bluuebunny/crossref_metadata_2025 huggingface dataset:
Ets2 Determines the Inflammatory State of Endothelial Cells in Advanced Atherosclerotic Lesions
Authors: Cheng Caroline , Tempel Dennie , Den Dekker Wijnand K. , Haasdijk Remco , Chrifi Ihsan , Bos Frank L. , Wagtmans Kim , van de Kamp Esther H. , Blonden Lau , Biessen Erik A.L. , Moll Frans , Pasterkamp Gerard , Serruys Patrick W. , Schulte-Merker Stefan , Duckers Henricus J.
Published: June 2011

Rationale:

Neovascularization is required for embryonic development and plays a central role in diseases in adults. In atherosclerosis, the role of neovascularization remains to be elucidated. In a genome-wide microarray-screen of Flk1+ angioblasts during murine embryogenesis, the v-ets erythroblastosis virus E26 oncogene homolog 2 (Ets2) transcription factor was identified as a potential angiogenic factor.

Objectives:

We assessed the role of Ets2 in endothelial cells during atherosclerotic lesion progression toward plaque instability.

Methods and Results:

In 91 patients treated for carotid artery disease, Ets2 levels showed modest correlations with capillary growth, thrombogenicity, and rising levels of tumor necrosis factor-α (TNFα), monocyte chemoattractant protein 1, and interleukin-6 in the atherosclerotic lesions. Experiments in ApoE
−/−
mice, using a vulnerable plaque model, showed that Ets2 expression was increased under atherogenic conditions and was augmented specifically in the vulnerable versus stable lesions. In endothelial cell cultures, Ets2 expression and activation was responsive to the atherogenic cytokine TNFα. In the murine vulnerable plaque model, overexpression of Ets2 promoted lesion growth with neovessel formation, hemorrhaging, and plaque destabilization. In contrast, Ets2 silencing, using a lentiviral shRNA construct, promoted lesion stabilization. In vitro studies showed that Ets2 was crucial for TNFα-induced expression of monocyte chemoattractant protein 1, interleukin-6, and vascular cell adhesion molecule 1 in endothelial cells. In addition, Ets2 promoted tube formation and amplified TNFα-induced loss of vascular endothelial integrity. Evaluation in a murine retina model further validated the role of Ets2 in regulating vessel inflammation and endothelial leakage.

Conclusions:

We provide the first evidence for the plaque-destabilizing role of Ets2 in atherosclerosis development by induction of an intraplaque proinflammatory phenotype in endothelial cells.
Restoration of Normal L-Type Ca
2+
Channel Function During Timothy Syndrome by Ablation of an Anchoring Protein
Authors: Cheng Edward P. , Yuan Can , Navedo Manuel F. , Dixon Rose E. , Nieves-Cintrón Madeline , Scott John D. , Santana Luis F.
Published: June 2011

Rationale:

L-type Ca
2+
(Ca
V
1.2) channels shape the cardiac action potential waveform and are essential for excitation–contraction coupling in heart. A gain-of-function G406R mutation in a cytoplasmic loop of Ca
V
1.2 channels causes long QT syndrome 8 (LQT8), a disease also known as Timothy syndrome. However, the mechanisms by which this mutation enhances Ca
V
1.2-LQT8 currents and generates lethal arrhythmias are unclear.

Objective:

To test the hypothesis that the anchoring protein AKAP150 modulates Ca
V
1.2-LQT8 channel gating in ventricular myocytes.

Methods and Results:

Using a combination of molecular, imaging, and electrophysiological approaches, we discovered that Ca
V
1.2-LQT8 channels are abnormally coupled to AKAP150. A pathophysiological consequence of forming this aberrant ion channel-anchoring protein complex is enhanced Ca
V
1.2-LQT8 currents. This occurs through a mechanism whereby the anchoring protein functions like a subunit of Ca
V
1.2-LQT8 channels that stabilizes the open conformation and augments the probability of coordinated openings of these channels. Ablation of AKAP150 restores normal gating in Ca
V
1.2-LQT8 channels and protects the heart from arrhythmias.

Conclusion:

We propose that AKAP150-dependent changes in Ca
V
1.2-LQT8 channel gating may constitute a novel general mechanism for Ca
V
1.2-driven arrhythmias.
Comments on “Have disaster losses increased due to anthropogenic climate change?”
Authors: Nicholls Neville
Published: June 2011

No Abstract available.
Reply
Authors: Bouwer Laurens M.
Published: June 2011

No Abstract available.
Mountain Forces and the Atmospheric Energy Budget
Authors: Egger Joseph
Published: June 2011

Although mountains are generally thought to exert forces on the atmosphere, the related transfers of energy between earth and atmosphere are not represented in standard energy equations of the atmosphere. It is shown that the axial rotation of the atmosphere must be included in the energy budget in order to resolve this issue. The energy transfer resulting from mountains turns out to be closely related to mountain torques. The energetic effects of a changing rotation of the earth are discussed, as well as those of friction torques and those of the nonspherical shape of the earth.
Restaurant Challenge Offers Healthful Meal Options and Builds Diabetes Awareness
Authors: Blair Angela M. , Drass Janice A. , Stone Marylou , Rhoades Deborah , Baldwin Susan A. , Russ Kelsey M.
Published: June 2011

Purpose

The Frederick Restaurant Challenge is an innovative project based on a collaborative effort among community organizations and partners designed to offer delicious healthful meal options at local restaurants during the month of November for American Diabetes Month. Local restaurants were challenged to participate and submitted recipes for healthful meals to the Frederick County Diabetes Coalition for review by registered dietitians. Diners voted on meals to determine the challenge winner(s), and were eligible to win prizes as well. Publicity prior to and during the month was effective in creating positive news about healthful meals when eating out, raised awareness about diabetes, and provided restaurants with desirable advertising opportunities. Feedback from restaurants and diners was overwhelmingly positive. The purpose of this article is to describe this successful low-budget project to encourage its replication in local communities.

Conclusions

The Frederick Restaurant Challenge proved to be a very successful, innovative, low-budget project that met its intended goals: to develop healthful meal options for people with diabetes (or for anyone wishing to eat healthier); to demonstrate that healthful food can taste delicious; and to encourage restaurants to continue offering healthful options on their menus beyond the challenge month. Community interventions such as the Frederick Restaurant Challenge offer unique and important strategies for affecting change and raising awareness not only for people with diabetes but also for the entire community.
Social Capital and Regional Social Infrastructure Investment
Authors: Roskruge Matthew , Grimes Arthur , McCann Philip , Poot Jacques
Published: June 2011

In this article, we link unique data on local social infrastructure expenditure with microlevel individual survey data of self-reported social capital measures of trust and participation in community activities. We use both probit and tobit models to estimate the impact of social infrastructure expenditure on social capital formation. Our results imply that the links between social capital, demographic characteristics, human capital, geography, and public social infrastructure investment are rather more subtle and complex than much of the literature implies. While we find evidence in support of many of the hypothesized relationships discussed in the social capital literature, our results also suggest that the impact of public social infrastructure investment is affected by both selection effects and free rider processes.
In Honest Officials We Trust
Authors: Grönlund Kimmo , Setälä Maija
Published: June 2011

This article analyzes trust in public institutions. In both theoretical literature and empirical research, a link between social trust and institutional trust has been established. Our aim is to cast additional light on this relationship. In particular, we test whether institutional trust is dependent on citizens’ perceptions of how well institutions live up to normative expectations held by the public. The focus on such normative expectations, such as incorruptibility and honesty, is different from much of the previous empirical work which often predominantly focuses on policy outputs, such as economic performance, as a determinant of political support. Two main hypotheses derived from the theoretical discussion are tested in the analysis: Generalized social trust is positively associated with institutional trust (Hypothesis 1) and Institutional trust depends on people’s perceptions of the extent to which institutions live up to such normative expectations as incorruptibility and honesty (Hypothesis 2). Using data from the European Social Survey, the analyses are first carried out at a country level and later at an individual level. Even though the hypotheses are verified to a large extent, the most powerful determinant of institutional trust proves to be satisfaction with policy outputs. Institutional trust is associated with social trust as well as with the perception that public officials act honestly, and the pattern is similar regarding trust in both parliament and the legal system. Furthermore, the analysis suggests that the societies’ average levels of social trust and corruption do not affect the causal mechanisms of institutional trust at the individual level.
Rebound following oxygen therapy in cluster headache
Authors: Geerlings Rianne PJ , Haane Danielle YP , Koehler Peter J
Published: June 2011

Background: Rapid recurrence of a new cluster headache attack following oxygen treatment was named the ‘rebound effect’ by Kudrow (1981). It has never been studied properly. To study this effect, we defined it as a more rapid than usual (for the individual patient) recurrent cluster headache attack after complete relief following oxygen therapy, or an increase in the number of attacks per 24 hours while using oxygen therapy as acute attack treatment. We reviewed the literature and searched our cluster headache study databases.

Case series: In our eight patients with rebound cluster headache, the effect was experienced following 87.5% of oxygen treated attacks. Duration until the next cluster headache attack was on average 894 minutes shorter and frequency was on average 1.6 cluster headache attacks per day higher than without oxygen therapy.

Conclusion: Although the 1981 trial reported a prevalence of 25%, rebound cluster headache following oxygen therapy is rarely reported nowadays. This may be due to better techniques in oxygen application, the use of higher oxygen flow rates or underreporting. The few literature data and data on our eight patients did not provide clues about the mechanism of the rebound effect. Further study, applying the proposed definition, seems useful.
In-patient versus out-patient withdrawal programmes for medication overuse headache: A 2-year randomized trial
Authors: Créac’h C , Frappe P , Cancade M , Laurent B , Peyron R , Demarquay G , Navez M
Published: June 2011

Background: Medication-overuse headache (MOH) management usually includes a medication withdrawal. The choice of withdrawal modalities remains a matter of debate.

Methods: We compared the efficacy of in-patient versus out-patient withdrawal programmes in 82 consecutive patients with MOH in an open-label prospective randomized trial. The main outcome measure was the reduction in number of headache days after 2 months and after 2 years. The responders were defined as patients who had reverted to episodic headaches and to an intake of acute treatments for headache less than 10 days per month.

Results: Seventy-one patients had a complete drug withdrawal (n = 36 in the out-patient group; n = 35 in the in-patient group). The reduction of headache frequency and subjective improvement did not differ between groups. The long-term responder rate was similar in the out- and in- patient groups (44% and 44%; p = 0.810). The only predictive factor of a bad outcome 2 years after withdrawal was an initial consumption of more than 150 units of acute treatments for headache per month (OR = 3.1; 95% confidence interval 1.1–9.3; p = 0.044).

Conclusion: Given that we did not observe any difference in efficacy between the in- and out-patient withdrawals, we would recommend out-patient withdrawal in the first instance for patients with uncomplicated MOH.
Changes in headache frequency in premenopausal obese women with migraine after bariatric surgery: A case series
Authors: Novack V , Fuchs L , Lantsberg L , Kama S , Lahoud U , Horev A , Loewenthal N , Ifergane G
Published: June 2011

Background: The association between migraine and obesity gives the clinician with an exciting possibility to alleviate migraine suffering through weight-reduction gastric-restrictive operations. We hypothesized that bariatric weight-reduction intervention (gastric banding) will be associated with reduction of migraine burden in this population.

Methods: A total of 105 women between 18 and 50 years of age, admitted for bariatric surgery between April 2006 and February 2007, were screened for migraine. Twenty-nine with diagnosis of migraine were enrolled into the prospective phase. We followed the migraine pattern of these patients for 6 months post bariatric surgery.

Results: Baseline median migraine frequency was six headache days a month. Post bariatric surgery, the migraine-suffering women reported of a lower frequency of migraine attacks ( p < 0.001), shorter duration of the attacks ( p = 0.02), lower medication use during the attack ( p = 0.005), less non-migraine pain (44.8 vs. 33%, p = 0.05), and post-bariatric surgery reduction in headache-related disability assessed by the MIDAS and HIT-6 scores. There was a reduction in migraine frequency among both episodic (from four to one episodes a month) and chronic (from 16.8 to 8.5 episodes per month) migraine patient cohorts separately and combined.

Conclusions: Among migraine-suffering premenopausal obese women, we found a reduced frequency of migraine attacks and improvement of headache-related disability post bariatric surgery. Our findings should be interpreted cautiously. The absence of a control group and the non-blinded nature of our small study make it difficult to draw firm conclusions about the causal nature of the headache changes observed in this population. Further study is needed to evaluate the possible specific effects of surgical weight loss on migraine in obese women.
Expression of MUC1 and MUC2 in Ampullary Cancer
Authors: Moriya Toshiyuki , Kimura Wataru , Hirai Ichiro , Takasu Naoki , Mizutani Masaomi
Published: June 2011

Background. Mucins are high-molecular-weight glycoproteins that play important roles in carcinogenesis or tumor invasion. The authors investigated the expression of mucins in ampullary cancer. Methods. MUC1 and MUC2 expressions were examined using immunohistochemistry. Tissue samples were obtained from 32 patients with ampullary cancer who underwent resection at Yamagata University Hospital, Japan. The authors classified the cases with ampullary cancer into 2 subtypes—pancreatobiliary type (PB type) and intestinal type (I type)—using H&E, MUC1, and MUC2 staining. Then, the authors made a comparison of the clinicopathologic data of the 2 subtypes. Results. Fourteen patients (44%) were classified as PB type and 18 patients (56%) as I type. The PB-type group had significantly worse histopathologic characteristics than the I-type group in nodal involvement (PB type 57% vs I type 22%; P = .04), perineural invasion (PB type 50% vs I type 17%; P = .04), duodenal invasion (PB type 100% vs I type 33%; P = .01), and pancreatic invasion (PB type 71% vs I type 33%; P = .03). The PB-type group had significantly worse outcome than the I-type group (5-year survival: PB type 40% vs I type 72%; P = .03). Conclusion. PB-type ampullary cancers were more aggressive than I-type carcinomas. MUC1 and MUC2 expression was useful for classification as PB or I type.
Don’t let knowledge walk away: Knowledge retention during employee downsizing
Authors: Schmitt Achim , Borzillo Stefano , Probst Gilbert
Published: June 2011

In today’s business environment, employee downsizing is a widespread strategy aimed at improving firm performance and competitiveness. The literature, however, highlights unequivocal findings that many downsizing initiatives fail to retain critical skills, capabilities, experience and knowledge. Employee downsizing may therefore lead to deteriorating quality, productivity and effectiveness. This article builds on this dilemma and develops a comprehensive framework to explore the relationships between employee downsizing and knowledge retention. By holding specific organizational levels responsible for knowledge retention, we derive propositions that contribute to a better understanding of how firms can retain and avoid critical knowledge losses during employee downsizing.
Beyond connection: Cultural cosmopolitan and ubiquitous media
Authors: Tomlinson John
Published: June 2011

In his media ethics, Roger Silverstone was particularly sceptical of the idea that increasing mediaconnectedness in itself is set to improve our overall moral condition or to foster a cosmopolitan cultural outlook. In arguing that we need to go ‘beyond connection’, he raised the broader issue of the cultural condition that an intensely connected environment is establishing, and posed questions of the kinds of relatedness, the sense of belonging, the moral horizons and awareness of responsibilities that such a condition entails. This article takes an historical approach to these issues by considering how mediated connectivity may have been regarded, particularly in relation to the ideas of internationalism and cosmopolitanism, during the 1930s. Considering this earlier period of modernity — in which media technologies and institutions were emerging as significant shapers of cultural attitudes, but before they had achieved the ubiquity and the taken-for-grantedness of today — can, it will suggested, offer a useful perspective on our own globalized, media-saturated times.
Charity and chilliness
Authors: Durham Peters John
Published: June 2011

This article discusses the five contributions to the special issue on Roger Silverstone’s work, focusing specifically on the interplay between Judeo-Christian and Stoic themes.
Queer Resistances in the Adult Animated Sitcom
Authors: Dhaenens Frederik , Van Bauwel Sofie
Published: June 2011

This article studies the representation of queer characters and themes in the contemporary adult animated sitcom. We argue that even though popular culture is often assumed to reiterate and consolidate the discourse of heteronormativity, adult animated sitcoms create space for queer resistance. Since the genre draws on postmodern strategies of representation, we argue that queer resistance is subversively articulated through instances of pastiche and parody. It is embedded in content that is both complicit with and critical of the heteronormal. Through a textual thematic analysis of Family Guy, this case study illustrates how postmodern textual strategies create deconstructionist instances that expose and subvert the hegemony of heteronormativity.
Sex Differences in Knee Abduction During Landing: A Systematic Review
Authors: Carson Daniel W. , Ford Kevin R.
Published: June 2011

Background: Females suffer injuries to the anterior cruciate ligament at rates significantly higher than males. Frontal plane knee motion and load have been identified as major risk factors for anterior cruciate ligament injury and in turn have been examined extensively.

Methods: A systematic review of MEDLINE, CINHAL, and SportDISCUS was performed (1982–June 2010). Criteria for inclusion were the use of 3-dimensional analyses of frontal plane knee motion and moments during landing between males and females.

Results: Twenty-seven studies met the inclusion criteria and were reviewed. Sixty-three percent of included studies identified sex differences in knee abduction when landing across a variety of landing conditions.

Conclusions: Females appear to land with increased knee abduction motion compared with males in most biomechanics studies.
Evaluation of Low Back Pain in Athletes
Authors: Daniels James M. , Pontius Gina , El-Amin Saadiq , Gabriel Keith
Published: June 2011

Context: Low back pain is a common complaint in athletes. Athletes differ from the general population physiologically, making it unclear if the evaluation of low back pain should differ between these 2 groups.

Evidence Acquisition: A literature search (PubMed, Ovid) was performed for the years 1995 through 2010. Keywords used were lumbar back pain, athletes, and adolescence.

Results: Athletes with low back pain represent a very diverse group. The evaluation depends on the athlete’s age and the presence of “red flags.” The most common causes of low back pain in the preadolescent population are infection, tumor, and trauma. In the adolescent population, trauma spondylolysis/spondylolisthesis and hyperlordosis are commonly seen. Leading causes in the adult population are mechanics and osteoarthritis. The elderly frequently present with osteoarthritis, spinal stenosis, and internal medical etiologies.

Conclusion: Athletes with back pain should have a diagnostic workup guided by their age, history, and physical examination. Although this work up is similar in nonathletes, the demands of the athlete must be taken into account in a treatment plan.
Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide
Authors: Østergaard Henrik , Bjelke Jais R. , Hansen Lene , Petersen Lars Christian , Pedersen Anette A. , Elm Torben , Møller Flemming , Hermit Mette B. , Holm Pernille K. , Krogh Thomas N. , Petersen Jørn M. , Ezban Mirella , Sørensen Brit B. , Andersen Mette D. , Agersø Henrik , Ahmadian Haleh , Balling Kristoffer W. , Christiansen Marie Louise S. , Knobe Karin , Nichols Timothy C. , Bjørn Søren E. , Tranholm Mikael
Published: June 2011

Current management of hemophilia B entails multiple weekly infusions of factor IX (FIX) to prevent bleeding episodes. In an attempt to make a longer acting recombinant FIX (rFIX), we have explored a new releasable protraction concept using the native N-glycans in the activation peptide as sites for attachment of polyethylene glycol (PEG). Release of the activation peptide by physiologic activators converted glycoPEGylated rFIX (N9-GP) to native rFIXa and proceeded with normal kinetics for FXIa, while the Km for activation by FVIIa–tissue factor (TF) was increased by 2-fold. Consistent with minimal perturbation of rFIX by the attached PEG, N9-GP retained 73%-100% specific activity in plasma and whole-blood–based assays and showed efficacy comparable with rFIX in stopping acute bleeds in hemophilia B mice. In animal models N9-GP exhibited up to 2-fold increased in vivo recovery and a markedly prolonged half-life in mini-pig (76 hours) and hemophilia B dog (113 hours) compared with rFIX (16 hours). The extended circulation time of N9-GP was reflected in prolonged correction of coagulation parameters in hemophilia B dog and duration of effect in hemophilia B mice. Collectively, these results suggest that N9-GP has the potential to offer efficacious prophylactic and acute treatment of hemophilia B patients at a reduced dosing frequency.
Aerobic exercise attenuates pulmonary injury induced by exposure to cigarette smoke
Authors: Toledo A.C. , Magalhaes R.M. , Hizume D.C. , Vieira R.P. , Biselli P.J.C. , Moriya H.T. , Mauad T. , Lopes F.D.T.Q.S. , Martins M.A.
Published: June 2011

It has recently been suggested that regular exercise reduces lung function decline and risk of chronic obstructive pulmonary disease (COPD) among active smokers; however, the mechanisms involved in this effect remain poorly understood.

The present study evaluated the effects of regular exercise training in an experimental mouse model of chronic cigarette smoke exposure.

Male C57BL/6 mice were divided into four groups (control, exercise, smoke and smoke+exercise). For 24 weeks, we measured respiratory mechanics, mean linear intercept, inflammatory cells and reactive oxygen species (ROS) in bronchoalveolar lavage (BAL) fluid, collagen deposition in alveolar walls, and the expression of antioxidant enzymes, matrix metalloproteinase 9, tissue inhibitor of metalloproteinase (TIMP)1, interleukin (IL)-10 and 8-isoprostane in alveolar walls.

Exercise attenuated the decrease in pulmonary elastance (p<0.01) and the increase in mean linear intercept (p=0.003) induced by cigarette smoke exposure. Exercise substantially inhibited the increase in ROS in BAL fluid and 8-isoprostane expression in lung tissue induced by cigarette smoke. In addition, exercise significantly inhibited the decreases in IL-10, TIMP1 and CuZn superoxide dismutase induced by exposure to cigarette smoke. Exercise also increased the number of cells expressing glutathione peroxidase.

Our results suggest that regular aerobic physical training of moderate intensity attenuates the development of pulmonary disease induced by cigarette smoke exposure.
Circulating fibrocytes are increased in children and young adults with pulmonary hypertension
Authors: Yeager M.E. , Nguyen C.M. , Belchenko D.D. , Colvin K.L. , Takatsuki S. , Ivy D.D. , Stenmark K.R.
Published: June 2011

Chronic inflammation is an important component of the fibroproliferative changes that characterise pulmonary hypertensive vasculopathy. Fibrocytes contribute to tissue remodelling in settings of chronic inflammation, including animal models of pulmonary hypertension (PH). We sought to determine whether circulating fibrocytes were increased in children and young adults with PH.

26 individuals with PH and 10 with normal cardiac anatomy were studied. Fresh blood was analysed by flow cytometry for fibrocytes expressing CD45 and procollagen. Fibrocyte numbers were correlated to clinical and haemodynamic parameters, and circulating CC chemokine ligand (CCL)2 and CXC chemokine ligand (CXCL)12 levels.

We found an enrichment of circulating fibrocytes among those with PH. No differences in fibrocytes were observed among those with idiopathicversussecondary PH. Higher fibrocytes correlated to increasing mean pulmonary artery pressure and age, but not to length or type of treatment. Immunofluorescence analysis confirmed flow sorting specificity. Differences in plasma levels of CCL2 or CXCL12, which could mobilise fibrocytes from the bone marrow, were not found.

We conclude that circulating fibrocytes are significantly increased in individuals with PH compared with controls. We speculate that these cells might play important roles in vascular remodelling in children and young adults with pulmonary hypertension.
Therapeutic efficacy of TBC3711 in monocrotaline-induced pulmonary hypertension
Authors: Kosanovic Djuro , Kojonazarov Baktybek , Luitel Himal , Dahal Bhola K , Sydykov Akylbek , Cornitescu Teodora , Janssen Wiebke , Brandes Ralf P , Davie Neil , Ghofrani Hossein A , Weissmann Norbert , Grimminger Friedrich , Seeger Werner , Schermuly Ralph T
Published: June 2011

Background

Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats.

Methods

Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed.

Results

The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling.

Conclusion

The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension.
Granulocyte colony-stimulating factor increases the therapeutic efficacy of bone marrow mononuclear cell transplantation in cerebral ischemia in mice
Authors: Zhang Xue-Mei , Du Fang , Yang Dan , Wang Rui , Yu Chun-Jiang , Huang Xiang-Nan , Hu Hong-Yan , Liu Wei , Fu Jin
Published: June 2011

Background

Bone marrow mononuclear cell (BMMC) transplantation is a promising therapy for cerebral ischemia; however, little is known if its therapeutic efficacy may be improved by co-administration of potential modulatory factors in vivo. To explore this possibility, the present study examined the effect of BMMCs and G-CSF on cell proliferation, early neuronal development and neurological function recovery in experimental cerebral ischemia relative to controls that received neither treatment.

Result

Ischemia/infarct area was significantly reduced in BMMCs+G-CSF group relative to animal groups treated with BMMCs only, G-CSF only or saline. Transplanted BMMCs were found to colocalize with the proliferative cell nuclear antigen (PCNA) and the immature neuronal marker doublecortin (DCX). The BMMCs+G-CSF group showed increased numerical density of cells expressing PCNA and DCX, improved performance in adhesive sticker removal test and reduced neurological function severity scores relative to other groups in a time-dependent manner.

Conclusion

BMMCs and G-CSF co-administration exhibits synergistic beneficial effect over time. This effect could be at least partially related to increased proliferation and differentiation of bone marrow stem cells and enhanced host brain regeneration and functional recovery. The results suggest that G-CSF can increase the therapeutic efficacy of BMMCs transplantation in an experimental mouse model of cerebral ischemia.
Severe morbidity and mortality in untreated HIV-infected children in a paediatric care programme in Abidjan, Côte d'Ivoire, 2004-2009
Authors: Desmonde Sophie , Coffie Patrick , Aka Edmond , Amani-Bosse Clarisse , Messou Eugène , Dabis François , Alioum Ahmadou , Ciaranello Andrea , Leroy Valériane
Published: June 2011

Background

Clinical evolution of HIV-infected children who have not yet initiated antiretroviral treatment (ART) is poorly understood in Africa. We describe severe morbidity and mortality of untreated HIV-infected children.

Methods

All HIV-infected children enrolled from 2004-2009 in a prospective HIV programme in two health facilities in Abidjan, Côte d'Ivoire, were eligible from their time of inclusion. Risks of severe morbidity (the first clinical event leading to death or hospitalisation) and mortality were documented retrospectively and estimated using cumulative incidence functions. Associations with baseline characteristics were assessed by competing risk regression models between outcomes and antiretroviral initiation.

Results

405 children were included at a median age of 4.5 years; at baseline, 66.9% were receiving cotrimoxazole prophylaxis, and 27.7% met the 2006 WHO criteria for immunodeficiency by age. The risk of developing a severe morbid event was 14% (95%CI: 10.7 - 17.8) at 18 months; this risk was lower in children previously exposed to any prevention of mother-to-child-transmission (PMTCT) intervention (adjusted subdistribution hazard ratio [sHR]: 0.16, 95% CI: 0.04 - 0.71) versus those without known exposure. Cumulative mortality reached 5.5% (95%CI: 3.5 - 8.1) at 18 months. Mortality was associated with immunodeficiency (sHR: 6.02, 95% CI: 1.28-28.42).

Conclusions

Having benefited from early access to care minimizes the severe morbidity risk for children who acquire HIV. Despite the receipt of cotrimoxazole prophylaxis, the risk of severe morbidity and mortality remains high in untreated HIV-infected children. Such evidence adds arguments to promote earlier access to ART in HIV-infected children in Africa and improve care interventions in a context where treatment is still not available to all.
Is Ankyrin a genetic risk factor for psychiatric phenotypes?
Authors: Gella Alejandro , Segura Mònica , Durany Núria , Pfuhlmann Bruno , Stöber Gerald , Gawlik Micha
Published: June 2011

Background

Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression.

Methods

We genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes.

Results

We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification.

Conclusion

Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases.
Design of an efficient medium for heterologous protein production in Yarrowia lipolytica: case of human interferon alpha 2b
Authors: Gasmi Najla , Ayed Atef , Nicaud Jean-Marc , Kallel Héla
Published: June 2011

Background

The non conventional yeastYarrowia lipolyticahas aroused a strong industrial interest for heterologous protein production. However most of the studies describing recombinant protein production by this yeast rely on the use of complex media, such media are not convenient for large scale production particularly for products intended for pharmaceutical applications. In addition medium composition can also affect the production yield. Hence it is necessary to design an efficient medium for therapeutic protein expression by this host.

Results

Five different media, including four minimal media and a complex medium, were assessed in shake flasks for the production of human interferon alpha 2b (hIFN α2b) byY. lipolyticaunder the control of POX2 promoter inducible with oleic acid. The chemically defined medium SM4 formulated by Invitrogen forPichia pastorisgrowth was the most suitable. Using statistical experimental design this medium was further optimized. The selected minimal medium consisting in SM4 supplemented with 10 mg/l FeCl3, 1 g/l glutamate, 5 ml/l PTM1 (PichiaTrace Metals) solution and a vitamin solution composed of myo-inositol, thiamin and biotin was called GNY medium. Compared to shake flask, bioreactor culture in GNY medium resulted in 416-fold increase of hIFN α2b production and 2-fold increase of the biological activity.

Furthermore, SM4 enrichment with 5 ml/l PTM1 solution contributed to protect hIFN α2b against the degradation by the 28 kDa protease identified by zymography gel in culture supernatant. The screening of the inhibitory effect of the trace elements present in PTM1 solution on the activity of this protease was achieved using a Box-Behnken design. Statistical data analysis showed that FeCl3and MnSO4had the most inhibitory effect.

Conclusion

We have designed an efficient medium for large scale production of heterologous proteins byY. lipolytica. The optimized medium GNY is suitable for the production of hIFN α2b with the advantage that no complex nitrogen sources with non-defined composition were required.
Conceptual frameworks and empirical approaches used to assess the impact of health research: an overview of reviews
Authors: Banzi Rita , Moja Lorenzo , Pistotti Vanna , Facchini Andrea , Liberati Alessandro
Published: June 2011

Background

How to assess the impact of research is of growing interest to funders, policy makers and researchers mainly to understand the value of investments and to increase accountability. Broadly speaking the term "research impact" refers to the contribution of research activities to achieve desired societal outcomes. The aim of this overview is to identify the most common approaches to research impact assessment, categories of impact and their respective indicators.

Methods

We systematically searched the relevant literature (PubMed, The Cochrane Library (1990-2009)) and funding agency websites. We included systematic reviews, theoretical and methodological papers, and empirical case-studies on how to evaluate research impact. We qualitatively summarised the included reports, as well the conceptual frameworks.

Results

We identified twenty-two reports belonging to four systematic reviews and 14 primary studies. These publications reported several theoretical frameworks and methodological approaches (bibliometrics, econometrics, ad hoc case studies). The "payback model" emerged as the most frequently used. Five broad categories of impact were identified: a) advancing knowledge, b) capacity building, c) informing decision-making, d) health benefits, e) broad socio-economic benefits. For each proposed category of impact we summarized a set of indicators whose pros and cons are presented and briefly discussed.

Conclusions

This overview is a comprehensive, yet descriptive, contribution to summarize the conceptual framework and taxonomy of an heterogeneous and evolving area of research. A shared and comprehensive conceptual framework does not seem to be available yet and its single components (epidemiologic, economic, and social) are often valued differently in different models.
Tocotrienol rich fraction supplementation improved lipid profile and oxidative status in healthy older adults: A randomized controlled study
Authors: Chin Siok-Fong , Ibahim Johari , Makpol Suzana , Abdul Hamid Noor Aini , Abdul Latiff Azian , Zakaria Zaiton , Mazlan Musalmah , Mohd Yusof Yasmin Anum , Abdul Karim Aminuddin , Wan Ngah Wan Zurinah
Published: June 2011

Background

Vitamin E supplements containing tocotrienols are now being recommended for optimum health but its effects are scarcely known. The objective was to determine the effects of Tocotrienol Rich Fraction (TRF) supplementation on lipid profile and oxidative status in healthy older individuals at a dose of 160 mg/day for 6 months.

Methods

Sixty-two subjects were recruited from two age groups: 35-49 years (n = 31) and above 50 years (n = 31), and randomly assigned to receive either TRF or placebo capsules for six months. Blood samples were obtained at 0, 3rd and 6th months.

Results

HDL-cholesterol in the TRF-supplemented group was elevated after 6 months (p < 0.01). Protein carbonyl contents were markedly decreased (p < 0.001), whereas AGE levels were lowered in the > 50 year-old group (p < 0.05). Plasma levels of total vitamin E particularly tocopherols were significantly increased in the TRF-supplemented group after 3 months (p < 0.01). Plasma total tocotrienols were only increased in the > 50 year-old group after receiving 6 months of TRF supplementation. Changes in enzyme activities were only observed in the > 50 year-old group. SOD activity was decreased after 3 (p < 0.05) and 6 (p < 0.05) months of TRF supplementation whereas CAT activity was decreased after 3 (p < 0.01) and 6 (p < 0.05) months in the placebo group. GPx activity was increased at 6 months for both treatment and placebo groups (p < 0.05).

Conclusion

The observed improvement of plasma cholesterol, AGE and antioxidant vitamin levels as well as the reduced protein damage may indicate a restoration of redox balance after TRF supplementation, particularly in individuals over 50 years of age.
Neuroprotective and anti-oxidant effects of caffeic acid isolated from Erigeron annuus leaf
Authors: Jeong Chang-Ho , Jeong Hee Rok , Choi Gwi Nam , Kim Dae-Ok , Lee Uk , Heo Ho Jin
Published: June 2011

Background

Since oxidative stress has been implicated in a neurodegenerative disease such as Alzheimer's disease (AD), natural antioxidants are promising candidates of chemopreventive agents. This study examines antioxidant and neuronal cell protective effects of various fractions of the methanolic extract of Erigeron annuus leaf and identifies active compounds of the extract.

Methods

Antioxidant activities of the fractions from Erigeron annuus leaf were examined with [2,2-azino-bis(3-ethylbenz thiazoline-6-sulfonic acid diammonium salt)] (ABTS) and ferric reducing antioxidant power (FRAP) assays. Neuroprotective effect of caffeic acid under oxidative stress induced by H2O2 was investigated with [3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) and lactate dehydrogenase (LDH) assays.

Results

This study demonstrated that butanol fraction had the highest antioxidant activity among all solvent fractions from methanolic extract E. annuus leaf. Butanol fraction had the highest total phenolic contents (396.49 mg of GAE/g). Caffeic acid, an isolated active compound from butanol fraction, showed dose-dependent in vitro antioxidant activity. Moreover, neuronal cell protection against oxidative stress induced cytotoxicity was also demonstrated.

Conclusion

Erigeron annuus leaf extracts containing caffeic acid as an active compound have antioxidative and neuroprotective effects on neuronal cells.
Automated Bayesian model development for frequency detection in biological time series
Authors: Granqvist Emma , Oldroyd Giles ED , Morris Richard J
Published: June 2011

Background

A first step in building a mathematical model of a biological system is often the analysis of the temporal behaviour of key quantities. Mathematical relationships between the time and frequency domain, such as Fourier Transforms and wavelets, are commonly used to extract information about the underlying signal from a given time series. This one-to-one mapping from time points to frequencies inherently assumes that both domains contain the complete knowledge of the system. However, for truncated, noisy time series with background trends this unique mapping breaks down and the question reduces to an inference problem of identifying the most probable frequencies.

Results

In this paper we build on the method of Bayesian Spectrum Analysis and demonstrate its advantages over conventional methods by applying it to a number of test cases, including two types of biological time series. Firstly, oscillations of calcium in plant root cells in response to microbial symbionts are non-stationary and noisy, posing challenges to data analysis. Secondly, circadian rhythms in gene expression measured over only two cycles highlights the problem of time series with limited length. The results show that the Bayesian frequency detection approach can provide useful results in specific areas where Fourier analysis can be uninformative or misleading. We demonstrate further benefits of the Bayesian approach for time series analysis, such as direct comparison of different hypotheses, inherent estimation of noise levels and parameter precision, and a flexible framework for modelling the data without pre-processing.

Conclusions

Modelling in systems biology often builds on the study of time-dependent phenomena. Fourier Transforms are a convenient tool for analysing the frequency domain of time series. However, there are well-known limitations of this method, such as the introduction of spurious frequencies when handling short and noisy time series, and the requirement for uniformly sampled data. Biological time series often deviate significantly from the requirements of optimality for Fourier transformation. In this paper we present an alternative approach based on Bayesian inference. We show the value of placing spectral analysis in the framework of Bayesian inference and demonstrate how model comparison can automate this procedure.
Hyperuricemia and the risk for subclinical coronary atherosclerosis - data from a prospective observational cohort study
Authors: Krishnan Eswar , Pandya Bhavik J , Chung Lorinda , Dabbous Omar
Published: June 2011

Introduction

Our purpose was to test the hypothesis that hyperuricemia is associated with coronary artery calcification (CAC) among a relatively healthy population, and that the extent of calcification is directly proportional to the serum uric acid (sUA) concentration.

Methods

Data from 2,498 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were analyzed using logistic regression models. Subjects were free of clinical heart disease, diabetes, and renal impairment. The main measure was the presence of any CAC by computerized tomography (Agatston score >0).

Results

Forty-eight percent of the study participants were male and 45% were African-American. Mean (± SD) age was 40 ± 4 years, body mass index 28 ± 6 kg/m2, Framingham risk score -0.7 ± 5%, blood pressure 113 ± 14/75 ± 11 mmHg, alcohol consumption 12 ± 27 ml/day, and sUA 297 ± 89 μmol/L (5.0 ± 1.5 mg/dL). Prevalence of CAC increased with sUA concentration among both men and women. Adjusted for age, gender, race, lipoproteins, triglycerides, smoking, blood pressure, presence of metabolic syndrome, C-reactive protein, waist circumference, alcohol use, creatinine, and serum albumin, the highest quartile of sUA (>393 μmol/L [6.6 mg/dL] for men and >274 μmol/L [4.6 mg/dL] for women) was associated with an odds ratio of 1.87 (1.19-2.93) compared to the lowest quartile (<291 μmol/L [4.9 mg/dL] for men and <196 μmol/L [3.3 mg/dL] for women). Among those with any CAC, each unit increase in sUA was associated with a 22% increase in Agatston score (P = 0.008) after adjusting for the above covariates.

Conclusions

Hyperuricemia is an independent risk factor for subclinical atherosclerosis in young adults.