bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of two different colloid priming strategies in infants weighing less than 5 kg undergoing on‐pump cardiac surgeries
Authors: Zhou Chun , Tong Yuanyuan , Feng Zhengyi , Cui Yongli , Zhao Mingxia , Hu Jinxiao , Liu Kai , Zhao Ju , Liu Jinping
Published: September 2019

Our aim was to explore the effect of two different priming strategies (artificial colloid only vs. artificial colloid combined with human serum albumin) on the prognosis of children weighing less than 5 kg undergoing on‐pump congenital heart disease (CHD) surgery. A total of 65 children weighing less than 5 kg who underwent on‐pump CHD surgery in our hospital from September 2016 to December 2017 were enrolled in this study. The children were randomly divided into two groups: artificial colloid priming group (AC group, n = 33) and artificial colloid combined albumin priming group (ACA group, n = 32). The primary clinical endpoint was the peri‐CPB colloid osmotic pressure (COP). Secondary clinical endpoints included perioperative blood product and hemostatic drug consumption, postoperative renal function, coagulation function, postoperative renal function, and postoperative recovery parameters. COP values were not significant in the priming system as well as peri‐CPB time points between the two groups (P > .05). Platelet consumption in the AC group was significantly lower than that in the ACA group (P < .05). There were no significant differences in the use of other blood products and hemostatic drugs as well as perioperative coagulation parameters between the two groups (P > .05). Postoperative length of stay in the AC group was significantly lower than that in the ACA group (P < .05). There were no significant differences in mortality, postoperative mechanical ventilation time, ICU time, and perioperative adverse events (including postoperative AKI) occurrences between the two groups (P > .05). In the on‐pump cardiac surgeries of patients weighing less than 5 kg, total colloidal priming would not affect peri‐CPB COP values, postoperative coagulation function, and blood products consumption. Total artificial colloidal priming strategy is feasible in low‐weight patients.
Clinical implications of LDH isoenzymes in hemolysis and continuous‐flow left ventricular assist device‐induced thrombosis
Authors: Gordon Jonathan S. , Wood Chelsey T. , Luc Jessica G. Y. , Watson Ryan A. , Maynes Elizabeth J. , Choi Jae Hwan , Morris Rohinton J. , Massey Howard Todd , Throckmorton Amy L. , Tchantchaleishvili Vakhtang
Published: September 2019

Pump‐induced thrombosis continues to be a major complication of continuous‐flow left ventricular assist devices (CF‐LVADs), which increases the risks of thromboembolic stroke, peripheral thromboembolism, reduced pump flow, pump failure, cardiogenic shock, and death. This is confounded by the fact that there is currently no direct measure for a proper diagnosis during pump support. Given the severity of this complication and its required treatment, the ability to accurately differentiate CF‐LVAD pump thrombosis from other complications is vital. Hemolysis measured by elevated lactate dehydrogenase (LDH) enzyme levels, when there is clinical suspicion of pump‐induced thrombosis, is currently accepted as an important metric used by clinicians for diagnosis; however, LDH is a relatively nonspecific finding. LDH exists as five isoenzymes in the body, each with a unique tissue distribution. CF‐LVAD pump thrombosis has been associated with elevated serum LDH‐1 and LDH‐2, as well as decreased LDH‐4 and LDH‐5. Herein, we review the various isoenzymes of LDH and their utility in differentiating hemolysis seen in CF‐LVAD pump thrombosis from other physiologic and pathologic conditions as reported in the literature.
Impact of left ventricular assist device therapy on the cardiac proteome and metabolome composition in ischemic cardiomyopathy
Authors: Shahinian Jasmin Hasmik , Rog‐Zielinska Eva A. , Schlimpert Manuel , Mayer Bettina , Tholen Stefan , Kammerer Bernd , Biniossek Martin L. , Beyersdorf Friedhelm , Schilling Oliver , Siepe Matthias
Published: September 2019

The changes in the myocardial proteome and metabolome associated with left ventricular assist device (LVAD) therapy in patients with ischemic cardiomyopathy (ICM) are poorly characterized. We investigated the impact of mechanical unloading following LVAD therapy on the myocardial proteome and metabolome. Matched samples of 5 patients’ myocardial tissue, harvested at the time of LVAD implant (“pre‐LVAD”) or heart transplant (“post‐LVAD”), were studied by quantitative proteomics and metabolomics as well as being probed for T‐tubule structure and connexin‐43 distribution. Moreover, pre‐LVAD proteome profiles of ICM context were bioinformatically compared to pre‐LVAD proteome profiles of dilated cardiac myopathy (DCM). More than 2120 proteins were reliably identified and quantified in paired patient samples. LVAD therapy led to proteomic remodeling, including reduced levels of α‐1‐antichymotrypsin together with an overall decrease of immune response proteins and an increase of proteins involved in membrane biology. Metabolomics highlighted increased glucose and glucose‐6‐phosphate levels in the left ventricle upon LVAD therapy. Wheat germ agglutinin staining demonstrated improved T‐tubule structure. Connexin‐43 displayed a trend for more pronounced intercalated disc localization. In comparing pre‐LVAD proteome profiles of ICM context with pre‐LVAD proteome profiles of dilated cardiac myopathy (DCM), we noticed an overrepresentation in ICM of proteins associated with humoral immune response. Our findings underline an impact of LVAD therapy on left ventricular biology in ICM. The proteomic, metabolomic, and structural alterations described here are typically associated with cardiac recovery. On the molecular level, our findings indicate the possibility of cardiac remodeling under LVAD therapy in ICM.
Effect of glaucoma drainage implant surgery on corneal topography: a prospective study
Authors: Koivusalo Riku , Välimäki Juha
Published: September 2019

Purpose

To study the effect of glaucoma drainage implant (GDI) surgery on corneal topography during the first postoperative year.

Methods

Twenty‐one adult glaucoma patients were implanted with a Molteno3 or a Baerveldt 250 GDI. Corneal topography measurements were taken preoperatively and at 6 and 12 months after surgery. Untreated opposite eyes served as controls.

Results

In the surgical group, the mean ± SD simulated average keratometry values were 44.36 ± 1.69 D, 44.08 ± 1.29 D (p = 0.266) and 44.15 ± 1.32 D (p = 0.554) before and 6 and 12 months after surgery, respectively. The corresponding simulated keratometry astigmatism values were 1.11 ± 1.11 D, 1.20 ± 1.01 D (p = 0.687) and 1.16 ± 0.71 D (p = 0.177). Posterior astigmatism and posterior average keratometry remained unchanged after GDI surgery as well. The mean ± SD central corneal thickness (CCT) was 530 ± 46 μm, 535 ± 56 μm (p = 0.049) and 536 ± 45 μm (p = 0.080) at 0, 6 and 12 months, respectively. A trend towards increased corneal thickness (CT) in response to GDI surgery was also seen in both the average peripheral and the tube‐quadrant peripheral CT values. At 12 months postoperatively, the mean endothelial cell density (ECD) had decreased by 8% centrally and by 9% peripherally. Corneal topography parameters, CT and ECD did not significantly change in the control group during follow‐up.

Conclusion

Glaucoma drainage implant (GDI) surgery did not significantly alter corneal keratometry parameters and thus seems to be an astigmatically neutral procedure. However a slight, although seemingly transient, increase in CCT was observed after GDI implantation.
Lamin A/C negatively regulated by miR‐124‐3p modulates apoptosis of vascular smooth muscle cells during cyclic stretch application in rats
Authors: Bao Han , Li Hai‐Peng , Shi Qian , Huang Kai , Chen Xiao‐Hu , Chen Yuan‐Xiu , Han Yue , Xiao Qian , Yao Qing‐Ping , Qi Ying‐Xin
Published: September 2019

Aim

Apoptosis of vascular smooth muscle cells (VSMCs) influenced by abnormal cyclic stretch is crucial for vascular remodelling during hypertension. Lamin A/C, a nuclear envelope protein, is mechano‐responsive, but the role of lamin A/C in VSMC apoptosis is still unclear.

Methods

FX‐5000T Strain Unit provided cyclic stretch (CS) in vitro. AnnexinV/PI and cleaved Caspase 3 ELISA detected apoptosis. qPCR was used to investigate the expression of miR‐124‐3p and a luciferase reporter assay was used to evaluate the ability of miR‐124‐3p binding to the Lmna 3’UTR. Protein changes of lamin A/C and relevant molecules were detected using western blot. Ingenuity Pathway Analysis and Protein/DNA array detected the potential transcription factors. Renal hypertensive rats verified these changes.

Results

High cyclic stretch (15%‐CS) induced VSMC apoptosis and repressed lamin A/C expressions compared with normal (5%‐CS) control. Downregulation of lamin A/C enhanced VSMC apoptosis. In addition, 15%‐CS had no significant effect on mRNA expression of Lmna, and lamin A/C degradation was not induced by autophagy. 15%‐CS elevated miR‐124‐3p bound to the 3’UTR of Lmna and negatively regulated protein expression of lamin A/C. Similar changes occurred in renal hypertensive rats compared with sham controls. Lamin A/C repression affected activity of TP53, CREB1, MYC, STAT1/5/6 and JUN, which may in turn affect apoptosis.

Conclusion

Our data suggested that the decreased expression of lamin A/C upon abnormal cyclic stretch and hypertension may induce VSMC apoptosis. These mechano‐responsive factors play important roles in VSMC apoptosis and might be novel therapeutic targets for vascular remodelling in hypertension.
Principal mode of Syndecan‐4 mechanotransduction for the endothelial glycocalyx is a scissor‐like dimer motion
Authors: Jiang Xi Zhuo , Luo Kai H. , Ventikos Yiannis
Published: September 2019

Aim

Endothelial glycocalyx (EG) plays a pivotal role in a plethora of diseases, like cardiovascular and renal diseases. One hallmark function of the EG as a mechanotransducer which transmits mechanical signals into cytoplasm has been documented for decades. However, the basic question ‐ how the glycocalyx transmits the flow shear stress— is unanswered so far. Our aim is to shed light on the fundamental mode of signal transmission from flow to the endothelial cytoskeleton.

Methods

We conduct a series of large‐scale molecular dynamics computational experiments to investigate the dynamics of glycocalyx under varying conditions (changing blood flow velocities and shedding of glycocalyx sugar chains).

Results

We have identified that the main pathway of signal transmission in this system manifests as a scissors‐like motion of the Syndecan‐4 core protein. Results have suggested that the force transmitted into the cytoskeleton with an order of 10 ~ 100 pN, and the main function of sugar chains of a glycocalyx element is to protect the core proteins from severe conformational changes thereby maintaining the functionality of the EG.

Conclusion

This research provides a reconciling explanation for a longstanding debate about the force transmission threshold based on our findings. A new explanation has also been provided to relate the role of the EG as a mechanotransducer to its function as a microvascular barrier: the EG regulates the mechanotransduction by altering the median value and variation range of the scissor angle, and the EG governs the microvascular barrier via controlling the scissor angle which will affect the intercellular cleft.
Stakeholder Engagement in Sustainability Reporting: Evidence of Reputation Risk Management in Large Australian Companies
Authors: Ardiana Putu Agus
Published: September 2019

The objective of this research is to examine whether stakeholder engagement in sustainability reporting constitutes the process of managing reputational risk. This research utilises Shrives and Brennan's (2017) framework of rhetorical strategies of non‐compliance to obtain empirical evidence of reputation risk management (RRM) in the context of stakeholder engagement in sustainability reporting. Quantitative and qualitative content analysis was undertaken on 154 sustainability disclosures in both the annual and sustainability reports of large Australian companies. This research finds that large Australian companies engage with their stakeholders to manage reputational risk: to increase market share and pre‐empt social issues. It is evident that large Australian companies use several forms of rhetorical statements in their sustainability disclosures with respect to RRM. However, there is no evidence that they shirk their responsibilities.
Confidence interval‐based sample size determination formulas and some mathematical properties for hierarchical data
Authors: Usami Satoshi
Published: September 2019

The use of hierarchical data (also called multilevel data or clustered data) is common in behavioural and psychological research when data of lower‐level units (e.g., students, clients, repeated measures) are nested within clusters or higher‐level units (e.g., classes, hospitals, individuals). Over the past 25 years we have seen great advances in methods for computing the sample sizes needed to obtain the desired statistical properties for such data in experimental evaluations. The present research provides closed‐form and iterative formulas for sample size determination that can be used to ensure the desired width of confidence intervals for hierarchical data. Formulas are provided for a four‐level hierarchical linear model that assumes slope variances and inclusion of covariates under both balanced and unbalanced designs. In addition, we address several mathematical properties relating to sample size determination for hierarchical data via the standard errors of experimental effect estimates. These include the relative impact of several indices (e.g., random intercept or slope variance at each level) on standard errors, asymptotic standard errors, minimum required values at the highest level, and generalized expressions of standard errors for designs with any‐level randomization under any number of levels. In particular, information on the minimum required values will help researchers to minimize the risk of conducting experiments that are statistically unlikely to show the presence of an experimental effect.
Prognostic value of blood and lymphatic vessel markers in tongue cancer: A systematic review
Authors: Almahmoudi Rabeia , Kasanen Merimaija , Sieviläinen Meri , Salem Abdelhakim , Pirinen Matti , Salo Tuula , Al‐Samadi Ahmed
Published: September 2019

Tongue squamous cell carcinoma (TSCC) has a poor prognosis due to its early metastasis through blood and lymphatic vessels. We undertook a systematic review to investigate the prognostic significance of blood microvessel density (MVD) and lymphatic vessel density (LVD) in TSCC patients. We carried out a systematic search in Ovid Medline, Scopus, and Cochrane libraries. All studies that evaluated the prognostic significance of MVD/LVD markers in TSCC were systematically retrieved. Our results showed that MVD/LVD markers, CD31, CD34, CD105, factor VIII, lymphatic vessel endothelial hyaluronan receptor‐1, and D2‐40 were evaluated in TSCC patients until 28 June 2018. Six out of 13 studies reported markers that were associated with poor prognosis in TSCC. Two out of three studies suggested that a high number of D2‐40+ vessels predicated low overall survival (OS); the third study reported that the ratio of D2‐40+ over factor VIII+ vessels is associated with low OS. Most of the other markers had controversial results for prognostication. We found higher expression of MVD/LVD markers were commonly, but not always, associated with shorter survival in TSCC patients. It is therefore not currently possible to recommend implementation of these markers as reliable prognosticators in clinical practice. More studies (especially for D2‐40) with larger patient cohorts are needed.
Dissection of gastric cancer heterogeneity for precision oncology
Authors: Ho Shamaine Wei Ting , Tan Patrick
Published: September 2019

Gastric cancer (GC) remains the fifth most prevalent cancer worldwide and the third leading cause of global cancer mortality. Comprehensive ‐omic studies have unveiled a heterogeneous GC landscape, with considerable molecular diversity both between and within tumors. Given the complex nature of GC, a long‐sought goal includes effective identification of distinct patient subsets with prognostic and/or predictive outcomes to enable tailoring of specific treatments (“precision oncology”). In this review, we highlight various approaches to molecular classification in GC, covering recent genomic, transcriptomic, proteomic and epigenomic features. We pay special attention to the translational significance of classifier systems and examine potential confounding factors which deserve further investigation. In particular, we discuss recent advancements in our knowledge of intra‐subtype, intra‐patient and intra‐tumor heterogeneity, and the pivotal role of the tumor stromal microenvironment.
A kojic acid derivative promotes intrinsic apoptotic pathway of hepatocellular carcinoma cells without incurring drug resistance
Authors: Oncul Selin , Karakaya Gulsah , Dilsiz Aytemir Mutlu , Ercan Ayse
Published: September 2019

Hepatocellular carcinoma is one of the most pervasive cancers with low prognosis, high frequency of recurrence, and metastasis. Studies conducted have focused on extricating novel strategies for successful treatment. Kojic acid and its derivatives are already proven to have depigmenting, anti‐inflammatory, and anti‐neoplastic properties. In the present study, kojic acid and its 10 distinct derivatives were tested on HEPG2 cell line for their possible anti‐cancer effect and seven of them were observed to be cytotoxic. Compound 6 was chosen to proceed as the IC50 dosage for HEPG2 cells was lower in comparison with the other derivatives and kojic acid itself. Further experiments pointed out that intrinsic apoptotic pathway was triggered with the exposure of the cells to IC50 concentration of the derivative as the treatment led to escalation of intracellular ROS, induction of TP53 gene, and activation of caspase 3/7. Pro‐apoptotic Jnk and Bax genes were not triggered suggesting that the apoptotic pathway advance through an alternative route. Complementary experiments are in need; howbeit, the current findings suggest that the derivative offers a novel promising approach against hepatocellular carcinoma as it is not detrimental to healthy cells within the concentrations applied, and it does not induce drug resistance.
Activation through toll‐like receptor 2 on group 2 innate lymphoid cells can induce asthmatic characteristics
Authors: Ishii Takashi , Muroi Masashi , Horiguchi Kazuhide , Tanamoto Ken‐ichi , Nagase Takahide , Yamashita Naomi
Published: September 2019

Background

Type 2 innate lymphoid cells (ILC2s) are one of the sources of IL‐5 and IL‐13 in allergic airway inflammation. Innate immune receptors such as Toll‐like receptors (TLRs) expressed on epithelial cells could contribute to ILC2 activation through IL‐33 production, but a direct effect of TLRs on ILC2s remains to be elucidated.

Objectives

We hypothesized that TLRs can directly activate lung ILC2s and participate in the pathogenesis of asthma.

Methods

After intranasal administration of IL‐33 to wild‐type (WT), TLR2KO and TLR4KO female mice, ILC2s were isolated from harvested lungs. ILC2s were incubated with IL‐2 and TLR stimulants (pam3csk4 (PAM), house dust mite extract (HDM)). In some experiments, TLR2 or dectin‐1 signalling inhibitors were used. As an in vivo model, the mice were treated with IL‐33 and rested until lung recruitment of eosinophils regressed. Then they were treated intranasally with PAM + HDM or vehicle and analysed.

Results

In vitro stimulation of isolated ILC2s showed that PAM could induce IL‐13 and IL‐5 production, and HDM had a synergistic effect on this stimulation. Both effects were dependent on TLR2 and NF‐κB signalling. PAM + HDM stimulation of WT mice led to increased ILC2s, airway hyperresponsiveness and increased levels of both neutrophils and eosinophils in bronchoalveolar lavage fluid. These observations were dependent on TLR2.

Conclusions & clinical relevance

TLR2 can directly activate lung ILC2s, an effect that is augmented by HDM. Asthmatic characteristics mediated through the TLR2 pathway were evident in the in vivo mice model. These data implicate a new pathway of ILC2 activation in the pathogenesis of asthma.
Associations of gene polymorphisms in interferon‐alpha signature‐related genes with autoimmune thyroid diseases
Authors: Lin Jiunn‐Diann , Yang Shun‐Fa , Wang Yuan‐Hung , Fang Wen‐Fang , Tang Kam‐Tsun , Cheng Chao‐Wen
Published: September 2019

Interferon (IFN)‐α treatment predisposes patients to the occurrence of autoimmune thyroid disease (AITD).

Methods

We investigated associations of single nucleotide polymorphisms (SNPs) of molecules participating in the IFN‐α signature, including rs2304204 and rs2304206 of IFN regulatory factor 3 (IRF3), rs1061501 of IRF7, and rs7708392 of TNFA1P3‐interacting protein 1 with serum IFN‐α levels and AITD in an ethnic Chinese (ie Taiwanese) population. Totally, 319 patients with Graves' disease (GD), 83 patients with Hashimoto's thyroiditis (HT) and 351 healthy controls were recruited.

Results

There were increased percentages of the C allele, and CC and TC + CC genotypes of rs1061501 in GD patients compared to the controls. HT patients had higher serum IFN‐α levels compared to the controls, while there was no difference in serum IFN‐α levels between patients with GD and controls. However, patients with GD in a remission status had lower serum IFN‐α levels than those without remission. On the other hand, the C allele of rs1061501 was only associated with serum IFN‐α levels in patients with HT.

Conclusions

The SNP rs1061501 of IRF7 was associated with the development of GD. Serum IFN‐α levels were associated with HT, while they might modify the disease status of GD. Moreover, a genetic effect of rs1061501 on regulating serum IFN‐α production was observed in HT.
Can implants move in bone? A longitudinal in vivo micro‐CT analysis of implants under constant forces in rat vertebrae
Authors: Becker Kathrin , Schwarz Frank , Rauch Nicole Jasmin , Khalaph Silava , Mihatovic Ilja , Drescher Dieter
Published: September 2019

Objectives

Whereas stationary stability of implants has been postulated for decades, recent studies suggested a phenomenon termed implant migration. This describes a change in position of implants as a reaction to applied forces. The present study aims at employing image registration of in vivo micro‐CT scans from different time points and to assess (a) if migration of continuously loaded implants is possible and (b) migration correlates with the force magnitude.

Material and methods

Two customized machined implants were placed in the dorsal portion of caudal vertebrae in n = 61 rats and exposed to standardized forces (0.5 N, 1.0 N, and 1.5 N) applied through a flat nickel–titanium contraction spring, or no forces (control). Micro‐CT scans were performed at 0, 1, 2, 4, 6, and 8 weeks after surgery. The baseline image was registered with the forthcoming scans. Implant migration was measured as the Euclidean distance between implant tips. Bone remodeling was assessed between the baseline and the forthcoming scans.

Results

The findings confirmed a positional change of the implants at 2 and 8 weeks of healing, and a linear association between applied force and velocity of movement (anterior implant: χ2 = 12.12, df = 3, and p = .007 and posterior implant: χ2 = 20.35, df = 3, and p < .001). Bone apposition was observed around the implants and accompanied by formation of load‐bearing trabeculae and a general cortical thickening close and also distant to the implants.

Conclusion

The present analysis confirmed that implants can migrate in bone. The applied forces seemed to stimulate bone thickening, which could explain why implants migrate without affecting stability.
The Analytic Truth and Falsity of Disjunctions
Authors: Quelhas Ana Cristina , Rasga Célia , Johnson‐Laird P.N.
Published: September 2019

Disjunctive inferences are difficult. According to the theory of mental models, it is because of the alternative possibilities to which disjunctions refer. Three experiments corroborated further predictions of the mental model theory. Participants judged that disjunctions, such as Either this year is a leap year or it is a common year are true. Given a disjunction such as Either A or B, they tended to evaluate the four cases in its ‘partition’: A and B, A and not‐B, not‐A and B, not‐A and not‐B, as ‘possible’ or ‘impossible’ in ways that bore out the difference between inclusive disjunctions (‘or both’) and exclusive disjunctions (‘but not both’). Knowledge usually concerns what is true, and so when participants judge that a disjunction is false, or contingent, and evaluate the cases in its partition, they depend on inferences that yield predictable errors. They tended to judge that disjunctions, such as follows: Either the food is cold or else it is tepid, but not both, are true, though in fact they could be false. They tended to infer ‘mirror‐image’ evaluations that yield the same possibilities for false disjunctions as those for true disjunctions. The article considers the implications of these results for alternative theories based on classical logic or on the probability calculus.
The Influence of Shared Visual Context on the Successful Emergence of Conventions in a Referential Communication Task
Authors: Müller Thomas F. , Winters James , Morin Olivier
Published: September 2019

Human communication is thoroughly context bound. We present two experiments investigating the importance of the shared context, that is, the amount of knowledge two interlocutors have in common, for the successful emergence and use of novel conventions. Using a referential communication task where black‐and‐white pictorial symbols are used to convey colors, pairs of participants build shared conventions peculiar to their dyad without experimenter feedback, relying purely on ostensive‐inferential communication. Both experiments demonstrate that access to the visual context promotes more successful communication. Importantly, success improves cumulatively, supporting the view that pairs establish conventional ways of using the symbols to communicate. Furthermore, Experiment 2 suggests that dyads with access to the visual context successfully adapt the conventions built for one color space to another color space, unlike dyads lacking it. In linking experimental pragmatics with language evolution, the study illustrates the benefits of exploring the emergence of linguistic conventions using an ostensive‐inferential model of communication.
Immunosuppression reduction in kidney transplant recipients during bacterial infection—A retrospective study
Authors: Yahav Dafna , Sulimani Omri , Green Hefziba , Margalit Ili , Ben‐Zvi Haim , Mor Eytan , Rozen‐Zvi Benaya
Published: September 2019

Background

Immunosuppression reduction is a common practice in the management of bacterial infection among kidney transplant recipients (KTRs). This practice, however, is based on limited evidence.

Methods

Retrospective study comparing clinical outcomes of KTRs whose antimetabolite was discontinued vs continued during hospitalization due to bacterial infection, considering calcineurin inhibitors (CNI) levels. Primary outcome was a composite of clinical failure at day 5; all‐cause mortality; and/or re‐hospitalization at 90 days. Multivariable analysis of risk factors for the primary outcome was performed using a propensity‐matched cohort.

Results

We included 183 KTRs hospitalized with bacterial infection. Neither discontinuation of antimetabolites nor lower levels of CNI at infection onset were associated with a significant decrease the composite primary outcome. No significant difference in graft loss or rejection was demonstrated between patients with low vs high CNI levels or discontinuation vs continuation of antimetabolite. In multivariable analysis, CNI levels and management of antimetabolite were not significantly associated with adverse outcome.

Conclusions

Immunosuppression reduction in hospitalized KTRs with bacterial infection did not offer a clinical advantage in terms of mortality, re‐hospitalization, or clinical success. An interventional study evaluating continuation of immunosuppression vs reduction should be considered.
Rabbit antithymocyte globulin for the treatment of chronic lung allograft dysfunction
Authors: January Spenser E. , Fester Keith A. , Bain Karen Bennett , Kulkarni Hrishikesh S. , Witt Chad A. , Byers Derek E. , Alexander‐Brett Jennifer , Trulock Elbert P. , Hachem Ramsey R.
Published: September 2019

Background

Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation. Several treatments have been used to prevent the progression or reverse the effects of CLAD. Cytolytic therapy with rabbit antithymocyte globulin (rATG) has previously shown to be a potential option. However, the effect on patients with restrictive allograft syndrome (RAS) versus bronchiolitis obliterans syndrome (BOS) and the effect of cumulative dosing are unknown.

Methods

The charts of lung transplant patients treated with rATG at Barnes‐Jewish Hospital from 2009 to 2016 were retrospectively reviewed. The primary outcome was response to rATG; patients were deemed responders if their FEV1 improved in the 6 months after rATG treatment. Safety endpoints included incidence of serum sickness, cytokine release syndrome, malignancy, and infectious complications.

Results

108 patients were included in this study; 43 (40%) patients were responders who experienced an increase in FEV1 after rATG therapy. No predictors of response to rATG therapy were identified. Serum sickness occurred in 22% of patients, 15% experienced cytokine release syndrome, and 19% developed an infection after therapy.

Conclusion

40% of patients with CLAD have an improvement in lung function after treatment with rATG although the improvement was typically minimal.
Evidence for the origin of the binaural interaction component of the auditory brainstem response
Authors: Tolnai Sandra , Klump Georg M.
Published: September 2019

The binaural interaction component (BIC) represents the mismatch between auditory brainstem responses (ABR) obtained with binaural stimulation and the sum of ABRs obtained with monaural left and right stimulation. It is generally assumed that the BIC reflects binaural integration. Its potential use as a diagnostic tool, however, is hampered by the lack of direct evidence about its origin. While an origin at the initial site of binaural integration seems likely, there is no general agreement on the contribution of the two primary candidate nuclei, the lateral and medial superior olives (LSO and MSO, respectively). Here, we recorded local field potentials (LFP) and responses of units in the LSO and MSO of Mongolian gerbils (Meriones unguiculatus), presenting clicks with an interaural time or level difference (ITD and ILD, respectively), while simultaneously recording ABR. We determined the BIC from the ABR and, importantly, from LFP and responses of units in the LSO and MSO. If stimulus‐induced changes in the ABR‐derived BIC have their source in the LSO and/or MSO, we expect coherent changes in the unit‐derived and the ABR‐derived BIC. We find that BIC obtained from LSO units exhibits the same ITD and ILD dependence as the ABR‐derived BIC. Neither BIC obtained from MSO units nor LFP‐derived BIC recorded in either LSO or MSO did. The data thus strongly suggest that it is the activity of LSO units in the gerbil that is decisive for the generation of the ABR‐derived BIC, determining its properties.
Nitric oxide regulates the firing rate of neuronal subtypes in the guinea pig ventral cochlear nucleus
Authors: Hockley Adam , Berger Joel I. , Smith Paul A. , Palmer Alan R. , Wallace Mark N.
Published: September 2019

The gaseous free radical, nitric oxide (NO) acts as a ubiquitous neuromodulator, contributing to synaptic plasticity in a complex way that can involve either long term potentiation or depression. It is produced by neuronal nitric oxide synthase (nNOS) which is presynaptically expressed and also located postsynaptically in the membrane and cytoplasm of a subpopulation of each major neuronal type in the ventral cochlear nucleus (VCN). We have used iontophoresis in vivo to study the effect of the NOS inhibitor L‐NAME (L‐NG‐Nitroarginine methyl ester) and the NO donors SIN‐1 (3‐Morpholinosydnonimine hydrochloride) and SNOG (S‐Nitrosoglutathione) on VCN units under urethane anaesthesia. Collectively, both donors produced increases and decreases in driven and spontaneous firing rates of some neurones. Inhibition of endogenous NO production with L‐NAME evoked a consistent increase in driven firing rates in 18% of units without much effect on spontaneous rate. This reduction of gain produced by endogenous NO was mirrored when studying the effect of L‐NAME on NMDA(N‐Methyl‐D‐aspartic acid)‐evoked excitation, with 30% of units showing enhanced NMDA‐evoked excitation during L‐NAME application (reduced NO levels). Approximately 25% of neurones contain nNOS and the NO produced can modulate the firing rate of the main principal cells: medium stellates (choppers), large stellates (onset responses) and bushy cells (primary‐like responses). The main endogenous role of NO seems to be to partly suppress driven firing rates associated with NMDA channel activity but there is scope for it to increase neural gain if there were a pathological increase in its production following hearing loss.
Speech‐in‐noise understanding in older age: The role of inhibitory cortical responses
Authors: Ross Bernhard , Dobri Simon , Schumann Annette
Published: September 2019

Studies of central auditory processing underlying speech‐in‐noise (SIN) recognition in aging have mainly concerned the degrading neural representation of speech sound in the auditory brainstem and cortex. Less attention has been paid to the aging‐related decline of inhibitory function, which reduces the ability to suppress distraction from irrelevant sensory input. In a response suppression paradigm, young and older adults listened to sequences of three short sounds during MEG recording. The amplitudes of the cortical P30 response and the 40‐Hz transient gamma response were compared with age, hearing loss and SIN performance. Sensory gating, indicated by the P30 amplitude ratio between the last and the first responses, was reduced in older compared to young listeners. Sensory gating was correlated with age in the older adults but not with hearing loss nor with SIN understanding. The transient gamma response expressed less response suppression. However, the gamma amplitude increased with age and SIN loss. Comparisons of linear multi‐variable modeling showed a stronger brain–behavior relationship between the gamma amplitude and SIN performance than between gamma and age or hearing loss. The findings support the hypothesis that aging‐related changes in the balance between inhibitory and excitatory neural mechanisms modify the generation of gamma oscillations, which impacts on perceptual binding and consequently on SIN understanding abilities. In conclusion, SIN recognition in older age is less affected by central auditory processing at the level of sensation, indicated by sensory gating, but is strongly affected at the level of perceptual organization, indicated by the correlation with the gamma responses.
The relationship of argyrophilic proteins of the nuclear‐organized regions and atopic dermatitis in children
Authors: Gunduz Mehmet , Okan Meliha A. , Sengil Ahmet Z. , Temel Hayrettin , Comert Murat , Okur Mesut
Published: September 2019

Background

The argyrophilic proteins of nuclear‐organized regions (AgNOR), visualised with colloidal silver methods as black dots are known as AgNOR. To date, the relationship between AgNOR and cancer and inflammatory conditions has been investigated. However, there has been no report investigating the relationship between AgNOR and atopic dermatitis. The aim of this study was to investigate the relationship between atopic dermatitis and AgNOR in paediatric patients.

Methods

Twenty‐nine children with atopic dermatitis and 23 healthy children were included in the study. AgNOR test results were analysed prospectively.

Results

The mean AgNOR number (40.19 ± 21.06) in the patient group was significantly higher than the control group (12.83 ± 10.40) (P < .001).

Conclusions

This study investigated the association between AgNOR and atopic dermatitis for the first time in the literature. In the study, atopic dermatitis and AgNOR were found to be related. In the study, for the first time with the ROC analysis, AgNOR limit values with high sensitivity and specificity levels were determined in the diagnosis of atopic dermatitis.
Potential impacts of horizontal gene transfer on human health and physiology and how anthropogenic activity can affect it
Authors: Boto Luis , Pineda Manuel , Pineda Rafael
Published: September 2019

Horizontal gene transfer (HGT) is widespread among prokaryotes driving their evolution. In this paper, we review the potential impact in humans of the HGT between prokaryotes living in close association with humans in two scenarios: horizontal transfer in human microbiomes and transfer between microbes living in human managed environments. Although our vision is focused on the possible impact of these transfers in the propagation of antibiotic resistance genes or pathogenicity determinants, we also discuss possible human physiological adaptations via gene transfer between resident and occasional bacteria in the human microbiome.
Protease‐activated receptor signaling in intestinal permeability regulation
Authors: Pontarollo Giulia , Mann Amrit , Brandão Inês , Malinarich Frano , Schöpf Marie , Reinhardt Christoph
Published: September 2019

Protease‐activated receptors (PARs) are a unique class of G‐protein‐coupled transmembrane receptors, which revolutionized the perception of proteases from degradative enzymes to context‐specific signaling factors. Although PARs are traditionally known to affect several vascular responses, recent investigations have started to pinpoint the functional role of PAR signaling in the gastrointestinal (GI) tract. This organ is exposed to the highest number of proteases, either from the gut lumen or from the mucosa. Luminal proteases include the host's digestive enzymes and the proteases released by the commensal microbiota, while mucosal proteases entail extravascular clotting factors and the enzymes released from resident and infiltrating immune cells. Active proteases and, in case of a disrupted gut barrier, even entire microorganisms are capable to translocate the intestinal epithelium, particularly under inflammatory conditions. Especially PAR‐1 and PAR‐2, expressed throughout the GI tract, impact gut permeability regulation, a major factor affecting intestinal physiology and metabolic inflammation. In addition, PARs are critically involved in the onset of inflammatory bowel diseases, irritable bowel syndrome, and tumor progression. Due to the number of proteases involved and the multiple cell types affected, selective regulation of intestinal PARs represents an interesting therapeutic strategy. The analysis of tissue/cell‐specific knockout animal models will be of crucial importance to unravel the intrinsic complexity of this signaling network. Here, we provide an overview on the implication of PARs in intestinal permeability regulation under physiologic and disease conditions.
The ubiquitin ligase adaptor SPOP in cancer
Authors: Cuneo Matthew J. , Mittag Tanja
Published: September 2019

The dysregulation of ubiquitin‐mediated proteasomal degradation has emerged as an important mechanism of pathogenesis in several cancers. The speckle‐type POZ protein (SPOP) functions as a substrate adaptor for the cullin3‐RING ubiquitin ligase and controls the cellular persistence of a diverse array of protein substrates in hormone signalling, epigenetic control and cell cycle regulation, to name a few. Mutations in SPOP and the resulting dysregulation of this proteostatic pathway play causative roles in the pathogenesis of prostate and endometrial cancers, whereas overexpression and mislocalization are associated with kidney cancer. Understanding the molecular mechanism of the normal function of SPOP as well as the cause of SPOP‐mediated oncogenesis is thus critical for eventual therapeutic targeting of SPOP and other related pathways. Here, we will review SPOP structure, function and the molecular mechanism of how this function is achieved. We will then review how mutations and protein mislocalization contribute to cancer pathogenesis and will provide a perspective on how SPOP may be targeted therapeutically.
Arginine methylation augments Sbp1 function in translation repression and decapping
Authors: Bhatter Nupur , Roy Raju , Shah Shanaya , Sastry Sneha P. , Parbin Sabnam , Iyappan Rajan , Kankaria Siddharth , Rajyaguru Purusharth I.
Published: September 2019

The fate of messenger RNA in cytoplasm plays a crucial role in various cellular processes. However, the mechanisms that decide whether mRNA will be translated, degraded or stored remain unclear. Single stranded nucleic acid binding protein (Sbp1), an Arginine‐Glycine‐Glycine (RGG‐motif) protein, is known to promote transition of mRNA into a repressed state by binding eukaryotic translation initiation factor 4G1 (eIF4G1) and to promote mRNA decapping, perhaps by modulation of Dcp1/2 activity. Sbp1 is known to be methylated on arginine residues in RGG‐motif; however, the functional relevance of this modification in vivo remains unknown. Here, we report that Sbp1 is arginine‐methylated in an hnRNP methyl transferase (Hmt1)‐dependent manner and that methylation is enhanced upon glucose deprivation. Characterization of an arginine‐methylation‐defective (AMD) mutant provided evidence that methylation affects Sbp1 function in vivo. The AMD mutant is compromised in causing growth defect upon overexpression, and the mutant is defective in both localizing to and inducing granule formation. Importantly, the Sbp1‐eIF4G1 interaction is compromised both for the AMD mutant and in the absence of Hmt1. Upon overexpression, wild‐type Sbp1 increases localization of another RGG motif containing protein, Scd6 (suppressor of clathrin deficiency) to granules; however, this property of Sbp1 is compromised in the AMD mutant and in the absence of Hmt1, indicating that Sbp1 repression activity could involve other RGG‐motif translation repressors. Additionally, the AMD mutant fails to increase localization of the decapping activator DEAD box helicase homolog to foci and fails to rescue the decapping defect of a dcp1‐2Δski8 strain, highlighting the role of Sbp1 methylation in decapping. Taken together, these results suggest that arginine methylation modulates Sbp1 role in mRNA fate determination.
Long non‐coding RNA RP11‐820 promotes extracellular matrix production via regulating miR‐3178/MYOD1 in human trabecular meshwork cells
Authors: Shen Wencui , Huang Bingqing , He Ye , Shi Liukun , Yang Jin
Published: September 2019

Primary open angle glaucoma (POAG) is the most common type of glaucoma. At the mechanistic level, POAG is thought to be caused by extracellular matrix (ECM) deposition in the trabecular meshwork (TM). Growing evidence has shown that long noncoding RNAs (lncRNAs) are involved in the fibrotic process underlying many diseases. This study was undertaken to explore the role of lncRNA‐RP11‐820 in ECM production of human TM cells (HTMCs). Our results revealed that lncRNA‐RP11‐820 was significantly upregulated under oxidative stress in HTMCs. Further investigation revealed that lncRNA‐RP11‐820 directly binds miR‐3178, through which the expression of MYOD1 is regulated. Importantly, MYOD1 can transcriptionally activate ECM genes in HTMCs, in complex with STAT3. Taken together, our data established that oxidative stress‐induced lncRNA‐RP11‐820 plays a key role in regulating the miR‐3178/MYOD1/ECM axis in HTMCs. These findings further elucidate the pathogenic mechanism and provide a novel therapeutic target relevant to POAG.
Benefits and trade‐offs of replacing synthetic fertilizers by animal manures in crop production in China: A meta‐analysis
Authors: Zhang Xiaoying , Fang Qunchao , Zhang Tao , Ma Wenqi , Velthof Gerard L. , Hou Yong , Oenema Oene , Zhang Fusuo
Published: September 2019

Recycling of livestock manure to agricultural land may reduce the use of synthetic fertilizer and thereby enhance the sustainability of food production. However, the effects of substitution of fertilizer by manure on crop yield, nitrogen use efficiency (NUE), and emissions of ammonia (NH3), nitrous oxide (N2O) and methane (CH4) as function of soil and manure properties, experimental duration and application strategies have not been quantified systematically and convincingly yet. Here, we present a meta‐analysis of these effects using results of 143 published studies in China. Results indicate that the partial substitution of synthetic fertilizers by manure significantly increased the yield by 6.6% and 3.3% for upland crop and paddy rice, respectively, but full substitution significantly decreased yields (by 9.6% and 4.1%). The response of crop yields to manure substitution varied with soil pH and experimental durations, with relatively large positive responses in acidic soils and long‐term experiments. NUE increased significantly at a moderate ratio (<40%) of substitution. NH3 emissions were significantly lower with full substitution (62%–77%), but not with partial substitution. Emissions of CH4 from paddy rice significantly increased with substitution ratio (SR), and varied by application rates and manure types, but N2O emissions decreased. The SR did not significantly influence N2O emissions from upland soils, and a relative scarcity of data on certain manure characteristic was found to hamper identification of the mechanisms. We derived overall mean N2O emission factors (EF) of 0.56% and 0.17%, as well as NH3 EFs of 11.1% and 6.5% for the manure N applied to upland and paddy soils, respectively. Our study shows that partial substitution of fertilizer by manure can increase crop yields, and decrease emissions of NH3 and N2O, but depending on site‐specific conditions. Manure addition to paddy rice soils is recommended only if abatement strategies for CH4 emissions are also implemented.