bluuebunny/crossref_metadata_2025 huggingface dataset:
Light Emitting Diode (LED) Phototherapy versus Conventional Phototherapy in Neonatal Hyperbilirubinemia: A Single Blinded Randomized Control Trial from Coastal India
Authors: Gutta Sreesravya , Shenoy Janardhan , Kamath Sowmini P. , Mithra Prasanna , Baliga B. Shantharam , Sarpangala Muralikeshava , Srinivasan Mukund
Published: April 2019

Neonatal hyperbilirubinemia is a common problem with potentiality to cause irreversible brain damage. Reduction of serum bilirubin level is essential to minimize such damage. Compact fluorescent tubes, halogen bulbs, fiber optic blankets, and LEDs are commonly used light sources for phototherapy with varying efficacies. This study aimed at evaluating the effect of LED versus conventional phototherapy on (a) rate of reduction in total serum bilirubin levels, (b) effect on urinary lumirubin excretion, and (c) comparing side effects of phototherapies among neonates with hyperbilirubinemia. In this randomized control trial, 166 neonates ≥ 35 weeks of age requiring phototherapy were recruited and further divided into 2 groups [LED (83) and conventional (83)] by using computer generated random numbers. Serial total serum bilirubin levels and random urinary lumirubin levels were collected and side effects of phototherapy were noted. Rate of fall in total serum bilirubin levels (TSB, μmol/L/hour) and random urinary lumirubin levels were computed. Data were collected using a pretested proforma. Analysis was done with Statistical Package for Social Sciences (SPSS) version 11.5. Independent sample “t” test and Chi-square tests were used with p value of <0.05 being significant. Significant difference was documented in mean rate of decrease of TSB (μmol/L/hour) in LED group (5.3 ± 2.91) when compared to conventional group (3.76 ± 2.39) (p <0.001). A significant increase in mean random urinary lumirubin levels (arbitrary units) was observed in LED group (129.01 ± 33.18) when compared to conventional group (114.44 ± 44.84) (p = 0.021). Side effects were minimal and comparable in both groups. This study concludes the rates of decrease in total serum bilirubin levels and increase in urinary lumirubin levels were significant with LED when compared with conventional phototherapy, implying LED to be more efficacious.
Stochastic Lattice Modelling of the Force‐Displacement and Cracking Behaviour of the Steel Reinforced Tie
Authors: Zabulionis Darius , Lukoševičienė Ona , Kačianauskas Rimantas , Tumonis Liudas , Kliukas Romualdas
Published: April 2019

The stochastic modelling of the microcracking and the force‐displacement behaviour of the tensile steel reinforced tie using the lattice model is presented in the current article. The three‐dimension problem of the modelling of the tie is reduced to the two‐dimensional so as the main stiffness parameters of the concrete and the reinforcement of the two‐dimensional model would be the same as for the three‐dimensional. The concrete and steel obey the Hook law. All elastic constants, as well as dimensions of the tie, were assumed as the deterministic quantities except for the critical concrete tensile strains which were treated as a two‐dimensional stationary uncorrelated truncated Gaussian random field. The discrete element approach and the explicit integration scheme have been used for the modelling. The estimations of the main parameters of the force‐displacement behaviour stochastic process and other statistical indexes were obtained using 72 realization of the force‐displacement behaviour of a chosen model. Extra two stochastic realizations of the two different models, as well as three deterministic models, were modelled to compare stochastic and deterministic behaviour of the force‐displacement behaviour. The analysis showed that the force‐displacement behaviour of the tie under tensile force cannot be treated as a Gaussian stochastic process when the p value is 0.05 at the small displacements and within the interval when the cracking of the concrete is very intensive. However, at the bigger displacements, when the cracking becomes less intensive, the tensile force can be treated as a Gaussian random variable.
MiR-455-5p Suppresses the Progression of Prostate Cancer by Targeting CCR5
Authors: Xing Qianwei , Xie Huyang , Zhu Bingye , Sun Zhiwei , Huang Yeqing
Published: April 2019

Accumulated evidence indicates that miR-455-5p functions as tumor suppressor in the progression of various cancers. However, the mechanism through which miR-455-5p influences the tumorigenesis of human prostate cancer (PCa) remains undetermined. In this study, reanalysis of data obtained from the Memorial Sloan Kettering Cancer Center showed that miR-455-5p can be used as biomarker for PCa diagnosis and predictor of poor prognosis. Functional assays indicated that miR-455-5p overexpression could suppress cellular proliferation, inhibit tumor growth, and trigger apoptosis by activating and cleaving caspase 3. We experimentally verified that miR-455-5p negatively regulated the C–C motif chemokine receptor 5 (CCR5). Overall, our data demonstrate that miR-455-5p suppressed PCa cellular proliferation and induced cell apoptosis by downregulating CCR5. Thus, miR-455-5p may be considered a new therapeutic strategy for PCa.
Epigenetic Modulation on Tau Phosphorylation in Alzheimer’s Disease
Authors: Yu Chao-Chao , Jiang Tao , Yang Ao-Fei , Du Yan-Jun , Wu Miao , Kong Li-Hong
Published: April 2019

Tau hyperphosphorylation is a typical pathological change in Alzheimer’s disease (AD) and is involved in the early onset and progression of AD. Epigenetic modification refers to heritable alterations in gene expression that are not caused by direct changes in the DNA sequence of the gene. Epigenetic modifications, such as noncoding RNA regulation, DNA methylation, and histone modification, can directly or indirectly affect the regulation of tau phosphorylation, thereby participating in AD development and progression. This review summarizes the current research progress on the mechanisms of epigenetic modification associated with tau phosphorylation.
Acceleration of Bone Regeneration in Critical-Size Defect Using BMP-9-Loaded nHA/ColI/MWCNTs Scaffolds Seeded with Bone Marrow Mesenchymal Stem Cells
Authors: Zhang Ran , Li Xuewen , Liu Yao , Gao Xiaobo , Zhu Tong , Lu Li
Published: April 2019

Biocompatible scaffolding materials play an important role in bone tissue engineering. This study sought to develop and characterize a nano-hydroxyapatite (nHA)/collagen I (ColI)/multi-walled carbon nanotube (MWCNT) composite scaffold loaded with recombinant bone morphogenetic protein-9 (BMP-9) for bone tissue engineering by in vitro and in vivo experiments. The composite nHA/ColI/MWCNT scaffolds were fabricated at various concentrations of MWCNTs (0.5, 1, and 1.5% wt) by blending and freeze drying. The porosity, swelling rate, water absorption rate, mechanical properties, and biocompatibility of scaffolds were measured. After loading with BMP-9, bone marrow mesenchymal stem cells (BMMSCs) were seeded to evaluate their characteristics in vitro and in a critical sized defect in Sprague-Dawley rats in vivo. It was shown that the 1% MWCNT group was the most suitable for bone tissue engineering. Our results demonstrated that scaffolds loaded with BMP-9 promoted differentiation of BMMSCs into osteoblasts in vitro and induced more bone formation in vivo. To conclude, nHA/ColI/MWCNT scaffolds loaded with BMP-9 possess high biocompatibility and osteogenesis and are a good candidate for use in bone tissue engineering.
Accidental Overdose of Paliperidone Palmitate
Authors: Ojimba Chiedozie , Oyelakin Ayotomide , Khandaker Taher
Published: April 2019

Long-acting injectable (LAI) antipsychotics first introduced in 1960s are useful in the treatment of schizophrenic patients with poor medication adherence due to their maintaining feature of therapeutic plasma level without daily administration. Paliperidone Palmitate is one of such LAI antipsychotic drugs used due to its benefit of maintaining a therapeutic plasma level with four-week interval of injections. We report the case of a 21-year-old male with a history of mental illness that presented with selective mutism, disorganized speech, thought process and behavior, and auditory hallucinations who accidentally received 624 mg Paliperidone Palmitate intramuscularly with no reported side effects after 2 weeks of monitoring and observation. Paliperidone is a D2, 5HT2A receptor antagonist with additional antagonist activity at α-1 and α-2, H-1 receptor sites, and four metabolic pathways identified for its metabolism. Studies have reported adverse effects such as acute dystonia, acute renal failure, and cardiovascular abnormalities with Paliperidone overdose; however there is no reported literature on Paliperidone Palmitate overdose, though there have been reported cases of Paliperidone Palmitate side effects of hypersexuality and angioedema with the standard dose.
Linking De Novo Assembly Results with Long DNA Reads Using the dnaasm-link Application
Authors: Kuśmirek Wiktor , Franus Wiktor , Nowak Robert
Published: April 2019

Currently, third-generation sequencing techniques, which make it possible to obtain much longer DNA reads compared to the next-generation sequencing technologies, are becoming more and more popular. There are many possibilities for combining data from next-generation and third-generation sequencing. Herein, we present a new application called dnaasm-link for linking contigs, the result of de novo assembly of second-generation sequencing data, with long DNA reads. Our tool includes an integrated module to fill gaps with a suitable fragment of an appropriate long DNA read, which improves the consistency of the resulting DNA sequences. This feature is very important, in particular for complex DNA regions. Our implementation is found to outperform other state-of-the-art tools in terms of speed and memory requirements, which may enable its usage for organisms with a large genome, something which is not possible in existing applications. The presented application has many advantages: (i) it significantly optimizes memory and reduces computation time; (ii) it fills gaps with an appropriate fragment of a specified long DNA read; (iii) it reduces the number of spanned and unspanned gaps in existing genome drafts. The application is freely available to all users under GNU Library or Lesser General Public License version 3.0 (LGPLv3). The demo application, Docker image, and source code can be downloaded from project homepage.
Decision Support Framework for Cycling Investment Prioritization
Authors: Glavić Draženko , Mladenović Miloš N. , Milenković Marina
Published: April 2019

Considering the significant potential for environmental, economic, social and health benefits from cycling, transport planners around the world are considering a wide variety of strategies for its promotion. However, cycling investments still have to find their place in a coherent package among other policies. Different constraints often imply a need for prioritization in cycling project implementation. The need for prioritization list of proposed investments can be caused by different factors such as available budget, available time, and regulatory constraints. Evaluation of investments in cycling infrastructure is a field of study that still requires further development, as previous research has mostly focused on questions of what to build and where. Previously used cost-benefit methods have substantive and procedural limitations in dealing with non-commensurable effects, and dealing with multiple conflicting objectives stemming from different stakeholders. On the contrary, development of prioritization list is formulated here as a semi-structured decision problem, thus belonging to the group of multi-criteria analysis (MCA) methods. The MCA methodology implemented in this decision-support framework is based on Preference Ranking Organization Method for Enrichment Evaluations (PROMETHEE). The expert-based decision-support framework includes procedures for defining list of evaluation criteria and their weights, scoring of alternatives, and sensitivity analysis. Presented decision-support framework is applied on six bicycle sections of the EuroVelo route 8 through Montenegro. Results provide a list of prioritized infrastructural investments, as well as list of criteria with weights, and sensitivity analysis. Decision-support framework is discussed in the context of further professionalizing of cycling planning, as well as short-term and long-term structuration of organization learning in the transition country context. Finally, this development opens up directions for further contextualization of decision criteria, and greater consideration of user attitudes in cycling promotion.
A Study of Probabilistic Diagnosis Method for Three Kinds of Internal Combustion Engine Faults Based on the Graphical Model
Authors: Liu Jiameng , Ma Bo , Jiang Zhinong
Published: April 2019

A strategy for increasing the accuracy rate of internal combustion engine (ICE) fault diagnosis based on the probabilistic graphical model is proposed. In this method, a three‐layer network with inference of probability is constructed, and both the material conditions and the signals collected from different engine parts are considered as the inputs of the system. Machine signals measured by sensors were processed in order to diagnose potential faults, which were presented as probabilities based on the components in layer 1, fault categories in layer 2, and fault symptoms in layer 3. The diagnosis model was built by using nodes and arcs, and the results depended on the connections between the fault categories and symptoms. The parameters of the network represented quantitative probabilistic relationships among all layers, and the conditional probabilities of each type of fault and relevant symptoms were summarized. Fault cases were simulated on a 12‐cylinder diesel engine, and three fault types that often occur on ICEs were tested based on five different fault symptoms with different loads, respectively. The diagnostic capability of the method was investigated, reporting high accuracy rates.
Higher Number of Night Shifts Associates with Good Perception of Work Capacity and Optimal Lung Function but Correlates with Increased Oxidative Damage and Telomere Attrition
Authors: Pavanello Sofia , Stendardo Mariarita , Mastrangelo Giuseppe , Casillo Valeria , Nardini Marco , Mutti Antonio , Campisi Manuela , Andreoli Roberta , Boschetto Piera
Published: April 2019

Sleep deprivation and the consequent circadian clock disruption has become an emergent health question being associated with premature aging and earlier chronic diseases onset. Night-shift work leads to circadian clock misalignment, which is linked to several age-related diseases. However, mechanisms of this association are not well understood. Aim of this study is to explore in night-shift workers early indicators of oxidative stress response and biological aging [oxidized/methylated DNA bases and leukocytes telomere length (LTL)] and late indicators of functional aging [lung function measurements (FEV1 and FVC)] in relation to personal evaluation of work capacity, measured by work ability index (WAI). One hundred fifty-five hospital workers were studied within the framework of a cross-sectional study. We collected physiological, pathological, and occupational history including pack-years, alcohol consumption, physical activity, and night shifts, together with blood and urine samples. Relationships were appraised by univariate and multivariate ordered-logistic regression models. We found that workers with good and excellent WAI present higher FEV1 (p< 0.01) and number of night-work shifts (p<0.05), but they reveal higher urinary levels of 8-oxoGua (p<0.01) and shorter LTL (p<0.05). We confirmed that higher work ability was prevalent among chronological younger workers (p<0.05), who have also a significant reduced number of diseases, particularly chronic (p<0.01) and musculoskeletal diseases (p<0.01). The new findings which stem from our work are that subjects with the highest work ability perception may have more demanding and burdensome tasks; they in fact present the highest number of night-shift work and produce unbalanced oxidative stress response that might induce premature aging.
Morinda Officinalis Polysaccharides Attenuate Varicocele-Induced Spermatogenic Impairment through the Modulation of Angiogenesis and Relative Factors
Authors: Zhu Zhu , Zhao Xiaozhen , Huang Feng , Wang Feng , Wang Wei
Published: April 2019

Evidence supporting best treatment practices for varicocele is lacking. The effects of a water-soluble polysaccharide extracted from Morinda officinalis (MOP) on the progression of varicocele were evaluated in the present study. The extracted MOP was confirmed as having a high purity of 98% with scant protein contamination, and it mainly consisted of glucose, lactose, and xylose at a molar ratio of 7.63:1.23:0.95 glucose:lactose:xylose. MOPs were administered to experimental left varicocele rats immediately after surgery at doses ranging from 25 to 200 mg/kg. As detected by sperm analysis and histopathological staining, the intragastric administration of 100 mg/kg MOPs significantly improved the sperm parameters of bilateral cauda epididymis, attenuated seminiferous epithelial structures, and inhibited germ cell apoptosis. The results of immunofluorescence and immunoblot showed that administration of 100 mg/kg MOPs effectively inhibited angiogenesis in the bilateral testes but modulated the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2), and MMP9 mildly. These results indicate that inhibition of angiogenesis may be one of the mechanisms by which MOP exerts its inhibitive activities on the progression of varicocele, whereas a relative upregulation of VEGF and MMP-9 may be crucial for the spermatogenetic protective effects of 100 mg/kg MOP administration.
Group Identification and Variable Selection in Quantile Regression
Authors: Alkenani Ali , Msallam Basim Shlaibah
Published: April 2019

Using the Pairwise Absolute Clustering and Sparsity (PACS) penalty, we proposed the regularized quantile regression QR method (QR-PACS). The PACS penalty achieves the elimination of insignificant predictors and the combination of predictors with indistinguishable coefficients (IC), which are the two issues raised in the searching for the true model. QR-PACS extends PACS from mean regression settings to QR settings. The paper shows that QR-PACS can yield promising predictive precision as well as identifying related groups in both simulation and real data.
Association between Early Acute Respiratory Distress Syndrome after Living-Donor Liver Transplantation and Perioperative Serum Biomarkers: The Role of Club Cell Protein 16
Authors: Wu Chun-Yu , Cheng Ya-Jung , Hung Ming-Hui , Lin I-Ju , Sun Wei-Zen , Chan Kuang-Cheng
Published: April 2019

Background. Acute respiratory distress syndrome (ARDS) after living-donor liver transplantation (LDLT) is not uncommon, but it lacks the biomarkers for early detection. Club cell protein 16 (CC16), high-motility group box 1 protein (HMGB1), interleukin-1β (IL-1β), and IL-10 have been reported as relevant to the development of ARDS. However, they have not been investigated during LDLT. Methods. Seventy-three consecutive recipients undergoing LDLT were enrolled and received the same perioperative care plan. Perioperative serum CC16, HMGB1, IL-1β, and IL-10 levels were measured at the pretransplant state, 30 minutes after reperfusion, postoperative day 1 (POD1), and POD3. ARDS was diagnosed according to the 2012 Berlin definition. Results. Of the 73 recipients, 13 developed ARDS with significantly longer durations of mechanical ventilation and intensive care unit stay. Serum CC16 levels on POD1 increased significantly from the pretransplant state in the ARDS group but not in the non-ARDS group. Pretransplant serum CC16 levels were also higher in the ARDS group. The area under the receiver operating characteristic curves for POD1 serum CC16 levels used to discriminate ARDS was 0.803 (95% confidence interval: 0.679 to 0.895; p < 0.001). By comparison, HMGB1, IL-1β, and IL-10 were not associated with ARDS after LDLT. Conclusion. The higher pretransplant serum CC16 level and its increased level on POD1 were associated with the development of early ARDS after LDLT. This trial is registered with NCT01936545, 27 August 2013.
Two‐Dimensional CFD Modeling of Hysteresis Behavior of MR Dampers
Authors: Guo Pengfei , Xie Jing
Published: April 2019

So far, most previous studies on the nonlinear hysteresis analysis of ER/MR dampers have been limited to one‐dimensional modeling techniques. A two‐dimensional (2D) axisymmetric CFD model of MR dampers is developed in this work. The main advantage of the proposed 2D model of MR dampers lies in that it can be used to predict dynamic behavior of MR devices of arbitrary geometries. The compressibility of MR fluids is the main factor responsible for the hysteresis behavior of MR dampers, and it has been rarely investigated in previous multidimensional modeling of MR damper. In our model, the compressibility of MR fluids is taken into account by the two‐dimensional constitutive model which is extended from a previous one‐dimensional physical model. The model is solved by using the finite element method, and the movement of the piston is described by the moving mesh technique. The MR damper in a reference is simulated, and the model predictions show good agreement with the experimental data in the reference.
Acute Effect of Toe Cap Choice on Toe Deviation Angle and Perceived Pain in Female Professional Ballet Dancers
Authors: Salzano Annamaria , Camuso Fabiana , Sepe Mario , Sellami Maha , Ardigò Luca P. , Padulo Johnny
Published: April 2019

Several classical dance complex movements, such aspointe, require body weight to be supported properly to avoid risk of foot injury. Regarding the choice of toe cap forpointeshoes, it is unclear which type can better alleviate pain symptoms and toe deviation angle in dancers. The aim of the current crossover study was to investigate the acute effect of using different types of toe caps among well-trained professional dancers on pain perception and toe deviation angle. Ten young female professional dancers volunteered to participate in the study. Each participant was tested during two separate sessions with an interval of 72 h in between. Participants were tested in the two sessions with a standard commercial or a customized prototype toe cap, always withpointeshoes, and in randomized order. An anteroposterior X-ray examination was performed separately for each participant and a visual analogue scale for pain perception was administered following each situation (with a standard commercial or a customized prototype toe cap). Significant amelioration was obtained when a customized toe cap prototype was used both for toe deviation angle and for visual analogue scale. Use of a customized toe cap prototype compared to a standard one may acutely reduce both toe deviation angle and pain in elite female professional dancers.
Ferritin Genes Overexpression in PBMC and a Rise in Exercise Performance as an Adaptive Response to Ischaemic Preconditioning in Young Men
Authors: Mieszkowski Jan , Kochanowicz Magdalena , Żychowska Małgorzata , Kochanowicz Andrzej , Grzybkowska Agata , Anczykowska Katarzyna , Sawicki Piotr , Borkowska Andzelika , Niespodzinski Bartłomiej , Antosiewicz Jedrzej
Published: April 2019

Objectives. The proposal of this study was to evaluate the effect of acute and ten-day ischaemic preconditioning (IPC) training procedure on the Wingate Anaerobic Test (WAnT), the ferritin H (FTH), ferritin L (FTL), and transferrin receptor 1 (TFRC) mRNA expression in peripheral blood mononuclear cells (PBMC), and anaerobic performance.Method. 34 healthy men volunteers (aged 20.7 ± 1.22 years) participated in the study. The effects of bilateral upper limb IPC and sham controlled condition were assessed in two experimental protocols: (a) the influence of acute (one time) IPC based on an experimental crossover study design and (b) the influence of ten-day IPC training treatment based on a random group assignment. At the beginning and at the end of each experiment upper body WAnT was performed and blood samples were collected to assess gene expression via quantitative PCR (qPCR).Results. No significant effect of one-time ischaemic preconditioning procedure was observed on upper body WAnT performance. Ten-day IPC training significantly increased upper limbs relative mean power (from 5.29 ± 0.50 to 5.79 ± 0.70 (W/kg), p<0.05). One-time IPC caused significant decrease inFTH,FTL, andTFRCmRNA levels while 10 days of IPC resulted in significant increase ofFTHandFTLmRNA (from 2 ∧254.2 to 2 ∧1678.6 (p = 0.01) forFTHand 2 ∧81.5 to 2 ∧923 (p = 0.01) forFTL) and decrease inTFRCmRNA.Conclusions. Our findings suggest that ten-day IPC training intervention significantly affects upper limb relative peak power. The observed overexpression of FTH and FTL genes could be associated with adaptation response induced by prolonged IPC.
Empathy in Youths with Conduct Disorder and Callous-Unemotional Traits
Authors: Milone Annarita , Cerniglia Luca , Cristofani Chiara , Inguaggiato Emanuela , Levantini Valentina , Masi Gabriele , Paciello Marinella , Simone Francesca , Muratori Pietro
Published: April 2019

Previous studies indicated that a lack of empathy could be considered the core feature of callous-unemotional (CU) traits in children and adolescents. The present study is aimed at exploring relationships among CU traits, cognitive and emotional dimensions of empathy, emotion recognition (basic, social, and complex emotions), and history of maltreatment in a sample of youths with conduct disorder diagnosis. The sample consisted of 60 Italian male patients (age range 11-17 years, mean age 13.27±1.90 years) referred to the Department of Child and Adolescent Psychiatry (Pisa, Italy). In the whole sample, the levels of CU traits were significantly negatively associated with both cognitive and emotional dimensions of empathy; in addition, the CD patients with high levels of CU traits show significantly lower levels of empathic concern compared to those with low levels of CU traits. Clinical implications of the findings are discussed.
Histologic Appearance of Iatrogenic Obstructive Hydrocephalus in the Fetal Lamb Model
Authors: Emery Stephen P. , Greene Stephanie , Murdoch Geoffrey , Wiley Clayton A.
Published: April 2019

Introduction: Documentation of histologic findings associated with congenital hydrocephalus in the fetal lamb model is a critical step in evaluating the efficacy of ventriculoamniotic shunting in the human fetus. Methods: Four fetal sheep had hydrocephalus induced at approximately 95 days’ gestation. Two co-twins remained as controls. The ewes were euthanized at term. The lamb brains were fixed in formalin, paraffin-embedded, stained, and analyzed for markers of neuropathology. Astrocytosis, microgliosis, and axonal loss were assessed with immunocytochemistry for glial fibrillary acidic protein, ionized calcium-binding adapter, and neurofilament/amyloid precursor protein, respectively. Cortical gray matter extracellular matrix was assessed with staining for the lectin Wisteria Floribunda agglutinin. Results: Hydrocephalic lamb brains demonstrated deep white matter damage with loss of projecting axonal tracts in regions physically distorted by hydrocephalus, similar to that seen in hydrocephalic humans. There was no evidence of abnormal neocortical neuronal migration; however, there was evidence for delayed maturation of the neocortical gray matter, possibly from increased intracerebral pressure and subsequent ischemia. Control lamb brains demonstrated none of the above findings. Conclusion: This histological approach can be used to further define the mechanism of brain damage associated with hydrocephalus and interpret the efficacy of ventriculoamniotic shunting on fetal lamb brain neuroanatomy.
The Changing Landscape in Supporting Preterm Infants at Birth
Authors: te Pas Arjan B. , Hooper Stuart B. , Dekker Janneke
Published: April 2019

Noninvasive ventilation for preterm infants at birth has been recommended and universally adopted. The umbilical cord is often clamped immediately in order to provide the support the infant needs for stabilization. However, recent scientific data from experimental studies that involve animals in transition and human studies using physiological measurements at birth have increased awareness as to how little we know about how these interventions interact and integrate with the infant’s changing physiology. It has become clear that in apneic infants the larynx is closed immediately after birth, which can completely negate the effect of noninvasive ventilation of the lung. For this reason, stimulating and supporting spontaneous breathing could enhance the success of noninvasive ventilation. Animal data also demonstrated that the large swings in blood pressure, blood flow, and oxygenation caused by immediate cord clamping can be avoided by postponing cord clamping until lung aeration has been established. In this review we will focus on these “game changers” that have the potential to completely change the approach used in stabilizing preterm infants at birth.
Why and How Should We Integrate Biomarkers into Complex Trials? A Discussion on Paradigms and Clinical Research Strategies
Authors: Musial Frauke , Mist  Scott , Warber Sara , Kreitzer Mary Jo , Ritenbaugh Cheryl , Kessler Christian
Published: April 2019

Background: Research in complementary and alternative medicine (CAM) encounters a variety of challenges, such as potentially synergistic, multimodal, and complex interventions which are often dependent on the relationship between practitioner and patient, on specific settings, and on patients’ individual preferences, expectations, beliefs, and motivations. Moreover, patients seeking CAM care often suffer from chronic disease conditions, and multiple symptoms and/or pathologies. On the other hand, CAM interventions are often challenged as being solely dependent on subjective and nonspecific factors without biologically based mechanisms of action. If we agree that biomarkers as outcomes are important for the understanding of CAM interventions, a hypothesis- and strategy-driven process for the selection of the most appropriate biomarkers is needed. Methods: This paper presents the results of an expert panel on how to integrate biomarkers in whole system research of an interdisciplinary workshop on research methodology in CAM held in November 2012. Results: The following main CAM research challenges were identified: (a) finding appropriate biomarkers, which are able to picture the complex pathophysiological pathways and likewise complex interventions under study; (b) integrating these biomarkers into clinical trials in CAM; and (c) identifying the biomarkers specific to the particular CAM intervention being applied. Conclusion: The paper provides a disease/condition/symptom- and intervention-driven strategy regarding how to identify the outcomes of interest and possible related biomarkers. The research approach presented here allows the selected biomarkers to be grounded in conventional physiology/pathophysiology as well as complementary and alternative concepts, including traditional systems of medicine. The goal is to provide researchers in the field with a framework on how to integrate biomarkers into complex trials.
What Is New about Transfusions for Preterm Infants? An Update
Authors: Kirpalani Haresh , Whyte Robin K.
Published: April 2019

Currently the question of whether to maintain a higher hemoglobin level by transfusing more liberally, as opposed to a more restrictive strategy with lower hemoglobin maintenance levels, has not been answered. We review summarized conclusions of a Cochrane systematic review and meta-analysis of 614 infants in 4 randomized controlled trials (RCT) pooling data. This suggests potential benefits of higher hemoglobin levels, i.e., a possible improved cognition of infants at 18–21 months’ corrected age and a reduction of apnea. However, the data on cognition is hypothesis generating as it derives from a post hoc analysis from a single trial in 451 infants. Moreover, the data on apnea need confirmation in larger trials. The effect of adding data of cognitive 2-year outcomes of 1,744 infants from 2 RCT, which will be reported soon, should expand our understanding. This new data will need to be integrated with the older generation of RCTs but also with emerging suggestions from observational data on potential risks of blood transfusions. We discuss some of these warnings from observational studies. Finally, we ask whether we are ready to individualize blood transfusion to physiological measures made in individual infants, and we point to some current difficulties hindering this step.
Turkish Ectodermal Dysplasia Cohort: From Phenotype to Genotype in 17 Families
Authors: Güven Yeliz , Bal Elodie , Altunoglu Umut , Yücel Esra , Hadj-Rabia Smail , Koruyucu Mine , Bahar Tuna Elif , Çıldır Şule , Aktören Oya , Bodemer Christine , Uyguner Zehra O. , Smahi Asma , Kayserili Hülya
Published: April 2019

Hypohidrotic or anhidrotic ectodermal dysplasia (HED/EDA) is characterized by impaired development of the hair, teeth, or sweat glands. HED/EDA is inherited in an X-linked, autosomal dominant, or autosomal recessive pattern and caused by the pathogenic variants in 4 genes: EDA, EDAR, EDARADD, and WNT10A. The aim of the present study was to perform molecular screening of these 4 genes in a cohort of Turkish individuals diagnosed with HED/EDA. We screened for pathogenic variants of WNT10A, EDA, EDAR, and EDARADD through Sanger sequencing. We further assessed the clinical profiles of the affected individuals in order to establish phenotype-genotype correlation. In 17 (63%) out of 27 families, 17 pathogenic variants, 8 being novel, were detected in the 4 well-known ectodermal dysplasia genes. EDAR and EDA variants were identified in 6 families each, WNT10A variants in 4, and an EDARADD variant in 1, accounting for 35.3, 35.3, 23.5, and 5.9% of mutation-positive families, respectively. The low mutation detection rate of the cohort and the number of the EDAR pathogenic variants being as high as the EDA ones were the most noteworthy findings which could be attributed to the high consanguinity rate.
European Consensus Guidelines on the Management of Respiratory Distress Syndrome – 2019 Update
Authors: Sweet David G. , Carnielli Virgilio , Greisen Gorm , Hallman Mikko , Ozek Eren , te Pas Arjan , Plavka Richard , Roehr Charles C. , Saugstad Ola D. , Simeoni Umberto , Speer Christian P. , Vento Maximo , Visser Gerhard H.A. , Halliday Henry L.
Published: April 2019

As management of respiratory distress syndrome (RDS) advances, clinicians must continually revise their current practice. We report the fourth update of “European Guidelines for the Management of RDS” by a European panel of experienced neonatologists and an expert perinatal obstetrician based on available literature up to the end of 2018. Optimising outcome for babies with RDS includes prediction of risk of preterm delivery, need for appropriate maternal transfer to a perinatal centre and timely use of antenatal steroids. Delivery room management has become more evidence-based, and protocols for lung protection including initiation of CPAP and titration of oxygen should be implemented immediately after birth. Surfactant replacement therapy is a crucial part of management of RDS, and newer protocols for its use recommend early administration and avoidance of mechanical ventilation. Methods of maintaining babies on non-invasive respiratory support have been further developed and may cause less distress and reduce chronic lung disease. As technology for delivering mechanical ventilation improves, the risk of causing lung injury should decrease, although minimising time spent on mechanical ventilation using caffeine and, if necessary, postnatal steroids are also important considerations. Protocols for optimising general care of infants with RDS are also essential with good temperature control, careful fluid and nutritional management, maintenance of perfusion and judicious use of antibiotics all being important determinants of best outcome.
High BrdU Sensitivity of Passeriformes Chromosomes: Conservation of BrdU-Sensitive Fragile Sites on Their Z Chromosomes during Evolution
Authors: Gerbault-Seureau Michèle , Fuchs Jérôme , Dutrillaux Bernard
Published: April 2019

Amongst 15 bird species, representative of 7 orders, recurrent breakages evocating the presence of fragile sites were detected in the chromosomes of the 5 species belonging to Passeriformes. These breaks appeared when 5-bromodeoxyuridine (BrdU) was added to the cell culture medium at a dose inefficient for inducing chromosome structure alterations in other birds and mammals. They involved, similarly in male and female, 3 loci on the Z chromosome of 3 Turdus species (Turdidae). Labeling by BrdU antibody confirmed the correlation between BrdU incorporation into DNA and breakage, especially around and in the sites of breakage. Thus, 3 BrdU-sensitive fragile sites were present in the Z chromosomes of these birds. Three fragile sites were also detected at different locations in the Z chromosomes of the European robin (Erithacus rubecula, Muscicapidae), suggesting that a structural rearrangement occurred during the evolution of Turdidae and Muscicapidae. Chromosome banding confirmed this interpretation. Finally, in the more distantly related species Parus major (Paridae), the almost acrocentric Z chromosome displayed a single BrdU-sensitive fragile site in its short arm, and the W appeared to be pulverized by BrdU incorporation. Although it cannot be excluded that the BrdU-sensitive fragile sites may be involved in rearrangements, their conservation in many species, and possibly all Passeriformes, provides evidence that they do not constitute a pejorative character during evolution.
IKZF1 Gene Deletion in Pediatric Patients Diagnosed with Acute Lymphoblastic Leukemia in Mexico
Authors: Ayón-Pérez Miriam F. , Pimentel-Gutiérrez Helia J. , Durán-Avelar Ma. de Jesús , Vibanco-Pérez Norberto , Pérez-Peraza Víctor M. , Pérez-González Óscar A. , Barrientos-Ríos Rehotbevely , Santillán-Ávila Christian F. , Zambrano-Zaragoza José F. , Agraz-Cibrián Juan M. , Gutiérrez-Franco Jorge , Vázquez-Reyes Alejandro
Published: April 2019

The IKZF1 gene is formed by 8 exons and encodes IKAROS, a transcription factor that regulates the expression of genes that control cell cycle progression and cell survival. In general, 15-20% of the patients with preB acute lymphoblastic leukemia (preB ALL) harbor IKZF1 deletions, and the frequency of these deletions increases in BCR-ABL1 or Ph-like subgroups. These deletions have been associated with poor treatment response and the risk of relapse. The aim of this descriptive study was to determine the frequency of IKZF1 deletions and the success of an induction therapy response in Mexican pediatric patients diagnosed with preB ALL in 2 hospitals from 2017 to August 2018. Thirty-six bone marrow samples from patients at the Instituto Nacional de Pediatría in Mexico City and the Centro Estatal de Cancerología in Tepic were analyzed. The IKZF1 deletion was identified by MLPA using the SALSA MLPA P335 ALL-IKZF1 probemix. Deletions of at least 1 IKZF1 exon were observed in 7/34 samples (20.6%): 3 with 1 exon deleted; 1 with 2 exons, 1 with 5 exons, 1 with 6 exons, and 1 patient with a complete IKZF1 deletion. This study was descriptive in nature; we calculated the frequency of the IKZF1 gene deletion in a Mexican pediatric population with preB ALL as 20.6%.
Hypoxia Triggers Osteochondrogenic Differentiation of Vascular Smooth Muscle Cells in an HIF-1 (Hypoxia-Inducible Factor 1)–Dependent and Reactive Oxygen Species–Dependent Manner
Authors: Balogh Enikő , Tóth Andrea , Méhes Gábor , Trencsényi György , Paragh György , Jeney Viktória
Published: April 2019

Objective—

Vascular calcification is associated with high risk of cardiovascular events and mortality. Osteochondrogenic differentiation of vascular smooth muscle cells (VSMCs) is the major cellular mechanism underlying vascular calcification. Because tissue hypoxia is a common denominator in vascular calcification, we investigated whether hypoxia per se triggers osteochondrogenic differentiation of VSMCs.

Approach and Results—

We studied osteochondrogenic differentiation of human aorta VSMCs cultured under normoxic (21% O
2
) and hypoxic (5% O
2
) conditions. Hypoxia increased protein expression of HIF (hypoxia-inducible factor)-1α and its target genes GLUT1 (glucose transporter 1) and VEGFA (vascular endothelial growth factor A) and induced mRNA and protein expressions of osteochondrogenic markers, that is, RUNX2 (runt-related transcription factor 2), SOX9 (Sry-related HMG box-9), OCN (osteocalcin) and ALP (alkaline phosphatase), and induced a time-dependent calcification of the extracellular matrix of VSMCs. HIF-1 inhibition by chetomin abrogated the effect of hypoxia on osteochondrogenic markers and abolished extracellular matrix calcification. Hypoxia triggered the production of reactive oxygen species, which was inhibited by chetomin. Scavenging reactive oxygen species by
N
-acetyl cysteine attenuated hypoxia-mediated upregulation of HIF-1α, RUNX2, and OCN protein expressions and inhibited extracellular matrix calcification, which effect was mimicked by a specific hydrogen peroxide scavenger sodium pyruvate and a mitochondrial reactive oxygen species inhibitor rotenone. Ex vivo culture of mice aorta under hypoxic conditions triggered calcification which was inhibited by chetomin and
N
-acetyl cysteine. In vivo hypoxia exposure (10% O
2
) increased RUNX2 mRNA levels in mice lung and the aorta.

Conclusions—

Hypoxia contributes to vascular calcification through the induction of osteochondrogenic differentiation of VSMCs in an HIF-1–dependent and mitochondria-derived reactive oxygen species–dependent manner.
Proinflammatory Effect of Endothelial Microparticles Is Mitochondria Mediated and Modulated Through MAPKAPK2 (MAPK-Activated Protein Kinase 2) Leading to Attenuation of Cardiac Hypertrophy
Authors: Tripathi Dipti , Biswas Bharti , Manhas Amit , Singh Abhinav , Goyal Dipika , Gaestel Matthias , Jagavelu Kumaravelu
Published: April 2019

Objective—

This study investigates the functional significance of mitochondria present in endothelial microparticles (EMP) and how MK2 (MAPKAPK2 [MAPK-activated protein kinase 2]) governs EMP production and its physiological effect on cardiac hypertrophy.

Approach and Results—

Flow cytometric analysis, confocal imaging, oxygen consumption rate measurement through Seahorse were used to confirm the presence of functionally active mitochondria in nontreated EMP (EMP derived from untreated control cells), lipopolysaccharide, and oligomycin treatment increased mitochondrial reactive oxygen species activity in EMP (EMP derived from cells treated with lipopolysaccharide and EMP derived from cells treated with oligomycin, respectively). The dysfunctional mitochondria contained in EMP derived from cells treated with lipopolysaccharide and EMP derived from cells treated with oligomycin induced the expression of proinflammatory mediators in the target endothelial cells leading to the augmented adhesion of human monocytic cell line on EA.hy926 cells. Multiphoton real-time imaging detected the increased adherence of EMP derived from cells treated with oligomycin at the site of carotid artery injury as compared to EMP derived from untreated control cells. MK2 regulates EMP generation during inflammation by reducing E-selectin expression and regulating the cytoskeleton rearrangement through ROCK-2 (Rho-associated coiled-coil containing protein kinase 2) pathway. MK2-deficient EMP reduced the E-selectin and ICAM-1 (intracellular adhesion molecule-1) expression on target endothelial cells leading to reduced monocyte attachment and reduced cardiac hypertrophy in mice.

Conclusions—

MK2 promotes the proinflammatory effect of EMP mediated through dysfunctional mitochondria. MK2 modulates the inflammatory effect induced during cardiac hypertrophy through EMP.
Genetic Deficiency of Flavin-Containing Monooxygenase 3 (
Fmo3
) Protects Against Thrombosis but Has Only a Minor Effect on Plasma Lipid Levels—Brief Report
Authors: Shih Diana M. , Zhu Weifei , Schugar Rebecca C. , Meng Yonghong , Jia Xun , Miikeda Aika , Wang Zeneng , Zieger Marina , Lee Richard , Graham Mark , Allayee Hooman , Cantor Rita M. , Mueller Christian , Brown J. Mark , Hazen Stanley L. , Lusis Aldons J.
Published: April 2019

Objective—

FMO (flavin-containing monooxygenase) 3 converts bacterial-derived trimethylamine to trimethylamine N-oxide (TMAO), an independent risk factor for cardiovascular disease. We generated FMO3 knockout (FMO3KO) mouse to study its effects on plasma TMAO, lipids, glucose/insulin metabolism, thrombosis, and atherosclerosis.

Approach and Results—

Previous studies with an antisense oligonucleotide (ASO) knockdown strategy targeting FMO3 in LDLRKO (low-density lipoprotein receptor knockout) mice resulted in major reductions in TMAO levels and atherosclerosis, but also showed effects on plasma lipids, insulin, and glucose. Although FMO3KO mice generated via CRISPR/Cas9 technology bred onto the LDLRKO background did exhibit similar effects on TMAO levels, the effects on lipid metabolism were not as pronounced as with the ASO knockdown model. These differences could result from either off-target effects of the ASO or from a developmental adaptation to the FMO3 deficiency. To distinguish these possibilities, we treated wild-type and FMO3KO mice with control or FMO3 ASOs. FMO3-ASO treatment led to the same extent of lipid-lowering effects in the FMO3KO mice as the wild-type mice, indicating off-target effects. The levels of TMAO in LDLRKO mice fed an atherogenic diet are very low in both wild-type and FMO3KO mice, and no significant effect was observed on atherosclerosis. When FMO3KO and wild-type mice were maintained on a 0.5% choline diet, FMO3KO showed a marked reduction in both TMAO and in vivo thrombosis potential.

Conclusions—

FMO3KO markedly reduces systemic TMAO levels and thrombosis potential. However, the previously observed large effects of an FMO3 ASO on plasma lipid levels appear to be due partly to off-target effects.
Secondary Bleeding During Acute Experimental Intracerebral Hemorrhage
Authors: Schlunk Frieder , Böhm Maximilian , Boulouis Gregoire , Qin Tao , Arbel Michal , Tamim Isra , Fischer Paul , Bacskai Brian J. , Frosch Matthew P. , Endres Matthias , Greenberg Steven M. , Ayata Cenk
Published: April 2019

Background and Purpose—

Mechanisms contributing to acute hematoma growth in intracerebral hemorrhage are not well understood. Neuropathological studies suggest that the initial hematoma may create mass effect that can tear vessels in the vicinity by shearing, causing further bleeding and hematoma growth.

Methods—

To test this in mice, we simulated initial intracerebral hemorrhage by intrastriatal injection of a liquid polymer that coagulates upon contact with tissue and measured the presence and volume of bleeding secondary to the mass effect using Hemoglobin ELISA 15 minutes after injection.

Results—

Secondary hemorrhage occurred in a volume-dependent (4, 7.5, or 15 μL of polymer) and rate-dependent (0.05, 0.5, or 5 μL/s) manner. Anticoagulation (warfarin or dabigatran) exacerbated the secondary hemorrhage volume. In a second model of hematoma expansion, we confirmed that intrastriatal whole blood injection (15 μL, 0.5 μL/s) also caused secondary bleeding, using acute Evans blue extravasation as a surrogate. Anticoagulation once again exacerbated secondary hemorrhage after intrastriatal whole blood injection. Secondary hemorrhage directly and significantly correlated with arterial blood pressures in both nonanticoagulated and anticoagulated mice, when modulated by phenylephrine or labetalol.

Conclusions—

Our study provides the first proof of concept for secondary vessel rupture and bleeding as a potential mechanism for intracerebral hematoma growth.