bluuebunny/crossref_metadata_2025 huggingface dataset:
Utility of broad-range 16S rRNA PCR assay versus conventional methods for laboratory diagnosis of bacterial endophthalmitis in a tertiary care hospital
Authors: Mishra Deepanshi , Satpathy Gita , Chawla Rohan , Venkatesh Pradeep , Ahmed Nishat Hussain , Panda Subrat Kumar
Published: October 2018

Background

Endophthalmitis, a sight-threatening intraocular infection, can be of postsurgical, post-traumatic or endogenous origin. Laboratory diagnosis-based appropriate therapy can be vision-saving. Conventional culture-based laboratory diagnosis takes time and lacks sensitivity. In this study a broad-range PCR assay was assessed against conventional and automated culture methods in vitreous specimens for accurate microbiological diagnosis.

Aims

To use broad-range PCR assay targeting 16S ribosomal RNA (rRNA) region of bacteria and to assess its performance vis-à-vis conventional and automated culture methods in the laboratory diagnosis of endophthalmitis.

Methods

Vitreous specimens from 195 patients with clinically diagnosed endophthalmitis were processed for classical and automated culture methods, antimicrobial sensitivity and broad-range PCR assay targeting 762 bp region of 16S rRNA followed by nucleotide sequencing by Sanger’s method. Causative agents were identified from the nucleotide sequences analysed against the GenBank database, and organisms were identified using the Clinical and Laboratory Standards Institute (CLSI) MM18A guidelines.

Results

Bacteria could be detected from 127 (65.13%) of the 195 vitreous specimens by broad-range PCR assay; bacterial isolation was possible from 17 (8.7%) and 60 (30.76%) of these specimens by conventional and automated culture methods, respectively (p<0.0001). PCR assay could detect two uncultured bacterium, and in five cases the bacterial identity could not be determined from NCBI database matching.

Conclusion

Broad-range PCR assay could provide definitive microbial diagnosis within 24 hours in significantly more patients (p<0.0001). Some rare organisms could be detected, useful in treatment modalities. Automated culture was significantly more sensitive than conventional culture.
The burden of congenital Chagas disease and implementation of molecular diagnostic tools in Latin America
Authors: Picado Albert , Cruz Israel , Redard-Jacot Maël , Schijman Alejandro G , Torrico Faustino , Sosa-Estani Sergio , Katz Zachary , Ndung’u Joseph Mathu
Published: October 2018

It is estimated that between 8000 and 15 000Trypanosoma cruziinfected babies are born every year to infected mothers in Chagas disease endemic countries. Currently, poor access to and performance of the current diagnostic algorithm, based on microscopy at birth and serology at 8–12 months after delivery, is one of the barriers to congenital Chagas disease (CCD) control. Detection of parasite DNA using molecular diagnostic tools could be an alternative or complement to current diagnostic methods, but its implementation in endemic regions remains limited. Prompt diagnosis and treatment of CCD cases would have a positive clinical and epidemiological impact. In this paper, we analysed the burden of CCD in Latin America, and the potential use of molecular tests to improve access to early diagnosis and treatment ofT. cruziinfected newborns.
Conceptual review of measuring functional impairment: findings from the Weiss Functional Impairment Rating Scale
Authors: Weiss Margaret D. , McBride Nicole Michelle , Craig Stephanie , Jensen Peter
Published: October 2018

Objective

This is a narrative review of validation and outcome studies using the Weiss Functional Impairment Rating Scale (WFIRS). The objective of the review is to establish a framework for understanding functional impairment and create a definition for functional response and remission.

Methods

We conducted a literature search via MEDLINE, EBSCO and Google Scholar with no date restrictions and reviewed bibliographies of selected publications. Publications found in languages other than English were translated and clarification obtained from the author(s) if needed. Inclusion criteria were any manuscript that was either a WFIRS psychometric validation study or a clinical trial using the WFIRS as an outcome. There were no exclusion criteria.

Results

The WFIRS has been validated in multiple cultures, and in clinical, research and control populations. The WFIRS has robust psychometric properties across ages, psychiatric status and informants. Outcome studies show variable improvement, with different response patterns between domains and among different interventions.

Conclusion

Symptom improvement and remission needs to be complemented with evaluation of functional improvement and remission to obtain a full picture of clinical status over the course of treatment.
Clinicopathological features and outcome of antibody-negative anti-glomerular basement membrane disease
Authors: Liang Dandan , Liang Shaoshan , Xu Feng , Zhang Mingchao , Li Xiaomei , Tu Yiyao , Liu Zhihong , Zeng Caihong
Published: October 2018

Aim

To explore the clinicopathological characteristics of patients with anti-GBM antibody-negative anti-GBM disease.

Methods

The clinical and renal pathological findings were retrospectively studied in 19 patients. All patients met the following inclusion criteria: linear GBM IgG deposition on immunofluorescence(IF); and lack of serum anti-GBM antibodies by ELISA and indirect immunofluorescence assay.

Results

There were 17 male and two female patients, with a median age of 36 years (range 15–61 years). Hypertension was present in 68% of cases, nephrotic-range proteinuria (> 3.5 g/24 hours) in 42%, nephrotic syndrome in 37%, microhaematuria in 95%, renal insufficiency in 63% and lung involvement in 16%. On biopsy all patients had linear GBM staining for polyclonal IgG by IF. The dominant IgG subtype was IgG4 or IgG1. By light microscopy, mesangial proliferative GN without crescents was seen in four patients; proliferative GN (mesangial proliferative GN in eight; endocapillary proliferative GN in two; and membranoproliferative GN in two) with crescents (focal in 11; diffuse in one) in 12 patients; and crescentic GN without mesangial or endocapillary proliferative or membranoproliferative changes in three patients. By electron microscopy, six patients showed scarce electron dense deposits in glomeruli and 11 patients had global podocyte effacement. Totally, 10 (53%) patients received immunosuppressive therapy. The median follow-up was 15 months and six (32%) patients progressed to end-stage renal disease.

Conclusions

Anti-GBM antibody-negative anti-GBM disease was different from classic anti-GBM disease clinically and pathologically. The pathogenesis of the renal injury in these patients has not been elucidated until now and it should be studied and identified further.
Efficacy and safety of non-pharmacological, pharmacological and surgical treatment for hand osteoarthritis: a systematic literature review informing the 2018 update of the EULAR recommendations for the management of hand osteoarthritis
Authors: Kroon Féline P B , Carmona Loreto , Schoones Jan W , Kloppenburg Margreet
Published: October 2018

To update the evidence on efficacy and safety of non-pharmacological, pharmacological and surgical interventions for hand osteoarthritis (OA), a systematic literature review was performed up to June 2017, including (randomised) controlled trials or Cochrane systematic reviews. Main efficacy outcomes were pain, function and hand strength. Risk of bias was assessed. Meta-analysis was performed when advisable. Of 7036 records, 127 references were included, of which 50 studies concerned non-pharmacological, 64 pharmacological and 12 surgical interventions. Many studies had high risk of bias, mainly due to inadequate randomisation or blinding. Beneficial non-pharmacological treatments included hand exercise and prolonged thumb base splinting, while single trials showed positive results for joint protection and using assistive devices. Topical and oral non-steroidal anti-inflammatory drugs (NSAIDs) proved equally effective, while topical NSAIDs led to less adverse events. Single trials demonstrated positive results for chondroitin sulfate and intra-articular glucocorticoid injections in interphalangeal joints. Pharmacological treatments for which no clear beneficial effect was shown include paracetamol, intra-articular thumb base injections of glucocorticoids or hyaluronic acid, low-dose oral glucocorticoids, hydroxychloroquine and anti-tumour necrosis factor. No trials compared surgery to sham or non-operative treatment. No surgical intervention for thumb base OA appeared more effective than another, although in general more complex procedures led to more complications. No interventions slowed radiographic progression. In conclusion, an overview of the evidence on efficacy and safety of treatment options for hand OA was presented and informed the task force for the updated European League Against Rheumatism management recommendations for hand OA.
Digital trichoblastoma treated with electrochemotherapy in a dog
Authors: Dos Anjos Denner Santos , Rossi Ygor Amaral , Magalhães Larissa Fernandes , Calazans Sabryna Gouveia , Fonseca‐Alves Carlos Eduardo
Published: October 2018

Canine trichoblastoma is a benign tumour derived from the trichoblastic epithelium, commonly affecting the head and neck and, less commonly, the limbs and trunk. Herein, the authors report a case of a dog with digital trichoblastoma successfully treated with electrochemotherapy (ECT). The dog received three sessions of ECT with systemic bleomycin. The tumour volume decreased throughout the ECT sessions, with a complete response after 81 days. The patient presented a disease‐free survival of 700 days. ECT may be a better approach than surgery for digital trichoblastomas because it avoids amputating the digit and provides a good cosmetic result.
Lessons learned from data-limited evaluations of data-rich reef fish species in the Gulf of Mexico: implications for providing fisheries management advice for data-poor stocks
Authors: Sagarese Skyler R. , Harford William J. , Walter John F. , Bryan Meaghan D. , Isely J. Jeffery , Smith Matthew W. , Goethel Daniel R. , Rios Adyan B. , Cass-Calay Shannon L. , Porch Clay E. , Carruthers Thomas R. , Cummings Nancie J.
Published: October 2018

Specifying annual catch limits for artisanal fisheries, low economic value stocks, or bycatch species is problematic due to data limitations. Many empirical management procedures (MPs) have been developed that provide catch advice based on achieving a stable catch or a historical target (i.e., instead of maximum sustainable yield). However, a thorough comparison of derived yield streams between empirical MPs and stock assessment models has not been explored. We first evaluate trade-offs in conservation and yield metrics for data-limited approaches through management strategy evaluation (MSE) of seven data-rich reef fish species in the Gulf of Mexico. We then apply data-limited approaches for each species and compare how catch advice differs from current age-based assessment models. MSEs identified empirical MPs (e.g., using relative abundance) as a compromise between data requirements and the ability to consistently achieve management objectives (e.g., prevent overfishing). Catch advice differed greatly among data-limited approaches and current assessments, likely due to data inputs and assumptions. Adaptive MPs become clearly viable options that can achieve management objectives while incorporating auxiliary data beyond catch-only approaches.
Resveratrol attenuates hIAPP amyloid formation and restores the insulin secretion ability in hIAPP-INS1 cell line via enhancing autophagy
Authors: Lv Wu , Zhang Jialin , Jiao Ao , Wang Bowen , Chen Baomin , Lin Jie
Published: October 2018

It has been proved that human islet amyloid polypeptide (hIAPP), the main constituent of islet amyloid deposition, is one of the important factors that can induce type 2 diabetes or graft failure after islet transplantation. As there is no research on whether resveratrol degrading the amyloid deposition by its special chemical structure or enhancing autophagy had been published, we decided to detect the function of resveratrol in degrading the amyloid deposition in pancreatic beta cells. We established stable hIAPP-INS1 cell line via transfecting INS1 cells by lentivirus that overexpresses hIAPP. Our research demonstrates that amyloid deposition existed in hIAPP-INS1 cell by the thioflavin S fluorescent staining, meanwhile the function of insulin secretion of hIAPP-INS1 cells was decreased significantly (p < 0.01). After treatment with resveratrol (20 μM) for 24 h, amyloid deposition in hIAPP-INS1 cells was decreased significantly, and the insulin secretion was restored significantly (p < 0.01). Once inhibited the autophagy of hIAPP-INS1 cells by 3-methyladenine for 24 h, resveratrol does not effectively remove hIAPP deposits again, and cannot improve the function of insulin secretion. These results provide a novel thought that resveratrol can degrade the amyloid deposition in type 2 diabetes and the graft after islet transplantation.
Effects of silica nanoparticles on endolysosome function in primary cultured neurons
Authors: Ye Yan , Hui Liang , Lakpa Koffi L. , Xing Yuqian , Wollenzien Hannah , Chen Xuesong , Zhao Julia Xiaojun , Geiger Jonathan D.
Published: October 2018

Silica nanoparticles (SiNPs) have been used as vehicles for drug delivery, molecular detection, and cellular manipulations in nanoneuromedicine. SiNPs may cause adverse effects in the brain including neurotoxicity, neuroinflammation, neurodegeneration, and enhancing levels of amyloid beta (Aβ) protein—all pathological hallmarks of Alzheimer’s disease. Therefore, the extent to which SiNPs influence Aβ generation and the underlying mechanisms by which this occurs deserve investigation. Our studies were focused on the effects of SiNPs on endolysosomes which uptake, traffic, and mediate the actions of SiNPs. These organelles are also where amyloidogenesis largely originates. We found that SiNPs, in primary cultured hippocampal neurons, accumulated in endolysosomes and caused a rapid and persistent deacidification of endolysosomes. SiNPs significantly reduced endolysosome calcium stores as indicated by a significant reduction in the ability of the lysosomotropic agent glycyl-l-phenylalanine 2-naphthylamide (GPN) to release calcium from endolysosomes. SiNPs increased Aβ1–40 secretion, whereas 2 agents that acidified endolysosomes, ML-SA1 and CGS21680, blocked SiNP-induced deacidification and increased generation of Aβ1–40. Our findings suggest that SiNP-induced deacidification of and calcium release from endolysosomes might be mechanistically linked to increased amyloidogenesis. The use of SiNPs might not be the best nanomaterial for therapeutic strategies against Alzheimer’s disease and other neurological disorders linked to endolysosome dysfunction.
Inhibition effect of phytoestrogen calycosin on TGF-β1-induced hepatic stellate cell activation, proliferation, and migration via estrogen receptor β
Authors: Deng Tan , Liu Jing , Zhang Mengmeng , Wang Yaxin , Zhu Guannan , Wang Jiajia
Published: October 2018

The present study was designed to investigate the effects of calycosin on hepatic stellate cell (HSC) function and to explore whether the drug exerts its effect through the estrogen receptor. HSC proliferation and migration were measured by MTT assay and transwell chamber assay, respectively. The mRNA and protein expression of α-SMA, COL-I, and ERβ were detected by real-time PCR and Western blotting. The co-localization and expression of α-SMA and ERβ protein were detected by immunofluorescence. All the studies were investigated in the absence or presence of ICI 182,780. The results showed that calycosin inhibited the proliferation of activated HSCs and remarkably inhibited HSC migration. Calycosin significantly reduced the expression of α-SMA and COL-I in activated HSCs. However, with co-treatment with ICI 182,780, the inhibitory effect of calycosin against the above effects was strongly negated. Importantly, calycosin significantly downregulated the expression of ERβ protein, while co-treatment with ICI 182,780 partially reversed the ERβ downregulation. In addition, α-SMA decreased with the decrease of ERβ expression and the subtype of ERβ on HSC is ERβ5. In conclusion, calycosin inhibits proliferation, activation, and migration of TGF-β1-induced HSCs. The effect may be related to binding and downregulation of ERβ5.
AUDIO MAGNETOTELLURIC SIGNAL-NOISE IDENTIFICATION AND SEPARATION BASED ON MULTIFRACTAL SPECTRUM AND MATCHING PURSUIT
Authors: LI JIN , ZHANG XIAN , TANG JINGTIAN , CAI JIN , LIU XIAOQIONG
Published: October 2018

To avoid the blindness of the overall de-noising method and retain useful low frequency signals that are not over processed, we proposed a novel audio magnetotelluric (AMT) signal-noise identification and separation method based on multifractal spectrum and matching pursuit. We extracted two sets of multifractal spectrum characteristic from AMT time-series data to analyze the singularity. We used a support vector machine approach to learn the multifractal spectrum characteristics in a sample’s library and generate a model of support vector machine to distinguish between sections with and without interference in the measured AMT data. The matching pursuit algorithm was used to separate only those sections identified as having interference. Experimental results showed that the proposed method can effectively identify interference in the EMTF mathematical model and measured AMT data. Sections without interference were accurately preserved and reconstructed AMT signals were close to the natural electromagnetic field. The resulting apparent resistivity-phase curve is more continuous and smooth, and effectively improves the quality of AMT data. Moreover, the proposed method provides more reliable AMT data for subsequent electromagnetic inversion.
Pullbacks of hyperplane sections for Lagrangian fibrations are primitive
Authors: Kamenova Ljudmila , Verbitsky Misha
Published: October 2018

Let [Formula: see text] be a Lagrangian fibration on a hyperkähler manifold of maximal holonomy (also known as IHS), and [Formula: see text] be the generator of the Picard group of [Formula: see text]. Assume that [Formula: see text] has no multiple fibers in codimension 1. We prove that [Formula: see text] is a primitive class on [Formula: see text].
Effective de Rham cohomology — The general case
Authors: Scheiblechner Peter
Published: October 2018

Grothendieck has proved that each class in the de Rham cohomology of a smooth complex affine variety can be represented by a differential form with polynomial coefficients. We prove a single exponential bound on the degrees of these polynomials for varieties of arbitrary dimension. More precisely, we show that the [Formula: see text]th de Rham cohomology of a smooth affine variety of dimension [Formula: see text] and degree [Formula: see text] can be represented by differential forms of degree [Formula: see text]. This result is relevant for the algorithmic computation of the cohomology, but is also motivated by questions in the theory of ordinary differential equations related to the infinitesimal Hilbert 16th problem.
Superharmonic functions associated with hypoelliptic non-Hörmander operators
Authors: Battaglia Erika , Biagi Stefano
Published: October 2018

In this paper, we consider a class of degenerate-elliptic linear operators [Formula: see text] in quasi-divergence form and we study the associated cone of superharmonic functions. In particular, following an abstract Potential-Theoretic approach, we prove the local integrability of any [Formula: see text]-superharmonic function and we characterize the [Formula: see text]-superharmonicity of a function [Formula: see text] in terms of the sign of the distribution [Formula: see text]; we also establish some Riesz-type decomposition theorems and we prove a Poisson–Jensen formula. The operators involved are [Formula: see text]-hypoelliptic but they do not satisfy the Hörmander Rank Condition nor subelliptic estimates or Muckenhoupt-type degeneracy conditions.
M. Forster Heddle: an intimate friendship
Authors: Johnston Hamish H.
Published: October 2018

A lifelong friendship began in 1852 between Archibald Geikie (1835–1924) and Matthew Forster Heddle (1828–97), the most eminent Scottish mineralogist of his day. This paper follows the two men from their birth, through their education and early employment, to their first meeting in Edinburgh. It then traces the progress of their complementary, but different, careers and recounts shared events in their professional and personal lives. It describes how the astute Geikie supported the clever but unworldly Heddle through his difficulties at the University of St Andrews and helped him achieve scientific recognition. It concludes by comparing and contrasting their personalities and approach to science and defining the nature of their enduring friendship.
Functional feasibility analysis of variability-intensive data flow-oriented applications over highly-configurable platforms
Authors: Lazreg Sami , Collet Philippe , Mosser Sébastien
Published: October 2018

Data-flow oriented embedded systems, such as automotive systems used to render HMI (e.g., instrument clusters, infotainments), are increasingly built from highly variable specifications while targeting different constrained hardware platforms configurable in a fine-grained way. These variabilities at two different levels lead to a huge number of possible embedded system solutions, which functional feasibility is extremely complex and tedious to predetermine. In this paper, we propose a tooled approach that capture high level specifications as variable dataflows, and targeted platforms as variable component models. Dataflows can then be mapped onto platforms to express a specification of such variability-intensive systems. The proposed solution transforms this specification into structural and behavioral variability models and reuses automated reasoning techniques to explore and assess the functional feasibility of all variants in a single run. We also report on the validation of the proposed approach. A qualitative evaluation has been conducted on an industrial case study of automotive instrument cluster, while a quantitative one is reported on large generated datasets.
Molecular Mechanisms of Wing Polymorphism in Insects
Authors: Zhang Chuan-Xi , Brisson Jennifer A. , Xu Hai-Jun
Published: October 2018

Many insects are capable of developing into either long-winged or short-winged (or wingless) morphs, which enables them to rapidly match heterogeneous environments. Thus, the wing polymorphism is an adaptation at the root of their ecological success. Wing polymorphism is orchestrated at various levels, starting with the insect's perception of environmental cues, then signal transduction and signal execution, and ultimately the transmitting of signals into physiological adaption in accordance with the particular morph produced. Juvenile hormone and ecdysteroid pathways have long been proposed to regulate wing polymorphism in insects, but rigorous experimental evidence is lacking. The breakthrough findings of ecdysone receptor regulation on transgenerational wing dimorphism in the aphid Acyrthosiphon pisum and of insulin signaling in the planthopper Nilaparvata lugens greatly broaden our understanding of wing polymorphism at the molecular level. Recently, the advent of high-throughput sequencing coupled with functional genomics provides powerful genetic tools for future insights into the molecular bases underlying wing polymorphism in insects.
Paradoxical arteriole constriction compromises cytosolic and mitochondrial oxygen delivery in the isolated saline-perfused heart
Authors: Giles Abigail V. , Sun Junhui , Femnou Armel N. , Kuzmiak-Glancy Sarah , Taylor Joni L. , Covian Raul , Murphy Elizabeth , Balaban Robert S.
Published: October 2018

The isolated saline-perfused heart is used extensively to study cardiac physiology. Previous isolated heart studies have demonstrated lower tissue oxygenation compared with in vivo hearts based on myoglobin oxygenation and the mitochondrial redox state. These data, consistent with small anoxic regions, suggest that the homeostatic balance between work and oxygen delivery is impaired. We hypothesized that these anoxic regions are caused by inadequate local perfusion due to a paradoxical arteriole constriction generated by a disrupted vasoregulatory network. We tested this hypothesis by applying two exogenous vasodilatory agents, adenosine and cromakalim, to relax vascular tone in an isolated, saline-perfused, working rabbit heart. Oxygenation was monitored using differential optical transmission spectroscopy and full spectral fitting. Increases in coronary flow over control with adenosine (27 ± 4 ml/min) or cromakalim (44 ± 4 ml/min) were associated with proportional spectral changes indicative of myoglobin oxygenation and cytochrome oxidase (COX) oxidation, consistent with a decrease in tissue anoxia. Quantitatively, adenosine decreased deoxymyoglobin optical density (OD) across the wall by 0.053 ± 0.008 OD, whereas the reduced form of COX was decreased by 0.039 ± 0.005 OD. Cromakalim was more potent, decreasing deoxymyoglobin and reducing the level of COX by 0.070 ± 0.019 OD and 0.062 ± 0.019 OD, respectively. These effects were not species specific, as Langendorff-perfused mouse hearts treated with adenosine demonstrated similar changes. These data are consistent with paradoxical arteriole constriction as a major source of regional anoxia during saline heart perfusion. We suggest that the vasoregulatory network is disrupted by the washout of interstitial vasoactive metabolites in vitro.

NEW & NOTEWORTHY Regional tissue anoxia is a common finding in the ubiquitous saline-perfused heart but is not found in vivo. Noninvasive optical techniques confirmed the presence of regional anoxia under control conditions and demonstrated that anoxia is diminished using exogenous vasodilators. These data are consistent with active arteriole constriction, occurring despite regional anoxia, generated by a disrupted vasoregulatory network. Washout of interstitial vasoactive metabolites may contribute to the disruption of normal vasoregulatory processes in vitro.
Deletion of Atm in Tumor but not Endothelial Cells Improves Radiation Response in a Primary Mouse Model of Lung Adenocarcinoma
Authors: Torok Jordan A. , Oh Patrick , Castle Katherine D. , Reinsvold Michael , Ma Yan , Luo Lixia , Lee Chang-Lung , Kirsch David G.
Published: October 2018

Stereotactic body radiotherapy is utilized to treat lung cancer. The mechanism of tumor response to high-dose radiotherapy (HDRT) is controversial, with competing hypotheses of increased direct tumor cell killing versus indirect effects on stroma including endothelial cells. Here we used dual recombinase technology in a primary murine lung cancer model to test whether tumor cells or endothelial cells are critical HDRT targets. Lenti-Cre deleted one or two copies of ataxia-telangiectasia mutated gene (Atm; KPAFL/+ or KPAFL/FL), whereas adeno-FlpO–infected mice expressed Cre in endothelial cells to delete one or both copies of Atm (KPVAFL/+ or KPVAFL/FL) to modify tumor cell or endothelial cell radiosensitivity, respectively. Deletion of Atm in either tumor cells or endothelial cells had no impact on tumor growth in the absence of radiation. Despite increased endothelial cell death in KPVAFL/FL mice following irradiation, tumor growth delay was not significantly increased. In contrast, a prolonged tumor growth delay was apparent in KPAFL/FL mice. Primary tumor cell lines lacking Atm expression also demonstrated enhanced radiosensitivity as determined via a clonogenic survival assay. These findings indicate that tumor cells, rather than endothelial cells, are critical targets of HDRT in primary murine lung cancer.

Significance:

These findings establish radiosensitizing tumor cells rather than endothelial cells as the primary mechanism of tumor response to high-dose radiotherapy, supporting efforts to maximize local control by radiosensitizing tumors cells.

See related commentary by Hallahan, p. 704
Pomalidomide Inhibits PD-L1 Induction to Promote Antitumor Immunity
Authors: Fujiwara Yuki , Sun Yi , Torphy Robert J. , He Jiadai , Yanaga Katsuhiko , Edil Barish H. , Schulick Richard D. , Zhu Yuwen
Published: October 2018

Thalidomide-like drugs have been approved for the treatment of human multiple myeloma, with their direct antitumor effects and immunomodulatory functions well documented. However, the exact molecular mechanisms that govern these effects remain unclear. Here we demonstrate that pomalidomide promotes immune response by inhibiting expression of PD-L1. Pomalidomide inhibited PD-L1 expression on tumor cells to promote CTL activity in vitro and suppressed PD-L1 upregulation on antigen-presenting cells to prevent peptide-induced T-cell tolerance. Knockout of PD-L1 on tumor cells or in mice completely eliminated the immunomodulatory effect of pomalidomide. Furthermore, pomalidomide synergized with other immunotherapies to improve anticancer therapy. Taken together, this study identifies a new mechanism for the immunomodulatory functions of pomalidomide in cancer therapy. These results also offer a clinical approach for blocking PD-L1 induction and potentially promoting antitumor immunity.

Significance:

These findings report that the immunomodulatory drug pomalidomide, widely used to treat myeloma and other cancers, enhances antitumor immunity by inhibiting PD-1/PD-L1 expression.
Deep Reinforcement Learning in Medicine
Authors: Jonsson Anders
Published: October 2018

Reinforcement learning has achieved tremendous success in recent years, notably in complex games such as Atari, Go, and chess. In large part, this success has been made possible by powerful function approximation methods in the form of deep neural networks. The objective of this paper is to introduce the basic concepts of reinforcement learning, explain how reinforcement learning can be effectively combined with deep learning, and explore how deep reinforcement learning could be useful in a medical context.
The Effect of Platelet-Rich Plasma on Peyronie’s Disease in Rat Model
Authors: Culha Mehmet Gokhan  , Erkan Erkan , Cay Tugce , Yücetaş Uğur
Published: October 2018

Purpose: The objective of this study was to evaluate the effects of intratunical injection of platelet rich plasma (PRP) for the treatment of Peyronie’s disease (PD) in a rat model. Materials and Methods: Twenty male Sprague-Dawley rats (300–350 g) were randomly divided into 4 groups: sham, PD, PD + PRP, and PRP. The PD + PRP groups received intratunical injections with 0.1 mL PRP on day 15 (treatment) or day 0 (PRP effect). Forty-five days following transforming growth factor-beta 1 injection, rats underwent pathological examination. Tissues were evaluated histologically for fibrosis grade (Haematoxylin & Eosin staining), collagen/smooth muscle ratio (Masson Trichrome staining) and type III/type I collagen ratio (Picro-sirius red staining). Statistical analysis was performed by Kruskal-Wallis and chi-square followed by the Mann-Whitney U test for post hoc comparisons. Results: Significant changes were found in all 3 groups compared to the sham group (p < 0.0001 for fibrosis, p = 0.001 for collagen/smooth muscle ratio and p = 0.003 for type III/type I collagen ratio). The values in the PRP group and the findings in the PD group are similar (p = 0.122 for fibrosis, p = 0.221 for collagen/smooth muscle ratio and p = 1.0 for type III/type I collagen ratio). Conclusion: This is the first study of PRP on PD. As a result of pathological examinations, PRP shows PD-like effects in rats. PRP may be a cheap, easily accessible, and an effective disease model for PD treatment research.
Mild Cognitive Impairment Affects Obstacle Negotiation in Older Adults: Results from “Gait and Brain Study”
Authors: Pieruccini-Faria Frederico , Sarquis-Adamson Yanina , Montero-Odasso Manuel
Published: October 2018

Background: Older adults with Mild Cognitive Impairment (MCI) are at higher risk of falls and injuries, but the underlying mechanism is poorly understood. Inappropriate anticipatory postural adjustments to overcome balance perturbations are affected by cognitive decline. However, it is unknown whether anticipatory gait control to avoid an obstacle is affected in MCI. Objective: Using the dual-task paradigm, we aim to assess whether gait control is affected during obstacle negotiation challenges in older adults with MCI. Methods: Seventy-nine participants (mean age = 72.0 ± 2.7 years; women = 30.3%) from the “Gait and Brain Study” were included in this study (controls = 27; MCI = 52). In order to assess the anticipatory control behaviour for obstacle negotiation, a 6-m electronic walkway embedded with sensors recorded foot prints to measure gait speed and step length variability, during early (3 steps before the late phase) and late (3 steps before the obstacle) pre-crossing phases of an ad hoc obstacle, set at 15% of participant’s height. Participants walked under single- and dual-task gait (counting backwards by 1’s from 100 while walking) conditions. Three-way mixed repeated-measures analysis of variance models examined differences in gait performance between groups when transitioning between pre-crossing phases towards an obstacle during single- and dual-task conditions. Analyses were adjusted for age, sex, years of education, lower limb function, fear of falling, medical status, depressive symptoms, baseline gait speed and executive function. Results: A significant three-way interaction among groups, pre-crossing phases and task showed that participants with MCI attenuated the gait deceleration (p = 0.02) and performed fewer step length adjustments (p = 0.03) when approaching the obstacle compared with controls while dual-tasking. These interactions were attenuated when executive function performance was added as a covariate in the adjusted statistical model. Conclusion: Older adults with MCI attenuate the anticipatory gait adjustments needed to avoid an obstacle when dual-tasking. Deficits in higher-order cognitive processing may limit obstacle negotiation capabilities in MCI populations, being a potential falls risk factor.
CD44+/CD24+-Expressing Cervical Cancer Cells and Radioresistant Cervical Cancer Cells Exhibit Cancer Stem Cell Characteristics
Authors: Zhang Jun , Chen Xi , Bian Lei , Wang Yujing , Liu Hong
Published: October 2018

Background: Radiation therapy is a mainstay in the treatment of cervical cancer. However, most advanced and metastatic cervical cancers are resistant to radiation therapy because of the presence of cancer stem cells (CSCs). To date, no specific markers were found for cervical CSCs. Methods: The fraction of CD44+/CD24+ cell subpopulation was detected with flow cytometry (FCM). The clonogenicity and radiosensitivity were detected using colony-formation and radiosensitivity assay. Matrigel-transwell invasion assay was used to compare the invading capacity. We compared the tumor formation capacity using Tumor Xenografts. The expressions of apoptosis related factor, epithelial-mesenchymal transition and stem cell markers were detected with real-time polymerase chain reaction and western blot analysis. Results: This study shows that radiation-resistant cervical cancer cells are rich in CD44+/CD24+-expressing cervical cancer cells. Moreover, these 2 cells exhibit the same CSC characteristics, such as increased expression of Bcl-2, survivin, and stem cell markers being more tumorigenic. These cells also showed phenotypic molecular changes that are consistent with epithelial-mesenchymal transition. Conclusion: Our data suggested that CD44+/CD24+-expressing cervical cancer cells may perform an important function in the radioresistance of cervical cancer. The therapy, which focuses on CD44+/CD24+-expressing cervical cancer cells, can increase the radiosensitivity of cervical cancer.
Gp91phox (NOX2) in Activated Microglia Exacerbates Neuronal Damage Induced by Oxygen Glucose Deprivation and Hyperglycemia in an in Vitro Model
Authors: Zeng Xianzhang , Ren Hongliang , Zhu Yana , Zhang Ruru , Xue Xinxin , Tao Tao , Xi Hongjie
Published: October 2018

Background/Aims: Peri-operative cerebral ischemia reperfusion injury is one of the most serious peri-operative complications that can be aggravated in patients with diabetes. A previous study showed that microglia NOX2 (a NADPH oxidase enzyme) may play an important role in this process. Here, we investigated whether increased microglial derived gp91phox, also known as NOX2, reduced oxygen glucose deprivation (OGD) after induction of hyperglycemia (HG). Methods: A rat neuronal-microglial in vitro co-culture model was used to determine the effects of gp91phox knockdown on OGD after HG using six treatment groups: A rat microglia and neuron co-culture model was established and divided into the following six groups: high glucose + scrambled siRNA transfection (HG, n = 5); HG + gp91phoxsiRNA transfection (HG-gp91siRNA, n = 5); oxygen glucose deprivation + scrambled siRNA transfection (OGD, n = 5); OGD + gp91phoxsiRNA transfection (OGD-gp91siRNA, n = 5); HG + OGD + scrambled siRNA transfection (HG-OGD, n = 5); and HG + OGD + gp91phoxsiRNA transfection (HG-OGD-gp91siRNA, n = 5). The neuronal survival rate was measured by the MTT assay, while western blotting was used to determine gp91phox expression. Microglial derived ROS and neuronal apoptosis rates were analyzed by flow cytometry. Finally, the secretion of cytokines, including IL-6, IL-8, TNF-α, and 8-iso-PGF2α was determined using an ELISA kit. Results: Neuronal survival rates were significantly decreased by HG and OGD, while knockdown of gp91phox reversed these rates. ROS production and cytokine secretion were also significantly increased by HG and OGD but were significantly inhibited by knockdown of gp91phoxsiRNA. Conclusion: Knockdown of gp91phoxsiRNA significantly reduced oxidative stress and the inflammatory response, and alleviated neuronal damage after HG and OGD treatment in a rat neuronal-microglial co-culture model.
Uterine Carcinosarcomas - Diagnosis and Management
Authors: Denschlag Dominik , Ulrich Uwe A.
Published: October 2018

Uterine carcinosarcomas are rare tumors that account for less than 5% of all uterine malignancies. These tumors (previously called malignant mixed Müllerian tumors) are dedifferentiated carcinomas that comprise carcinomatous and sarcomatous elements and arise from a single malignant clone. They are considered a high-risk variant of endometrial adenocarcinoma because carcinosarcomas share more similarities in epidemiology, risk factors, and clinical behavior with endometrial carcinoma than with uterine sarcomas. The clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma will be discussed in this review.
Mannose-Binding Lectin Drives Platelet Inflammatory Phenotype and Vascular Damage After Cerebral Ischemia in Mice via IL (Interleukin)-1α
Authors: Orsini Franca , Fumagalli Stefano , Császár Eszter , Tóth Krisztina , De Blasio Daiana , Zangari Rosalia , Lénárt Nikolett , Dénes Ádám , De Simoni Maria-Grazia
Published: October 2018

Objective—

Circulating complement factors are activated by tissue damage and contribute to acute brain injury. The deposition of MBL (mannose-binding lectin), one of the initiators of the lectin complement pathway, on the cerebral endothelium activated by ischemia is a major pathogenic event leading to brain injury. The molecular mechanisms through which MBL influences outcome after ischemia are not understood yet.

Approach and Results—

Here we show that MBL-deficient (MBL
−/−
) mice subjected to cerebral ischemia display better flow recovery and less plasma extravasation in the brain than wild-type mice, as assessed by in vivo 2-photon microscopy. This results in reduced vascular dysfunction as shown by the shift from a pro- to an anti-inflammatory vascular phenotype associated with MBL deficiency. We also show that platelets directly bind MBL and that platelets from MBL
−/−
mice have reduced inflammatory phenotype as indicated by reduced IL-1α (interleukin-1α) content, as early as 6 hours after ischemia. Cultured human brain endothelial cells subjected to oxygen-glucose deprivation and exposed to platelets from MBL
−/−
mice present less cell death and lower CXCL1 (chemokine [C-X-C motif] ligand 1) release (downstream to IL-1α) than those exposed to wild-type platelets. In turn, MBL deposition on ischemic vessels significantly decreases after ischemia in mice treated with IL-1 receptor antagonist compared with controls, indicating a reciprocal interplay between MBL and IL-1α facilitating endothelial damage.

Conclusions—

We propose MBL as a hub of pathogenic vascular events. It acts as an early trigger of platelet IL-1α release, which in turn favors MBL deposition on ischemic vessels promoting an endothelial pro-inflammatory phenotype.
Palmitoylethanolamide Promotes a Proresolving Macrophage Phenotype and Attenuates Atherosclerotic Plaque Formation
Authors: Rinne Petteri , Guillamat-Prats Raquel , Rami Martina , Bindila Laura , Ring Larisa , Lyytikäinen Leo-Pekka , Raitoharju Emma , Oksala Niku , Lehtimäki Terho , Weber Christian , van der Vorst Emiel P.C. , Steffens Sabine
Published: October 2018

Objective—

Palmitoylethanolamide is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by
N
-acyl phosphatidylethanolamine phospholipase D. Its biological actions are primarily mediated by PPAR-α (peroxisome proliferator-activated receptors α) and the orphan receptor GPR55. Palmitoylethanolamide exerts potent anti-inflammatory actions but its physiological role and promise as a therapeutic agent in chronic arterial inflammation, such as atherosclerosis remain unexplored.

Approach and Results—

First, the polarization of mouse primary macrophages towards a proinflammatory phenotype was found to reduce
N
-acyl phosphatidylethanolamine phospholipase D expression and palmitoylethanolamide bioavailability.
N
-acyl phosphatidylethanolamine phospholipase D expression was progressively downregulated in the aorta of apolipoprotein E deficient (ApoE
−/−
) mice during atherogenesis.
N
-acyl phosphatidylethanolamine phospholipase D mRNA levels were also downregulated in unstable human plaques and they positively associated with smooth muscle cell markers and negatively with macrophage markers. Second, ApoE
−
/−
mice were fed a high-fat diet for 4 or 16 weeks and treated with either vehicle or palmitoylethanolamide (3 mg/kg per day, 4 weeks) to study the effects of palmitoylethanolamide on early established and pre-established atherosclerosis. Palmitoylethanolamide treatment reduced plaque size in early atherosclerosis, whereas in pre-established atherosclerosis, palmitoylethanolamide promoted signs of plaque stability as evidenced by reduced macrophage accumulation and necrotic core size, increased collagen deposition and downregulation of M1-type macrophage markers. Mechanistically, we found that palmitoylethanolamide, by activating GPR55, increases the expression of the phagocytosis receptor MerTK (proto-oncogene tyrosine-protein kinase MER) and enhances macrophage efferocytosis, indicative of proresolving properties.

Conclusions—

The present study demonstrates that palmitoylethanolamide protects against atherosclerosis by promoting an anti-inflammatory and proresolving phenotype of lesional macrophages, representing a new therapeutic approach to resolve arterial inflammation.
Characterization of Endothelial Cilia Distribution During Cerebral-Vascular Development in Zebrafish (
Danio rerio
)
Authors: Eisa-Beygi Shahram , Benslimane Fatiha M. , El-Rass Suzan , Prabhudesai Shubhangi , Abdelrasoul Mahmoud Khatib Ali , Simpson Pippa M. , Yalcin Huseyin C. , Burrows Patricia E. , Ramchandran Ramani
Published: October 2018

Objective—

Endothelial cells (ECs) sense and respond to flow-induced mechanical stress, in part, via microtubule-based projections called primary cilia. However, many critical steps during vascular morphogenesis occur independent of flow. The involvement of cilia in regulating these stages of cranial vascular morphogenesis is poorly understood because cilia have not been visualized in primary head vessels. The objective of this study was to investigate involvement of cilia in regulating the early stages of cranial vascular morphogenesis.

Approach and Results—

Using high-resolution imaging of the
Tg(kdrl:mCherry-CAAX
)

y171

;(bactin::Arl13b:GFP
) zebrafish line, we showed that cilia are enriched in the earliest formed cranial vessels that assemble via vasculogenesis and in angiogenic hindbrain capillaries. Cilia were more prevalent around the boundaries of putative intravascular spaces in primary and angiogenic vessels. Loss of cardiac contractility and blood flow, because of knockdown of cardiac troponin T type 2a (
tnnt2a
) expression, did not affect the distribution of cilia in primary head vasculature. In later stages of development, cilia were detected in retinal vasculature, areas of high curvature, vessel bifurcation points, and during vessel anastomosis. Loss of genes crucial for cilia biogenesis (
ift172
and
ift81
) induced intracerebral hemorrhages in an EC-autonomous manner. Exposure to high shear stress induced premature cilia disassembly in brain ECs and was associated with intracerebral hemorrhages.

Conclusions—

Our study suggests a functional role for cilia in brain ECs, which is associated with the emergence and remodeling of the primary cranial vasculature. This cilia function is flow-independent, and cilia in ECs are required for cerebral-vascular stability.
Time-Dependent Hypotensive Effect of Aspirin in Mice
Authors: Chen Lihong , Yang Guangrui , Zhang Jiayang , Ren Baoyin , Tang Soonyew , Li Xuanwen , FitzGerald Garret A.
Published: October 2018

Objective—

Evening but not morning administration of low-dose aspirin has been reported to lower blood pressure in hypertensive patients. The present study was designed to determine whether this phenomenon could be replicated in mice, and if so, whether a time-dependent effect of aspirin on blood pressure was because of alteration of circadian clock function.

Approach and Results—

We recapitulated the protective effect of aspirin (50 μg/d for 7 days) at zeitgeber time 0 (active-to-rest transit), but not at zeitgeber time 12, on a high-salt diet–induced increase of blood pressure. However, the time of aspirin administration did not influence expression of canonical clock genes or their acetylation. We used mouse Bmal1 and Per2-luciferase reporters expressed in U2OS cells to determine the real-time effect of aspirin on circadian function but found that the oscillation of bioluminescence was unaltered. Timing of aspirin administration also failed to alter urinary prostaglandin metabolites or catecholamines, or the acetylation of its COX-1 (cyclooxygenase-1) target in platelets.

Conclusions—

The time-dependent hypotensive effect of aspirin in humans has been recapitulated in hypertensive mice. However, this does not seem to reflect a direct impact of aspirin on circadian clocks or on acetylation of platelet COX-1.