bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer Drug Development and the Evolving Regulatory Framework for Companion Diagnostics in the European Union
Authors: Pignatti Francesco , Ehmann Falk , Hemmings Robert , Jonsson Bertil , Nuebling Micha , Papaluca-Amati Marisa , Posch Martin , Rasi Guido
Published: March 2014

The European Union (EU) legal framework for medical device regulation is currently under revision. The European Commission has proposed a new framework to ensure that medical devices serve the needs and ensure the safety of European citizens, aiming for a framework that is fit for purpose, more transparent, and better adapted to scientific and technological progress. The proposed new framework is described as an evolution of the current regime keeping the same legal approach. An important proposed change is that companion diagnostics will no longer be considered as low risk and subject to self-certification by the manufacturer. According to the new proposal, companion diagnostics will be classified as high individual risk or moderate public health risk (category C) and require conformity assessment by a notified body. It has also been proposed that evidence of the clinical utility of the device for the intended purpose should be required for companion diagnostics. In this article, we review the EU legal framework relevant for companion diagnostics, describe the proposed changes, and summarize the available scientific guidance from the European Medicines Agency and its regulatory experience with cancer drug development including companion diagnostics.

See all articles in this CCR Focus section, “The Precision Medicine Conundrum: Approaches to Companion Diagnostic Co-development.”

Clin Cancer Res; 20(6); 1458–68. ©2014 AACR.
Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib
Authors: Wagle Nikhil , Grabiner Brian C. , Van Allen Eliezer M. , Hodis Eran , Jacobus Susanna , Supko Jeffrey G. , Stewart Michelle , Choueiri Toni K. , Gandhi Leena , Cleary James M. , Elfiky Aymen A. , Taplin Mary Ellen , Stack Edward C. , Signoretti Sabina , Loda Massimo , Shapiro Geoffrey I. , Sabatini David M. , Lander Eric S. , Gabriel Stacey B. , Kantoff Philip W. , Garraway Levi A. , Rosenberg Jonathan E.
Published: March 2014

Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or “personalized”) medicine approaches to screen patients with cancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.

Significance: The study of exceptional responders represents a promising approach to better understanding the mechanisms that underlie sensitivity to targeted anticancer therapies. Here, we identify two activating mTOR mutations in a patient with exquisite sensitivity to everolimus and pazopanib, suggesting an approach to identifying patients who might benefit most from mTOR inhibitors. Cancer Discov; 4(5); 546–53. ©2014 AACR.

See related commentary by Rejto and Abraham, p. 513

This article is highlighted in the In This Issue feature, p. 495
Salt Loading Promotes Kidney Injury via Fibrosis in Young Female Ren2 Rats
Authors: Habibi Javad , Hayden Melvin R. , Ferrario Carlos M. , Sowers James R. , Whaley-Connell Adam T.
Published: March 2014

Background/Aims: It is increasingly recognized that there is sexual dimorphism in kidney disease progression; however, this disparity is lost in the presence of diabetes where women progress at a similar rate to men. The renin-angiotensin-aldosterone system (RAAS) is known to regulate diabetes-induced kidney injury, and recent literature would suggest that gender differences exist in RAAS-dependent responses in the kidney. In this regard, these gender differences may be overcome by excessive salt intake. Thereby, we hypothesized that salt would promote proteinuria in transgenic female rats under conditions of excess tissue angiotensin (Ang) II and circulating aldosterone. Materials and Methods: We utilized young female transgenic (mRen2)27 (Ren2) rats and Sprague-Dawley (SD) littermates and fed a high-salt diet (4%) over 3 weeks. Results: Compared to SD and Ren2 controls, female Ren2 rats fed a high-salt diet displayed increases in proteinuria, periarterial and interstitial fibrosis as well as ultrastructural evidence of basement membrane thickening, loss of mitochondrial elongation, mitochondrial fragmentation and attenuation of basilar canalicular infoldings. These findings occurred temporally with increases in transforming growth factor-β but not indices of oxidant stress. Conclusions: Our current data suggest that a diet high in salt promotes progressive kidney injury as measured by proteinuria and fibrosis associated with transforming growth factor-β under conditions of excess tissue Ang II and circulating aldosterone.
Probiotic Administration Attenuates Myocardial Hypertrophy and Heart Failure After Myocardial Infarction in the Rat
Authors: Gan Xiaohong Tracey , Ettinger Grace , Huang Cathy X. , Burton Jeremy P. , Haist James V. , Rajapurohitam Venkatesh , Sidaway James E. , Martin Glynn , Gloor Gregory B. , Swann Jonathan R. , Reid Gregor , Karmazyn Morris
Published: March 2014

Background—

Probiotics are extensively used to promote gastrointestinal health, and emerging evidence suggests that their beneficial properties can extend beyond the local environment of the gut. Here, we determined whether oral probiotic administration can alter the progression of postinfarction heart failure.

Methods and Results—

Rats were subjected to 6 weeks of sustained coronary artery occlusion and administered the probiotic
Lactobacillus rhamnosus
GR-1 or placebo in the drinking water ad libitum. Culture and 16s rRNA sequencing showed no evidence of GR-1 colonization or a significant shift in the composition of the cecal microbiome. However, animals administered GR-1 exhibited a significant attenuation of left ventricular hypertrophy based on tissue weight assessment and gene expression of atrial natriuretic peptide. Moreover, these animals demonstrated improved hemodynamic parameters reflecting both improved systolic and diastolic left ventricular function. Serial echocardiography revealed significantly improved left ventricular parameters throughout the 6-week follow-up period including a marked preservation of left ventricular ejection fraction and fractional shortening. Beneficial effects of GR-1 were still evident in those animals in which GR-1 was withdrawn at 4 weeks, suggesting persistence of the GR-1 effects after cessation of therapy. Investigation of mechanisms showed a significant increase in the leptin:adiponectin plasma concentration ratio in rats subjected to coronary ligation, which was abrogated by GR-1. Metabonomic analysis showed differences between sham control and coronary artery ligated hearts particularly with respect to preservation of myocardial taurine levels.

Conclusions—

The study suggests that probiotics offer promise as a potential therapy for the attenuation of heart failure.
Ly-6C
high
Monocytes Depend on Nr4a1 to Balance Both Inflammatory and Reparative Phases in the Infarcted Myocardium
Authors: Hilgendorf Ingo , Gerhardt Louisa M.S. , Tan Timothy C. , Winter Carla , Holderried Tobias A.W. , Chousterman Benjamin G. , Iwamoto Yoshiko , Liao Ronglih , Zirlik Andreas , Scherer-Crosbie Marielle , Hedrick Catherine C. , Libby Peter , Nahrendorf Matthias , Weissleder Ralph , Swirski Filip K.
Published: March 2014

Rationale:

Healing after myocardial infarction involves the biphasic accumulation of inflammatory lymphocyte antigen 6C (Ly-6C)
high
and reparative Ly-6C
low
monocytes/macrophages (Mo/MΦ). According to 1 model, Mo/MΦ heterogeneity in the heart originates in the blood and involves the sequential recruitment of distinct monocyte subsets that differentiate to distinct macrophages. Alternatively, heterogeneity may arise in tissue from 1 circulating subset via local macrophage differentiation and polarization. The orphan nuclear hormone receptor, nuclear receptor subfamily 4, group a, member 1 (Nr4a1), is essential to Ly-6C
low
monocyte production but dispensable to Ly-6C
low
macrophage differentiation; dependence on Nr4a1 can thus discriminate between systemic and local origins of macrophage heterogeneity.

Objective:

This study tested the role of Nr4a1 in myocardial infarction in the context of the 2 Mo/MΦ accumulation scenarios.

Methods and Results:

We show that Ly-6C
high
monocytes infiltrate the infarcted myocardium and, unlike Ly-6C
low
monocytes, differentiate to cardiac macrophages. In the early, inflammatory phase of acute myocardial ischemic injury, Ly-6C
high
monocytes accrue in response to a brief C–C chemokine ligand 2 burst. In the second, reparative phase, accumulated Ly-6C
high
monocytes give rise to reparative Ly-6C
low
F4/80
high
macrophages that proliferate locally. In the absence of Nr4a1, Ly-6C
high
monocytes express heightened levels of C–C chemokine receptor 2 on their surface, avidly infiltrate the myocardium, and differentiate to abnormally inflammatory macrophages, which results in defective healing and compromised heart function.

Conclusions:

Ly-6C
high
monocytes orchestrate both inflammatory and reparative phases during myocardial infarction and depend on Nr4a1 to limit their influx and inflammatory cytokine expression.
Optimal Perfusion Computed Tomographic Thresholds for Ischemic Core and Penumbra Are Not Time Dependent in the Clinically Relevant Time Window
Authors: Qiao Yujie , Zhu Guangming , Patrie James , Xin Wenjun , Michel Patrik , Eskandari Ashraf , Jovin Tudor , Wintermark Max
Published: March 2014

Background and Purpose—

This study aims to determine whether perfusion computed tomographic (PCT) thresholds for delineating the ischemic core and penumbra are time dependent or time independent in patients presenting with symptoms of acute stroke.

Methods—

Two hundred seventeen patients were evaluated in a retrospective, multicenter study. Patients were divided into those with either persistent occlusion or recanalization. All patients received admission PCT and follow-up imaging to determine the final ischemic core, which was then retrospectively matched to the PCT images to identify optimal thresholds for the different PCT parameters. These thresholds were assessed for significant variation over time since symptom onset.

Results—

In the persistent occlusion group, optimal PCT parameters that did not significantly change with time included absolute mean transit time, relative mean transit time, relative cerebral blood flow, and relative cerebral blood volume when time was restricted to 15 hours after symptom onset. Conversely, the recanalization group showed no significant time variation for any PCT parameter at any time interval. In the persistent occlusion group, the optimal threshold to delineate the total ischemic area was the relative mean transit time at a threshold of 180%. In patients with recanalization, the optimal parameter to predict the ischemic core was relative cerebral blood volume at a threshold of 66%.

Conclusions—

Time does not influence the optimal PCT thresholds to delineate the ischemic core and penumbra in the first 15 hours after symptom onset for relative mean transit time and relative cerebral blood volume, the optimal parameters to delineate ischemic core and penumbra.
Emulating a Portuguese Model
Authors: Dewulf Jeroen
Published: March 2014

This article presents a new perspective on the master-slave relationship in New Netherland in order to complement the existing theories on the treatment of slaves in that Dutch colony. It shows how prior to the loss of Dutch Brazil, the West India Company modeled its slave policy after Portuguese practices, such as the formation of black militias and the use of Christianity as a means to foster slave loyalty. It also points out that in the initial slave policy of the Dutch Reformed Church was characterized by the ambition to replace the Iberian Catholic Church in the Americas. While the Reformed Church in the early decades of the Dutch colonial expansion was characterized by a community-building spirit and a flexible attitude toward newcomers, the loss of Brazil shattered the dream of a Protestant American continent and gave way to a more exclusivist approach with a much stronger emphasis on orthodoxy. This led to a dramatic change in attitude vis-à-vis slaves, which is reflected in the segregationist policies―both at a social and a religious level―in later Dutch slave colonies such as Suriname.
Relicts of a forested past: Southernmost distribution of the hairy frog genus Trichobatrachus Boulenger, 1900 (Anura: Arthroleptidae) in the Serra do Pingano region of Angola with comments on its taxonomic status
Authors: ERNST RAFFAEL , NIENGUESSO ALVARO BRUNO TOTO , LAUTENSCHLÄGER THEA , BAREJ MICHAEL F. , SCMITZ ANDREAS , HÖLTING MONIQUE
Published: March 2014

The monotypic genus Trichobatrachus, with its sole representative, the hairy frog, Trichobatrachus robustus Boulenger, 1900, could be considered one of the most well-known frogs of Africa. Despite its broad recognition and the fact that it is considered wide-spread and locally common (Amiet & Burger 2004), surprisingly little is known about the actual distribution and the specific occurrence patterns of the species. It was originally described by Boulenger (1900) from the Benito River, previously erroneously stated to be located in Gabon. However, Lötters et al. (2001) clarified that the type locality was actually situated in Equatorial Guinea, then part of French Congo, and subsequently provided the first confirmed country record for Gabon. Hairy frogs were previously included in the herpetofaunal lists of Cameroon (Parker 1936; Perret & Mertens 1957), the Democratic Republic of Congo (Laurent 1956), and Nigeria (Schiøtz 1963). More recently published accounts list them for Cameroon (Euskirchen et al. 1999; Herrmann et al. 2005; Gonwouo & Rödel 2008), Equatorial Guinea (De la Riva 1994; Lasso et al. 2002), Gabon (Lötters et al. 2001; Rödel & Pauwels 2003; Burger et al. 2004; Pauwels & Rödel 2007; Bell et al. 2011), and the Democratic Republic of Congo (DRC, Fretey et al. 2011), and speculate about their potential occurrence in Congo and the Cabinda enclave of Angola (Amiet & Burger 2004). The DRC record so far represented the most southerly distribution, while the most northerly account comes from the Adamaoua Province of northern Cameroon (Tadpole voucher MHNG-AMP/ERPI-1035.006 from Bénoué source, Northern cliff Ngaoundéré, Adamaoua, Cameroon/Adamaoua Province, cf. Perret 1966). Specimens stored in the collection at the Royal Museum of Central Africa, Tervuren (RMCA) under collection numbers RMCA B 90060.0004-11 confirm the occurrence of the species in Congo. To our knowledge, these specimens represent yet unpublished first country records.
Impact of Otitis Media Severity on Children's Quality of Life
Authors: Grindler David J. , Blank Sarah J. , Schulz Kristine A. , Witsell David L. , Lieu Judith E. C.
Published: March 2014

Objective

Children with otitis media (OM) suffer sleep disturbances, loss of appetite, earache, and behavioral problems. Our objective was to quantitate the average burden of OM and to compare the associated impact of tympanostomy tubes on infant health related quality of life (HR‐QoL).

Study Design

Multi‐institutional prospective cross‐sectional study.

Setting

Otolaryngology, family practice, and pediatric clinics.

Subjects and Methods

Children ages 6 to 24 months of age with or without recurrent OM. Patient history, the PedsQL Infant QoL survey, and the 6‐item child with OM survey (Otitis Media 6 [OM‐6]) were collected from providers and parents.

Results

Data from 1208 patients were analyzed. Mean age was 14.7 months, and 54% were male. The mean OM‐6 score of children with recurrent OM was 3.3, whereas similarly aged well‐children had a mean OM‐6 score of 2.5. The mean PedsQL Infant scores of recurrent OM patients were significantly worse than those of children from well‐child visits. Worse OM‐6 scores were correlated with poorer PedsQL Infant scores, Pearson r = −0.581 (1‐12 months) and −0.558 (13‐24 months), P <. 001. Otolaryngology patients who were recommended to undergo ear tube placement had significantly poorer OM‐6 scores and worse PedsQL Infant scores, whereas patients with prior tube placement had significantly better OM‐6 and PedsQL Infant scores.

Conclusion

Children with recurrent OM had significantly worse HR‐QoL than similarly aged healthy children. Increased burden of OM strongly affected HR‐QoL, and recommendation for tube placement was associated with increased disease burden and poorer HR‐QoL. The presence of tympanostomy tubes was associated with better OM‐6 and PedsQL Infant scores.
Immunomodulatory Effect of Mesenchymal Stem Cells on T Lymphocyte and Cytokine Expression in Nasal Polyps
Authors: Cho Kyu‐Sup , Kim Yong‐Wan , Kang Myoung Joo , Park Hee‐Young , Hong Sung‐Lyong , Roh Hwan‐Jung
Published: March 2014

Objectives

Adipose tissue–derived stem cells (ASCs) have been reported to have immunomodulatory effects in various inflammatory diseases, including asthma and allergic rhinitis, through the induction of T cell anergy. Nasal polyps (NPs) are a chronic inflammatory disease in the nose and paranasal sinus characterized histologically by the infiltration of inflammatory cells, such as eosinophils or lymphocytes. This study was performed to investigate whether ASCs have immunomodulatory effects on T lymphocyte and cytokine expression in eosinophilic NPs.

Study Design

Basic science experimental study.

Setting

University tertiary care facility.

Subjects and Methods

NP specimens were obtained from 20 patients with chronic rhinosinusitis and eosinophilic NPs. ASCs were isolated and cultured from the abdominal fat of 15 subjects undergoing intra‐abdominal surgery. Infiltrating cells (1 × 106) were isolated from NP tissue and co‐cultured with 1 × 105 ASCs. To determine whether ASCs affect infiltrating T lymphocyte and cytokine expression in eosinophilic NP, T lymphocyte subsets and cytokine expression were analyzed before and after ASC treatment.

Results

ASC treatment significantly decreased the proportions of CD4+ and CD8+ T cells. After ASC treatment, Th2 cytokine (interleukin [IL]–4 and IL‐5) levels decreased significantly. In contrast, levels of Th1 (interferon‐γ and IL‐2) and regulatory cytokines (transforming growth factor–β and IL‐10) increased significantly after ASC treatment.

Conclusions

ASCs have immunomodulatory effects in the eosinophilic inflammation of NPs, characterized by down‐regulation of activated T lymphocytes and a Th2 immune response. These effects would be expected, over time, to significantly contribute to the control of eosinophilic inflammation and, possibly, growth of eosinophilic NPs.
Systematic Review: Efficacy of Gufoni Maneuver for Treatment of Lateral Canal Benign Paroxysmal Positional Vertigo with Geotropic Nystagmus
Authors: van den Broek Emke Mechelina Josephina Margo , van der Zaag‐Loonen Hester Josephine , Bruintjes Tjasse Doewe
Published: March 2014

Objective

In this rapid systematic review, we studied the efficacy of the Gufoni maneuver for the treatment of lateral canal benign paroxysmal positional vertigo (BPPV) with geotropic nystagmus.

Methods

A comprehensive search, including PubMed, Embase, Web of Science, and Cochrane as data sources, resulted in 44 original papers for randomized trials that compared the Gufoni maneuver with other maneuvers (date of search: April 23, 2013). Three studies (389 patients) remained after screening of title, abstract, and full text.

Results

After method assessment, 2 of these 3 studies were considered to have a low risk of bias and a high level of validity. The third study did not properly report the treatment allocation and blinding; moreover, outcome data were incomplete. The first 2 studies compared the Gufoni maneuver with a sham maneuver (and the barbecue roll in one study). The third study compared the Gufoni maneuver with a treatment with vestibular suppressants and with the barbecue roll (plus forced prolonged positioning). All 3 studies reported short‐term results. Midterm results (1 month) were reported in 2 studies.

Conclusion and Recommendation

Given the variety in the comparative treatments and follow‐up duration, all 3 studies showed that the Gufoni maneuver was more effective than the sham maneuver or treatment with vestibular suppressants. All agreed that the maneuver was easy to perform, which made it suitable for older, immobile, and obese patients. However, there were insufficient data to establish the relative efficacy of the Gufoni maneuver compared with other maneuvers.
Moses’ Farewell Address according to 1QWords of Moses (1Q22)
Authors: Feldman Ariel
Published: March 2014

This article explores the reworking of Moses’ farewell address to Israel in 1Q22 (1QWords of Moses). Analyzing exegetical techniques employed by this scroll and illuminating some of its passages that have not been adequately read and understood, the article suggests that the scroll's recasting of the Deuteronomic account of the Mosaic farewell discourse is modeled on the Sinai revelation.
Does Self-Defense Training Prevent Sexual Violence Against Women?
Authors: Hollander Jocelyn A.
Published: March 2014

Self-defense classes are offered across the nation as a strategy for reducing women’s vulnerability to sexual assault. Yet there has been little systematic research assessing the effectiveness of these classes. In this article, I use data from a mixed methods study of a 10-week, university-based, feminist self-defense class to examine the effectiveness of self-defense training over a 1-year follow-up period. My analyses indicate that women who participate in self-defense training are less likely to experience sexual assault and are more confident in their ability to effectively resist assault than similar women who have not taken such a class.
Void distributions and permeability prediction for rotationally moulded polymers
Authors: Murray BR , Leen SB , Brádaigh CM Ó
Published: March 2014

An experimental study of void distributions for rotationally moulded polyethylene is presented. The effects of key variables such as maximum process temperature and nominal wall thickness (via powder mass) are studied. Analytical models and finite element mass diffusion models for the permeability of heterogeneous polymers with air voids are presented and comparatively assessed. The FE method allows modelling of realistic (measured) void distributions. A preliminary estimation method for void volume fraction and mean void radius is presented. This approach is based on hot plate measurements and is shown to give good correlation with the rotationally moulded material for different process temperatures. Key objectives of the present work are (i) to develop an understanding of the factors affecting gas permeability in rotationally moulded polymers and (ii) to develop experimental and computational methods to help design low permeability rotomoulded polymer liners.
Featured Article: Autophagic activation with Nimotuzumab enhanced chemosensitivity and radiosensitivity of esophageal squamous cell carcinoma
Authors: Song Haizhu , Pan Banzhou , Yi Jun , Chen Longbang
Published: March 2014

Chemotherapy and radiotherapy are two indispensible methods for esophageal squamous cell carcinoma (ESCC), especially for those recurring and metastatic ones, but therapeutic toxicity remains a major problem to overcome. In the present study, the potential therapeutic value of nimotuzumab (an antiepidermal growth factor receptor [EGFR] monoclonal antibody) in combination with chemotherapy and radiotherapy was evaluated on Eca109 and TE-1 ESCC cells, with high and low expression of EGFR, respectively. It was shown that nimotuzumab enhanced the sensitivity of Eca109 cells to other cytotoxic agents (paclitaxel and cis-platinum) and X-ray radiation, and the cytotoxicity was associated with increased autophagy. Conversely, the chemo- and radio-sensitivity of TE-1 cells showed no improvement with addition of nimotuzumab, but could be increased by combining with rapamycin, an autophagy inducer. Therefore, it was concluded that autophagic activation mediated by nimotuzumab could promote autophagic cell death and produce additive antitumor effects.
Safety in numbers: multiple occurrences of highly similar homologs among Azotobacter vinelandiicarbohydrate metabolism proteins probably confer adaptive benefits
Authors: Mærk Mali , Johansen Jostein , Ertesvåg Helga , Drabløs Finn , Valla Svein
Published: March 2014

Background

Gene duplication and horizontal gene transfer are common processes in bacterial and archaeal genomes, and are generally assumed to result in either diversification or loss of the redundant gene copies. However, a recent analysis of the genome of the soil bacterium Azotobacter vinelandii DJ revealed an abundance of highly similar homologs among carbohydrate metabolism genes. In many cases these multiple genes did not appear to be the result of recent duplications, or to function only as a means of stimulating expression by increasing gene dosage, as the homologs were located in varying functional genetic contexts. Based on these initial findings we here report in-depth bioinformatic analyses focusing specifically on highly similar intra-genome homologs, or synologs, among carbohydrate metabolism genes, as well as an analysis of the general occurrence of very similar synologs in prokaryotes.

Results

Approximately 900 bacterial and archaeal genomes were analysed for the occurrence of synologs, both in general and among carbohydrate metabolism genes specifically. This showed that large numbers of highly similar synologs among carbohydrate metabolism genes are very rare in bacterial and archaeal genomes, and that the A. vinelandii DJ genome contains an unusually large amount of such synologs. The majority of these synologs were found to be non-tandemly organized and localized in varying but metabolically relevant genomic contexts. The same observation was made for other genomes harbouring high levels of such synologs. It was also shown that highly similar synologs generally constitute a very small fraction of the protein-coding genes in prokaryotic genomes. The overall synolog fraction of the A. vinelandii DJ genome was well above the data set average, but not nearly as remarkable as the levels observed when only carbohydrate metabolism synologs were considered.

Conclusions

Large numbers of highly similar synologs are rare in bacterial and archaeal genomes, both in general and among carbohydrate metabolism genes. However, A. vinelandii and several other soil bacteria harbour large numbers of highly similar carbohydrate metabolism synologs which seem not to result from recent duplication or transfer events. These genes may confer adaptive benefits with respect to certain lifestyles and environmental factors, most likely due to increased regulatory flexibility and/or increased gene dosage.
Invasive pneumococcal diseases in children and adolescents– a single centre experience
Authors: Schnappauf Christin , Rodloff Arne , Siekmeyer Werner , Hirsch Wolfgang , Sorge Ina , Schuster Volker , Kiess Wieland
Published: March 2014

Background

S. pneumoniae is a major cause of meningitis, pneumonia and sepsis in children. In 2006 universal pneumococcal vaccination was recommended in Germany for all children up to their second birthday. We have compared the prevalence and outcome of IPD at a single hospital before and after the introduction of vaccination.

Findings

55 cases of IPD were identified over an 11 year period. Almost half of the patients were younger than 2 years of age. Most of the children were affected by pneumonia. The second highest incidence seen was for meningitis and sepsis. 17 patients exhibited additional complications. Significant pre-existing and predisposing disorders, such as IRAK 4 defect, ALPS or SLE were identified in 4 patients. Complete recovery was seen in 78% of affected children; 11% had a fatal outcome and 11% suffered from long term complications. Only 31% overall had been vaccinated. The most common serotype was 14. Serotypes not covered by any of the current vaccines were also found. Antibiotic treatment commenced with cephalosporins in over 90%.

Conclusion

Frequency of IPD in our hospital did not decrease after initiation of the pneumococcal vaccination. This might be due to vaccinations not being administered satisfactorily as well as to poor education about the need of the vaccination. Pre-existing diseases must be monitored and treated accordingly and rare deficiencies taken into account when IPD takes a foudroyant course. In addition, antibiotic stewardship has been initiated at this hospital centre as a consequence of the high cephalosporin use detected in this study.
Promising potential of new generation translocator protein tracers providing enhanced contrast of arthritis imaging by positron emission tomography in a rat model of arthritis
Authors: Gent Yoony YJ , Weijers Karin , Molthoff Carla FM , Windhorst Albert D , Huisman Marc C , Kassiou Michael , Jansen Gerrit , Lammertsma Adriaan A , van der Laken Conny J
Published: March 2014

Introduction

Early diagnosis of and subsequent monitoring of therapy for rheumatoid arthritis (RA) could benefit from detection of (sub)clinical synovitis. Imaging of (sub)clinical arthritis by targeting the translocator protein (TSPO) on activated macrophages is feasible using (R)-[11C] PK11195-based positron emission tomography (PET), but clinical applications are limited by background uptake in peri-articular bone/bone marrow. The purpose of the present study was to evaluate two other TSPO ligands with potentially lower background uptake in neurological studies, [11C]DPA-713 and [18F]DPA-714, in a rat model of arthritis.

Methods

TSPO binding of DPA-713, DPA-714 and PK11195 were assessed by in vitro competition studies with [3H]DPA-713 using human macrophage THP-1 cells and CD14+ monocytes from healthy volunteers. In vivo studies were performed in rats with methylated bovine serum albumin-induced knee arthritis. Immunohistochemistry with anti-TSPO antibody was performed on paraffin-embedded sections. Rats were imaged with [11C]DPA-713 or [18F]DPA-714 PET, followed by ex vivo tissue distribution studies. Results were compared with those obtained with the tracer (R)-[11C]PK11195, the established ligand for TSPO.

Results

In THP-1 cells, relative TSPO binding of DPA-713 and DPA-714 were 7-fold and 25-fold higher, respectively, than in PK11195. Comparable results were observed in CD14+ monocytes from healthy volunteers. In the arthritis rat model, immunohistochemistry confirmed the presence of TSPO-positive inflammatory cells in the arthritic knee. PET images showed that uptake of [11C]DPA-713 and [18F]DPA-714 in arthritic knees was significantly increased compared with contralateral knees and knees of normal rats. Uptake in arthritic knees could be largely blocked by an excess of PK11195. [11C]DPA-713 and [18F]DPA-714 provided improved contrast compared with (R)-[11C]PK11195, as was shown by significantly higher arthritic knee-to-bone ratios of [11C]DPA-713 (1.60 ± 0.31) and [18F]DPA-714 (1.55 ± 0.10) compared with (R)-[11C]PK11195 (1.14 ± 0.19).

Conclusions

[11C]DPA-713 and [18F]DPA-714 clearly visualized arthritis and exhibited lower (peri-articular) bone/bone marrow uptake than (R)-[11C]PK11195. These features merit further investigation of these tracers for early diagnosis and therapy monitoring of RA in a clinical setting.
Are Near-Fault Fling Effects Captured in the New NGA West2 Ground Motion Models?
Authors: Kamai Ronnie , Abrahamson Norman
Published: March 2014

We evaluate how much of the fling effect is removed from the NGA database and accompanying GMPEs due to standard strong motion processing. The analysis uses a large set of finite-fault simulations, processed with four different high-pass filter corners, representing the distribution within the PEER ground motion database. The effects of processing on the average horizontal component, the vertical component, and peak ground motion values are evaluated by taking the ratio between unprocessed and processed values. The results show that PGA, PGV, and other spectral values are not significantly affected by processing, partly thanks to the maximum period constraint used when developing the NGA GMPEs, but that the bias in peak ground displacement should not be ignored.
Real-World Outcomes in Metastatic Renal Cell Carcinoma: Insights From a Joint Community-Academic Registry
Authors: Harrison Michael R. , Hirsch Bradford R. , George Daniel J. , Walker Mark S. , Chen Connie , Korytowsky Beata , Stepanski Edward , Abernethy Amy P.
Published: March 2014

mRCC survival outcomes are different by pattern, with general findings consistent with trial-based expectations in similar patient populations.
Implementation of Electronic Chemotherapy Ordering: An Opportunity to Improve Evidence-Based Oncology Care
Authors: Adelson Kerin B. , Qiu Ying Chun , Evangelista Michelle , Spencer-Cisek Patricia , Whipple Clare , Holcombe Randall F.
Published: March 2014

The authors anticipate that the Epic Beacon platform will allow them to capture data on chemotherapy regimen use for each disease by stage, individual regimen toxicity, and patients' clinical outcome.
Options for Oncologists to Preserve Independent Private Practice
Authors: Blau Michael L.
Published: March 2014

Whether, when, and the extent to which payers will reward oncology medical homes for implementing value-based care will vary from payer to payer and from market to market. The author concludes it is prudent to implement oncology medical home arrangements until enough payers are ready to recognize and pay for such value-based care.
The Changing Landscape of Conflict of Interest Supports Further Study of ASCO Authorship Restrictions for Research Studies
Authors:   American Society of Clinical Oncology, Alexandria, VA
Published: March 2014

The American Society of Clinical Oncology's conflict of interest policy reaffirms a commitment to transparency and independence in the development and presentation of scientific and educational content as well as the responsibility to analyze, present, and discuss the most important research results with the potential to improve the lives of patients.
Axon degeneration and PGC1α-mediated protection in a vertebrate model of α-synuclein toxicity
Authors: O'Donnell Kelley C. , Lulla Aaron , Stahl Mark C. , Wheat Nickolas D. , Bronstein Jeff M. , Sagasti Alvaro
Published: March 2014

α-Synuclein (aSyn) expression is implicated in neurodegenerative processes, including Parkinson disease (PD) and dementia with Lewy bodies (DLB). In animal models of these diseases, axon pathology often precedes cell death, raising the question of whether aSyn has compartment-specific toxic effects that may require early and/or independent therapeutic intervention. The relevance of axonal pathology to degeneration can only be addressed through longitudinal, in vivo monitoring of different neuronal compartments. With current imaging methods, dopaminergic neurons do not readily lend themselves to such a task in any vertebrate system. We therefore expressed human wild-type aSyn in zebrafish peripheral sensory neurons, which project elaborate superficial axons that can be continuously imaged in vivo. Axonal outgrowth was normal in these neurons, but by 2 days post-fertilization (dpf), many aSyn-expressing axons became dystrophic, with focal varicosities or diffuse beading. Approximately 20% of aSyn-expressing cells died by 3 dpf. Time-lapse imaging revealed that focal axonal swelling, but not overt fragmentation, usually preceded cell death. Co-expressing aSyn with a mitochondrial reporter revealed deficits in mitochondrial transport and morphology even when axons appeared overtly normal. The axon-protective protein Wallerian degeneration slow (WldS) delayed axon degeneration but not cell death caused by aSyn. By contrast, the transcriptional co-activator PGC-1α, which has roles in the regulation of mitochondrial biogenesis and reactive oxygen species detoxification, abrogated aSyn toxicity in both the axon and the cell body. The rapid onset of axonal pathology in this system, and the relatively moderate degree of cell death, provide a new model for the study of aSyn toxicity and protection. Moreover, the accessibility of peripheral sensory axons will allow effects of aSyn to be studied in different neuronal compartments, and may have utility in screening for novel disease-modifying compounds.
An endoplasmic reticulum-retained atrial fibrillation-linked connexin40 mutant impairs atrial gap junction channel function
Authors: Sun Yiguo , Tong Xiaoling , Chen Honghong , Huang Tao , Shao Qing , Huang Weixiong , Laird Dale W. , Bai Donglin
Published: March 2014

Connexin40 (Cx40)-containing gap junction channels are expressed in the atrial myocardium and provide a low resistance passage for rapid impulse propagation. A germline mutation in the GJA5 gene encoding Cx40 resulting in a truncated Cx40 (Q49X) was identified in a large Chinese family with lone atrial fibrillation (AF). This mutation co-segregated with seven AF probands in an autosomal dominant way over generations. To test the hypothesis that this Cx40 mutant affects the distribution and function of atrial gap junctions, we studied the Q49X mutant in gap junction deficient HeLa and N2A cells. The Q49X mutant was typically localized in the cytoplasm and failed to form gap junction plaques at cell-cell interfaces distinct from that of wild type Cx40. When the Q49X mutant was co-expressed with Cx40 or Cx43, the mutant substantially reduced the gap junction plaque formation of Cx40 and Cx43. Electrophysiological studies revealed no electrical coupling of cell pairs expressing the mutant alone and a significant decrease in the coupling conductance when the mutant was co-expressed with Cx40 or Cx43. Further colocalization experiments with the organelle residential proteins indicate that Q49X was retained in the endoplasmic reticulum. These findings provide evidence that the Q49X mutant is capable to impair the gap junction distribution and function of key atrial connexins which may play a role in the predisposition and onset of AF.
Chiral Porous TADDOL-Embedded Organic Polymers for Asymmetric Diethylzinc Addition to Aldehydes
Authors: Wang Xiuren , Zhang Jie , Liu Yan , Cui Yong
Published: March 2014

Two chiral porous organic polymers (CPOPs) were synthesized by linking a TADDOL-embedded building block with arylethynylenes units. The CPOPs are highly stable to thermal treatment, moisture, acidity, and basicity. The dihydroxy groups of TADDOL inside the pores promise the CPOPs as good asymmetric catalysts after postsynthesis modification with a secondary metal center. After being treated with Ti(OiPr)4, the CPOPs could be used as highly effective and reusable heterogeneous catalyst for asymmetric diethylzinc addition to aldehydes with up to 99% conversion and 95% ee. This work promises the potential of generating chiral solid catalysts with unique and practically useful enantioselective functions via a modular approach.
Photocrosslinking of the Exterior of a Fullerene Bilayer that Prevents Vesicle Aggregation
Authors: Harano Koji , Narita Akimitsu , Nakamura Eiichi
Published: March 2014

An amphiphilic molecule bearing a coumarin moiety attached to a water-soluble fullerene via an alkyl linker forms a water-soluble fullerene bilayer vesicle in water that spontaneously agglomerates and fuses upon standing. The agglomeration–fusion ability of the vesicle was endowed probably by the intervesicular interaction between the coumarin group and the fullerene core, as judged by the lack of such ability for the vesicles bearing only alkyl groups and by complete inhibition by conversion of the coumarin group into a photodimer.
Practical considerations for volumetric wear analysis of explanted hip arthroplasties
Authors: Langton D. J. , Sidaginamale R. P. , Holland J. P. , Deehan D. , Joyce T. J. , Nargol A. V. F. , Meek R. D. , Lord J. K.
Published: March 2014

Objectives

Wear debris released from bearing surfaces has been shown to provoke negative immune responses in the recipient. Excessive wear has been linked to early failure of prostheses. Analysis using coordinate measuring machines (CMMs) can provide estimates of total volumetric material loss of explanted prostheses and can help to understand device failure. The accuracy of volumetric testing has been debated, with some investigators stating that only protocols involving hundreds of thousands of measurement points are sufficient. We looked to examine this assumption and to apply the findings to the clinical arena.

Methods

We examined the effects on the calculated material loss from a ceramic femoral head when different CMM scanning parameters were used. Calculated wear volumes were compared with gold standard gravimetric tests in a blinded study.

Results

Various scanning parameters including point pitch, maximum point to point distance, the number of scanning contours or the total number of points had no clinically relevant effect on volumetric wear calculations. Gravimetric testing showed that material loss can be calculated to provide clinically relevant degrees of accuracy.

Conclusions

Prosthetic surfaces can be analysed accurately and rapidly with currently available technologies. Given these results, we believe that routine analysis of explanted hip components would be a feasible and logical extension to National Joint Registries. Cite this article: Bone Joint Res 2014;3:60–8.
La migración de Rumanía: nuevos y antiguos escenarios para la movilidad
Authors: Baldoni Emiliana
Published: March 2014

Este trabajo analiza el fenómeno de la movilidad desde Rumanía (interna, internacional y transfronteriza), recorriendo las fases históricas y las principales características antes y después de que este país se integrara en la Unión Europea. El “sistema de inmigración de Rumanía” tiene sus raices en la movilidad interna del período Socialista, y actualmente se caracteriza por el predominio de los movimientos circulares que, como en el caso italiano, coexisten sin embargo con una marcada tendencia a la estabilización.
Algunas reflexiones sobre la migración altamente cualificada: políticas, mercados laborales y restricciones
Authors: Padilla Beatriz
Published: March 2014

El presente artículo tiene por objeto reflexionar sobre la migración altamente cualificada, teniendo en cuenta los países de origen y de destino, empleando contribuciones de la literatura internacional, principalmente de Latinoamérica, y examinando ejemplos del Sur de Europa. Estas reflexiones han inspirado algunas recomendaciones sobre políticas para mejorar el papel de las diásporas con talento.
La aplicación del modelo espacial de la ideología al sistema de partidos alemán durante la reunificación (1983-1998)
Authors: Alaminos Chica Antonio
Published: March 2014

El Modelo Espacial Ideológico especificado por Hinich and Munger (1994), se ofrece como un desarrollo dentro de la Teoría Espacial del Voto que permite simplificar el análisis multidimensional del comportamiento electoral. Empleamos aquí el modelo espacial de la ideología como instrumento de medición de la percepción del sistema de partidos de los ciudadanos alemanes. El modelo estadístico empleado parte de las concepciones teóricas de Almond y Verba (1970) y demuestra sensibilidad a las diferencias de cultura política en la sociedad alemana. El modelo permite estimar empiricamente una aproximación al concepto de elasticidad del espacio ideológico (Sartori, 1976).
Seedling establishment and growth after direct seeding with Pinus sylvestris: effects of seed type, seed origin, and seeding year
Authors: Wennström Ulfstand , Bergsten Urban , Nilsson Jan-Erik
Published: March 2014

The early effects of seed type, seed origin, and seeding year on seedling emergence, survival, and growth after one to four years was quantified and examined. Two experimental series of Scots pine located at 61Â°N and 64Â°N and six orchard seed lots and six stand seed lots of adequate geographical origins in each series were used. Both series were replicated at five sites for up to five years. On average, orchard seed lots had 16% and 12% higher seedling emergence, in relation to sown germinable seeds, than stand seed lots in the northern and southern series. The survival from year 1 to year 4 was also higher for orchard seedlings than for stand seedlings; there was a 77% and 72% survival rate in the northern series and a 58% and 49% survival rate in the southern series for orchard and stand seedlings respectively. On average, after four years orchard seedlings were 26% taller in the northern series and 13% taller in the southern series. The gain in height growth for the orchard seeds was positive at all seeding years, at all sites, and at all seedling ages. If survival was calculated to the height of a four-year-old seedling, the survival of orchard seedlings increased by 3% in the northern and 1% in the southern series as the result of the higher growth of orchard seedlings. Using orchard seeds resulted in 6 percent units higher growth gain when the clear cuts were regenerated with direct seeding than with plants using the same seed material. Changes in the ranking of seed lots and seed types at different sites and seeding years for seedling emergence is an effect of external factors such as grazing and foraging that cannot be related directly to the tested factors.
Comparison of approaches to integrate energy wood estimation into the Finnish compartment inventory system
Authors: Tahvanainen Timo , Kaartinen Kalle , Pukkala Timo , Maltamo Matti
Published: March 2014

The harvesting of energy wood from young stands is increasing as the demand for renewable wood fuel is growing. Energy wood consists of stems, tree tops, branches and needles, depending on the size of the trees and the logging method used. The current forest inventory and planning systems used in private forests in Finland do not produce estimates of energy wood components. In stands typical for energy wood harvesting, a large share of energy wood consists of trees smaller than the minimum size for pulpwood. In this study, energy wood was included into the calculation system of compartment inventory, and a procedure for simulating the thinning treatments in young stands was developed. The results for six inventory alternatives and prediction of energy wood were compared with the use of inventory material from 37 young stands that have plenty of energy wood. The measurement of additional stand characteristics and the use of a calibration estimation method was tested, as well as the use of plot-level inventory data instead of stand level data. The results showed that the measurement of the number of trees per hectare, in addition to stand basal area and mean diameter, improved the energy wood estimates. The additional minimum and maximum diameters improved the precision of the estimates, but did not affect bias. The removal estimates were more precise when plot-level data was used, rather than stand-level data. The removal estimates were higher with plot-level data. The results suggest that, in heterogeneous young stands, plot by plot prediction would give more accurate removal estimates than the calculation of a corresponding prediction at the stand-level.