bluuebunny/crossref_metadata_2025_split huggingface dataset:
CYP2D6Basic Genotyping of Patients with Chronic Pain Receiving Tramadol or Codeine. A Study in a Greek Cohort
Authors: Batistaki Chrysanthi , Chrona Eleni , Kostroglou Andreas , Kostopanagiotou Georgia , Gazouli Maria 
Published: April 2020

AbstractObjectiveTo assess CYP2D6 genotype prevalence in chronic pain patients treated with tramadol or codeine.DesignProspective cohort study.SettingGeneral hospital, pain management unit.SubjectsPatients with chronic pain, treated with codeine or tramadol.MethodsPatients’ pain was assessed at baseline (numeric rating scale [NRS]; 0–10). Prescription of codeine or tramadol was selected randomly. The assessment of patients’ response to the drug in terms of pain relief and adverse effects was performed after 24 hours. Reduction of pain intensity of &gt;50% or an NRS &lt;4 was considered a positive response. Patients’ blood samples were collected during the first visit. Genotyping for the common variants CYP2D6 *2, *3, *4, *5, *6, *9, *10, *14, and *17 was performed, and alleles not carrying any polymorphic allele were classified as CYP2D6*1 (wild-type [wt]).ResultsSeventy-six consecutive patients were studied (20 males, 56 females), aged 21–85 years. Thirty-four received tramadol and 42 codeine. The main genotypes of CYP2D6 identified were the wt/wt (35.5%), the *4/wt (17.1%), and the *6/wt (10.5%). Adverse effects were common, especially in carriers of *9/*9, *5/*5, *5/*4, and *10/*10, as well as in variants including the 4 allele (*4/*1 [38.4%] and *4/*4 [42.8%]).ConclusionsGenotyping can facilitate personalized pain management with opioids, as specific alleles are related to decreased efficacy and adverse effects.
Meta-Analysis of Sensorimotor Gating Deficits in Patients With Schizophrenia Evaluated by Prepulse Inhibition Test
Authors: San-Martin Rodrigo , Castro Leonardo Andrade , Menezes Paulo Rossi , Fraga Francisco José , Simões Priscyla Waleska , Salum Cristiane 
Published: April 2020

AbstractsPrepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating that is often impaired in patients with schizophrenia. Despite the large number of studies, there is considerable variation in PPI outcomes reported. We conducted a systematic review and meta-analysis investigating PPI impairment in patients with schizophrenia compared with healthy control subjects, and examined possible explanations for the variation in results between studies. Major databases were screened for observational studies comparing healthy subjects and patients with schizophrenia for the prepulse and pulse intervals of 60 and 120 ms as primary outcomes, ie, PPI-60 and PPI-120. Standardized mean difference (SMD) and 95% confidence intervals (CI) were extracted and pooled using random effects models. We then estimated the mean effect size of these measures with random effects meta-analyses and evaluated potential PPI heterogeneity moderators, using sensitivity analysis and meta-regressions. Sixty-seven primary studies were identified, with 3685 healthy and 4290 patients with schizophrenia. The schizophrenia group showed reduction in sensorimotor gating for both PPI-60 (SMD = −0.50, 95% CI = [−0.61, −0.39]) and PPI-120 (SMD = −0.44, 95% CI = [−0.54, −0.33]). The sensitivity and meta-regression analysis showed that sample size, gender proportion, imbalance for gender, source of control group, and study continent were sources of heterogeneity (P &lt; .05) for both PPI-60 and PPI-120 outcomes. Our findings confirm a global sensorimotor gating deficit in schizophrenia patients, with overall moderate effect size for PPI-60 and PPI-120. Methodological consistency should decrease the high level of heterogeneity of PPI results between studies.
PeSTZ1 confers salt stress tolerance by scavenging the accumulation of ROS through regulating the expression of PeZAT12 and PeAPX2 in Populus
Authors: He Fang , Niu Meng-Xue , Feng Cong-Hua , Li Hui-Guang , Su Yanyan , Su Wan-Long , Pang Hongguang , Yang Yanli , Yu Xiao , Wang Hou-Ling , Wang Jie , Liu Chao , Yin Weilun , Xia Xinli 
Published: April 2020

AbstractZINC FINGER OF ARABIDOPSIS THALIANA12 (ZAT12) plays an important role in stress responses, but the transcriptional regulation of ZAT12 in response to abiotic stress remains unclear. In this study, we confirmed that a SALT TOLERANCE ZINC FINGER1 transcription factor from Populus euphratica (PeSTZ1) could regulate the expression of PeZAT12 by dual-luciferase reporter (DLR) assay and electrophoretic mobility shift assay. The expression of PeSTZ1 was rapidly induced by NaCl and hydrogen peroxide (H2O2) treatments. Overexpressing PeSTZ1 in poplar 84K (Populus alba × Populus glandulosa) plant was endowed with a strong tolerance to salt stress. Under salt stress, transgenic poplar exhibited higher expression levels of PeZAT12 and accumulated a larger amount of antioxidant than the wild-type plants. Meanwhile, ASCORBATE PEROXIDASE2 (PeAPX2) can be activated by PeZAT12 and PeSTZ1, promoting the accumulation of cytosolic ascorbate peroxidase (APX) to scavenge reactive oxygen species (ROS) under salt stress. This new regulatory model (PeSTZ1–PeZAT12–PeAPX2) was found in poplar, providing a new idea and insight for the interpretation of poplar resistance. Transgenic poplar reduced the accumulation of ROS, restrained the degradation of chlorophyll and guaranteed the photosynthesis and electron transport system. On the other hand, transgenic poplar slickly adjusted K+/Na+ homeostasis to alleviate salt toxicity in photosynthetic organs of plants under salt stress and then increased biomass accumulation. In summary, PeSTZ1 confers salt stress tolerance by scavenging the accumulation of ROS through regulating the expression of PeZAT12 and PeAPX2 in poplar.
No evidence for distinct types in the evolution of SARS-CoV-2
Authors: MacLean Oscar A , Orton Richard J , Singer Joshua B , Robertson David L 
Published: April 2020

AbstractA recent study by Tang et al. claimed that two major types of severe acute respiratory syndrome-coronavirus-2 (CoV-2) had evolved in the ongoing CoV disease-2019 pandemic and that one of these types was more ‘aggressive’ than the other. Given the repercussions of these claims and the intense media coverage of these types of articles, we have examined in detail the data presented by Tang et al., and show that the major conclusions of that paper cannot be substantiated. Using examples from other viral outbreaks, we discuss the difficulty in demonstrating the existence or nature of a functional effect of a viral mutation, and we advise against overinterpretation of genomic data during the pandemic.
Roles of Nitric Oxide and Prostanoid Mediators in the Adaptation of the Cerebrocortical Blood Flow to Carotid Artery Occlusion
Authors: Hricisak Laszlo , Pal Eva , Izsa Gergely Tamas , Polycarpou Andreas , Dobrydnio Laura Simoes , Jabronka Nikolett , Ruisanchez Eva , Fulop Agnes , Benyo Zoltan 
Published: April 2020

The understanding of cerebral autoregulation has become of notable importance due to the increased incidence of carotid artery stenosis in the elderly population which entails an increased risk of stroke, the 2nd most common cause of mortality worldwide. Many debates, regarding its exact mechanisms, exist in the scientific literature including the role of endothelial and neuronal nitric oxide (NO) synthases (eNOS and nNOS) and prostanoid mediators (PMs). According to our previous observations, eNOS, surprisingly, does not seem to play an important role in the autoregulation of the cerebrocortical blood flow (CoBF) to unilateral common carotid artery occlusion (CAO)
(1). In our recent study we aimed to analyze the combined lack of eNOS and nNOS and the role of PMs in cerebrovascular autoregulation by analyzing the changes of CoBF after reducing the cerebral perfusion pressure by unilateral (left) CAO in wild‐type (WT), as well as in eNOS/nNOS double knock‐out (KO) male mice. The role of PMs was tested by indomethacin administration (1 mg/kg, i.p.) and in thromboxane knock‐out (TPR‐KO) male mice. Using the high temporal and spatial resolution of laser‐speckle imaging regional CoBF changes were analyzed after CAO in anesthetized adult male mice. In wild‐type animals CoBF reduction in the left temporal cortex started immediately after CAO, reaching its maximum (−27%) at 6–9 s. Thereafter, CoBF recovered close to the pre‐occlusion level within 30 s indicating the activation of regulatory pathway(s). Interestingly, the frontoparietal cerebrocortical regions also showed CoBF reduction in the left (−17–19%) hemisphere, indicating a stealing effect through pial collateral vessels from the frontoparietal to the more ischemic temporal cortex. Surprisingly, in eNOS/nNOS double KO animals the acute CoBF reduction after CAO was unaltered in all cerebrocortical regions, but the recovery of CoBF was worsened as compared to controls. Indomethacin treatment resulted in a faster recovery in the temporal region, specifically 9–21 s after the occlusion. In TPR‐KO animals, however, the recovery of the CoBF was slightly diminished. These results indicate that (1) the Willis circle alone is not sufficient to provide an immediate compensation for the loss of one carotid artery, (2) the combined lack of eNOS and nNOS impairs only the subacute phase of the recovery after unilateral CAO and (3) indomethacin treatment results in a faster recovery, probably by inhibiting the release of a vasoconstrictor prostanoid, which is not thromboxane A2.Support or Funding InformationEFOP‐3.6.3‐VEKOP‐16‐2017‐00009, OTKA K‐125174, OTKA K‐112964, NVKP‐16‐1‐2016‐0042
High‐throughput proteome analysis using 50 cm long micro pillar array columns (μPAC&[trade])
Authors: Pervez Ali , Van Raemdonck Geert Geert 
Published: April 2020

The practice of bottom‐up proteomics relies to a large extent on the separation performance that can be achieved with state‐of‐the art nano LC‐MS/MS equipment. Depending on the sample complexity or the instrument time that can be dedicated to a certain sample, different LC columns and corresponding LC‐MS/MS methods are required. When aiming for comprehensive proteome analysis with deep coverage, relatively long columns (lengths up to 75 cm) are typically operated with long and shallow solvent gradients, delivering the highest chromatographic performance. However, daily routine proteome analysis often deals with much less complex samples or demands increased sample throughput, making total analysis times above 120 min undesirable or even impossible. The LC columns typically used for this type of analyses do not exceed 25 cm in length, with a focus on workflow robustness and efficiency rather than on maximizing chromatographic performance or peak capacity
(1).In the past few years, micro pillar array column (μPAC™) technology has evolved from a tool to perform fundamental LC research to a powerful alternative for classical nano LC columns. The inherent high permeability and low ‘on‐column’ dispersion obtained by the perfect order of the separation bed makes pillar array based chromatography unique in its kind. The peak dispersion originating from heterogeneous flow paths in the separation bed is drastically reduced and therefore components remain much more concentrated during separation
(2). Apart from an improved efficiency, pillar array columns can also be designed with substantially lower flow resistances compared to packed bed columns. The distance between the pillars can be independently controlled from the pillar size, enabling the fabrication of columns over a range of external porosities.Using a 50 cm long reversed phase C18 μPAC™ nano LC column in combination with a Thermo Orbitrap Elite mass spectrometer for detection, we demonstrate extremely robust and high‐throughput proteome analysis at capillary flow rates up to 2 μl/min. At these flow rates, sample throughput can be increased to 20, 30, 60 and even 100 samples per day with corresponding peak capacity values (nC) of respectively 300, 250, 200 and 150. When comparing the chromatographic performance that could be obtained for single protein and cell lysate tryptic digest samples to state‐of‐the art packed bed nano LC columns (packed with sub 2 μm silica particles), average peptide peak widths could be reduced by a factor of 1.6. For complex HeLa cell digest samples, this resulted in an increase in peptide and protein group identifications of respectively 60 and 40%.
Inhibition of warm temperature‐sensitive and Ca2+‐permeable TRPV3 channel by a novel compound QDULM‐12 for anti‐pruritus and dermatitis
Authors: Lv Mengqi , Wu Han , Sun Xiaoying , Zhang Zhongyin , Wang KeWei 
Published: April 2020

Transient receptor potential vanilloid 3 (TRPV3) channel as a member of thermoTRPV subfamily is primarily expressed in the keratinocytes of the skin and sensory neurons. Genetic gain‐of‐function mutations of TRPV3 gene cause skin‐related diseases such as pruritus and dermatitis, indicating that pharmacological inhibition of overactive TRPV3 may be beneficial for skin health and diseases. However, there is a significant lack of specific tools that can be used to validate TRPV3 channel as therapeutic target for skin diseases or indications yet to be defined. Recently, we made a serial modifications on natural bioactive compound and evaluated their inhibitory activities on human TRPV3 channels expressed in HEK293 cells using whole‐cell patch clamp recordings. We identified a hit compound QDULM‐12 that exhibited a dose‐dependent inhibition of hTRPV3 channel current activated by agonist 2‐APB (50 μM) with an IC50 value in a range of 0.1 μM. The selectivity of QDULM‐12 compound over other thermoTRP channels and its biological effects on in vitro keratinocytes and in vivo pruritus and dermatitis are currently underway.Support or Funding InformationThis work was supported by research grants awarded to XYS from the National Natural Sciences Foundation of China (81903734), the Natural Science Foundation of Shandong Province (ZR2017BH020), and to WKW from the National Natural Sciences Foundation of China (81573410), the Ministry of Science and Technology of China (2018ZX09711001‐004‐006).
A novel and potent neuronal Kv7 channel opener SCR2682 alleviates chronic pain in rats
Authors: Wang Jing , Liu Yani , Hu Fang , Ju Chuanxia , Wang Kewei 
Published: April 2020

Activation of neuronal Kv7/KCNQ/M‐current emerges as an effective intervention for treatment of hyperexcitability‐related neurological diseases including chronic pain that is prevalent and unmet medical need. The aim of this study was to evaluate the anti‐nociceptive effects of a novel and potent Kv7/KCNQ/M channel opener SCR2682 on chronic pain in rats. The pharmacological effects of SCR2682 on native M current and firing of dorsal root ganglia (DRG) neurons were examined using electrophysiological recordings. Two in vivo rat models of complete Freund’s adjuvant (CFA)‐induced inflammatory pain and spared nerve injury (SNI)‐induced neuropathic pain were used to evaluate anti‐nociceptive effects of SCR2682 by measuring the paw withdrawal mechanical threshold (PWMT) and/or thermal latency (PWTL). Locomotor activity in normal rats was tested for safety evaluation. The expression of KCNQ2 in L4 and L5 DRGs of rat SNI model was detected by quantitative RT‐PCR and western blot.We found that SCR2682 (0.1 μM) or an FDA approved anti‐epileptic drug retigabine (RTG) (10 μM) increased M current in rat DRG neurons approximately 30%, which was blocked by Kv7 channel inhibitor XE991 (3 μM). SCR2682 caused the resting membrane potential (RMP) hyperpolarization to −66.4 ± 3.7 mV from −56.7 ± 2.8 mV. Current clamp recordings revealed that perfusion of SCR2682 abolished the firing spikes of DRG neurons. In rat model of CFA‐induced inflammatory pain, intraperitoneal (i.p.) administration of SCR2682 at doses of 0.5, 1 and 2 mg/kg increased the PWMT and PWTL in a dose‐dependent manner, as compared with RTG (7 mg/kg) that also increased the PWMT and PWTL. In the model of SNI‐induced neuropathic pain, SCR2682 (0.5, 1 and 2 mg/kg) or RTG (7 mg/kg) increased the PWMT, and the anti‐nociceptive effect of SCR2682 (2 mg/kg) could be reversed by the channel specific blocker XE991 (3 mg/kg, i.p.). Furthermore, SCR2682 (2 mg/kg.) or RTG (7 mg/kg) significantly increased the expression of KCNQ2 mRNA and protein in DRG of SNI rats, and co‐injection of XE991 (3 mg/kg) with SCR2682 reduced the expression levels of KCNQ2. In the open field test, there was no significant difference in the travel total distance and mean speed of rats treated with RTG (7 mg/kg) or SCR2682 (0.5, 1 and 2 mg/kg). Taken together, our data show that the novel compound SCR2682 reduces the excitability of DRG sensory neurons by activating Kv7 channel, and intraperitoneal administration of SCR2682 alleviates chronic pain in rats.Support or Funding InformationThis project was supported by grants awarded to K.W. from National Natural Sciences Foundation of China (81573410) and the Ministry of Science and Technology of China (2018ZX09711001‐004‐006) and Science and Technology Program of Guangdong (2018B030334001).
Mesenchymal Stem Cell–Derived Extracellular Vesicles Alleviate Acute Lung Injury Via Transfer of miR-27a-3p*
Authors: Wang Jiangmei , Huang Ruoqiong , Xu Qi , Zheng Guoping , Qiu Guanguan , Ge Menghua , Shu Qiang , Xu Jianguo 
Published: April 2020

Objectives:
The goal of this study was to determine the role of microRNA transfer in mediating the effects of mesenchymal stem cell–derived extracellular vesicles in acute lung injury.

Design:
Experimental cell and animal studies.

Setting:
University-based research laboratory.

Subjects:
THP-1 monocytes, bone marrow–derived macrophages, and C57BL/6 mice.

Interventions:
To determine the microRNA transfer in vitro, mesenchymal stem cells and mesenchymal stem cell–derived extracellular vesicles were cultured with THP-1 cells and bone marrow–derived macrophages and then assayed for microRNA expression in the target cells. To examine the role of microRNA transfer in vivo, mesenchymal stem cell–derived extracellular vesicles were administered to mice with lipopolysaccharide-induced lung injury.

Measurements and Main Results:
Mesenchymal stem cell–derived extracellular vesicles were efficiently taken up by macrophages in vitro and in vivo. miR-27a-3p was one of the most highly expressed microRNAs in THP-1 cells in microarray analysis and was transferred from mesenchymal stem cells and mesenchymal stem cell–derived extracellular vesicles to THP-1/bone marrow–derived macrophages. Mesenchymal stem cell–derived extracellular vesicles promoted M2 polarization in bone marrow–derived macrophages, which was inhibited by lentiviral anti-miR-27a-3p transduction. Mesenchymal stem cell–derived extracellular vesicles administered systemically and intratracheally were as effective as mesenchymal stem cells in alleviating acute lung injury, elevating miR-27a-3p levels in alveolar macrophages, and promoting M2 macrophage polarization. Treatment of mesenchymal stem cell–derived extracellular vesicles concurrently decreased alveolar macrophage expression of nuclear factor kappa B subunit 1, a target of miR-27a-3p. Lentiviral transduction of mesenchymal stem cells with anti-miR-27a-3p or knockdown of miR-27a-3p in vivo abolished the effects of mesenchymal stem cell–derived extracellular vesicles on acute lung injury and M2 macrophage polarization.

Conclusions:
Mesenchymal stem cell–derived extracellular vesicles mitigate acute lung injury at least partially via transferring miR-27a-3p to alveolar macrophages. miR-27a-3p acts to target NFKB1 and is a crucial regulator of M2 macrophage polarization.
Sepsis and Septic Shock in Patients With Malignancies: A Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique Study*
Authors: Lemiale Virginie , Pons Stéphanie , Mirouse Adrien , Tudesq Jean-Jacques , Hourmant Yannick , Mokart Djamel , Pène Frédéric , Kouatchet Achille , Mayaux Julien , Nyunga Martine , Bruneel Fabrice , Meert Anne-Pascale , Borcoman Edith , Bisbal Magali , Legrand Matthieu , Benoit Dominique , Azoulay Elie , Darmon Michaël , Zafrani Lara 
Published: April 2020

Objectives:
Cancer affects up to 20% of critically ill patients, and sepsis is one of the leading reasons for ICU admission in this setting. Early signals suggested that survival might be increasing in this population. However, confirmation studies have been lacking. The goal of this study was to assess trends in survival rates over time in cancer patients admitted to the ICU for sepsis or septic shock over the last 2 decades.

Data Source:
Seven European ICUs.

Study Selection:
A hierarchical model taking into account the year of admission and the source dataset as random variables was used to identify risk factors for day 30 mortality.

Data Extraction:
Data from cancer patients admitted to ICUs for sepsis or septic shock were extracted from the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique database (1994–2015).

Data Synthesis:
Overall, 2,062 patients (62% men, median [interquartile range] age 59 yr [48–67 yr]) were included in the study. Underlying malignancies were solid tumors (n = 362; 17.6%) or hematologic malignancies (n = 1,700; 82.4%), including acute leukemia (n = 591; 28.7%), non-Hodgkin lymphoma (n = 461; 22.3%), and myeloma (n = 244; 11.8%). Two-hundred fifty patients (12%) underwent allogeneic hematopoietic stem cell transplantation and 640 (31.0%) were neutropenic at ICU admission. Day 30 mortality was 39.9% (823 deaths). The year of ICU admission was associated with significant decrease in day 30 mortality over time (odds ratio, 0.96; 95% CI, 0.93–0.98; p = 0.001). Mechanical ventilation (odds ratio, 3.25; 95% CI, 2.52–4.19; p < 0.01) and vasopressors use (odds ratio, 1.42; 95% CI, 1.10–1.83; p < 0.01) were independently associated with day 30 mortality, whereas underlying malignancy, allogeneic hematopoietic stem cell transplantation, and neutropenia were not.

Conclusions:
Survival in critically ill oncology and hematology patients with sepsis improved significantly over time. As outcomes improve, clinicians should consider updating admission policies and goals of care in this population.