bluuebunny/crossref_metadata_2025 huggingface dataset:
Spontaneous fluctuations in cerebral blood flow regulation: contribution of PaCO2
Authors: Panerai R. B. , Dineen N. E. , Brodie F. G. , Robinson T. G.
Published: October 2010

To investigate the temporal variability of dynamic cerebral autoregulation (CA), the transient response of cerebral blood flow to rapid changes in arterial blood pressure, a new approach was introduced to improve the temporal resolution of dynamic CA assessment. Continuous bilateral recordings of cerebral blood flow velocity (transcranial Doppler, middle cerebral artery), end-tidal Pco2 (PetCO2, infrared capnograph), and blood pressure (Finapres) were obtained at rest and during breath hold in 30 young subjects (25 ± 6 yr old) and 30 older subjects (64 ± 4 yr old). Time-varying estimates of the autoregulation index [ARI( t)] were obtained with an autoregressive-moving average model with coefficients expanded by orthogonal decomposition. The temporal pattern of ARI( t) varied inversely with PetCO2, decreasing with hypercapnia. At rest, ARI( t) showed spontaneous fluctuations that were significantly different from noise and significantly correlated with spontaneous fluctuations in PetCO2 in the majority of recordings (young: 72% and old: 65%). No significant differences were found in ARI( t) due to aging. This new approach to improve the temporal resolution of dynamic CA parameters allows the identification of physiologically meaningful fluctuations in dynamic CA efficiency at rest and in response to changes in arterial CO2.
Existence of Local Saddle Points for a New Augmented Lagrangian Function
Authors: Zhao Wenling , Zhang Jing , Zhou Jinchuan
Published: September 2010

We give a new class of augmented Lagrangian functions for nonlinear
programming problem with both equality and inequality constraints. The close relationship
between local saddle points of this new augmented Lagrangian and local optimal
solutions is discussed. In particular, we show that a local saddle point is a local optimal
solution and the converse is also true under rather mild conditions.
Effect of Feeding Status on Adjuvant Arthritis Severity, Cachexia, and Insulin Sensitivity in Male Lewis Rats
Authors: Stofkova Andrea , Zelezna Blanka , Romzova Marianna , Ulicna Olga , Kiss Alexander , Skurlova Martina , Jurcovicova Jana
Published: September 2010

We studied the effect of food restriction, overfeeding, and normofeeding on cachexia, inflammatory and metabolic parameters, and insulin sensitivity in chronic adjuvant arthritis (AA) in rats. Food restriction during AA increased circulating ghrelin, corticosterone, decreased leptin, and ameliorated arthrogram score and systemic inflammation compared to normofeeding. Overfeeding worsened arthrogram score and systemic inflammation, and led to lipid accumulation in the liver, but not to alterations of adipokine and ghrelin plasma levels relative to normofeeding. Independently of feeding status, AA induced cachexia, in which modulation of mRNA expressions for appetite-regulating neuropeptides (NPY, AgRP, POMC, CART) in the arcuate nucleus (ARC) does not play a primary role. The overexpression of IL-1βmRNA in the ARC suggests its role in the mechanisms of impaired energy balance during AA under all feeding conditions. Normal HOMA index in all arthritic groups does not indicate the development of insulin resistance by feeding interventions in these rats.
Dynamic Fuzzy Logic-Ant Colony System-Based Route Selection System
Authors: Salehinejad Hojjat , Talebi Siamak
Published: September 2010

Route selection in metropolises based on specific desires is a major problem for city travelers as well as a challenging demand of car navigation systems. This paper introduces a multiparameter route selection system which employs fuzzy logic (FL) for local pheromone updating of an ant colony system (ACS) in detection of optimum multiparameter direction between two desired points, origin and destination (O/D). The importance rates of parameters such as path length and traffic are adjustable by the user. In this system, online traffic data are supplied directly by a traffic control center (TCC) and further minutes traffic data are predicted by employing artificial neural networks (ANNs). The proposed system is simulated on a region of London, United Kingdom, and the results are evaluated.
Reoperation as a Result of Raised Intracranial Pressure Associated with Cyst Formation in Tumor Cavity after Intracranial Tumor Resection: A Report of Two Cases
Authors: Yu Jinlu , Xiong Wenji , Qu Limei , Huang Haiyan
Published: September 2010

Reoperation as a result of increased intracranial pressure (ICP) associated with cyst formation in an intracranial tumor resection cavity is a rare clinical condition. We report two cases of reoperation as a result of raised ICP associated with cyst formation in the tumor resection cavity, one arising after glioma resection and the other after meningioma resection. In both cases, a “valve”-like structure was noted intraoperatively in the roof region of the tumor resection cavity. Surgical resection of the “valve”-like structure led to slow regression over several months after the reoperation rather than to immediate disappearance of the cyst. Both cases illustrate that the “valve”-like structure formed in the roof region of the tumor resection cavity may be responsible for cyst formation. Surgical resection of it provides good long-term outcomes in such patients though short-term outcomes are unsatisfactory; we speculate that if the resection of the cortical tissue around the “valve”-like structure is enough wide, its return may be avoided.
12/15-Lipoxygenase Is an Interleukin-13 and Interferon-γCounterregulated-Mediator of Allergic Airway Inflammation
Authors: Lindley Alexa R. , Crapster-Pregont Margaret , Liu Yanjun , Kuperman Douglas A.
Published: September 2010

Interleukin-13 and interferon-γare important effectors of T-helper cells. Interleukin-13 increases expression of the arachidonic acid-metabolizing enzyme, 15-lipoxygenase-1, in a variety of cell types. 15-lipoxygenase-1 is dramatically elevated in the airways of subjects with asthma. Studies in animals indicate that 15-lipoxygenase-1 contributes to the development of allergic airway inflammation but is protective in some other forms of inflammation. We tested the hypothesis that the ability of interleukin-13 and interferon-γto counterregulate allergic airway inflammation was potentially mediated by counterregulation of 12/15-lipoxygenase, the mouse ortholog of 15-lipoxygenase-1. The airways of mice were treated with interleukin-13 or interferon-γone day prior to each of the four allergen exposures. Interleukin-13 augmented and interferon-γinhibited allergic airway inflammation independently of systemic IgE and mucosal IgA responses but in association with counterregulation of 12/15-lipoxygenase. Interleukin-13 and interferon-γcounterregulate 12/15-lipoxygenase potentially contributing to the effects of these cytokines on allergic airway inflammation.
Dysregulation of the Mitogen Granulin in Human Cancer through the miR-15/107 microRNA Gene Group
Authors: Wang Wang-Xia , Kyprianou Natasha , Wang Xiaowei , Nelson Peter T.
Published: October 2010

Granulin (GRN) is a potent mitogen and growth factor implicated in many human cancers, but its regulation is poorly understood. Recent findings indicate that GRN is regulated strongly by the microRNA miR-107, which functionally overlaps with miR-15, miR-16, and miR-195 due to a common 5′ sequence critical for target specificity. In this study, we queried whether miR-107 and paralogs regulated GRN in human cancers. In cultured cells, anti-argonaute RNA coimmunoprecipitation with downstream microarray analyses indicates that GRN mRNA is directly targeted by numerous miR-15/107 miRNAs. We further tested this association in human tumors. MiR-15 and miR-16 are known to be downregulated in chronic lymphocytic leukemia (CLL). Using pre-existing microarray datasets, we found that GRN expression is higher in CLL relative to nonneoplastic lymphocytes (P < 0.00001). By contrast, other prospective miR-15/miR-16 targets in the dataset (BCL-2 and cyclin D1) were not upregulated in CLL. Unlike in CLL, GRN was not upregulated in chronic myelogenous leukemia (CML) where miR-107 paralogs are not known to be dysregulated. Prior studies have shown that GRN is also upregulated, and miR-107 downregulated, in prostate carcinoma. Our results indicate that multiple members of the miR-107 gene group indeed repress GRN protein levels when transfected into prostate cancer cells. At least a dozen distinct types of cancer have the pattern of increased GRN and decreased miR-107 expression. These findings indicate for the first time that the mitogen and growth factor GRN is dysregulated via the miR-15/107 gene group in multiple human cancers, which may provide a potential common therapeutic target. Cancer Res; 70(22); 9137–42. ©2010 AACR.
Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death
Authors: Zappasodi Roberta , Pupa Serenella M. , Ghedini Gaia C. , Bongarzone Italia , Magni Michele , Cabras Antonello D. , Colombo Mario P. , Carlo-Stella Carmelo , Gianni Alessandro M. , Di Nicola Massimo
Published: October 2010

Increasing evidence argues that the success of an anticancer treatment may rely on immunoadjuvant side effects including the induction of immunogenic tumor cell death. Based on the assumption that this death mechanism is a similar prerequisite for the efficacy of an active immunotherapy using killed tumor cells, we examined a vaccination strategy using dendritic cells (DC) loaded with apoptotic and necrotic cell bodies derived from autologous tumors. Using this approach, clinical and immunologic responses were achieved in 6 of 18 patients with relapsed indolent non–Hodgkin's lymphoma (NHL). The present report illustrates an impaired ability of the neoplastic cells used to vaccinate nonresponders to undergo immunogenic death on exposure to a cell death protocol based on heat shock, γ-ray, and UVC ray. Interestingly, when compared with doxorubicin, this treatment increased surface translocation of calreticulin and cellular release of high-mobility group box 1 and ATP in histologically distinct NHL cell lines. In contrast, treated lymphoma cells from responders displayed higher amounts of calreticulin and heat shock protein 90 (HSP90) compared with those from nonresponders and boosted the production of specific antibodies when loaded into DCs for vaccination. Accordingly, the extent of calreticulin and HSP90 surface expression in the DC antigenic cargo was significantly associated with the clinical and immunologic responses achieved. Our results indicate that a positive clinical effect is obtained when immunogenically killed autologous neoplastic cells are used for the generation of a DC-based vaccine. Therapeutic improvements may thus be accomplished by circumventing the tumor-impaired ability to undergo immunogenic death and prime the antitumor immune response. Cancer Res; 70(22); 9062–72. ©2010 AACR.
Synergistic Killing Effect between Vorinostat and Target of CD146 in Malignant Cells
Authors: Ma Xiaoli , Liu Jia , Wu Jiang , Yan Xiyun , Wu Peng , Liu Yong , Li Shuang , Tian Yuan , Cao Yang , Chen Gang , Meng Li , Xu Gang , Wang Shixuan , Lu Yunping , Ma Ding , Zhou Jianfeng
Published: October 2010

Purpose:

Although histone deacetylase inhibitors (HDACi) are emerging as a new class of anticancer agents, one of the most significant concerns is that interactions with a wide array of substrates using these agents might initiate both therapeutic and undesired protective responses. Here, we sought to identify the potential protective reactions initiated by HDACi and determine whether targeting these reactions would enhance the antitumoral activity of HDACi.

Experimental Design:

Gene expression profiles were analyzed by cDNA microarray in Molt-4 cells before and after treatment of vorinostat. Induction of CD146 by vorinostat was examined in a wide range of tumors and nonmalignant cells. AA98, an anti-CD146 monoclonal antibody, was used to target CD146 function. Synergistic antitumoral and antiangiogenic effects between AA98 and vorinostat were examined both in vitro and in vivo. The potential effect of combined AA98 and vorinostat treatment on the AKT pathway was determined by Western blotting.

Results:

The induction of CD146 is a common phenomenon in vorinostat-treated cancer but not in nonmalignant cells. Targeting of CD146 with AA98 substantially enhanced vorinostat-induced killing via the suppression of activation of AKT pathways in cancer cells. Moreover, AA98 in combination with vorinostat significantly inhibited angiogenesis. In vivo, AA98 synergized with vorinostat to inhibit tumor growth and metastasis.

Conclusion:

The present study provided the first evidence that an undesired induction of CD146 could serve as a protective response to offset the antitumor efficacy of vorinostat. On the other hand, targeting CD146 in combination with vorinostat could be exploited as a novel strategy to more effectively kill cancer cells. Clin Cancer Res; 16(21); 5165–76. ©2010 AACR.
EGFR Fluorescence In situ Hybridization Pattern of Chromosome 7 Disomy Predicts Resistance to Cetuximab in KRAS Wild-type Metastatic Colorectal Cancer Patients
Authors: Li Yu-Hong , Wang Fang , Shen Lin , Deng Yan-Ming , Shao Qiong , Feng Fen , An Xin , Wang Feng-Hua , Wang Zhi-Qiang , Xu Rui-Hua , Shao Jian-Yong
Published: October 2010

Purpose: Metastatic colorectal cancer patients with low epidermal growth factor receptor (EGFR) gene copy number are unlikely to respond to anti-EGFR monoclonal antibody (mAb) treatment. The objective of this study was to investigate EGFR fluorescence in situ hybridization (FISH) patterns of chromosome 7 disomy with efficacy of cetuximab therapy in metastatic colorectal cancer patients.

Experimental Design: We detected the EGFR FISH patterns and KRAS status in 74 tumors from cetuximab-treated metastatic colorectal cancer patients and analyzed with response rate (RR) and progression-free survival (PFS).

Results: One of the 16 (6.25%) patients with chromosome 7 homogeneous disomy (defined as FISH negative) had objective response to cetuximab. A total of 53(76.8%) patients with chromosome 7 pattern of variable ratios of disomy versus polysomy (defined as FISH positive) had a significantly higher RR (37.7% versus 6.25%; P = 0.01), a trend towards longer PFS (4.5 versus 2.9 months; P = 0.07). Among 54 KRAS wild-type patients, EGFR FISH-positive patients had significantly higher RR (51.3% versus 9%; P = 0.01) and longer PFS (5.0 versus 2.3 months; P = 0.02) than EGFR FISH-negative patients. However, among 20 KRAS mutant-type patients, there was no difference in RR (0% versus 0%) and PFS (2.5 versus 3.8 months; P = 0.51) between EGFR FISH-positive and -negative patients.

Conclusion: Our results show firstly that patients with EGFR FISH pattern of chromosome 7 disomy have a very low chance to benefit from cetuximab-based therapy. EGFR FISH pattern of chromosome 7 disomy may be as a negative predicative factor for cetuximab response in KRAS wild-type metastatic colorectal cancer patients. Clin Cancer Res; 17(2); 382–90. ©2011 AACR.
A Randomized Trial ofEx vivoCD40L Activation of a Dendritic Cell Vaccine in Colorectal Cancer Patients: Tumor-Specific Immune Responses Are Associated with Improved Survival
Authors: Barth Richard J. , Fisher Dawn A. , Wallace Paul K. , Channon Jacqueline Y. , Noelle Randolph J. , Gui Jiang , Ernstoff Marc S.
Published: October 2010

Purpose: To determine whether an autologous dendritic cell (DC) vaccine could induce antitumor immune responses in patients after resection of colorectal cancer metastases and whether these responses could be enhanced by activating DCs with CD40L.

Experimental Design: Twenty-six patients who had undergone resection of colorectal metastases were treated with intranodal injections of an autologous tumor lysate– and control protein [keyhole limpet hemocyanin (KLH)]–pulsed DC vaccine. Patients were randomized to receive DCs that had been either activated or not activated with CD40L. All patients were followed for a minimum of 5.5 years.

Results: Immunization induced an autologous tumor-specific T-cell proliferative or IFNγ enzyme-linked immunospot response in 15 of 24 assessable patients (63%) and a tumor-specific DTH response in 61%. Patients with evidence of a vaccine-induced, tumor-specific T-cell proliferative or IFNγ response 1 week after vaccination had a markedly better recurrence-free survival (RFS) at 5 years (63% versus 18%, P = 0.037) than nonresponders. In contrast, no association was observed between induction of KLH-specific immune responses and RFS. CD40L maturation induced CD86 and CD83 expression on DCs but had no effect on immune responses or RFS.

Conclusion: Adjuvant treatment of patients after resection of colorectal metastases with an autologous tumor lysate–pulsed, DC vaccine–induced, tumor-specific immune responses in a high proportion of patients. There was an association between induction of tumor-specific immune responses and RFS. Activation of this DC vaccine with CD40L did not lead to increased immune responses. Clin Cancer Res; 16(22); 5548–56. ©2010 AACR.
Daunorubicin induces procoagulant activity of cultured endothelial cells through phosphatidylserine exposure and microparticles release
Authors: Li Huibo , Cao Fenglin , Su Yanhua , Fan Shengjin , Li Yinghua , Wang Shuye , Li Limin , Gilbert Gary E. , Fu Yueyue , Zhou Jin , Shi Jialan
Published: October 2010

Administration of various chemotherapeutic agents is associated with an increased risk of thrombotic events. Although vascular endothelium plays a predominant role in blood coagulation and fibrinolysis, the effect of cytotoxic drugs on the procoagulant activity (PCA) of endothelial cells has not been well evaluated. Our study aims to investigate the possibility that daunorubicin, a chemotherapeutic agent, exerts prothrombotic effect on endothelial cells. We tested the impact of daunorubicin on phosphatidylserine (PS) exposure, endothelial microparticles (EMPs) release and consequent PCA. Human umbilical vein endothelial cells (HUVECs) were treated with daunorubicin (0.1, 0.2, 0.5, 1, 2 μM) for 24 hours. PCA of HUVECs was measured using clotting time and purified coagulation complex assays. Counts and PCA of EMPs were evaluated by flow cytometry and clotting time assay, respectively. Lactadherin was used as a novel probe for detection of PS exposure and EMPs release. We found that daunorubicin dose-dependently increased the PS exposure and consequent PCA of HUVECs. Moreover, daunorubicin treatment also enhanced the release of EMPs which were highly procoagulant. This increment was especially significant at 0.2 μM of daunorubicin or more. Blockade of PS with lactadherin inhibited over 90% of HUVECs and EMPs PCA. However, anti-TF antibody had no significant inhibition effect. Our results demonstrate that daunorubicin treatment enhanced PCA of HUVECs through PS exposure and shedding of procoagulant EMPs. Lactadherin acts as an efficient anticoagulant in this process.
Optimisation of the diagnostic strategy for suspected deep-vein thrombosis in primary care
Authors: van der Velde Eit , ten Cate Arina , Prins Martin , van Weert Henk , Stoffers H. E. Jelle , Buller Harry , Oudega Ruud , Hoes Arno , Janssen Kristel , Toll Diane , Moons Karel
Published: October 2010

Recently, a diagnostic score was developed to safely exclude deep-vein thrombosis (DVT) in primary care. A large prospective study, in which general practitioners used this diagnostic score to decide which patients needed referral, revealed that the number of referrals for ultra-sound measurements was reduced by almost 50%, at the cost of an acceptably low risk (1.4%, 95% confidence interval [CI] 0.6% to 2.9%) of venous thromboembolic events in non-referred patients. However, simple adjustments to the diagnostic score (so-called updating) might further improve the accuracy; i.e. reduce the proportion of missed diagnoses (safety) or increase the proportion of patients who do not need to be referred (efficiency). We applied two updating methods to determine whether adjusting the weights of the predictors or adding new predictors could further improve the accuracy of the diagnostic score. The weights of the predictors did not need to be adjusted, but inclusion of ‘history of DVT’ and ‘prolonged travelling’ significantly added predictive value (p-values 0.014 and 0.023, respectively). However, adding these predictors to the diagnostic score did not improve the safety and efficiency: at equal safety (1.4% missed diagnoses among the non-referred patients), the efficiency was lower (43.5%, 95% CI 40.4% to 46.6% compared to 49.4%, 95% CI 46.3% to 52.5%). The diagnostic score for excluding DVT in primary care has good accuracy in its original form and could not be improved by including additional predictors. This suggests that the original diagnostic score can be used to safely exclude clinically suspected DVT in primary care.
Prospective study of ABO blood type and the risk of pulmonary embolism in two large cohort studies
Authors: Kabrhel Christopher , Varraso Raphaëlle , Kraft Peter , Rimm Eric , Goldhaber Samuel , Camargo Carlos , Fuchs Charles , Wolpin Brian
Published: October 2010

Prior studies have suggested an association of ABO blood type and the risk of venous thromboembolism; however, most studies were retrospective and lacked important covariates or validated endpoints. Moreover, risk estimates varied widely across studies. Therefore, we prospectively examined the association of blood type and the risk of incident pulmonary embolism (PE) in two large cohort studies, the Nurses’ Health Study and Health Professionals Follow-up Study. During 1,010,378 person-years of follow-up among 77,025 women and 30,105 men, 499 participants developed PE. Compared to those with O-blood type, participants with non-O blood type had multivariable-adjusted hazard ratios (HR) of 1.86 (95% CI, 1.35–2.57) for idiopathic PE, 1.29 (95% CI, 1.03–1.62) for non-idiopathic PE, and 1.46 (95% CI, 1.22–1.76) for any PE. Hazard ratios were similar for participants with blood types A, B, and AB. Age-adjusted absolute rates of idiopathic PE over 10 years of follow-up differed by blood type: 0.11% for O, 0.20% for A, 0.19% for AB, and 0.21% for B. For idiopathic PE, the population attributable fraction was 33% for inheritance of non-O blood type. Among past and current smokers, participants with non-O vs. O-blood type had a HR for idiopathic PE of 2.56 (95% CI, 1.61–4.08). Among never smokers, the HR for idiopathic PE was 1.30 (95% CI, 0.82–2.05; Pinteraction=0.04). In two large, prospective cohorts, ABO blood type was significantly associated with the risk of idiopathic and non-idiopathic PE, with even greater risk for idiopathic PE among current and past smokers with non-O blood type.
Effect of the time of diagnosis on outcome in patients with acute venous thromboembolism
Authors: Lecumberri Ramón , Soler Silvia , Toro Jorge Del , Barba Raquel , Rosa Vladimir , Ciammaichella Maurizio , Monreal Manuel ,   the RIETE Investigators
Published: October 2010

The influence of the day of diagnosis (weekends vs. weekdays) on outcome in patients with acute venous thromboembolism (VTE) has not been thoroughly studied. We used the RIETE database to compare the clinical characteristics, treatment details, and mortality rate at 7 and 30 days, of all patients diagnosed with acute VTE on weekends versus those diagnosed on weekdays. Up to January 2010, 30,394 patients were included in RIETE, of whom 5,479 (18%) were diagnosed on weekends. Most clinical characteristics were similar in both groups, but patients diagnosed on weekends had less often cancer (20% vs. 22%; p=0.004), and presented more likely with pulmonary embolism (PE) than those diagnosed on weekdays (52% vs. 47%; p <0.001). Most patients in both groups received initial therapy with low-molecular-weight heparin (90% and 91%, respectively; p=0.01), then switched to vitamin K antagonists (72% and 71%, respectively; p=0.007). The 7-day mortality rate in patients presenting with PE was 2.75% in those diagnosed on weekends versus 3.00% in those diagnosed on weekdays (p=0.49). At 30 days, the mortality rate was 6.51% versus 6.06%, respectively (p=0.38). In patients presenting with deep vein thrombosis alone, the 7-day mortality rate in those diagnosed on weekends was 1.04% versuss 0.66% in those diagnosed on weekdays (p=0.053). The mortality rate at 30 days was of 3.41% versus 2.88% (p=0.14), respectively. In RIETE, the clinical characteristics, treatment strategies, and 7– and 30-day mortality rates of patients diagnosed on weekends were similar to those in patients diagnosed on weekdays.
Premature Senescence of Vascular Cells Is Induced by HIV Protease Inhibitors
Authors: Lefèvre Chloé , Auclair Martine , Boccara Franck , Bastard Jean-Philippe , Capeau Jacqueline , Vigouroux Corinne , Caron-Debarle Martine
Published: October 2010

Objective—

To determine whether and how protease inhibitors (PIs) could affect vascular aging.

Methods and Results—

HIV therapy with PIs is associated with an increased risk of premature cardiovascular disease. The effect of ritonavir and a combination of lopinavir and ritonavir (for 30 days) on senescence, oxidative stress, and inflammation was evaluated in human coronary artery endothelial cells (HCAECs). These HCAECs were either cotreated or not cotreated with pravastatin or farnesyl transferase inhibitor (FTI)-277 or with 2 antioxidants (manganese [III] tetrakis [4-benzoic acid] porphyrin [MnTBAP] and N-acetyl cysteine). Senescence markers were evaluated in peripheral blood mononuclear cells (PBMCs) from HIV-infected patients under PI treatment. PIs induced senescence markers, prelamin A accumulation, oxidative stress, and inflammation in HCAECs. Senescence markers and prelamin A were also observed in PBMCs from HIV-infected patients under ritonavir-boosted PIs. Pravastatin, FTI-277, and antioxidants improved PI adverse effects in HCAECs. Senescence markers were lower in PBMCs from PI-treated patients cotreated with statins.

Conclusion—

PIs triggered premature senescence in endothelial cells by a mechanism involving prelamin A accumulation. Accordingly, circulating cells from HIV-infected patients receiving PI therapy expressed senescence markers and prelamin A. Statin was associated with improved senescence in endothelial cells and patient PBMCs. Thus, PIs might promote vascular senescence in HIV-infected patients; and statins might exert beneficial effects in these patients.
PGC-1 Coactivators in Cardiac Development and Disease
Authors: Rowe Glenn C. , Jiang Aihua , Arany Zolt
Published: September 2010

The beating heart requires a constant flux of ATP to maintain contractile function, and there is increasing evidence that energetic defects contribute to the development of heart failure. The last 10 years have seen a resurgent interest in cardiac intermediary metabolism and a dramatic increase in our understanding of transcriptional networks that regulate cardiac energetics. The PPAR-γ coactivator (PGC)-1 family of proteins plays a central role in these pathways. The mechanisms by which PGC-1 proteins regulate transcriptional networks and are regulated by physiological cues, as well as the roles they play in cardiac development and disease, are reviewed here.
RGS6/Gβ5 Complex Accelerates
I
KACh
Gating Kinetics in Atrial Myocytes and Modulates Parasympathetic Regulation of Heart Rate
Authors: Posokhova Ekaterina , Wydeven Nicole , Allen Kevin L. , Wickman Kevin , Martemyanov Kirill A.
Published: October 2010

Rationale:

The parasympathetic reduction in heart rate involves the sequential activation of m2 muscarinic cholinergic receptors (m
2
Rs), pertussis toxin–sensitive (Gi/o) heterotrimeric G proteins, and the atrial potassium channel
I
KACh
. Molecular mechanisms regulating this critical signal transduction pathway are not fully understood.

Objective:

To determine whether the G protein signaling regulator Rgs6/Gβ5 modulates m
2
R-
I
KACh
signaling and cardiac physiology.

Methods and Results:

Cardiac expression of Rgs6, and its interaction with Gβ5, was demonstrated by immunoblotting and immunoprecipitation.
Rgs6
−/−
mice were generated by gene targeting, and the cardiac effects of
Rgs6
ablation were analyzed by whole-cell recordings in isolated cardiomyocytes and ECG telemetry. Loss of Rgs6 yielded profound delays in m
2
R-
I
KACh
deactivation kinetics in both neonatal atrial myocytes and adult sinoatrial nodal cells.
Rgs6
−/−
mice exhibited mild resting bradycardia and altered heart rate responses to pharmacological manipulations that were consistent with enhanced m
2
R-
I
KACh
signaling.

Conclusions:

The cardiac Rgs6/Gβ5 complex modulates the timing of parasympathetic influence on atrial myocytes and heart rate in mice.
Thrombospondin-4 Regulates Vascular Inflammation and Atherogenesis
Authors: Frolova Ella G. , Pluskota Elzbieta , Krukovets Irene , Burke Tim , Drumm Carla , Smith Jonathan D. , Blech Lauren , Febbraio Maria , Bornstein Paul , Plow Edward F. , Stenina Olga I.
Published: October 2010

Rationale:

Thrombospondin (TSP)-4 is an extracellular protein that has been linked to several cardiovascular pathologies. However, a role for TSP-4 in vascular wall biology remains unknown.

Objective:

We have examined the effects of TSP-4 gene (
Thbs4
) knockout on the development of atherosclerotic lesions in
ApoE
−/−
mice.

Methods and Results:

Deficiency in TSP-4 reduced atherosclerotic lesions: at 20 weeks of age, the size of the aortic root lesions in
Thbs4
−/−
/
ApoE
−/−
mice was decreased by 48% in females and by 39% in males on chow diets; in mice on Western diets, lesions in the descending aorta were reduced by 30% in females and 33% in males. In
ApoE
−/−
mice, TSP-4 was abundant in vessel areas prone to lesion development and in the matrix of the lesions themselves. TSP-4 deficiency reduced the number of macrophages in lesions in all groups by ≥2-fold. In addition, TSP-4 deficiency reduced endothelial cell activation (expression of surface adhesion molecules) and other markers of inflammation in the vascular wall (decreased production of monocyte chemoattractant protein-1 and activation of p38). In vitro, both the adhesion and migration of wild-type macrophages increased in the presence of purified recombinant TSP-4 in a dose-dependent manner (up to 7- and 4.7-fold, respectively). These responses led to p38-MAPkinase activation and were dependent on β
2
and β
3
integrins, which recognize TSP-4 as a ligand.

Conclusions:

TSP-4 is abundant in atherosclerotic lesions and in areas prone to development of lesions and may influence the recruitment of macrophages by activating endothelial cells and directly interacting with macrophages to increase their adhesion and migration. Our observations suggest an important role for this matricellular protein in the local regulation of inflammation associated with atherogenesis.
International Operational Aerosol Observability Workshop
Authors: Reid Jeffrey S. , Benedetti Angela , Colarco Peter R. , Hansen James A.
Published: October 2010

No Abstract available.
A Study on the Feasibility of Dual-Wavelength Radar for Identification of Hydrometeor Phases
Authors: Liao Liang , Meneghini Robert
Published: October 2010

An important objective for the dual-wavelength Ku-/Ka-band precipitation radar (DPR) that will be on board the Global Precipitation Measurement (GPM) core satellite is to identify the phase state of hydrometeors along the range direction. To assess this, radar signatures are simulated in snow and rain to explore the relation between the differential frequency ratio (DFR), defined as the difference of radar reflectivity factors between Ku and Ka bands, and the radar reflectivity factor at Ku band ZKu for different hydrometeor types. Model simulations indicate that there is clear separation between snow and rain in the ZKu–DFR plane assuming that the snow follows the Gunn–Marshall size distribution and rain follows the Marshall–Palmer size distribution. In an effort to verify the simulated results, the data collected by the Airborne Second-Generation Precipitation Radar (APR-2) in the Wakasa Bay Advanced Microwave Scanning Radiometer for Earth Observing System (AMSR-E) campaign are employed. Using the signatures of linear depolarization ratio at Ku band, the APR-2 data can be easily divided into the regions of snow, mixed phase, and rain for stratiform storms. These results are then superimposed onto the theoretical curves computed from the model in the ZKu–DFR plane. For over 90% of the observations from a cold-season stratiform precipitation event, snow and rain can be distinguished if the Ku-band radar reflectivity exceeds 18 dBZ (the minimum detectable level of the GPM DPR at Ku band). This is also the case for snow and mixed-phase hydrometeors. Although snow can be easily distinguished from rain and melting hydrometeors by using Ku- and Ka-band radar, the rain and mixed-phase particles are not always separable. It is concluded that Ku- and Ka-band dual-wavelength radar might provide a potential means to identify the phase state of hydrometeors.
Systemic cytokine response in patients with community-acquired pneumonia
Authors: Endeman H. , Meijvis S.C.A. , Rijkers G.T. , van Velzen–Blad H. , van Moorsel C.H.M. , Grutters J.C. , Biesma D.H.
Published: October 2010

The role of individual cytokines and polymorphisms in pneumonia has been described, but the relationship between different cytokines and polymorphisms in relation to causative microorganisms, antibiotics, corticosteroids and clinical course has not. This study questions the relationship between cytokines, polymorphisms and clinical characteristics of pneumonia.

Patients diagnosed with pneumonia were included in the study. Serum cytokine levels were measured during hospital stay, genotyping was performed, causative microorganisms were identified and patients were monitored throughout the hospital stay.

In 201 patients with pneumonia interleukin (IL)-1 receptor antagonist (IL-1RA), IL-6, IL-8 and IL-10 acted as acute phase proteins. After admission, the levels of these cytokines decreased rapidly. Single nucleotide polymorphisms did not influence cytokine production and were not associated with clinical outcome. Cytokine serum levels were significantly higher in patients with pneumococcal pneumonia. The decrease in levels of cytokines was independently influenced by the start of corticosteroid therapy.

IL-1RA, IL-6, IL-8 and IL-10 are acute phase proteins, independent of genotype. Their levels are influenced by the nature of the causative microorganism and the start of corticosteroids therapy.
Scoring of senescence signalling in multiple human tumour gene expression datasets, identification of a correlation between senescence score and drug toxicity in the NCI60 panel and a pro-inflammatory signature correlating with survival advantage in peritoneal mesothelioma
Authors: Lafferty-Whyte Kyle , Bilsland Alan , Cairney Claire J , Hanley Lorna , Jamieson Nigel B , Zaffaroni Nadia , Oien Karin A , Burns Sharon , Roffey Jon , Boyd Susan M , Keith W Nicol
Published: October 2010

Background

Cellular senescence is a major barrier to tumour progression, though its role in pathogenesis of cancer and other diseases is poorly understood in vivo. Improved understanding of the degree to which latent senescence signalling persists in tumours might identify intervention strategies to provoke "accelerated senescence" responses as a therapeutic outcome. Senescence involves convergence of multiple pathways and requires ongoing dynamic signalling throughout its establishment and maintenance. Recent discovery of several new markers allows for an expression profiling approach to study specific senescence phenotypes in relevant tissue samples. We adopted a "senescence scoring" methodology based on expression profiles of multiple senescence markers to examine the degree to which signals of damage-associated or secretory senescence persist in various human tumours.

Results

We first show that scoring captures differential induction of damage or inflammatory pathways in a series of public datasets involving radiotherapy of colon adenocarcinoma, chemotherapy of breast cancer cells, replicative senescence of mesenchymal stem cells, and progression of melanoma. We extended these results to investigate correlations between senescence score and growth inhibition in response to ~1500 compounds in the NCI60 panel. Scoring of our own mesenchymal tumour dataset highlighted differential expression of secretory signalling pathways between distinct subgroups of MPNST, liposarcomas and peritoneal mesothelioma. Furthermore, a pro-inflammatory signature yielded by hierarchical clustering of secretory markers showed prognostic significance in mesothelioma.

Conclusions

We find that "senescence scoring" accurately reports senescence signalling in a variety of situations where senescence would be expected to occur and highlights differential expression of damage associated and secretory senescence pathways in a context-dependent manner.
TNFRSF11B computational development network construction and analysis between frontal cortex of HIV encephalitis (HIVE) and HIVE-control patients
Authors: Huang Ju X , Wang L , Jiang Ming H
Published: September 2010

Background

TNFRSF11B computational development network construction and analysis of frontal cortex of HIV encephalitis (HIVE) is very useful to identify novel markers and potential targets for prognosis and therapy.

Methods

By integration of gene regulatory network infer (GRNInfer) and the database for annotation, visualization and integrated discovery (DAVID) we identified and constructed significant molecule TNFRSF11B development network from 12 frontal cortex of HIVE-control patients and 16 HIVE in the same GEO Dataset GDS1726.

Results

Our result verified TNFRSF11B developmental process only in the downstream of frontal cortex of HIVE-control patients (BST2, DGKG, GAS1, PDCD4, TGFBR3, VEZF1 inhibition), whereas in the upstream of frontal cortex of HIVE (DGKG, PDCD4 activation) and downstream (CFDP1, DGKG, GAS1, PAX6 activation; BST2, PDCD4, TGFBR3, VEZF1 inhibition). Importantly, we datamined that TNFRSF11B development cluster of HIVE is involved in T-cell mediated immunity, cell projection organization and cell motion (only in HIVE terms) without apoptosis, plasma membrane and kinase activity (only in HIVE-control patients terms), the condition is vital to inflammation, brain morphology and cognition impairment of HIVE. Our result demonstrated that common terms in both HIVE-control patients and HIVE include developmental process, signal transduction, negative regulation of cell proliferation, RNA-binding, zinc-finger, cell development, positive regulation of biological process and cell differentiation.

Conclusions

We deduced the stronger TNFRSF11B development network in HIVE consistent with our number computation. It would be necessary of the stronger TNFRSF11B development function to inflammation, brain morphology and cognition of HIVE.
Characterization of an H3N2 triple reassortant influenza virus with a mutation at the receptor binding domain (D190A) that occurred upon virus transmission from turkeys to pigs
Authors: Yassine Hadi M , Khatri Mahesh , Lee Chang W , Saif Yehia M
Published: September 2010

The hemagglutinin (HA) protein of influenza virus mediates essential viral functions including the binding to host receptor and virus entry. It also has the antigenic sites required for virus neutralization by host antibodies. Here, we characterized an H3N2 triple reassortant (TR) influenza virus (A/turkey/Ohio/313053/04) with a mutation at the receptor binding domain (Asp190Ala) that occurred upon virus transmission from turkeys to pigs in an experimental infection study. The mutant virus replicated less efficiently than the parental virus in human, pig and turkey primary tracheal/bronchial epithelial cells, with more than 3-log10 difference in virus titer at 72 hours post infection. In addition, the mutant virus demonstrated lower binding efficiency to plasma membrane preparations from all three cell types compared to the parental virus. Antisera raised against the parental virus reacted equally to both homologous and heterlogous viruses, however, antisera raised against the mutant virus showed 4-8 folds lower reactivity to the parental virus.
Beyond allostery: Catalytic regulation of a deoxyribozyme through an entropy-driven DNA amplifier
Authors: Eckhoff Grace , Codrea Vlad , Ellington Andrew D , Chen Xi
Published: October 2010

The programmability and replicability of RNA and DNA have respectively enabled the design and selection of a number of allosteric ribozymes and deoxyribozymes. These catalysts have been adapted to function as signal transducers in biosensors and biochemical reaction networks both in vitro and in vivo. However, allosteric control of nucleic acid catalysts is currently limited by the fact that one molecule of effector (input) generally regulates at most one molecule of ribozyme or deoxyribozyme (output). In consequence, allosteric control is usually inefficient when the concentration of input molecules is low. In contrast, catalytic regulation of protein enzymes, as in protein phosphorylation cascades, generally allows one input molecule (e.g., one kinase molecule) to regulate multiple output molecules (e.g., kinase substrates). Achieving such catalytic signal amplification would also be of great utility for nucleic acid circuits. Here we show that allosteric regulation of nucleic acid enzymes can be coupled to signal amplification in an entropy-driven DNA circuit. In this circuit, kinetically trapped DNA logic gates are triggered by a specific sequence, and upon execution generate a peroxidase deoxyribozyme that converts a colorless substrate (ABTS) into a green product (ABTS•+). This scheme provides a new paradigm for the design of enzyme-free biosensors for point-of-care diagnostics.
Robust erythrophagocytosis leads to macrophage apoptosis via a hemin-mediated redox imbalance: role in hemolytic disorders
Authors: Cambos Mathieu , Scorza Tatiana
Published: October 2010

MP from the RES are responsible for the clearance of senescent RBC. Although the frequency of senescent RBC is low under steady-state conditions, it increases dramatically during hemolytic disorders, resulting in enhanced erythrophagocytosis. As erythrophagocytosis has been involved in MP dysfunction and as certain hemolytic disorders associate to MP apoptosis, a possible link between erythrophagocytosis and the viability of phagocytes was investigated herein. To mimic hemolytic disorders, two distinct in vitro models, artificially oxidized RBC and DSRBC, were chosen to study the erythrophagocytosis impact on the viability of J774A.1 MP. Although CRBC were weakly phagocytosed and did not affect MP viability significantly, erythrophagocytosis of oxidized RBC and DSRBC was robust and resulted in a sharp decrease of MP viability via apoptosis. Under these conditions, Hb-derived HE was shown to be involved in the induction of apoptosis. Moreover, oxidized RBC, DSRBC, and HE generated ROS species, which were responsible for the apoptosis of MP. Furthermore, HO-1, strongly induced in response to treatment with oxidized RBC, DSRBC, or HE, was shown to protect MP partially against apoptosis, suggesting that robust erythro-phagocytosis may exceed the detoxification capabilities of MP. Taken together, these results suggest that enhanced erythrophagocytosis associated to hemolytic disorders leads to MP apoptosis in vitro and may have critical implications for the control of malaria infection and for the exacerbated susceptibility to bacterial infections during hemolytic disorders.
Efficient loop antenna modeling for zero-offset, off-ground electromagnetic induction in multilayered media
Authors: Moghadas Davood , André Frédéric , Vereecken Harry , Lambot Sébastien
Published: October 2010

Retrieval of the subsurface electrical properties from electromagnetic induction (EMI) data using inverse modeling relies in particular on the accuracy of the considered EMI model. We have developed a new EMI approach whereby a zero-offset, off-ground loop antenna is efficiently modeled using frequency-dependent, complex linear transfer functions and the air subsurface is described by a Green’s function for wave propagation in 3D multilayered media. To ensure proper calibration of the system, vector network analyzer (VNA) technology is used as the transmitter and receiver. An optimal integration path is proposed for fast evaluation of the spatial Green’s function from its spectral counterpart. We validated the antenna model in laboratory conditions with measurements performed with a loop antenna in free space and at different heights above a perfect electrical conductor. Provided that the loop antenna is high enough above the reflector (off-ground condition), the measured and modeled Green’s functions agreed remarkably well. In addition, inversion of the EMI data resulted in accurate estimates of the antenna heights. Yet, as expected, signal-to-noise-ratio issues occurred for the higher antenna heights and frequencies away from the loop resonant frequency. The method appears to be promising for accurate and robust soil characterization, but needs high VNA dynamic range and antenna gain.
Cost-effectiveness of improved primary care treatment of depression in women in Chile
Authors: Siskind Dan , Araya Ricardo , Kim Jane
Published: September 2010

Background

Low- and middle-income countries lack information on contextualised mental health interventions to aid resource allocation decisions regarding healthcare.

Aims

To undertake a cost-effectiveness analysis of treatments for depression contextualised to Chile.

Methods

Using data from studies in Chile, we developed a computer-based Markov cohort model of depression among Chilean women to evaluate the cost-effectiveness of usual care or improved stepped care.

Results

The incremental cost-effectiveness ratio (ICER) of usual care was I$113 per quality-adjusted life-year (QALY) gained, versus no treatment, whereas stepped care had an ICER of I$468 per QALY versus usual care. This compared favourably with Chile's per-capita GDP. Results were most sensitive to variation in recurrent episode coverage, marginally sensitive to cost of treatment, and insensitive to changes in health-state utility of depression and rate of recurrence.

Conclusions

Our results suggest that treatments for depression in lowand middle-income countries may be more cost-effective than previously estimated.
Evaluation of antipsychotic information on UK schizophrenia websites
Authors: Akram Gazala , Boyter Anne , Thomson Alison
Published: September 2010

Aims and method

To evaluate the quality of information about medication on 33 UK schizophrenia websites using a bespoke tool known as the Strathclyde Website Evaluation Form (SWEF).

Results

The mean total SWEF score was 26 out of a maximum of 52. For website content, the mean score was 15.3 out of a maximum of 32. Most websites mentioned antipsychotics (n = 23), but only 10 described the differences between typical and atypical classes. Three websites mentioned the different injectable formulations. Information about side-effects, particularly from atypicals was limited. Comprehensive details about clozapine including the blood monitoring requirements were found on two websites. Currency was reasonable with 20 websites being less than 3 years old.

Clinical implications

Information about antipsychotic medication on UK schizophrenia websites is basic and incomplete.