bluuebunny/crossref_metadata_2025_split huggingface dataset:
Usefulness of Interleukin-18 as a Diagnostic Biomarker to Differentiate Adult-Onset Still’s Disease With/Without Macrophage Activation Syndrome From Other Secondary Hemophagocytic Lymphohistiocytosis in Adults
Authors: Shiga Toshihiko , Nozaki Yuji , Tomita Daisuke , Kishimoto Kazuya , Hirooka Yasuaki , Kinoshita Koji , Funauchi Masanori , Matsumura Itaru 
Published: October 2021

BackgroundInterleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the ‘cytokine storm’ such as adult-onset Still’s disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). The differences in IL-18 between AOSD and HLH, especially in adults, is uncertain. Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH. In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group).Patients and MethodsWe enrolled 46 patients diagnosed with AOSD including 9 patients with MAS and 31 patients in the adult HLH group, which excluded AOSD-associated MAS. The clinical features and laboratory data were compared between the AOSD and adult HLH groups. In addition, we subdivided the AOSD group (with or without MAS) and the adult HLH group (whether lymphoma-associated or not) and compared the four groups. A logistic regression analysis was used to identify factors with high efficacy in differentiating the two groups, followed by a receiver operating characteristic (ROC) curve analysis to evaluate the differential diagnostic ability of IL-18. We analyzed the correlation between IL-18 and various laboratory parameters in the AOSD group.ResultsSerum IL-18 levels of patients in the AOSD groups were significantly higher than those of the adult HLH groups, and were closely correlated with ferritin, soluble interleukin-2 receptor (sIL-2R), and other laboratory data. Univariate and multivariate logistic regression analyses revealed that IL-18, sIL-2R, and ‘arthralgia or arthritis’ are independent factors useful in the differential diagnosis of AOSD from adult HLH. In the differential diagnosis of both groups, the area under the curve obtained from the ROC curve of IL-18 with a cutoff value of 18,550 pg/mL was 0.91 (95% confidence interval 0.83–1.00; sensitivity 90.3%, specificity 93.5%), and the differential diagnosis ability of IL-18 was superior to that of other laboratory data.ConclusionsIL-18 could be a useful biomarker for the differential diagnosis of AOSD and adult HLH.
Case Report: Post-CAR-T Infusion HBV Reactivation in Two Lymphoma Patients Despite Entecavir Preventive Therapy
Authors: Ma Yaxian , Yang Li , Bao Yuhan , Yang Yang , Chen Liting , Zheng Miao 
Published: October 2021

Hepatitis B virus (HBV) reactivation is a common complication in chronic or resolved HBV infection patients undergoing immunosuppressive chemotherapy. Furthermore, few articles have been published regarding the risk of HBV reactivation in lymphoma patients receiving chimeric antigen receptor (CAR) T-cell therapy and anti-HBV prophylaxis. Few guidelines or clear optimal strategies are available for managing these patients. Here, we present two cases of patients who underwent CAR-T-cell cocktail therapy with anti-CD19 and anti-CD22 CAR (CAR19/22) T cell for lymphoma. Patients had previous history of HBV infection, and blood tests on initial admission indicated positive results for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and antibody to hepatitis B e antigen (anti-HBe), while serum HBV DNA level was undetectable. Therefore, two patients received entecavir as antiviral prophylactic therapy during their entire treatment. They were diagnosed with HBV reactivation based on positive serum HBV DNA test results, 2 weeks after CAR-T-cell infusion. Liver function assay indicated elevated levels of alanine transaminase (ALT) and aspartate transaminase (AST), combined with increased levels of total bilirubin (TBIL) and direct bilirubin (DBIL). Subsequently, they received anti-HBV treatment with entecavir and tenofovir. As a result, their serum HBV DNA copies and AST/ALT levels returned to normal after 1 week. These cases show that there is a risk of HBV reactivation in lymphoma patients with CAR-T-cell therapy despite entecavir preventive therapy, and combination treatment of entecavir and tenofovir may be an effective treatment option for such patients with HBV reactivation.
Construction of Hierarchical Porous Architecture on Ni Foam for Efficient Oxygen Evolution Reaction Electrode
Authors: Ao Guang-Hong , Zhao Pei-Zhi , Peng Zhi-Gang , Wang Shuo , Guo Ying-Shuang , Chen Chun-Tian , Wang Zhi-Hong 
Published: October 2021

Nickel foam (NF) with a three-dimensional porous structure plays an important role in a wide variety of applications such as energy storage and conversion, catalysis, and sensor due to its high porosity, low density, and excellent conductivity. However, the main drawback of NF is that its ligaments are very smooth, and thus the surface area is relatively low. In this work, we propose a novel strategy, oxidization and reduction process, in situ to construct micron/nano pores on the ligaments of commercial NF to fabricate a typical hierarchical porous architecture. This process is simple and green, avoiding the use of sacrificial materials. Furthermore, MnO2 is coated on the micron/nano-porous Ni foam (MPNF) to construct an oxygen evolution reaction (OER) electrode through pulse electrodeposition. The designed MPNF-MnO2 electrode presents enhanced OER electrocatalysis activity with a low overpotential of 363.5 mV at the current density of 10 mA cm−2 in an alkaline solution, which is 66.4 mV lower than that of the NF-MnO2 electrode in the same operating conditions. Furthermore, the porous and wrinkled structures of the MPNF also improve the mechanical integrity of the electrode, resulting in super-long stability.
PNPLA3, TM6SF2, and MBOAT7 Influence on Nutraceutical Therapy Response for Non-alcoholic Fatty Liver Disease: A Randomized Controlled Trial
Authors: Dallio Marcello , Masarone Mario , Romeo Mario , Tuccillo Concetta , Morisco Filomena , Persico Marcello , Loguercio Carmelina , Federico Alessandro 
Published: October 2021

Introduction: PNPLA3, TM6SF2, and MBOAT7 genes play a crucial role in non-alcoholic fatty liver disease (NAFLD) development and worsening. However, few data are available on their treatment response influence. The aim of this trial is to explore the effect derived from silybin-phospholipids complex (303 mg of silybin-phospholipids complex, 10 μg of vitamin D, and 15 mg of vitamin E twice a day for 6 months) oral administration in NAFLD patients carrying PNPLA3-rs738409, TM6SF2-rs58542926, or MBOAT7-rs641738 genetic variants.Materials and Methods: In all, 92 biopsy-proven NAFLD patients were grouped in 30 NAFLD wild type controls, 30 wild type treated patients, and 32 mutated treated ones. We assessed glycemia (FPG), insulinemia, HOMA-IR, aspartate and alanine aminotransferases (AST, ALT), C-reactive protein (CRP), thiobarbituric acid reactive substance (TBARS), stiffness, controlled attenuation parameter (CAP), dietary daily intake, and physical activity at baseline and end of treatment.Results: The wild-type treated group showed a significant improvement of FPG, insulinemia, HOMA-IR, ALT, CRP, and TBARS (p &lt; 0.05), whereas no improvements were recorded in the other two study groups. NAFLD wild type treated patients showed higher possibilities of useful therapeutic outcome (p &lt; 0.01), obtained from the prescribed therapeutic regimen, independently from age, sex, comorbidities, medications, CAP, and stiffness in comparison to the mutated group.Discussion: The assessed mutations are independently associated with no response to a silybin-based therapeutic regimen and could be considered as useful predictive markers in this context.Clinical Trial Registry Number:www.ClinicalTrials.gov, identifier: NCT04640324.
First Attempt at Using Electrical Impedance Tomography to Predict High Flow Nasal Cannula Therapy Outcomes at an Early Phase
Authors: Li Zhe , Zhang Zhiyun , Xia Qian , Xu Danling , Qin Shaojie , Dai Meng , Fu Feng , Gao Yuan , Zhao Zhanqi 
Published: October 2021

Objective: Spatial and temporal ventilation distributions in patients with acute respiratory failure during high flow nasal cannula (HFNC) therapy were previously studied with electrical impedance tomography (EIT). The aim of the study was to explore the possibility of predicting HFNC failure based on various EIT-derived parameters.Methods: High flow nasal cannula failure was defined reintubation within 48 h after HFNC. EIT was performed with the patients spontaneously breathing in the supine position at the start of HFNC. EIT-based indices (comprising the global inhomogeneity index, center of ventilation, ventilation delay, rapid shallow breathing index, minute volume, and inspiration to expiration time) were explored and evaluated at three time points (prior to HFNC, T1; 30 min after HFNC started, T2; and 1 h after, T3).Results: A total of 46 subjects were included in the final analysis. Eleven subjects had failed HFNC. The time to failure was 27.8 ± 12.4 h. The ROX index (defined as SpO2/FiO2/respiratory rate) for HFNC success patients was 8.3 ± 2.7 and for HFNC failure patients, 6.2 ± 1.8 (p = 0.23). None of the investigated EIT-based parameters showed significant differences between subjects with HFNC failure and success. Further subgroup analysis indicated that a significant difference in ventilation inhomogeneity was found between ARDS and non-ARDS [0.54 (0.37) vs. 0.46 (0.28) as evaluated with GI, p &lt; 0.01]. Ventilation homogeneity significantly improved in ARDS after 60-min HFNC treatment [0.59 (0.20) vs 0.57 (0.19), T1 vs. T3, p &lt; 0.05].Conclusion: Spatial and temporal ventilation distributions were slightly but insignificantly different between the HFNC success and failure groups. HFNC failure could not be predicted by changes in EIT temporal and spatial indexes of ventilation distribution within the first hour. Further studies are required to predict the outcomes of HFNC.
Mechanistic Effects of Aerobic Exercise in Alzheimer's Disease: Imaging Findings From the Pilot FIT-AD Trial
Authors: Yu Fang , Mathiason Michelle A. , Han SeungYong , Gunter Jeffrey L. , Jones David , Botha Hugo , Jack Clifford 
Published: October 2021

Despite strong evidence from animal models of Alzheimer's disease (AD) supporting aerobic exercise as a disease-modifying treatment for AD, human mechanistic studies are limited with mixed findings. The objective of this pilot randomized controlled trial was to examine the effects of 6-month aerobic exercise on hippocampal volume, temporal meta-regions of interest (ROI) cortical thickness, white matter hyperintensity (WMH) volume, and network failure quotient (NFQ), measured with MRI, in community-dwelling older adults with AD dementia. Additionally, the relationships between 6- and 12-month changes in MRI biomarkers and the AD Assessment Scale-Cognition (ADAS-Cog) were examined. Sixty participants were randomized, but one was excluded because baseline MRI failed quality control: 38 randomized to cycling and 21 to stretching. The intervention was moderate-intensity cycling for 20–50 mins, three times a week for 6 months. Control was low-intensity stretching. The study outcomes include hippocampal volume, temporal meta-ROI cortical thickness, WMH volume, and NFQ. Outcomes were measured at baseline, 6 months, and 12 months. The sample averaged 77.3 ± 6.3 years old with 15.6 ± 2.9 years of education and 53% men. Both groups experienced significant declines over 6 months in hippocampal volume (2.64% in cycling vs. 2.89% in stretching) and temporal meta-ROI cortical thickness (0.94 vs. 1.54%), and over 12 months in hippocampal volume (4.47 vs. 3.84%) and temporal meta-ROI cortical thickness (2.27 vs. 1.79%). These declines did not differ between groups. WMH volume increased significantly with the cycling group increasing less (10.9%) than stretching (24.5%) over 6 months (f = 4.47, p = 0.04) and over 12 months (12.1 vs. 27.6%, f = 5.88, p = 0.02). NFQ did not change significantly over time. Pairwise correlational analyses showed a significant negative correlation between 6-month changes in hippocampal volume and ADAS-Cog (r = −0.34, p &lt; 0.05). To conclude, aerobic exercise may reduce the decline in hippocampal volume and temporal meta-ROI cortical thickness during the intervention period, but the effect sizes are likely to be very small and dose-dependent and reverse once the intervention stops. Aerobic exercise is effective on slowing down WMH progression but has no effect on NFQ. Hippocampal atrophy was associated with cognitive decline during the intervention period.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT01954550.
Intracranial EEG Biomarkers for Seizure Lateralization in Rapidly-Bisynchronous Epilepsy After Laser Corpus Callosotomy
Authors: Khuvis Simon , Hwang Sean T. , Mehta Ashesh D. 
Published: October 2021

Objective: It has been asserted that high-frequency analysis of intracranial EEG (iEEG) data may yield information useful in localizing epileptogenic foci.Methods: We tested whether proposed biomarkers could predict lateralization based on iEEG data collected prior to corpus callosotomy (CC) in three patients with bisynchronous epilepsy, whose seizures lateralized definitively post-CC. Lateralization data derived from algorithmically-computed ictal phase-locked high gamma (PLHG), high gamma amplitude (HGA), and low-frequency (filtered) line length (LFLL), as well as interictal high-frequency oscillation (HFO) and interictal epileptiform discharge (IED) rate metrics were compared against ground-truth lateralization from post-CC ictal iEEG.Results: Pre-CC unilateral IEDs were more frequent on the more-pathologic side in all subjects. HFO rate predicted lateralization in one subject, but was sensitive to detection threshold. On pre-CC data, no ictal metric showed better predictive power than any other. All post-corpus callosotomy seizures lateralized to the pathological hemisphere using PLHG, HGA, and LFLL metrics.Conclusions: While quantitative metrics of IED rate and ictal HGA, PHLG, and LFLL all accurately lateralize based on post-CC iEEG, only IED rate consistently did so based on pre-CC data.Significance: Quantitative analysis of IEDs may be useful in lateralizing seizure pathology. More work is needed to develop reliable techniques for high-frequency iEEG analysis.
Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors
Authors: Sigaud Romain , Dussault Nadège , Berenguer-Daizé Caroline , Vellutini Christine , Benyahia Zohra , Cayol Mylène , Parat Fabrice , Mabrouk Kamel , Vázquez Ramiro , Riveiro Maria E. , Metellus Philippe , Ouafik L’Houcine 
Published: October 2021

VE-cadherin is an essential adhesion molecule in endothelial adherens junctions, and the integrity of these complexes is thought to be regulated by VE-cadherin tyrosine phosphorylation. We have previously shown that adrenomedullin (AM) blockade correlates with elevated levels of phosphorylated VE-cadherin (pVE-cadherinY731) in endothelial cells, associated with impaired barrier function and a persistent increase in vascular endothelial cell permeability. However, the mechanism underlying this effect is unknown. In this article, we demonstrate that the AM-mediated dephosphorylation of pVE-cadherinY731 takes place through activation of the tyrosine phosphatase SHP-2, as judged by the rise of its active fraction phosphorylated at tyrosine 542 (pSHP-2Y542) in HUVECs and glioblastoma-derived-endothelial cells. Both pre-incubation of HUVECs with SHP-2 inhibitors NSC-87877 and SHP099 and SHP-2 silencing hindered AM-induced dephosphorylation of pVE-cadherinY731 in a dose dependent-manner, showing the role of SHP-2 in the regulation of endothelial cell contacts. Furthermore, SHP-2 inhibition impaired AM-induced HUVECs differentiation into cord-like structures in vitro and impeded AM-induced neovascularization in in vivo Matrigel plugs bioassays. Subcutaneously transplanted U87-glioma tumor xenograft mice treated with AM-receptors-blocking antibodies showed a decrease in pSHP-2Y542 associated with VE-cadherin in nascent tumor vasculature when compared to control IgG-treated xenografts.Our findings show that AM acts on VE-cadherin dynamics through pSHP-2Y542 to finally modulate cell-cell junctions in the angiogenesis process, thereby promoting a stable and functional tumor vasculature.
Berberine and Its Main Metabolite Berberrubine Inhibit Platelet Activation Through Suppressing the Class I PI3Kβ/Rasa3/Rap1 Pathway
Authors: Wang Can , Cheng Yangyang , Zhang Yuanhui , Jin Hongtao , Zuo Zengyan , Wang Aiping , Huang Jianmei , Jiang Jiandong , Kong Weijia 
Published: October 2021

Background: Berberine (BBR), a natural product, was reported to inhibit platelet aggregation; however, the molecular mechanisms remain unclear. This study aims to investigate the effects and mechanisms of BBR in inhibiting platelet activation and thrombus formation.Methods: Flow cytometry, immunofluorescence, and Western blot were used to determine the inhibitory effects and mechanisms of BBR and its main metabolite berberrubine (M2) on platelet activation in vitro and ex vivo. Purified integrin αIIbβ3, class I PI3K kit, and molecular docking were used to identify the possible targets of BBR and M2. A carrageenan-induced mouse thrombosis model was used to evaluate the effects of BBR on thrombus formation in vivo.Results:In vitro, BBR and M2 significantly inhibited ADP-induced integrin αIIbβ3 activation, reduced the level of P-selectin on the platelet membrane, and suppressed the binding of fibrinogen to the platelets. In this process, BBR and M2 greatly suppressed the PI3K/Akt pathway and inhibited Rasa3 membrane translocation and Rap1 activation. Furthermore, BBR and M2 selectively inhibited class I PI3Kβ, perhaps through binding to its active site. The activities of BBR were stronger than those of M2. After oral administration, BBR significantly inhibited the PI3K/Akt pathway and Rap1 activation and suppressed ADP-induced platelet activation and carrageenan-induced thrombosis in mice without prolonging bleeding time.Conclusions: We reveal for the first time the possible targets and mechanisms of BBR and M2 in inhibiting platelet activation. Our research may support the future clinical application of BBR as an antiplatelet drug in the prevention or treatment of thrombotic diseases.
Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy
Authors: Al-Shorbagy Muhammad Y. , Wadie Walaa , El-Tanbouly Dalia M. 
Published: October 2021

Mitochondrial oxidative status exerts an important role in modulating glia–neuron interplay during epileptogenesis. Trimetazidine (TMZ), a well-known anti-ischemic drug, has shown promising potential against a wide range of neurodegenerative disorders including epilepsy. Nevertheless, the exact mechanistic rationale behind its anti-seizure potential has not been fully elucidated yet. Herein, the impact of TMZ against mitochondrial oxidative damage as well as glutamate homeostasis disruption in the hippocampus has been investigated in rats with lithium/pilocarpine (Li/PIL) seizures. Animals received 3 mEq/kg i.p. LiCl3 followed by PIL (single i.p.; 150 mg/kg) 20 h later for induction of seizures with or without TMZ pretreatment (25 mg/kg; i.p.) for five consecutive days. Seizure score and seizure latency were observed. Mitochondrial redox status as well as ATP and uncoupling protein 2 was recorded. Moreover, glutamate homeostasis was unveiled. The present findings demonstrate the TMZ-attenuated Li/PIL seizure score and latency. It improved mitochondrial redox status, preserved energy production mechanisms, and decreased reactive astrocytes evidenced as decreased glial fibrillary acidic protein immune-stained areas in hippocampal tissue. In addition, it modulated phosphorylated extracellular signal-regulated kinases (p-ERK1/2) and p-AMP–activated protein kinase (p-AMPK) signaling pathways to reflect a verified anti-apoptotic effect. Consequently, it upregulated mRNA expression of astroglial glutamate transporters and reduced the elevated glutamate level. The current study demonstrates that TMZ exhibits robust anti-seizure and neuroprotective potentials. These effects are associated with its ability to modulate mitochondrial redox status, boost p-ERK1/2 and p-AMPK signaling pathways, and restore glutamate homeostasis in hippocampus.
Kidney Disease Management in the Hospital Setting: A Focus on Inappropriate Drug Prescriptions in Older Patients
Authors: Arcoraci Vincenzo , Barbieri Maria Antonietta , Rottura Michelangelo , Nobili Alessandro , Natoli Giuseppe , Argano Christiano , Squadrito Giovanni , Squadrito Francesco , Corrao Salvatore ,   on behalf of the REPOSI investigators
Published: October 2021

Aging with multimorbidity and polytherapy are the most significant factors that could led to inappropriate prescribing of contraindicated medications in patients with chronic kidney disease (CKD). The aim of this study was to evaluate the prescriptions of contraindicated drugs in older adults in CKD and to identify their associated factors in a hospital context. An observational retrospective study was carried out considering all patients ≥65 years with at least one serum creatinine value recorded into the REPOSI register into 2010–2016 period. The estimated glomerular filtration rate (eGFR) was applied to identify CKD. A descriptive analysis was performed to compare demographic and clinical characteristics; logistic regression models were used to estimate factors of inappropriate and percentage changes of drug use during hospitalization. A total of 4,713 hospitalized patients were recorded, of which 49.8% had an eGFR &lt;60 ml/min/1.73 m2; the 21.9% were in treatment with at least one inappropriate drug at the time of hospital admission with a decrease of 3.0% at discharge (p = 0.010). The probability of using at least one contraindicated drug was significantly higher in patients treated with more several drugs (OR 1.21, 95% CI 1.16–1.25, p &lt;0.001) and with CKD end-stages (G4: 16.90, 11.38–25.12, p &lt; 0.001; G5: 19.38, 11.51–32.64, p &lt; 0.001). Low-dose acetylsalicylic acid was the contraindicated drug mainly used at the time of admission, reducing 1.2% at discharge. An overall increase in therapeutic appropriateness in hospitalized older patients with CKD was observed, despite a small percentage of therapeutic inappropriateness at discharge that underlines the need for a closer collaboration with the pharmacologist to improve the drug management.