bluuebunny/crossref_metadata_2025 huggingface dataset:
Platelet Aggregation Induced by DAS in Vitro: Some Investigations on Its Mechanism of Action
Authors: Benner K. U , Schumacher K. A , Classen H. G
Published: June 2018

The effect of the depressor active substance (DAS) on platelets of men, cats, pigs, dogs, rats, and rabbits has been studied by the method of Born (1962). DAS was found to induce platelet aggregation only in human and feline platelet rich plasma (PRP). Nevertheless, there are some striking similarities between platelet aggregation induced by DAS and ADP (i.e. inhibition by the same compounds, such as adenosine, tosylarginine methylester, or p-chloromercuribenzoic acid). The species specifity and a marked tachyphylactic action on platelets of both species makes DAS clearly discernible from all the other aggregation inducing substances which have been studied so far. From additional experiments there is evidence that DAS acts on human and cat platelets via a release reaction of cellular substances known to enhance platelet aggregation in a second phase. This process is strongly dependent on the presence of Ca++.
Acute Phase Reaction Following Intravenous Administration of Streptokinase
Authors: Spöttl F , Kaiser R , Mosuni M. S
Published: June 2018

SK-therapy regularly is followed by a marked elevation of those plasma proteins known as “acute phase reactants” (α 1-antitrypsin, orosomucoid, β 1 C-globulin, ceruloplasmin). In short-time therapy of myocardial infarction also a transitory presence of CRP is demonstrable. After an initial decrease of fibrinogen caused by fibrinogenolysis, this protein increases significantly too. The high level of α 1-antitrypsin (slow reacting antiplasmin) and/or fibrinogen may lead to rheological consequences which may result in thrombosis.
Crosslinking of Rabbit Fibrin in Vivo
Authors: Finlayson J. S , Aronson D. L
Published: June 2018

Crosslinking found in clots produced in vivo by inducing thrombosis in the rabbit jugular vein was compared with that in platelet-poor rabbit plasma clots formed in vitro. Polyacrylamide gel electrophoresis of the dissolved washed clots showed that the sequence of events in vivo was the same as has previously been observed in vitro and that γ dimerization was followed by α polymerization, with extensive crosslinking being evident in even the earliest clots.
Prolonged Plasma Clotting Time and Decreased Fibrinolysis after Long Term Treatment with α-Tocopherol
Authors: Korsan-Bengtsen K , Elmfeldt D , Holm T
Published: June 2018

Blood platelet function, blood clotting and fibrinolysis were studied in a group of 9 male post myocardial infarction patients once a week for 5 consecutive weeks after which α-tocopherol 300 mg/day was given. The group was again investigated after 2, 6, 18, 44 and 64 weeks of α-tocopherol treatment. After 18, 44 and 64 weeks of treatment a highly significant prolongation of the plasma clotting time was observed. On the basis of the analyses made it is concluded that the prolongation is probably due to a decreased platelet factor 3 activity. The ability to increase fibrinolytic activity after stasis of the arm is reduced after long term α-tocopherol treatment. There were no changes in the number of platelets, platelet adhesiveness, factor II-VII-X activity, factor VIII, fibrinogen, antithrombin III, α1-antitrypsin, α2-macroglobulin, total anti-fibrinolytic activity or plasminogen. Our hypothesis to explain the results is that α-tocopherol influences on the cell membranes of the platelets and the endothelial cells and thus causes a reduced release of platelet factor 3 and activators of fibrinolysis. This is in line with many other observations indicating that α-tocopherol is of importance for the cell membrane function.
The Purification of Activated Hageman Factor from Human Granulocytes
Authors: Prokopowicz J , Wołosowicz N , Szmitkowski M
Published: June 2018

Activated Hageman factor has been isolated from human granulocytes, utilizing aluminium hydroxide gel, diatomaceous earth, CM-cellulose. The preparation was applied on the column prepared from DEAE-Sephadex A-50. Two peaks with Hageman activity were obtained. The product was purified 4162-18750-fold as measured by the method of Schoenmakers et al.

The preparation was devoid of factor I, II, III, V, VIII, IX and plasminogen. Some relationship between granulocyte and plasma Hageman factor are briefly discussed.
Potentiation by Synthetic Fibrinolytic Agents of Vascular Activator- and Urokinase-Induced Lysis of Human Plasma Clots as Demonstrated by Thrombelastography
Authors: Aoki N , von Kaulla K. N
Published: June 2018

The enhancement of vascular activator- and urokinase-induced lysis of human plasma clots following preincubation of the plasma with flufenamate - a fibrinolytic organic anion - was assessed by thrombelastography. Thrombelastograms clearly demonstrated an acceleration of activator-induced clot lysis by flufenamate. Based on the results of previous studies it is concluded that this chemical potentiation of activator-induced fibrinolysis results from inactivation of inhibitors of the fibrinolytic enzyme system, especially antiactivator, by the compound. The potential therapeutical implications of these findings are discussed.
14C-Warfarin Excretion in the Rat
Authors: Losito R , Rousseau Marie-Andree
Published: June 2018

The excretion of 14C-warfarin and its metabolites in bile and urine was studied in rats with or without biliary fistulas. After oral administration of the drug, 39.4% of the 14C could be isolated in the bile and 18.9% in the urine at the end of 96 h. After i.v. administration 47.5% and 21.3% of the 14C was found in the bile and the urine respectively. In animals without biliary fistulas, 41% of the dose was found in the urine after intravenous injection and 43% via the oral route. In bile, five radioactive components were detected; one component was identified as warfarin and represented 3.9% (oral) and 8.5% (I.V.) of the 14C in the bile. Another component of bile (17.7% to 19.6% of 14C) was identified as 6-hydroxywarfarin. In urine, three 14C components were found; the major component in urine was found to be warfarin and represented close to 75% of the 14C in the urine. Two 14C metabolites which were present in the urine were also present in the bile. Biliary fistula did not prevent radioactivity from being discharged into the urine. In feces, 9.3% of the dose could be isolated and was similar to warfarin. In the liver, at the end of four hours, 19% of the 14C could be isolated; only 74% of this could be extracted and was established as warfarin. The liver failed to show the presence of any metabolites.
Density Gradient Separation of Human Platelets from Plasma and the Role of Plasma in Adenosine Diphosphate Induced Platelet Electrophoretic Mobility Changes
Authors: Nicholls D. G , Hampton J. R
Published: June 2018

1. An albumin density gradient separation technique is described for separating human blood platelets from plasma.

2. The platelet resuspensions aggregate on the addition of 10-6 M adenosine diphosphate (ADP) in the presence of calcium and fibrinogen.

3. Platelet resuspension in the presence of plasma show a time dependant recovery of reversible aggregation.

4. In the presence of calcium and fibrinogen platelet resuspensions show ADP- induced electrophoretic mobility changes which are the same as those of platelets not separated from their native plasma.

5. Abnormal electrophoretic sensitivity to ADP in platelets from subjects with a history of occlusive arterial disease is retained on separation from plasma.

6. The electrophoretic response of platelet resuspensions to phosphatidyl choline is similar to that of unwashed platelets. The use of resuspended platelets has shown that calcium and fibrinogen are not required for this response.
Bleeding Tendency with Platelet Dysfunction and Albinism
Authors: Murakami M , Odake K , Matsuda T , Manmi S , Takase M , Imura M , Toyama T
Published: June 2018

A Japanese boy, who had combined congenital defects - a hemorrhagic disorder due to abnormal platelet function and incomplete albinism, was described. His parents were first cousins. Platelet aggregation by collagen and epinephrine was markedly defective. A rapid disaggregation was observed in ADP-induced aggregation. Platelet factor 3 availability and in vitro adhesiveness were subnormal, while platelet factor 3 activity was normal. Defective ADP release was associated with impaired aggregation by collagen. Before aggregation, labeled adenine nucleotide pattern in patient’s platelets was not different from that in normal platelets. The increase of intermediates of platelet ATP breakdown, such as AMP and IMP, was less in patient’s platelets after collagen-induced aggregation. The release of labeled ATP and ADP in patient’s plasma was less than that in normal plasma.
The Plasminogen Activator Content of the Arterial Wall in Occlusive Arterial Diseases
Authors: Constantini R , Hilbe G , Spöttl F , Holzknecht F
Published: June 2018

The plasminogen activator of the Arteria tibialis posterior of 8 patients with occlusive arterial diseases of the leg was determined in comparison to the plasminogen activator of normal subjects. The histochemical method of Todd (15) was used. The plasminogen activator of the pathological adventitia and the intima was significantly decreased. An impaired fibrinolytic system seems to be one of the important factors of atherogenesis. It could at least explain the frequent incidence of thrombotic complications.
Non-criticality criteria for Abelian sandpile models with sources and sinks
Authors: Redig Frank , Ruszel Wioletta M. , Saada Ellen
Published: June 2018

We prove that the Abelian sandpile model on a random binary and binomial tree, as introduced in Redig, Ruszel, and Saada [J. Stat. Phys. 147, 653–677 (2012)], is not critical for all branching probabilities p < 1; by estimating the tail of the annealed survival time of a random walk on the binary tree with randomly placed traps, we obtain some more information about the exponential tail of the avalanche radius. Next we study the sandpile model on Zd with some additional dissipative sites: we provide examples and sufficient conditions for non-criticality; we also make a connection with the parabolic Anderson model. Finally we initiate the study of the sandpile model with both sources and sinks and give a sufficient condition for non-criticality in the presence of a finite number of sources, using a connection with the homogeneous pinning model.
Exponentially time decaying susceptible-informed (SIT) model for information diffusion process on networks
Authors: Bao Wei , Michailidis George
Published: June 2018

Modeling information diffusion on networks is a timely topic due to its significance in massive online social media platforms. Models motivated by disease epidemics, such as the Susceptible-Infected-Removed and Susceptible-Infected-Susceptible (SIS), ones have been used for this task, together with threshold models. A key limitation of these models is that the intrinsic time value of information is not accounted for, an important feature for social media applications, since “old” piece of news does not attract adequate attention. We obtain results pertaining to the diffusion size across the diffusion's evolution over time, as well as for early time points that enable us to calculate the phase transition epoch and the epidemic threshold, using mean field approximations. Further, we explicitly calculate the total probability of getting informed for each node depending on its actual path to the single seed node and then propose a novel approach by constructing a Maximum Weight Tree (MWT) to approximate the final fraction of diffusion, with the weight of each node approximating the total probability of getting informed. The MWT approximation is a novel approach that is exact for tree-like network and is specifically designed for sparse networks. It is also fast to compute and provides another general tool for the analyst to obtain accurate approximations of the “epidemic's” size. Extensive comparisons with results based on Monte Carlo simulation of the information diffusion process show that the derived mean field approximations, as well as that employing the MWT one, provide very accurate estimates of the quantities of interest.
Detecting chaotic behaviors in dynamic complex social networks using a feature diffusion-aware model
Authors: Yasami Yasser , Safaei Farshad
Published: June 2018

This paper contributes in detecting chaotic behaviors in dynamic complex social networks using a new feature diffusion-aware model from two perspectives of abnormal links as well as abnormal nodes. The proposed approach constructs a probabilistic model of dynamic complex social networks and subsequently, applies it to detect chaotic behaviors by measuring deviations from the model. The predictive model considers the main processes of features' dynamics, evolution of nodes' features, feature diffusion, and link generation processes in dynamic complex social networks. The feature diffusion process indicates the process in which each node former features influence the future features of its neighbors. The proposed approach is validated by experiments on two real dynamic complex social network datasets of Google+ and Twitter. The approach uses some Markov Chain Monte Carlo sampling methods like Metropolis-Hastings algorithm and Slice sampling strategy to extract the model parameters, given these real datasets. Experimental results indicate the improved performance characteristics of the proposed approach in comparison with baseline approaches in terms of the performance measures of accuracy, F1-score, Matthews Correlation Coefficient, recall, precision, area under ROC curve, and log-likelihood.
Unitary coupled-cluster based self-consistent polarization propagator theory: A third-order formulation and pilot applications
Authors: Liu Junzi , Asthana Ayush , Cheng Lan , Mukherjee Debashis
Published: June 2018

In this article, the development of a third-order self-consistent polarization propagator method based on unitary coupled-cluster (UCC) parametrization of the ground-state wavefunction and the excitation manifold comprising unitary-transformed excitation operators, hereafter referred to as UCC3, is reported. The UCC3 method is designed to provide excitation energies correct up to the third order for excited states dominated by single excitations. An expansion for the UCC transformed Hamiltonian involving Bernoulli numbers as expansion coefficients is adopted in the derivation of UCC3 working equations. Interestingly, UCC-based polarization propagator theory offers an alternative derivation for the strict version of the third-order algebraic diagrammatic construction [ADC(3)-s] method. The UCC3 results for the excitation energies of excited states in H2O, HF, N2, Ne, CH2, BH, and C2 molecules are compared with benchmark full configuration interaction values as well as ADC(3) and equation-of-motion coupled-cluster singles and doubles results to demonstrate the accuracy of the UCC3 method. UCC-based self-consistent polarization propagator theory appears to be a promising framework for developing non-perturbative hermitian formulations for treating electronically excited states.
Induced-charge electrokinetics in rotating electric fields: A linear asymptotic analysis
Authors: Ren Yukun , Liu Weiyu , Wang Zhijie , Tao Ye
Published: June 2018

Concerning the electroconvective analyte manipulation in microfluidics, we describe the basic physics of fluid flow driven by rotating induced-charge electro-osmosis (ROT-ICEO), which occurs on the planar surface of a single floating electrode in an external rotating electric field. First, based on a linear asymptotic analysis, the dynamic flow stagnation line in ROT-ICEO induced on the bipolar electrode from a rotary Debye screening charge revolves synchronously with the applied rotating fields. A net hydrodynamic torque is then generated that acts on any fluid or particle sample to produce either a synchronous or asynchronous co-field rotation depending on the frequency of the ac signal. Next, from the synergy between the hydrodynamic and electrochemical ion relaxations, an analytical solution of the sample rotation rate subject to ROT-ICEO slipping on an ideally polarizable surface is obtained for different frequency ranges and determined by the transient nature of the rotating electro-osmotic flow oscillating at twice the field frequency. To visualize the flow field in ROT-ICEO, experiments were performed with fluorescent tracer nanoparticles; they exhibited concentric rotational behavior at the polarized phase interface. Formed like the arms of a nebula disk, the four twisted tails of nanoparticles can be arbitrarily directed under voltage-phase rectification. These experimental results are in good agreement with our mathematical simulations using the Debye–Hückel approximation on ROT-ICEO.
Impacts of improved extension services on awareness, knowledge, adoption rates and perceived benefits of smallholder dairy farmers in Pakistan
Authors: Warriach H. M. , Wynn P. C. , Ishaq M. , Arif S. , Bhatti A. , Latif S. , Kumbher A. , Batool Z. , Majeed S. , Bush R. D. , Pasha T. N. , McGill D. M.
Published: June 2018

The provision of effective extension services to smallholder farmers across both developing and developed countries remains a challenge worldwide. The objective of the study is to demonstrate the impacts of improved extension services on awareness, knowledge, adoption rates and perceived benefits of smallholder dairy farmers in Pakistan. An extension program was developed and implemented in five districts of Punjab (Okara, Pakpattan, Jhelum, Kasur and Bhakkar) and two districts of Sindh (Thatta and Badin) provinces. The extension program involved the provision of research-based information on a monthly basis to smallholder farming families (FF = 523) over a 4-year period. The extension program was primarily a knowledge transfer-based system, but also relied on farmer engagement and feedback to help drive research and topics for discussion. No financial incentives were provided to the farmers for their participation. A ‘whole-family approach’ was used in the extension program, where comprehensive interdisciplinary training on the whole dairy-farming system was provided to the males, females and children of the farming household. To encourage greater participation and support different learning strategies, several information transfer media were used (including group discussions, one-on-one visits, practical demonstrations, problem-based learning techniques and videos). To assess the impact of this extension program on farms involved, data on farmer awareness, knowledge, adoption and their perceived benefits were collected using a mixed-method approach from three different groups of farmers; registered (IMPreg = 179) farmers directly involved in the extension program, non-registered (IMPnon-reg = 116) farmers indirectly benefiting from the program and traditional (IMPtrad = 104) farmers not associated with any project activities. Overall awareness, knowledge and adoption rates relating to seven different recommendations in the extension program were significantly (P < 0.05) higher in the registered farmers than in the non-registered and traditional farmers. The perceived benefits of the adopted recommendations varied between the different extension messages, but farmers described that they observed increases in milk production, improvements in animal health (body condition and morbidity) and labour efficiency (time savings). These results suggest that adopting improved extension services using a whole-family approach we can significantly achieve higher adoption rates, leading to on-farm benefits to smallholder dairy farmers and their families.
Relational mobility predicts social behaviors in 39 countries and is tied to historical farming and threat
Authors: Thomson Robert , Yuki Masaki , Talhelm Thomas , Schug Joanna , Kito Mie , Ayanian Arin H. , Becker Julia C. , Becker Maja , Chiu Chi-yue , Choi Hoon-Seok , Ferreira Carolina M. , Fülöp Marta , Gul Pelin , Houghton-Illera Ana Maria , Joasoo Mihkel , Jong Jonathan , Kavanagh Christopher M. , Khutkyy Dmytro , Manzi Claudia , Marcinkowska Urszula M. , Milfont Taciano L. , Neto Félix , von Oertzen Timo , Pliskin Ruthie , San Martin Alvaro , Singh Purnima , Visserman Mariko L.
Published: June 2018

Significance

Biologists and social scientists have long tried to understand why some societies have more fluid and open interpersonal relationships—differences in relational mobility—and how those differences influence individual behaviors. We measure relational mobility in 39 societies and find that relationships are more stable and hard to form in east Asia, North Africa, and the Middle East, while they are more fluid in the West and Latin America. Results show that relationally mobile cultures tend to have higher interpersonal trust and intimacy. Exploring potential causes, we find greater environmental threats (like disease and warfare) and sedentary farming are associated with lower relational mobility. Our society-level index of relational mobility for 39 societies is a resource for future studies.
S4–S5 linker movement during activation and inactivation in voltage-gated K
+
channels
Authors: Kalstrup Tanja , Blunck Rikard
Published: June 2018

Significance

Excitability in heart and nervous system is based on sensing and propagation of the membrane potential by voltage-gated ion channels. Despite the increasing availability of high-resolution structures of voltage-gated ion channels, key questions about their dynamics remain elusive. Here we followed the movements of the gating machinery on the cytosolic surface of the Shaker K
V
channel by introducing a fluorescent noncanonical amino acid at different positions along the linker between voltage sensor and pore. We can thus map the movement of each position and reconstruct the dynamics of the gating machinery during activation and inactivation. Considering that the Shaker channel serves as a model system, the mechanisms are likely conserved among those K
V
channels containing a sizeable S4–S5 linker.
Extreme stability in de novo-designed repeat arrays is determined by unusually stable short-range interactions
Authors: Geiger-Schuller Kathryn , Sforza Kevin , Yuhas Max , Parmeggiani Fabio , Baker David , Barrick Doug
Published: June 2018

Significance

We apply a statistical thermodynamic formalism to quantify the cooperativity of folding of de novo-designed helical repeat proteins (DHRs). This analysis provides a fundamental thermodynamic description of folding for de novo-designed proteins and permits comparison with naturally occurring repeat protein thermodynamics. We find that individual DHR units are intrinsically stable, unlike those of naturally occurring proteins. This observation reveals local (intrarepeat) interactions as a source of high stability in Rosetta-designed proteins and suggests that different types of DHR repeats may be combined in a single polypeptide chain, expanding the repertoire of folded DHRs for applications such as molecular recognition. Favorable intrinsic stability imparts a downhill shape to the energy landscape, suggesting that DHRs fold fast and through parallel pathways.
The role of heritage tourism in the management and promotion of pilgrimage trails and routes.
Authors: Boyd S. W.
Published: June 2018

This chapter begins by first addressing pilgrimage as linked to trails and routes, before considering the role that heritage tourism can play regarding pilgrimage spaces. The chapter looks at both heritage tourism and pilgrimages from a theoretical and conceptual perspective, addressing the issue of whether key elements and principles of heritage tourism can enable effective management and promotion of pilgrimage routes, regardless of their type.
A Systematic Review and Meta-analysis of Ventilator-associated Pneumonia in Adults in Asia: An Analysis of National Income Level on Incidence and Etiology
Authors: Bonell Ana , Azarrafiy Ryan , Huong Vu Thi Lan , Viet Thanh Le , Phu Vu Dinh , Dat Vu Quoc , Wertheim Heiman , van Doorn H Rogier , Lewycka Sonia , Nadjm Behzad
Published: June 2018

Background

Ventilator-associated pneumonia (VAP) is the commonest hospital-acquired infection (HAI) in intensive care. In Asia, VAP is increasingly caused by resistant gram-negative organisms. Despite the global antimicrobial resistance crisis, the epidemiology of VAP is poorly documented in Asia.

Methods

We systematically reviewed literature published on Ovid Medline, Embase Classic, and Embase from 1 January 1990 to 17 August 2017 to estimate incidence, prevalence, and etiology of VAP. We performed a meta-analysis to give pooled rates and rates by country income level.

Results

Pooled incidence density of VAP was high in lower- and upper-middle-income countries and lower in high-income countries (18.5, 15.2, and 9.0 per 1000 ventilator-days, respectively). Acinetobacter baumannii (n = 3687 [26%]) and Pseudomonas aeruginosa (n = 3176 [22%]) were leading causes of VAP; Staphylococcus aureus caused 14% (n = 1999). Carbapenem resistance was common (57.1%).

Conclusions

VAP remains a common cause of HAI, especially in low- and middle-income countries, and antibiotic resistance is high.
A chronological pharmacovigilance network analytics approach for predicting adverse drug events
Authors: Davazdahemami Behrooz , Delen Dursun
Published: June 2018

Objectives

This study extends prior research by combining a chronological pharmacovigilance network approach with machine-learning (ML) techniques to predict adverse drug events (ADEs) based on the drugs’ similarities in terms of the proteins they target in the human body. The focus of this research, though, is particularly centered on predicting the drug-ADE associations for a set of 8 common and high-risk ADEs.

Materials and methods

large collection of annotated MEDLINE biomedical articles was used to construct a drug-ADE network, and the network was further equipped with information about drugs’ target proteins. Several network metrics were extracted and used as predictors in ML algorithms to predict the existence of network edges (ie, associations or relationships).

Results

Gradient boosted trees (GBTs) as an ensemble ML algorithm outperformed other prediction methods in identifying the drug-ADE associations with an overall accuracy of 92.8% on the validation sample. The prediction model was able to predict drug-ADE associations, on average, 3.84 years earlier than they were actually mentioned in the biomedical literature.

Conclusion

While network analysis and ML techniques were used in separation in prior ADE studies, our results showed that they, in combination with each other, can boost the power of one another and predict better. Moreover, our results highlight the superior capability of ensemble-type ML methods in capturing drug-ADE patterns compared to the regular (ie, singular), ML algorithms.
Emigration in Politics and Imaginations
Authors: Carpenter Kirsty
Published: June 2018

Emigration during the French Revolution has many different layers of historical reality, but the most defining of these was the legislation that condemned émigrés to death in 1793, and that was not altered until after Napoleon came to power. This legislation was not without its critics from its inception, and it is important to challenge the very inflexible notion that all émigrés were automatically traitors. The problems of getting émigré protests heard, and the imaginary aspect of their ideal France—usually a constitutional monarchy—was harder to convey while the legislation was in place. Furthermore the issue of justice for a significant minority group tests the principles of the revolutionaries inside France, and has a context that concerns not only the émigrés, but what the Republicans imagined as well. This chapter deals with the elaboration of the legislation and the difficulties of overcoming a very uncompromising stance on the guilt of the émigrés as a collective. These émigrés were in fact genuine refugees, and like any refugees their plight was the worse for the length of time the conflict lasted.
ZBED6 negatively regulates insulin production, neuronal differentiation, and cell aggregation in MIN6 cells
Authors: Wang Xuan , Jiang Lin , Wallerman Ola , Younis Shady , Yu Qian , Klaesson Axel , Tengholm Anders , Welsh Nils , Andersson Leif
Published: June 2018

Zinc finger BED domain containing protein 6 (Zbed6) has evolved from a domesticated DNA transposon and encodes a transcription factor unique to placental mammals. The aim of the present study was to investigate further the role of ZBED6 in insulin‐producing cells, using mouse MIN6 cells, and to evaluate the effects of Zbed6 knockdown on basal β‐cell functions, such as morphology, transcriptional regulation, insulin content, and release. Zbed6‐silenced cells and controls were characterized with a range of methods, including RNA sequencing, chromatin immunoprecipitation sequencing, insulin content and release, subplasma membrane Ca2+ measurements, cAMP determination, and morphologic studies. More than 700 genes showed differential expression in response to Zbed6 knockdown, which was paralleled by increased capacity to generate cAMP, as well as by augmented subplasmalemmal calcium concentration and insulin secretion in response to glucose stimulation. We identified >4000 putative ZBED6‐binding sites in the MIN6 genome, with an enrichment of ZBED6 sites at upregulated genes, such as the β‐cell transcription factors v‐maf musculoaponeurotic fibrosarcoma oncogene homolog A and Nk6 homeobox 1. We also observed altered morphology/growth patterns, as indicated by increased cell clustering, and in the appearance of axon‐like Neurofilament, medium polypeptide and tubulin β 3, class III‐positive protrusions. We conclude that ZBED6 acts as a transcriptional regulator in MIN6 cells and that its activity suppresses insulin production, cell aggregation, and neuronal‐like differentiation.—Wang, X., Jiang, L., Wallerman, O., Younis, S., Yu, Q., Klaesson, A., Tengholm, A., Welsh, N., Andersson, L. ZBED6 negatively regulates insulin production, neuronal differentiation, and cell aggregation in MIN6 cells. FASEB J. 33, 88–100 (2019). www.fasebj.org
LRRC8A is essential for swelling‐activated chloride current and for regulatory volume decrease in astrocytes
Authors: Formaggio Francesco , Saracino Emanuela , Mola Maria Grazia , Rao Shreyas Balachandra , Amiry-Moghaddam Mahmood , Muccini Michele , Zamboni Roberto , Nicchia Grazia Paola , Caprini Marco , Benfenati Valentina
Published: June 2018

Consolidated evidence indicates that astroglial cells are critical in the homeostatic regulation of cellular volume by means of ion channels and aquaporin‐4. Volume‐regulated anion channel (VRAC) is the chloride channel that is activated upon cell swelling and critically contributes to cell volume regulation in astrocytes. The molecular identity of VRAC has been recently defined, revealing that it belongs to the leucine‐rich repeat‐containing 8 (LRRC8) protein family. However, there is a lack of evidence demonstrating that LRRC8A underpins VRAC currents in astrocyte. Nonetheless, direct evidence of the role of LRRC8A in astrocytic regulatory volume decrease remains to be proved. Here, we aim to bridge this gap in knowledge by combining RNA interference specific for LRRC8A with patch‐clamp analyses and a water‐permeability assay. We demonstrated that LRRC8A molecular expression is essential for swelling‐activated chloride current via VRAC in primary‐cultured cortical astrocytes. The knockdown of LRRC8A with a specific short interference RNA abolished the recovery of the cell volume after swelling induced by hypotonic challenge. In addition, immunoblotting, immunofluorescence, confocal imaging, and immunogold electron microscopy demonstrated that LRRC8A is expressed in the plasma membrane of primary cortical astrocytes and in situ in astrocytes at the perivascular interface with endothelial cells. Collectively, our results suggest that LRRC8A is an essential subunit of VRAC and a key factor for astroglial volume homeostasis.—Formaggio, F., Saracino, E., Mola, M. G., Rao, S. B., Amiry‐Moghaddam, M., Muccini, M., Zamboni, R., Nicchia, G. P., Caprini, M., Benfenati, V. LRRC8A is essential for swelling‐activated chloride current and for regulatory volume decrease in astrocytes. FASEB J. 33, 101–113 (2019). www.fasebj.org
Chemotherapy‐generated cell debris stimulates colon carcinoma tumor growth via osteopontin
Authors: Chang Jaimie , Bhasin Swati S. , Bielenberg Diane R. , Sukhatme Vikas P. , Bhasin Manoj , Huang Sui , Kieran Mark W. , Panigrahy Dipak
Published: June 2018

Colon cancer recurrence after therapy, such as 5‐fluorouracil (5‐FU), remains a challenge in the clinical setting. Chemotherapy reduces tumor burden by inducing cell death; however, the resulting dead tumor cells, or debris, may paradoxically stimulate angiogenesis, inflammation, and tumor growth. Here, we demonstrate that 5‐FU‐generated colon carcinoma debris stimulates the growth of a subthreshold inoculum of living tumor cells in subcutaneous and orthotopic models. Debris triggered the release of osteopontin (OPN) by tumor cells and host macrophages. Both coinjection of debris and systemic treatment with 5‐FU increased plasma OPN levels in tumor‐bearing mice. RNA expression levels of secreted phosphoprotein 1, the gene that encodes OPN, correlate with poor prognosis in patients with colorectal cancer and are elevated in chemotherapy‐treated patients who experience tumor recurrence vs. no recurrence. Pharmacologic and genetic ablation of OPN inhibited debris‐stimulated tumor growth. Systemic treatment with a combination of a neutralizing OPN antibody and 5‐FU dramatically inhibited tumor growth. These results demonstrate a novel mechanism of tumor progression mediated by OPN released in response to chemotherapy‐generated tumor cell debris. Neutralization of debris‐stimulated OPN represents a potential therapeutic strategy to overcome the inherent limitation of cytotoxic therapies as a result of the generation of cell debris.—Chang, J., Bhasin,S. S., Bielenberg,D. R., Sukhatme,V. P., Bhasin,M., Huang,S., Kieran,M. W., Panigrahy,D.Chemotherapy‐generated cell debris stimulates colon carcinoma tumor growth via osteopontin. FASEB J. 33,114–125 (2019). www.fasebj.org
Novel noncanonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4
Authors: Kanugula Anantha K. , Adapala Ravi K. , Midha Priya , Cappelli Holly C. , Meszaros J. Gary , Paruchuri Sailaja , Chilian William M. , Thodeti Charles K.
Published: June 2018

VEGF signaling via VEGF receptor‐2 (VEGFR2) is a major regulator of endothelial cell (EC) functions, including angiogenesis. Although most studies of angiogenesis focus on soluble VEGF signaling, mechanical signaling also plays a critical role. Here, we examined the consequence of disruption of mechanical signaling on soluble signaling pathways. Specifically, we observed that small interfering RNA (siRNA) knockdown of a mechanosensitive ion channel, transient receptor potential vanilloid 4 (TRPV4), significantly reduced perinuclear (Golgi) VEGFR2 in human ECs with a concomitant increase in phosphorylation at Y1175 and membrane translocation. TRPV4 knockout (KO) ECs exhibited increased plasma membrane localization of phospho‐VEGFR2 compared with normal ECs. The knockdown also increased phospho‐VEGFR2 in whole cell lysates and membrane fractions compared with control siRNA‐treated cells. siRNA knockdown of TRPV4 enhanced nuclear localization of mechanosensitive transcription factors, yes‐associated protein/transcriptional coactivator with PDZ‐binding motif via rho kinase, which were shown to increase VEGFR2 trafficking to the plasma membrane. Furthermore, TRPV4 deletion/knockdown enhanced VEGF‐mediated migration in vitro and increased expression of VEGFR2 in vivo in the vasculature of TRPV4 KO tumors compared with wild‐type tumors. Our results thus show that TRPV4 channels regulate VEGFR2 trafficking and activation to identify novel cross‐talk between mechanical (TRPV4) and soluble (VEGF) signaling that controls EC migration and angiogenesis.—Kanugula, A. K., Adapala, R. K., Midha, P., Cappelli, H. C., Meszaros, J. G., Paruchuri, S., Chilian, W. M., Thodeti, C. K., Novel noncanonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4. FASEB J. 33, 195–203 (2019). www.fasebj.org
Compliance With the National SEP-1 Quality Measure and Association With Sepsis Outcomes: A Multicenter Retrospective Cohort Study*
Authors: Rhee Chanu , Filbin Michael R. , Massaro Anthony F. , Bulger Amy L. , McEachern Donna , Tobin Kathleen A. , Kitch Barrett T. , Thurlo-Walsh Bert , Kadar Aran , Koffman Alexandra , Pande Anupam , Hamad Yasir , Warren David K. , Jones Travis M. , O’Brien Cara , Anderson Deverick J. , Wang Rui , Klompas Michael
Published: June 2018

Objectives:

Many septic patients receive care that fails the Centers for Medicare and Medicaid Services’ SEP-1 measure, but it is unclear whether this reflects meaningful lapses in care, differences in clinical characteristics, or excessive rigidity of the “all-or-nothing” measure. We compared outcomes in cases that passed versus failed SEP-1 during the first 2 years after the measure was implemented.

Design:

Retrospective cohort study.

Setting:

Seven U.S. hospitals.

Patients:

Adult patients included in SEP-1 reporting between October 2015 and September 2017.

Interventions:

None.

Measurements and Main Results:

Of 851 sepsis cases in the cohort, 281 (33%) passed SEP-1 and 570 (67%) failed. SEP-1 failures had higher rates of septic shock (20% vs 9%; p < 0.001), hospital-onset sepsis (11% vs 4%; p = 0.001), and vague presenting symptoms (46% vs 30%; p < 0.001). The most common reasons for failure were omission of 3- and 6-hour lactate measurements (228/570 failures, 40%). Only 86 of 570 failures (15.1%) had greater than 3-hour delays until broad-spectrum antibiotics. Cases that failed SEP-1 had higher in-hospital mortality rates (18.4% vs 11.0%; odds ratio, 1.82; 95% CI, 1.19–2.80; p = 0.006), but this association was no longer significant after adjusting for differences in clinical characteristics and severity of illness (adjusted odds ratio, 1.36; 95% CI, 0.85–2.18; p = 0.205). Delays of greater than 3 hours until antibiotics were significantly associated with death (adjusted odds ratio, 1.94; 95% CI, 1.04–3.62; p = 0.038), whereas failing SEP-1 for any other reason was not (adjusted odds ratio, 1.10; 95% CI, 0.70–1.72; p = 0.674).

Conclusions:

Crude mortality rates were higher in sepsis cases that failed versus passed SEP-1, but there was no difference after adjusting for clinical characteristics and severity of illness. Delays in antibiotic administration were associated with higher mortality but only accounted for a small fraction of SEP-1 failures. SEP-1 may not clearly differentiate between high- and low-quality care, and detailed risk adjustment is necessary to properly interpret associations between SEP-1 compliance and mortality.
A Case for Change in Adult Critical Care Training for Physicians in the United States: A White Paper Developed by the Critical Care as a Specialty Task Force of the Society of Critical Care Medicine*
Authors: Tisherman Samuel A. , Spevetz Antoinette , Blosser Sandralee A. , Brown Daniel , Chang Cherylee , Efron Philip A. , O’Connor Michael , Sevransky Jonathan E. , Wessman Brian T.
Published: June 2018

Objectives:

In the United States, physician training in Critical Care Medicine has developed as a subspecialty of different primary boards, despite significant commonality in knowledge and skills. The Society of Critical Care Medicine appointed a multidisciplinary Task Force to examine alternative approaches for future training.

Design:

The Task Force reviewed the literature and conducted informal discussions with key stakeholders. Specific topics reviewed included the history of critical care training, commonalities among subspecialties, developments since a similar review in 2004, international experience, quality patient care, and financial and workforce issues.

Main Results:

The Task Force believes that options for future training include establishment of a 1) primary specialty of critical care; 2) unified fellowship and certification process; or 3) unified certification process with separate fellowship programs within the current specialties versus 4) maintaining multiple specialty-based fellowship programs and certification processes.

Conclusions:

1) Changing the current Critical Care Medicine training paradigms may benefit trainees and patient care. 2) Multiple pathways into critical care training for all interested trainees are desirable for meeting future intensivist workforce demands. 3) The current subspecialties within separate boards are not “distinct and well-defined field[s] of medical practice” per the American Board of Medical Specialties. Recommendations for first steps are as follows: 1) as the society representing multidisciplinary critical care, the Society of Critical Care Medicine has an opportunity to organize a meeting of all stakeholders to discuss the issues regarding Critical Care Medicine training and consider cooperative approaches for the future. 2) A common Critical Care Medicine examination, possibly with a small percentage of base-specialty–specific questions, should be considered. 3) Institutions with multiple Critical Care Medicine fellowship programs should consider developing joint, multidisciplinary training curricula. 4) The boards that offer Critical Care Medicine examinations, along with national critical care societies, should consider ways to shorten training time.
Addressing Administration Challenges Associated With Blinatumomab Infusions
Authors: Szoch Stephanie , Boord Christina , Duffy Alison , Patzke Ciera
Published: June 2018

Blinatumomab has shown great potential for patients with chemotherapy-resistant B-cell acute lymphocytic leukemia. Blinatumomab's toxicity profile includes central nervous system toxicities, as well as cytokine release syndrome. Although neurological toxicities associated with blinatumomab are almost always reversible, early detection and intervention of these toxicities is vital to ensure that patients continue their full course of treatment. Guidelines for the preparation and administration of blinatumomab in both inpatient and outpatient settings, as well as a standardized neurological nursing assessment, were developed to ensure safe and effective administration of blinatumomab.
Cancer and the Broken Heart
Authors: Boyle Deborah A.
Published: June 2018

The growing number of adult long-term cancer survivors has expanded our knowledge of negative physiologic sequelae associated with curative therapies. Of note are the cardiovascular corollaries of chest radiotherapy and some commonly used chemotherapy agents. A contemporary understanding of risk factors has facilitated the development of guidelines for prevention and surveillance of cardiac compromise. The future holds promise with enhanced opportunities to use cardioprotectant drugs and biomarkers to prevent and detect early myocardial changes. Infusion therapy nurses must keep abreast of these developments to facilitate their roles as patient educators and advocates in the face of this toxicity's prevalence.
Reproductive Coercion
Authors: Kovar Cheryl L.
Published: June 2018

Background and Purpose: Reproductive coercion involves behavior that interferes with the individual's unique ability to make decisions about their reproductive health. The concept was first recognized in 2010. Reproductive coercion is intended to maintain power and control in a relationship by someone past, present, or future wishing to be involved in an intimate or dating relationship with an adult or adolescent. Three forms of coercion have been identified: contraceptive sabotage, pregnancy pressure, and control of pregnancy outcomes. Methods: A search for scientific literature was conducted examining studies involving reproductive coercion as well as evidence-based interventions that could be used by nurses in the clinic setting. Conclusions: Prevalence of reproductive coercion is estimated to range from 8% to 16%. There is a high association between intimate partner violence (IPV), sexually transmitted infections (STIs), and unintended pregnancy. Adolescents are at greater risk for reproductive coercion than older women. Implications for Practice: There are interventions we can incorporate into our clinical practices to screen and assess women for reproductive coercion. Women experiencing reproductive coercion are at risk for unintended pregnancy, STIs, IPV, and forced pregnancy outcomes.
Maternity Nurses' Knowledge and Practice of Breastfeeding in Mississippi
Authors: Alakaam Amir , Lemacks Jennifer , Yadrick Kathleen , Connell Carol , Choi Hwanseok Winston , Newman Ray G.
Published: June 2018

Background:

Mississippi has the lowest rates of breastfeeding of all states at 6 months and at 1 year. Registered nurses working in the maternity setting can be influential in mothers' decision to breastfeed.

Purpose:

The purpose of this study was to examine registered nurses' knowledge and practice related to breastfeeding; and to identify facilitators and barriers to implementing the Ten Steps to Successful Breastfeeding in Mississippi hospitals.

Methods:

302 Registered nurses working in hospital maternity/birthing settings in Mississippi completed a questionnaire. Breastfeeding knowledge and practices overall scores were categorized into: poor and good. Chi-square analysis and Spearman correlations were used to determine correlations among the variables.

Results:

Overall breastfeeding knowledge and practices of respondents was good. Only 4% earned a perfect score. Most believed they were effective (77%) in meeting the needs of new mothers. Significant positive associations were noted among knowledge and effectiveness, and other variables. Resistance to change and staffing shortages were the main barriers to implementing the Ten Steps; raising awareness about the importance of the Ten Steps and providing a lactation consultant were the main facilitators.

Conclusion:

More research is needed to understand reasons behind low breastfeeding rates in Mississippi.
Is There a Relationship Between Gestational Diabetes and Perinatal Depression?
Authors: Clevesy Marcia A. , Gatlin Tricia K. , Strebel Kord T.
Published: June 2018

Perinatal depression (PND) is one of the leading complications associated with childbirth. Early detection and treatment of depression, particularly during the perinatal period, is essential for the promotion of positive maternal–child outcomes. Gestational diabetes mellitus (GDM) has been suggested as a confounding factor associated with PND. Concerns associated with PND include interference with maternal–newborn bonding and long-term effects of neurobehavioral consequences. An exemplar case describing one woman's experience with GDM and her subsequent complications associated with PND is presented to discuss maternal depression and its plausible association with GDM. Recommendations include universal screening with the validated Edinburgh Postnatal Depression Scale screening tool during the early perinatal period to reduce incidence of maternal–newborn complications associated with PND and promote underpinnings for best practice.