bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Heat Stress on Seed Protein Composition and Ultrastructure of Protein Storage Vacuoles in the Cotyledonary Parenchyma Cells of Soybean Genotypes That Are Either Tolerant or Sensitive to Elevated Temperatures
Authors: Krishnan Hari B. , Kim Won-Seok , Oehrle Nathan W. , Smith James R. , Gillman Jason D.
Published: July 2020

High growth temperatures negatively affect soybean (Glycine max (L.) Merr) yields and seed quality. Soybean plants, heat stressed during seed development, produce seed that exhibit wrinkling, discoloration, poor seed germination, and have an increased potential for incidence of pathogen infection and an overall decrease in economic value. Soybean breeders have identified a heat stress tolerant exotic landrace genotype, which has been used in traditional hybridization to generate experimental genotypes, with improved seed yield and heat tolerance. Here, we have investigated the seed protein composition and ultrastructure of cotyledonary parenchyma cells of soybean genotypes that are either susceptible or tolerant to high growth temperatures. Biochemical analyses of seed proteins isolated from heat-tolerant and heat-sensitive genotypes produced under 28/22 °C (control), 36/24 °C (moderate), and 42/26 °C (extreme) day/night temperatures revealed that the accumulation in soybean seeds of lipoxygenase, the β-subunit of β-conglycinin, sucrose binding protein and Bowman-Birk protease inhibitor were negatively impacted by extreme heat stress in both genotypes, but these effects were less pronounced in the heat-tolerant genotype. Western blot analysis showed elevated accumulation of heat shock proteins (HSP70 and HSP17.6) in both lines in response to elevated temperatures during seed fill. Transmission electron microscopy showed that heat stress caused dramatic structural changes in the storage parenchyma cells. Extreme heat stress disrupted the structure and the membrane integrity of protein storage vacuoles, organelles that accumulate seed storage proteins. The detachment of the plasma membrane from the cell wall (plasmolysis) was commonly observed in the cells of the sensitive line. In contrast, these structural changes were less pronounced in the tolerant genotype, even under extreme heat stress, cells, for the most part, retained their structural integrity. The results of our study demonstrate the contrasting effects of heat stress on the seed protein composition and ultrastructural alterations that contribute to the tolerant genotype’s ability to tolerate high temperatures during seed development.
Emerging Roles of Matricellular Proteins in Systemic Sclerosis
Authors: Feng Daniel , Gerarduzzi Casimiro
Published: July 2020

Systemic sclerosis is a rare chronic heterogenous disease that involves inflammation and vasculopathy, and converges in end-stage development of multisystem tissue fibrosis. The loss of tight spatial distribution and temporal expression of proteins in the extracellular matrix (ECM) leads to progressive organ stiffening, which is a hallmark of fibrotic disease. A group of nonstructural matrix proteins, known as matricellular proteins (MCPs) are implicated in dysregulated processes that drive fibrosis such as ECM remodeling and various cellular behaviors. Accordingly, MCPs have been described in the context of fibrosis in sclerosis (SSc) as predictive disease biomarkers and regulators of ECM synthesis, with promising therapeutic potential. In this present review, an informative summary of major MCPs is presented highlighting their clear correlations to SSc- fibrosis.
Regulation of Hematopoietic Stem Cell Fate and Malignancy
Authors: Cho Hee Jun , Lee Jungwoon , Yoon Suk Ran , Lee Hee Gu , Jung Haiyoung
Published: July 2020

The regulation of hematopoietic stem cell (HSC) fate decision, whether they keep quiescence, self-renew, or differentiate into blood lineage cells, is critical for maintaining the immune system throughout one’s lifetime. As HSCs are exposed to age-related stress, they gradually lose their self-renewal and regenerative capacity. Recently, many reports have implicated signaling pathways in the regulation of HSC fate determination and malignancies under aging stress or pathophysiological conditions. In this review, we focus on the current understanding of signaling pathways that regulate HSC fate including quiescence, self-renewal, and differentiation during aging, and additionally introduce pharmacological approaches to rescue defects of HSC fate determination or hematopoietic malignancies by kinase signaling pathways.
Immunopathology of SARS-CoV-2 Infection: Immune Cells and Mediators, Prognostic Factors, and Immune-Therapeutic Implications
Authors: Allegra Alessandro , Di Gioacchino Mario , Tonacci Alessandro , Musolino Caterina , Gangemi Sebastiano
Published: July 2020

The present is a comprehensive review of the immunopathology of Covid-19. The immune reaction to SARS-CoV-2 infection is characterized by differentiation and proliferation of a variety of immune cells with immune mediator production and release, and activation of other pathogen resistance mechanisms. We fully address the humoral and cellular immune changes induced by the virus, with particular emphasis on the role of the “cytokine storm” in the evolution of the disease. Moreover, we also propose some immune alterations (i.e., inflammatory parameters, cytokines, leukocytes and lymphocyte subpopulations) as prognostic markers of the disease. Furthermore, we discuss how immune modifying drugs, such as tocilizumab, chloroquine, glucocorticoids and immunoglobulins, and blood purification therapy, can constitute a fundamental moment in the therapy of the infection. Finally, we made a critical analysis of a number of substances, not yet utilized, but potentially useful in SARS-CoV-2 patients, such as IFN lambda, TNF blockers, ulinastatin, siponimod, tacrolimus, mesenchymal stem cells, inhibitors of mononuclear macrophage recruitment, IL-1 family antagonists, JAK-2 or STAT-3 inhibitors.
The NLRP1 Inflammasome in Human Skin and Beyond
Authors: Fenini Gabriele , Karakaya Tugay , Hennig Paulina , Di Filippo Michela , Beer Hans-Dietmar
Published: July 2020

Inflammasomes represent a group of protein complexes that contribute to host defense against pathogens and repair processes upon the induction of inflammation. However, aberrant and chronic inflammasome activation underlies the pathology of numerous common inflammatory diseases. Inflammasome assembly causes activation of the protease caspase-1 which in turn activates proinflammatory cytokines and induces a lytic type of cell death termed pyroptosis. Although NLRP1 (NACHT, leucine-rich repeat and pyrin domain containing 1) was the first inflammasome sensor, described almost 20 years ago, the molecular mechanisms underlying its activation and the resulting downstream events are incompletely understood. This is partially a consequence of the poor conservation of the NLRP1 pathway between human and mice. Moreover, recent evidence demonstrates a complex and multi-stage mechanism of NLRP1 inflammasome activation. In contrast to other inflammasome sensors, NLRP1 possesses protease activity required for proteolytic self-cleavage and activation mediated by the function-to-find domain (FIIND). CARD8 is a second FIIND protein and is expressed in humans but not in mice. In immune cells and AML (acute myeloid leukemia) cells, the anti-cancer drug talabostat induces CARD8 activation and causes caspase-1-dependent pyroptosis. In contrast, in human keratinocytes talabostat induces NLRP1 activation and massive proinflammatory cytokine activation. NLRP1 is regarded as the principal inflammasome sensor in human keratinocytes and UVB radiation induces its activation, which is believed to underlie the induction of sunburn. Moreover, gain-of-function mutations of NLRP1 cause inflammatory skin syndromes and a predisposition for the development of skin cancer. SNPs (single nucleotide polymorphisms) of NLRP1 are associated with several (auto)inflammatory diseases with a major skin phenotype, such as psoriasis or vitiligo. Here, we summarize knowledge about NLRP1 with emphasis on its role in human keratinocytes and skin. Due to its accessibility, pharmacological targeting of NLRP1 activation in epidermal keratinocytes represents a promising strategy for the treatment of the numerous patients suffering from NLRP1-dependent inflammatory skin conditions and cancer.
Gradient-Free and Gradient-Based Optimization of a Radial Turbine
Authors: Lachenmaier Nicolas , Baumgärtner Daniel , Schiffer Heinz-Peter , Kech Johannes
Published: July 2020

A turbocharger’s radial turbine has a strong impact on the fuel consumption and transient response of internal combustion engines. This paper summarizes the efforts to design a new radial turbine aiming at high efficiency and low inertia by applying two different optimization techniques to a parametrized CAD model. The first workflow wraps 3D fluid and solid simulations within a meta-model assisted genetic algorithm to find an efficient turbine subjected to several constraints. In the next step, the chosen turbine is re-parametrized and fed into the second workflow which makes use of a gradient projection algorithm to further fine-tune the design. This requires the computation of gradients with respect to the CAD parametrization, which is done by calculating and combining surface sensitivities and design velocities. Both methods are applied successfully, i.e., the first delivers a well-performing turbine, which, by the second method, is further improved by 0.34% in efficiency.
Combined Optic-Acoustic Monitoring of Combustion in a Gas Turbine
Authors: Giuliani Fabrice , Andracher Lukas , Moosbrugger Vanessa , Paulitsch Nina , Hofer Andrea
Published: July 2020

The need for better combustion monitoring in gas turbines has become more acute with the latest technical requirements, standards, and policies in terms of safety, environment, efficiency, operation flexibility, and operation costs. Combustion Bay One e.U. and FH JOANNEUM GmbH initiated in 2015 an experimental research program about the feasibility and first assessments of placing optical systems near the combustor. The project’s acronym “emootion” stands for “Engine health MOnitOring and refined combusTION control based on optical diagnostic techniques embedded in the combustor”. The motivation of the project is twofold. On one side, one wants to exploit the radiative feature of the flame and to transform it into a piece of reliable information about the combustion status. On the other side, this information can be useful in terms of data interpretation or data reconciliation with other information coming from other sensors such as temperature probes, fast pressure probes, or accelerometers. The focus is put on several aspects of combustor operations: on detection of the flame, on monitoring of the ignition process, on a quality assessment of combustion based on its spectral contents (including soot formation), and on the detection of possible combustion instabilities. Promising results were obtained using photodiodes that offer an adequate trade-off between narrow-band sensitivity and signal time response. It is shown that it is convenient to combine a fast-pressure sensor with an optical sensor in a compact form; this combination has led to the so-called Rayleigh Criterion Probe (RCP). The split in red, green, and blue (RGB) light components and their further analysis allows for mapping the different types of operation. Regarding the probe packaging aspect, it is discussed that the level of light collection needed to keep an acceptable signal-to-noise ratio has been so far a restraint for the use of optical fibres. Solutions are proposed to bring the optical sensor as close as possible to the optical interface and to make it operational and reliable in prevailing heat. This contribution closes with a description of the pressure tests in a new combustion facility built for this purpose. A compact and portable combustion monitoring system including at least 3 RCPs can become an instrumentation standard within the next decade.
An Empirical Study on the Evolution of Design Smells
Authors: Aversano Lerina , Carpenito Umberto , Iammarino Martina
Published: July 2020

The evolution of software systems often leads to its architectural degradation due to the presence of design problems. In the literature, design smells have been defined as indicators of such problems. In particular, the presence of design smells could indicate the use of constructs that are harmful to system maintenance activities. In this work, an investigation on the nature and presence of design smells has been performed. An empirical study has been conducted considering the complete history of eight software systems, commit by commit. The detection of instances of multiple design smell types has been performed at each commit, and the analysis of the relationships between the detected smells and the maintenance activities, specifically due to refactoring activities, has been investigated. The proposed study evidenced that classes affected by design smells are more subject to change, especially when multiple smells are detected in the same classes. Moreover, it emerged that in some cases these smells are removed, and this occurs involving more smells at the same time. Finally, results indicate that smells removals are not correlated to the refactoring activities.
CT-Dose Measurement of the Spinal Cord Region Using XR-QA2 Radiochromic Films and TLD 100H Dosimeters
Authors: Pace Martina , Stella Giuseppe , Tonghi Letizia Barone , Mazzaglia Stefania , Gueli Anna Maria
Published: July 2020

The European Directive 2013/59/Euratom focuses on the radiation protection and patient dosimetry. In particular, the dose absorbed by serial organs such as the spinal cord due to diagnostic exams plays a crucial role in the appraisal of medical exposure. In this work, a comparison between dose measurements performed with GafchromicTM XR-QA2 and TLD 100H is presented. The dosimeters—after a calibration procedure through an X-ray tube—were placed within the thorax region of an anthropomorphic phantom corresponding to the spinal cord area exposed to a thoracic CT procedure. The mean-dose value was measured with GafchromicTM first, and it was then compared to the dose value obtained with TLDs, resulting in a good agreement between the two dosimetric methodologies. Additionally, the results showed that—due to the usage of the automatic exposure control (EC) system—the discrepancy between the two methods is proportional to the current output of the CT system.
Techno-Economic Comparative Analysis of Renewable Energy Systems: Case Study in Zimbabwe
Authors: Al-Ghussain Loiy , Samu Remember , Taylan Onur , Fahrioglu Murat
Published: July 2020

Fluctuations in fossil fuel prices significantly affect the economies of countries, especially oil-importing countries, hence these countries are thoroughly investigating the increase in the utilization of renewable energy resources as it is abundant and locally available in all the countries despite challenges. Renewable energy systems (RES) such as solar and wind systems offer suitable alternatives for fossil fuels and could ensure the energy security of countries in a feasible way. Zimbabwe is one of the African countries that import a significant portion of its energy needs which endanger the energy security of the country. Several studies in the literature discussed the feasibility of different standalone and hybrid RES either with or without energy storage systems to either maximize the technical feasibility or the economic feasibility; however, none of the studies considered maximizing both feasibilities at the same time. Therefore, we present a techno-economic comparison of standalone wind and solar photovoltaic (PV) in addition to hybrid PV/wind systems based on maximizing the RES fraction with levelized cost of electricity (LCOE) being less than or equal to the local grid tariff where Gwanda, Zimbabwe, is the case study. The methodology suggested in this study could increase the utilization of renewable energy resources feasibly and at the same time increase the energy security of the country by decreasing dependency on imported energy. The results indicate that the PV/wind hybrid system does not only have the best economic benefits represented by the net present value (NPV) and the payback period (PBP), but also the best technical performance; where the maximum feasible size of the hybrid system-2 MW wind and 1 MW PV-has RES fraction of 65.07%, LCOE of 0.1 USD/kWh, PBP of 3.94 years, internal rate of return of 14.04% and NPV of 3.06 × 106 USD. Having similar systems for different cities in Zimbabwe will decrease the energy bill significantly and contribute toward the energy security of the country.
Multi-Nozzle Pneumatic Extrusion-Based Additive Manufacturing System for Printing Sensing Pads
Authors: Chen Kai-Wei , Tsai Ming-Jong , Lee Heng-Sheng
Published: July 2020

This paper developed a multi-nozzle pneumatic extrusion-based additive manufacturing (AM) system and applied it to print multi-material polymers and conductive sensing pads. We used pneumatic extrusion nozzles to extrude the liquid material and then cured it by an ultraviolet (UV) light source. The multi-nozzle pneumatic extrusion-based additive manufacturing system mainly integrates both PC-based HMI and CNC controller to operate the three-axis motion and the extrusion flow control. Moreover, the peripheral I/Os include both positive and negative pressure and also the curing light source. A D/A controller is also applied to control the value of the pneumatic pressure. The coding part utilizes the numerical control software along with the PLC planning to operate the AM machine automatically. Our experiment is conducted by using Simplify3D, a commercial 3D printing slicing software. Different requirements were set for extrusion nozzles with different materials, and then we executed the path controlling G-code data by Python Language. Our system successfully prints multi-material polymer structure pads which include the hard and soft material pad fabricated in double-layers, triple-layers and also the grid structure. Finally, we find that the printed pad has conductivity.
Accuracy of Pulse Wave Velocity Predicting Cardiovascular and All-Cause Mortality. A Systematic Review and Meta-Analysis
Authors: Sequí-Domínguez Irene , Cavero-Redondo Iván , Álvarez-Bueno Celia , Pozuelo-Carrascosa Diana P , Nuñez de Arenas-Arroyo Sergio , Martínez-Vizcaíno Vicente
Published: July 2020

Increased arterial stiffness has been associated with an increased risk of developing cardiovascular diseases and all-cause mortality. Pulse wave velocity (PWV) is an innovative and affordable measurement of arterial stiffness which may be an accessible tool to estimate mortality risk; however, no meta-analysis has estimated its predictive performance for cardiovascular and all-cause mortality. Moreover, reference values for PWV have only been established by consensus for healthy populations. The aim of this review was to estimate PWV and especially carotid femoral PWV performance predicting cardiovascular and all-cause mortality as well as comparing the resulting cfPWV thresholds with already established values in order to increase its validity. Original studies measuring PWV thresholds and its association with cardiovascular and all-cause mortality were systematically searched. The DerSimonian and Laird method was used to compute pooled estimates of diagnostic odds ratio (dOR), and overall test performances were summarized in hierarchical summary receiver operating characteristic curves (HSROC). Six studies were included in the meta-analysis. The pooled dOR values for the predictive performance of cfPWV were 11.23 (95 % CI, 7.29–1.29) for cardiovascular mortality and 6.52 (95% CI, 4.03–10.55) for all-cause mortality. The area under the HSROC curve for cfPWV was 0.75 (95% CI, 0.69–0.81) for cardiovascular mortality and 0.78 (95% CI, 0.74–0.83) for all-cause mortality, where the closest cut-off point to the summary point was 10.7 and 11.5, respectively. This systematic review and meta-analysis demonstrates that cfPWV is a useful and accurate cardiovascular mortality predictor and that its previously estimated reference values for estimating risk may be used in high-risk populations.
The Inflammatory Response to Alcohol Consumption and Its Role in the Pathology of Alcohol Hangover
Authors: van de Loo Aurora J.A.E. , Mackus Marlou , Kwon Oran , Krishnakumar Illathu Madhavamenon , Garssen Johan , Kraneveld Aletta D. , Scholey Andrew , Verster Joris C.
Published: July 2020

An increasing number of studies are focusing on the inflammatory response to alcohol as a potentially important determinant of hangover severity. In this article, data from two studies were re-evaluated to investigate the relationship between hangover severity and relevant biomarkers of alcohol metabolism, oxidative stress and the inflammatory response to alcohol. Hangover severity was significantly and positively correlated with blood concentrations of biomarkers of the inflammatory response to alcohol, in particular, Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP). At 4 h after alcohol consumption, blood ethanol concentration (but not acetaldehyde) was significantly and positively associated with elevated levels of IL-6, suggesting a direct inflammatory effect of ethanol. In addition, biomarkers of oxidative stress, i.e., malondialdehyde and 8-isoprostrane, were significantly correlated with hangover severity, suggesting that oxidative stress also contributes to the inflammatory response. The timing of the assessments suggests initial slow elimination of ethanol in the first hours after alcohol consumption. As a consequence, more ethanol is present in the second half of the night and the next morning, which will elicit more oxidative stress and a more profound inflammatory response. Together, these processes result in more severe hangovers.
A Novel Approach for the Identification of Pharmacogenetic Variants in MT-RNR1 through Next-Generation Sequencing Off-Target Data
Authors: Lanillos Javier , Santos María , Carcajona Marta , Roldan-Romero Juan María , Martinez Angel M. , Calsina Bruna , Monteagudo María , Leandro-García Luis Javier , Montero-Conde Cristina , Cascón Alberto , Maietta Paolo , Alvarez Sara , Robledo Mercedes , Rodriguez-Antona Cristina
Published: July 2020

Specific genetic variants in the mitochondrially encoded 12S ribosomal RNA gene (MT-RNR1) cause aminoglycoside-induced irreversible hearing loss. Mitochondrial DNA is usually not included in targeted sequencing experiments; however, off-target data may deliver this information. Here, we extract MT-RNR1 genetic variation, including the most relevant ototoxicity variant m.1555A>G, using the off-target reads of 473 research samples, sequenced through a capture-based, custom-targeted panel and whole exome sequencing (WES), and of 1245 diagnostic samples with clinical WES. Sanger sequencing and fluorescence-based genotyping were used for genotype validation. There was a correlation between off-target reads and mitochondrial coverage (rcustomPanel = 0.39, p = 2 × 10−13 and rWES = 0.67, p = 7 × 10−21). The median read depth of MT-RNR1 m.1555 was similar to the average mitochondrial genome coverage, with saliva and blood samples giving comparable results. The genotypes from 415 samples, including three m.1555G carriers, were concordant with fluorescence-based genotyping data. In clinical WES, median MT-RNR1 coverage was 56×, with 90% of samples having ≥20 reads at m.1555 position, and one m.1494T and three m.1555G carriers were identified with no evidence for heteroplasmy. Altogether, this study shows that obtaining MT-RNR1 genotypes through off-target reads is an efficient strategy that can impulse preemptive pharmacogenetic screening of this mitochondrial gene.
Amniodrainage-Induced Circulatory Dysfunction in Women Treated for Twin-To-Twin Transfusion Syndrome
Authors: Greimel Patrick , Klaritsch Philipp , Simonis Holger , Csapó Bence , Pohl Maximilian , Schneditz Daniel
Published: July 2020

Twin-to-twin transfusion syndrome (TTTS) in monochorionic-diamniotic twin pregnancies usually requires fetoscopic laser ablation (FLA) followed by amniodrainage (AD). Perioperative maternal hemodynamic changes and hemodilution have been observed. Little is known about the underlying pathophysiology. We aimed to evaluate the impact of high volume amniodrainage on intrauterine pressure, placental thickness and maternal blood characteristics. A total of 18 cases of TTTS were included in this prospective pilot study. All patients were treated with FLA and subsequent AD. Intrauterine pressure and placental thickness were assessed before, during and after amniodrainage. Maternal hemoglobin, hematocrit and serum albumin were measured at admission and 24 h after the intervention. Amniodrainage led to a decrease in mean intrauterine pressure (from 30.1 ± 8.1 mmHg to 17.6 ± 3.6 mmHg (p < 0.001)) and an increase in mean placental thickness (from 16.8 ± 6.4 mm to 31.83 ± 8.64 mm (p < 0.001)). There was a positive correlation between changes in placental thickness and the amount of amniodrainage during intervention (Pearson’s Rho 0.73; p = 0.001). Hematocrit decreased from 33.4 ± 3.8 (%) to 28.4 ± 3.5 (%), i.e., an increase in relative blood volume by 18 ± 10.2% (p < 0.001). Albumin decreased from 37.9 ± 0.9 g/L to 30.7 ± 2.2 g/L, i.e., an increase in relative plasma volume by 24 ± 8.1% (p < 0.001). Amniodrainage leads to uterine decompression, increased placental thickness and subsequent maternal hemodilution. We propose the term “amniodrainage-induced circulatory dysfunction” for these specific maternal hemodynamic changes in the treatment of twin-to-twin transfusion syndrome.
Assessment of Cardiac Remodeling—A Chance for Novel Cardiac Biomarkers?
Authors: Jirak Peter , Mirna Moritz , Wernly Bernhard , Paar Vera , Hoppe Uta C. , Lichtenauer Michael
Published: July 2020

Biomarkers are defined as “cellular, biochemical or molecular alterations that are measurable in biological media such as human tissues, cells, or fluids”, providing “biological characteristics that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention “according to Hulka et al [...]
New Insights into Immunological Involvement in Congenital Disorders of Glycosylation (CDG) from a People-Centric Approach
Authors: Francisco Rita , Pascoal Carlota , Marques-da-Silva Dorinda , Brasil Sandra , Pimentel-Santos Fernando M. , Altassan Ruqaiah , Jaeken Jaak , Grosso Ana Rita , dos Reis Ferreira Vanessa , Videira Paula A.
Published: July 2020

Congenital disorders of glycosylation (CDG) are rare diseases with variable phenotypes and severity. Immunological involvement remains a largely uncharted topic in CDG, mainly due to lack of robust data. To better characterize immune-related manifestations’ prevalence, relevance, and quality-of-life (QoL) impact, we developed electronic questionnaires targeting (1) CDG patients and (2) the general “healthy” population. Two-hundred and nine CDG patients/caregivers and 349 healthy participants were included in this study. PMM2-CDG was the most represented CDG (n = 122/209). About half of these participants (n = 65/122) described relevant infections with a noteworthy prevalence of those affecting the gastrointestinal tract (GI) (63.1%, n = 41/65). Infection burden and QoL impact were shown as infections correlated with more severe clinical phenotypes and with a set of relevant non-immune PMM2-CDG signs. Autoimmune diseases had only a marginal presence in PMM2-CDG (2.5%, n = 3/122), all being GI-related. Allergy prevalence was also low in PMM2-CDG (33%, n = 41/122) except for food allergies (26.8%, n = 11/41, of PMM2-CDG and 10.8%, n = 17/158, of controls). High vaccination compliance with greater perceived ineffectiveness (28.3%, n = 17/60) and more severe adverse reactions were described in PMM2-CDG. This people-centric approach not only confirmed literature findings, but created new insights into immunological involvement in CDG, namely by highlighting the possible link between the immune and GI systems in PMM2-CDG. Finally, our results emphasized the importance of patient/caregiver knowledge and raised several red flags about immunological management.
Epidemiological Trends in the Timing of In-Hospital Death in Acute Myocardial Infarction-Cardiogenic Shock in the United States
Authors: Vallabhajosyula Saraschandra , Dunlay Shannon M. , Bell Malcolm R. , Miller P. Elliott , Cheungpasitporn Wisit , Sundaragiri Pranathi R. , Kashani Kianoush , Gersh Bernard J. , Jaffe Allan S. , Holmes David R. , Barsness Gregory W.
Published: July 2020

Background: There are limited data on the epidemiology and timing of in-hospital death (IHD) in patients with acute myocardial infarction-cardiogenic shock (AMI-CS). Methods: Adult admissions with AMI-CS with IHDs were identified using the National Inpatient Sample (2000–2016) and were classified as early (≤2 days), mid-term (3–7 days), and late (>7 days). Inter-hospital transfers and those with do-not-resuscitate statuses were excluded. The outcomes of interest included the epidemiology, temporal trends and predictors for IHD timing. Results: IHD was noted in 113,349 AMI-CS admissions (median time to IHD 3 (interquartile range 1–7) days), with early, mid-term and late IHD in 44%, 32% and 24%, respectively. Compared to the mid-term and late groups, the early IHD group had higher rates of ST-segment-elevation AMI-CS (74%, 63%, 60%) and cardiac arrest (37%, 33%, 29%), but lower rates of acute organ failure (68%, 79%, 89%), use of coronary angiography (45%, 56%, 67%), percutaneous coronary intervention (33%, 36%, 42%), and mechanical circulatory support (31%, 39%, 50%) (all p < 0.001). There was a temporal increase in the early (adjusted odds ratio (aOR) for 2016 vs. 2000 2.50 (95% confidence interval (CI) 2.22–2.78)) and a decrease in mid-term (aOR 0.75 (95% CI 0.71–0.79)) and late (aOR 0.34 (95% CI 0.31–0.37)) IHD. ST-segment-elevation AMI-CS and cardiac arrest were associated with the increased risk of early IHD, whereas advanced comorbidity and acute organ failure were associated with late IHD. Conclusions: Early IHD after AMI-CS has increased between 2000 and 2016. The populations with early vs. late IHD were systematically different.
The Conceptual Framework of Dual Disorders and Its Flaws
Authors: Pacini Matteo , Maremmani Angelo G. I. , Maremmani Icro
Published: July 2020

When psychiatric illness and substance use disorder coexist, the clinical approach to the patient is, unsurprisingly, awkward. This fact is due to a cultural context and, more directly, to the patient’s psychiatric condition and addiction behaviors—a situation that does not favor a scientific approach. In dual disorder facilities, several types of professionals work together: counselors, social workers, psychologists, and psychiatrists. Treatment approaches vary from one service to another and even within the same service. It is crucial to provide dual disorder patients with multiple treatments, comprising hospitalization, rehabilitative and residential programs, case management, and counselling. Still, when treating dual disorder (DD) heroin use disorder (HUD) patients, it is advisable to follow a hierarchical algorithm. First, we must deal with addiction: by detoxification, whenever possible. This means starting most patients on anti-craving pharmacological maintenance, though aversion therapy may be appropriate for a few of them. Opiate antagonists may be used with heroin-addicted patients as long as those patients are only mildly ill. In contrast, agonist opioid medications, i.e., buprenorphine and methadone suit moderately and severely ill patients, respectively. Achieving control of mood instability or psychotic episodes is the next step, to be followed by a prevention strategy to counteract residual cravings and dominate mood disorders or psychotic episodes through long-term pharmacological maintenance that is focused on a double target.
Enhanced Salivary and General Oxidative Stress in Hashimoto’s Thyroiditis Women in Euthyreosis
Authors: Morawska Katarzyna , Maciejczyk Mateusz , Popławski Łukasz , Popławska-Kita Anna , Krętowski Adam , Zalewska Anna
Published: July 2020

Hashimoto’s thyroiditis (HT) is one of the most common autoimmune diseases. Although HT is inextricably linked to oxidative stress, there have been no studies assessing salivary redox homeostasis or salivary gland function in patients with HT. This study is the first to compare antioxidant defense and oxidative stress biomarkers in non-stimulated (NWS) and stimulated (SWS) whole saliva and plasma/erythrocytes of HT patients compared to controls. The study included 45 women with HT in the euthyreosis period as well as an age- and gender-matched control group. We showed that NWS secretion was significantly lower in HT patients compared to healthy controls, similar to salivary amylase activity in NWS and SWS. Catalase and peroxidase activities were considerably higher in NWS and SWS of HT patients, while the concentrations of reduced glutathione and uric acid were significantly lower in comparison with healthy subjects. Total antioxidant potential was significantly lower, while total oxidant status and the level of oxidation products of proteins (advanced glycation end products, advanced oxidation protein products) and lipids (malondialdehyde, lipid hydroperoxides) were significantly higher in NWS, SWS and plasma of HT patients. In conclusion, in both salivary glands of women with HT in euthyreosis, the ability to maintain redox homeostasis was hindered. In HT patients we observed oxidative damage to salivary proteins and lipids; thus, some biomarkers of oxidative stress may present a potential diagnostic value.
Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach
Authors: Greco Maria Francesca , Sirtori Cesare R. , Corsini Alberto , Ezhov Marat , Sampietro Tiziana , Ruscica Massimiliano
Published: July 2020

It is well-known that elevated lipoprotein(a)—Lp(a)—levels are associated with a higher risk of cardiovascular (CV) mortality and all-cause mortality, although a standard pharmacotherapeutic approach is still undefined for patients with high CV risk dependent on hyperlipoproteinemia(a). Combined with high Lp(a) levels, familial hypercholesterolemia (FH) leads to a greater CVD risk. In suspected FH patients, the proportion of cases explained by a rise of Lp(a) levels ranges between 5% and 20%. In the absence of a specific pharmacological approach able to lower Lp(a) to the extent required to achieve CV benefits, the most effective strategy today is lipoprotein apheresis (LA). Although limited, a clear effect on Lp(a) is exerted by PCSK9 antagonists, with apparently different mechanisms when given with statins (raised catabolism) or as monotherapy (reduced production). In the era of RNA-based therapies, a new dawn is represented by the use of antisense oligonucleotides APO(a)Lrx, able to reduce Lp(a) from 35% to over 80%, with generally modest injection site reactions. The improved knowledge of Lp(a) atherogenicity and possible prevention will be of benefit for patients with residual CV risk remaining after the most effective available lipid-lowering agents.
Temperature-Induced Changes in Reperfused Stroke: Inflammatory and Thrombolytic Biomarkers
Authors: Ávila-Gómez Paulo , Hervella Pablo , Da Silva-Candal Andrés , Pérez-Mato María , Rodríguez-Yáñez Manuel , López-Dequidt Iria , Pumar José M. , Castillo José , Sobrino Tomás , Iglesias-Rey Ramón , Campos Francisco
Published: July 2020

Although hyperthermia is associated with poor outcomes in ischaemic stroke (IS), some studies indicate that high body temperature may benefit reperfusion therapies. We assessed the association of temperature with effective reperfusion (defined as a reduction of ≥8 points in the National Institute of Health Stroke Scale (NIHSS) within the first 24 h) and poor outcome (modified Rankin Scale (mRS) > 2) in 875 retrospectively-included IS patients. We also studied the influence of temperature on thrombolytic (cellular fibronectin (cFn); matrix metalloproteinase 9 (MMP-9)) and inflammatory biomarkers (tumour necrosis factor-alpha (TNF-α), interleukin 6 (IL-6)) and their relationship with effective reperfusion. Our results showed that a higher temperature at 24 but not 6 h after stroke was associated with failed reperfusion (OR: 0.373, p = 0.001), poor outcome (OR: 2.190, p = 0.005) and higher IL-6 levels (OR: 0.958, p < 0.0001). Temperature at 6 h was associated with higher MMP-9 levels (R = 0.697; p < 0.0001) and effective reperfusion, although this last association disappeared after adjusting for confounding factors (OR: 1.178, p = 0.166). Our results suggest that body temperature > 37.5 °C at 24 h, but not at 6 h after stroke, is correlated with reperfusion failure, poor clinical outcome, and infarct size. Mild hyperthermia (36.5–37.5 °C) in the first 6 h window might benefit drug reperfusion therapies by promoting clot lysis.
The Role of Ranolazine for the Treatment of Residual Angina beyond the Percutaneous Coronary Revascularization
Authors: Calcagno Simone , Infusino Fabio , Salvi Nicolò , Taccheri Temistocle , Colantonio Riccardo , Bruno Emanuele , Birtolo Lucia Ilaria , Severino Paolo , Lavalle Carlo , Pucci Mariateresa , Sardella Gennaro , Mancone Massimo , Fedele Francesco
Published: July 2020

Introduction. Despite a successful percutaneous coronary intervention (PCI), several studies reported that the recurrence of angina after revascularization, even complete, is a particularly frequent occurrence in the first year after PCI. Methods. The aim was to evaluate the efficacy of treatment with ranolazine in addition to conventional anti-ischemic therapy in patients who underwent coronary angiography for persistent/recurrent angina after PCI and residual ischemia only due to small branches not suitable for further revascularization. Forty-nine consecutive patients were included in our registry, adding the ranolazine (375 mg b.i.d) to optimal medical therapy (OMT). The Exercise ECG Test (EET) was performed in all patients before to start the therapy (baseline BL) and at 30 days (T1) after enrollment. Results. The average duration of the exercise was increased after the therapy with ranolazine comparing to baseline (RG 9’1” ± 2’ versus BL 8’10” ± 2’, p = 0.01). Seven (14.3%) patients after receiving ranolazine had not crossed the threshold of six minutes (75 watts) compared to 20 (40.8%) of BL (p = 0.0003). Stress angina appeared more frequently at BL than at 30 days (T1 4.1% versus BL 16.3%, p = 0.04) as well as exercise-induced arrhythmias (BL 30.6% versus T1 14.3%, p = 0.05). Conclusions. The addition of ranolazine to standard anti-ischemic therapy showed a significant improvement in EET results after one month of therapy, including reduced exercise angina, increased exercise tolerance, and reduced exercise arrhythmias.
The Multifaced Perspectives of Genetic Testing in Pediatric Cardiomyopathies and Channelopathies
Authors: Popa-Fotea Nicoleta-Monica , Cojocaru Cosmin , Scafa-Udriste Alexandru , Micheu Miruna Mihaela , Dorobantu Maria
Published: July 2020

Pediatric inherited cardiomyopathies (CMPs) and channelopathies (CNPs) remain important causes of death in this population, therefore, there is a need for prompt diagnosis and tailored treatment. Conventional evaluation fails to establish the diagnosis of pediatric CMPs and CNPs in a significant proportion, prompting further, more complex testing to make a diagnosis that could influence the implementation of lifesaving strategies. Genetic testing in CMPs and CNPs may help unveil the underlying cause, but needs to be carried out with caution given the lack of uniform recommendations in guidelines about the precise time to start the genetic evaluation or the type of targeted testing or whole-genome sequencing. A very diverse etiology and the scarce number of randomized studies of pediatric CMPs and CNPs make genetic testing of these maladies far more particular than their adult counterpart. The genetic diagnosis is even more puzzling if the psychological impact point of view is taken into account. This review aims to put together different perspectives, state-of-the art recommendations—synthetizing the major indications from European and American guidelines—and psychosocial outlooks to construct a comprehensive genetic assessment of pediatric CMPs and CNPs.
Nomogram Predicting the Likelihood of Parametrial Involvement in Early-Stage Cervical Cancer: Avoiding Unjustified Radical Hysterectomies
Authors: Benoit Louise , Balaya Vincent , Guani Benedetta , Bresset Arnaud , Magaud Laurent , Bonsang-Kitzis Helene , Ngô Charlotte , Mathevet Patrice , Lécuru Fabrice
Published: July 2020

Background: We aimed to establish a tool predicting parametrial involvement (PI) in patients with early-stage cervical cancer and select a sub-group of patients who would most benefit from a less radical surgery. Methods: We retrospectively reviewed patients from two prospective multicentric databases—SENTICOL I and II—from 2005 to 2012. Patients with early-stage cervical cancer (FIGO 2018 IA with lympho-vascular involvement to IIA1), undergoing radical surgery (hysterectomy or trachelectomy) with bilateral sentinel lymph node (SLN) mapping with no metastatic node or PI on pre-operative imaging, were included. Results: In total, 5.2% patients (11/211) presented a histologic PI. After univariate analysis, SLN status, lympho-vascular space invasion, deep stromal invasion and tumor size were significantly associated with PI and were included in our nomogram. Our predictive model had an AUC of 0.92 (IC95% = 0.86–0.98) and presented a good calibration. A low risk group, defined according to the optimal sensitivity and specificity, presented a predicted probability of PI of 2%. Conclusion: Patients could benefit from a two-step approach. Final surgery (i.e. radical surgery and/or lymphadenectomy) would depend on the SLN status and the probability PI calculated after an initial conization with bilateral SLN mapping.
Trends of Hospitalization for Acute Alcohol Intoxication in Slovenian Children and Adolescents with and without Dual Disorder. Implications for a Correct Intervention
Authors: Lovrecic Mercedes , Lovrecic Barbara , Rok Simon Mateja , Korosec Ales , Della Rocca Filippo , Maremmani Angelo , Maremmani Icro
Published: July 2020

Background: Binge drinking and other forms of ethanol abuse are, when present, a serious problem in preteens and adolescents worldwide. Aim: The present study has analyzed the trend in alcohol-related intoxications requiring the hospitalization of children, adolescents and young adults aged less than 21 years in Slovenia in the 1999–2018 period. Methods: We performed a retrospective study on patients discharged after hospitalizations due to mental and behavioral disorders due to acute alcohol intoxication (MBDAAI) or hospitalizations due to the toxic effects of alcohol (TEA We considered three groups: children (aged 10–14), adolescents (aged 15–19) and young adults (20–21 years old). Hospitalization rates and time trends were analyzed using joinpoint regression to obtain the annually calculated age- and sex-specific rates and the annual percentage of change (APC). Results: Considering a total of 2912 MBDAAI-hospitalizations, 15–19-year-old subjects showed a significantly higher hospitalization rate compared to the immediately younger and older age groups and a significant increase in hospitalization rates in the period 1999–2011, followed by a significant decrease. Considering 1143 TEA-hospitalizations, we observed a continuous decrease in the hospitalization rates for children and young adults and, conversely, a continuous even if less than significant increase for adolescents aged 15–19. Conclusions: Alcohol consumption in Slovenian children and adolescents is a highly important health concern. Special attention to public health problem of severe alcohol abuse requiring hospitalization in children and adolescents is needed, especially with possible crisis of SARS-CoV-2/Covid-19 situation.
Orthopaedic Surgery Elicits a Systemic Anti-Inflammatory Signature
Authors: Heim Cortney E. , Yamada Kelsey J. , Fallet Rachel , Odvody Jessica , Schwarz Dana M. , Lyden Elizabeth R. , Anderson Matthew J. , Alter Roxanne , Vidlak Debbie , Hartman Curtis W. , Konigsberg Beau S. , Cornett Chris A. , Garvin Kevin L. , Mohamed Naglaa , Anderson Annaliesa S. , Kielian Tammy
Published: July 2020

Little information is available on the functional activity of leukocytes after arthroplasty or the expansion of populations with immune suppressive properties during the acute post-operative period. Synovial fluid and matched pre- and post-surgical blood samples were collected from total hip and knee arthroplasty patients (THA and TKA, respectively) to examine the impact of surgery on peripheral blood leukocyte frequency, bactericidal activity, and inflammatory mediator expression. For spinal surgeries, inflammatory mediator production by peripheral blood mononuclear cells (PBMCs) pre- and post-surgery was examined. An expansion of immune suppressive granulocytic myeloid-derived suppressor cells (G-MDSCs) was observed following arthroplasty, which correlated with significantly increased serum interleukin-10 (IL-10) levels. Analysis of synovial fluid from THA and TKAs revealed reduced granulocyte colony-stimulating factor (G-CSF) and soluble CD40 ligand (sCD40L) and increased interleukin-6 (IL-6), monocyte chemoattractant protein 2 (CCL2) and Fms-like tyrosine kinase 3 ligand (Flt-3L) compared to pre- and post-surgical serum. For the spinal surgery cohort, stimulation of PBMCs isolated post-surgery with bacterial antigens produced significantly less pro-inflammatory (IL-1α, IL-1β, interleukin-1 receptor antagonist (IL-1RA), IL-12p40, growth-related oncogene-α/GRO-α (CXCL1) and 6Ckine (CCL21)) and more anti-inflammatory/tissue repair mediators (IL-10, G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF)) compared to PBMCs recovered before surgery. The observed bias towards systemic anti-inflammatory changes without concomitant increases in pro-inflammatory responses may influence susceptibility to infection following orthopaedic surgery in the context of underlying co-morbidities or risk factors.
Sex-Specific Outcomes in Patients with Acute Coronary Syndrome
Authors: Neumann Johannes T. , Goßling Alina , Sörensen Nils A. , Blankenberg Stefan , Magnussen Christina , Westermann Dirk
Published: July 2020

Sex differences in patients with acute coronary syndrome (ACS) are a matter of debate. We investigated sex-specific differences in the incidence, outcomes, and related interventions in patients diagnosed with ACS in Germany over the past decade. All ACS cases from 2005 to 2015 were collected. Procedures and inhospital mortality were assessed by sex. Age-adjusted incidence rates were calculated. In total, 1,366,045 females and 2,431,501 males presenting with ACS were recorded. Females were older than males (73.1 vs. 66.4 years of age), had a longer mean hospital stay (7.7 vs. 6.9 days), and less frequently underwent coronary angiographies (55% vs. 66%) and coronary interventions (35% vs. 47%). The age-adjusted incidence rate of ACS was lower in females than in males, and decreased in both sexes from 2005 to 2015. The age-adjusted inhospital mortality rate was substantially higher in females than in males, but decreased in both sexes over time (in females, from 87 to 71 cases per 1000 person years; in males, from 57 to 51 cases per 1000 person years). In conclusion, we reported sex differences in the incidence, treatment, and outcomes of ACS patients in Germany within the past decade. Women had a substantially higher mortality rate and lower rate of coronary interventions.