bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of NMDA receptor inhibition by diarylamidine compounds
Authors: Dron Mikhail Y. , Zhigulin Arseniy S. , Barygin Oleg I.
Published: October 2019

Pentamidine, diminazene and 4′,6‐diamidino‐2‐phenylindole (DAPI) are antiprotozoal diarylamidine compounds. In the present work, we have studied their action on native N‐methyl‐D‐aspartate (NMDA) receptors in rat hippocampal pyramidal neurons. All three compounds inhibited NMDA receptors at −80 mV holding voltage with IC50 of 0.41 ± 0.08, 13 ± 3 and 3.1 ± 0.6 μM, respectively. The inhibition by pentamidine was strongly voltage‐dependent, while that of DAPI was practically voltage‐independent. Inhibition by diminazene had both voltage‐dependent and voltage‐independent components. Diminazene and DAPI demonstrated tail currents and overshoots suggesting “foot‐in‐the‐door” mechanism of action. In contrast, pentamidine was partially trapped in the closed NMDA receptor channels. Such difference in the mechanism of action can be explained by the difference in the 3D structure of compounds. In the pentamidine molecule, two benzamidine groups are connected with a flexible linker, which allows the molecule to fold up and fit in the cavity of a closed NMDA receptor channel. Diminazene and DAPI, in contrast, have an extended form and could not be trapped.
Prevention of parvovirus B19‐induced repetitive acute kidney failure by subcutaneous immunoglobulins
Authors: Bailly Elodie , Stefic Karl , Gatault Philippe , Miquelestorena‐Standley Elodie , Machet Marie‐Christine , Barbet Christelle , Barin Francis , Halimi Jean‐Michel
Published: October 2019

Human parvovirus B19 has been associated with various cases of kidney injuries with different glomerular phenotypes. In immunocompromised individuals, insufficient production of neutralizing antibodies can lead to chronic PVB19 carriage and manifestations. However, PVB19 DNA has been detected in bone marrow and peripheral blood for months or years in seemingly immunocompetent individuals, despite the presence of neutralizing antibodies. We report here PVB19‐induced recurrent anuric acute kidney failures in a 57‐year‐old man over a 7‐year period with persistent PVB19 infection and then PVB19‐associated cryoglobulinemia. Acute renal failures were preceded by influenza‐like syndrome associated with arthralgia, skin rash, and low‐grade fever. Serum, bone marrow, renal, and digestive PVB19 replication was found in the different episodes. Endocapillary proliferative glomerulonephritis evolved into membranoproliferative glomerulonephritis. Complete renal recovery occurred after each bout. Off‐label subcutaneous immunoglobulin therapy resulted in disappearance of blood and bone marrow PVB19 viral load and stopped the glomerulonephritis recurrence. Subcutaneous immunoglobulin therapy withdrawal resulted in renal relapse with cryoglobulin‐associated manifestations.
Identification and classification of epithelial cells in nephron segments by actin cytoskeleton patterns
Authors: Kumaran Girishkumar Kaitholil , Hanukoglu Israel
Published: October 2019

The basic functional unit in a kidney is the nephron, which is a long and morphologically segmented tubule. The nephron begins with a cluster of capillaries called glomerulus through which the blood is filtered into the Bowman's space. The filtrate flows through the nephron segments. During this flow, electrolytes and solutes are reabsorbed by channels and transport systems into the capillaries wrapped around the nephron. Many questions related to renal function focus on identifying the sites of expression of these systems. In this study, we mapped whole kidney sections by confocal microscopic imaging of fluorescent phalloidin, which binds to actin filaments. In tile scans (composed of hundreds of images) of these sections, the cortex and the medullary regions (outer and inner stripes of the outer medulla, and inner medulla) could be easily identified by their cytoskeletal patterns. At a higher resolution, we identified distinct features of the actin cytoskeleton in the apical, basal, and lateral borders of the cells. These features could be used to identify segments of a nephron (the proximal tubule, thin and thick segments of Henle's loop, and distal tubule), the collecting duct system, the papillary ducts in the papilla, and the urothelium that covers the pelvis. To verify our findings, we used additional markers, including aquaporin isoforms, cytokeratin 8‐18, and WGA lectin. This study highlights the power of high‐resolution confocal microscopy for identifying specific cell types using the simple probe of F‐actin‐binding phalloidin.
Frontal fibrosing alopecia in Asians: a retrospective clinical study
Authors: Suchonwanit Poonkiat , Pakornphadungsit Kallapan , Leerunyakul Kanchana , Khunkhet Saranya , Sriphojanart Tueboon , Rojhirunsakool Salinee
Published: October 2019

Background

Frontal fibrosing alopecia (FFA) is a distinctive form of primary lymphocytic cicatricial alopecia and predominantly occurs in postmenopausal women. The condition is increasing in prevalence worldwide. However, there is a paucity of information regarding FFA in Asians because of a lack of published literature. We aimed to describe the demographics, clinical and trichoscopic features, and treatment outcomes of FFA in Asian patients.

Methods

We conducted a retrospective clinical study including patients diagnosed with FFA. Data regarding demographics, clinical and trichoscopic findings, and treatment outcomes were collected. The data were analyzed using descriptive statistics.

Results

Fifty‐six Thai patients with FFA met the inclusion criteria. There were 54 females (96.4%) and two males (3.6%), and the average age of disease onset was 51.3 ± 6.3 years. All patients presented with frontotemporal hairline recession, and 49 patients (87.5%) experienced eyebrow loss. Trichoscopy in 35 patients revealed follicular dropout, perifollicular erythema, and lonely hair in 35 (100%), 29 (82.8%) and 26 patients (74.2%), respectively. Disease stabilization was superiorly observed in patients treated with a combination of topical corticosteroids and hydroxychloroquine or finasteride (79.3% and 73.3%, respectively).

Conclusion

Our study presents the largest series of FFA in Asians and reports mixed clinical patterns between Caucasian and African patients. Combination therapy of topical corticosteroids and hydroxychloroquine or the use of topical corticosteroids and finasteride may halt the progression of FFA in Asians.
Empowering leadership and meaningful work: the mediating role of learning goal orientation
Authors: Matsuo Makoto , Arai Kohei , Matsuo Takami
Published: October 2019

Drawing on positive psychology and self‐determination theories, this study investigates the direct and indirect effects of empowering leadership on meaningful work of employees, particularly through the mediation of learning goal orientation. Longitudinal survey data of 388 employees in medical institutions were used to test the hypotheses. The results support the direct positive relationship between empowering leadership and meaningful work, but also emphasize the mediating effect of learning goal orientation within this relationship. This study is among the first to examine the effect of mediation by learning goal orientation upon the relationship between empowering leadership and meaningful work.
Origins of global mountain plant biodiversity: Testing the ‘mountain‐geobiodiversity hypothesis’
Authors: Muellner‐Riehl Alexandra N. , Schnitzler Jan , Kissling W. Daniel , Mosbrugger Volker , Rijsdijk Kenneth F. , Seijmonsbergen Arie C. , Versteegh Hannes , Favre Adrien
Published: October 2019

Aim

Our objective is to analyse global‐scale patterns of mountain biodiversity and the driving forces leading to the observed patterns. More specifically, we test the ‘mountain geobiodiversity hypothesis’ (MGH) which is based on the assumption that it is not mountain‐uplift alone which drives the evolution of mountain biodiversity, but rather the combination of geodiversity evolution and Neogene and Pleistocene climate changes. We address the following questions: (a) Do areas of high geodiversity and high biodiversity in mountains overlap, that is can mountain geodiversity predict mountain biodiversity? (b) What is the role of Pleistocene climate change in shaping mountain biodiversity? (c) Did diversification rate shifts occur predominantly with the onset of more pronounced climate fluctuations in the late Neogene and Pleistocene fostering a ‘species pump’ effect, as predicted by the MGH?

Location

Global.

Taxon

Vascular plants.

Methods

We used generalized linear models to test to what extent vascular plant species diversity in mountains is explained by net primary productivity (NPP), geodiversity and Pleistocene climate fluctuations (i.e. changes in temperature between the Last Glacial Maximum [LGM] and today). In addition, we compiled dates of diversification rate shifts from mountain systems and investigated whether these shifts occurred predominantly before or after the global major climatic fluctuations of the late Neogene and Pleistocene.

Results

Both NPP and elevation range show a positive relationship, whereas Pleistocene climatic fluctuations show a negative impact on plant species diversity. The availability of climatic niche space during the LGM differs markedly among mountain systems. Shifts to higher diversification rates or starts of radiations showed the highest concentration from the late Miocene towards the Pleistocene, supporting the MGH. The most commonly inferred drivers of diversification were key innovations, geological processes (uplift) and climate.

Main conclusions

Our analyses point towards an important role of historical factors on mountain plant species richness. Mountain systems characterized by small elevational ranges and strong modifications of temperature profiles appear to harbour fewer radiations, and fewer species. In contrast, mountain systems with the largest elevational ranges and stronger overlap between today´s and LGM temperature profiles are also those where most plant radiations and highest species numbers were identified.
Chemical imaging of evolving amyloid plaque pathology and associated Aβ peptide aggregation in a transgenic mouse model of Alzheimer’s disease
Authors: Michno Wojciech , Wehrli Patrick , Meier Silvio R. , Sehlin Dag , Syvänen Stina , Zetterberg Henrik , Blennow Kaj , Hanrieder Jörg
Published: October 2019

One of the major hallmarks of Alzheimer’s disease (AD) pathology is the formation of extracellular amyloid β (Aβ) plaques. While Aβ has been suggested to be critical in inducing and, potentially, driving the disease, the molecular basis of AD pathogenesis is still under debate. Extracellular Aβ plaque pathology manifests itself upon aggregation of distinct Aβ peptides, resulting in morphologically different plaque morphotypes, including mainly diffuse and cored senile plaques. As plaque pathology precipitates long before any clinical symptoms occur, targeting the Aβ aggregation processes provides a promising target for early interventions. However, the chain of events of when, where and what Aβ species aggregate and form plaques remains unclear. The aim of this study was to investigate the potential of matrix‐assisted laser desorption/ionization imaging mass spectrometry as a tool to study the evolving pathology in transgenic mouse models for AD. To that end, we used an emerging, chemical imaging modality – matrix‐assisted laser desorption/ionization imaging mass spectrometry – that allows for delineating Aβ aggregation with specificity at the single plaque level. We identified that plaque formation occurs first in cortical regions and that these younger plaques contain higher levels of 42 amino acid‐long Aβ (Aβ1–42). Plaque maturation was found to be characterized by a relative increase in deposition of Aβ1–40, which was associated with the appearance of a cored morphology for those plaques. Finally, other C‐terminally truncated Aβ species (Aβ1–38 and Aβ1–39) exhibited a similar aggregation pattern as Aβ1–40, suggesting that these species have similar aggregation characteristics. These results suggest that initial plaque formation is seeded by Aβ1–42; a process that is followed by plaque maturation upon deposition of Aβ1–40 as well as deposition of other C‐terminally modified Aβ species.

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Benefits and Disadvantages of Individuals’ Multiple Team Membership: The Moderating Role of Organizational Tenure
Authors: van de Brake Hendrik J. , Walter Frank , Rink Floor A. , Essens Peter J. M. D. , van der Vegt Gerben S.
Published: October 2019

Many employees in today’s organizations are involved in more than one team at the same time. Building on the challenge‐hindrance stressor framework, this study investigates potential benefits and disadvantages of such multiple team membership (MTM) for individual employees. Furthermore, we extend this framework with insights from the job demands‐resources model to propose that, depending on an employee’s organizational tenure, individual MTM will differentially shape his or her perceptions of work challenge and role ambiguity, subsequently influencing the employee’s job performance and absenteeism. We tested our conceptual model using time‐lagged multi‐source data from a large organization of applied research (N = 1211). Our results demonstrate that, for employees with relatively low organizational tenure, MTM was negatively associated with perceived work challenge and positively associated with perceived role ambiguity, which in turn associated with lower job performance and higher absenteeism. For employees with higher organizational tenure, by contrast, MTM associated positively with their work challenge perceptions and subsequent performance outcomes, whereas MTM was unrelated to perceived role ambiguity as well as absenteeism. These findings identify relevant psychological mechanisms and a key contingency factor that explain when and why MTM may have positive or negative individual‐level consequences.
Cooled Radiofrequency Ablation Treatment of the Genicular Nerves in the Treatment of Osteoarthritic Knee Pain: 18‐ and 24‐Month Results
Authors: Hunter Corey , Davis Tim , Loudermilk Eric , Kapural Leonardo , DePalma Michael
Published: October 2019

Objective

The primary objective of this observational, prospective, multicenter study was to evaluate the long‐term outcomes, including pain, function, and perceived effect of treatment, in subjects undergoing cooled radiofrequency ablation (CRFA) who have pain due to osteoarthritis (OA) of the knee.

Methods

This analysis included a subset of subjects previously enrolled in a prospective, multicenter randomized study comparing the safety and effectiveness of CRFA and intra‐articular steroid injection in patients with knee OA through 12 months who were contacted to participate in this extension study. Subjects were enrolled if they agreed to participate in up to 2 additional follow‐ups, at 18 and 24 months.

Results

Eighty‐three subjects from the 5 participating sites underwent CRFA during the original study and were contacted for this extension study. Of the 33 subjects enrolled, 25 were evaluated at 18 months after CRFA treatment, and their mean numeric rating scale (NRS) score was 3.1 ± 2.7, with 12 subjects reporting ≥50% pain relief compared to baseline. At 24 months, 18 subjects reported a mean NRS score of 3.6 ± 2.8, with 11 demonstrating ≥50% pain relief. Functional improvement as measured by the Oxford Knee Score continued to be present, with an overall mean change from baseline of 26.0 ± 9.6 points at 18 months and 29.9 ± 10.4 points at 24 months.

Conclusion

In this subset of subjects from a randomized controlled trial, CRFA provided sustained pain relief, improved function, and perceived positive effect through 24 months for subjects with OA knee pain with no safety concerns identified.
Non‐invasive ventilation versus oxygen therapy in cystic fibrosis: Long‐term effects – Reply
Authors: Milross Maree A. , Piper Amanda J. , Dwyer Tiffany J. , Bye Peter T.P.
Published: October 2019

See Letter
By failing to prepare, you are preparing your anterior cruciate ligament to fail
Authors: Staynor Jonathan M. D. , Alderson Jacqueline A. , Byrne Sean , Rossi Marcel , Donnelly Cyril J.
Published: October 2019

There is strong evidence linking an athlete's movement technique during sidestepping with anterior cruciate ligament (ACL) injury risk. However, it is unclear how these injurious postures are influenced by prior movement. We aim to describe preparatory trunk and thigh kinematics at toe‐off of the penultimate‐step and flight‐phase angular momenta, and explore their associations with frontal‐plane risk factors during unplanned sidestepping maneuvers. We analyzed kinematic and kinetic data of 33 male Australian Football players performing unplanned sidestepping tasks (103 trials). Linear mixed models tested for reliable associations between ACL injury risk during weight acceptance of the execution‐step, with preparatory kinematics and angular momenta of the trunk and thigh during the penultimate‐step. Multi‐planar flight‐phase trunk momenta along with hip abduction angle at penultimate‐step toe‐off were significantly associated with peak knee valgus moments during the execution‐step (R2 = .21, P < .01). Execution‐step trunk lateral flexion was significantly predicted by frontal and sagittal‐plane preparatory trunk positioning at toe‐off of the penultimate‐step (R2 = .44, P < .01). Multi‐planar flight‐phase trunk momenta as well as multi‐planar trunk and hip positioning at penultimate‐step toe‐off were associated with hip abduction during the execution‐step (R2 = .53, P < .01). Preparatory positioning of the trunk and hip, along with flight‐phase trunk momentum adjusting this positioning are linked to known ACL injury risk factors. We recommend that during the penultimate‐step athletes maintain an upright trunk, as well as minimize frontal‐plane trunk momentum and transverse‐plane trunk momentum toward the sidestep direction to reduce risk of ACL injury during unplanned sidesteps.
HLA‐C*07:06:01:06—A new HLA‐C allele identified in an Ao tribal individual from Nagaland, North‐East India
Authors: Keppen Chenole , Sharma Akanksha , Gautam Shashi K. , Khamo Vinotsole , Kanga Uma
Published: October 2019

Two nucleotide changes in the 3′untranslated region of HLA‐C*07:06:01:01 results in the novel allele, HLA‐C*07:06:01:06.
Evaluation of the role of transhepatic flow in postoperative outcomes following major hepatectomy (THEFLOW): study protocol for a single-centre, non-interventional cohort study
Authors: Golriz Mohammad , Lemekhova Anastasia , Khajeh Elias , Ghamarnejad Omid , Al-Saeedi Mohammed , Strobel Oliver , Hackert Thilo , Müller-Stich Beat , Schneider Martin , Berchtold Christoph , Tinoush Parham , Mayer Philipp , Chang De-Hua , Weiss Karl Heinz , Hoffmann Katrin , Mehrabi Arianeb
Published: October 2019

Introduction

Liver resection is the only curative treatment for primary and secondary hepatic tumours. Improvements in perioperative preparation of patients and new surgical developments have made complex liver resections possible. However, small for size and flow syndrome (SFSF) is still a challenging issue, rendering patients inoperable and causing postoperative morbidity and mortality. Although the role of transhepatic flow in the postoperative outcome has been shown in small partial liver transplantation and experimental studies of SFSF, this has never been studied in the clinical setting following liver resection. The aim of this study is to systematically evaluate transhepatic flow changes following major liver resection and its correlation with postoperative outcomes.

Methods and analysis

The TransHEpatic FLOW (THEFLOW) study is a single-centre, non-interventional cohort study, and aims to enrol 50 patients undergoing major hepatectomy (defined as hemihepatectomy or extended hepatectomy based on the Brisbane classification) with or without prior chemotherapy. The portal venous flow, hepatic artery flow and portal venous pressure are measured before and after each resection. All patients are followed-up for 3 months after the operation. During each evaluation, standard clinical data, posthepatectomy liver failure and overall morbidity and mortality will be recorded. THEFLOW study was initiated on 25 March 2018 and is expected to progress for 2 years.

Ethics and dissemination

This protocol study received approval from the Ethics Committee of the University of Heidelberg (registration number: S576/2017). The results of this study will be published in a peer-reviewed journal, and will also be presented at medical meetings.

Trial registration number

NCT03762876.
Prevalence and factors associated with frailty among community-dwelling older people in rural Thanjavur district of South India: a cross-sectional study
Authors: Kendhapedi Kirubakaran Kesavan , Devasenapathy Niveditha
Published: October 2019

Objective

There is sparse data on the prevalence of frailty from rural parts of India. Our aim was to estimate prevalence of frailty among community-dwelling older people in rural South Indian population and explore socio-demographic factors associated with frailty. We further explored the associations between frailty with fear of falling and falls.

Design

Community based cross-sectional study.

Setting

Four villages in Thanjavur district of Southern India.

Participants

Random sample of adults aged 60 years and above from four villages.

Methods

We sampled community-dwelling older adults from the electoral list of four villages using stratified random sampling. We report prevalence of frailty as defined by physical definition (Fried’s Phenotype), accumulation of deficits (Frailty Index) and multi-domain definition (Tilburg Frailty Indicator). We report proportion of agreement of frailty status between the frailty tools. We used logistic regressions with robust SEs to examine the associations between socio-demographic determinants with frailty and the association between frailty with fear of falling and falls.

Results

Among the 408 participants, the weighted (non-response and poststratification for sex) prevalence and 95% CI of frailty was 28% (18.9 to 28.1) for physical definition, 59% (53.9 to 64.3) for accumulation of deficits and 63% (57.4 to 67.6) for multi-domain definition. Frailty Index and Tilburg Frailty Indicator had good agreement (80%). Age, female, lower education, lower socioeconomic status, minimum physical activity in routine work were independently associated with frailty irrespective of the frailty definitions. Frail elderly had higher odds of falls as well as fear of falling compared with non-frail, irrespective of the definitions.

Conclusion

Prevalence of frailty among older people in rural Thanjavur district of South India was high compared with low-income and middle-income countries. Understanding the modifiable determinants of frailty can provide a valuable reference for future prevention and intervention.
Complete trajectory reconstruction from sparse mobile phone data
Authors: Chen Guangshuo , Viana Aline Carneiro , Fiore Marco , Sarraute Carlos
Published: October 2019

Mobile phone data are a popular source of positioning information in many recent studies that have largely improved our understanding of human mobility. These data consist of time-stamped and geo-referenced communication events recorded by network operators, on a per-subscriber basis. They allow for unprecedented tracking of populations of millions of individuals over long periods that span months. Nevertheless, due to the uneven processes that govern mobile communications, the sampling of user locations provided by mobile phone data tends to be sparse and irregular in time, leading to substantial gaps in the resulting trajectory information. In this paper, we illustrate the severity of the problem through an empirical study of a large-scale Call Detail Records (CDR) dataset. We then propose Context-enhanced Trajectory Reconstruction, a new technique that hinges on tensor factorization as a core method to complete individual CDR-based trajectories. The proposed solution infers missing locations with a median displacement within two network cells from the actual position of the user, on an hourly basis and even when as little as 1% of her original mobility is known. Our approach lets us revisit seminal works in the light of complete mobility data, unveiling potential biases that incomplete trajectories obtained from legacy CDR induce on key results about human mobility laws, trajectory uniqueness, and movement predictability.
Testicular melanization in anuran species: ontogeny and sexual maturity
Authors: Goldberg Javier , Valverde Bruno S.L. , Franco-Belussi Lilian
Published: October 2019

Testicular melanization in anurans may be absent or present with different degrees of intensity. When present, the color is due to the concentration of melanocytes in external (surface) and interstitial tissue. The function of this coloration is not fully known and we ask if melanization during testicular development, in species with highly pigmented testes in adults, is correlated with germ cells maturation. To do so, we selected four anuran species with highly pigmented testes. Species differed in the amount of interstitial melanin. Pigmentation increased throughout ontogeny, but with interspecific variation in the onset and rate. The rate of melanization progressed with testicular differentiation. A threshold for interstitial pigmentation seems to be reached with the advancement of spermatogenesis. Overall, testicular pigmentation adds a new chapter to the study of sexual maturity in anurans.
Pathogenicity of the root-lesion nematode, Pratylenchus zeae, on rice genotypes under different hydro-ecologies in Tanzania
Authors: Nzogela Yasinta Beda , Landschoot Sofie , Kihupi Ashura-Luzi , Coyne Danny L. , Gheysen Godelieve
Published: October 2019

The root-lesion nematode, Pratylenchus zeae, is commonly found in upland rice fields. To measure the impact of the nematode on rice production, a screenhouse experiment was conducted using two farmer-adapted Oryza sativa cultivars, ‘Supa’ (‘SurinamV-880’) and ‘SARO-5’ (‘TXD 306’), under flooded, upland and drought water regimes imposed at 7 days post-inoculation of mixed-stage nematodes (200, 500, 1000, 3000 and 10 000 plant−1). Growth and yield parameters were recorded, and the experiment was terminated after 5 months. ‘Supa’ was shown to be resistant to P. zeae, while ‘SARO-5’ was susceptible. Pratylenchus zeae reduced the growth and yield of both cultivars, though more for ‘SARO-5’ than for ‘Supa’. Yield decreased with increasing final nematode densities. Pratylenchus zeae reproduction was highest at 200 and 500 inoculum levels and under upland water conditions. The yield of ‘SARO-5’ was greater than that of ‘Supa’ under flooded conditions and with no or 200 and 500 nematode inoculum levels, but with high P. zeae inoculum ‘Supa’ yield was better than ‘SARO-5’.
The Construction of a Philosophical Textbook: Some Remarks on Nikephoros Blemmydes’ Epitome physica
Authors: Valente Stefano
Published: October 2019

The Compendium on Physics (Epitome physica) by the Byzantine theologian and philosopher Nikephoros Blemmydes (13th cent.) was a very successful textbook on Natural Philosophy containing a summary of physics, meteorology and astronomy. This compendium was also conceived for being used as support for teaching. For his purposes, Blemmydes combined passages taken from different sources into a new text: Aristotle and his commentators as well as Cleomedes were his main sources. Since a manuscript with an earlier version of the text still survives, it is also possible to go deeper into the workshop of this Byzantine author and to investigate the use of the sources in both textual stages. This paper will therefore be devoted to analysing the inner structure of the Epitome physica and Blemmydes’ activity as an author.
La metodologia del Commento nei trattati sull’interpretatio iuris di età umanistica
Authors: Luongo Dario
Published: October 2019

In this paper we examine some treatises about interpretatio iuris that encode the methodology of the Italian ‘scuola del commento’, from the end of the Middle Ages onwards. Those writings reaffirm the primacy of the mens or sensus over the verba of the law. In all these treatises, the law is considered the expression of ratio rather than of the voluntas principis: therefore, its efficacy must be addressed by means of specific and different jurisprudential work. We illustrate this methodology through a detailed analysis of the treatises by C. Rogerio, B. Cepolla, S. Federici, P. A. Gammaro.
Cioran–Eliade, la correspondance de jeunesse
Authors: Brad Rodica Maria
Published: October 2019

Emile Cioran et Mircea Eliade ont été liés par une amitié à part, de très longue durée. Cette amitié spéciale qui les a unis s’exprime aussi dans leur correspondance de jeunesse, précisément dans les lettres réciproques écrites en roumain de 1933 à 1946. Nous reconstituons cet échange épistolaire à travers deux sources: les lettres de Cioran à Eliade publiées dans le volume Scrisori către cei de-acasă (1995a) et les lettres d’Eliade à Cioran publiées par Mircea Handoca dans le volume de correspondance Mircea Eliade, Europa, Asia, America . . . (1999). Documents biographiques importants, ces lettres permettent de pénétrer dans l’intimité de ces deux jeunes auteurs.
Linkage of lncRNA CRNDE sponging miR-181a-5p with aggravated inflammation underlying sepsis
Authors: Wang Yijun , Xu Ziqiang , Yue Dongyou , Zeng Zhenhua , Yuan Weijie , Xu Ke
Published: October 2019

This investigation was performed to verify whether lncRNA CRNDE sponging miR-181a-5p was involved with sepsis-relevant inflammatory dysfunctions. Aggregately 136 sepsis patients and 151 healthy people were recruited, and their fasting peripheral blood was gathered to detect expressions of CRNDE and miR-181a-5p. In addition, THP-1 cells were transfected with si-CRNDE, miR-181a-5p mimic, pcDNA3.1-TLR4 and si-TLR4, and then sepsis-specific inflammatory cytokines within the cells were quantified. The sponging relationships between CRNDE and miR-181a-5p, as well as between miR-181a-5p and TLR4, were ascertained by means of luciferase reporter gene assay. The experimental results revealed that over-expressed CRNDE and under-expressed miR-181a-5p were associated with shortened lifespan of sepsis patients. Mechanically, si-CRNDE-1 and miR-181a-5p mimic were able to reverse the promoting effects of LPS on production of NF-kB, TNF-α, IL-1β and IL-6 by THP-1 cells. Moreover, the expressional change of miR-181a-5p in THP-1 cells was in part owing to its being sponged by CRNDE. Lastly, TLR4, subjected to targeted modification of miR-181a-5p, was capable of disturbing the contribution of CRNDE and miR-181a-5p to THP-1 cells’ release of NF-kB, TNF-α, IL-1β and IL-6. Collectively, the CRNDE/miR-181a-5p/TLR4 axis seemed to have potential in modifying sepsis-related inflammatory pathogenesis, which offered a direction for sepsis diagnosis and treatment.
AMIS and antigen modulation: of mice and men
Authors: Westhoff Connie M.
Published: October 2019

In this issue of Blood, Liu et al investigated the mechanism of action in antibody-mediated immune suppression (AMIS) and the fate of antigen in a KEL mouse model system.1
Looking up for AML in Down syndrome
Authors: Shand Jessica C.
Published: October 2019

In this issue of Blood, Taub et al report improved survival with reduced-intensity therapy and the prognostic significance of end-induction residual disease from the largest prospective trial to date in children with myeloid leukemia of Down syndrome (ML-DS): the Children’s Oncology Group AAML0431 study.1
Targeting EBV-positive B- and T/NK-cell lymphomas
Authors: Long Heather M.
Published: October 2019

In this issue of Blood, McLaughlin et al demonstrate the safety and efficacy of donor-derived Epstein-Barr virus (EBV) latent membrane protein (LMP)-specific T cells to prevent relapse of aggressive EBV-positive B- or T/NK-cell lymphomas following allogeneic hematopoietic stem cell transplantation (HSCT).1
Natural History of Renal Vein Thrombosis: Incidence of Recurrent Venous Thromboembolism and Survival.
Authors: Wysokinski Waldemar E. , Gosk-Bierska Izabela , Karnicki Krzysztof , Pruthi Rajiv K. , McBane Robert D.
Published: October 2019

Renal vein thrombosis (RVT), although uncommon, is associated with considerable morbidity and mortality. Neither the etiology nor the natural history of RVT has been adequately described in a large case series.

Objective: To determine whether incident RVT is associated with an increased likelihood of recurrent local and systemic venous thromboembolic disease.

Methods: Cases were identified by reviewing the Diagnostic Index for all patients with RVT at our institution between 1981 and 2000.

Results: The study group consisted of 240 patients (34% women) with a mean age 55± 19 years. The diagnosis of RVT was made by CT (35%), Duplex Ultrasound (35%), MRI±gadolinium (10%) and either at surgery or autopsy in the remainder. The underlying etiology was deemed to be malignancy in 65% of cases. Of these, renal cell carcinoma (74%) and Wilms tumor (3%) made up the majority. Nephrotic syndrome primarily membranous glomerulonephritis was the second most common underlying etiology (23%). Of those tested, a definable thrombophilia was found in only 13 cases including lupus anticoagulant/antiphospholipid antibody (n=4); deficiencies of protein C or S, (n=2 each); heparin induced thrombocytopenia (n=2); antithrombin deficiency, dysfibrinogenemia and hyperhomocysteinemia (n=1 each). Eighty-one patients (34%) were treated with warfarin. Over a mean follow up of 3 years, the rate of recurrence of venous thrombosis at any site was 5%. The mortality rate over this time period was 49%.

Conclusion: RVT represents a distinct clinical entity relative to venous thromboembolism of the lower extremity. The observed low rate of recurrence may be explained by the high mortality rate owing to a high percentage of renal malignancy. RVT should prompt an evaluation for an underlying renal malignancy.
Protein Profiling in Childhood Precursor B Acute Lymphoblastic Leukemia using Surface Enhanced Laser Desorption/Ionization (SELDI) Mass Spectrometry: A Study of Archival Samples.
Authors: Czader Magdalena , Dobrolecki Lacey , Ragg Suzanne , Orazi Attilio , Hickey Robert
Published: October 2019

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Even though the risk-group adjusted therapies have dramatically improved the outcome, approximately 25% of ALL patients experience relapse of the disease. Recent gene microarray studies showed distinct gene expression profiles for immunophenotypically and genetically defined ALL subgroups and their association with treatment outcome. However, not only transcriptional control, but also a variety of post-transcriptional/post-translational modifications, play an important role in regulating protein expression and function, and ultimately may prove informative for predicting tumor behavior. In this pilot study, we hypothesize that in childhood precursor B ALL surface enhanced laser desorption/ionization mass spectrometry can identify proteins discriminating between age and WBC defined risk-groups. Ultimately, specific proteins may emerge that will provide predictive information beyond currently known prognostic factors. Our pilot series consisted of 78 pediatric precursor B ALL patients. The protein samples were obtained from archival Wright-Giemsa stained bone marrow aspirate smears. Initial experiments, using CM10 and IMAC30 chips demonstrated that the latter provided superior resolution and presented more numerous protein peaks. The protein mass spectra were originally generated using laser intensities of 150 and 160 arbitrary units. Data obtained at laser intensity of 160 was used for further analysis. Twenty-three protein peaks common to all samples were identified within examined range (up to 30 kDa; CiphergenExpressData Manager software, Ciphergen, Fremont, CA). These proteins span the spectrum between 1.0 to 15.2 kDa. The comparison of protein profiles between standard- and high-risk groups (SR and HR, respectively), WBC subgroups (less and more than 50 K/ul) and in the prognostic age groups was performed. Two protein peaks, 3.0 and 1.7 kDa, discriminated between SR and HR (p=0.001 and p=0.04, respectively). Both proteins showed significantly higher intensity in SR group. The protein peak of 3.0 kDa was further confirmed to discriminate between patients with low and high presentation WBC (p=0.01). Our results demonstrate that reliable quality protein profiles can be obtained using archival Wright-Giemsa stained bone marrow aspirate smears. Using this technology, specific proteins were found to discriminate between prognostic risk-groups. We are currently analyzing precursor B-cells sorted from non-neoplastic bone marrows to compare protein profiles to our pilot precursor B ALL series in a cluster analysis. The use of archival material facilitates analysis of large patient series and identification of protein panels with prognostic power, which can be validated in prospective studies.
Microrna Expression Profiling in Acute Myelogenous Leukemia.
Authors: Suarez Saiz Fernando J. , San-Marina Serban , Minden Mark D.
Published: October 2019

Acute myelogenous leukemia (AML) arises due to changes in gene expression that block or alter the normal differentiation program of hematopoietic stem cells. A variety of mutations in protein-encoding genes have been shown to contribute to the development of leukemia. Recently a new class of genes called microRNAs (miRNAs) have been identified. miRNAs are a subgroup of highly conserved, non-coding RNAs found only in eukaryotes. They do not encode proteins, and appear to have a significant effect on the proteome of a cell. Their conservation between species suggests their involvement in important biological functions, and in fact been shown to be involved in hematopoietic differentiation. While the function of most miRNAs is still unknown, it is believed that they regulate expression of target mRNAs by using the siRNA machinery either to promote degradation of the mRNA or to block its translation. To begin to understand the role of miRNAs in AML, we used Quantitative Polymerase Chain Reaction (QPCR) to measure the expression level of 20 miRNA precursors in the pro erythroid cell line K562, the pro-myelocytic cell line NB4, the myelomococytic cell line OCI/AML2, AML patients’ blasts and in normal bone marrow (NBM). The investigated miRNAs included some that are known to be specific for hematopoietic tissues or involved in hematopoietic differentiation, as well as all the miRNAs in chromosome 7, a hot spot for gene deletion in AML. Our findings indicate that miRNAs are differentially expressed in patients and cell lines when compared among themselves and against normal bone marrow. For example pre-miR-142 was expressed in NBM and K562 but was found to be elevated in OCI/AML2, NB4 and in all patient samples. Pre-miR-20 was found to be overexpressed in only a subset of patients. Other miRNAs like pre-miR-335 and pre-miR-148a were expressed in NBM and in some patients and not in the cell lines. In an effort to identify possible regulators of miRNA expression, we analyzed the upstream region of pre-miR-142 and found an LMO2 binding site. In AML, the LMO2 gene can be overexpressed relative to normal bone marrow and healthy lymphocytes. This transcription factor is involved in the regulation of genes important in the development of blood cells. To investigate if LMO2 could be involved in the regulation of miR-142 expression, we performed chromatin immunoprecipitation (ChIP) from K562 using an anti-LMO2 antibody. Only the LMO2 immunoprecipitation, and not those from the pre-immune control, were enriched in promoter DNA for pre-miR-142. This is consistent with the observation that miRNAs and coding RNAs can be regulated by the same environmental signals. Based on this observation we propose that oncogenes regulate in part the phenotype and biological behaviour of leukemia by affecting the expression of miRNAs. This further suggests that different forms of leukemia may be recognized based upon the spectrum of miRNAs they express.
Pegfilgrastim Shows Safety and Efficacy Similar to Filgrastim in Patients Undergoing Autologous Stem Cell Transplantation for Hematological Malignancies.
Authors: Neumeister Peter , Holub Robert , Staber Phillipe B. , Linkesch Werner
Published: October 2019

Infectious complications are frequent events in patients undergoing high dose cytotoxic chemotherapy with subsequent autologous hematopoietic stem cell transplantation. In order to determine whether a single subcutaneous injection of pegfilgrastim (6mg) is as safe and effective as daily filgrastim (5mcg/kg/d) for reducing duration of grade 4 neutropenia and infectious complications, 60 consecutive autologous stem cell transplantations (ASCT) performed for various hematological malignancies have been analyzed retrospectively at our institution. 24 patients undergoing 30 consecutive ASCT received a single subcutaneous injection of 6 mg pegfilgrastim on day 5 after transplantation and were compared retrospectively to 30 patients receiving 5mcg/kg/d of filgrastim starting from day 7 post-transplantation. Both patient cohorts were comparable with respect to baseline patient and transplant characteristics. Duration of grade 4 neutropenia, infectious complications including incidence of febrile neutropenia, microbiological surveillance data and safety parameters were assessed. The mean duration of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 8.3 and 9.5 days, respectively (p=0,058). The results of the two groups were also not significantly different for febrile neutropenia, time to neutrophil recovery and toxicity profile, including bone pain episodes. However, a higher incidence of infectious complications associated with the filgrastim vs the pegfilgrastim group could be observed (50% vs 20%) (p=0,011). Pegfilgrastim was safe and well tolerated in this patient population. A single injection of pegfilgrastim administered at day 5 post-transplant shows comparable safety and efficacy profiles to that provided by daily injections of filgrastim. A fixed-dose pegfilgrastim facilitates the management of aplasia following autologous stem cell transplantation and may offer significant benefits for patients and health care providers. Consequently, it may serve as an attractive alternative to a repetitive single G-CSF administration modus. However, prospective randomized studies are warranted to corroborate the results obtained by this retrospective analysis.
Increased Bone Marrow Iron Stores, Severe Mucositis and Large Area under the Curve (AUC) of Profound Neutropenia Predict Severe Infection in 382 Myeloma Patients Undergoing Melphalan - Autologous Stem Cell Transplantation (MEL-ASCT).
Authors: Anaissie Elias J. , Miceli Marisa H. , Dong Li , Grazziutti Monica L. , Rajan Sabitha , Talamo Giampaolo , Thertulien Raymond , Fassas Anasthasios , Tricot Guido , Barlogie Bart
Published: October 2019

Background: MEL-ASCT is standard therapy for multiple myeloma (MM) but is associated with severe infections, at times life-threatening.

Objective: To determine the risk factors for severe infection (bacteremia, septic shock, colitis, pneumonia) following MEL - ASCT for MM.

Materials and Methods: 382 consecutive MM patients (pts) enrolled in our Total Therapy 2 protocol and who received their first MEL - ASCT between 10/1998 and 12/2002 were included. Variables evaluated included age, sex and MM remission status, severity of mucositis and others. Because of the known association between increased body iron stores and infection, pre-ASCT bone marrow (BM) iron stores were also evaluated. The AUC for severe neutropenia (<100 absolute neutrophils (ANC) / mL) was used as a single variable accounting for both the depth and duration of neutropenia.

Results: Median age was 56 years (range: 30–76) and 235 pts (62 %) were males. Severe infections developed in 77 pts (20%) including pneumonia (42 pts). Pre-ASCT risk factors for infection by univariate analysis were increased BM iron stores (OR= 3.601; 95%CI 1.795–7.222; p<0.0007) and low platelets counts (OR for -1000 platelets/μL = 0.997; 95% CI 0.994 – 1; p=0.0381). Increased BM iron stores remained significant by multivariate analysis (OR= 3.601; 95% CI 1.795–7.222; p<0.0007). Post-ASCT risk factors that were significant by both univariate and multivariate analysis were severe mucositis (Grades 3–4 by NCI Common Toxicity Criteria) (OR=1.916; 95% 1.093–3.36; p=0.02) and AUC of severe neutropenia (OR= 1.001/unit; 95% 1–1.002; p=0.03). Neither the duration (days with ANC <1000 / mL) nor the depth of moderate neutropenia (AUC < 1000 neutrophils / mL) predicted infection.

Conclusion: MM pts scheduled to undergo MEL - ASCT and who have increased BM iron stores, and those who develop severe mucositis and / or prolonged and profound neutropenia following ASCT should be considered at greater risk for developing severe infection. AUC of severe neutropenia is a useful single marker of both depth and duration of neutropenia and should be included in studies evaluating risk for infection in neutropenic pts.
NK Cell Recognition of Hepatocellular Carcinoma by Specific Induction of NKG2D Ligands Following Treatment with the Histone Deacetylase Inhibitor Sodium Valproate.
Authors: Salih Helmut R. , Armeanu Sorin , Lauer Ulrich M. , Venturelli Sascha , Pathil Anita , Smirnow Irina , Wagner Annika , Kanz Lothar , Steinle Alexander L. , Bitzer Michael
Published: October 2019

Histone deacetylase inhibitors (HDAC-I) are currently being evaluated as novel treatment for various malignancies. Recently, the HDAC-I sodium valproate (VPA) was shown to exert anti-neoplastic effects on human hepatoma cells while being well tolerated by primary human hepatocytes (PHH). However, the mechanisms underlying this differential mode of action are unclear. In this study, we used microarray analysis to unravel alterations of genes in hepatoma cells upon treatment with VPA. VPA induced the transcription of MICA and MICB, the ligands of the activating immunoreceptor NKG2D which is expressed on cytotoxic lymphocytes and has been shown to play a central role in the immune surveillance of tumors. Changes in MIC mRNA were mirrored by an increase of cell surface, soluble and total MIC protein as determined by immunofluorescense, flow cytometry and ELISA techniques. No significant changes of the NKG2D ligands (NKG2DL) ULBP1-3 were observed. Most importantly, VPA treatment did not induce MIC protein expression in PHH. The VPA-induced MIC expression profoundly triggered lysis of hepatoma cells by NK92 NK cells, which was abrogated by addition of a NKG2D antibody. Since the strength of an anti-tumor response by NK cells and CD8 T cells is critically depending on NKG2DL expression levels and the HDAC-I VPA mediates lysis of hepatoma cells via specific induction of NKG2DL, our results suggest a potential use of VPA in priming tumor cells for innate immune effector mechanisms.