fuzzy Laplace transform was used to obtain the solutions of FFDEs. Then, some new results regarding the relation between some types of differentiability have been obtained. Finally, some applicable examples are solved in order to show the ability of the proposed method.
Global Stability of a HIV-1 Model with General Nonlinear Incidence and Delays
Authors: Wang Yaping , Sun Fuqin
Published: November 2013

A HIV-1 model with two distributed intracellular delays and general incidence function is studied. Conditions are given under which the system exhibits the threshold behavior: the disease-free equilibriumE0is globally asymptotically stable ifR0≤1; ifR0>1, then the unique endemic equilibriumE1is globally asymptotically stable. Finally, it is shown that the given conditions are satisfied by several common forms of the incidence functions.
Periodic Solutions of Duffing Equation with an Asymmetric Nonlinearity and a Deviating Argument
Authors: Wang Zaihong , Li Jin , Ma Tiantian
Published: November 2013

We study the existence of periodic solutions of the second-order differential equationx′′+ax+-bx-+g(x(t-τ))=p(t), wherea,bare two constants satisfying1/a+1/b=2/n,n∈N,τis a constant satisfying0≤τ<2π,g,p:R→Rare continuous, andpis2π-periodic. When the limitslimx→±∞g(x)=g(±∞)exist and are finite, we give some sufficient conditions for the existence of2π-periodic solutions of the given equation.
The Role of Polo-like Kinase 1 in Carcinogenesis: Cause or Consequence?
Authors: Cholewa Brian D. , Liu Xiaoqi , Ahmad Nihal
Published: November 2013

Polo-like kinase 1 (Plk1) is a well-established mitotic regulator with a diverse range of biologic functions continually being identified throughout the cell cycle. Preclinical evidence suggests that the molecular targeting of Plk1 could be an effective therapeutic strategy in a wide range of cancers; however, that success has yet to be translated to the clinical level. The lack of clinical success has raised the question of whether there is a true oncogenic addiction to Plk1 or if its overexpression in tumors is solely an artifact of increased cellular proliferation. In this review, we address the role of Plk1 in carcinogenesis by discussing the cell cycle and DNA damage response with respect to their associations with classic oncogenic and tumor suppressor pathways that contribute to the transcriptional regulation of Plk1. A thorough examination of the available literature suggests that Plk1 activity can be dysregulated through key transformative pathways, including both p53 and pRb. On the basis of the available literature, it may be somewhat premature to draw a definitive conclusion on the role of Plk1 in carcinogenesis. However, evidence supports the notion that oncogene dependence on Plk1 is not a late occurrence in carcinogenesis and it is likely that Plk1 plays an active role in carcinogenic transformation. Cancer Res; 73(23); 6848–55. ©2013 AACR.
MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition
Authors: Wagle Nikhil , Van Allen Eliezer M. , Treacy Daniel J. , Frederick Dennie T. , Cooper Zachary A. , Taylor-Weiner Amaro , Rosenberg Mara , Goetz Eva M. , Sullivan Ryan J. , Farlow Deborah N. , Friedrich Dennis C. , Anderka Kristin , Perrin Danielle , Johannessen Cory M. , McKenna Aaron , Cibulskis Kristian , Kryukov Gregory , Hodis Eran , Lawrence Donald P. , Fisher Sheila , Getz Gad , Gabriel Stacey B. , Carter Scott L. , Flaherty Keith T. , Wargo Jennifer A. , Garraway Levi A.
Published: November 2013

Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP–ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2Q60P). MEK2Q60P conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal–regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.

Significance: This study represents an initial clinical genomic study of acquired resistance to combined RAF/MEK inhibition in BRAF-mutant melanoma, using WES and RNA-seq. The presence of diverse resistance mechanisms suggests that serial biopsies and genomic/molecular profiling at the time of resistance may ultimately improve the care of patients with resistant BRAF-mutant melanoma by specifying tailored targeted combinations to overcome specific resistance mechanisms. Cancer Discov; 4(1); 61–8. ©2013 AACR.

See related commentary by Solit and Rosen, p. 27

This article is highlighted in the In This Issue feature, p. 1
Hypothermia Protects against Fulminant Hepatitis in Mice by Reducing Reactive Oxygen Species Production
Authors: Sakurai Toshiharu , Kudo Masatoshi , Watanabe Tomohiro , Itoh Katsuhiko , Higashitsuji Hiroaki , Arizumi Tadaaki , Inoue Tatsuo , Hagiwara Satoru , Ueshima Kazuomi , Nishida Naoshi , Fukumoto Manabu , Fujita Jun
Published: November 2013

Objective: Mild hypothermia (32-33°C) shows protective effects in patients with brain damage and cardiac arrest. Although cold-inducible RNA-binding protein (CIRP) contributes to the protective effects of hypothermia through extracellular signal-regulated kinase activation in fibroblasts, the effects of hypothermia in the liver remain unclear. Methods: We analysed the effects of cold temperature on fulminant hepatitis, a potentially fatal disease, using the D-galactosamine (GalN)/lipopolysaccharide (LPS) and concanavalin (con) A-induced hepatitis models in mice. After GalN/LPS administration and anaesthesia, mice in the hypothermia group were kept at 25°C and those in control group were kept at 35°C. After concanavalin A (con A) administration, the mice in the hypothermia group were placed in a chamber with an ambient temperature of 6°C for 1.5 h. Results: Hypothermia attenuated liver injury and prolonged survival. Activation of c-Jun N-terminal kinase and Akt, which are involved in reactive oxygen species (ROS) accumulation, was suppressed by low temperature. Hypothermia significantly decreased oxidized protein levels, and treatment with N-acetyl-L-cysteine, an antioxidant, attenuated GalN/LPS-induced liver injury. In con A-induced hepatitis, CIRP expression was upregulated and Bid expression was downregulated, resulting in decreased apoptosis of hepatocytes in the hypothermia group. Conclusions: These data suggest that hypothermia directly protects hepatocytes from cell death via reduction of ROS production in fulminant hepatitis.
Novel Mouse Models of Hepatocarcinogenesis with Stepwise Accumulation of Genetic Alterations
Authors: Kim Soo Ki , Marusawa Hiroyuki , Eso Yuji , Chiba Tsutomu , Kudo Masatoshi
Published: November 2013

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Various risk factors are involved in hepatocarcinogenesis. Among them, chronic inflammation, including chronic hepatitis and cirrhosis mainly caused by hepatitis B virus and/or hepatitis C virus infection, plays an important role in HCC development. On the other hand, comprehensive genetic analyses of HCC using whole genome and exome sequencing revealed that cancer cells possess a large number of somatic mutations, suggesting that a wide variety of genetic alterations and the resultant dysregulated molecular pathways contribute to the development of HCC. Activation-induced cytidine deaminase (AID) is a nucleotide-editing enzyme, and aberrant expression of AID induced by inflammatory responses contributes to hepatocarcinogenesis via the accumulation of genetic alterations in various tumor-related genes. Constitutive expression of AID in hepatocyte-lineage cells provides novel mouse models that recapitulate the tumorigenesis of human HCC through stepwise accumulation of genetic alterations.
CD34 Expression in Noncancerous Liver Tissue Predicts Multicentric Recurrence of Hepatocellular Carcinoma
Authors: Tsuji Naoko , Ishiguro Shingo , Sasaki Yo , Kudo Masatoshi
Published: November 2013

Background: Metachronous multicentric recurrence of hepatocellular carcinoma (HCC) is a common cause of morbidity and mortality following curative surgical resection. Clinical and laboratory predictors of these processes can markedly aid in managing these patients. Capillarization of hepatic sinusoids is also a well-known phenomenon in many liver diseases, especially in neoplastic liver diseases. Here, we investigated the clinical features, fibrosis scores and distribution of CD34 in noncancerous hepatic tissues of postresection patients with and without multicentric recurrence. Methods: Eighteen patients with multicentric recurrence of HCC diagnosed by histological examination of repeated hepatectomy specimens and 72 HCC patients with more than 5-year disease-free survival postresection participated in the study. We compared the clinicopathological features of these two groups. We examined noncancerous hepatic tissues for iron deposition by Prussian blue staining and computed the CD34-labeling index (LI) through immunohistochemistry using anti-CD34 antibody. Results: CD34-LI was significantly higher in the multicentric recurrence group (p < 0.001) and staging scores of fibrosis were also significantly higher in the recurrence group (p = 0.035). A high histological activity grade (p = 0.057) and a high alanine aminotransferase level (p = 0.060) were also associated with recurrence. There were no significant differences between the two groups in age, sex, hepatitis B virus surface antigen and anti-hepatitis C virus antibody levels, or grade of iron deposition. On multivariate analysis, high CD34-LI was the only independent risk factor (p = 0.001) for metachronous multicentric recurrence. Conclusion: CD34 expression in the capillaries and sinusoids of noncancerous hepatic tissue is a risk factor for multicentric recurrence of HCC. Histologic assessment of hepatic tissue with CD34 immunohistochemistry might be useful for the prognostic evaluation of HCC patients after surgery.
Radiofrequency Ablation for Hepatic Malignancies: Is Needle Tract Cauterization Necessary for Preventing Iatrogenic Bleeding?
Authors: Minami Yasunori , Hayaishi Sosuke , Kudo Masatoshi
Published: November 2013

Objective: To evaluate whether iatrogenic hemorrhage can be prevented by intrahepatic tract ablation following radiofrequency ablation (RFA) therapy for hepatic malignancies. Methods: A retrospective cohort study analyzing a prospective database in a single institution was conducted. The incidence of postprocedural complications was compared in two groups: one with cauterization of the needle tracts after RFA and the other without. Results: The complication rates of intraperitoneal hemorrhage were 1.05% (4/380) and 0.92% (6/652) in the nonablation group and the ablation group, respectively (p = 0.90). All of these 10 patients with iatrogenic bleeding were classified as Child-Pugh grade A. Among the 15 hemodialysis patients in this study, hemorrhage was seen in 2 (13.3%), compared with 8 (0.79%) of the nonhemodialysis patients (p = 0.0002). There were no statistically significant differences in the incidence of other complications including pleural effusion, serous ascites, pneumothorax, hemothorax, hepatic infarction, bile duct injury and pericardial effusion between the two groups. Gastrointestinal perforation, peritonitis or tumor seeding were not observed. Conclusion: Our study found a high incidence of bleeding after RFA among hemodialysis patients. Irrespective of tract ablation being after RFA, iatrogenic hemorrhage appeared to be equivalent in this population.
Vascular Endothelial Growth Factor Improves Liver Regeneration and Survival after 90% Hepatectomy in a Rat Model of Diet-Induced Steatosis
Authors: Gu Yanli , Sowa Jan-Peter , Paul Andreas , Gerken Guido , Schlaak Joerg F.
Published: November 2013

Background/Aims: Fatty liver disease increases the risk in major liver resection for patients. As previous studies suggested that vascular endothelial growth factor (VEGF) and erythropoietin (EPO) might improve liver regeneration in nonobese animals, we investigated their effect after subtotal hepatectomy (SH) in rats with diet-induced steatosis. Methods: Male Wistar rats were fed with fatty liver-inducing diet (FLD) or normal diet (control) for 11-12 weeks followed by 90% SH. Animals were treated either with EPO, VEGF or NaCl on postoperative days 0, 1 and 3 and sacrificed 24 h or 7 days after SH. Survival rate, liver regeneration and biochemical markers were assessed. Expression of inflammatory cytokines (TNF-α, IL-6) and apoptosis-related genes (PUMA, Bcl-2) was measured by qRT-PCR. Results: Seven-day survival after SH was significantly decreased in the FLD group compared to controls (50 vs. 100%, p < 0.05). In FLD animals, treatment with VEGF increased 7-day survival to 90% compared to only 40% in the EPO group. After surgery, blood glucose levels of VEGF but not EPO- or NaCl-treated animals remained normal. Inflammatory genes were markedly upregulated in the EPO group 24 h after SH. Conclusions: Steatosis severely impairs survival and regeneration after extensive liver resection, which can be counteracted at least in part by perioperative treatment with VEGF.
Clinical Efficacy of Infliximab in Moderate to Severe Ulcerative Colitis in a Latin American Referral Population
Authors: Juliao Fabian , Marquez Juan , Aristizabal Natalia , Yepes Carlos , Zuleta Julio , Gisbert Javier P.
Published: November 2013

Background: Previous research has shown that infliximab (IFX) is effective in the management of moderate to severe active ulcerative colitis (UC). Latin American studies are lacking. Aim: To evaluate the efficacy of IFX treatment (including corticosteroid withdrawal, complete mucosal healing, colectomy and hospitalization rates) in patients with moderate to severe UC. Methods: A retrospective and descriptive study was conducted on patients with UC in Medellín (Colombia). We included patients steroid dependent or refractory to conventional treatment. Results: Between October 2005 and July 2011, 28 patients with moderate to severe UC received IFX infusions; the median of the follow-up was 27.4 months (range: 1-69 months). Twenty-four patients (86%) had a short-term primary response, whilst 19 (68%) achieved initial clinical remission. After 1 year, 17 (71%) out of the 24 patients who had an initial response were also showing a sustained response, and 10 (42%) remained in clinical remission. At 6 months, complete mucosal healing was observed in 29% of patients and endoscopic improvement in 57%. Conclusions: This is the first study to evaluate the IFX use in patients with moderate to severe active UC in a Latin American population. We found that IFX therapy is effective for inducing clinical remission, and that most patients who had an initial response showed a long-term sustained response.
Hypertension Knowledge, Awareness, and Self-Management Behaviors Affect Hypertension Control: A Community-Based Study in Xuhui District, Shanghai, China
Authors: Gu Jie , Zhang Xiang-Jie , Wang Tian-Hao , Zhang Yuan , Chen Qian
Published: November 2013

Objective: To investigate correlations between hypertensive patients' knowledge of hypertension, awareness of hypertension education, self-management behaviors, and hypertension control. Methods: Hypertensive patients from 5 community health centers in Xuhui District, Shanghai, China, were enrolled into this study. Data were collected via patient interviews and a questionnaire survey. Independent influence factors for hypertension control were identified by logistic regression analysis. Results: In total, 3,328 hypertensive patients, including 1,935 females and 1,390 males with a mean age 70.6 years, were studied. The mean systolic blood pressure was 133.1 mm Hg. The mean diastolic blood pressure was 80.5 mm Hg. Hypertension was controlled in 1,050 (36.1%) patients. Independent influence factors for failed hypertension control were comorbidities, including diabetes mellitus, coronary artery disease, and stroke. Patients who knew that ‘high blood pressure is related to salt intake' and were willing to receive regular health education were less likely to fail in hypertension control. Patients who visited clinics because of fear of complications and visited medical institutions other than community health centers for hypertension were more likely to fail in hypertension control. Conclusions: In Shanghai, failed hypertension control is significantly associated with chronic disease history. Limiting salt intake, receiving regular health education, and visiting community health centers for hypertension care may help control hypertension.
Signal Changes on T2*-Weighted Magnetic Resonance Imaging from the Acute to Chronic Phases in Patients with Subarachnoid Hemorrhage
Authors: Inoue Takashi , Takada Shihomi , Shimizu Hiroaki , Niizuma Kuniyasu , Fujimura Miki , Sato Kenichi , Endo Hidenori , Tominaga Teiji
Published: November 2013

Background: Timing of the onset of subarachnoid hemorrhage (SAH) is important for treatment decision-making, especially as some patients visit hospital several weeks after the onset of SAH. T2*-weighted (T2*W) magnetic resonance (MR) imaging is regarded as a sensitive method for the detection of deoxyhemoglobin or hemosiderin deposits. This study investigated the characteristics of the abnormal low intensity changes on T2*W imaging in patients with SAH, how long the abnormal low intensity persisted, and whether the day of onset could be predicted based on the T2*W imaging changes. Methods: The study included patients treated for SAH associated with ruptured cerebral aneurysms, or who had previously suffered such SAH and were followed up at our hospital, between 2006 and 2007. MR imaging was performed using a whole-body 3.0-tesla MR scanner. All patients underwent gradient recalled echo (GRE) and echo planar (EP) T2*W imaging. The strength of the low intensity areas was evaluated as the following 5 grades: grade 0, no abnormal low intensity on both GRE and EP T2*W images; grade 1, no abnormal intensity on GRE T2*W images and low intensity on EP T2*W images; grade 2, spotty abnormal low intensity on both GRE and EP T2*W images; grade 3, medium abnormal low intensity (<5 mm) on both GRE and EP T2*W images, and grade 4, large abnormal low intensity (≥5 mm) on both GRE and EP T2*W images. Results: A total of 50 patients with 74 MR images were included during the study period. Abnormal low intensity on T2*W imaging was observed in all patients. The T2* score gradually decreased from the onset of SAH until day 90, showing a significant negative linear correlation (R2 = 0.25, p = 0.0002). On the other hand, the T2* score did not change after 1 year. The square correlation coefficient between the recorded and calculated days from the onset of SAH was 0.29 (p = 0.0107). The pure error was ±10 days. Conclusion: The T2* score gradually decreased until 90 days from the onset of SAH, but persisted for 16 years after the onset. We could predict the day of onset with pure error ±10 days in patients with SAH within 90 days of onset using our grading system for T2*W images.
RAS, BRAF, and TP53 Gene Mutations in Taiwanese Colorectal Cancer Patients
Authors: Chang Ya-Sian , Chang Shun-Jen , Yeh Kun-Tu , Lin Tsai-Hsiu , Chang Jan-Gowth
Published: November 2013

Background: Colorectal cancer (CRC) plays an important role in cancer mortality and morbidity. This study examined colorectal tissues for RAS, BRAF, and TP53 gene mutations to assess their value as indicators of outcomes of CRC therapy. Material and Methods: DNA was extracted from tissues taken from 165 patients with CRC. RAS gene mutations (exons 2 and 3) were detected by primer extension analysis. BRAF gene mutations (V600E) were detected by high resolution melting (HRM) analysis. TP53 gene mutations (exons 5-8) were detected by direct sequencing. Results: RAS, BRAF, and TP53 mutations occurred in 36.97% (61/165), 4.24% (7/165), and 37.58% (62/165), respectively. The KRAS mutation is a predictor for poor 5-year survival (p = 0.05), and the co-presence of KRAS and TP53 mutations correlates with lymph node involvement (p = 0.029), tumor stage (p = 0.029), and poor survival (p = 0.021). Multivariate analysis adjusted for tumor size, histologic grade, lymph node metastasis, sex, and age also indicated that KRAS mutations correlate significantly with overall survival (p = 0.036). Conclusion: The KRAS mutation is not present in about one-third of CRC patients, and therefore other gene mutations need to be investigated to better understand the molecular mechanisms of CRC and its treatment.
Patient-Related Delay in Presentation for Cutaneous Squamous Cell Carcinoma. A Cross-Sectional Clinical Study
Authors: Kakagia Despoina , Trypsiannis Gregory , Karanikas Michael , Mitrakas Alexandros , Lyratzopoulos Nikolaos , Polychronidis Alexandros
Published: November 2013

Background: Delayed diagnosis of squamous cell carcinoma (SCC) increases recurrence, metastatic potential, and management costs. This study aims to identify risk factors of patient-related delayed presentation in cutaneous SCC. Patients and Methods: A total of 513 patients, who first sought care for cutaneous lesions that were subsequently removed and histologically confirmed as SCCs, were included. Attitude to symptoms, psychosocial profile, and reasons for delayed presentation were obtained via a structured questionnaire-based interview. First presentation > 3 months from the onset of symptoms was considered as delayed. Results: Mean presentation time was 3.90 ± 2.05 months, while 186 patients delayed presentation. Multivariate logistic regression analysis revealed that serious co-morbidity (p = 0.003), low education level (p < 0.001), non-recognition of the seriousness of symptoms (p < 0.001), a ‘wait and see' attitude (p < 0.001), and fatalism (p = 0.005) were independent determinants of significantly higher risk for delayed presentation. In contrast, female sex (p = 0.006), new lesion (p = 0.012), accessible topography (p = 0.019), size increase (p = 0.002), color change (p = 0.017), non-healing wound (p = 0.048), and presence of social support/advice (p < 0.001) were independent determinants significantly associated with early presentation. Conclusion: Recognition of symptom seriousness and elimination of factors hindering self-referral may increase awareness and promote early patient presentation and diagnosis of cutaneous SCC.
Platelet-derived PF4 reduces neutrophil apoptosis following arterial occlusion
Authors: Hartwig Helene , Drechsler Maik , Lievens Dirk , Kramp Birgit , Hundelshausen Philipp von , Lutgens Esther , Weber Christian , Döring Yvonne , Soehnlein Oliver
Published: November 2013

Note: The editorial process for this manuscript was fully handled by Gregory Y. H. Lip, Editor in Chief.
Effect of Mediterranean Diet With and Without Weight Loss on Apolipoprotein B
100
Metabolism in Men With Metabolic Syndrome
Authors: Richard Caroline , Couture Patrick , Ooi Esther M.M. , Tremblay André J. , Desroches Sophie , Charest Amélie , Lichtenstein Alice H. , Lamarche Benoît
Published: November 2013

Objective—

To assess the effect of a Mediterranean diet (MedDiet) with and without weight loss (WL) on apolipoprotein B
100
(apoB
100
) metabolism in men with metabolic syndrome.

Approach and Results—

The diet of 19 men with metabolic syndrome (age, 24–62 years) was first standardized to a North American isoenergetic control diet for 5 weeks, followed by an isoenergetic MedDiet for an additional 5 weeks under full-feeding conditions (MedDiet−WL). Participants next underwent a 20-week supervised WL program under free-living conditions (−10.2±2.9% body weight;
P
<0.01) and finally consumed the MedDiet (5 weeks) under weight-stabilizing feeding conditions (MedDiet+WL). In vivo kinetic of apoB
100
was assessed in the fasted state at the end of the 3 controlled diets using a bolus of D
3
-leucine. Compared with the control diet, MedDiet−WL reduced low-density lipoprotein (LDL)-apoB
100
pool size (−14.2%,
P
<0.01) primarily through an increase in LDL-apoB
100
fractional catabolic rate (+30.4%,
P
=0.02) and increased LDL particle size (
P
<0.01) but had no effect on very-LDL (VLDL)-apoB
100
pool size or triglyceride concentrations, despite a significant increase in VLDL-apoB
100
fractional catabolic rate (+25.6%;
P
=0.03). MedDiet+WL had no further effect on LDL-apoB
100
pool size and fractional catabolic rate but further increased LDL particle size and reduced VLDL-apoB
100
pool size versus the control diet primarily through an increase in VLDL-apoB
100
fractional catabolic rate (+30.7%;
P
<0.01).

Conclusions—

Consumption of MedDiet increases LDL size and reduces LDL-apoB
100
concentrations primarily by increasing the catabolism of LDL even in the absence of WL in men with metabolic syndrome. MedDiet seems to have a trivial effect on VLDL concentrations and kinetics unless accompanied by significant WL.

Clinical Trial Registration

—URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00988650.
Deficiency of Endogenous Acute Phase Serum Amyloid A Does Not Affect Atherosclerotic Lesions in Apolipoprotein E–Deficient Mice
Authors: De Beer Maria C. , Wroblewski Joanne M. , Noffsinger Victoria P. , Rateri Debra L. , Howatt Deborah A. , Balakrishnan Anju , Ji Ailing , Shridas Preetha , Thompson Joel C. , van der Westhuyzen Deneys R. , Tannock Lisa R. , Daugherty Alan , Webb Nancy R. , De Beer Frederick C.
Published: November 2013

Objective—

Although elevated plasma concentrations of serum amyloid A (SAA) are associated strongly with increased risk for atherosclerotic cardiovascular disease in humans, the role of SAA in the pathogenesis of lesion formation remains obscure. Our goal was to determine the impact of SAA deficiency on atherosclerosis in hypercholesterolemic mice.

Approach and Results—

Apolipoprotein E–deficient (apoE
−/−
) mice, either wild type or deficient in both major acute phase SAA isoforms, SAA1.1 and SAA2.1, were fed a normal rodent diet for 50 weeks. Female mice, but not male apoE−/− mice deficient in SAA1.1 and SAA2.1, had a modest increase (22%;
P
≤0.05) in plasma cholesterol concentrations and a 53% increase in adipose mass compared with apoE−/− mice expressing SAA1.1 and SAA2.1 that did not affect the plasma cytokine levels or the expression of adipose tissue inflammatory markers. SAA deficiency did not affect lipoprotein cholesterol distributions or plasma triglyceride concentrations in either male or female mice. Atherosclerotic lesion areas measured on the intimal surfaces of the arch, thoracic, and abdominal regions were not significantly different between apoE−/− mice deficient in SAA1.1 and SAA2.1 and apoE−/− mice expressing SAA1.1 and SAA2.1 in either sex. To accelerate lesion formation, mice were fed a Western diet for 12 weeks. SAA deficiency had effect neither on diet-induced alterations in plasma cholesterol, triglyceride, or cytokine concentrations nor on aortic atherosclerotic lesion areas in either male or female mice. In addition, SAA deficiency in male mice had no effect on lesion areas or macrophage accumulation in the aortic roots.

Conclusions—

The absence of endogenous SAA1.1 and 2.1 does not affect atherosclerotic lipid deposition in apolipoprotein E–deficient mice fed either normal or Western diets.
G-Protein–Coupled Receptor-2–Interacting Protein-1 Is Required for Endothelial Cell Directional Migration and Tumor Angiogenesis via Cortactin-Dependent Lamellipodia Formation
Authors: Majumder Syamantak , Sowden Mark P. , Gerber Scott A. , Thomas Tamlyn , Christie Christine K. , Mohan Amy , Yin Guoyong , Lord Edith M. , Berk Bradford C. , Pang Jinjiang
Published: November 2013

Objective—

Recent evidence suggests G-protein–coupled receptor-2–interacting protein-1 (GIT1) overexpression in several human metastatic tumors, including breast, lung, and prostate. Tumor metastasis is associated with an increase in angiogenesis. We have showed previously that GIT1 is required for postnatal angiogenesis during lung development. However, the functional role of GIT1 in pathological angiogenesis during tumor growth is unknown.

Approach and Results—

In the present study, we show inhibition of angiogenesis in matrigel implants as well as reduced tumor angiogenesis and melanoma tumor growth in GIT1-knockout mice. We demonstrate that this is a result of impaired directional migration of GIT1-depleted endothelial cells toward a vascular endothelial growth factor gradient. Cortactin-mediated lamellipodia formation in the leading edge is critical for directional migration. We observed a significant reduction in cortactin localization and lamellipodia formation in the leading edge of GIT1-depleted endothelial cells. We specifically identified that the Spa homology domain (aa 250–420) of GIT1 is required for GIT1–cortactin complex localization to the leading edge. The mechanisms involved extracellular signal-regulated kinases 1 and 2–mediated Cortactin-S405 phosphorylation and activation of Rac1/Cdc42. Finally, using gain of function studies, we show that a constitutively active mutant of cortactin restored directional migration of GIT1-depleted cells.

Conclusion—

Our data demonstrated that a GIT1–cortactin association through GIT1-Spa homology domain is required for cortactin localization to the leading edge and is essential for endothelial cell directional migration and tumor angiogenesis.
Growth Factor Receptor–Bound Protein 2 Contributes to (Hem)Immunoreceptor Tyrosine-Based Activation Motif–Mediated Signaling in Platelets
Authors: Dütting Sebastian , Vögtle Timo , Morowski Martina , Schiessl Sarah , Schäfer Carmen M. , Watson Stephanie K. , Hughes Craig E. , Ackermann Jochen A. , Radtke Daniel , Hermanns Heike M. , Watson Steve P. , Nitschke Lars , Nieswandt Bernhard
Published: November 2013

Rationale:

Platelets are anuclear cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity but may also cause pathological vessel occlusion. One major pathway of platelet activation is triggered by 2 receptors that signal through an (hem)immunoreceptor tyrosine-based activation motif (ITAM), the activating collagen receptor glycoprotein (GP) VI and the C-type lectin-like receptor 2 (CLEC-2). Growth factor receptor–bound protein 2 (Grb2) is a ubiquitously expressed adapter molecule involved in signaling processes of numerous receptors in different cell types, but its function in platelets and MKs is unknown.

Objective:

We tested the hypothesis that Grb2 is a crucial adapter protein in (hem)immunoreceptor tyrosine-based activation motif signaling in platelets.

Methods and Results:

Here, we show that genetic ablation of Grb2 in MKs and platelets did not interfere with MK differentiation or platelet production. However, Grb2-deficiency severely impaired glycoprotein VI–mediated platelet activation because of defective stabilization of the linker of activated T-cell (LAT) signalosome and activation of downstream signaling proteins that resulted in reduced adhesion, aggregation, and coagulant activity on collagen in vitro. Similarly, CLEC-2–mediated signaling was impaired in Grb2-deficient platelets, whereas the cells responded normally to stimulation of G protein–coupled receptors. In vivo, this selective (hem)immunoreceptor tyrosine-based activation motif signaling defect resulted in prolonged bleeding times but affected arterial thrombus formation only after concomitant treatment with acetylsalicylic acid, indicating that defective glycoprotein VI signaling in the absence of Grb2 can be compensated through thromboxane A
2
–induced G protein–coupled receptor signaling pathways.

Conclusions:

These results reveal an important contribution of Grb2 in (hem)immunoreceptor tyrosine-based activation motif signaling in platelets in hemostasis and thrombosis by stabilizing the LAT signalosome.
Within-Day and Weekly Variations of Thrombolysis in Acute Ischemic Stroke
Authors: Lorenzano Svetlana , Ahmed Niaz , Tatlisumak Turgut , Gomis Meritxell , Dávalos Antoni , Mikulik Robert , Sevcik Petr , Ollikainen Jyrki , Wahlgren Nils , Toni Danilo
Published: November 2013

Background and Purpose—

Temporal variations of thrombolysis delivery and their influence on outcome have been reported with controversial results. In this large cohort study, we evaluated whether thrombolytic treatment has a within-day and weekly variability corresponding to circadian and weekly patterns of ischemic stroke onset, and whether these have impact on clinical outcome.

Methods—

We retrospectively analyzed patients with acute ischemic stroke receiving intravenous alteplase, prospectively included in the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register. Patients were grouped by treatment on day hours (08:00–19:59) or night hours (20:00–07:59) and treatment on weekdays and weekends. For each subgroup, we analyzed frequency of thrombolytic treatments, time intervals, and outcomes (3-month modified Rankin Scale score 0–2 as good functional outcome, mortality, symptomatic intracerebral hemorrhage).

Results—

We included 21 513 patients. Considering the mean expected number of patients treated per hour (0.4) and per day of the week (9.8), if no temporal variations were present, patients were significantly treated more during day hours and weekdays (
P
<0.0001). Median door-to-needle and onset-to-treatment times were longer for patients treated during night hours and on weekends (
P
<0.01). After adjustment for confounding variables, treatment during day hours was an independent predictor of good functional outcome (odds ratio, 1.12; 95% confidence interval, 1.04–1.21;
P
=0.004), and patients treated during weekdays were at risk of higher mortality (odds ratio, 1.15; 95% confidence interval, 1.04–1.28;
P
=0.008).

Conclusions—

Frequency of thrombolytic treatment seems to follow the same circadian pattern of stroke incidence, whereas its correspondence to a weekly pattern is less clear. Time of treatment is an independent predictor of outcome.
Socioeconomic Deprivation and Survival After Stroke
Authors: Chen Ruoling , McKevitt Christopher , Rudd Anthony G. , Wolfe Charles D.A.
Published: November 2013

Background and Purpose—

Previous findings of the association between socioeconomic deprivation (SED) and survival after stroke are inconsistent. There is less investigation on long-term survival. We assessed the associations in a multi-ethnic population in England.

Methods—

We examined data from 4398 patients (3103 whites, 932 blacks, and 253 Asians/others) with first-ever stroke, collected by a population-based stroke register in South London from 1995 to 2011. SED was measured using the Carstairs index score—the higher score, the more deprived. It was analyzed in multivariate Cox regression models in relation to survival after stroke.

Results—

During 17-year follow-up 2754 patients died. The quartile data of Carstairs score showed no significant association of SED with survival in patients, except for black Caribbeans and Africans. Black patients with the fourth quartile SED had a multivariate adjusted hazard ratio of 1.76 (95% confidence interval, 1.06–2.94) for 3-month mortality and 1.54 (1.00–2.37) for 1-year mortality. After adjustment for acute stroke care provisions, these were no longer significant. However, the sextile data of Carstairs score showed a consistent association of SED with survival after stroke; all patients with the sixth sextile had a fully adjusted hazard ratio of 1.23 (1.05–1.44) for 3-month mortality and 1.13 (1.01–1.25) for 17-year mortality.

Conclusions—

There is a weak but significant association of SED with reduced survival after stroke in England. SED in blacks may have a stronger impact on short-term survival when compared with white patients. Further efforts are required to achieve equality in survival among patients with stroke of different socioeconomic groups.
Touching Curvature and Feeling Size: a Contrast Illusion
Authors: Plaisier Myrthe A. , Ernst Marc O.
Published: November 2013

We know that our eyes can be deceiving. Here we demonstrate that we should not always trust our sense of touch either. Previous studies have shown that when pinching an object between thumb and index finger, we can under many circumstances accurately perceive its size. In contrast, the current results show that the local curvature at the areas of contact between the object and the fingers causes systematic under- or overestimation of the object’s size. This is rather surprising given that local curvature is not directly related to the object’s size. We suggest an explanation in terms of a contrast between the finger separation and an inferred relationship between local curvature and size. This study provides the first demonstration of an illusory haptic size percept caused by local curvature in a pinch grip.