bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiological and Pathophysiological Aspects of Primary Cilia—A Literature Review with View on Functional and Structural Relationships in Cartilage
Authors: Barsch Friedrich , Niedermair Tanja , Mamilos Andreas , Schmitt Volker H. , Grevenstein David , Babel Maximilian , Burgoyne Thomas , Shoemark Amelia , Brochhausen Christoph
Published: July 2020

Cilia are cellular organelles that project from the cell. They occur in nearly all non-hematopoietic tissues and have different functions in different tissues. In mesenchymal tissues primary cilia play a crucial role in the adequate morphogenesis during embryological development. In mature articular cartilage, primary cilia fulfil chemo- and mechanosensitive functions to adapt the cellular mechanisms on extracellular changes and thus, maintain tissue homeostasis and morphometry. Ciliary abnormalities in osteoarthritic cartilage could represent pathophysiological relationships between ciliary dysfunction and tissue deformation. Nevertheless, the molecular and pathophysiological relationships of ‘Primary Cilia’ (PC) in the context of osteoarthritis is not yet fully understood. The present review focuses on the current knowledge about PC and provide a short but not exhaustive overview of their role in cartilage.
Structure of Nanotubes Self-Assembled from a Monoamide Organogelator
Authors: Zapién-Castillo Samuel , Díaz-Zavala Nancy P. , Melo-Banda José A. , Schwaller Duncan , Lamps Jean-Philippe , Schmutz Marc , Combet Jérôme , Mésini Philippe J.
Published: July 2020

Some organic compounds are known to self-assemble into nanotubes in solutions, but the packing of the molecules into the walls of the tubes is known only in a very few cases. Herein, we study two compounds forming nanotubes in alkanes. They bear a secondary alkanamide chain linked to a benzoic acid propyl ester (HUB-3) or to a butyl ester (HUB-4). They gel alkanes for concentrations above 0.2 wt.%. The structures of these gels, studied by freeze fracture electron microscopy, exhibit nanotubes: for HUB-3 their external diameters are polydisperse with a mean value of 33.3 nm; for HUB-4, they are less disperse with a mean value of 25.6 nm. The structure of the gel was investigated by small- and wide-angle X-ray scattering. The evolution of the intensities show that the tubes are metastable and transit slowly toward crystals. The intensities of the tubes of HUB-4 feature up to six oscillations. The shape of the intensities proves the tubular structure of the aggregates, and gives a measurement of 20.6 nm for the outer diameters and 11.0 nm for the inner diameters. It also shows that the electron density in the wall of the tubes is heterogeneous and is well described by a model with three layers.
Loss of Dystroglycan Drives Cellular Senescence via Defective Mitosis-Mediated Genomic Instability
Authors: Jimenez-Gutierrez Guadalupe Elizabeth , Mondragon-Gonzalez Ricardo , Soto-Ponce Luz Adriana , Gómez-Monsiváis Wendy Lilián , García-Aguirre Ian , Pacheco-Rivera Ruth Abigail , Suárez-Sánchez Rocío , Brancaccio Andrea , Magaña Jonathan Javier , C.R. Perlingeiro Rita , Cisneros Bulmaro
Published: July 2020

Nuclear β-dystroglycan (β-DG) is involved in the maintenance of nuclear architecture and function. Nonetheless, its relevance in defined nuclear processes remains to be determined. In this study we generated a C2C12 cell-based DG-null model using CRISPR-Cas9 technology to provide insights into the role of β-DG on nuclear processes. Since DG-null cells exhibited decreased levels of lamin B1, we aimed to elucidate the contribution of DG to senescence, owing to the central role of lamin B1 in this pathway. Remarkably, the lack of DG enables C2C12 cells to acquire senescent features, including cell-cycle arrest, increased senescence-associated-β-galactosidase activity, heterochromatin loss, aberrant nuclear morphology and nucleolar disruption. We demonstrated that genomic instability is one driving cause of the senescent phenotype in DG-null cells via the activation of a DNA-damage response associated with mitotic failure, as shown by the presence of multipolar mitotic spindles, which in turn induced the formation of micronuclei and γH2AX foci (DNA-damage marker), telomere shortening and p53/p21 upregulation. Altogether, these events might ultimately lead to premature senescence, impeding the replication of the damaged genome. In summary, we present evidence supporting a role for DG in protecting against senescence, through the maintenance of proper lamin B1 expression/localization and proper mitotic spindle organization.
EPA and DHA Fatty Acids Induce a Remodeling of Tumor Vasculature and Potentiate Docetaxel Activity
Authors: Goupille Caroline , Vibet Sophie , Frank Philippe G. , Mahéo Karine
Published: July 2020

n-3 long chain Polyunsaturated Fatty Acids (n-3 LCPUFA) have been shown to improve the efficacy of conventional chemotherapies used for breast cancer treatment. In addition to their reported ability to increase the chemosensitivity of cancer cells, we hypothesized that n-3 LCPUFA could induce a remodeling of the vascular network in mammary tumors. A contrast-enhanced ultrasound method was used to monitor the vascular architecture during docetaxel treatment of mammary tumors in rats fed either a control or an n-3 LCPUFA-enriched diet (docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA)). The vascular network was remodeled in favor of smaller vessels (microvascularization), which represented 54% of the vasculature in n-3 LCPUFA tumors but only 26% in control tumors after 2 weeks of chemotherapy. Importantly, vascularization changes occurred both before and during docetaxel treatment. The density of smaller vessels quantified before chemotherapy was correlated with improved tumor size reduction by docetaxel treatment. Furthermore, transcript levels of the angiogenesis-specific genes epiregulin and amphiregulin were reduced by ~4.5- and twofold in tumors obtained from rats fed an n-3 LCPUFA-enriched diet compared to those of rats fed a control diet, respectively. Their expression levels were negatively correlated with tumor regression after chemotherapy. Taken together, this preclinical data strengthen the potential usefulness of n-3 LCPUFA as a complementary clinical strategy to improve drug efficiency via remodeling of the tumor vasculature.
The Role of Adipokines and Bone Marrow Adipocytes in Breast Cancer Bone Metastasis
Authors: Shin Eunah , Koo Ja Seung
Published: July 2020

The morbidity and mortality of breast cancer is mostly due to a distant metastasis, especially to the bone. Many factors may be responsible for bone metastasis in breast cancer, but interactions between tumor cells and other surrounding types of cells, and cytokines secreted by both, are expected to play the most important role. Bone marrow adipocyte (BMA) is one of the cell types comprising the bone, and adipokine is one of the cytokines secreted by both breast cancer cells and BMAs. These BMAs and adipokines are known to be responsible for cancer progression, and this review is focused on how BMAs and adipokines work in the process of breast cancer bone metastasis. Their potential as suppressive targets for bone metastasis is also explored in this review.
Cloning and Functional Analysis of Dwarf Gene Mini Plant 1 (MNP1) in Medicago truncatula
Authors: Guo Shiqi , Zhang Xiaojia , Bai Quanzi , Zhao Weiyue , Fang Yuegenwang , Zhou Shaoli , Zhao Baolin , He Liangliang , Chen Jianghua
Published: July 2020

Plant height is a vital agronomic trait that greatly determines crop yields because of the close relationship between plant height and lodging resistance. Legumes play a unique role in the worldwide agriculture; however, little attention has been given to the molecular basis of their height. Here, we characterized the first dwarf mutant mini plant 1 (mnp1) of the model legume plant Medicago truncatula. Our study found that both cell length and the cell number of internodes were reduced in a mnp1 mutant. Using the forward genetic screening and subsequent whole-genome resequencing approach, we cloned the MNP1 gene and found that it encodes a putative copalyl diphosphate synthase (CPS) implicated in the first step of gibberellin (GA) biosynthesis. MNP1 was highly homologous to Pisum sativum LS. The subcellular localization showed that MNP1 was located in the chloroplast. Further analysis indicated that GA3 could significantly restore the plant height of mnp1-1, and expression of MNP1 in a cps1 mutant of Arabidopsis partially rescued its mini-plant phenotype, indicating the conservation function of MNP1 in GA biosynthesis. Our results provide valuable information for understanding the genetic regulation of plant height in M. truncatula.
The Smallest Isoform of Metridia longa Luciferase as a Fusion Partner for Hybrid Proteins
Authors: Larionova Marina D. , Markova Svetlana V. , Tikunova Nina V. , Vysotski Eugene S.
Published: July 2020

Bioluminescent proteins are widely used as reporter molecules in various in vitro and in vivo assays. The smallest isoform of Metridia luciferase (MLuc7) is a highly active, naturally secreted enzyme which, along with other luciferase isoforms, is responsible for the bright bioluminescence of marine copepod Metridia longa. In this study, we report the construction of two variants of a hybrid protein consisting of MLuc7 and 14D5a single-chain antibody to the surface glycoprotein E of tick-borne encephalitis virus as a model fusion partner. We demonstrate that, whereas fusion of a single-chain antibody to either N- or C-terminus of MLuc7 does not affect its bioluminescence properties, the binding site on the single-chain antibody influences its binding capacity. The affinity of 14D5a-MLuc7 hybrid protein (KD = 36.2 nM) where the C-terminus of the single-chain antibody was fused to the N-terminus of MLuc7, appeared to be 2.5-fold higher than that of the reverse, MLuc7-14D5a (KD = 87.6 nM). The detection limit of 14D5a-MLuc7 hybrid protein was estimated to be 45 pg of the recombinant glycoprotein E. Although the smallest isoform of M. longa luciferase was tested as a fusion partner only with a single-chain antibody, it is reasonable to suppose that MLuc7 can also be successfully used as a partner for genetic fusion with other proteins.
Punicalagin Ameliorates Lupus Nephritis via Inhibition of PAR2
Authors: Seo Yohan , Mun Chin Hee , Park So-Hyeon , Jeon Dongkyu , Kim Su Jeong , Yoon Taejun , Ko Eunhee , Jo Sungwoo , Park Yong-Beom , Namkung Wan , Lee Sang-Won
Published: July 2020

Lupus nephritis (LN) is the most frequent phenotype in patients with systemic lupus erythematosus (SLE) and has a high rate of progression to end-stage renal disease, in spite of intensive treatment and maintenance therapies. Recent evidence suggests that protease-activated receptor-2 (PAR2) is a therapeutic target for glomerulonephritis. In this study, we performed a cell-based high-throughput screening and identified a novel potent PAR2 antagonist, punicalagin (PCG, a major polyphenol enriched in pomegranate), and evaluated the effects of PCG on LN. The effect of PCG on PAR2 inhibition was observed in the human podocyte cell line and its effect on LN was evaluated in NZB/W F1 mice. In the human podocyte cell line, PCG potently inhibited PAR2 (IC50 = 1.5 ± 0.03 µM) and significantly reduced the PAR2-mediated activation of ERK1/2 and NF-κB signaling pathway. In addition, PCG significantly decreased PAR2-induced increases in ICAM-1 and VCAM-1 as well as in IL-8, IFN-γ, and TNF-α expression. Notably, the intraperitoneal administration of PCG significantly alleviated kidney injury and splenomegaly and reduced proteinuria and renal ICAM-1 and VCAM-1 expression in NZB/W F1 mice. Our results suggest that PCG has beneficial effects on LN via inhibition of PAR2, and PCG is a potential therapeutic agent for LN.
Efficient Paradigm to Measure Street-Crossing Onset Time of Pedestrians in Video-Based Interactions with Vehicles
Authors: Faas Stefanie M. , Mattes Stefan , Kao Andrea C. , Baumann Martin
Published: July 2020

With self-driving vehicles (SDVs), pedestrians can no longer rely on a human driver. Previous research suggests that pedestrians may benefit from an external Human–Machine Interface (eHMI) displaying information to surrounding traffic participants. This paper introduces a natural methodology to compare eHMI concepts from a pedestrian’s viewpoint. To measure eHMI effects on traffic flow, previous video-based studies instructed participants to indicate their crossing decision with interfering data collection devices, such as pressing a button or slider. We developed a quantifiable concept that allows participants to naturally step off a sidewalk to cross the street. Hidden force-sensitive resistor sensors recorded their crossing onset time (COT) in response to real-life videos of approaching vehicles in an immersive crosswalk simulation environment. We validated our method with an initial study of N = 34 pedestrians by showing (1) that it is able to detect significant eHMI effects on COT as well as subjective measures of perceived safety and user experience. The approach is further validated by (2) replicating the findings of a test track study and (3) participants’ reports that it felt natural to take a step forward to indicate their street crossing decision. We discuss the benefits and limitations of our method with regard to related approaches.
Evaluation of the Physiological Host Range for the Parasitoid Ooencyrtus mirus, a Potential Biocontrol Agent of Bagrada hilaris
Authors: Power Nancy , Ganjisaffar Fatemeh , Perring Thomas M.
Published: July 2020

The thelytokous egg parasitoid Ooencyrtus mirus Triapitsyn and Power (Hymenoptera: Encyrtidae) was recovered from brassica plant debris in Pakistan in an effort to find a biological control agent of the invasive bug Bagrada hilaris (Burmeister) (Heteroptera: Pentatomidae) in North America. As the first step in determining the overall host range of this parasitoid, adult females were exposed to the eggs of eight alternate pentatomid host species, two non-pentatomid heteropterans, and two lepidopterans, in choice and no-choice tests. Although O. mirus was more successful on B. hilaris than the other species in terms of the number of the eggs laid, the number of emerged progeny, and the developmental time of the progeny, it was able to reproduce on all of the alternate hosts except for one of the lepidopterans, whose eggs appeared too small for this parasitoid. The results show O. mirus to be a generalist parasitoid species with a preference for B. hilaris. The results also indicate that there is a linear relationship between the mean body length of O. mirus females and the mean host egg weight with an adjusted R 2 of 0.90. The implications of this study on the release of O. mirus for the control of B. hilaris are discussed.
Enzymatic Defense Response of Apple Aphid Aphis pomi to Increased Temperature
Authors: Dampc Jan , Kula-Maximenko Monika , Molon Mateusz , Durak Roma
Published: July 2020

Climate change, and in particular the increase in temperature we are currently observing, can affect herbivorous insects. Aphids, as poikilothermic organisms, are directly exposed to temperature increases that influence their metabolism. Heat stress causes disturbances between the generations and the neutralization of reactive oxygen species (ROS). The aim of this work is focused on explaining how the aphid, using the example of Aphis pomi, responds to abiotic stress caused by temperature increase. The experiment was carried out under controlled conditions at three temperatures: 20, 25, and 28 °C. In the first stage, changes in the activity of enzymatic markers (superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), β-glucosidase, polyphenol oxidase (PPO), and peroxidase (POD)) were determined in aphid tissues, at each temperature. In the second stage, microcalorimetry monitored changes in heat emitted by aphids, at each temperature. Our results showed that A. pomi defense responses varied depending on temperature and were highest at 28 °C. The flexible activity of enzymes and increase in the metabolic rate played the role of adaptive mechanisms and ran more effectively at higher temperatures. The A. pomi thus protected itself against ROS excessive induction and the aphids were able to respond quickly to environmental stress.
A Survey of Neotropiella Handschin, 1942 (Collembola, Neanuridae, Pseudachorutinae) with the Description of a New Brazilian Species
Authors: Bellini Bruno C. , Weiner Wanda M. , Queiroz Gabriel C. , Paz Raiane V.
Published: July 2020

Neotropiella Handschin, 1942 is a pantropical genus of Pseudachorutinae with 18 species, 16 of which are from the Neotropical Region and 13 from Brazil. The genus has several species with unclear descriptions. Herein, we describe a new species of Neotropiella, survey the genus based on published papers and discuss its morphology, providing an updated genus diagnosis plus a detailed comparison table and a key to all known species. Neotropiella arretada sp. nov. is unique in the combination of a postantennal organ with 14–20 vesicles, its mandible with five teeth, its maxilla apically pointed and its unguis with a pair of reduced teeth. Widely distributed taxa may be species complexes, especially due to their unclear descriptions.
Clinical Characteristics and Treatment Outcomes of Pathologically Confirmed Aspergillus Nodules
Authors: Kang Noeul , Park Jiyeon , Jhun Byung Woo
Published: July 2020

Aspergillus nodules represent a subtype of chronic pulmonary aspergillosis, but details on their characteristics and outcomes are limited. We evaluated 80 patients with pathologically confirmed Aspergillus nodules between January 2009 and December 2016. The median age of the patients was 59 years, and 46 (58%) were women. Seventy-three (91%) patients were surgically diagnosed with Aspergillus nodules and the remaining seven (9%) patients were diagnosed by percutaneous transthoracic needle biopsy. The median long-axis diameter of nodules was 22 mm, and nodules had an internal cavity in 49 (61%) patients. Spiculation and calcification were observed in 20% and 39% of patients, respectively. Ninety percent (18/20) of nodules showed uptake on positron emission tomography. Serum Aspergillus precipitin IgG antibody was positive in 42% (10/24) of tested patients. Seventy-three (91%) patients underwent surgery without (n = 58) or with (n = 15) adjuvant antifungal therapy, and the remaining seven (9%) patients received antifungal therapy alone (n = 5) or no treatment (n = 2). Three patients experienced postoperative pulmonary complications: pneumothorax, hemoptysis, and acute lung injury (n = 1 each). There was no recurrence during the median follow-up period of 36.8 months. In conclusion, surgery could be a treatment strategy worth considering for most Aspergillus nodules. However, given that our study population was heterogeneous, further well-designed studies are need.
Preserved Capacity for Adaptations in Strength and Muscle Regulatory Factors in Elderly in Response to Resistance Exercise Training and Deconditioning
Authors: Fritzen Andreas Mæchel , Thøgersen Frank D. , Qadri Khaled Abdul Nasser , Krag Thomas , Sveen Marie-Louise , Vissing John , Jeppesen Tina D.
Published: July 2020

Aging is related to an inevitable loss of muscle mass and strength. The mechanisms behind age-related loss of muscle tissue are not fully understood but may, among other things, be induced by age-related differences in myogenic regulatory factors. Resistance exercise training and deconditioning offers a model to investigate differences in myogenic regulatory factors that may be important for age-related loss of muscle mass and strength. Nine elderly (82 ± 7 years old) and nine young, healthy persons (22 ± 2 years old) participated in the study. Exercise consisted of six weeks of resistance training of the quadriceps muscle followed by eight weeks of deconditioning. Muscle biopsy samples before and after training and during the deconditioning period were analyzed for MyoD, myogenin, insulin-like growth-factor I receptor, activin receptor IIB, smad2, porin, and citrate synthase. Muscle strength improved with resistance training by 78% (95.0 ± 22.0 kg) in the elderly to a similar extent as in the young participants (83.5%; 178.2 ± 44.2 kg) and returned to baseline in both groups after eight weeks of deconditioning. No difference was seen in expression of muscle regulatory factors between elderly and young in response to exercise training and deconditioning. In conclusion, the capacity to gain muscle strength with resistance exercise training in elderly was not impaired, highlighting this as a potent tool to combat age-related loss of muscle function, possibly due to preserved regulation of myogenic factors in elderly compared with young muscle.
Mental Disorders, Musculoskeletal Disorders and Income-Driven Patterns: Evidence from the Global Burden of Disease Study 2017
Authors: Tyrovolas Stefanos , Moneta Victoria , Giné Vázquez Iago , Koyanagi Ai , Abduljabbar Adel S. , Haro Josep Maria
Published: July 2020

Background: The aim of the present study was to use the extensive Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) database from 1990–2017 to evaluate the levels and temporal correlation trends between disability adjusted life years (DALYs) attributed to musculoskeletal (MSK) disorders, all mental disorders collectively and by mental disorder sub-category. Methods: We utilized results of the GBD 2017 to describe the correlation patterns between DALYs due to MSK disorders, mental disorders and other diseases among 195 countries. Mixed model analysis was also applied. Results: A consistent relation was reported between age-adjusted DALYs attributed to MSK and mental disorders (in total) among the 195 countries, in both sexes, for 1990 to 2017 (1990 Rho = 0.487; 2017 Rho = 0.439 p < 0.05). Distinct regional and gender correlation patterns between age-adjusted DALYs due to MSK and mental disorders were reported. No correlation was reported between DALYs due to MSK and all mental disorders collectively, among Low- or Middle-income countries. However, in High-income countries (HICs), the correlation was strong and consistent between 1990 and 2017 (1990 Rho = 0.735; 2017 Rho = 0.727, p < 0.05). Conclusions: The reported correlation patterns call for targeted preventive strategies and intervention policies for mental and MSK disorders internationally. Special attention is needed among HICs.
Impacts of High Intra- and Inter-Individual Variability in Tacrolimus Pharmacokinetics and Fast Tacrolimus Metabolism on Outcomes of Solid Organ Transplant Recipients
Authors: Thongprayoon Charat , Hansrivijit Panupong , Kovvuru Karthik , Kanduri Swetha R. , Bathini Tarun , Pivovarova Aleksandra , Smith Justin R. , Cheungpasitporn Wisit
Published: July 2020

Tacrolimus is a first-line calcineurin inhibitor (CNI) and an integral part of the immunosuppressive strategy in solid organ transplantation. Being a dose-critical drug, tacrolimus has a narrow therapeutic index that necessitates periodic monitoring to maintain the drug’s efficacy and reduce the consequences of overexposure. Tacrolimus is characterized by substantial intra- and inter-individual pharmacokinetic variability. At steady state, the tacrolimus blood concentration to daily dose ratio (C/D ratio) has been described as a surrogate for the estimation of the individual metabolism rate, where a low C/D ratio reflects a higher rate of metabolism. Fast tacrolimus metabolism (low C/D ratio) is associated with the risk of poor outcomes after transplantation, including reduced allograft function and survival, higher allograft rejection, CNI nephrotoxicity, a faster decline in kidney function, reduced death-censored graft survival (DCGS), post-transplant lymphoproliferative disorders, dyslipidemia, hypertension, and cardiovascular events. In this article, we discuss the potential role of the C/D ratio in a noninvasive monitoring strategy for identifying patients at risk for potential adverse events post-transplant.
Accuracy of a Symptom-Based Approach to Identify Hypertensive Emergencies in the Emergency Department
Authors: Vallelonga Fabrizio , Carbone Federica , Benedetto Francesco , Airale Lorenzo , Totaro Silvia , Leone Dario , Astarita Anna , Avenatti Eleonora , Maule Simona , Veglio Franco , Lupia Enrico , Milan Alberto
Published: July 2020

Background: A hierarchical symptoms-based diagnostic strategy relying on the presence of five main symptoms (chest pain, acute dyspnea, neurological symptoms, headache, visual impairment) was recently proposed to diagnose patients with hypertensive emergency. However, poor scientific evidence is available about the role of symptoms in both diagnosis and management of acute hypertensive disorders. Methods: Data from 718 patients presenting to the emergency department of the “Città della Salute e della Scienza” Hospital of Turin with systolic blood pressure > 180 and/or diastolic blood pressure > 110 mm/Hg were retrospectively analyzed. The accuracy of the typical symptoms for identification of hypertensive emergencies was assessed. Results: A total of 79 (11%) out of 718 patients were diagnosed with hypertensive emergencies (51% had cardiovascular and 49% neurovascular acute organ damage). Patients with hypertensive emergencies were older and with higher prevalence of coronary artery disease and chronic heart failure than patients with uncontrolled hypertension. Typical symptoms could discriminate true hypertensive emergency from uncontrolled hypertension with 64% accuracy, 94% sensitivity, and 60% specificity. Conclusion: Typical symptoms might be used as a simple screening test (99% negative predictive value) in the emergency department to select for further evaluations of patients with suspected hypertensive emergencies among those with acute hypertensive disorders.
Cognitive Impairment, Chronic Kidney Disease, and 1-Year Mortality in Older Patients Discharged from Acute Care Hospital
Authors: Di Rosa Mirko , D’Alia Sonia , Guarasci Francesco , Soraci Luca , Pierpaoli Elisa , Lenci Federica , Ricci Maddalena , Onder Graziano , Volpato Stefano , Ruggiero Carmelinda , Cherubini Antonio , Corsonello Andrea , Lattanzio Fabrizia
Published: July 2020

The prognostic interaction between chronic kidney disease (CKD) and cognitive impairment is still to be elucidated. We investigated the potential interaction of overall cognitive impairment or defective constructional praxis and CKD in predicting 1-year mortality among 646 older patients discharged from hospital. The estimated glomerular filtration rate (eGFR) was calculated using the Berlin Initiative Study (BIS) equation. Cognitive impairment was assessed by the Mini Mental State Exam (MMSE) and defective constructional praxis was ascertained by the inherent MMSE item. The study outcome was 1-year mortality. Statistical analysis was carried out using Cox regression. After adjusting for potential confounders, the co-occurrence of eGFR <30 and overall cognitive impairment (Hazard Ratio (HR) = 3.12, 95% Confidence Interval (CI) = 1.26–7.77) and defective constructional praxis (HR = 2.50, 95% CI = 1.08–5.77) were associated with the outcome. No significant prognostic interaction of eGFR < 30 with either overall cognitive impairment (HR = 1.99, 95% CI = 0.38–10.3) or constructional apraxia (HR = 1.68, 95% CI = 0.33–8.50) was detectable, while only cognitive deficits were found significantly associated with the outcome in the interaction models (HR = 3.12, 95% CI = 1.45–6.71 for overall cognitive impairment and HR = 2.16, 95% CI = 1.05–4.45 for constructional apraxia). Overall cognitive impairment and defective constructional praxis may be associated with increased risk of 1-year mortality among older hospitalized patients with severe CKD. However, no significant prognostic interaction between CKD and cognitive impairment could be observed.
Prevention and Management of Hormonal Crisis during Theragnosis with LU-DOTA-TATE in Neuroendocrine Tumors. A Systematic Review and Approach Proposal
Authors: del Olmo-García Maria Isabel , Muros Maria Angustias , López-de-la-Torre Martín , Agudelo Marc , Bello Pilar , Soriano Jose M. , Merino-Torres Juan-Francisco
Published: July 2020

Neuroendocrine tumors (NETs) frequently overexpress somatostatin receptors (SSTR) on their cell surface. The first-line pharmacological treatment for inoperable metastatic functioning well-differentiated NETs are somatostatin analogs. On second line, Lu-DOTA-TATE (177Lu-DOTA0 Tyr 3 octreotate) has shown stabilization of the disease and an increase in progression free survival, as well as effectiveness in controlling symptoms and increasing quality of life. The management of functional NETs before and during LU-DOTA-TATE treatment is specially challenging, as several complications such as severe carcinoid and catecholamine crisis have been described. The aim of this review is to establish practical guidance for the management and prevention of the most common hormonal crises during radionuclide treatment with Lu-DOTA-TATE: carcinoid syndrome (CS) and catecholamine hypersecretion, as well as to provide a brief commentary on other infrequent metabolic complications. To establish a practical approach, a systematic review was performed. This systematic review was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and conducted using MEDLINE (accessed from PubMed), Google Scholar and ClinicalTrials.gov. Literature searches found 449 citations, and finally nine were considered for this systematic review.
A Retrospective Comparison of DLI and gDLI for Post-Transplant Treatment
Authors: Lamure Sylvain , Paul Franciane , Gagez Anne-Laure , Delage Jérémy , Vincent Laure , Fegueux Nathalie , Sirvent Anne , Gehlkopf Eve , Veyrune Jean Luc , Yang Lu Zhao , Kanouni Tarik , Cacheux Valère , Moreaux Jérôme , Bonafoux Beatrice , Cartron Guillaume , De Vos John , Ceballos Patrice
Published: July 2020

Donor lymphocyte infusion (DLI) is used to prevent or treat haematological malignancies relapse after allogeneic stem cell transplantation (allo-SCT). Recombinant human granulocyte colony-stimulated factor primed DLI (gDLI) is derived from frozen aliquots of the peripheral blood stem cell collection. We compared the efficacy and safety of gDLI and classical DLI after allo-SCT. We excluded haploidentical allo-SCT. Initial diseases were acute myeloblastic leukaemia (n = 45), myeloma (n = 38), acute lymphoblastic leukaemia (n = 20), non-Hodgkin lymphoma (n = 10), myelodysplasia (n = 8), Hodgkin lymphoma (n = 8), chronic lymphocytic leukaemia (n = 7), chronic myeloid leukaemia (n = 2) and osteomyelofibrosis (n = 1). Indications for DLI were relapse (n = 96) or pre-emptive treatment (n = 43). Sixty-eight patients had classical DLI and 71 had gDLI. The response rate was 38.2%, the 5-year progression-free survival (PFS) rate was 38% (29–48) and the 5-year overall survival (OS) rate was 37% (29–47). Graft versus host disease rate was 46.7% and 10.1% of patients died from toxicity. There were no differences between classical DLI and gDLI in terms of response (p = 0.28), 5-year PFS (p = 0.90), 5-year OS (p. 0.50), GvHD (p = 0.86), treated GvHD (p = 0.81) and cause of mortality (p. 0.14). In conclusion, this study points out no major effectiveness or toxicity of gDLI compared to classical DLI.
Limited Agreement between Classifications of Diabetes and Prediabetes Resulting from the OGTT, Hemoglobin A1c, and Fasting Glucose Tests in 7412 U.S. Adults
Authors: Tucker Larry A.
Published: July 2020

This investigation was designed to determine the degree of concordance resulting from tests of fasting plasma glucose (FPG) and hemoglobin A1c (A1c) compared to the oral glucose tolerance test (OGTT) for detecting prediabetes and diabetes in undiagnosed adults. Another objective was to measure concordance within subsamples of women and men, and within three age groups. Lastly, the value of combining the FPG and A1c for detecting diabetes was compared to the OGTT. A total of 7412 randomly selected adults from the National Health and Nutrition Examination Survey (NHANES) were included. With outcomes classified as normal, prediabetes, or diabetes, according to standard guidelines, overall test agreements were low. With an OGTT diagnosis of diabetes, concordance was only 34% for the A1c assessment and 44% for the FPG assay. Delimited to older adults, agreement between the OGTT and A1c was only 25%, and between the OGTT and FPG, concordance was only 33.5%. Given the large percentage of discordant results associated with the FPG and A1c, clinicians should be cautious about employing these tests as lone assessments. Using both the FPG and A1c helped with accurately diagnosing diabetes and normal glycemia, but not prediabetes. The OGTT is a good choice to reduce misdiagnosis.
Augmented Reality-Assisted Periosteum Pedicled Flap Harvesting for Head and Neck Reconstruction: An Anatomical and Clinical Viability Study of a Galeo-Pericranial Flap
Authors: Battaglia Salvatore , Ratti Stefano , Manzoli Lucia , Marchetti Claudio , Cercenelli Laura , Marcelli Emanuela , Tarsitano Achille , Ruggeri Alessandra
Published: July 2020

Head and neck reconstructive surgeons have recently explored new perspectives in bone restoration using periosteum carrier flaps. Following this idea, we explored the possibility of harvesting a galeo-pericranial flap. The present work studies the vascular supply of the pericranial temporo-parietal region in order to assess the possibility of harvesting a galeo-pericranial flap based on the superficial temporalis vascularization. Anatomical dissections were performed at the Anatomical Institute of the University of Bologna on eight donor cadavers. Then we performed the harvesting of the flap in vivo on eight patients. We introduced augmented reality (AR) to facilitate anatomical visualisation during free flap harvesting. Augmented reality merges virtual and actual objects, allowing direct observation of patient anatomy and the surgical field. No post-operative major or minor complications occurred. We encountered no post-operative functional issues on the donor or recipient sites, and good clinical healing was observed in all patients. In conclusion, we believe that the galea-pericranium flap could represent a new donor site for the harvesting of a periosteum carrier flap.
Pathophysiology and Diagnosis of Drug-Induced Immune Thrombocytopenia
Authors: Vayne Caroline , Guéry Eve-Anne , Rollin Jérôme , Baglo Tatiana , Petermann Rachel , Gruel Yves
Published: July 2020

Drug-induced immune thrombocytopenia (DITP) is a life-threatening clinical syndrome that is under-recognized and difficult to diagnose. Many drugs can cause immune-mediated thrombocytopenia, but the most commonly implicated are abciximab, carbamazepine, ceftriaxone, eptifibatide, heparin, ibuprofen, mirtazapine, oxaliplatin, penicillin, quinine, quinidine, rifampicin, suramin, tirofiban, trimethoprim-sulfamethoxazole, and vancomycin. Several different mechanisms have been identified in typical DITP, which is most commonly characterized by severe thrombocytopenia due to clearance and/or destruction of platelets sensitized by a drug-dependent antibody. Patients with typical DITP usually bleed when symptomatic, and biological confirmation of the diagnosis is often difficult because detection of drug-dependent antibodies (DDabs) in the patient’s serum or plasma is frequently not possible. This is in contrast to heparin-induced thrombocytopenia (HIT), which is a particular DITP caused in most cases by heparin-dependent antibodies specific for platelet factor 4, which can strongly activate platelets in vitro and in vivo, explaining why affected patients usually have thrombotic complications but do not bleed. In addition, laboratory tests are readily available to diagnose HIT, unlike the methods used to detect DDabs associated with other DITP that are mostly reserved for laboratories specialized in platelet immunology.
Thiopurines’ Metabolites and Drug Toxicity: A Meta-Analysis
Authors: Sousa Paula , Estevinho Maria Manuela , Dias Cláudia Camila , Ministro Paula , Kopylov Uri , Danese Silvio , Peyrin-Biroulet Laurent , Magro Fernando
Published: July 2020

Many questions remain unanswered regarding therapeutic drug monitoring (TDM) utility with thiopurines. This study aims to establish a relationship between thiopurines’ metabolites and drug toxicity. We performed a systematic review with inclusion of studies evaluating the relationship between thiopurines’ metabolites and drug toxicity. Meta-analysis of mean difference (MD), correlations and odds ratio (OR) was performed. We identified 21,240 records, 72 of which were eligible for meta-analysis. Levels of 6-thioguanine nucleotides (6-TGN) were higher in patients with leukopenia (MD 127.06 pmol/8 × 108 RBC) and gastrointestinal intolerance (MD 201.46 pmol/8 × 108 RBC), and lower in patients with hepatotoxicity (MD −40.6 pmol × 108 RBC). We established a significant correlation between 6-TGN and leukocytes (r = −0.21), neutrophils (r = −0.24) and alanine aminotransferase levels (r = −0.24). OR for leukopenia in patients with elevated 6-TGN was 4.63 (95% CI 2.24; 9.57). An optimal cut-off of 135 pmol/8 × 108 RBC for leukopenia was calculated (sensitivity 75.4%; specificity 46.4%). 6-methylmercaptopurine ribonucleotides (6-MMPR) were significantly associated with hepatotoxicity (MD 3241.2 pmol/8 × 108 RBC; OR 4.28; 95% CI 3.20; 5.71). Levels of 6-MMPR measured in the first 8 weeks of treatment were associated with leukopenia. We conclude that TDM could be used to prevent thiopurines’ toxicity. As optimal metabolites level may vary according to indication, physicians may adapt posology to decrease toxicity without compromising efficacy.
Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa
Authors: Moore Spencer M. , Skowronska-Krawczyk Dorota , Chao Daniel L.
Published: July 2020

Retinitis pigmentosa (RP) is an inherited retinal dystrophy (IRD) with a prevalence of 1:4000, characterized by initial rod photoreceptor loss and subsequent cone photoreceptor loss with accompanying nyctalopia, visual field deficits, and visual acuity loss. A diversity of causative mutations have been described with autosomal dominant, autosomal recessive, and X-linked inheritance and sporadic mutations. The diversity of mutations makes gene therapy challenging, highlighting the need for mutation-agnostic treatments. Neural leucine zipper (NRL) and NR2E3 are factors important for rod photoreceptor cell differentiation and homeostasis. Germline mutations in NRL or NR2E3 leads to a loss of rods and an increased number of cones with short wavelength opsin in both rodents and humans. Multiple groups have demonstrated that inhibition of NRL or NR2E3 activity in the mature retina could endow rods with certain properties of cones, which prevents cell death in multiple rodent RP models with diverse mutations. In this review, we summarize the literature on NRL and NR2E3, therapeutic strategies of NRL/NR2E3 modulation in preclinical RP models, as well as future directions of research. In summary, inhibition of the NRL/NR2E3 pathway represents an intriguing mutation agnostic and disease-modifying target for the treatment of RP.
Clinical Characterization of the Frequent Exacerbator Phenotype in Asthma
Authors: Sprio Andrea Elio , Carriero Vitina , Levra Stefano , Botto Carlotta , Bertolini Francesca , Di Stefano Antonino , Maniscalco Mauro , Ciprandi Giorgio , Ricciardolo Fabio Luigi Massimo
Published: July 2020

Background: Asthma exacerbation is episodic worsening of respiratory symptoms in conjunction with the deterioration of lung function, which may occur independently from the asthma severity hampering asthmatics’ quality of life. This study aimed to characterize the patient phenotype more prone to asthma exacerbation (oral corticosteroid burst ≥2 per year) to allow the proper identification of such patients. Methods: This real-life, observational, cross-sectional study evaluated 464 asthmatic patients stratified according to the asthma exacerbations experienced in the previous year. Clinical, functional, and blood parameters were retrieved from chart data and were representative of patients in stable conditions. Results: The frequent asthma exacerbator was more commonly female, suffered from chronic rhinosinusitis with nasal polyposis, had reduced lung function and peripheral oxygen saturation, and had increased daily activity limitations. These patients often had severe asthma and more frequently needed hospitalization in their lives. Furthermore, the frequent asthma exacerbator had higher concentrations of serum immunoglobulin E (IgE) and exhaled nitric oxide with cut-off risk values of 107.5 kU/L (OR = 4.1) and 43.35 ppb (OR = 3.8), respectively. Conclusions: This study illustrates the clinical features of the frequent asthma exacerbator phenotype. Nevertheless, serum IgE and exhaled nitric oxide could allow the identification of this phenotype and the establishment of an appropriate therapeutic approach.
Impact of Galectin-3 Circulating Levels on Frailty in Elderly Patients with Systolic Heart Failure
Authors: Komici Klara , Gnemmi Isabella , Bencivenga Leonardo , Vitale Dino Franco , Rengo Giuseppe , Di Stefano Antonino , Eleuteri Ermanno
Published: July 2020

Background: Heart Failure (HF), a leading cause of morbidity and mortality, represents a relevant trigger for the development of frailty in the elderly. Inflammation has been reported to play an important role in HF and frailty pathophysiology. Galectin-3 (Gal-3), whose levels increase with aging, exerts a relevant activity in the processes of cardiac inflammation and fibrosis. The aim of the present study was to investigate the potential of Galectin-3 to serve as a biomarker of frailty in HF patients. Methods: 128 consecutive patients aged 65 and older with the diagnosis of systolic HF underwent a frailty assessment and blood sample collection for serum Gal-3 detection. A multivariable regression analysis and decision curve analysis (DCA) were used to identify significant predictors of frailty. Results: Frailty was present in 42.2% of patients. Age: Odds Ratio (OR) = 3.29; 95% Confidence Interval CI (CI) = 1.03–10.55, Cumulative Illness Rating Scale Comorbidity Index (CIRS-CI): OR = 1.85; 95% CI = 1.03–3.32, C-Reactive phase Protein (CRP) OR = 3.73; 95% CI = 1.24–11.22, N-terminal-pro-Brain Natriuretic Peptide (NT-proBNP): OR = 2.39; 95% CI = 1.21–4.72 and Gal-3: OR = 5.64; 95% CI = 1.97–16.22 resulted in being significantly and independently associated with frailty. The DCA demonstrated that the addition of Gal-3 in the prognostic model resulted in an improved clinical ‘net’ benefit. Conclusions: Circulating levels of Gal-3 are independently associated with frailty in elderly patients with systolic HF.
Kurarinone Inhibits HCoV-OC43 Infection by Impairing the Virus-Induced Autophagic Flux in MRC-5 Human Lung Cells
Authors: Min Jung Sun , Kim Dong Eon , Jin Young-Hee , Kwon Sunoh
Published: July 2020

Kurarinone is a prenylated flavonone isolated from the roots of Sophora flavescens. Among its known functions, kurarinone has both anti-apoptotic and anti-inflammatory properties. Coronaviruses (CoVs), including HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2, are the causative agents of respiratory virus infections that range in severity from the common cold to severe pneumonia. There are currently no effective treatments for coronavirus-associated diseases. In this report, we examined the anti-viral impact of kurarinone against infection with the human coronavirus, HCoV-OC43. We found that kurarinone inhibited HCoV-OC43 infection in human lung fibroblast MRC-5 cells in a dose-dependent manner with an IC50 of 3.458 ± 0.101 µM. Kurarinone inhibited the virus-induced cytopathic effect, as well as extracellular and intracellular viral RNA and viral protein expression. Time-of-addition experiments suggested that kurarinone acted at an early stage of virus infection. Finally, we found that HCoV-OC43 infection increased the autophagic flux in MRC-5 cells; kurarinone inhibited viral replication via its capacity to impair the virus-induced autophagic flux. As such, we suggest that kurarinone may be a useful therapeutic for the treatment of diseases associated with coronavirus infection.
Age-Related Risk Factors at the First Stroke Event
Authors: Soto-Cámara Raúl , González-Bernal Jerónimo J. , González-Santos Josefa , Aguilar-Parra José M. , Trigueros Rubén , López-Liria Remedios
Published: July 2020

(1) Background: Stroke is a multifactorial disease, which can affect individuals at any age. Risk factors (RFs) associated with the first stroke event have been well identified; however, the influence of these RFs on the patient’s age needs to be studied. (2) Objective: This study aimed to examine the effect of modifiable RFs on the age at which a stroke occurs. (3) Methods: A cross-sectional study was conducted on patients admitted consecutively with a first-ever acute stroke at the Burgos University Hospital (Spain). Data on sociodemographic and clinical parameters were collected (high blood pressure (HBP), smoking habit, diabetes mellitus (DM), dyslipemia, abdominal obesity, sedentary lifestyle, alcohol consumption, and cardiovascular diseases). The possible associations between RFs and age were studied using univariate and multivariate regression analyses and a decision tree. (4) Results: A total of 436 patients with a mean age of 75.39 years (standard deviation (SD) ± 12.67) were included. HBP and overweight/obesity were the most prevalent stroke RFs. Being an active smoker (OR 21.48; 95% confidence interval (CI) 8.80–52.41), having a sedentary lifestyle (OR 3.24; 95% CI 1.97–5.31), being an excessive alcohol drinker (OR 2.36; 95% CI 1.45–3.84), or being overweight or obese (OR 1.95; 95% CI 1.14–3.34) increased the risk of having an acute cerebrovascular event in individuals aged 75 years or below. However, a personal history of HBP (OR 0.40; 95% CI 0.24–0.67) was significantly associated with a greater likelihood of having an acute stroke in individuals aged more than 75 years. (5) Conclusions: This study showed that the modifiable RFs strongly influence the first stroke event in patients aged below 75 years, which will be useful in guiding different prevention strategies.