bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative Analysis of Conjunctival and Retinal Vessels in Fabry Disease
Authors: Sodi Andrea , Lenzetti Chiara , Bacherini Daniela , Finocchio Lucia , Verdina Tommaso , Borg Isabella , Cipollini Francesca , Patwary Fatema Ullah , Tanini Ilaria , Zoppetti Claudia , Rizzo Stanislao , Virgili Gianni
Published: April 2019

Fabry Disease (FD) is a rare X-linked lysosomal storage disorder characterized by systemic and ocular involvement. It has been described an increasing in retinal and conjunctival vessel tortuosity and this feature represents an important marker for the disease. Currently, there is not an objective method to measure and quantify this parameter. We tested a new semi-automatic software measuring retinal and conjunctival vessel tortuosity from eye fundus and conjunctival digital images in a group of FD patients. We performed an observational case-control study evaluating three mathematical parameters describing tortuosity (sum of angle metric [SOAM], product of angle distance [PAD], triangular index [I2e]) obtained from fundus and conjunctival pictures of 11 FD patients and 11 age and sex-matched controls. Both eyes were considered. Mann–Whitney test was used to compare the FD group versus the control group and, within the FD group, male versus female patients. Linear regression analysis was performed to evaluate the possible association of retinal and conjunctival vessels tortuosity parameters with age and with specific markers of systemic disease’s progression. The tortuosity parameters (SOAM, PAD and I2e) were significantly higher in retinal vessels and in conjunctival nasal vessels in FD patients in comparison with the controls (p=0.003, p=0.002, p=0.001 respectively for retina) (p=0.023, p=0.014, p=0.001 respectively for nasal conjunctiva). No significant association was found between retinal and conjunctival tortuosity parameters and increasing age or systemic involvement markers. Vessel tortuosity represents an important clinical manifestation in FD. A computer-assisted analysis of retinal and conjunctival vasculature demonstrated an increased vessels tortuosity in patients affected by Fabry disease. This non-invasive technique might be useful to help the diagnosis in early stages, to establish disease severity and monitor its progression.
A Protective Role of Paeoniflorin in Fluctuant Hyperglycemia-Induced Vascular Endothelial Injuries through Antioxidative and Anti-Inflammatory Effects and Reduction of PKCβ1
Authors: Wang Jing-Shang , Huang Ye , Zhang Shuping , Yin Hui-Jun , Zhang Lei , Zhang Yan-Hong , Song Ye-Wen , Li Dan-Dan
Published: April 2019

Hyperglycemia fluctuation is associated with diabetes mellitus (DM) complications when compared to persistent hyperglycemia. Previous studies have shown that paeoniflorin (PF), through its antiapoptosis, anti-inflammation, and antithrombotic properties, effectively protects against cardiovascular and cerebrovascular disease. However, the mechanism underlying the protection from PF against vascular injuries induced by hyperglycemia fluctuations remains poorly understood. Herein, we investigated the potential protective role of PF on human umbilical vein endothelial cells (HUVECs) subjected to intermittent glucose levels in vitro and in DM rats with fluctuating hyperglycemia in vivo. A remarkable increased apoptosis associated with elevated inflammation, increased oxidative stress, and high protein level of PKCβ1 was induced in HUVECs by intermittently changing glucose for 8 days, and PF recovered those detrimental changes. LY333531, a potent PKCβ1 inhibitor, and metformin manifested similar effects. Additionally, in DM rats with fluctuating hyperglycemia, PF protected against vascular damage as what has been observed in vitro. Taken together, PF attenuates the vascular injury induced by fluctuant hyperglycemia through oxidative stress inhibition, inflammatory reaction reduction, and PKCβ1 protein level repression, suggesting its perspective clinical usage.
Quasistatic Cyclic Tests and Finite Element Analysis of Low‐Aspect Ratio Double Steel Concrete Composite Walls
Authors: Ma Kaize , Ma Yudong , Liu Boquan
Published: April 2019

An innovative double steel concrete (DSC) composite wall was developed to enhance constructability and lateral load resistance of buildings. Three low‐aspect ratio DSC composite walls were constructed and tested to study the shear behavior. Under different testing parameters, the failure modes, hysteresis behavior, lateral load resisting capacity, deformation, and energy dissipation of the composite walls were observed. The results showed that all specimens failed in shear behavior with steel plate buckling and concrete compressive crushing. The pinching behavior was obvious for hysteresis loops of composite walls. Moreover, the lateral load resisting capacity and deformation were significantly affected with axial compression ratio and steel ratio. Beyond that, the ductility coefficients of specimens reached 3.30. The finite element (FE) method was performed to analyze the failure process of the specimens with cyclic analysis. The concrete damage plastic model (CPDM) was selected to simulate the damage progress of concrete. Validation of the FE models against the experimental results showed good agreement.
Development and External Validation of Web-Based Models to Predict the Prognosis of Remnant Gastric Cancer after Surgery: A Multicenter Study
Authors: Chen Qi-Yue , Zhong Qing , Zhou Jun-Feng , Qiu Xian-Tu , Dang Xue-Yi , Cai Li-Sheng , Su Guo-Qiang , Xu Dong-Bo , Liu Zhi-Yu , Li Ping , Guo Kai-Qing , Xie Jian-Wei , Chen Qiu-Xian , Wang Jia-Bin , Li Teng-Wen , Lin Jian-Xian , Lin Shuang-Ming , Lu Jun , Cao Long-Long , Lin Mi , Tu Ru-Hong , Huang Ze-Ning , Lin Ju-Li , Lin Wei , He Qing-Liang , Zheng Chao-Hui , Huang Chang-Ming
Published: April 2019

Background. Remnant gastric cancer (RGC) is a rare malignant tumor with poor prognosis. There is no universally accepted prognostic model for RGC. Methods. We analyzed data for 253 RGC patients who underwent radical gastrectomy from 6 centers. The prognosis prediction performances of the AJCC7th and AJCC8th TNM staging systems and the TRM staging system for RGC patients were evaluated. Web-based prediction models based on independent prognostic factors were developed to predict the survival of the RGC patients. External validation was performed using a cohort of 49 Chinese patients. Results. The predictive abilities of the AJCC8th and TRM staging systems were no better than those of the AJCC7th staging system (c-index: AJCC7th vs. AJCC8th vs. TRM, 0.743 vs. 0.732 vs. 0.744; P>0.05). Within each staging system, the survival of the two adjacent stages was not well discriminated (P>0.05). Multivariate analysis showed that age, tumor size, T stage, and N stage were independent prognostic factors. Based on the above variables, we developed 3 web-based prediction models, which were superior to the AJCC7th staging system in their discriminatory ability (c-index), predictive homogeneity (likelihood ratio chi-square), predictive accuracy (AIC, BIC), and model stability (time-dependent ROC curves). External validation showed predictable accuracies of 0.780, 0.822, and 0.700, respectively, in predicting overall survival, disease-specific survival, and disease-free survival. Conclusions. The AJCC TNM staging system and the TRM staging system did not enable good distinction among the RGC patients. We have developed and validated visual web-based prediction models that are superior to these staging systems.
The Use of Medicinal Plants in the Riverside Community of the Mazagão River in the Brazilian Amazon, Amapá, Brazil: Ethnobotanical and Ethnopharmacological Studies
Authors: Ferreira Rodrigues Sarquis Rosângela do Socorro , Rodrigues Sarquis Ícaro , Rodrigues Sarquis Iann , Fernandes Caio Pinho , Araújo da Silva Gabriel , Borja Lima e Silva Raullyan , Gonçalves Jardim Mário Augusto , Sánchez-Ortíz Brenda Lorena , Carvalho José Carlos Tavares
Published: April 2019

The inhabitants of the floodplain of the Mazagão River in the State of Amapá in the Brazilian Amazon have inherited from indigenous African and Cabocla cultures indications for the use and forms of preparation of medicinal plants to cure diseases of the body and spirit. This study aimed to perform an ethnopharmacological survey of medicinal plants used by the riparian community of the floodplains of the Mazagão River, in the State of Amapá. In this study, we chose semistructured interviews with socioeconomic, ethnopharmacological, and ethnobotanical aims. The collection of medicinal plants occurred during guided tours. The Use Value (UV), Informant Consensus Factor (ICF), Correction Factor (CF), and Fidelity level (FL) were calculated. There were 130 species of medicinal plants, distributed in 116 genera and 57 families; Fabaceae (16), Lamiaceae (14), Euphorbiaceae (7), and Arecaceae (6) include 33.33% of the total species sampled. All 95 native species of floodplain forests were previously described, and 35 are exotic species. The species with the highest UV (≥ 0.5) at the mouth of the Mazagão River were Carapa guianensis (0.91), Pentachlethra macroloba (0.83), Dalbergia subcymosa (0.77), Uncaria tomentosa (0.75), Otacanthus azureus (0.62), Virola surinamensis (0.62), Hura crepitans (0.58), Euterpe oleracea (0.56), and Arrabidaea chica (0.51). These species were also the ones that presented the highest ICF among the informants and 100% in FL for a specific therapeutic use. The study is comprised of 16 categories of therapeutic use, of which the majority of the plants used are related to diseases such as microbial infections (20.67%, 73 species), gastrointestinal disorders (13.31%), and inflammation (11.61%). The results showed that knowledge about the use of medicinal plants along the rivers and streams that form the mouth of the Mazagão River is evenly distributed. Most of the interviewees present diversified knowledge about the medicinal resources because they have a close relationship with the floodplain forest. Native species of this forest predominate among the most commonly used medicinal plants as subsidies for future pharmacological studies.
Influence of Interleukin-8 and Neutrophil Extracellular Trap (NET) Formation in the Tumor Microenvironment: Is There a Pathogenic Role?
Authors: Gonzalez-Aparicio Manuela , Alfaro Carlos
Published: April 2019

In this review, we will highlight several studies that revolve around interleukin-8 (IL-8) and show the multiple facets that could take in the tumor microenvironment. Chemokines that attract neutrophils (to a large extent, IL-8) can have a bimodal behavior inducing the migration of them in the first place and later favoring the formation of NETs in the place of emission focus of the chemokine. Also, this mechanism occurs when neutrophils migrate to tumor cells and where the extrusion of NETs in the tumor is observed. A possible participation of NETs in cancer progression was considered; however, until now, it is difficult to decide if NETosis plays a pro- or antitumor role, although it is necessary to emphasize that there is more experimentation focused on the protumorigenic aspect of the NETs. The formation of NETs has a relevant role in the inhibition of the immune response against the tumor generated by neutrophils and in turn favoring the processes involved in the development of tumor metastasis. It is striking that we do not have more complete information about the effects of circulating chemokines on neutrophils in cancer patients and hence the suitability of this review. No one has observed to date the impact that it could have on other cell populations to inhibit the arrival of neutrophils and the formation/elimination of NETs. However, the extent to which NETs affect the function of other cells of the immune system in the tumor context has not been directly demonstrated. It is necessary to identify possible combinations of immunotherapy that involve the modulation of neutrophil activity with other strategies (immunomodulatory antibodies or adoptive cell therapy). Therefore, knowing the mechanisms by which tumors take advantage of this ability of neutrophils to form NETs is very important in the search for antitumor therapies and thus be able to take advantage of the possible immunotherapeutic combinations that we currently have in clinical practice.
Calcitriol Inhibits the Proliferation of Triple-Negative Breast Cancer Cells through a Mechanism Involving the Proinflammatory Cytokines IL-1βand TNF-α
Authors: Martínez-Reza Isela , Díaz Lorenza , Barrera David , Segovia-Mendoza Mariana , Pedraza-Sánchez Sigifredo , Soca-Chafre Giovanny , Larrea Fernando , García-Becerra Rocío
Published: April 2019

Triple-negative breast cancer (TNBC) is one of the most aggressive tumors, with poor prognosis and high metastatic capacity. The aggressive behavior may involve inflammatory processes characterized by deregulation of molecules related to the immunological responses in which interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) are involved. It is known that calcitriol, the active vitamin D metabolite, modulates the synthesis of immunological mediators; however, its role in the regulation of IL-1βand TNF-αin TNBC has been scarcely studied. In the present study, we showed that TNBC cell lines SUM-229PE and HCC1806 expressed vitamin D, IL-1β, and TNF-αreceptors. Moreover, calcitriol, its analogue EB1089, IL-1β, and TNF-αinhibited cell proliferation. In addition, we showed that synthesis of both IL-1βand TNF-αwas stimulated by calcitriol and its analogue. Interestingly, the antiproliferative activity of calcitriol was significantly abrogated when the cells were treated with anti-IL-1βreceptor 1 (IL-1R1) and anti-TNF-αreceptor type 1 (TNFR1) antibodies. Furthermore, the combination of calcitriol with TNF-αresulted in a greater antiproliferative effect than either agent alone, in the two TNBC cell lines and an estrogen receptor-positive cell line. In summary, this study demonstrated that calcitriol exerted its antiproliferative effects in part by inducing the synthesis of IL-1βand TNF-αthrough IL-1R1 and TNFR1, respectively, in TNBC cells, highlighting immunomodulatory and antiproliferative functions of calcitriol in TNBC tumors.
A Rare Culprit of Infective Endocarditis in an IV Drug User: Burkholderia cepacia
Authors: Nnaoma Christopher , Chika-Nwosuh Ogechukwu , Sossou Christoph
Published: April 2019

Infective endocarditis (IE) is an infection of the cardiac native or prosthetic valves typically caused by Staphylococcus aureus, viridans streptococci group, and coagulase-negative staphylococci. Risk factors include congenital heart disease, structural and valvular heart disease, implantation of prosthetic heart valves, and intravenous (IV) drug abuse. IE caused by organisms such as Burkholderia cepacia is rarely seen. We herein present a case of a patient with a history of IV drug abuse previously treated for Staphylococcus aureus IE with newly diagnosed IE secondary to B. cepacia. He was taken to the operating room for mitral valve replacement after an echocardiogram revealed severe mitral regurgitation. He was successfully treated with antibiotics. After 2 months, at follow-up, the patient remained free from mechanical valve-related events, had no new occurrences of fever, and had no other symptoms of infection. He reported good exercise tolerance.
Modern Machine Learning Techniques for Univariate Tunnel Settlement Forecasting: A Comparative Study
Authors: Hu Min , Li Wei , Yan Ke , Ji Zhiwei , Hu Haigen
Published: April 2019

Tunnel settlement commonly occurs during the tunnel construction processes in large cities. Existing forecasting methods for tunnel settlements include model‐based approaches and artificial intelligence (AI) enhanced approaches. Compared with traditional forecasting methods, artificial neural networks can be easily implemented, with high performance efficiency and forecasting accuracy. In this study, an extended machine learning framework is proposed combining particle swarm optimization (PSO) with support vector regression (SVR), back‐propagation neural network (BPNN), and extreme learning machine (ELM) to forecast the surface settlement for tunnel construction in two large cities of China P.R. Based on real‐world data verification, the PSO‐SVR method shows the highest forecasting accuracy among the three proposed forecasting algorithms.
Characteristics of Fracture Propagation Induced by Supercritical CO2 in Inter-Salt-Shale Reservoir
Authors: Zhang Yixiang , He Jianming , Li Fengxia , Fan Xin , Li Xiao
Published: April 2019

Hydraulic fracturing using freshwater is difficult for the commercial exploitation of a shale oil reservoir in Jianghan Basin with a continental saline lake basin sedimentary background. Supercritical CO2 (SC-CO2) is a promising fracturing fluid under consideration for the reservoir stimulation, especially in the case of the presence of water sensible salt layers. In this study, SC-CO2 fracturing experiments on the inter-salt-shale and salt specimens, which were obtained from the drilling well, were carried out in the laboratory. The characteristics of fracture propagation, including morphology and width variation, were analyzed based on the observations of a stereoscopic microscope, X-ray micro-CT scanner, and 3D scanner. The existing weak planes in the shale can really impact the fracture propagation in SC-CO2 fracturing. Deflection, branching, and approaching can occur during the process of fracture propagation. The average width value of the reactivated natural fracture is bigger than that of a newly created fracture. In addition, the fracturing results indicate the greater breakdown pressure of rock salt if compared with the inter-salt-shale. The induced fractures in the salt specimen are compact and smaller in average width than those in the shale specimen. The higher breakdown pressure and relatively smaller fracture width of rock salt are real challenges for the fracturing of an inter-salt-shale oil reservoir.
Seasonal and Gender Differences in Presence of Rickettsia felis and Blood meals Provide Additional Evidence of a Vector Role for Mosquitoes
Authors: Zhang Jilei , Lu Guangwu , Kelly Patrick John , Wang Chengming
Published: April 2019

Rickettsia felis belongs to spotted fever group Rickettsia and is an emerging human pathogen most commonly transmitted by a range of fleas and ticks. While recent evidence has suggested mosquitoes are infected with R. felis, there is little information about the role of mosquitoes in the organism’s transmission. In this study, around 100 mosquitoes were collected monthly between 2013 and 2014 from the same residential dwelling at Yangzhou, China. The collected mosquitoes were identified for their species and gender, followed by gltA-based PCR and hydroxymethylbilane synthase-based PCR to determine the prevalence of Rickettsia and blood meal. Three mosquito species (Culex pipiens: 76%, 996/1,304; C. tritaeniorhynchus: 17%, 216/1,304; Aedes albopictus: 7%, 92/1,304) were identified. For 1,088 female mosquitoes, 31% of them n=336 were positive for blood meal and 7% n=77 carried R. felis DNA. In a strong contrast, none of the 216 male mosquitoes were positive for blood meal but two males were positive for Rickettsia. Interestingly, 63% of R. felis-positive mosquitoes (50/79) were negative for blood meal, being significantly higher than 37% of mosquitoes and being positive for both R. felis and blood meal P=0.008. Furthermore, we compared the prevalence of Rickettsia and blood meal in the mosquitoes collected in the months with temperature below and above 23°C, the minimum temperature required for mosquito egg hatching. Mosquitoes captured in the months below 23°C showed significant higher positivity of R. felis(71/936, 7.6% vs. 8/368, 2.2%; P=0.002) and blood meal (294/936, 31.4% vs. 36/368, 9.8%; P<10−4) than in the months above 23°C. Collectively, the seasonal and gender differences of R. felis and blood meal in mosquitoes add to the existing evidence, supporting a potential vector role of mosquitoes in the transmission of R. felis. Studies with a R. felis infection model covering the full life cycle of mosquitoes is necessary to unambiguously prove the transstadial and transovarial transmission of R. felis in mosquitoes.
The Relationship between Current Ground Stress and Permeability of Coal in Superimposed Zones of Multistage Tectonic Movement
Authors: Ni Xiaoming , Jia Qifeng , Wang Yanbin
Published: April 2019

According to the characteristics of the paleostress field and tectonic features at the key moments during tectonic movement after the formation of the no. 3 coal seam, the superimposed areas of different folding zones in the southern section of Shizhuang in central and southern Qinshui Basin were divided. The reservoir permeability of the coal in different superimposed areas was obtained by integrating a laboratory in situ measurement technique, geological strength indices, and multiple parameter fitting of acoustic logging data. The maximum and minimum horizontal principal stresses in different superimposed areas were gained through analysis of the fracturing curve and acoustic logging data. Thus, the relationships between ground stress and permeability in different superimposed areas were revealed. The results show that the relationships between different stresses and permeability were not obvious without considering multistage tectonic superposition. The relationships between the varying stresses and permeability in the same superimposed areas were exponential. The deformation of coal seams in the superimposed areas on the wings of fold belts striking north-central direction was relatively weak, and its permeability was the highest. The permeability in the superimposed areas of the wings of different fold belts in a southeasterly direction was lower than that in the superimposed areas of the wings and the cores of folds. The permeability is the worst in the superimposed areas by the cores and wings of the folds. The results can provide a reference for the study of the heterogeneous deformation of coal reservoirs.
Effects of Subjective Memory Complaints (SMCs) and Social Capital on Self-Rated Health (SRH) in a Semirural Malaysian Population
Authors: Yap Kwong Hsia , Mohan Devi , Stephan Blossom C. M. , Warren Narelle , Allotey Pascale , Reidpath Daniel D.
Published: April 2019

Subjective memory complaints (SMCs) and social capital were known to be related to self-rated health (SRH). Despite this, no studies have examined the potential interaction of SMC and social capital on SRH. Using data from a cross-sectional health survey of men and women aged 56 years and above (n = 6,421), we examined how SMCs and social capital explained SRH in a population of community-dwelling older adults in a semirural area in Malaysia. We also evaluated whether SRH’s relationship with SMCs is moderated by social capital. The association of SMC and social capital with poor SRH was investigated using multivariable logistic regression. Social capital (OR = 0.86, 95% CI = 0.82–0.89), mild SMC (OR = 1.70, 95% CI = 1.50–1.94), and moderate SMC (OR = 1.90, 95% CI = 1.63–2.20) were found to be associated with poor SRH after adjustment for sociodemographic factors and depression in the initial regression model. SMC was found to have partial interaction effects with social capital which was included in the subsequent regression model. Unlike individuals with no SMC and mild SMC, those who reported moderate SMC did not show decreasing probabilities of poor SRH despite increasing levels of social capital. Nevertheless, this analysis suggests that social capital and SMC are independent predictors of poor SRH. Further research needs to be targeted at improving the understanding on how social capital and SMC moderate and interact with the perception of health in older adults.
Inversion Modeling of Dam‐Zoning Elasticity Modulus for Heightened Concrete Dam Using ICS‐IPSO Algorithm
Authors: Chen Yijun , Gu Chongshi , Wu Bangbin , Shao Chenfei , Wu Zhongru , Dai Bo
Published: April 2019

A new approach was developed for the inversion modeling of dam‐zoning elasticity modulus for heightened concrete dam, with old and new concrete zones. The proposed inversion modeling procedure takes advantage of the improved cuckoo search (ICS) algorithm and improved particle swarm optimization (IPSO) algorithm to adjust the mechanical parameters, which are used as input. An objective function is constructed based on the horizontal displacement increment by using the finite element method (FEM) and statistical analysis of the prototype monitoring data. One ideal arch dam model and one actual heightened concrete dam were taken as examples. The proposed method was used to implement the optimal selection of the dam‐zoning elasticity modulus. The inversion analysis results indicate that the mechanical parameters identification method for heightened concrete gravity dams proposed in this article is accurate and has a fast convergence rate. Consequently, it can be applied as a reliable model to identify the dam‐zoning elasticity modulus in practical engineering applications.
Meta-Analysis of Neuropsychological Studies in Panic Disorder Patients: Evidence of Impaired Performance during the Emotional Stroop Task
Authors: Harber Lillian , Hamidian Reza , Bani-Fatemi Ali , Wang Kevin Z. , Dada Oluwagbenga , Messina Giovanni , Monda Marcellino , Chieffi Sergio , De Luca Vincenzo
Published: April 2019

Background: Recent investigations have highlighted significant differences in verbal recall between patients with panic disorder (PD) and controls. These studies have highlighted that verbal memory and working memory could be impaired in PD. Objectives: The objective of the present meta-analysis is to confirm this hypothesis, reviewing the studies that have investigated neurocognitive testing in PD. Methods: We performed a systematic literature search for studies published between 1980 and 2015 that reported cognitive measurements in PD patients and controls. Effect size estimates were computed using the restricted maximum likelihood model. Only case-control studies were selected for this meta-analysis. We included studies that made a direct comparison between PD subjects and healthy controls. The diagnostic group consisted of adult patients aged over 18 years diagnosed with PD. We excluded the studies that did not employ a case-control design. All statistical analyses were carried out on R using the “metafor” package version 1.9-8. The effect size for each study neuropsychological test was calculated using the mean and SD of performance results, and p values < 0.05 were considered significant. Results: We identified few studies that tested verbal memory and executive functions in PD patients and controls, and this difference was not significant. On the other hand, there are several studies that have used the emotional Stroop task to assess cognitive functions in PD. There is no robust evidence of impairment of memory function in PD; however, when considering the emotional Stroop task, it was found that PD patients performed slower (p < 0.01) than healthy controls for all three types of stimuli (neutral, negative, positive). Conclusion: This meta-analysis included a small number of studies, which may have introduced bias into the analysis. However, there is some evidence of impairment of neurocognitive functions in PD when performing the emotional Stroop task. Furthermore, the paucity of studies evaluating neurocognition in PD suggests the need for further research in this field in order to draw meaningful conclusions.
The Role of Intravenous Iron in the Treatment of Anemia Associated with Cancer and Chemotherapy
Authors: Rodgers George M. , Gilreath Jeffrey A. 
Published: April 2019

Cancer-related anemia (CRA) is a commonly occurring problem for patients with cancer regardless of whether they are receiving treatment with chemotherapy or immunotherapy. It may result from one or more processes (decreased production, increased destruction, or increased loss of red blood cells, RBC). Perturbations in iron availability form the primary basis for anemia in many patients with cancer-related anemia. Functional iron deficiency (FID) anemia is a condition in which the patient has adequate or increased iron stores, but this iron pool is not available for erythropoiesis. Erythropoiesis-stimulating agents (ESAs) were the original treatment for FID; over time, however, if the supply of iron cannot keep pace with increased RBC synthesis driven by ESAs, FID may eventually lead to the lack or loss of ESA responsiveness. Subsequent clinical trials reported that intravenous (IV) iron could enhance the erythropoietic response to ESAs. This chapter reviews the pathogenesis of FID and summarizes the literature on the treatment of cancer- and chemotherapy-induced anemia. Clinical trials using IV iron with or without ESAs are reviewed in addition to the currently available IV iron products. The consensus conclusions from these trials, as well as guideline recommendations, support the use of IV iron in these patients to enhance ESA responsiveness, decrease ESA dosage, and reduce RBC transfusions. Little data have been published on the long-term safety of IV iron or its impact on tumor growth. This paper also briefly explores novel approaches for the treatment of FID anemia, which has relevance in treating not only cancer patients but also patients with benign inflammatory disorders.
Isolated Intraocular Rosai-Dorfman Disease
Authors: Fogt Franz , Rüediger Thomas , Augustin Albert J. , Frank Dale M. , Rosenwald Andreas , Wellmann Axel , Lee Vivian
Published: April 2019

Background/Aims: To report a case of Rosai-Dorfman disease (RDD) presenting as a solitary, choroidal mass, initially suspicious for uveal melanoma, in a 72-year-old woman. Methods: Retrospective case report of a single patient. Results: A 72-year-old woman presented with sudden vision loss in the right eye. A month prior, visual acuity was 20/40, but she was noted to have a choroidal mass confirmed with B-scan ultrasonography. Patient’s vision deteriorated significantly a month later and a shallow retinal detachment was newly noted. Magnetic resonance imaging was obtained, demonstrating a hyperintense intraocular tumor on TI imaging. Patient underwent enucleation of the right eye for suspicion of a uveal melanoma. Pathology revealed a mixed cellular infiltrate with histiocytes, some exhibiting emperipolesis. Macrophage immunohistochemical stains were positive, while melanocytic markers were negative. A diagnosis of RDD was made. Subsequently, the patient had a negative workup for systemic involvement. A final diagnosis of intraocular RDD without extraocular and systemic involvement was determined. Conclusion: We describe a rare presentation of RDD as a solitary choroidal mass in an elderly patient with overlapping features of uveal melanoma. Definitive diagnosis could only be made on histology. RDD should be considered in the differential diagnosis of a choroidal lesion in the elderly.
TGF-β1 Impairs Vitamin D-Induced and Constitutive Airway Epithelial Host Defense Mechanisms
Authors: Schrumpf Jasmijn A. , Ninaber Dennis K. , van der Does Anne M. , Hiemstra Pieter S.
Published: April 2019

Airway epithelium is an important site for local vitamin D (VD) metabolism; this can be negatively affected by inflammatory mediators. VD is an important regulator of respiratory host defense, for example, by increasing the expression of hCAP18/LL-37. TGF-β1 is increased in chronic obstructive pulmonary disease (COPD), and known to decrease the expression of constitutive host defense mediators such as secretory leukocyte protease inhibitor (SLPI) and polymeric immunoglobulin receptor (pIgR). VD has been shown to affect TGF-β1-signaling by inhibiting TGF-β1-induced epithelial-to-mesenchymal transition. However, interactions between VD and TGF-β1, relevant for the understanding host defense in COPD, are incompletely understood. Therefore, the aim of the present study was to investigate the combined effects of VD and TGF-β1 on airway epithelial cell host defense mechanisms. Exposure to TGF-β1 reduced both baseline and VD-induced expression of hCAP18/LL-37, partly by increasing the expression of the VD-degrading enzyme CYP24A1. TGF-β1 alone decreased the number of secretory club and goblet cells and reduced the expression of constitutive host defense mediators SLPI, s/lPLUNC and pIgR, effects that were not modulated by VD. These results suggest that TGF-β1 may decrease the respiratory host defense both directly by reducing the expression of host defense mediators, and indirectly by affecting VD-mediated effects such as expression of hCAP18/LL-37.
The Elusive Role of Placental Macrophages: The Hofbauer Cell
Authors: Zulu Michael Z. , Martinez Fernando O. , Gordon Siamon , Gray Clive M.
Published: April 2019

In this review, we discuss the often overlooked tissue-resident fetal macrophages, Hofbauer cells, which are found within the chorionic villi of the human placenta. Hofbauer cells have been shown to have a phenotype associated with regulatory and anti-inflammatory functions. They are thought to play a crucial role in the regulation of pregnancy and in the maintenance of a homeostatic environment that is crucial for fetal development. Even though the numbers of these macrophages are some of the most abundant immune cells in the human placenta, which are sustained throughout pregnancy, there are very few studies that have identified their origin, their phenotype, and functions and why they are maintained throughout gestation. It is not yet understood how Hofbauer cells may change in function throughout normal pregnancy, and especially in those complicated by maternal gestational diabetes, preeclampsia, and viral infections, such as Zika, cytomegalovirus, and human immunodeficiency virus. We review what is known about the origin of these macrophages and explore how common complications of pregnancy dysregulate these cells leading to adverse birth outcomes in humans. Our synthesis sheds light on areas for human studies that can further define these innate regulatory cells.
Compared to Controls, Individuals with Lichen Planopilaris Have More Depression, a Lower Self-Esteem, and a Lower Quality of Life
Authors: Alirezaei Pedram , Ahmadpanah Mohammad , Rezanejad Aliasghar , Soltanian Alireza , Sadeghi Bahmani Dena , Brand Serge
Published: April 2019

Background: Individuals with lichen planopilaris (LPP) typically present with hair loss and an irritated scalp, with signs and symptoms such as itching, erythema, scaling, and burning. Both hair loss and reddened skin may be visible also for other people. Therefore, it is conceivable that individuals with LPP might report a lower mental health status. Accordingly, in the present study, we compared dimensions of mental health between individuals with LPP and healthy controls. Method: A total of 38 individuals with LPP (mean age: 38.24 years, 47.4% females) and 58 gender- and age-matched controls took part in this study. They completed questionnaires covering dimensions of quality of life and self-esteem; experts rated participants’ symptoms of depression and anxiety. Furthermore, dermatologists reported on the illness duration, the LPP activity index, and the severity of alopecia. Results: Compared to healthy controls, individuals with LPP reported lower scores of self-esteem, physical functioning, and mental health and higher scores of role limitations (physical and emotional). Likewise, experts rated higher depression scores in individuals with LPP compared to controls. In individuals with LPP, a higher LPP disease activity and a higher severity of hair loss were associated with higher depression and lower quality-of-life scores. Further, a higher LPP activity index, a lower self-esteem, and higher anxiety scores predicted a poorer quality of life, while illness duration was statistically unrelated. Conclusions: Compared to controls, and irrespectively of the illness duration, individuals with LPP reported a lower quality of life and a lower self-esteem, and experts’ ratings observed higher scores of depression. Experts treating individuals with LPP might pay special attention to the individuals’ mental health status.
Deletion of Protein Tyrosine Phosphatase Nonreceptor Type 2 in Intestinal Epithelial Cells Results in Upregulation of the Related Phosphatase Protein Tyrosine Phosphatase Nonreceptor Type 23
Authors: Ulugöl Sima , Hering Larissa , Manzini Roberto , Montalban Arques Ana , Gottier Claudia , Lang Silvia , Scharl Michael , Spalinger Marianne R.
Published: April 2019

Background/Aims: Knockdown of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) exaggerates IFN-γ-induced intestinal barrier defects, but mice constitutively lacking PTPN2 in epithelial cells (PTPN2xVilCre mice) do not show changes in epithelial function or enhanced susceptibility to experimental colitis. Here, we investigated whether PTPN2 modulates the expression of related tyrosine phosphatases. Methods: PTPN2 knockdown in HT-29 cells was induced using siRNA constructs. Acute colitis in PTPN2xVilCre mice was induced by 2% dextran sulfate sodium (DSS) in drinking water for 7 days. Colitis-associated tumors were induced by injection of azoxymethane prior to treatment with DSS for 3 consecutive cycles. Results: In HT-29 cells, PTPN2 depletion resulted in enhanced mRNA expression of PTPN11 and PTPN23 and in parallel to upregulation of IL-18 mRNA upon treatment with TNF for 24 h. DSS treatment of PTPN2-deficient mice resulted in a strong induction of Ptpn23 mRNA in colon tissue in vivo. In the tumor model, Ptpn23 mRNA was again clearly upregulated in nontumor tissue from PTPN2-deficient mice; however, this was not observed in tumor tissue. Conclusions: Our experiments show that PTPN23 function might, at least partially, compensate lack of PTPN2 in epithelial cells. Upregulation of PTPN23 might therefore crucially contribute to the lack of a colitis phenotype in PTPN2-VilCre mice.
Prevention and Management of Chemotherapy-Induced Polyneuropathy
Authors: Jordan Berit , Jahn Franziska , Sauer Sandra , Jordan Karin
Published: April 2019

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe and common side effect caused by a variety of antineoplastic agents. Approximately 30–40% of patients treated with agents such as taxanes, vinca alkaloids, or platinum derivatives will develop CIPN. CIPN presents predominantly as a sensory axonal neuro(no)pathy with occasional motor and autonomic dysfunction exhibiting considerable variability of clinical symptoms ranging from mild tingling sensation to severe neuropathic pain. Typical symptoms include numbness (“minus symptom”), weakness, and abnormal gait as well as paresthesia and pain (“positive symptoms”). As CIPN symptoms potentially lead to long-term morbidity and can even aggravate after cessation of therapy, patients’ quality of life can be tremendously affected. In view of improved breast cancer survival outcomes, the late effects of CIPN are an unmet need in these patients. Therefore, early detection and assessment of first symptoms is important to effectively prevent severe CIPN. Therapeutic options for patients with CIPN are still limited, and pharmacological treatment focuses primarily on reduction or relief of neuropathic pain. CIPN is usually acutely managed by dose reduction or discontinuation of causative chemotherapy, potentially compromising treatment outcome. Currently, there is no causative proven therapy for the prevention of CIPN.
Physical and Psychological Impairments Associated with Mucositis after Oral Cancer Treatment and Their Impact on Quality of Life
Authors: Jehn Philipp , Stier Rebecca , Tavassol Frank , Dittmann Jan , Zimmerer Rüdiger , Gellrich Nils-Claudius , Krüskemper Gertrud , Spalthoff Simon
Published: April 2019

Background: Posttherapeutic mucositis is a common secondary effect of oral cancer treatment. Mucositis affects the oral mucosa, which leads to specific physical impairments in oral function and a negative impact on quality of life. Objective: To evaluate the impairments associated with oral mucositis and their impact on posttherapeutic quality of life. Methods: A retrospective analysis was conducted on 1,652 patients treated for oral cancer during the multicenter rehabilitation study of the German-Austrian-Swiss Cooperative Group on Tumors of the Maxillofacial Region (DÖSAK), which included 43 clinics from Germany, Austria, and Switzerland. The analysis was based on questionnaires filled out by patients following treatment. Results: Approximately 10% of 1,652 patients included in our study had physical or psychological impairments due to increased posttreatment oral mucositis; this was mainly due to adjuvant radiotherapy or radiochemotherapy administered. Oral mucositis was significantly associated with specific physical impairments, especially xerostomia and pain (p = 0.000), which required supportive care and analgesia (p = 0.000). Additionally, impaired ingestion and speech significantly led to psychological disorders such as public avoidance behavior and social isolation (p = 0.001). Depressive coping of disease (p = 0.001) and concomitant depressive tendencies (p = 0.004) were highly associated with mucositis, which was accompanied by diminished general condition (p = 0.001), bleak future prospects (p = 0.006), and a reduction in quality of life (p = 0.002). Conclusion: Minimizing mucositis-related impairments should be a main effort in oral cancer treatment to optimize patient outcome and improve quality of life after therapy.
PLOJDY ANALYSIS AND DNA CONTENT OF MUTANT BANAN "PISANG BERANGAN" USING FLOW CYTOMETRY
Authors: OTHMAN ROFINA YASMIN , SHADIA ABDELGADIR RAYIS , CHAI MAK
Published: April 2019

Mutagens cause random changes in the nuclear DNA or cytoplasmic organelles, resulting in gene, chromosomal or genomic mutations and hence, create variability. In this study, flow cytometry (FCM) was used to determine ploidy levels and DNA content in gamma-irradiated variants of mutated Pisang Berangan (cv. Intan, AAA) - a local banana genotype. Induced variants such as short plant stature (stunted growth), late flowering plants (late maturity) and abnormalities in bunch characters were selected to study possible changes at the DNA level. The study showed that DNA content of mutated plants differed from non-irradiated control and that irradiation had the most effect at high doses (40 and 60 Gy). The increase of DNA content in 20 Gy and 30 Gy treated plants was not more than that of the control plants. The values of genomic DNA content of gamma-irradiation variants decreased as the dose of irradiation increased from 20 to 60 Gy, indicating that the high dose of gamma-irradiation had a significant effect on the genome of the plants. The analysis further showed that phenotypic variation due to mutagenesis was reflected in the DNA content of the plants. The results also showed that ploidy levels were not affected by gamma-irradiation even at high doses. Keywords: Musa spp./mutation breeding/ flow cytometry/Â  ploidy level/ DNA content
Sacubitril/Valsartan Decreases Cardiac Fibrosis in Left Ventricle Pressure Overload by Restoring PKG Signaling in Cardiac Fibroblasts
Authors: Burke Ryan M. , Lighthouse Janet K. , Mickelsen Deanne M. , Small Eric M.
Published: April 2019

Background

Heart failure (HF) is invariably accompanied by development of cardiac fibrosis, a form of scarring that increases muscular tissue rigidity and decreases cardiac contractility. Cardiac fibrosis arises from a pathological attempt to repair tissue damaged during maladaptive remodeling. Treatment options to block or reverse fibrosis have proven elusive. Neprilysin is an endopeptidase that degrades vasoactive peptides, including atrial natriuretic peptide. Thus, neprilysin inhibition reduces hypertension, ultimately limiting maladaptive cardiac remodeling. LCZ696, which consists of an angiotensin receptor blocker (valsartan [VAL]) and a neprilysin inhibitor (sacubitril [SAC]), was shown to be well tolerated and significantly reduced the risk of death and hospitalization in HF patients with reduced ejection fraction. We hypothesized that SAC/VAL directly inhibits fibroblast activation and development of pathological fibrosis.

Methods and Results

We used a mouse model of left ventricle pressure overload coupled to in vitro studies in primary mouse and human cardiac fibroblasts (CFs) to study the impact of SAC/VAL on CF activation and cardiac fibrosis. SAC/VAL significantly ameliorated pressure overload–induced cardiac fibrosis by blocking CF activation and proliferation, leading to functional improvement. Mechanistically, the beneficial impact of SAC/VAL at least partially stemmed from restoration of PKG (protein kinase G) signaling in HF patient-derived CF, which inhibited Rho activation associated with myofibroblast transition.

Conclusions

This study reveals that SAC/VAL acts directly on CF to prevent maladaptive cardiac fibrosis and dysfunction during pressure overload–induced hypertrophy and suggests that SAC/VAL should be evaluated as a direct antifibrotic therapeutic for conditions such as HF with preserved ejection fraction.
Body Mass Index Trajectories During Young Adulthood and Incident Hypertension: A Longitudinal Cohort in Chinese Population
Authors: Fan Bingbing , Yang Yachao , Dayimu Alim , Zhou Guangshuai , Liu Yanxun , Li Shengxu , Chen Wei , Zhang Tao , Xue Fuzhong
Published: April 2019

Background

This longitudinal study aims to characterize longitudinal body mass index (
BMI
) trajectories during young adulthood (20–40 years) and examine the impact of level‐independent
BMI
trajectories on hypertension risk.

Methods and Results

The cohort consisted of 3271 participants (1712 males and 1559 females) who had
BMI
and blood pressure (
BP
) repeatedly measured 4 to 11 times during 2004 to 2015 and information on incident hypertension. Four distinct trajectory groups were identified using latent class growth mixture model: low‐stable (n=1497), medium‐increasing (n=1421), high‐increasing (n=291), sharp‐increasing (n=62). Model‐estimated levels and linear slopes of
BMI
at each age point between ages 20 and 40 were calculated in 1‐year intervals using the
latent class growth mixture
model parameters and their first derivatives, respectively. Compared with the low‐stable group, the hazard ratios and 95% CI were 2.42 (1.88, 3.11), 4.25 (3.08, 5.87), 11.17 (7.60, 16.41) for the 3 increasing groups, respectively. After adjusting for covariates, the standardized odds ratios and 95%
CI
of model‐estimated
BMI
level for incident hypertension increased in 20 to 35 years, ranging from 0.80 (0.72–0.90) to 1.59 (1.44–1.75); then decreased gradually to 1.54 (1.42–1.68). The standardized
odds ratio
s of level‐adjusted linear slopes increased from 1.22 (1.09–1.37) to 1.79 (1.59–2.01) at 20 to 24 years; then decreased rapidly to 1.12 (0.95–1.32).

Conclusions

These results indicate that the level‐independent
BMI
trajectories during young adulthood have significant impact on hypertension risk. Age between 20 and 30 years is a crucial period for incident hypertension, which has implications for early prevention.
Obesity‐Induced Hypertension: Heavy on the Accelerator
Authors: Roush George C.
Published: April 2019

See Article
Fan et al