bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnitude and Factors Associated with Precervical Cancer among Screened Women in Southern Ethiopia
Authors: Teka Terefu , Kote Mesfin , Kejela Gemechu , Getachew Tagel
Published: May 2019

Background. Cervical cancer is one of the major noncommunicable public health problems among the female population affecting not only the women but also the whole community. Annually, more than half a million new patients are diagnosed with it and over 270,000 deaths occur worldwide. There are very few research efforts conducted on prevalence and associated factors of specific target group in the region. So, this study tries to show the magnitude on all women screened for precervical cancer and serves as a secondary data for other research. Objective. The aim of the study was to assess magnitude of precervical cancer and associated factors among screened women in Arba Minch town and zuria woreda health institutions, southern Ethiopia. Methods. A facility based cross-sectional study was conducted in three health facilities at Arba Minch town and zuria woreda, southern Ethiopia, from June 2015 to June 2017. Data were collected by two nurses that are working in the area of expertise and one health officer as supervisor. Data of 528 screened clients were entered into Epi data version 3.1 using checklist, double data entry verification done and exported to SPSS version 20.0. After cleaning the data, descriptive analysis was done and multivariable logistic regression model was employed to identify predictors of precervical cancer. Finally, statistical significance was declared at P < 0.05. Result. In this study, the magnitude of precervical cancer is 27.7% [95%CI] (24.1-31.4)]. Having primary educational status (AOR [95% CI]) = 0.2 [0.1, 0.96)] and secondary educational status (AOR[95% CI]) = 0.1 [0.02,0.3]), having history of smoking [AOR (95% CI) = 3.7 (1.4-9.9)], having two and more than two life time sexual partners [AOR (95% CI) = 2.2 (1.1-4.7)], having age at first sexual intercourse less than eighteen years [AOR (95% CI) = 6.6 (3.14-13.0)] were significantly associated with precervical cancer. Conclusion and Recommendation. The magnitude of precervical cancer is 27.7% as shown in the result of the present study. Level of education, age at first sexual intercourse, history of smoking, and number of sexual partners were predictors of precervical cancer in this study. Thus, any cervical cancer prevention and control effort at the study area should address those predictors pointed out in the present study and should encourage to screen for precervical cancer.
Systemic Level of Oxidative Stress during Orthodontic Treatment with Fixed Appliances
Authors: Kovac Vito , Poljsak Borut , Perinetti Giuseppe , Primozic Jasmina
Published: May 2019

The aim of the study was to assess the level of selected systemic oxidative stress parameters during the first week of orthodontic treatment with fixed appliances. Fifty-four males with malocclusion and having a similar lifestyle were randomized using a computer based procedure and allocated to either the treatment group (TG; n=27;24.6 ± 1.7 years) or control group (CG; n=27;24.7 ± 1.7 years). Capillary blood was collected at baseline and 6 hours, 24 hours, and 7 days after archwire insertion. At the same time points, capillary blood was retrieved in the CG. In order to determine the oxidative stress, both the reactive oxygen species (ROS) formation and the antioxidative defense (AD) potential were measured using the ROS testing and oxygen free radicals defense (equivalent to antioxidant defense) testing, respectively, by a blinded operator. The ratio between ROS and AD (ROS/AD) was calculated and data were analyzed using nonparametric tests. No drop-outs or harms were detected. At baseline, neither ROS (1.54 [1.22;2.12] and 1.74 [1.40;2.01] for the TG and CG, respectively), AD (1.19 [0.66;1.50] and 1.19 [0.57;1.42] for the TG and CG, respectively), nor ROS/AD levels were significantly different (p>0.05). After 24 hours, the ROS level significantly increased in the TG (2.05 [1.71;2.26]) and was higher compared to the CG ROS level (1.67 [1.29;1.95]; p=0.025), while for the AD level, no marked between and within group differences were detected. A notable change of ROS/AD ratio was observed over time only within the TG (p=0.026). Moreover, a significantly higher ROS/AD ratio was detected 24 hours after archwire insertion in the TG compared to the CG (2.69 [1.44;3.89] and 1.79 [1.45;2.35], respectively), followed by a decrease. Orthodontic treatment with fixed appliances might induce systemic oxidative stress in the short-term, since ROS levels and ROS/AD levels are normalized within 7 days after archwire insertion.
Differences in College Engagement Benchmark Scores as a Function of Honors Course Enrollment for Community College Students: A Nationwide Study
Authors: Korah Abraham , Slate John R. , Moore George W. , Lunenburg Frederick C.
Published: May 2019

In this investigation, the extent to which differences were present in benchmark scores as a function of community college student honors course enrollment status was investigated using data from the Community College Survey of Student Engagement. Statistically significant differences were revealed for all 5 benchmark scores (i.e., active and collaborative learning, student effort, academic challenge, student-faculty, and support for learners). Students who had been enrolled in an honors course had benchmark scores that were 9 to 16 points higher than their peers who had not been enrolled in an honors course, reflecting higher levels of scholastic engagement, deeper connections with instructors and peers, and greater use of academic and student support services.
Sugarcane Bagasse Ash Micronized Using Air Jet Mills for Green Pozzolan in Brazil
Authors: Molin Filho Rafael G. D. , Rosso Jaciele M. , Volnistem Eduardo A. , Vanderlei Romel D. , Colpini Leda M. S. , Ferrer Mateus M. , Paraíso Paulo R. , Jorge Luiz M. de M.
Published: May 2019

This study provided a basis for new possibilities concerning the use of the sugarcane bagasse ash as a green pozzolanic addition to the Portland cement composite. To that effect, a simple micronization method using air jet milling without any other additional thermal procedure was used to control the characteristics of ash particles. This procedure not only maintains the required characteristics of the residues but can also improve some of them. Sugarcane bagasse ash is a residue produced on large scale in Brazil by ethanol and sugar plants as a result of the burning of sugarcane bagasse in energy cogeneration. The residue used in this study was initially characterized by scanning electron microscopy, granulometric and specific mass analyses, N2 adsorption measurements, X-ray diffraction, X-ray fluorescence spectroscopy, and thermogravimetric analysis with differential thermal analysis. Pozzolanic ash activity was evaluated according to the axial compressive strength at 28 days and the modified Chapelle methods. The results showed that the milling fly sugarcane bagasse ash samples presented satisfactory pozzolanic activity.
Enterococci: Between Emerging Pathogens and Potential Probiotics
Authors: Ben Braïek Olfa , Smaoui Slim
Published: May 2019

Enterococci are ubiquitous microorganisms that could be found everywhere; in water, plant, soil, foods, and gastrointestinal tract of humans and animals. They were previously used as starters in food fermentation due to their biotechnological traits (enzymatic and proteolytic activities) or protective cultures in food biopreservation due to their produced antimicrobial bacteriocins called enterocins or as probiotics, live cells with different beneficial characteristics such as stimulation of immunity, anti-inflammatory activity, hypocholesterolemic effect, and prevention/treatment of some diseases. However, in the last years, the use of enterococci in foods or as probiotics caused an important debate because of their opportunistic pathogenicity implicated in several nosocomial infections due to virulence factors and antibiotic resistance, particularly the emergence of vancomycin-resistant enterococci. These virulence traits of some enterococci are associated with genetic transfer mechanisms. Therefore, the development of new enterococcal probiotics needs a strict assessment with regard to safety aspects for selecting the truly harmless enterococcal strains for safe applications. This review tries to give some data of the different points of view about this question.
Deviations for Jumping Times of a Branching Process Indexed by a Poisson Process
Authors: Zhang Yanhua , Gao Zhenlong
Published: May 2019

Consider a continuous time process , where {Zn} is a supercritical Galton–Watson process and {Nt} is a Poisson process which is independent of {Zn}. Let τn be the n−th jumping time of {Yt}, we obtain that the typical rate of growth for {τn} is n/λ, where λ is the intensity of {Nt}. Probabilities of deviations {|n−1τn − λ−1| > δ} are estimated for three types of positive δ.
Idiopathic Macular Hole: A Comprehensive Review of Its Pathogenesis and of Advanced Studies on Metamorphopsia
Authors: Chen Qi , Liu Zao-xia
Published: May 2019

Vitreous anteroposterior traction is an important factor that affects macular hole (MH) formation at the early stage, and vitreous tangential traction can lead to further hole expansion after hole formation. Recent studies have highlighted the significance of Müller cells for the pathogenesis of MH. Since the advent of MH treatment, success rates for MH closure have significantly improved, as has postoperative visual acuity. However, metamorphopsia, an initial and common symptom of MH, still exists. Metamorphopsia is significantly related to the deterioration of visual quality of life and can be used as an independent index to evaluate visual function before and after surgery. In MH patients, metamorphopsia has different manifestations representing different clinical implications. M-CHARTS, as a new means of inspection, can quantify the degrees of metamorphopsia, and with the development of optical coherence tomography (OCT), layer-by-layer scanning of the retinal structure has become possible. These methods enable detailed analysis of the connections between the degree of metamorphopsia and relevant OCT parameters. Preoperative OCT parameters can be used to evaluate the prognosis of the postoperative visual function of MH patients and are therefore of great significance in guiding the treatment of MH patients.
Attention Deficits in Stroke Patients: The Role of Lesion Characteristics, Time from Stroke, and Concomitant Neuropsychological Deficits
Authors: Spaccavento Simona , Marinelli Chiara Valeria , Nardulli Roberto , Macchitella Luigi , Bivona Umberto , Piccardi Laura , Zoccolotti Pierluigi , Angelelli Paola
Published: May 2019

Attention impairments are frequent in stroke patients with important consequences on the rehabilitation outcomes and quality of life. The aim of the study was to perform a comprehensive assessment of selective and intensive attention processes in a large population of brain-damaged patients, evaluating the influence of the side and site of the brain lesion, the time from stroke, and the concomitant presence of aphasia or neglect. We assessed 204 patients with a first unilateral brain lesion and 42 healthy individuals with three subtests of the Test of Attentional Performance (TAP): Alertness, Go-No Go, and Divided Attention. 44.4% of patients had an impairment in both intensive and selective aspects of attention, 5.6% had deficits only in the intensive component, and 31.8% had deficits only in selective tasks. More than 80% of the patients fell below the cut-off point on at least one task. Patients with a right hemispheric lesion (RHL) were more impaired than patients with a left hemispheric lesion (LHL) especially in tonic and phasic alertness. Patients with total anterior infarcts (TACI) presented the worst profile compared to other stroke subtypes, with a difference between total and lacunar subtypes in the Alertness test, independent of the presence of warning. Patients in the chronic phase had shorter RTs than acute patients only in the Alertness test. In patients with LHL, the presence of aphasia was associated with a greater deficit in selective attention. In patients with RHL, the presence of unilateral neglect was associated with impaired alertness and selective attention. Attention deficits are common after a unilateral first stroke. In keeping with the hierarchical organization of attention functions, results confirm the important role of the right hemisphere for the intensive components of attention, also highlighting the involvement of left hemisphere functioning for the selective aspects, possibly indicating a role of its linguistic functions.
A New Type of Combination Synchronization among Multiple Chaotic Systems
Authors: Wang Xingxu , Sun Lin , Wang Bingji , Huang Tousheng
Published: May 2019

Based on former combination synchronization studies, a new type of combination synchronization approach is developed in this research, with the consideration of parallel combination of drive systems. This new synchronization approach is referred to as combination synchronization‐II. As a representative case, the combination synchronization‐II between three drive systems and one response system is studied. Applying Lyapunov stability theorem and active backstepping design, sufficient conditions for the proposed combination synchronization approach are derived. Numerical simulations are performed to show the feasibility and effectiveness of the proposed approach. Based on the investigation in this research, the proposed approach provides an applicable method for designing universal combination synchronization among multiple chaotic systems.
Noninvasive Vehicle‐to‐Load Energy Management Strategy to Prevent Li‐Ion Batteries Premature Degradation
Authors: Rodríguez-Licea Martín-Antonio , Perez-Pinal Francisco-J. , Soriano-Sánchez Allan-Giovanni , Vázquez-López José-Antonio
Published: May 2019

Today, electric vehicles available in the market aspire to offer different connections to the end user, for instance, Vehicle to Grid (V2G), Vehicle to Building (V2B), Vehicle to Home (V2H), Vehicle to Vehicle (V2V), and Vehicle to Load (V2L), among others. Notwithstanding these versatility options toward the development of a sustainable society, the additional degradation of the energy storage systems once those operate in extra discharge modes is inevitable. Therefore, in this paper, an energy management strategy (EMS) which operates autonomously and noninvasively as an additional layer to the battery management system (BMS) is proposed. The EMS limits the current flow avoiding high and low temperatures, low state of charge (SoC), high deep of discharge (DoD), noncentered DoD around an optimal SoC point, and high charge and discharge rates. The proposed EMS is evaluated by long‐term simulations with a Li‐Ion battery degradation model and realistic weather conditions, during standard driving cycles including the V2L operation. The effectiveness and simplicity of tuning of the proposed EMS allow estimating and increasing the life expectancy of the Li‐Ion battery bank, by limiting the energy used for V2L operation.
Inhibitory Effect of Lactobacillus plantarum CQPC02 Isolated from Chinese Sichuan Pickles (Paocai) on Constipation in Mice
Authors: Liu Bihui , Yang Xin , Guo Liujin , Zhang Jing , Zhou Xianrong , Yi Ruokun , Zhao Xin
Published: May 2019

Sichuan pickles (Paocai) are a traditional Chinese fermented vegetable food that is rich in beneficial microorganisms. In this study, the inhibition of constipation by Lactobacillus plantarum CQPC02 (LP-CQPC02) isolated from Sichuan Paocai was studied by establishing a constipation model of mice using activated carbon. The constipation inhibition effect of LP-CQPC02 was determined by observing the defecation of mice, rate of active carbon propulsion, pathological section observation, serum index, and small intestinal mRNA expression. The results showed that LP-CQPC02 inhibited the decrease in body weight caused by constipation in mice. At the same time, LP-CQPC02 also increased the propulsion rate of activated carbon in the small intestine and shortened the time of discharge for the first black stool. LP-CQPC02 increased gastrin (Gas), motilin (MTL), endothelin (ET), and acetylcholinesterase (AChE) in constipated mice, and it also decreased the level of somatostatin (SS). qPCR results showed that LP-CQPC02 upregulated the expression of c-Kit, stem cell factor (SCF), and glial cell-derived neurotrophic factor (GDNF) and downregulated the expression of transient receptor potential cation channel subfamily V member 1 (TRPV1) and inducible nitric oxide synthase (iNOS) in mice with constipation, and a stronger effect was observed with a high concentration of LP-CQPC02. The experimental results showed that LP-CQPC02 has a stronger constipation inhibitory effect than the commonly used commercial Lactobacillus delbrueckii subsp. bulgaricus (LB), and the inhibitory effect of LP-CQPC02 on constipation increases with increasing concentration of LP-CQPC02. Therefore, LP-CQPC02 is a high-quality microbial resource with a good constipation inhibition effect and probiotic potential.
Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication Stress
Authors: Young Lucy A. , O'Connor Lenka Oplustil , de Renty Christelle , Veldman-Jones Margaret H. , Dorval Thierry , Wilson Zena , Jones David R. , Lawson Deborah , Odedra Rajesh , Maya-Mendoza Apolinar , Reimer Corinne , Bartek Jiri , Lau Alan , O'Connor Mark J.
Published: May 2019

DNA damage checkpoint kinases ATR and WEE1 are among key regulators of DNA damage response pathways protecting cells from replication stress, a hallmark of cancer that has potential to be exploited for therapeutic use. ATR and WEE1 inhibitors are in early clinical trials and success will require greater understanding of both their mechanism of action and biomarkers for patient selection. Here, we report selective antitumor activity of ATR and WEE1 inhibitors in a subset of non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL) cell lines, characterized by high MYC protein expression and CDKN2A/B deletion. Activity correlated with the induction of replication stress, indicated by increased origin firing and retardation of replication fork progression. However, ATR and WEE1 inhibitors caused different amounts of DNA damage and cell death in distinct phases of the cell cycle, underlying the increased potency observed with WEE1 inhibition. ATR inhibition caused DNA damage to manifest as 53BP1 nuclear bodies in daughter G1 cells leading to G1 arrest, whereas WEE1 inhibition caused DNA damage and arrest in S phase, leading to earlier onset apoptosis. In vivo xenograft DLBCL models confirmed differences in single-agent antitumor activity, but also showed potential for effective ATR inhibitor combinations. Importantly, insights into the different inhibitor mechanisms may guide differentiated clinical development strategies aimed at exploiting specific vulnerabilities of tumor cells while maximizing therapeutic index. Our data therefore highlight clinical development opportunities for both ATR and WEE1 inhibitors in non-GCB DLBCL subtypes that represent an area of unmet clinical need.

Significance:

ATR and WEE1 inhibitors demonstrate effective antitumor activity in preclinical models of DLBCL associated with replication stress, but new mechanistic insights and biomarkers of response support a differentiated clinical development strategy.
Pathogen Molecular Pattern Receptor Agonists: Treating Cancer by Mimicking Infection
Authors: Aleynick Mark , Svensson-Arvelund Judit , Flowers Christopher R. , Marabelle Aurélien , Brody Joshua D.
Published: May 2019

Immunotherapies such as checkpoint blockade have achieved durable benefits for patients with advanced stage cancer and have changed treatment paradigms. However, these therapies rely on a patient's own a priori primed tumor-specific T cells, limiting their efficacy to a subset of patients. Because checkpoint blockade is most effective in patients with inflamed or “hot” tumors, a priority in the field is learning how to “turn cold tumors hot.” Inflammation is generally initiated by innate immune cells, which receive signals through pattern recognition receptors (PRR)–a diverse family of receptors that sense conserved molecular patterns on pathogens, alarming the immune system of an invading microbe. Their immunostimulatory properties can reprogram the immune suppressive tumor microenvironment and activate antigen-presenting cells to present tumors antigens, driving de novo tumor-specific T-cell responses. These features, among others, make PRR-targeting therapies an attractive strategy in immuno-oncology. Here, we discuss mechanisms of PRR activation, highlighting ongoing clinical trials and recent preclinical advances focused on therapeutically targeting PRRs to treat cancer.
Recent Developments of Novel Pharmacologic Therapeutics for Prevention of Chemotherapy-Induced Peripheral Neuropathy
Authors: Hu Shuiying , Huang Kevin M. , Adams Elizabeth J. , Loprinzi Charles L. , Lustberg Maryam B.
Published: May 2019

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity, negatively affecting both quality of life and disease outcomes. To date, there is no proven preventative strategy for CIPN. Although multiple randomized trials have evaluated a variety of pharmacologic interventions for the treatment of CIPN, only duloxetine has shown clear efficacy in a phase III study. The National Cancer Institute's Symptom Management and Health-Related Quality of Life Steering Committee has identified CIPN as a priority for translational research in cancer care. Promising advances in preclinical research have identified several novel preventative and therapeutic targets, which have the potential to transform the care of patients with this debilitating neurotoxicity. Here, we provide an overarching view of emerging strategies and therapeutic targets that are currently being evaluated in CIPN.
NME1 Drives Expansion of Melanoma Cells with Enhanced Tumor Growth and Metastatic Properties
Authors: Wang Ying , Leonard M. Kathryn , Snyder Devin E. , Fisher Matthew L. , Eckert Richard L. , Kaetzel David M.
Published: May 2019

Melanoma is a lethal skin cancer prone to progression and metastasis, and resistant to therapy. Metastasis and therapy resistance of melanoma and other cancers are driven by tumor cell plasticity, largely via acquisition/loss of stem-like characteristics and transitions between epithelial and mesenchymal phenotypes (EMT/MET). NME1 is a metastasis suppressor gene that inhibits metastatic potential when its expression is enforced in melanoma and other cancers. Herein, we have unmasked a novel role for NME1 as a driver of melanoma growth distinct from its canonical function as a metastasis suppressor. NME1 promotes expansion of stem-like melanoma cells that exhibit elevated expression of stem cell markers (e.g., Sox2, Sox10, Oct-4, KLF4, and Ccnb-1), enhanced growth as melanoma spheres in culture, and enhanced tumor growth and lung colonizing activities in vivo. In contrast, NME1 expression did not affect the proliferation of melanoma cell lines in monolayer culture conditions. Silencing of NME1 expression resulted in a dramatic reduction in melanoma sphere size, and impaired tumor growth and metastatic activities of melanoma sphere cells when xenografted in immunocompromised mice. Individual cells within melanoma sphere cultures displayed a wide range of NME1 expression across multiple melanoma cell lines. Cell subpopulations with elevated NME1 expression were fast cycling and displayed enhanced expression of stem cell markers.

Implications:

Our findings suggest the current model of NME1 as a metastasis-suppressing factor requires refinement, bringing into consideration its heterogeneous expression within melanoma sphere cultures and its novel role in promoting the expansion and tumorigenicity of stem-like cells.
Responses to Dasatinib as a Second- and Third-Line Tyrosine Kinase Inhibitor in Chronic Phase Chronic Myeloid Leukaemia Patients
Authors: Tan Jiaqi , Xue Mengxing , Pan Jinlan , Cen Jiannong , Qi Xiaomei , Liu Ping , Zhao Xiaohong , Wu Pin , Wang Qinrong , Liu Dandan , Liu Yuejun , Chen Suning , Wang Zhi
Published: May 2019

We retrospectively evaluated the efficacy and safety of dasatinib among 48 Chinese patients with chronic phase chronic myeloid leukaemia. The proportions of patients achieving the optimal molecular responses at 3, 6, and 12 months, a major molecular response (MMR) rate and a complete cytogenetic response (CCyR) rate were 87.0, 87.0, 72.2, 45.8, and 72.7% for patients with dasatinib as second-line therapy, and 34.8, 34.8, 33.3, 20.8, and 46.2% as third-line therapy, respectively. A BCR-ABL1 transcript level on the International Scale (BCR-ABL1IS) of ≤10% at the initiation of ­dasatinib treatment was found to be associated with a higher probability of achieving MMR. Among patients with a ­BCR-ABL1IS higher than 10% at initiation of dasatinib treatment, dasatinib showed better performance as a second-line therapy than as a third-line therapy. The patients who achieved an optimal molecular response at 3 months had a superior cumulative incidence of MMR and CCyR compared with patients who failed to achieve such a response. Dasatinib induced considerable responses as a second-line treatment, especially in patients with a BCR-ABL1IS ≤10% at initiation of treatment, whereas the efficacy was limited in patients receiving third-line therapy with a BCR-ABL1IS >10% at the initiation of treatment.
Lung Ultrasound to Assess the Etiology of Persistent Pulmonary Hypertension of the Newborn (LUPPHYN Study): A Pilot Study
Authors: del Rey Hurtado de Mendoza Beatriz , Sánchez-de-Toledo Joan , Bobillo Perez Sara , Girona Mónica , Balaguer Gargallo Mónica , Rodríguez-Fanjul Javier
Published: May 2019

Introduction: Persistent pulmonary hypertension of the newborn (PPHN) is a neonatal syndrome associated with significant morbidity and mortality that is caused by the failure of postnatal drop in pulmonary vascular resistance. In extreme cases, patients may require extracorporeal membrane oxygenation therapy (ECMO). The aim of this study was to explore lung ultrasound (LUS) patterns in newborns with PPHN requiring ECMO. Patients and Methods: From January 2014 to January 2018, LUS was performed on patients with PPHN admitted for ECMO treatment. PPHN diagnosis was based on clinical and echocardiographic findings. LUS was performed before patients underwent ECMO cannulation. An underlying diagnosis was made taking into account the patient’s complete medical history, excluding LUS information. A blinded physician, unaware of the patient’s clinical condition, analyzed the stored ultrasound images. Results were then compared with chest x-ray (CXR) diagnoses. Results: Seventeen patients were recruited; 12 were male (70.6%). The median gestational age was 38.7 weeks, with 13 term newborns (76.5%). Twelve were cannulated for VA ECMO, with a median ECMO run of 111.2 h. Six patients (35%) survived. Patients with alveolar capillary dysplasia with misaligned pulmonary veins, fetal ductus arteriosus constriction, or sepsis had normal LUS patterns (A-lines with lung sliding). LUS showed a better sensitivity (88.9%) and specificity (85%) than CXR (55.6 and 77.5%, respectively) in identifying patients with nonparenchymal lung disease. Conclusions: LUS can provide essential information to help diagnose the underlying cause of PPHN in an earlier and more effective way than CXR. LUS is suitable for routine utilization in the intensive care unit.
Infection of Rat Osteoblasts with Junin Virus Promotes the Expression of Bone Morphogenetic Protein 6, an Osteogenic Differentiation Inducer
Authors: Ayala-Peña Victoria B. , Armiento María N. , Fernández Bell Fano Pablo M. , Santillán Graciela E. , Scolaro Luis A.
Published: May 2019

Background: The arenavirus Junin virus (JUNV), causative agent of the argentine hemorrhagic fever, is able to modulate several signaling pathways involved in cell survival and multiplication. Objectives: We aimed to characterize the infection of rat osteoblasts (OBCs) with JUNV and its consequence on the modulation of osteogenic genes expression, thus studying the ability of this virus to induce cell differentiation. In addition, we evaluated the effect of purinergic agonists on viral replication. Method: Quantification of infectivity by plaque forming unit (PFU) assay, synthesis of viral proteins by western blot and immunofluorescence, and expression of osteogenic differentiation markers (ODM) by quantitative real-time polymerase chain reaction were employed. Results: Infection of OBCs with JUNV (MOI 0.01 PFU/cell) showed a peak of infectivity, reaching 1.5 × 105 PFU/mL at the second day post-infection (p.i.). A marked restriction in multiplication was detected at day 7 p.i. that did not impair the establishment of a persistent stage of infection in OBCs. Analysis of mRNAs corresponding to ODM such as alkaline phosphatase, bone sialo-protein, and bone morphogenetic proteins (BMPs) 4 and 6 revealed that only the levels of BMP-6 were significantly higher in infected cells. Treatment with the purinergic agonists ATPγS, UTP, ADP, or UDP diminished viral titer and reduced the expression of the viral nucleoprotein. Also, treatment with 10 μM ATPγS reduced the stimulation of BMP-6 expression induced by the infection. Conclusions: These data demonstrate that JUNV is capable of infecting OBCs and point out BMP-6 as a key factor during this process.
Modeling the Effects of Yoga on the Progression of Alzheimer’s Disease in a Dish
Authors: Hassan Adithy , Robinson Meghan , Willerth Stephanie M.
Published: May 2019

Alzheimer’s disease (AD) accounts for 80% of all dementia cases, making it the most common form of dementia. Aging serves as the main risk factor for AD, but early onset AD can also occur in individuals younger than 65 years. AD results from progressive neurodegeneration leading to dysfunctional synaptic transmission in the brain. The cascade hypothesis of AD states that amyloid precursor protein (APP) metabolism becomes impaired either by mutation or an interleukin-mediated stress response to injury, resulting in the splicing of harmful oligomeric forms of amyloid beta (Aβ). These oligomers disrupt extracellular receptor binding, intracellular function, and cellular membrane integrity. Yoga and meditative practices slow the progression of the cognitive decline associated with AD. However, the biological mechanisms underlying this therapeutic effect remain elusive. Here, we investigated the ability of neurotransmitters released during yoga and meditative practices to rescue neurons from synaptic dysfunction in an in vitro Alzheimer’s model created by culturing basal forebrain cholinergic neurons with physiologically relevant levels of the I-42 isoform of oligomeric Aβ (OΑβI-42). We found that the neurotransmitters dopamine and histamine produce a cooperative action with serotonin to reverse the loss of choline acetyltransferase (CHaT) by OΑβI-42. The loss of ChaT, the enzyme responsible for processing the cholinergic neurotransmitter acetylcholine, contributes to the synaptic dysfunction experienced during AD. These neurotransmitters inhibit nitric oxide synthesis caused by OΑβI-42, preventing oxidative and nitrosative stress. Serotonin activates an alternate cleavage of APP to produce a fragment with known neurotrophic effects, giving it the unique ability to inhibit the OΑβI-42 production cycle. We hypothesize here that these concerted actions lead to the protection of cholinergic synaptic transmission in AD.
Importance of Genetic Diagnostics in Adult-Onset Focal Segmental Glomerulosclerosis
Authors: Snoek Rozemarijn , Nguyen Tri Q. , van der Zwaag Bert , van Zuilen Arjan D. , Kruis Hannah M.E. , van Gils-Verrij Liesbeth A. , Goldschmeding Roel , Knoers Nine V.A.M. , Rookmaaker Maarten B. , van Eerde Albertien M.
Published: May 2019

Focal segmental glomerulosclerosis (FSGS) is a histological pattern of podocyte and glomerulus injury. FSGS can be primary and secondary to other diseases or due to a genetic cause. Strikingly, genetic causes for adult-onset FSGS are often overlooked, likely because identifying patients with genetic forms of FSGS based on clinical presentation and histopathology is difficult. Yet diagnosing genetic FSGS does not only have implications for prognostication and therapy but also for family and family planning. In this case series, we present 3 adult patients who presented with advanced renal disease with the histological picture of FSGS and proved to have a genetic cause of the disease, namely, variants in INF2, COL4A4 and HNF1B, respectively. We show the possibilities of identifying genetic FSGS based on clinical clues of a positive family history, early age at onset of disease, and/or severe therapy-resistant disease. We discuss ways to select the method of genetic testing for individual patients. Finally, we examine how the judicious use of genetic investigations can obviate potential harmful diagnostic procedures and direct clinical decisions in patients and their relatives.
Rationale of Hemoadsorption during Extracorporeal Membrane Oxygenation Support
Authors: Napp L. Christian , Ziegeler Stephan , Kindgen-Milles Detlef
Published: May 2019

Extracorporeal membrane oxygenation (ECMO) and extracorporeal life support are increasingly used for treating various forms of shock, lung failure, protected interventions and life support including resuscitation. Most patients on ECMO are affected by a systemic inflammatory response caused by the underlying disease as well as the ECMO support itself, which contributes to vasoplegia, multi-organ failure, deterioration and death. Unfortunately, effective strategies for control of inflammation and related organ failure and shock on ECMO are lacking. Recently, a new polystyrene-based device for hemoadsorption, which aims to reduce excessive levels of inflammatory molecules such as interleukins, cytokines as well as damage- and pathogen-associated molecular patterns, has become available. Here we summarize the rationale, available data and technical aspects of polystyrene-based hemoadsorption during ECMO support, and give recommendations based on existing experience.
One-Year Outcomes of Intravitreal Conbercept for Treatment-Resistant Neovascular Age-Related Macular Degeneration
Authors: Li Xun , Zhang Yun , Zhang Zirong , Xu Yunyi , Zhang Meixia
Published: May 2019

Purpose: To evaluate the efficacy of intravitreal conbercept injections in patients with treatment-resistant neovascular age-related macular degeneration (nvAMD). Methods: Retrospective review of patients with resistance (persistent exudation) to ranibizumab (0.5 mg) that were switched to treatment with 3 monthly intravitreal injections of conbercept (0.5 mg), followed by dosing on an as-needed basis. The demographic data, visual acuities, central retinal thickness (CRT), and the maximum pigment epithelial detachment (PED) height were reviewed. Results: Outcomes observed in 34 eyes from 26 patients with a mean of 7.68 (range 6–14) previous ranibizumab injections were compiled. Twelve months after switching to conbercept, there were significant reductions of CRT (402.59 ± 163.85 vs. 473.18 ± 164.84 μm, p = 0.002) and maximum PED height (218.59 ± 106.89 vs. 295.32 ± 179.80 μm, p = 0.006) compared with the baseline. No statistical change in visual acuity logarithm of the minimal angle of resolution occurred after 12 months (0.68 ± 0.48 vs. 0.78 ± 0.63 letters, p = 0.17) despite 27 of 34 eyes (79.41%) remaining stable or having improvement visual acuity. Conclusions: Intravitreal injections of conbercept appear to be beneficial in patients with nvAMD who exhibit persistent fluid despite previous treatment with ranibizumab.
Long-Term Effectiveness of Cognitive Behavioral Therapy in Routine Outpatient Care: A 5- to 20-Year Follow-Up Study
Authors: von Brachel Ruth , Hirschfeld Gerrit , Berner Arleta , Willutzki Ulrike , Teismann Tobias , Cwik Jan Christopher , Velten Julia , Schulte Dietmar , Margraf Jürgen
Published: May 2019

Objective: Long-term follow-ups several years after receiving cognitive behavioral therapy (CBT) are scarce and most of the existing literature describes follow-up data of randomized-controlled trials. Thus, very little is known about the long-term effects of CBT in routine care. Methods: We investigated psychological functioning in a sample of 263 former outpatients who had received CBT for a variety of mental disorders such as depression, anxiety-, eating- or somatoform disorders 8.06 (SD 5.08) years after treatment termination. All participants completed a diagnostic interview as well as the Brief-Symptom Inventory (BSI) and the Beck Depression Inventory (BDI). Effect sizes and response rates according to Jacobson and Truax [J Consult Clin Psychol 1991;59:12–9] were calculated from pre- to posttreatment and from pretreatment to follow-up assessment. Results: Pre- to posttreatment effect sizes ranged between 0.75 (BDI) and 0.63 (BSI) and pretreatment to follow-up effect sizes were 0.92 (BDI) and 0.75 (BSI). Of all patients, 29% (BDI) and 17% (BSI) experienced clinically significant change at posttreatment and 42% (BDI) and 24% (BSI) at follow-up. Conclusion: The results point to the long-term effectiveness of CBT under routine conditions for a wide array of problems, especially when compared to the long-term effects of medical treatment. It is noteworthy that the results at follow-up were even better than at posttreatment, indicating further improvement. However, about a quarter of the patients did not respond sufficiently to therapy, neither concerning short-term nor long-term effects.
Acute Kidney Injury in Kidney Transplants: New Insights
Authors: Mannon Roslyn B.
Published: May 2019

Delayed allograft function (DGF) is defined as dialysis treatment in the kidney transplant recipient in the first week following transplantation. With the demand for kidney transplants growing and the supply limited, as well as implementation of a national allocation scheme for deceased donor kidneys, rates of DGF remain high, on average, 30% for recipients of deceased donor kidneys. DGF is associated with inferior allograft outcomes, and there are no FDA-approved therapies to mitigate this disorder. There is renewed interest in this therapeutic arena, and there are several recent clinical trials that have considered interventions within the recipient to reduce injury. A critical issue is that of trial design and end points as well as translating from acute kidney injury (AKI) trials in cardiac bypass to the more complicated kidney transplant scenario. DGF is a significant clinical outcome after kidney transplantation without known approved therapy beyond clinical support. This mini-review highlights our presentation at the 24th International Conference on Advances in Critical Care Nephrology and UAB/UCSD O’Brien Center AKI Pre-Meeting.
Association between Growth Differentiation Factor 15 and Non-Dipping Circadian Pattern in Patients with Newly Diagnosed Essential Hypertension
Authors: Sökmen Erdoğan , Uçar Cahit , Sivri Serkan , Çelik Mustafa , Boduroğlu Yalçın , Erer Murat , Yıldırım Alp , İlanbey Bilal
Published: May 2019

Objective: Non-dipper hypertension (HT) confers greater risk compared with dipper HT. Growth differentiation factor 15 (GDF-15) recently emerged as a novel and independent marker of cardiovascular disease, both in diagnostic and prognostic scopes. Our aim was to evaluate the relationship of circadian blood pressure (BP) pattern with serum GDF-15 level in newly diagnosed HT patients without left ventricular hypertrophy. Subjects and Methods: Newly diagnosed non-dipper (n = 66) and dipper (n = 60) HT patients were selected according to 24-h ambulatory BP monitoring (ABPM). The controls comprised healthy normotensive subjects (n = 31). Data was collected through physical examination, laboratory analysis, ABPM, and echocardiography. GDF-15 was measured using ELISA. Results: Greater GDF-15 level was found in the non-dippers compared with the dippers and the controls (557.53 ± 91.7, 513.79 ± 62.86, and 494.44 ± 79.30 ng/L, respectively, p < 0.001). In bivariate linear correlation analysis, GDF-15 correlated positively with glomerular filtration rate (r = 0.180, p =0.030), total cholesterol (r = 0.170, p = 0.038), septal E/E′ ratio (r = 0.344, p = 0.001), lateral E/E′ ratio (r = 0.366, p < 0.001), nighttime systolic BP (r = 0.166, p = 0.046), and nighttime diastolic BP (r = 0.188, p = 0.024); however, it correlated negatively with septal and lateral E′ velocities (r = 0.268, p = 0.005 and r = 0.236, p = 0.013, respectively). Furthermore, GDF-15 level and nighttime diastolic BP remained independently associated with non-dipper HT. In ROC analysis, optimal cutoff value for GDF-15 was 524.6 ng/L with 56.7% sensitivity and 72.4% specificity (AUC: 0.676, 95% CI: 0.580–0.772, p < 0.05). Conclusion: Our results showed GDF-15 upregulation in the non-dipper HT group. GDF-15 and nighttime diastolic BP were independently associated with the non-dipping pattern. This study may suggest possible utilization of GDF-15 in the prediction of non-dipper HT.
Cardiovascular Outcomes of Romosozumab and Protective Role of Alendronate
Authors: Asadipooya Kamyar , Weinstock Ada
Published: May 2019

Osteoporosis and cardiovascular diseases are major public health issues. Bone and cardiovascular remodeling share multiple biological markers and pathways. Medical intervention, such as using romosozumab, an antisclerostin antibody, improves the clinical outcome of osteoporosis. However, blocking sclerostin leads to Wnt (wingless/integrated) activation and participation in the cardiovascular remodeling process, which could potentially lead to adverse events. Based on the opposing roles of bisphosphonates and the Wnt pathway on endothelial dysfunction, lipid accumulation and calcification of the vessel walls, the combination of romosozumab and bisphosphonates could be a new therapeutic approach to reducing the risks of adverse cardiovascular events in romosozumab receivers.

Visual Overview—

An online visual overview is available for this article.
Endothelial PAI-1 (Plasminogen Activator Inhibitor-1) Blocks the Intrinsic Pathway of Coagulation, Inducing the Clearance and Degradation of FXIa (Activated Factor XI)
Authors: Puy Cristina , Ngo Anh T.P. , Pang Jiaqing , Keshari Ravi S. , Hagen Matthew W. , Hinds Monica T. , Gailani David , Gruber András , Lupu Florea , McCarty Owen J.T.
Published: May 2019

Objective—

Activation of coagulation FXI (factor XI) by FXIIa (activated factor XII) is a prothrombotic process. The endothelium is known to play an antithrombotic role by limiting thrombin generation and platelet activation. It is unknown whether the antithrombotic role of the endothelium includes sequestration of FXIa (activated factor XI) activity. This study aims to determine the role of endothelial cells (ECs) in the regulation of the intrinsic pathway of coagulation.

Approach and Results—

Using a chromogenic assay, we observed that human umbilical veins ECs selectively blocked FXIa yet supported kallikrein and FXIIa activity. Western blotting and mass spectrometry analyses revealed that FXIa formed a complex with endothelial PAI-1 (plasminogen activator inhibitor-1). Blocking endothelial PAI-1 increased the cleavage of a chromogenic substrate by FXIa and the capacity of FXIa to promote fibrin formation in plasma. Western blot and immunofluorescence analyses showed that FXIa–PAI-1 complexes were either released into the media or trafficked to the early and late endosomes and lysosomes of ECs. When baboons were challenged with
Staphylococcus aureus
to induce a prothrombotic phenotype, an increase in circulating FXIa–PAI-1 complex levels was detected by ELISA within 2 to 8 hours postchallenge.

Conclusions—

PAI-1 forms a complex with FXIa on ECs, blocking its activity and inducing the clearance and degradation of FXIa. Circulating FXIa–PAI-1 complexes were detected in a baboon model of
S. aureus
sepsis. Although ECs support kallikrein and FXIIa activity, inhibition of FXIa by ECs may promote the clearance of intravascular FXIa.

Visual Overview—

An online visual overview is available for this article.
Stimulating Cardiogenesis as a Treatment for Heart Failure
Authors: Heallen Todd R. , Kadow Zachary A. , Kim Jong H. , Wang Jun , Martin James F.
Published: May 2019

After myocardial injury, cardiomyocyte loss cannot be corrected by using currently available clinical treatments. In recent years, considerable effort has been made to develop cell-based cardiac repair therapies aimed at correcting for this loss. An exciting crop of recent studies reveals that inducing endogenous repair and proliferation of cardiomyocytes may be a viable option for regenerating injured myocardium. Here, we review current heart failure treatments, the state of cardiomyocyte renewal in mammals, and the molecular signals that stimulate cardiomyocyte proliferation. These signals include growth factors, intrinsic signaling pathways, microRNAs, and cell cycle regulators. Animal model cardiac regeneration studies reveal that modulation of exogenous and cell-intrinsic signaling pathways can induce reentry of adult cardiomyocytes into the cell cycle. Using direct myocardial injection, epicardial patch delivery, or systemic administration of growth molecules, these studies show that inducing endogenous cardiomyocytes to self-renew is an exciting and promising therapeutic strategy to treat cardiac injury in humans.
Novel Therapies for Prevention and Early Treatment of Cardiomyopathies
Authors: Repetti Giuliana G. , Toepfer Christopher N. , Seidman Jonathan G. , Seidman Christine E.
Published: May 2019

Heritable cardiomyopathies are a class of heart diseases caused by variations in a number of genetic loci. Genetic variants on one allele lead to either a degraded protein, which causes a haploinsufficiency of that protein, or a nonfunctioning protein that subverts the molecular system within which the protein works. Over years, both of these mechanisms eventually lead to diseased heart tissue and symptoms of a failing heart. Most cardiomyopathy treatments repurpose heart failure drugs to manage these symptoms and avoid adverse outcomes. There are few therapies that correct the underlying pathogenic genetic or molecular mechanism. This review will reflect on this unmet clinical need in genetic cardiomyopathies and consider a variety of therapies that address the mechanism of disease rather than patient symptoms. These therapies are genetic, targeting a defective gene or transcript, or ameliorating a genetic insufficiency. However, there are also a number of small molecules under exploration that modulate downstream faulty protein products affected in cardiomyopathies.
Heart Failure With Preserved Ejection Fraction In Perspective
Authors: Pfeffer Marc A. , Shah Amil M. , Borlaug Barry A.
Published: May 2019

Approximately half of the patients with signs and symptoms of heart failure have a left ventricular ejection fraction that is not markedly abnormal. Despite the historically initial surprise, heightened risks for heart failure specific major adverse events occur across the broad range of ejection fraction, including normal. The recognition of the magnitude of the problem of heart failure with preserved ejection fraction in the past 20 years has spurred an explosion of clinical investigation and growing intensity of informative outcome trials. This article addresses the historic development of this component of the heart failure syndrome, including the epidemiology, pathophysiology, and existing and planned therapeutic studies. Looking forward, more specific phenotyping and even genotyping of subpopulations should lead to improvements in outcomes from future trials.