bluuebunny/crossref_metadata_2025 huggingface dataset:
Balanced versus chloride-rich solutions for fluid resuscitation in brain-injured patients: a randomised double-blind pilot study
Authors: Roquilly Antoine , Loutrel Olivier , Cinotti Raphael , Rosenczweig Elise , Flet Laurent , Mahe Pierre Joachim , Dumont Romain , Marie Chupin Anne , Peneau Catherine , Lejus Corinne , Blanloeil Yvonnick , Volteau Christelle , Asehnoune Karim
Published: April 2013

Introduction

We sought to investigate whether the use of balanced solutions reduces the incidence of hyperchloraemic acidosis without increasing the risk for intracranial hypertension in patients with severe brain injury.

Methods

We conducted a single-centre, two-arm, randomised, double-blind, pilot controlled trial in Nantes, France. Patients with severe traumatic brain injury (Glasgow Coma Scale score ≤8) or subarachnoid haemorrhage (World Federation of Neurosurgical Society grade III or higher) who were mechanically ventilated were randomised within the first 12 hours after brain injury to receive either isotonic balanced solutions (crystalloid and hydroxyethyl starch; balanced group) or isotonic sodium chloride solutions (crystalloid and hydroxyethyl starch; saline group) for 48 hours. The primary endpoint was the occurrence of hyperchloraemic metabolic acidosis within 48 hours.

Results

Forty-two patients were included, of whom one patient in each group was excluded (one consent withdrawn and one use of forbidden therapy). Nineteen patients (95%) in the saline group and thirteen (65%) in the balanced group presented with hyperchloraemic acidosis within the first 48 hours (hazard ratio = 0.28, 95% confidence interval [CI] = 0.11 to 0.70; P = 0.006). In the saline group, pH (P = .004) and strong ion deficit (P = 0.047) were lower and chloraemia was higher (P = 0.002) than in the balanced group. Intracranial pressure was not different between the study groups (mean difference 4 mmHg [-1;8]; P = 0.088). Seven patients (35%) in the saline group and eight (40%) in the balanced group developed intracranial hypertension (P = 0.744). Three patients (14%) in the saline group and five (25%) in the balanced group died (P = 0.387).

Conclusions

This study provides evidence that balanced solutions reduce the incidence of hyperchloraemic acidosis in brain-injured patients compared to saline solutions. Even if the study was not powered sufficiently for this endpoint, intracranial pressure did not appear different between groups.

Trial registration

EudraCT 2008-004153-15 andNCT00847977

The work in this trial was performed at Nantes University Hospital in Nantes, France.
Biological activity and magnetic resonance imaging of superparamagnetic iron oxide nanoparticles-labeled adipose-derived stem cells
Authors: Fan Jingjing , Tan Yanbin , Jie Liyong , Wu Xinying , Yu Risheng , Zhang Minming
Published: April 2013

Introduction

No comparative study of adipose-derived stem cells (ADSCs) and bone marrow mesenchymal stem cells (BMSCs) by using superparamagnetic iron oxide nanoparticles (SPIOs)-labeling and magnetic resonance imaging (MRI) has been performed.

Methods

We studied the biological activity and MRI of ADSCs by labeling them with SPIOs and comparing them with BMSCs. After incubating the cells in culture medium with different levels of SPIOs (control group: 0 μg/ml; Groups 1 to 3: 25, 50, and 100 μg/ml) for 24 hours, we compared ADSCs with BMSCs in terms of intracellular iron content, labeling efficiency, and cell viability. Stem cells in the culture medium containing 50 μg/ml SPIOs were induced into osteoblasts and fat cells. Adipogenic and osteogenic differentiation potentials were compared. R2* values of MRI in vitro were compared.

Results

The results showed that labeling efficiency was highest in Group 2. Intracellular iron content and R2* values increased with increasing concentrations of SPIOs, whereas cell viability decreased with increasing concentrations of SPIOs, and adipogenic and osteogenic differentiation potentials decreased. However, we found no significant difference between the two kinds of cells for any of these indexes.

Conclusions

ADSCs can be labeled and traced as easily as BMSCs in vitro. Given their abundance and higher proliferative capacity, as was previously shown, ADSCs may be better suited to stem cell therapy than are BMSCs.
Role of BAFF in Opsoclonus-Myoclonus syndrome, a bridge between cancer and autoimmunity
Authors: Raffaghello Lizzia , Fuhlhuber Verena , Bianchi Giovanna , Conte Massimo , Blaes Franz , Gambini Claudio , Pistoia Vito
Published: April 2013

OMS is a rare paraneoplastic disorder that affects adults and children. Pediatric OMS is often associated with NB, a common, solid tumor of childhood, derived from the sympathetic nervous system. The detection of autoantibodies and lymphocytic infiltration in NB patients led to advance an autoimmune hypothesis for the pathogenesis of OMS-related NB. BAFF is a potent modulator of B cell growth and survival upon interaction with its receptors BAFF-R and BCMA. The aim of this study was to investigate mechanism(s) involved in ectopic lymphoid neogenesis in OMS-associated NB. We investigated BAFF, BAFF-R, and BCMA expression in NB tumors associated or not with OMS. Furthermore, we evaluated BAFF expression and secretion in NB cell lines, treated or untreated with differentiating agents. Immunohistochemically, lymphocytes infiltrating NB tumors from patients, with or without OMS, expressed BAFF, BAFF-R, and BCMA, whereas neuroblasts expressed BAFF and BCMA but not BAFF-R. By flow cytometry, BAFF was found to be consistently expressed in NB cell lines. Similarly to the results obtained in tissue lesions, BCMA but not BAFF-R was detected on the surface of all NB cell lines under basal conditions. De novo synthesis of BAFF-R and up-regulation of BCMA were observed in NB cell lines upon treatment with IFN-γ or 13-cis retinoic acid. This study provides new insights in the mechanisms driving the neogenesis of lymphoid follicles and in the functional interactions between tumor and immune cells in OMS-associated NB.
Dual regulation of osteopontin production by TLR stimulation in dendritic cells
Authors: Salvi Valentina , Scutera Sara , Rossi Silvia , Zucca Mario , Alessandria Manuela , Greco Deborah , Bosisio Daniela , Sozzani Silvano , Musso Tiziana
Published: April 2013

OPN, a cytokine produced, among others, by DCs, is involved in inflammation and defense against pathogens. Here, we report that the activation of the MyD88 pathway by TLR2, TLR5, and TLR7/8 agonists or IL-1β induces high levels of OPN in human DCs. Conversely, LPS and Poly I:C, two TLR3 and TLR4 agonists that engage the TRIF pathway, were ineffective. TLR2 agonists were the strongest OPN inducers, and OPN production was highly stimulated by TLR2-triggering bacteria (Staphylococcus aureus) but not by TLR4-triggering Escherichia coli. Costimulation experiments revealed that TLR3 and TLR4 agonists, beyond being inactive by themselves, sharply limited TLR2-dependent OPN production by activating a TRIF-dependent inhibition of the MyD88-dependent OPN production. MyD88 silencing impaired TLR2-dependent OPN induction, whereas TRIF pathway blockage by chloroquine, dynasore, or TRIF knockdown prevented the TLR3/4 agonist-mediated inhibition, which was independent from the endogenous production of type I IFN, IL-29, IL-10, or TGF-β. LPS and Poly I:C inhibitory activity was associated with the release of a >10-kDa protein factor(s). We also demonstrated that the higher OPN levels produced by S. aureus-treated DCs compared with E. coli-treated DCs were responsible for a markedly increased production of IL-17 by CD4+ T cells. These results highlight the biological relevance of the differential OPN induction by TLR2 and TLR4 agonists and emphasize the importance of TLR cross-talk in OPN induction. This implies that OPN regulation by TLR signaling is critical in shaping inflammatory responses and may modulate IL-17 production in response to pathogens.
Identification of novel oligonucleotides from mitochondrial DNA that spontaneously induce plasmacytoid dendritic cell activation
Authors: Ries Moritz , Schuster Philipp , Thomann Sabrina , Donhauser Norbert , Vollmer Jörg , Schmidt Barbara
Published: April 2013

This study tested the hypothesis that mtDNA fragments carry immunostimulatory motifs that naturally induce immune activation by PDC. Genomic and mtDNA induced similar IFN-α production after transfection into PBMCs using the liposomal transfection reagent DOTAP. Shortening of mtDNA to CpG islands enhanced the immunostimulatory activity, based on the presence of unmethylated CpG DNA. Further fragmentation into mtODN, which exhibited similarities to published CpG ODN, resulted in a strong immunostimulatory activity in addition to PDC maturation and migration. The addition of the human cathelicidin LL-37 to CpG islands induced spontaneous PDC IFN-α production. Notably, one phosphodiester mtODN with a double-palindromic structure induced PDC IFN-α production in the absence of DOTAP. Flow cytometry, life-cell, and confocal imaging revealed attachment and spontaneous uptake into PDC, colocalizing, in part, with TLR9 in early endosomal vesicles. This process was accompanied by a moderate but significant PDC maturation in addition to B cell and NK cell activation (P<0.05). Altogether, our data indicate that fragmented mtDNA, which may be released as a consequence of apoptotic, necrotic, and necroptotic cell death, can act as a DAMP. For the first time, our study provides a mechanism how longer and shorter mtDNA fragments can be taken up naturally by the PDC and thus, may contribute to acute and chronic immune activation.
ROS production in phagocytes: why, when, and where?
Authors: Dupré-Crochet Sophie , Erard Marie , Nüβe Oliver
Published: April 2013

In the phagocytosis field, ROS production by the phagocyte NOX has been associated with pathogen killing for the last 50 years. Since the discovery of nonphagocyte NOX, numerous other roles for ROS production have been identified. Oxidative stress and ROS-mediated signaling have received much attention in recent years. Much lower concentrations of ROS may be required for signaling compared with microbial killing. Based on the discoveries in nonphagocytic cells, it became logical to look for ROS functions distinct from pathogen killing, even in phagocytes. ROS are now linked to various forms of cell death, to chemotaxis, and to numerous modifications of cellular processes, including the NOX itself. ROS functions are clearly concentration-dependent over a wide range of concentrations. How much is required for which function? Which species are required for how much time? Is ROS signaling only a side effect of bactericidal ROS production? One major obstacle to answer these questions is the difficulty of reliable quantitative ROS detection. Signal transduction often takes place on a subcellular scale over periods of seconds or minutes, so the detection methods need to provide appropriate time and space resolution. We present examples of local ROS production, decreased degradation, signaling events, and potentially ROS-sensitive functions. We attempt to illustrate the current limitations for quantitative spatiotemporal ROS detection and point out directions for ongoing development. Probes for localized ROS detection and for combined detection of ROS, together with protein localization or other cellular parameters, are constantly improved.
Mammographic Density Reduction Is a Prognostic Marker of Response to Adjuvant Tamoxifen Therapy in Postmenopausal Patients With Breast Cancer
Authors: Li Jingmei , Humphreys Keith , Eriksson Louise , Edgren Gustaf , Czene Kamila , Hall Per
Published: April 2013

Purpose

Tamoxifen treatment is associated with a reduction in mammographic density and an improved survival. However, the extent to which change in mammographic density during adjuvant tamoxifen therapy can be used to measure response to treatment is unknown.

Patients and Methods

Overall, 974 postmenopausal patients with breast cancer who had both a baseline and a follow-up mammogram were eligible for analysis. On the basis of treatment information abstracted from medical records, 474 patients received tamoxifen treatment and 500 did not. Mammographic density was measured by using an automated thresholding method and expressed as absolute dense area. Change in mammographic density was calculated as percentage change from baseline. Survival analysis was performed by using delayed-entry Cox proportional hazards regression models, with death as a result of breast cancer as the end point. Analyses were adjusted for a range of patient and tumor characteristics.

Results

During a 15-year follow-up, 121 patients (12.4%) died from breast cancer. Women treated with tamoxifen who experienced a relative density reduction of more than 20% between baseline and first follow-up mammogram had a reduced risk of death as a result of breast cancer of 50% (hazard ratio, 0.50; 95% CI, 0.27 to 0.93) compared with women with stable mammographic density. In the no-tamoxifen group, there was no statistically significant association between mammographic density change and survival. The survival advantage was not observed when absolute dense areas at baseline or follow-up were evaluated separately.

Conclusion

A decrease in mammographic density after breast cancer diagnosis appears to serve as a prognostic marker for improved long-term survival in patients receiving adjuvant tamoxifen, and these data should be externally validated.
Survival of Patients With Peripheral T-Cell Lymphoma After First Relapse or Progression: Spectrum of Disease and Rare Long-Term Survivors
Authors: Mak Vivien , Hamm Jeremey , Chhanabhai Mukesh , Shenkier Tamara , Klasa Richard , Sehn Laurie H. , Villa Diego , Gascoyne Randy D. , Connors Joseph M. , Savage Kerry J.
Published: April 2013

Introduction

A number of novel therapies are under investigation in relapsed or refractory peripheral T-cell lymphoma (PTCL); however, their relative impact on outcome is unknown. We examined the survival of patients with PTCL after relapse or progression in the absence of hematopoietic stem-cell transplantation and explored factors influencing survival. The three most common subtypes encountered in North America were evaluated: PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large-cell lymphoma (ALCL; anaplastic lymphoma kinase [ALK] positive and ALK negative.

Patients and Methods

After exclusions, 153 patients were analyzed (PTCL-NOS, n = 79 [52%]; AITL, n = 38 [25%]; ALK-positive ALCL, n = 11 [7%]; ALK-negative ALCL, n = 27 [16%; including ALK status unknown, n = 1]).

Results

Median time from initial diagnosis to relapse or progression after primary therapy was 6.7 months, and median age at relapse was 66 years (ALK-positive ALCL, 39 years). Median overall survival (OS) and median progression-free survival (PFS) after relapse or progression (second PFS) were 5.5 and 3.1 months, respectively, and were only marginally better in patients who received chemotherapy at relapse (n = 89 [58%]; 6.5 and 3.7 months, respectively). Patients with good performance status (PS) of 0 or 1 (n = 47) at relapse who received chemotherapy had a more favorable OS (P < .001; median OS, 13.7 months) and PFS (P = .006; median second PFS, 5.0 months), which remained significant in multivariate analysis (OS: hazard ratio [HR], 2.09; P = .002; second PFS: HR, 1.66; P = .030).

Conclusion

Most patients with relapsed or refractory PTCL have poor outcomes with short survival. Select patients with good PS have more favorable outcomes with standard chemotherapy.
Lung Cancer That Harbors an HER2 Mutation: Epidemiologic Characteristics and Therapeutic Perspectives
Authors: Mazières Julien , Peters Solange , Lepage Benoit , Cortot Alexis B. , Barlesi Fabrice , Beau-Faller Michéle , Besse Benjamin , Blons Hélène , Mansuet-Lupo Audrey , Urban Thierry , Moro-Sibilot Denis , Dansin Eric , Chouaid Christos , Wislez Marie , Diebold Joachim , Felip Enriqueta , Rouquette Isabelle , Milia Julie D. , Gautschi Oliver
Published: April 2013

Purpose

HER2 mutations are identified in approximately 2%of non–small-cell lung cancers (NSCLC). There are few data available that describe the clinical course of patients with HER2-mutated NSCLC.

Patients and Methods

We retrospectively identified 65 NSCLC, diagnosed with a HER2 in-frame insertion in exon 20. We collected clinicopathologic characteristics, patients' outcomes, and treatments.

Results

HER2 mutation was identified in 65 (1.7%) of 3,800 patients tested and was almost an exclusive driver, except for one single case with a concomitant KRAS mutation. Our population presented with a median age of 60 years (range, 31 to 86 years), a high proportion of women (45 women v 20 men; 69%), and a high proportion of never-smokers (n= 34; 52.3%). All tumors were adenocarcinomas and 50% were stage IV at diagnosis. For these latter cases, 22 anti–human epidermal growth factor receptor 2 (HER2) treatments were administered after conventional chemotherapy in 16 patients. Subsequently, four patients experienced progressive disease, seven experienced disease stabilizations, and 11 experienced partial responses (overall response rate, 50%; disease control rate [DCR], 82%). Specifically, we observed a DCR of 93% for trastuzumab-based therapies (n = 15) and a DCR of 100% for afatinib (n = 3) but no response to other HER2-targeted drugs (n = 3). Progression-free survival for patients with HER2 therapies was 5.1 months. Median survival was of 89.6 and 22.9 months for early-stage and stage IV patients, respectively.

Conclusion

This study, the largest to date dedicated to HER2-mutated NSCLC, reinforces the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.
Prognosis of Women With Primary Breast Cancer Diagnosed During Pregnancy: Results From an International Collaborative Study
Authors: Amant Frédéric , von Minckwitz Gunter , Han Sileny N. , Bontenbal Marijke , Ring Alistair E. , Giermek Jerzy , Wildiers Hans , Fehm Tanja , Linn Sabine C. , Schlehe Bettina , Neven Patrick , Westenend Pieter J. , Müller Volkmar , Van Calsteren Kristel , Rack Brigitte , Nekljudova Valentina , Harbeck Nadia , Untch Michael , Witteveen Petronella O. , Schwedler Kathrin , Thomssen Christoph , Van Calster Ben , Loibl Sibylle
Published: April 2013

Purpose

We aimed to determine the prognosis of patients with breast cancer diagnosed during pregnancy (BCP).

Patients and Methods

In this cohort study, a multicentric registry of patients with BCP (from Cancer in Pregnancy, Leuven, Belgium, and GBG 29/BIG 02-03) compiled pro- and retrospectively between 2003 and 2011 was compared with patients who did not have associated pregnancies, using an age limit of 45 years. Patients with a diagnosis postpartum were excluded. The main analysis was performed using Cox proportional hazards regression of disease-free survival (DFS) and overall survival (OS) on exposure (pregnant or not), adjusting for age, stage, grade, hormone receptor status, human epidermal growth factor 2 status, histology, type of chemotherapy, use of trastuzumab, radiotherapy, and hormone therapy.

Results

The registry contained 447 women with BCP, mainly originating from Germany and Belgium, of whom 311 (69.6%) were eligible for analysis. The nonpregnant group consisted of 865 women. Median age was 33 years for the pregnant and 41 years for the nonpregnant patients. Median follow-up was 61 months. The hazard ratio of pregnancy was 1.34 (95% CI, 0.93 to 1.91; P = .14) for DFS and 1.19 (95% CI, 0.73 to 1.93; P = .51) for OS. Cox regression estimated that the 5-year DFS rate for pregnant patients would have increased from 65% to 71% if these patients had not been pregnant. Likewise, the 5-year OS rate would have increased from 78% to 81%.

Conclusion

The results show similar OS for patients diagnosed with BCP compared with nonpregnant patients. This information is important when patients are counseled and supports the option to start treatment with continuation of pregnancy.
Receipt of Psychosocial Care Among Cancer Survivors in the United States
Authors: Forsythe Laura P. , Kent Erin E. , Weaver Kathryn E. , Buchanan Natasha , Hawkins Nikki A. , Rodriguez Juan L. , Ryerson A. Blythe , Rowland Julia H.
Published: April 2013

Purpose

Given the importance of psychosocial care for cancer survivors, this study used population-based data to characterize survivors who reported a discussion with health care provider(s) about the psychosocial effects of cancer and who reported using professional counseling or support groups (PCSG) and tested associations between receipt of psychosocial care and satisfaction with care.

Patients and Methods

We examined survivors of adult cancers from the 2010 National Health Interview Survey (N = 1,777). Multivariable logistic regression models examined factors associated with receipt of and satisfaction with psychosocial care.

Results

Most survivors (55.1%) reported neither provider discussions nor use of PCSG; 31.4% reported provider discussion only, 4.4% reported use of PCSG only, and 8.9% reported both. Non-Hispanic blacks (v non-Hispanic whites), married survivors, survivors of breast cancer (v prostate or less prevalent cancers), those treated with chemotherapy, and survivors reporting past research study/clinical trial participation were more likely to report provider discussion(s) (P < .01). Hispanics (v non-Hispanic whites), survivors age 40 to 49 years (v ≤ 39 years), survivors of breast cancer (v melanoma or less prevalent cancers), those diagnosed ≤ 1 year ago (v > 5 years ago), survivors treated with radiation, and past research participants were more likely to report use of PCSG (P < .05). Survivors reporting any psychosocial care were more likely to be “very satisfied” with how their needs were met (P < .001).

Conclusion

Many survivors do not report a discussion with providers about the psychosocial effects of cancer, which reflects a missed opportunity to connect survivors to psychosocial services. These data can benchmark the success of efforts to improve access to cancer-related psychosocial care.
17β-Estradiol Rapidly Attenuates P2X3 Receptor-Mediated Peripheral Pain Signal Transduction via ERα and GPR30
Authors: Lu Yi , Jiang Qian , Yu Lihua , Lu Zhan-ying , Meng Shuang-ping , Su Dingfeng , Burnstock Geoffrey , Ma Bei
Published: April 2013

Estrogen has been reported to affect pain perception, although the underlying mechanisms remain unclear. In this investigation, pain behavior testing, patch clamp recording, and immunohistochemistry were used on rats and transgenic mice to determine which estrogen receptors (ERs) and the related signaling pathway are involved in the rapid modulation of estrogen on P2X3 receptor-mediated events. The results showed that 17β-estradiol (E2) rapidly inhibited pain induced by α,β-methylene ATP (α,β-me-ATP), a P2X1 and P2X3 receptor agonist in ovariectomized rats and normal rats in diestrus. The ERα agonist 4,49,499-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) and G protein-coupled receptor 30 (GPR30) agonist G-1 mimicked the estrogen effect, whereas the ERβ agonist diarylpropionitrile (DPN) had no effect. In cultured rat dorsal root ganglion (DRG) neurons, PPT and G-1 but not DPN significantly attenuated α,β-me-ATP–mediated currents, with the dose-response curve of these currents shifted to the right. The inhibitory effect of E2 on P2X3 currents was blocked by G-15, a selective antagonist to the GPR30 estrogen receptor. E2 lacked this effect in DRG neurons from ERα-knockout mice but partly remained in those from ERβ-knockout mice. The P2X3 and GPR30 receptors were coexpressed in the rat DRG neurons. Furthermore, the ERK1/2 inhibitor U0126 reversed the inhibitory effect of E2 on α,β-me-ATP–induced pain and of PPT or G-1 on P2X3 receptor-mediated currents. The cAMP-protein kinase A (PKA) agonist forskolin, but not the PKC agonist phorbol-12-myristate-13-acetate (PMA), mimicked the estrogen-inhibitory effect on P2X3 receptor currents, which was blocked by another ERK1/2 inhibitor, PD98059. These results suggest that estrogen regulates P2X3-mediated peripheral pain by acting on ERα and GPR30 receptors expressed in primary afferent neurons, which probably involves the intracellular cAMP-PKA-ERK1/2 pathway.
Bernard de Gordon (f1. 1270–1330): medieval physician and teacher
Authors: Pearn John
Published: April 2013

The Montpellier physician Bernard de Gordon flourished in the late Middle Ages in the era when university education first evolved in the training of European physicians. Fragmentary details of his life and medical influence are known from seven books, particularly his extensive (163 chapters) text Lilium Medicine and from Chaucer's reference to him in the Canterbury Tales. Chaucer lists Bernard de Gordon as one whose writings were part of the core curriculum of the best-trained European doctors of medieval Europe. Bernard de Gordon was one of that small group of medieval physicians who reverently followed Galenic lore which had endured for a thousand years yet who began to challenge its details and to experiment clinically with new methods of treatment. In his writings, Bernard de Gordon made the first reference to spectacles and to the hernial truss. His writings also contained detailed desiderata for the ethical best practice of medicine of his day, extending the principles of both Hippocrates and Haly ibn Abbas. Unlike many of the surviving writings of other medieval medical teachers, his texts have within them a tone of humility and acknowledged fallibility. Bernard de Gordon holds a small but significant place in the evolving pre-Renaissance chronology of medical professionalism.
Rosemary Biggs MD FRCP (1912–2001) and Katharine Dormandy MD FRCP (1926–78): from laboratory to treatment and care of people with haemophilia
Authors: Hawgood Barbara J
Published: April 2013

In 1977 the Haemophilia Society presented the first RG Macfarlane Award to Katharine Dormandy for her outstanding contribution towards the social and physical wellbeing of people with haemophilia and related disorders. In 1978 Rosemary Biggs was the second recipient of the Award given for similarly outstanding personal contributions. Dr Biggs worked under Dr RG Macfarlane at Oxford and in 1952 devised a laboratory test that identified two forms of haemophilia. Macfarlane realized the potential for replacement therapy which subsequently transformed the lives of haemophiliacs in the UK. Dr Biggs was director of the Oxford Haemophilia Centre (1967–77) and instrumental in documenting the increase in incidence of jaundice with the import of concentrates for infusion. Katharine Dormandy, Consultant Haematologist at the Royal Free Hospital in London, set up one of the country's foremost haemophilia centres, pioneered home treatment for haemophilic children and with Rosemary Biggs was involved in the social and educational welfare of affected families.
RNA recognition by the DNA end-binding Ku heterodimer
Authors: Dalby Andrew B. , Goodrich Karen J. , Pfingsten Jennifer S. , Cech Thomas R.
Published: April 2013

Most nucleic acid-binding proteins selectively bind either DNA or RNA, but not both nucleic acids. The Saccharomyces cerevisiae Ku heterodimer is unusual in that it has two very different biologically relevant binding modes: (1) Ku is a sequence-nonspecific double-stranded DNA end-binding protein with prominent roles in nonhomologous end-joining and telomeric capping, and (2) Ku associates with a specific stem–loop of TLC1, the RNA subunit of budding yeast telomerase, and is necessary for proper nuclear localization of this ribonucleoprotein enzyme. TLC1 RNA-binding and dsDNA-binding are mutually exclusive, so they may be mediated by the same site on Ku. Although dsDNA binding by Ku is well studied, much less is known about what features of an RNA hairpin enable specific recognition by Ku. To address this question, we localized the Ku-binding site of the TLC1 hairpin with single-nucleotide resolution using phosphorothioate footprinting, used chemical modification to identify an unpredicted motif within the hairpin secondary structure, and carried out mutagenesis of the stem–loop to ascertain the critical elements within the RNA that permit Ku binding. Finally, we provide evidence that the Ku-binding site is present in additional budding yeast telomerase RNAs and discuss the possibility that RNA binding is a conserved function of the Ku heterodimer.
Company as a system of institutions microeconomic
Authors: Кукушкин  , Kukushkin Sergey
Published: April 2013

The company, being a component of a complex institutional environment itself acts as a complex system of microinstitutions. Microinstitutions are classified as: effectiveness, limitations, results, development, etc. Microinstitutions have a certain set of properties.
Do Customers Learn from Experience? Evidence from Retail Banking
Authors: Ater Itai , Landsman Vardit
Published: April 2013

We study customers' adoption and subsequent switching decisions with regard to a menu of three-part tariff plans offered by a commercial bank. Using a rich panel data set covering 70,510 fee-based checking accounts over 30 months, before and after the introduction of the plans, we find that most customers adopt non-cost-minimizing plans, preferring plans with large monthly allowances and high fixed payments. Furthermore, after adoption, customers who exceed their allowances and consequently pay overage fees are more likely to switch to plans with larger allowances than customers who do not experience such fees. Notably, after switching, these overage-paying customers pay higher monthly payments than before. In contrast, switching customers who did not pay overage payments before switching pay less after switching. Our findings, unlike those of previous research on experience-based learning, suggest that the behavior of experienced customers does not converge to the predictions of neoclassical models. We propose that “overage aversion,” which is closely related to loss aversion and mental accounting, is the most plausible explanation for our findings.

This paper was accepted by John List, behavioral economics.
Do Job Seekers Benefit from Contacts? A Direct Test with Contemporaneous Searches
Authors: Obukhova Elena , Lan George
Published: April 2013

Although it is intuitively plausible that a job seeker benefits by using contacts in her job search, the literature is plagued by theoretical disagreements and inconclusive empirical evidence. Single-firm studies consistently find that job seekers applying through referrals achieve better labor-market outcomes than job seekers applying without referrals, but the evidence from job-seeker studies is mixed. To solve this puzzle, we clarify the distinction between having social capital and using contacts as a search method. We present theoretical reasons to suggest that the lack of an association between a job seeker's social capital and whether or not she uses social networks to search for a job should not be taken to imply that job seekers who use social networks to search for jobs do not benefit from using contacts. We exploit a strategic research setting, the school-to-work transition of 291 university graduates who engaged in 3,112 contemporaneous job searches, to show that although a job seeker's social capital may not affect whether or not she uses contacts to search for a job, using contacts as a job-search method does improve her job-search outcomes. We conclude by discussing the implications of our findings for the literature on job search and social networks.

This paper was accepted by Jesper Sørensen, organizations.
Tempus Fugit: Time Pressure in Risky Decisions
Authors: Kocher Martin G. , Pahlke Julius , Trautmann Stefan T.
Published: April 2013

We study the effects of time pressure on risky decisions for pure gain prospects, pure loss prospects, and mixed prospects involving both gains and losses. In two experiments we find that time pressure has no effect on risk attitudes for gains, but increases risk aversion for losses. For mixed prospects, subjects become simultaneously more loss averse and more gain seeking under time pressure, depending on the framing of the prospects. The results suggest the importance of aspiration levels, and thus the overall probability to break even, under time pressure. We discuss the implications of our findings for decision-making situations that involve time pressure.

This paper was accepted by Uri Gneezy, behavioral economics.
Hypothalamic Inhibition of Acetyl-CoA Carboxylase Stimulates Hepatic Counter-Regulatory Response Independent of AMPK Activation in Rats
Authors: Santos Gustavo A. , Pereira Vinícius D. , Roman Erika A. F. R. , Ignacio-Souza Leticia , Vitorino Daniele C. , de Moura Rodrigo Ferreira , Razolli Daniela S. , Torsoni Adriana S. , Velloso Licio A. , Torsoni Marcio A.
Published: April 2013

Background

Hypothalamic AMPK acts as a cell energy sensor and can modulate food intake, glucose homeostasis, and fatty acid biosynthesis. Intrahypothalamic fatty acid injection is known to suppress liver glucose production, mainly by activation of hypothalamic ATP-sensitive potassium (K(ATP)) channels. Since all models employed seem to involve malonyl-CoA biosynthesis, we hypothesized that acetyl-CoA carboxylase can modulate the counter-regulatory response independent of nutrient availability.

Methodology/Principal Findings

In this study employing immunoblot, real-time PCR, ELISA, and biochemical measurements, we showed that reduction of the hypothalamic expression of acetyl-CoA carboxylase by antisense oligonucleotide after intraventricular injection increased food intake and NPY mRNA, and diminished the expression of CART, CRH, and TRH mRNA. Additionally, as in fasted rats, in antisense oligonucleotide-treated rats, serum glucagon and ketone bodies increased, while the levels of serum insulin and hepatic glycogen diminished. The reduction of hypothalamic acetyl-CoA carboxylase also increased PEPCK expression, AMPK phosphorylation, and glucose production in the liver. Interestingly, these effects were observed without modification of hypothalamic AMPK phosphorylation.

Conclusion/Significance

Hypothalamic ACC inhibition can activate hepatic counter-regulatory response independent of hypothalamic AMPK activation.
Ländliche jüdische Siedlungen und Niederlassungen in Aschkenas. Vom Hochmittelalter bis ins 16. Jahrhundert. Typologie, Struktur und Vernetzung
Authors: Barzen Rainer Josef
Published: April 2013

Research on Jewish settlement in the German lands during the high and later medieval periods has tended to focus on the lives of Jews in their urban communities. The present study aims at elucidating the history of medieval Jewish settlements from the perspective of the rural periphery. It shows that the incomplete picture of a predominantly urban Jewish population has to be complemented by a continuity of Jewish presence in rural contexts. Sources of mostly non-Jewish provenance can serve to delineate the spread of rural Jewish settlements, while the terminology used for them can be derived from medieval Hebrew documents. Internal Jewish sources also offer insights concerning the autonomy enjoyed by rural Jewish settlers and their dependence on the urban communities. The development of a rural Jewish presence is traced in light of the question whether there was any continuity with the early modern institution of territorial Jewries (
Jiddische Varietäten im Berlin des 19. Jahrhunderts: Die »Lebenserinnerungen« Aron Hirsch Heymanns
Authors: Schäfer Lea
Published: April 2013

Aron Hirsch Heymann ’s (1803–1880) biography is an invaluable source of information on the German Jewry of the 19
»Platzmachen für Gott« – Else Lasker-Schüler , Rabbiner Kurt Wilhelm und der religiöse Liberalismus in Palästina
Authors: Kohler George Y.
Published: April 2013

The article traces the involvement of the German-Jewish poetess Else Lasker-Schüler in the diverse activities of the only non-orthodox community in Jerusalem of the 1940s and its founding rabbi, Kurt Wilhelm – himself also a German immigrant. It further demonstrates how Rabbi Wilhelm attempted to transfer to Palestine the tenets of German Jewish liberalism: education, religious tolerance, humanism and meaningful religious services, and how the European Liberal Movement of Judaism supported this endeavour. In addition the essay shows how other prominent German Jewish immigrants like Martin Buber , Hugo Bergmann or Ernst Simon responded to Wilhelm’s liberalism by gathering around his Jerusalem community – and how, as a consequence, this group had a decisive influence on Else Lasker-Schüler ’s final years and works.
Globalization, Convergence, and the Transformation of International Production Networks in Electronics in East Asia
Authors: Ernst Dieter , Ravenhill John
Published: April 2013

Globalization is often said to lead to convergence among firm strategies. Significant differences existed in the organization of the production networks of Japanese and US firms in electronics in East Asia at the beginning of the 1990s. The sources of these differences lie in part in the relative newness of the export-orientation of Japanese companies, in weaknesses in Japanese corporate governance, in the geographical proximity of East Asian plants to Japan, and in the product mix of Japanese firms. An opening of Japanese production networks occurred in the first half of the 1990s in part in response to pressures associated with various forces of globalization, including the diffusion of capabilities, changes in technology, and the internationalization of the Japanese economy. This opening of Japanese networks caused them to converge towards their American counterparts. Partial convergence, however, coexisted with persistent diversity relative to the behavior of US networks. While nationality continued to matter, other factors affecting firms have to be incorporated into the analysis to explain the persistent diversity of firm behaviors.
Pivotal Politics: A Refinement of Nonmarket Analysis for Voting Institutions
Authors: Krehbiel Keith
Published: April 2013

With increasing regularity managers must address nonmarket as well as market problems. A common U.S. manifestation of this often-unwelcome reality is the abrupt emergence of a “Washington problem,” such as a piece of hostile legislation gathering momentum in the Congress. Although most business leaders today realize that doing nothing is rarely a viable response many activist nonmarket strategies are likewise problematic. For example even in the rare instances in which companies have the resources to devote to last-minute cover-the-Capitol blitzes such strategies are rarely effective and invariably wasteful. On any given issue a significant minority of legislators will oppose the lobbying manager's recommendations no matter what and a sizeable minority will favor them no matter what. Effective nonmarket strategies in contrast consist of knowing enough about governmental processes to ascertain who are the likely pivotal voters. This article presents a theory that provides a parsimonious way to think about pivotal voters in separation-of-power situations. Ultimately the theory provides guidance for the formation of more efficient and effective nonmarket strategies.
Integrated Market and Nonmarket Strategies in Client and Interest Group Politics
Authors: Baron David P.
Published: April 2013

This paper provides a model of integrated market and nonmarket strategies in the context of an industry facing regulation that differentially affects the firms in the industry. The regulation is chosen in a majority rule institution, and to affect the stringency of the regulation, the firms in the industry can take nonmarket action in the form of providing support to legislators based on how they vote. The nonmarket action is considered in the context of client and interest group politics, where the latter involves competition with an environmental interest group. An integrated strategy is composed of the firm's strategy for its market environment and its strategy for its nonmarket environment. Also the integrated strategies of the firms must constitute an equilibrium in their market competition and an equilibrium for their nonmarket competition, including that with the environmental interest group. Collective action in the form of coalition building and rent chain mobilization is also considered.
Much Ado About Nothing? The Economic Impact of US Foreign Trade Mission Participation
Authors: Schnietz Karen E. , Schuler Douglas A.
Published: April 2013

The activist foreign trade missions of the Clinton Administration are intended to open strategically important, but often difficult-to-enter, emerging markets to US foreign investment with government-to-government negotiations. Some research streams suggest that participation in a trade mission should benefit firms, while others suggest that participation should have no discernible benefit. This paper performs several event studies to analyze the stock return of a portfolio of the publicly traded firms participating in trade missions from 1993 to 1996. It finds that participants did not experience positive or significant abnormal stock returns as a result of mission participation, regardless of how the event date is defined or the data segmented.
Market and Nonmarket Strategies During Deregulation: The Case of British Telecom
Authors: Bonardi Jean-Philippe
Published: April 2013

From the 1970s to the 1990s, British Telecom (BT), the main telecommunications operator in Britain, underwent a dramatic revolution. The former public administration, often considered inefficient and hardly innovative, became a private company, and now aims to become one of the most dynamic giant telecom players, delivering everything from simple voice calls to advanced eCommerce services all over the world. These changes in the market arena were accompanied by some wide changes in the nonmarket arena, i.e. the institutional and regulatory environment of the British telecom market. This case study analyzes the changes in these two arenas to understand how market and nonmarket strategies may be combined by British Telecom to generate a competitive advantage in a deregulated environment.
Comparative Economic Organization—Within and Between Countries
Authors: Henisz Witold J. , Williamson Oliver E.
Published: April 2013

This paper explores the implications of going beyond transaction cost theory's implicit focus on domestic investors to include multinational actors. As developed herein, the discriminating alignment between the level of hazards (contractual and/or political) and the mode of governance carries over. In the open-economy context, such an alignment reflects the hazards that arise from the nature of the transaction and those that arise from the nature of the political and regulatory environment.
Prices, Politics, Institutions: Oil Exporters in the International Economy
Authors: Chaudhry Kiren
Published: April 2013

This essay tests the hypotheses and claims of models of internationalization that draw on neo-classical trade theory. Using the influential Frieden-Rogowski model, it examines the responses of Iraq and Algeria to the oil price shocks of the 1980s and 1990s. The cases demonstrate that even the most basic assumptions and predictions of this economistic model are flawed. The Frieden-Rogowski model misrepresents the mechanisms through which price shocks are translated into policy, makes inaccurate predictions about how terms of trade affect policy or sectoral performance, fails to explain the duration of lags between price changes and policy changes, and neglects important differences in a variety of major outcomes. I argue that even in the very similar cases of Algeria and Iraq, policy changed not in response to domestic pressures generated from changes in relative prices, but as a result of a severe fiscal crisis that stripped both governments of their ability to protect domestic constituents from world prices.
Moduli of unipotent representations II: Wide representations and the width
Authors: Dan-Cohen Ishai
Published: April 2013

With this work and its prequel [Ann. Inst. Fourier (Grenoble) 62 (2012), no. 3, 1123–1187] we initiate a study of the finite dimensional representations of a unipotent group over a field of characteristic zero from the modular point of view. Let G be such a group. The stack of all representations of a fixed finite dimension n is badly behaved. We introduce an invariant, w, of G, its width, as well as a certain nondegeneracy condition on representations, and we prove that nondegenerate representations of dimension n ≤ w + 1 form a quasi-projective variety. Our definition of the width is opaque; as a first attempt to elucidate its behavior, we prove that it is bounded by the length of a composition series.
Effect of Silicon Content on Wear Behavior of Heat Treated Powder Metallurgy Steels
Authors: Tekeli Süleyman , Güral Ahmet
Published: April 2013

Three different steel compositions with 1, 3 and 5 mass% Si were prepared using atomized iron (ASC.100.29) and 0.35 mass% natural graphite powders. The mixed powders were cold pressed at 700 MPa and sintered at 1200 °C for 30 min under pure Ar gas atmosphere. Some of the sintered specimens was quenched from 850 °C and then tempered at 100 °C for 1 h. The other sintered specimens were annealed at intercritical heat treatment temperature of 750 °C for 10 min and rapidly water-quenched. The experimental results showed that in as-sintered specimens inhomogeneously dispersed typical pearlitic structure in the ferrite matrix formed and its amount decreased with increasing Si content. In intercritically annealed specimens, the microstructure obtained was a mixture of partially transformed martensite and ferrite + pearlite. In quenched plus tempered specimens, beside tempered martensite, ferritic structure formed and its amount increased with increasing Si content. The wear tests were carried out under dry sliding conditions using a pin-on-disk type machine at constant load, speed and sliding distance. It was seen that, in all specimens, the friction coefficient and the wear rate both increased with increasing Si content. The increase of these values was less in the heat treated specimen than the as-sintered specimen.
Synergistic Effect between Sb2O3 Nanostructure and Brominated Compound on the Flame Retardant Properties of the Polymeric Matrixes
Authors: Gholamian Forozan , Nabiyouni Gholamreza , Ghanbari Davood , Jalajerdi Rouhollah , Aminifazl Alireza
Published: April 2013

We have successfully synthesized Sb2O3 nanostructures using ultrasonic waves. We have also synthesized a brominated compound via a simple chemical reaction. In order to improve the thermal stability of the polymeric nanocomposites, Sb2O3 and brominated compound were added to the poly methyl methacrylate (PMMA) acrylonitrile-butadiene-styrene (ABS), cellulose acetate (CA) and poly styrene (PS). The influence of flame retardant additives on the thermal properties of polymer matrixes was studied using thermogravimetric analysis (TGA) and derivative thermogravimetric analysis (DTG). We found that the thermal decomposition of the nanocomposites shifts towards higher temperatures as a result of synergistic effect between Sb2O3 and brominated compound. The nanocomposites were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier transform infrared (FT-IR) spectroscopy.