bluuebunny/crossref_metadata_2025 huggingface dataset:
Downregulation of miR-224-5p Promotes Migration and Proliferation in Human Dental Pulp Stem Cells
Authors: Ke Zhihong , Qiu Zailing , Xiao Tingting , Zeng Jianchai , Zou Luning , Lin Xuemei , Hu Xuegang , Lin Shihan , Lv Hongbing
Published: July 2019

Introduction. Pulp regeneration, as a treatment for pulp necrosis, has significant advantages over root canal therapy for the preservation of living pulp. To date, research on pulp regeneration has mainly focused on the transplantation of pulp stem cells into the root canal, but there is still a lack of research on the migration of pulp cells into the root canal via cell homing. Stem cells from the apical tooth papilla (SCAP) are recognized as multidirectional stem cells, but these cells are difficult to obtain. MicroRNAs are small noncoding RNAs that play crucial roles in regulating normal and pathologic functions. We hypothesized that some types of microRNAs might improve the migration and proliferation function of dental pulp stem cells (DPSCs), which are easily obtained in clinical practice, and as a result, DPSCs might replace SCAP and provide valuable information for regenerative endodontics. Methods. Magnetic activated cell sorting of DPSCs and SCAP was performed. Next-generation sequencing was performed to examine DPSCs and SCAP miRNAs expression and to identify the most significant differentially expressed miRNA. CCK-8 and transwell assays were used to determine the impact of this miRNA on DPSCs proliferation and migration. Results. The most significant differentially expressed miRNA between DPSCs and SCAP was miR-224-5p. Downregulating miR-224-5p promoted DPSCs proliferation and migration; the opposite results were observed when miR-224-5p was upregulated. Conclusion. MiR-224-5p promotes proliferation and migration in DPSCs, a finding that is of great significance for further exploring the role of dental pulp stem cells in regenerative endodontics.
Analysis of Protein–Protein Functional Associations by Using Gene Ontology and KEGG Pathway
Authors: Yuan Fei , Pan Xiaoyong , Chen Lei , Zhang Yu-Hang , Huang Tao , Cai Yu-Dong
Published: July 2019

Protein–protein interaction (PPI) plays an extremely remarkable role in the growth, reproduction, and metabolism of all lives. A thorough investigation of PPI can uncover the mechanism of how proteins express their functions. In this study, we used gene ontology (GO) terms and biological pathways to study an extended version of PPI (protein–protein functional associations) and subsequently identify some essential GO terms and pathways that can indicate the difference between two proteins with and without functional associations. The protein–protein functional associations validated by experiments were retrieved from STRING, a well-known database on collected associations between proteins from multiple sources, and they were termed as positive samples. The negative samples were constructed by randomly pairing two proteins. Each sample was represented by several features based on GO and KEGG pathway information of two proteins. Then, the mutual information was adopted to evaluate the importance of all features and some important ones could be accessed, from which a number of essential GO terms or KEGG pathways were identified. The final analysis of some important GO terms and one KEGG pathway can partly uncover the difference between proteins with and without functional associations.
Prevalence of Pneumonia in Sheep and Goats Slaughtered at Elfora Bishoftu Export Abattoir, Ethiopia: A Pathological Investigation
Authors: Mekibib Berhanu , Mikir Tadesse , Fekadu Amene , Abebe Rahmeto
Published: July 2019

Accurate clinical diagnosis of pneumonia, the leading cause of mortality in small ruminants, is difficult and usually requires postmortem examination of the lungs. An active abattoir survey was conducted between November 2017 and April 2018 to estimate the prevalence and characterize the gross and histopathological lesions of pneumonic lungs in 864 clinically healthy young small ruminants (490 sheep and 374 goats aged 1.5 to 3 years) raised for meat in different parts of the country and slaughtered at Elfora Bishoftu export abattoir, Ethiopia. Out of the total lungs examined grossly, pneumonic lesions were found in 158 (18.29%) lungs. On histopathological examination of the lungs with gross pneumonic lesion, however, typical pneumonic lesions were diagnosed in 148 (17.13%) lungs only. No significant (p>0.05) difference was noted in the prevalence of pneumonia between sheep (17.14%) and goats (17.11%) in histopathological examination. Based on the predominant histopathological findings, the pneumonic lesions were characterized as interstitial pneumonia (41.9%), acute suppurative bronchopneumonia (25.7%), acute fibrinous bronchopneumonia (24.3%), chronic bronchopneumonia (6.1%), aspiration pneumonia (4.7%), bronchointerstitial pneumonia (3.4%), and ovine pulmonary adenomatosis (3.4%). The study further showed the spread of ovine pulmonary adenomatosis and ovine progressive pneumonia (Maedi) from the central highlands to areas that were previously free from these diseases. Due to its better diagnostic capacity, histopathology should be employed routinely as an ancillary test in the major abattoirs and regional veterinary laboratories to generate additional epidemiological data for a better disease control and prevention measures. Further studies are also recommended to identify the etiological agents of pneumonia in sheep and goats and thereby to formulate feasible and cost-effective interventions.
Effects of a 6-Week Faroese Chain Dance Programme on Postural Balance, Physical Function, and Health Profile in Elderly Subjects: A Pilot Study
Authors: Hofgaard Jóhan , Ermidis Georgios , Mohr Magni
Published: July 2019

The present pilot study investigates the impact of a Faroese chain dance intervention on health profile, mobility, and postural balance in elderly subjects. Healthy elderly subjects (n=27; age 75 ± 5 yrs) were randomised into an intervention group (IG) and a control group (CG). IG performed twice-weekly sessions of Faroese chain dance over 6 weeks. Dancing sessions lasted 30 min in the initial 3 weeks and 45 min in the final 3 weeks. Health profile was determined before and after intervention by measuring blood pressure, resting heart rate, muscle mass, and body fat content. Postural balance was evaluated using the Berg Balance Scale (BBS) and Fullerton Advanced Balance Scale (FAB) tests, while mobility was assessed using the Short Physical Performance Battery (SPPB), the Timed Up & Go (TUG) test, the 6-min walk test, and the 30-s sit-to-stand test. Systolic and diastolic blood pressure were lowered (9 ± 6 and 6 ± 3 mmHg, respectively) in IG, with a tendency (P=0.07) for a greater change score than in CG. Mean arterial pressure declined (P<0.05) by 7 ± 3 mmHg in IG, which tended (P=0.09) to be greater than in CG. IG improved (P<0.05) on BBS and FAB scores by 3.6 ± 2.1% and 15.8 ± 8.3%, with the change score for FAB being greater (P<0.05) than in CG (0.3 ± 1.6). Moreover, the postintervention SPPB score was improved (P<0.05) more in IG (13.9 ± 7.4%) compared to CG, while performance in the 30-s sit-to-stand, 6-min walk, and TUG tests improved (4–15%; P<0.05) in IG only. Body fat content was reduced (P<0.05) from 36.3 ± 2.8% to 34.8 ± 2.8% in IG, with no between-group differences and no change in CG (34.1 ± 2.8% to 33.7 ± 3.1%). In conclusion, a 6-week Faroese chain dance programme lowers blood pressure and improves postural balance and physical function in elderly.
User Association and Small-Cell Base Station On/Off Strategies for Energy Efficiency of Ultradense Networks
Authors: Gao Jing , Ren Qing , Gu Pei Shang , Song Xin
Published: July 2019

The widespread application of wireless mobile services and requirements of ubiquitous access have resulted in drastic growth of the mobile traffic and huge energy consumption in ultradense networks (UDNs). Therefore, energy-efficient design is very important and is becoming an inevitable trend. To improve the energy efficiency (EE) of UDNs, we present a joint optimization method considering user association and small-cell base station (SBS) on/off strategies in UDNs. The problem is formulated as a nonconvex nonlinear programming problem and is then decomposed into two subproblems: user association and SBS on/off strategies. In the user association strategy, users associate with base stations (BSs) according to their movement speeds and utility function values, under the constraints of the signal-to-interference ratio (SINR) and load balancing. In particular, taking care of user mobility, users are associated if their speed exceeds a certain threshold. The macrocell base station (MBS) considers user mobility, which prevents frequent switching between users and SBSs. In the SBS on/off strategy, SBSs are turned off according to their loads and the amount of time required for mobile users to arrive at a given SBS to further improve network energy efficiency. By turning off SBSs, negative impacts on user associations can be reduced. The simulation results show that relative to conventional algorithms, the proposed scheme achieves energy efficiency performance enhancements.
Cell Type Specific Expression of Toll-Like Receptors in Human Brains and Implications in Alzheimer’s Disease
Authors: Frederiksen Henriette R. , Haukedal Henriette , Freude Kristine
Published: July 2019

Toll-like receptors mediate important cellular immune responses upon activation via various pathogenic stimuli such as bacterial or viral components. The activation and subsequent secretion of cytokines and proinflammatory factors occurs in the whole body including the brain. The subsequent inflammatory response is crucial for the immune system to clear the pathogen(s) from the body via the innate and adaptive immune response. Within the brain, astrocytes, neurons, microglia, and oligodendrocytes all bear unique compositions of Toll-like receptors. Besides pathogens, cellular damage and abnormally folded protein aggregates, such as tau and Amyloid beta peptides, have been shown to activate Toll-like receptors in neurodegenerative diseases such as Alzheimer’s disease. This review provides an overview of the different cell type-specific Toll-like receptors of the human brain, their activation mode, and subsequent cellular response, as well as their activation in Alzheimer’s disease. Finally, we critically evaluate the therapeutic potential of targeting Toll-like receptors for treatment of Alzheimer’s disease as well as discussing the limitation of mouse models in understanding Toll-like receptor function in general and in Alzheimer’s disease.
A New Simple Method for the Strength of High‐Strength Steel Thin‐Walled Box Columns Subjected to Axial Force and Biaxial End Moments
Authors: Shen Hong-Xia
Published: July 2019

The strength of Q460 steel welded thin‐walled box columns under biaxial bending is investigated by an FE model. The numerical results, together with available experimental data, are compared with the American Specification ANSI/AISC 360‐10. It shows that ANSI/AISC 360‐10 provides a good estimate over a wide range of column slenderness ratios; but it severely underestimates the strengths of beam‐columns with large slenderness ratios and slightly underestimates those of beam‐columns made from HSS with fy = 741 MPa, and the calculation is more complicated because of using an effective width concept. Therefore, a simple and effective calculation method is proposed. Also, a comparison is made between the proposed formulas and the available experimental results. It shows that the proposed formulas can precisely evaluate the local‐overall interactive buckling strength of HSS beam‐columns and, in most cases, are also suitable for beam‐columns fabricated from mild steels. The proposed formulas are simple and, meanwhile, achieve the same level of accuracy as ANSI/AISC 360‐10.
Classification, History, and Future Prospects of Maxillofacial Prosthesis
Authors: de Caxias Fernanda Pereira , dos Santos Daniela Micheline , Bannwart Lisiane Cristina , de Moraes Melo Neto Clovis Lamartine , Goiato Marcelo Coelho
Published: July 2019

This review presents a classification system for maxillofacial prostheses, while explaining its types. It also aims to describe their origin and development, currently available materials, and techniques, predicts the future requirements, and subsequently discusses its avenues for improvement as a restorative modality. A literature search of the PubMed/Medline database was performed. Articles that discussed the history, types, materials, fabrication techniques, clinical implications, and future expectations related to maxillofacial prostheses and reconstruction were included. Fifty-nine articles were included in this review. Maxillofacial prostheses were classified as restorative or complementary with subclassifications based on the prostheses finality. The origin of maxillofacial prostheses is unclear; however, fabrication techniques and materials have undergone several changes throughout history. Currently, silicones and acrylic resins are the most commonly used materials to fabricate customized prostheses. Maxillofacial prostheses not only restore several types of orofacial defects but also improve the patients’ quality of life. Although the current clinical scenario concerning the field of maxillofacial prostheses is promising, improvements in material quality and techniques for maxillofacial prostheses may be expected in the future, to produce better results in the treatment of patients.
Assessment and Management of Postoperative Pain among Nurses at a Resource-Constraint Teaching Hospital in Ghana
Authors: Mahama Faisal , Ninnoni Jerry P. K.
Published: July 2019

Background. Postoperative pain remains one of the greatest concerns for patients following surgical procedures. Nurses play an essential role in postoperative pain assessment and management, especially within the first few days after surgery. Objective. The study investigated how nurses in a resource-constraint hospital in Ghana assessed and managed postoperative pain. Methods. This was an explorative qualitative study involving 12 registered nurses practising in the largest referral hospital in Ghana. Data was gathered using a semistructured interview guide. Demographic characteristics of participants were summarized using descriptive statistics. Data were analysed using Kvale’s three phases for analysing qualitative data. First, the entire text was read again to identify meaning units which were then condensed. Second, the condensed texts were read again and interpreted. Finally, the condensed data containing similar meaning were coded and then sorted into subthemes. Results. It was found that some nurses have never used any pain assessment tool due to lack of standard tool for assessing postoperative pain. The majority of nurses reported that managing pain by using medication was the norm especially in the first 24 hours after surgery. Conclusion. Although participants may have some knowledge of assessing and managing postoperative pain, this knowledge was not largely used to manage postoperative pain effectively, partly because of resource constraints. Therefore, there is the need for adequate training and with provision of resources, it is imperative that the use of standardized pain assessment scales could help in the proper assessment and management of postoperative pain in this setting.
A Potential Constraints Method of Finding Nonclassical Symmetry of PDEs Based on Wu’s Method
Authors: Bai Tonglaga , Chaolu Temuer
Published: July 2019

Solving nonclassical symmetry of partial differential equations (PDEs) is a challenging problem in applications of symmetry method. In this paper, an alternative method is proposed for computing the nonclassical symmetry of PDEs. The method consists of the following three steps: firstly, a relationship between the classical and nonclassical symmetries of PDEs is established; then based on the link, we give three principles to obtain additional equations (constraints) to extend the system of the determining equations of the nonclassical symmetry. The extended system is more easily solved than the original one; thirdly, we use Wu’s method to solve the extended system. Consequently, the nonclassical symmetries are determined. Due to the fact that some constraints may produce trivial results, we name the candidate constraints as “potential” ones. The method gives a new way to determine a nonclassical symmetry. Several illustrative examples are given to show the efficiency of the presented method.
Xiao-Qing-Long Tang Prevents Cardiomyocyte Hypertrophy, Fibrosis, and the Development of Heart Failure with Preserved Ejection Faction in Rats by Modulating the Composition of the Gut Microbiota
Authors: Zhou Guo-Feng , Jiang Yue-Hua , Ma Du-Fang , Wang Yong-Cheng , Yang Jin-Long , Chen Ji-Ye , Chi Chen-Yu , Han Xiao-wei , Li Zhao-Yu , Li Xiao
Published: July 2019

Background. Changes in the gut microbiota are associated with cardiovascular disease progression. Xiao-Qing-Long Tang (XQLT), a traditional herbal formula, has an anti-inflammatory effect and regulates the steady state of the immune system, which is also associated with the progression of heart failure with preserved ejection faction (HFpEF). In this study, we investigated whether XQLT could contribute to prevent the development of HFpEF and whether the modulation of the gut microbiota by this herbal formula could be involved in such effect. Methods. The gut microbiota, SCFAs, the histology/function of the heart, and systolic blood pressure were examined to evaluate the effect of XQLT on the gut microbiota and the progression of HFpEF after oral administration of XQLT to model rats. Furthermore, we evaluated, through fecal microbiota transplantation experiments, whether the favorable effects of XQLT could be mediated by the gut microbiota. Results. Oral administration of XQLT contributed to the reduction of elevated blood pressure, inflammation, and compensatory hypertrophy, features that are associated with the progression of HFpEF. The gut microbiota composition, SCFA levels, and intestinal mucosal histology were improved after treatment with XQLT. Moreover, fecal transfer from XQLT-treated rats was sufficient to prevent the progression of HFpEF. Conclusions. These data suggested that XQLT prevented the development of HFpEF in model rats by regulating the composition of the gut microbiota.
Association between Serum Matrix Metalloproteinase- (MMP-) 3 Levels and Systemic Lupus Erythematosus: A Meta-analysis
Authors: Lee Jiwon M. , Kronbichler Andreas , Park Se Jin , Kim Seong Heon , Han Kyoung Hee , Kang Hee Gyung , Ha Il Soo , Cheong Hae Il , Kim Ki Hwan , Kim Gaeun , Kim Dong Soo , Chae Hyun Wook , Lee Chul Ho , Lee Keum Hwa , Shin Jae Il
Published: July 2019

Introduction. Matrix metalloproteinase (MMP) is an emerging disease marker in rheumatic diseases. This is a meta-analysis aimed at systematically reviewing association between serum MMP-3 levels and systematic lupus erythematosus (SLE) activity, which sought to raise interest in MMP-3 as a putative biomarker. Methods. We conducted a meta-analysis of serum MMP-3 levels in patients with SLE and controls. We performed a PubMed search, EMBASE search, and forward search of the retrieved articles published until Oct. 1, 2018. In addition to this, we included data from a case-control study on a national pediatric SLE cohort, in which serum MMP-3 levels were measured in 11 SLE patients and 9 controls (unpublished). Subgroup analyses based on gender and disease activity were performed. Results. A total of 662 cases and 771 controls including 651 patients and 762 controls from 11 publications were studied. We observed significantly higher MMP-3 levels in SLE patients compared to healthy controls (P<0.001, Hedges’ g: 2.104, 95% CI 1.426-2.782). In subgroup analyses, we found a significant elevation of MMP-3 in the patients with nephritis compared to those without (P=0.006, Hedges’ g: 0.611, 95% CI 0.611-1.704). This finding was consistent between patients with persistent proteinuria and those without (P=0.023, Hedges’ g: 1.535, 95% CI 0.207-2.862). Meta-analysis showed no association between MMP-3 levels and gender or anti-double strand DNA antibody titer. Conclusions. Our meta-analysis demonstrated significantly higher MMP-3 levels in SLE patients than in controls and in patients with renal involvement than in those without.
Receptor Tyrosine Kinase Signaling Networks Define Sensitivity to ERBB Inhibition and Stratify Kras-Mutant Lung Cancers
Authors: Talwelkar Sarang S. , Nagaraj Ashwini S. , Devlin Jennifer R. , Hemmes Annabrita , Potdar Swapnil , Kiss Elina A. , Saharinen Pipsa , Salmenkivi Kaisa , Mäyränpää Mikko I. , Wennerberg Krister , Verschuren Emmy W.
Published: July 2019

Most non–small cell lung cancers (NSCLC) contain nontargetable mutations, including KRAS, TP53, or STK11/LKB1 alterations. By coupling ex vivo drug sensitivity profiling with in vivo drug response studies, we aimed to identify drug vulnerabilities for these NSCLC subtypes. Primary adenosquamous carcinoma (ASC) or adenocarcinoma (AC) cultures were established from KrasG12D/+;Lkb1fl/fl (KL) tumors or AC cultures from KrasG12D/+;p53fl/fl (KP) tumors. Although p53-null cells readily propagated as conventional cultures, Lkb1-null cells required conditional reprograming for establishment. Drug response profiling revealed short-term response to MEK inhibition, yet long-term clonogenic assays demonstrated resistance, associated with sustained or adaptive activation of receptor tyrosine kinases (RTK): activation of ERBBs in KL cultures, or FGFR in AC cultures. Furthermore, pan-ERBB inhibition reduced the clonogenicity of KL cultures, which was exacerbated by combinatorial MEK inhibition, whereas combinatorial MEK and FGFR inhibition suppressed clonogenicity of AC cultures. Importantly, in vivo studies confirmed KL-selective sensitivity to pan-ERBB inhibition, which correlated with high ERBB ligand expression and activation of ERBB receptors, implying that ERBB network activity may serve as a predictive biomarker of drug response. Interestingly, in human NSCLCs, phosphorylation of EGFR or ERBB3 was frequently detected in ASCs and squamous cell carcinomas. We conclude that analysis of in situ ERBB signaling networks in conjunction with ex vivo drug response profiling and biochemical dissection of adaptive RTK activities may serve as a valid diagnostic approach to identify tumors sensitive to ERBB network inhibition.
The Altered Transcriptome and DNA Methylation Profiles of Docetaxel Resistance in Breast Cancer PDX Models
Authors: Gómez-Miragaya Jorge , Morán Sebastián , Calleja-Cervantes Maria Eréndira , Collado-Sole Alejandro , Paré Laia , Gómez Antonio , Serra Violeta , Dobrolecki Lacey E. , Lewis Michael T. , Diaz-Lagares Angel , Eroles Pilar , Prat Aleix , Esteller Manel , González-Suárez Eva
Published: July 2019

Taxanes are standard therapy in clinical practice for metastatic breast cancer; however, primary or acquired chemoresistance are a common cause of mortality. Breast cancer patient-derived xenografts (PDX) are powerful tools for the study of cancer biology and drug treatment response. Specific DNA methylation patterns have been associated to different breast cancer subtypes but its association with chemoresistance remains unstudied. Aiming to elucidate docetaxel resistance mechanisms, we performed genome-wide DNA methylation in breast cancer PDX models, including luminal and triple-negative breast cancer (TNBC) models sensitive to docetaxel, their matched models after emergence of chemoresistance and residual disease after short-term docetaxel treatment. We found that DNA methylation profiles from breast cancer PDX models maintain the subtype-specific methylation patterns of clinical samples. Two main DNA methylation clusters were found in TNBC PDX and remain stable during the emergence of docetaxel resistance; however, some genes/pathways were differentially methylated according to docetaxel response. A DNA methylation signature of resistance able to segregate TNBC based on chemotherapy response was identified. Transcriptomic profiling of selected sensitive/resistant pairs and integrative analysis with methylation data demonstrated correlation between some differentially methylated and expressed genes in docetaxel-resistant TNBC PDX models. Multiple gene expression changes were found after the emergence of docetaxel resistance in TNBC. DNA methylation and transcriptional changes identified between docetaxel-sensitive and -resistant TNBC PDX models or residual disease may have predictive value for chemotherapy response in TNBC.

Implications:

Subtype-specific DNA methylation patterns are maintained in breast cancer PDX models. While no global methylation changes were found, we uncovered differentially DNA methylated and expressed genes/pathways associated with the emergence of docetaxel resistance in TNBC.
Lower Gastrointestinal Kaposi Sarcoma in HIV/AIDS: A Diagnostic Challenge
Authors: Olanipekun Titilope , Kagbo-Kue Suaka , Egwakhe Adekunbi , Mayette Maxi , Fransua Mesfin , Flood Michael
Published: July 2019

Gastrointestinal Kaposi sarcoma (GI-KS) is the most common extra-cutaneous site of KS in HIV/AIDS, and the majority (75%) of affected patients are asymptomatic. GI-KS rarely occurs in the absence of cutaneous lesions. Opportunistic GI infections in HIV/AIDS and GI-KS can present with similar symptoms especially diarrhea, creating a diagnostic challenge. We present a 46-year-old homosexual male with a medical history of HIV/AIDS and neurosyphilis, who presented with 2 weeks of nonbloody diarrhea and abdominal discomfort. He was initially worked up for infectious diarrhea, initiated on highly active anti-retroviral (HAART) and supportively managed with rehydration therapy and analgesia. However, his clinical symptoms did not improve, necessitating abdomen/pelvic CT scan which revealed extensive recto-sigmoid colon thickening and pelvic lymphadenopathy. Due to a high suspicion of malignancy, diagnostic endoscopy and biopsy were done which showed colonic KS. He was treated with intravenous pegylated doxorubicin in addition to HAART which evidently resulted in significant clinical and radiological improvement. The diagnosis of GI-KS could be challenging in the presence of overlapping features with opportunistic GI infections and the absence of cutaneous manifestations of KS because clinicians tend to focus more on infectious etiology. We suggest that clinicians should consider GI-KS in the differential diagnosis of patients with HIV/AIDS that present with diarrhea and other nonspecific abdominal symptoms. Early endoscopic evaluation with biopsy could help to ensure the timely diagnosis and management of GI-KS and ultimately improve outcomes.
The Loss in Expectation of Life due to Early-Onset Mild Cognitive Impairment and Early-Onset Dementia in Norway
Authors: Strand Bjørn Heine , Knapskog Anne-Brita , Persson Karin , Holt Edwin Trine , Bjertness Espen , Engedal Knut , Selbaek Geir
Published: July 2019

Introduction: Whether patients with early-onset dementia have poorer or improved survival compared with those with a late onset largely depends on the survival measure. Survival estimates for early-onset mild cognitive impairment (MCI) diagnosis are particularly scarce. We aimed to estimate life expectancy (LE) in patients with early-onset dementia or early MCI, and loss in expectation of life (LEL) for these groups. Comparisons were made with the general Norwegian population and a subgroup of patients with late-onset dementia. Methods: Early onset was defined as receiving a diagnosis of MCI or dementia before age 65 years. LE and LEL were predicted using flexible parametric survival models. Our study population was comprised of newly diagnosed (incident) cases (n = 4,906), aged 50–90 years at the time of diagnosis (672 were diagnosed before age 65 years, of which 291 were diagnosed with dementia), in the Norwegian register of persons assessed for cognitive symptoms (NorCog) between 2009 and 2017, and patients were followed up for mortality or censorship until January 2018. Results: Among the early-onset patients, 8 and 23% died during follow-up, in the MCI and dementia groups, respectively. Both early-onset MCI and especially early-onset dementia were associated with lower LE than in the general Norwegian population; LE for 60-year-old women in 2016 was 26 years in the general population, 20 years in MCI patients, and 7 years in dementia patients. The corresponding LE at 80 years was 10, 6, and 5 years. Thus, LEL were particularly pronounced for patients with early dementia. The diagnosis-specific LE pattern in men was similar to that in women. Discussion: Early-onset MCI was associated with substantial life years lost (5–6 years), but the loss was particularly pronounced for those with early-onset dementia, reducing the expected life length by 2 decades.
Gastric Antral Vascular Ectasia: An Uncommon Cause of Anemia in the Elderly
Authors: Unnikrishnan Rahul , Vijayakumar Priya , Senan Sunil , Paul George
Published: July 2019

Gastric antral vascular ectasia (GAVE), also referred to as “watermelon stomach,” is an uncommon, under-reported, yet significant cause of acute or chronic gastrointestinal blood loss in the elderly. It accounts for about 4% of the nonvariceal upper GI bleeds, and diagnosis is established by the demonstration of characteristic watermelon stripes on upper GI endoscopy. The exact cause is unknown but is often associated with many systemic conditions and characterized by chronic anemia. With this case, we wish to emphasize the need to do upper GI endoscopy in all elderly patients undergoing anemia evaluation and to consider this possibility even in the very elderly individuals.
Glycoproteomic Analysis of the Aortic Extracellular Matrix in Marfan Patients
Authors: Yin (殷晓科) Xiaoke , Wanga Shaynah , Fellows Adam L. , Barallobre-Barreiro Javier , Lu Ruifang , Davaapil Hongorzul , Franken Romy , Fava Marika , Baig Ferheen , Skroblin Philipp , Xing Qiuru , Koolbergen David R. , Groenink Maarten , Zwinderman Aeilko H. , Balm Ron , de Vries Carlie J.M. , Mulder Barbara J.M. , Viner Rosa , Jahangiri Marjan , Reinhardt Dieter P. , Sinha Sanjay , de Waard Vivian , Mayr Manuel
Published: July 2019

Objective:

Marfan syndrome (MFS) is caused by mutations in FBN1 (fibrillin-1), an extracellular matrix (ECM) component, which is modified post-translationally by glycosylation. This study aimed to characterize the glycoproteome of the aortic ECM from patients with MFS and relate it to aortopathy.

Approach and Results:

ECM extracts of aneurysmal ascending aortic tissue from patients with and without MFS were enriched for glycopeptides. Direct N-glycopeptide analysis by mass spectrometry identified 141 glycoforms from 47 glycosites within 35 glycoproteins in the human aortic ECM. Notably, MFAP4 (microfibril-associated glycoprotein 4) showed increased and more diverse N-glycosylation in patients with MFS compared with control patients. MFAP4 mRNA levels were markedly higher in MFS aortic tissue. MFAP4 protein levels were also increased at the predilection (convexity) site for ascending aorta aneurysm in bicuspid aortic valve patients, preceding aortic dilatation. In human aortic smooth muscle cells, MFAP4 mRNA expression was induced by TGF (transforming growth factor)-β1 whereas siRNA knockdown of MFAP4 decreased FBN1 but increased elastin expression. These ECM changes were accompanied by differential gene expression and protein abundance of proteases from ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family and their proteoglycan substrates, respectively. Finally, high plasma MFAP4 concentrations in patients with MFS were associated with a lower thoracic descending aorta distensibility and greater incidence of type B aortic dissection during 68 months follow-up.

Conclusions:

Our glycoproteomics analysis revealed that MFAP4 glycosylation is enhanced, as well as its expression during the advanced, aneurysmal stages of MFS compared with control aneurysms from patients without MFS.
Apolipoprotein E4 Expression Causes Gain of Toxic Function in Isogenic Human Induced Pluripotent Stem Cell-Derived Endothelial Cells
Authors: Rieker Claus , Migliavacca Eugenia , Vaucher Angélique , Mayer Fiona C. , Baud Gilles , Marquis Julien , Charpagne Aline , Hegde Nagabhooshan , Guignard Laurence , McLachlan Michael , Pooler Amy M.
Published: July 2019

Objective:

The ApoE (apolipoprotein) allele epsilon 4 is a major genetic risk factor for Alzheimer disease, cardiovascular disorders, and stroke, indicating that it significantly impacts cerebral and vascular systems. However, very little is known about how
APOE
genotype affects brain endothelial cells, which form a network of tight junctions to regulate communication between the brain and circulating blood factors.

Approach and Results:

Here, we present a novel model of endothelial dysfunction using isogenic human induced pluripotent stem cell-derived cells harboring different alleles of the
APOE
gene, specifically ApoE 3/3, 3/4, and 4/4. We show for the first time that ApoE4 expression by endothelial cells is sufficient to cause a toxic gain of cellular dysfunction. Using RNAseq, we found significant effects of ApoE4 on signaling pathways involved in blood coagulation and barrier function. These changes were associated with altered cell function, including increased binding of platelets to ECs with the 3/4 or 4/4 genotype. ApoE4-positive cells exhibited a proinflammatory state and prothrombotic state, evidenced by higher secretion of Aβ (amyloid-β) 40 and 42, increased release of cytokines, and overexpression of the platelet-binding protein VWF (vonWillebrand factor). Immunohistochemistry of human brain Alzheimer disease brains also showed increased VWF expression with the ApoE4/4 genotype. Finally, pharmacological inhibition of inflammation in ECs by celastrol rescued overexpression of VWF in cells expressing ApoE4.

Conclusions:

These cells provide novel insight into ApoE4-mediated endothelial dysfunction and provide a new platform to test potential therapies for vascular disorders.
Short-Acting Anti-VWF (von Willebrand Factor) Aptamer Improves the Recovery, Survival, and Hemostatic Functions of Refrigerated Platelets
Authors: Chen Wenchun , Voos Kayleigh M. , Josephson Cassandra D. , Li Renhao
Published: July 2019

Objective:

Refrigeration-induced binding of VWF (von Willebrand factor) to platelets contributes to the rapid clearance of refrigerated platelets. In this study, we investigate whether inhibiting VWF binding by a DNA-based aptamer ameliorates the clearance of refrigerated platelets without significantly impeding hemostatic functions.

Approach and Results:

Platelets were refrigerated with or without aptamer ARC1779 for 48 hours. VWF binding, the effective lifetime of ARC1779, platelet post-transfusion recovery and survival, and the hemostatic function were measured. ARC1779 treatment during refrigeration inhibited the platelet-VWF interaction. ARC1779-treated refrigerated murine platelets exhibited increased post-transfusion recovery and survival than untreated ones (recovery of ARC1779-treated platelets: 76.7±5.5%; untreated: 63.7±0.8%;
P
<0.01. Half-life: 31.4±2.36 hours versus 28.1±0.86 hours;
P
<0.05). A similar increase was observed for refrigerated human platelets (recovery: 49.4±4.4% versus 36.8±2.1%,
P
<0.01; half-life: 9.2±1.5 hours versus 8.7±0.9 hours, ns). The effective lifetime of ARC1779 in mice was 2 hours. Additionally, ARC1779 improved the long-term (2 hours after transfusion) hemostatic function of refrigerated platelets (tail bleeding time of mice transfused with ARC1779-treated refrigerated platelets: 160±65 seconds; untreated: 373±96 seconds;
P
<0.01). The addition of an ARC1779 antidote before transfusion improved the immediate (15 minutes after transfusion) hemostatic function (bleeding time of treated platelets: 149±21 seconds; untreated: 320±36 seconds;
P
<0.01).

Conclusions:

ARC1779 improves the post-transfusion recovery of refrigerated platelets and preserves the long-term hemostatic function of refrigerated platelets. These results suggest that a short-acting inhibitor of the platelet-VWF interaction may be a potential therapeutic option to improve refrigeration of platelets for transfusion treatment.
Association Between ApoA-I (Apolipoprotein A-I) Immune Complexes and Adverse Cardiovascular Events—Brief Report
Authors: Henson David , Tahhan Ayman Samman , Nardo David , Quyyumi Arshed Ali , Venditto Vincent J.
Published: July 2019

Objective:

The immune response is linked to the progression of atherosclerotic cardiovascular disease (CVD). Free autoantibodies targeting ApoA-I (apolipoprotein A-I) have been identified as a component of the inflammatory milieu in patients and have a moderate association with CVD progression. Based on the presence of these antibodies and the high concentration of circulating ApoA-I, we hypothesized that antibodies bound to ApoA-I as an immune complex would be predictive of incident adverse CVD outcomes.

Approach and Results:

The presence of ApoA-I/IgG immune complexes (ICs) in plasma was confirmed by ELISA in 3 subject cohorts. Characterization of the protein components of ApoAI/IgG ICs indicate that ICs are not correlated with total ApoA-I concentration and are enriched in the anti-inflammatory subclass, IgG4, relative to total plasma IgG (>30% versus 6%). In 359 patients with coronary artery disease (CAD), there were 71 incident adverse CVD events (death, myocardial infarction, and stroke) during a median 4.1-year follow-up. In Cox proportional hazard regression analysis, low levels of ApoA-I/IgG ICs were independent predictors of adverse cardiovascular outcomes after adjustment for age, sex, diabetes mellitus, estimated glomerular filtration rate, presence of obstructive CAD, heart failure, total cholesterol, and HDL (high-density lipoprotein) cholesterol (adjusted hazard ratio of 1.90 [95% CI, 1.03–3.49;
P
=0.038] between the lowest and the highest tertiles).

Conclusions:

Low levels of ApoA-I/IgG ICs are associated with an increased risk of adverse events in patients with CAD, raising their potential to be used as a biomarker to predict CVD progression.
Allele-Specific Silencing Ameliorates Restrictive Cardiomyopathy Attributable to a Human Myosin Regulatory Light Chain Mutation
Authors: Zaleta-Rivera Kathia , Dainis Alexandra , Ribeiro Alexandre J.S. , Cordero Pablo , Rubio Gabriel , Shang Ching , Liu Jing , Finsterbach Thomas , Parikh Victoria N. , Sutton Shirley , Seo Kinya , Sinha Nikita , Jain Nikhil , Huang Yong , Hajjar Roger J. , Kay Mark A. , Szczesna-Cordary Danuta , Pruitt Beth L. , Wheeler Matthew T. , Ashley Euan A.
Published: July 2019

Background:

Restrictive cardiomyopathy is a rare heart disease associated with mutations in sarcomeric genes and with phenotypic overlap with hypertrophic cardiomyopathy. There is no approved therapy directed at the underlying cause. Here, we explore the potential of an interfering RNA (RNAi) therapeutic for a human sarcomeric mutation in
MYL2
causative of restrictive cardiomyopathy in a mouse model.

Methods:

A short hairpin RNA (M7.8L) was selected from a pool for specificity and efficacy. Two groups of myosin regulatory light chain N47K transgenic mice were injected with M7.8L packaged in adeno-associated virus 9 at 3 days of age and 60 days of age. Mice were subjected to treadmill exercise and echocardiography after treatment to determine maximal oxygen uptake and left ventricular mass. At the end of treatment, heart, lung, liver, and kidney tissue was harvested to determine viral tropism and for transcriptomic and proteomic analysis. Cardiomyocytes were isolated for single-cell studies.

Results:

A one-time injection of AAV9-M7.8L RNAi in 3-day-old humanized regulatory light chain mutant transgenic mice silenced the mutated allele (RLC-47K) with minimal effects on the normal allele (RLC-47N) assayed at 16 weeks postinjection. AAV9-M7.8L RNAi suppressed the expression of hypertrophic biomarkers, reduced heart weight, and attenuated a pathological increase in left ventricular mass. Single adult cardiac myocytes from mice treated with AAV9-M7.8L showed partial restoration of contraction, relaxation, and calcium kinetics. In addition, cardiac stress protein biomarkers, such as calmodulin-dependent protein kinase II and the transcription activator Brg1 were reduced, suggesting recovery toward a healthy myocardium. Transcriptome analyses further revealed no significant changes of argonaute (
AGO1
,
AGO2
) and endoribonuclease dicer (
DICER1
) transcripts, and endogenous microRNAs were preserved, suggesting that the RNAi pathway was not saturated.

Conclusions:

Our results show the feasibility, efficacy, and safety of RNAi therapeutics directed towards human restrictive cardiomyopathy. This is a promising step toward targeted therapy for a prevalent human disease.
Ischemic Stroke in Adults With Congenital Heart Disease: A Population‐Based Cohort Study
Authors: Pedersen Mette Glavind Bülow , Olsen Morten S. , Schmidt Morten , Johnsen Søren P. , Learn Christopher , Laursen Henning B. , Madsen Nicolas L.
Published: July 2019

Background

Congenital heart disease (
CHD
) is associated with risk factors for ischemic stroke including cardiac arrhythmias and heart failure. However, few long‐term follow‐up data exist on ischemic stroke risk and associated mortality in adults with
CHD
.

Methods and Results

Using Danish nationwide registries, we identified individuals aged ≥18 years diagnosed with
CHD
, at any age, from 1963 to 2017 and a sex and birth year‐matched (1:10) general population comparison cohort. We computed risks, as well as sex and birth year‐adjusted hazard ratios (
aHR
s) for ischemic stroke and 30‐day post‐stroke mortality in
CHD
adults compared with the general population. Analyses were stratified according to age <60 years (young) and ≥60 years (older). We identified 16 836 adults with
CHD
. The risk of ischemic stroke at age 60 years was 7.4% in the
CHD
cohort and 2.9% in the general population cohort. The adjusted hazard ratios for ischemic stroke compared with the general population was 3.8 (95%
CI
: 3.3–4.3) in young
CHD
adults and 1.6 (95%
CI
: 1.4–1.9) in older
CHD
adults. The adjusted hazard ratios for post‐stroke mortality compared with the general population was 2.3 (95%
CI
: 1.2–4.4) in young
CHD
adults and 1.3 (95%
CI
: 0.9–1.9) in older
CHD
adults.

Conclusions

Both younger and older
CHD
adults have an increased risk of ischemic stroke and by 60 years of age 7.4% of
CHD
adults will have had an ischemic stroke. Post‐stroke mortality was also increased in
CHD
adults compared with the general population.
Racial Disparities in the Utilization and Outcomes of Structural Heart Disease Interventions in the United States
Authors: Alkhouli Mohamad , Alqahtani Fahad , Holmes David R. , Berzingi Chalak
Published: July 2019

Background

Data on race‐ and ethnicity‐based disparities in the utilization and outcomes of structural heart disease interventions in the United States are scarce.

Methods and Results

We used the National Inpatient Sample (2011‐2016) to examine racial and ethnic differences in the utilization, in‐hospital outcomes, and cost of structural heart disease interventions among patients ≥65 years of age. A total of 106 119 weighted hospitalizations for transcatheter aortic valve replacement, transcatheter mitral valve repair, and left atrial appendage occlusion were included. The utilization rates (defined as the number of procedures performed per 100 000
US
people >65 years of age) were higher in whites compared with blacks and Hispanics for transcatheter aortic valve replacement (43.1 versus 18.0 versus 21.1), transcatheter mitral valve repair (5.0 versus 3.2 versus 3.2), and left atrial appendage occlusion (6.6 versus 2.1 versus 3.5), respectively (
P
<0.001). Black and Hispanic patients had distinctive socioeconomic and clinical risk profiles compared with white patients. There were no significant differences in the adjusted in‐hospital mortality or key complications between patients of white race, black race, and Hispanic ethnicity following transcatheter aortic valve replacement, transcatheter mitral valve repair, or left atrial appendage occlusion. No difference in cost was observed between white and black patients following any of the 3 procedures. However, Hispanic patients incurred modestly higher cost with transcatheter mitral valve repair and left atrial appendage occlusion compared with white patients.

Conclusions

Racial and ethnic disparities exist in the utilization of structural heart disease interventions in the United States. Nonetheless, adjusted in‐hospital outcomes were comparable among white, black, and Hispanic patients. Further studies are needed to understand the reasons for these utilization disparities.
Ficophagus curtipes n. sp. (Nematoda: Aphelenchoididae), an associate of Ficus curtipes in China
Authors: Zhang Dayuan , Zeng Wensheng , Huang Jianfeng , Zeng Yongsan , Peng Yanqiong , Ye Weimin , Huang Jianghua , Giblin-Davis Robin M.
Published: July 2019

A new nematode species was recovered from the syconia of Ficus curtipes from Xishuangbanna Tropical Botanical Garden, Yunnan, China. It is described herein as Ficophagus curtipes n. sp. and is differentiated from all currently described species in the genus by the possession of a spicule with a ventrally recurved tip (terminal barb). It is further characterised by possessing a short post-uterine sac, an ovoid spermatheca, presence of crustaformeria, excretory pore located near the head, amoeboid sperm, three pairs of subventral papillae on the male tail, rounded male tail tip without mucron, rose-thorn-shaped spicules without cucullus and absence of gubernaculum (= apophysis). Ficophagus curtipes n. sp. was differentiated from other sequenced species by the partial small subunit rRNA gene and D2-D3 expansion segments of the large subunit rRNA gene. Phylogenetic analyses suggested that F. curtipes n. sp. has a closer relationship with F. benjamina and F. microcarpus in the same highly supported monophyletic clade than to the other sequenced Ficophagus and Schistonchus s.l. species.
Molecular characterisation of some stubby root nematodes (Nematoda: Trichodoridae) from the USA and other countries
Authors: Subbotin Sergei A. , Cid Del Prado Vera Ignacio , Inserra Renato N. , Chizhov Vladimir N. , Decraemer Wilfrida
Published: July 2019

The stubby root nematodes are world-wide distributed polyphagous root ectoparasites and can cause damage to a wide range of crops and natural vegetation. In this study, 22 valid and putative species of stubby root nematodes were identified in 37 samples collected in Malaysia, Mexico, Russia, and the USA (California, Florida, Minnesota and Nevada). The analysis of 58 new sequences of the D2-D3 expansion fragments of 28S rRNA gene revealed the following species: Nanidorus minor from California, Florida and Mexico, N. renifer from Florida, two unidentified Nanidorus species from California and Malaysia, respectively, Paratrichodorus allius from Florida and Minnesota, P. pachydermus and Paratrichodorus sp. from Russia, Trichodorus californicus, T. intermedius, and T. obscurus from California, T. obtusus from Florida, eight unidentified Trichodorus species from California, one unidentified Trichodorus species from Nevada, and two unidentified species of stubby root nematodes, one of Trichodorus and another undetermined species from Mexico. Molecular characterisation of T. californicus, T. intermedius and T. obscurus is given for the first time. The phylogenetic tree reconstructed from the analysis of 108 D2-D3 of 28S rRNA gene sequences of 58 valid and putative species of the stubby root nematodes contained five major clades: i) Trichodorus from Europe, Asia and North America; ii) Nanidorus and Trichodorus from Asia; iii) Trichodorus from California; iv) Paratrichodorus from several distant geographical regions; and v) Monotrichodorus from Central and South America. It has been hypothesised that the California Floristic Province is one of the centres of origin and diversification of stubby root nematodes. There is no information on the economic importance of the stubby root nematode species found in California and Mexico. The confirmation of the occurrence of N. renifer and P. allius in Florida should be of concern for the blueberry and potato industries in the state.