bluuebunny/crossref_metadata_2025 huggingface dataset:
Complex Regional Pain Syndrome: a review
Authors: Field J.
Published: January 2013

Complex regional pain syndrome, formally known as reflex sympathetic dystrophy, is a poorly understood condition that describes a collection of clinical symptoms and signs occurring in the peripheries most commonly after trauma. Pain is the main problem. It is generally out of proportion to the degree of injury and can be unresponsive to narcotics. In addition joint stiffness, temperature and colour changes, and swelling occur. The diagnosis and treatment are challenging for any clinician and a multidisciplinary approach is often necessary with physiotherapy, occupational therapy, and the pain team. The hand surgeon is involved for two reasons, firstly as the upper limb is the most frequently involved, and secondly because the condition may be a complication of the patient’s surgery and result in a much prolonged recovery. This review elucidates the recent advances in the knowledge of the aetiology, classification and treatment of this fascinating condition.
Carpal tunnel release: a randomized comparison of three surgical methods
Authors: Larsen M. B. , Sørensen A. I. , Crone K. L. , Weis T. , Boeckstyns M. E. H.
Published: January 2013

A single-blind, randomized, controlled trial was done to compare the results of carpal tunnel release using classic incision, short incision, or endoscopic technique. In total, 90 consecutive cases were included. Follow-up was 24 weeks. We found a significantly shorter sick leave in the endoscopic group. No significant differences in pain, paraesthesiae, range of motion, pillar pain, and grip strength could be found at 24 weeks of follow-up, although intermediate significant differences were seen, especially in grip strength, in favour of endoscopic technique. No major advantage to using a short incision could be found. There were no serious complications in either group. The results indicate that the endoscopic procedure is safe and has the benefit of faster rehabilitation and return to work.
Identification of a synthetic muramyl peptide derivative with enhanced Nod2 stimulatory capacity
Authors: Rubino Stephen J , Magalhaes Joao G , Philpott Dana , Bahr George M , Blanot Didier , Girardin Stephen E
Published: January 2013

Muramyl peptides (MPs) represent the building blocks of bacterial peptidoglycan, a critical component of bacterial cell walls. MPs are well characterized for their immunomodulatory properties, and numerous studies have delineated the role of MPs or synthetic MP analogs in host defense, adjuvanticity and inflammation. More recently, Nod1 and Nod2 have been identified as the host sensors for specific MPs, and, in particular, Nod2 was shown to detect muramyl dipeptide (MDP), a MP found in both Gram-positive and Gram-negative bacterial cell walls. Because mutations in Nod2 are associated with the etiology of Crohn’s disease, there is a need to identify synthetic MP analogs that could potentiate Nod2-dependent immunity. Here, we analyzed the Nod2-activating property of 36 MP analogs that had been tested previously for their adjuvanticity and anti-infectious activity. Using a luciferase-based screen, we demonstrate that addition of a methyl group to the second amino acid of MDP generates a MDP derivative with enhanced Nod2-activating capacity. We further validated these results in murine macrophages, human dendritic cells and in vivo. These results offer a basis for the rational development of synthetic MPs that could be used in the treatment of inflammatory disorders that have been associated with Nod2 dysfunction, such as Crohn’s disease.
On canons, cannons and the rapier
Authors: Mayhew Robert J
Published: January 2013

Whilst in general welcoming the call to rethink the need for canons in human geography offered by Keighren et al. (2012), this paper suggests the need for a more nuanced argument in several respects. Physical geographers need to be brought on board and more clarity is required about the relationship between ‘canons’ and ‘classics’. Above all, the claim that geography is unusual in its historical superficiality and indifference to its earlier generations needs qualification. Only then can the call for canons in geography to create historical depth to our understanding and to aid in disciplinary identity formation, which the authors champion, prove successful.
The return of the living dead
Authors: Hubbard Phil
Published: January 2013

This response disputes the notion that geography has a collective amnesia about the contributions of its founding figures. Recent work in the discipline has indeed done much to explore the situated influence of key thinkers, encouraging re-engagement with both acknowledged ‘classics’ and lesser known texts. This response nonetheless concurs that geography could do more to explore the processes by which certain texts become identified as key influences on the trajectories of academic thought, particularly in an Anglo-American academy that remains dominated by linguistic and disciplinary traditions which can easily overlook the contributions of non-Anglophone authors and those who practised geography outside geography departments.
P110α-mediated constitutive PI3K signaling limits the efficacy of p110δ-selective inhibition in mantle cell lymphoma, particularly with multiple relapse
Authors: Iyengar Sunil , Clear Andrew , Bödör Csaba , Maharaj Lenushka , Lee Abigail , Calaminici Maria , Matthews Janet , Iqbal Sameena , Auer Rebecca , Gribben John , Joel Simon
Published: January 2013

Key Points

The increased expression of PI3K p110α in mantle cell lymphoma, particularly at relapse, suggests a role for p110α in disease progression. A high PIK3CA/PIK3CD ratio identifies patients unlikely to respond to p110δ inhibitors and supports use of dual p110α/p110δ inhibitors in MCL.
Some geometric properties of the metric space "Equation missing"
Authors: Çinar Muhammed , Karakaş Murat , Et Mikail
Published: January 2013

In this study, we consider the space

V
[
λ
,
p
]

with an invariant metric. Then, we examine some geometric properties of the linear metric space

V
[
λ
,
p
]

such as property (β), property (H) and k-NUC property.

MSC:40A05, 46A45, 46B20.
Detecting recurrent gene mutation in interaction network context using multi-scale graph diffusion
Authors: Babaei Sepideh , Hulsman Marc , Reinders Marcel , Ridder Jeroen de
Published: January 2013

Background

Delineating the molecular drivers of cancer, i.e. determining cancer genes and the pathways which they deregulate, is an important challenge in cancer research. In this study, we aim to identify pathways of frequently mutated genes by exploiting their network neighborhood encoded in the protein-protein interaction network. To this end, we introduce a multi-scale diffusion kernel and apply it to a large collection of murine retroviral insertional mutagenesis data. The diffusion strength plays the role of scale parameter, determining the size of the network neighborhood that is taken into account. As a result, in addition to detecting genes with frequent mutations in their genomic vicinity, we find genes that harbor frequent mutations in their interaction network context.

Results

We identify densely connected components of known and putatively novel cancer genes and demonstrate that they are strongly enriched for cancer related pathways across the diffusion scales. Moreover, the mutations in the clusters exhibit a significant pattern of mutual exclusion, supporting the conjecture that such genes are functionally linked. Using multi-scale diffusion kernel, various infrequently mutated genes are found to harbor significant numbers of mutations in their interaction network neighborhood. Many of them are well-known cancer genes.

Conclusions

The results demonstrate the importance of defining recurrent mutations while taking into account the interaction network context. Importantly, the putative cancer genes and networks detected in this study are found to be significant at different diffusion scales, confirming the necessity of a multi-scale analysis.
Fabrication of low-temperature solid oxide fuel cells with a nanothin protective layer by atomic layer deposition
Authors: Ji Sanghoon , Chang Ikwhang , Lee Yoon Ho , Park Joonho , Paek Jun Yeol , Lee Min Hwan , Cha Suk Won
Published: January 2013

Anode aluminum oxide-supported thin-film fuel cells having a sub-500-nm-thick bilayered electrolyte comprising a gadolinium-doped ceria (GDC) layer and an yttria-stabilized zirconia (YSZ) layer were fabricated and electrochemically characterized in order to investigate the effect of the YSZ protective layer. The highly dense and thin YSZ layer acted as a blockage against electron and oxygen permeation between the anode and GDC electrolyte. Dense GDC and YSZ thin films were fabricated using radio frequency sputtering and atomic layer deposition techniques, respectively. The resulting bilayered thin-film fuel cell generated a significantly higher open circuit voltage of approximately 1.07 V compared with a thin-film fuel cell with a single-layered GDC electrolyte (approximately 0.3 V).
Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth
Authors: Griffiths Beatrice , Lewis Caroline A , Bensaad Karim , Ros Susana , Zhang Qifeng , Ferber Emma C , Konisti Sofia , Peck Barrie , Miess Heike , East Philip , Wakelam Michael , Harris Adrian L , Schulze Almut
Published: January 2013

Background

Regulation of lipid metabolism via activation of sterol regulatory element binding proteins (SREBPs) has emerged as an important function of the Akt/mTORC1 signaling axis. Although the contribution of dysregulated Akt/mTORC1 signaling to cancer has been investigated extensively and altered lipid metabolism is observed in many tumors, the exact role of SREBPs in the control of biosynthetic processes required for Akt-dependent cell growth and their contribution to tumorigenesis remains unclear.

Results

We first investigated the effects of loss of SREBP function in non-transformed cells. Combined ablation of SREBP1 and SREBP2 by siRNA-mediated gene silencing or chemical inhibition of SREBP activation induced endoplasmic reticulum (ER)-stress and engaged the unfolded protein response (UPR) pathway, specifically under lipoprotein-deplete conditions in human retinal pigment epithelial cells. Induction of ER-stress led to inhibition of protein synthesis through increased phosphorylation of eIF2α. This demonstrates for the first time the importance of SREBP in the coordination of lipid and protein biosynthesis, two processes that are essential for cell growth and proliferation. SREBP ablation caused major changes in lipid composition characterized by a loss of mono- and poly-unsaturated lipids and induced accumulation of reactive oxygen species (ROS) and apoptosis. Alterations in lipid composition and increased ROS levels, rather than overall changes to lipid synthesis rate, were required for ER-stress induction.

Next, we analyzed the effect of SREBP ablation in a panel of cancer cell lines. Importantly, induction of apoptosis following SREBP depletion was restricted to lipoprotein-deplete conditions. U87 glioblastoma cells were highly susceptible to silencing of either SREBP isoform, and apoptosis induced by SREBP1 depletion in these cells was rescued by antioxidants or by restoring the levels of mono-unsaturated fatty acids. Moreover, silencing of SREBP1 induced ER-stress in U87 cells in lipoprotein-deplete conditions and prevented tumor growth in a xenograft model.

Conclusions

Taken together, these results demonstrate that regulation of lipid composition by SREBP is essential to maintain the balance between protein and lipid biosynthesis downstream of Akt and to prevent resultant ER-stress and cell death. Regulation of lipid metabolism by the Akt/mTORC1 signaling axis is required for the growth and survival of cancer cells.
Anti-cyclic citrullinated peptide antibody titer predicts time to rheumatoid arthritis onset in patients with undifferentiated arthritis: results from a 2-year prospective study
Authors: Bizzaro Nicola , Bartoloni Elena , Morozzi Gabriella , Manganelli Stefania , Riccieri Valeria , Sabatini Paola , Filippini Matteo , Tampoia Marilina , Afeltra Antonella , Sebastiani Giandomenico , Alpini Claudia , Bini Vittorio , Bistoni Onelia , Alunno Alessia , Gerli Roberto ,   the Forum Interdisciplinare per la Ricerca nelle Malattie Autoimmuni (FIRMA Group)
Published: January 2013

Introduction

The diagnostic, predictive and prognostic role of anti-cyclic citrullinated peptide (CCP) antibodies in rheumatoid arthritis (RA) patients is widely accepted. Moreover, detection of these antibodies in subjects presenting with undifferentiated arthritis (UA) is associated with a significant risk to develop the disease. On the other hand, clinical and prognostic significance of evaluating anti-CCP levels in subjects with inflammatory arthritis at disease onset has not been fully clarified. The goal of this prospective study is to analyze the value and prognostic significance of anti-CCP titer quantification in UA subjects.

Methods

Serial anti-CCP assays were measured in 192 consecutive patients presenting with UA lasting less than 12 weeks. Clinical and serological data and arthritis outcome were evaluated every 6 months until two years of follow-up.

Results

Anti-CCP positivity, at both low and high titer, and arthritis of hand joints significantly predicted RA at two years, risk increasing in subjects with high anti-CCP titers at baseline. Moreover, time to RA diagnosis was shorter in patients with high anti-CCP2 titers at enrollment with respect to those with low antibody concentration.

Conclusions

Presence of anti-CCP antibodies, at both low and high concentration, is significantly associated with RA development in subjects with recent onset UA. However, time interval from the onset of the first symptoms to the fulfilment of the classification criteria appears to be directly related to the initial anti-CCP level.
Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus
Authors: Rullo Ornella J , Woo Jennifer MP , Parsa Miriam F , Hoftman Alice DC , Maranian Paul , Elashoff David A , Niewold Timothy B , Grossman Jennifer M , Hahn Bevra H , McMahon Maureen , McCurdy Deborah K , Tsao Betty P
Published: January 2013

Introduction

Osteopontin (OPN) has been implicated as a mediator of Th17 regulation via type I interferon (IFN) receptor signaling and in macrophage activity at sites of tissue repair. This study assessed whether increased circulating plasma OPN (cOPN) precedes development of organ damage in pediatric systemic lupus erythematosus (pSLE) and compared it to circulating plasma neutrophil gelatinase-associated lipocalin (cNGAL), a predictor of increased SLE disease activity.

Methods

cOPN and cNGAL were measured in prospectively followed pSLE (n = 42) and adult SLE (aSLE; n = 23) patients and age-matched controls. Time-adjusted cumulative disease activity and disease damage were respectively assessed using adjusted-mean SLE disease activity index (SLEDAI) (AMS) and SLICC/ACR damage index (SDI).

Results

Compared to controls, elevated cOPN and cNGAL were observed in pSLE and aSLE. cNGAL preceded worsening SLEDAI by 3-6 months (P = 0.04), but was not associated with increased 6-month AMS. High baseline cOPN, which was associated with high IFNalpha activity and expression of autoantibodies to nucleic acids, positively correlated with 6-month AMS (r = 0.51 and 0.52, P = 0.001 and 0.01 in pSLE and aSLE, respectively) and was associated with SDI increase at 12 months in pSLE (P = 0.001). Risk factors for change in SDI in pSLE were cOPN (OR 7.5, 95% CI [2.9-20], P = 0.03), but not cNGAL, cumulative prednisone, disease duration, immunosuppression use, gender or ancestry using univariate and multivariate logistic regression. The area under the curve (AUC) when generating the receiver-operating characteristic (ROC) of baseline cOPN sensitivity and specificity for the indication of SLE patients with an increase of SDI over a 12 month period is 0.543 (95% CI 0.347-0.738; positive predictive value 95% and negative predictive value 38%).

Conclusion

High circulating OPN levels preceded increased cumulative disease activity and organ damage in SLE patients, especially in pSLE, and its value as a predictor of poor outcome should be further validated in large longitudinal cohorts.
Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models
Authors: Issa Amine , Gill Jason W , Heideman Marinus R , Sahin Ozgur , Wiemann Stefan , Dey Julien H , Hynes Nancy E
Published: January 2013

Introduction

Targeting receptor tyrosine kinases (RTKs) with kinase inhibitors is a clinically validated anti-cancer approach. However, blocking one signaling pathway is often not sufficient to cause tumor regression and the effectiveness of individual inhibitors is often short-lived. As alterations in fibroblast growth factor receptor (FGFR) activity have been implicated in breast cancer, we examined in breast cancer models with autocrine FGFR activity the impact of targeting FGFRs in vivo with a selective kinase inhibitor in combination with an inhibitor of PI3K/mTOR or with a pan-ErbB inhibitor.

Methods

Using 4T1 or 67NR models of basal-like breast cancer, tumor growth was measured in mice treated with an FGFR inhibitor (dovitinib/TKI258), a PI3K/mTOR inhibitor (NVP-BEZ235) or a pan-ErbB inhibitor (AEE788) individually or in combination. To uncover mechanisms underlying inhibitor action, signaling pathway activity was examined in tumor lysates and transcriptome analysis carried out to identify pathways upregulated by FGFR inhibition. Anti-phosphotyrosine receptor antibody arrays (P-Tyr RTK) were also used to screen 4T1 tumors.

Results

The combination of dovitinib + NVP-BEZ235 causes tumor stasis and strong down-regulation of the FRS2/Erk and PI3K/Akt/mTOR signaling pathways. P-Tyr RTK arrays identified high levels of P-EGFR and P-ErbB2 in 4T1 tumors. Testing AEE788 in the tumor models revealed that the combination of dovitinib + AEE788 resulted in blockade of the PI3K/Akt/mTOR pathway, prolonged tumor stasis and in the 4T1 model, a significant decrease in lung metastasis. The results show that in vivo these breast cancer models become dependent upon co-activation of FGFR and ErbB receptors for PI3K pathway activity.

Conclusions

The work presented here shows that in the breast cancer models examined, the combination of dovitinib + NVP-BEZ235 or dovitinib + AEE788 results in strong inhibition of tumor growth and a block in metastatic spread. Only these combinations strongly down-regulate the FGFR/FRS2/Erk and PI3K/Akt/mTOR signaling pathways. The resultant decrease in mitosis and increase in apoptosis was consistently stronger in the dovitinib + AEE788 treatment-group, suggesting that targeting ErbB receptors has broader downstream effects compared to targeting only PI3K/mTOR. Considering that sub-classes of human breast tumors co-express ErbB receptors and FGFRs, these results have implications for targeted therapy.
Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a Phase III Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing the Addition of Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: BIG 02-98
Authors: Loi Sherene , Sirtaine Nicolas , Piette Fanny , Salgado Roberto , Viale Giuseppe , Van Eenoo Françoise , Rouas Ghizlane , Francis Prudence , Crown John P.A. , Hitre Erika , de Azambuja Evandro , Quinaux Emmanuel , Di Leo Angelo , Michiels Stefan , Piccart Martine J. , Sotiriou Christos
Published: January 2013

Purpose

Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT—in this case, anthracycline-only CT—in selected BC subtypes.

Patients and Methods

We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years.

Results

There was no significant prognostic association in the global nor estrogen receptor (ER) –positive/human epidermal growth factor receptor 2 (HER2) –negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018).

Conclusion

In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes.
Phase II Study of Gemcitabine, Carboplatin, and Bevacizumab in Patients With Advanced Unresectable or Metastatic Urothelial Cancer
Authors: Balar Arjun V. , Apolo Andrea B. , Ostrovnaya Irina , Mironov Svetlana , Iasonos Alexia , Trout Alisa , Regazzi Ashley M. , Garcia-Grossman Ilana R. , Gallagher David J. , Milowsky Matthew I. , Bajorin Dean F.
Published: January 2013

Purpose

Although gemcitabine and carboplatin (GCa) is a standard option for patients with advanced urothelial cancer (UC) who are ineligible for cisplatin, outcomes remain poor. This trial evaluated the efficacy and safety of bevacizumab with GCa in advanced UC.

Patients and Methods

Patients with Karnofsky performance status of 60% to 70%, creatinine clearance less than 60 mL/min, visceral metastasis, or solitary kidney were eligible and received a lead-in dose of bevacizumab 10 mg/kg followed 2 weeks later by gemcitabine 1,000 mg/m2 on days 1 and 8 and carboplatin at area under the [concentration-time] curve (AUC) 5.0 or 4.5 and bevacizumab 15 mg/kg on day 1 every 21 days for six cycles. Patients achieving at least stable disease (SD) continued bevacizumab 15 mg/kg every 21 days for 18 additional cycles. The study was powered to detect a 50% improvement in median progression-free survival (PFS) over a historical control.

Results

Fifty-one patients, median age 67 years (range, 42 to 83 years), were enrolled onto the study and were evaluable for toxicity. Twenty (39%) experienced grade 3 to 4 toxicity, and 10 (20%) had thromboembolic events (deep venous thrombosis or pulmonary embolism). Four received one or fewer cycles leaving 47 evaluable for outcomes. Twenty-three (49%) achieved response (three complete; 20 partial), and 11 had SD. Median PFS was 6.5 months (95% CI, 4.7 to 7.8 months); PFS was greater in the carboplatin AUC 5.0 group (P = .04). Median overall survival (OS) was 13.9 months.

Conclusion

The 95% one-sided lower confidence bound of 4.77 months for median PFS did not meet the predesignated PFS of more than 4.8 months considered sufficient for further study. Median OS was greater than expected. An ongoing phase III trial in patients who are eligible for therapy with cisplatin will define the role of bevacizumab in UC.
TBS (Trabecular Bone Score) and Diabetes-Related Fracture Risk
Authors: Leslie William D. , Aubry-Rozier Berengère , Lamy Olivier , Hans Didier ,   for the Manitoba Bone Density Program
Published: January 2013

Context:

Type 2 diabetes is associated with increased fracture risk but paradoxically greater bone mineral density (BMD). Trabecular bone score (TBS) is derived from the texture of the spine dual x-ray absorptiometry (DXA) image and is related to bone microarchitecture and fracture risk, providing information independent of BMD.

Objective:

This study evaluated the ability of lumbar spine TBS to account for increased fracture risk in diabetes.

Design and Setting:

We performed a retrospective cohort study using BMD results from a large clinical registry for the province of Manitoba, Canada.

Patients:

We included 29,407 women 50 years old and older with baseline DXA examinations, among whom 2356 had diagnosed diabetes.

Main Outcome Measures:

Lumbar spine TBS was derived for each spine DXA examination blinded to clinical parameters and outcomes. Health service records were assessed for incident nontraumatic major osteoporotic fractures (mean follow-up 4.7 years).

Results:

Diabetes was associated with higher BMD at all sites but lower lumbar spine TBS in unadjusted and adjusted models (all P < .001). The adjusted odds ratio (aOR) for a measurement in the lowest vs the highest tertile was less than 1 for BMD (all P < .001) but was increased for lumbar spine TBS [aOR 2.61, 95% confidence interval (CI) 2.30–2.97]. Major osteoporotic fractures were identified in 175 women (7.4%) with and 1493 (5.5%) without diabetes (P < .001). Lumbar spine TBS was a BMD-independent predictor of fracture and predicted fractures in those with diabetes (adjusted hazard ratio 1.27, 95% CI 1.10–1.46) and without diabetes (hazard ratio 1.31, 95% CI 1.24–1.38). The effect of diabetes on fracture was reduced when lumbar spine TBS was added to a prediction model but was paradoxically increased from adding BMD measurements.

Conclusions:

Lumbar spine TBS predicts osteoporotic fractures in those with diabetes, and captures a larger portion of the diabetes-associated fracture risk than BMD.
Tyrosyl Phosphorylated PAK1 Regulates Breast Cancer Cell Motility in Response to Prolactin through Filamin A
Authors: Hammer Alan , Rider Leah , Oladimeji Peter , Cook Leslie , Li Quanwen , Mattingly Raymond R. , Diakonova Maria
Published: January 2013

The p21-activated serine-threonine kinase (PAK1) is activated by small GTPase-dependent and -independent mechanisms and regulates cell motility. Both PAK1 and the hormone prolactin (PRL) have been implicated in breast cancer by numerous studies. We have previously shown that the PRL-activated tyrosine kinase JAK2 (Janus tyrosine kinase 2) phosphorylates PAK1 in vivo and identified tyrosines (Tyr) 153, 201, and 285 in the PAK1 molecule as sites of JAK2 tyrosyl phosphorylation. Here, we have used human breast cancer T47D cells stably overexpressing PAK1 wild type or PAK1 Y3F mutant in which Tyr(s) 153, 201, and 285 were mutated to phenylalanines to demonstrate that phosphorylation of these three tyrosines are required for maximal PRL-dependent ruffling. In addition, phosphorylation of these three tyrosines is required for increased migration of T47D cells in response to PRL as assessed by two independent motility assays. Finally, we show that PAK1 phosphorylates serine (Ser) 2152 of the actin-binding protein filamin A to a greater extent when PAK1 is tyrosyl phosphorylated by JAK2. Down-regulation of PAK1 or filamin A abolishes the effect of PRL on cell migration. Thus, our data presented here bring some insight into the mechanism of PRL-stimulated motility of breast cancer cells.
Competition and the Use of Foggy Pricing
Authors: Miravete Eugenio J
Published: January 2013

Firms engage in foggy pricing when the menu of tariff options aims at profiting from consumer mistakes. The analysis of this paper concludes that the transition from monopoly to competition in the early US cellular telephone industry does not generally foster the use of such deceptive strategies. I offer three alternative measures to account for the fogginess of the menu of options offered by cellular carriers. All results are robust to the existence of uncertainty regarding future consumption at the time of choosing a particular tariff option, as well as to consumers' heterogeneity with respect to cellular telephone usage. (JEL D03, L11, L12, L13, L96)
Green Service Practices: Performance Implications and the Role of Environmental Management Systems
Authors: Wong Christina W. Y. , Wong Chee Yew , Boon-itt Sakun
Published: January 2013

Research on the effects of environmental management has largely neglected the importance of green service practices and their impact on environmental protection and cost reduction. There is also little knowledge on how service-oriented firms may leverage their efforts in providing green services to achieve performance improvement through their existing environmental management system (EMS). Grounded in the natural resource-based view in conjunction with the contingency theory, we develop a model linking two key green service practices, green service delivery and green service support, to cost and environmental performance. The model considers the moderating role of the existing EMS that may affect the performance results of green service practices. This differs from previous studies that focus on the direct performance impact of EMS. Using survey data from 206 service firms, results indicate that green service delivery and support contributed to cost reduction and environmental performance. However, performance impact was strengthened by the adoption of uncertified EMS instead of certified EMS. This study contributes to the conceptual development of green service practices, the understanding of their impact on cost and environmental performance, and the role of EMS in supporting service-oriented firms to achieve such performance.
Prolonged Infusion Antibiotics for Suspected Gram-Negative Infections in the ICU: A Before-After Study
Authors: Arnold Heather M , Hollands James M , Skrupky Lee P , Smith Jennifer R , Juang Paul H , Hampton Nicholas B , McCormick Sandra , Reichley Richard M , Hoban Alex , Hoffmann Justin , Micek Scott T , Kollef Marin H
Published: January 2013

BACKGROUND:

β-Lactam antibiotics demonstrate time-dependent killing. Prolonged infusion of these agents is commonly performed to optimize the time the unbound concentration of an antibiotic remains greater than the minimum inhibitory concentration and decrease costs, despite limited evidence suggesting improved clinical results.

OBJECTIVE:

To determine whether prolonged infusion of β-lactam antibiotics improves outcomes in critically ill patients with suspected gram-negative infection.

METHODS:

We conducted a single-center, before-after, comparative effectiveness trial between January 2010 and January 2011 in the intensive care units at Barnes-Jewish Hospital, an urban teaching hospital affiliated with the Washington University School of Medicine in St. Louis, MO. Outcomes were compared between patients who received standardized dosing of meropenem, piperacillin-tazobactam, or cefepime as an intermittent infusion over 30 minutes (January 1, 2010, to June 30, 2010) and patients who received prolonged infusion over 3 hours (August 1, 2010, to January 31, 2011).

RESULTS:

A total of 503 patients (intermittent infusion, n = 242; prolonged infusion, n = 261) treated for gram-negative infection were included in the clinically evaluable population. Approximately 50% of patients in each group received cefepime and 20% received piperacillin-tazobactam. More patients in the intermittent infusion group received meropenem (35.5% vs 24.5%; p = 0.007). Baseline characteristics were similar between groups, with the exception of a greater occurrence of chronic obstructive pulmonary disease (COPD) in the intermittent infusion group. Treatment success rates in the clinically evaluable group were 56.6% for intermittent infusion and 51.0% for prolonged infusion (p = 0.204), and in the microbiologically evaluable population, 55.2% for intermittent infusion and 49.5% for prolonged infusion (p = 0.486). Fourteen-day, 30-day, and inhospital mortality rates in the clinically evaluable population for the intermittent and prolonged infusion groups were 13.2% versus 18.0% (p = 0.141), 23.6% versus 25.7% (p = 0.582), and 19.4% versus 23.0% (p = 0.329).

CONCLUSIONS:

Routine use of prolonged infusion of time-dependent antibiotics for the empiric treatment of gram-negative bacterial infections offers no advantage over intermittent infusion antibiotic therapy with regard to treatment success, mortality, or hospital length of stay. These results were confirmed after controlling for potential confounders in a multivariate analysis.
Price and Advertising Effectiveness over the Business Cycle
Authors: Van Heerde Harald J. , Gijsenberg Maarten J. , Dekimpe Marnik G. , Steenkamp Jan-Benedict E.M.
Published: January 2013

Firms are under increasing pressure to justify their marketing expenditures. This evolution toward greater accountability is reinforced in harsh economic times when marketing budgets are among the first to be reconsidered. To make such decisions, managers must know whether, and to what extent, marketing's effectiveness varies with the economic tide; however, surprisingly little research addresses this issue. Therefore, the authors conduct a systematic investigation of the business cycle's impact on the effectiveness of two important marketing instruments: price and advertising. To do so, they estimate time-varying short- and long-term advertising and price elasticities for 150 brands across 36 consumer packaged goods categories, using 18 years of monthly U.K. data from 1993 to 2010. The long-term price sensitivity tends to decrease during economic expansions, whereas long-term advertising elasticities increase. During contractions, the long-term own and cross price elasticities increase. Moreover, throughout the observation period, the short-term price elasticity became significantly stronger. Finally, patterns differ across categories and brands, which presents opportunities for firms that know how to ride the economic tide.
Service Innovativeness and Firm Value
Authors: Dotzel Thomas , Shankar Venkatesh , Berry Leonard L.
Published: January 2013

Service innovativeness, or the propensity to introduce service innovations to satisfy customers and improve firm value at acceptable risk, has become a critical organizational capability. Service innovations are enabled primarily by the Internet or people, corresponding to two types of innovativeness: e- and p-innovativeness. The authors examine the determinants of service innovativeness and its interrelationships with firm-level customer satisfaction, firm value, and firm risk and investigate the differences between e- and p-innovativeness in these relationships. They develop a conceptual model and estimate a system of equations on a unique panel data set of 1049 innovations over five years, using zero-inflated negative binomial regression and seemingly unrelated regression approaches. The results reveal important asymmetries between e- and p-innovativeness. Whereas e-innovativeness has a positive and significant direct effect on firm value, p-innovativeness has an overall significantly positive effect on firm value through its positive effect on customer satisfaction but only in human-dominated industries. Both e- and p-innovativeness are positively associated with idiosyncratic risk, but customer satisfaction partially mediates this relationship for p-innovativeness to lower this risk in human-dominated industries. The findings suggest that firms should nurture e-innovativeness in most industries and p-innovativeness in human-dominated industries.
The Upregulation of Translocator Protein (18 kDa) Promotes Recovery from Neuropathic Pain in Rats
Authors: Wei Xu-Hong , Wei Xiao , Chen Feng-Ying , Zang Ying , Xin Wen-Jun , Pang Rui-Ping , Chen Yuan , Wang Jun , Li Yong-Yong , Shen Kai-Feng , Zhou Li-Jun , Liu Xian-Guo
Published: January 2013

At present, effective drug for treatment of neuropathic pain is still lacking. Recent studies have shown that the ligands of translocator protein (TSPO, 18 kDa), a peripheral receptor for benzodiazepine, modulate inflammatory pain. Here, we report that TSPO was upregulated in astrocytes and microglia in the ipsilateral spinal dorsal horn of rats following L5 spinal nerve ligation (L5 SNL), lasting until the vanishing of the behavioral signs of neuropathic pain (∼50 d). Importantly, a single intrathecal injection of specific TSPO agonists Ro5-4864 or FGIN-1-27 at 7 and 21 d after L5 SNL depressed the established mechanical allodynia and thermal hyperalgesia dramatically, and the effect was abolished by pretreatment with AMG, a neurosteroid synthesis inhibitor. Mechanically, Ro5-4864 substantially inhibited spinal astrocytes but not microglia, and reduced the production of tumor necrosis factor-α (TNF-α)in vivoandin vitro. The anti-neuroinflammatory effect was also prevented by AMG. Interestingly, TSPO expression returned to control levels or decreased substantially, when neuropathic pain healed naturally or was reversed by Ro5-4864, suggesting that the role of TSPO upregulation might be to promote recovery from the neurological disorder. Finally, the neuropathic pain and the upregulation of TSPO by L5 SNL were prevented by pharmacological blockage of Toll-like receptor 4 (TLR4). These data suggested that TSPO might be a novel therapeutic target for the treatment of neuropathic pain.
Sustained Transcription of the Immediate Early GeneArcin the Dentate Gyrus after Spatial Exploration
Authors: Ramirez-Amaya Victor , Angulo-Perkins Arafat , Chawla Monica K. , Barnes Carol A. , Rosi Susanna
Published: January 2013

After spatial exploration in rats,ArcmRNA is expressed in ∼2% of dentate gyrus (DG) granule cells, and this proportion ofArc-positive neurons remains stable for ∼8 h. This long-term presence ofArcmRNA following behavior is not observed in hippocampal CA1 pyramidal cells. We report here that in rats ∼50% of granule cells with cytoplasmicArcmRNA, induced some hours previously during exploration, also showArcexpression in the nucleus. This suggests that recent transcription can occur long after the exploration behavior that elicited it. To confirm that the delayed nuclearArcexpression was indeed recent transcription, Actinomycin D was administered immediately after exploration. This treatment resulted in inhibition of recentArcexpression both when evaluated shortly after exploratory behavior as well as after longer time intervals. Together, these data demonstrate a unique kinetic profile forArctranscription in hippocampal granule neurons following behavior that is not observed in other cell types. Among a number of possibilities, this sustained transcription may provide a mechanism that ensures that the synaptic connection weights in the sparse population of granule cells recruited during a given behavioral event are able to be modified.
Indian Hedgehog b Function Is Required for the Specification of Oligodendrocyte Progenitor Cells in the Zebrafish CNS
Authors: Chung Ah-Young , Kim Suhyun , Kim Eunmi , Kim Dohyun , Jeong Inyoung , Cha Young Ryun , Bae Young-ki , Park Seung Woo , Lee Jehee , Park Hae-Chul
Published: January 2013

A subset of ventral spinal cord precursors, known as pMN precursor cells, initially generate motor neurons and then oligodendrocyte progenitor cells (OPCs), which migrate and differentiate as myelinating oligodendrocytes in the developing neural tube. The switch between motor neuron and oligodendrocyte production by the pMN neural precursors is an important step in building a functional nervous system. However, the precise mechanism that orchestrates the sequential generation of motor neurons and oligodendrocytes within the common population of pMN precursors is still unclear. The current study demonstrates that Indian Hedgehog b (Ihhb), previously known as Echidna Hedgehog, begins to be expressed in the floor plate cells of the ventral spinal cord at the time of OPC specification in zebrafish embryos. Ihhb loss-of-function analysis revealed that Ihhb function is required for OPC specification from pMN precursors by negatively regulating the proliferation of neural precursors. Finally, results showed that Sonic Hedgehog (Shh) could not replace Ihhb function in OPC specification, suggesting that Ihhb and Shh play separate roles in OPC specification. Altogether, data from the present study suggested a novel mechanism, mediated by Ihhb, for the sequential generation of motor neurons and oligodendrocytes from pMN precursors in the ventral spinal cord of zebrafish embryos.
Go Configure: The Mix of Purchasing Practices to Choose for Your Supply Base
Authors: Lindgreen Adam , Vanhamme Joëlle , van Raaij Erik M. , Johnston Wesley J.
Published: January 2013

Purchasing and supply management professionals recognize the value of aggressive transactional sourcing as well as of having cooperative relationships with suppliers. But what mix of transactional and relational purchasing are organizations using, and which should they use? A novel instrument is developed to measure organizations' use of transaction purchasing electronic purchasing interactive purchasing and network purchasing. Four mixes of practices are identified and labeled “transactional,” “interpersonal dyadic,” “interpersonal network,” and “integrative relational” configurations. Organizations using an integrative relational configuration generally outperform others. Irrespective of configuration, organizations use more interactive and network purchasing with suppliers of direct inputs but more transaction purchasing with suppliers of indirect inputs.
Administering ascorbic acid to rats undergoing ageing processes: effects on myosin-V immunoreactive myenteric neurons
Authors: Mello Sônia A. , Marese Angélica C.M. , Brancalhão Rose M.C. , Zanoni Jacqueline N. , Natali Maria Raquel M.
Published: January 2013

During the ageing process the enteric nervous system undergoes morphofunctional changes, such as enteric neurodegeneration. Neuronal death can be attributed to increase radicals free, and ascorbic acid (AA), known antioxidant, could minimize damage cause by oxidative stress. The objective of this study is to analyse the behaviour of morphoquantative myenteric neurons in the duodenum of adult Wistar rats with aged 90 (C90), 345 (E345) and 428 (E428) days, as well as animals of the same age who received ascorbic acid supplementation for 120 days (EA345 and EA428). Whole-mount preparations of muscle layer from the duodenum of the animals were immunostained by the method myosin V. 80 microscopic fields were quantified (14.8 mm2/animal) and measured 100 neuronal cell bodies per animal. During the aging process, there was a reduction in neuronal density in all animals groups, indicating that the effects of age were not attenuated with AA supplementation. The increase in the neuronal area of the cell bodies in 428-day-old animals proved the influence of age on this parameter. There was no observed a neuroprotective effect of AA (1 mL/g body weight) on the neuronal population myenteric myosin V immunoreactive.
Ética e educação: caminhos buberianos
Authors: Röhr Ferdinand
Published: January 2013

A relação entre ética e Educação está sendo abordada em três aspectos: a educação ética, compreendida como iniciativa educacional, que visa ajudar o educando a se tornar ser ético; a ética pedagógica, que trata da ética do agir do educador; e a ética da comunidade dos educadores, que se volta para questões éticas envolvidas na colaboração dos educadores em projetos pedagógicos. Escolheu-se, como objeto de análise, o pensamento filosófico e pedagógico de Martin Buber enquanto proposta que se distingue tanto do dogmatismo quanto do relativismo ético. Não encontramos em Buber imperativos do agir ético, mas uma descrição de atitudes que nos auxiliam a identificar o caminho para uma vida ética. Em seu livro "O Caminho do Homem segundo a Doutrina Hassídica", utiliza-se de lendas que expressam o caminho ético-existencial a ser tomado pelo homem. O intento da nossa interpretação é abstrair o conteúdo religioso-místico das lendas e apresentar os fundamentos antropológicos e filosóficos do seu pensamento sobre a ética.
Produção de saúde como afirmação de vida
Authors: Costa Márcio Luis , Bernardes Anita Guazzelli
Published: January 2013

Este artigo discute o conceito de saúde e doença como forma de contribuir para o debate e implementação do Sistema Único de Saúde (SUS). Explora-se as possibilidades de articulação entre a Psicologia Social e a Fenomenologia de Lévinas. A articulação permite percorrer o solo de construção da saúde como ausência de doença, para a saúde como forma de produção de diferença, de alteridade e vida. Este texto discute o conceito de saúde e doença no marco da episteme moderna; a partir disso, a reflexão encaminha-se para a discussão de novos marcadores, como o nome próprio, o simulacro e o tempo, identificados como outras formas de operar com a saúde desvinculada do conceito de doença, o que permite pensar o conceito de saúde articulado aos de produção e alteridade.
Qual é a sua atitude?: Narrativas de homens jovens universitários sobre os cuidados preventivos com a AIDS
Authors: Rebello Lúcia Emilia Figueiredo de Sousa , Gomes Romeu
Published: January 2013

Objetivou-se analisar 22 narrativas de homens jovens universitários, focalizando os sentidos atribuídos à sexualidade e prevenção da AIDS. As narrativas, coletadas em 2009, são parte do acervo da pesquisa Sexualidade Masculina e Cuidados de Saúde realizada (RJ). O marco teórico privilegia os conceitos de masculinidade hegemônica e roteiro sexual. O desenho metodológico é de estudo de narrativas. Partiu-se do pressuposto de que, para além da escolaridade, marcas identitárias masculinas hegemônicas influenciam os sentidos atribuídos e a adesão à prevenção da AIDS. Destaca-se a necessidade de revisão das ações em saúde sexual masculina levando-se em conta aspectos culturais associados à construção da identidade dos sujeitos e espaços de informação e atendimento que favoreçam atitude de prevenção.
Abortamento induzido: vivência de mulheres baianas
Authors: Pereira Vanessa do Nascimento , Oliveira Flávia Aelo de , Gomes Nadirlene Pereira , Couto Telmara Menezes , Paixão Gilvânia Patrícia do Nascimento
Published: January 2013

O abortamento representa grave problema de saúde pública, que envolve questões legais, econômicas, sociais e psicológicas. Estudo qualitativo que teve como objetivo identificar situações que interferem na decisão pelo aborto e os sentimentos diante do processo de abortar. O estudo foi realizado em uma Maternidade Pública, no Município de Salvador-BA, e os sujeitos foram constituídos por nove mulheres hospitalizadas por aborto provocado. Para a coleta de dados, utilizamos a entrevista acompanhada por um formulário semiestruturado. Foram considerados os aspectos éticos baseados na Resolução 196/96 do Conselho Nacional de Saúde. Para a análise das falas, usamos como referencial a técnica de análise de conteúdo de Bardin. A amostra caracterizou-se por mulheres adultas eminentemente negras; casadas/união estável; dependentes financeiramente do companheiro. Na análise dos discursos, surgiram dois temas: Motivação e Sentimentos. Dentre os motivos que levam ao aborto, encontram-se a dificuldade financeira, o número de filhos, a vivência de violência conjugal e a perda de sua autonomia. O processo de abortamento gera medo de morrer, tristeza e alívio. As mulheres vivenciam o aborto induzido, revelando um processo muito doloroso, desde o momento em que descobrem a gravidez, passando pela difícil decisão de interrompê-la. Quando não são ajudadas, essas mulheres perpetuam essa dor, vivendo dias de angústia e culpa. O exercício da escuta e do acolhimento devem estar presentes na vida dos profissionais de saúde, independentemente de suas opiniões com relação ao aborto, a fim de que a mulher possa expressar seus sentimentos, e então obter ajuda e encaminhamento adequados.