bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial dysfunction and the risk of heart failure in a community‐based study: the Multi‐Ethnic Study of Atherosclerosis
Authors: Ärnlöv Johan , Sang Yingying , Ballew Shoshana H. , Vaidya Dhananjay , Michos Erin D. , Jacobs David R. , Lima Joao , Shlipak Michael G. , Bertoni Alain G. , Coresh Josef , Blaha Michael , Post Wendy S. , Matsushita Kunihiro
Published: October 2020

Aims

We aimed to investigate the association between endothelial dysfunction, assessed by brachial flow‐mediated dilation (FMD), and the incidence of heart failure (HF) in the community‐based Multi‐Ethnic Study of Atherosclerosis.

Methods and results

Brachial artery FMD was measured in a nested case‐cohort sample including 3496 of 6814 Multi‐Ethnic Study of Atherosclerosis participants without prevalent cardiovascular disease (mean age 61 years, 50% women). Multivariable probability‐weighted Cox proportional hazards analysis was used to examine the association between FMD and incident HF. We also investigated the association between FMD and HF with reduced vs. preserved ejection fraction [HFrEF (left ventricular ejection fraction <45%) vs. HFpEF (left ventricular ejection fraction ≥45%)]. During follow‐up (median 12 years), 149 participants developed incident HF (incidence rate 3.7 events per 1000 person years). There were 56 HFrEF and 69 HFpEF events (incidence rates 1.4 and 1.7 events per 1000 person years, respectively). In multivariable models adjusted for established HF risk factors (age, sex, race/ethnicity, body mass index, systolic blood pressure, antihypertensive treatment, heart rate, diabetes mellitus, history of myocardial infarction, current smoker, and former smoker status), individuals in the highest quartile of FMD (reflecting better endothelial function) had a lower HF risk compared with individuals in the lowest quartile [hazard ratio 0.53, 95% confidence interval (CI) 0.31–0.95]. Lower risk according to higher FMD was particularly evident for HFrEF, but not for HFpEF (hazard ratio per standard deviation increase 0.79, 95% CI 0.64–0.97 vs. 0.99, 95% CI 0.78–1.26, respectively). Results remained similar after adjustment for baseline natriuretic peptide levels. The addition of FMD to established HF risk factors generally rendered no or only modest improvement in C‐statistics [C‐statistics for model with established HF risk factors: 0.774, and with the addition of FMD: 0.776 (delta C 0.002, 95% confidence interval −0.002 to 0.006)].

Conclusions

Endothelial dysfunction was independently associated with HF in this community cohort, suggesting a pathophysiological contribution of endothelial function to the development of HF, in particular HFrEF. However, the value of FMD measurements for HF risk prediction seems limited.
Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and long‐term extension study
Authors: Damy Thibaud , Garcia‐Pavia Pablo , Hanna Mazen , Judge Daniel P. , Merlini Giampaolo , Gundapaneni Balarama , Patterson Terrell A. , Riley Steven , Schwartz Jeffrey H. , Sultan Marla B. , Witteles Ronald
Published: October 2020

Aims

Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR‐CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT). While ATTR‐ACT was not designed for a dose‐specific assessment, further analysis from ATTR‐ACT and its long‐term extension study (LTE) can guide determination of the optimal dose.

Methods and results

In ATTR‐ACT, patients were randomized (2:1:2) to tafamidis 80 mg, 20 mg, or placebo for 30 months. Patients completing ATTR‐ACT could enrol in the LTE (with placebo‐treated patients randomized to tafamidis 80 or 20 mg; 2:1) and all patients were subsequently switched to high‐dose tafamidis. All‐cause mortality was assessed in ATTR‐ACT combined with the LTE (median follow‐up 51 months). In ATTR‐ACT, the combination of all‐cause mortality and cardiovascular‐related hospitalizations over 30 months was significantly reduced with tafamidis 80 mg (P = 0.0030) and 20 mg (P = 0.0048) vs. placebo. All‐cause mortality vs. placebo was reduced with tafamidis 80 mg [Cox hazards model (95% confidence interval): 0.690 (0.487–0.979), P = 0.0378] and 20 mg [0.715 (0.450–1.137), P = 0.1564]. The mean (standard error) change in N‐terminal pro‐B‐type natriuretic peptide from baseline to Month 30 was −1170.51 (587.31) (P = 0.0468) with tafamidis 80 vs. 20 mg. In ATTR‐ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80 vs. 20 mg [0.700 (0.501–0.979), P = 0.0374]. Incidence of adverse events in both tafamidis doses were comparable to placebo.

Conclusion

Tafamidis, both 80 and 20 mg, effectively reduced mortality and cardiovascular‐related hospitalizations in patients with ATTR‐CM. The longer‐term survival data and the lack of dose‐related safety concerns support tafamidis 80 mg as the optimal dose.

Clinical Trial Registration: ClinicalTrials.gov NCT01994889; NCT02791230.
Mycobacterium tuberculosis PPE18 protein inhibits MHC class II antigen presentation and B cell response in mice
Authors: Dolasia Komal , Nazar Faiza , Mukhopadhyay Sangita
Published: October 2020

PPE18 protein belongs to PE/PPE family of Mycobacterium tuberculosis. We reported earlier that PPE18 protein provides survival advantage to M. tuberculosis during infection. In the current study, we found that PPE18 inhibits MHC class II‐mediated antigen presentation by macrophages in a dose‐dependent manner without affecting the surface level of MHC class II or co‐stimulatory molecules. PPE18 does not affect antigen uptake or presentation of preprocessed peptide by macrophages. Antigen degradation was found to be inhibited by PPE18 protein due to perturbation in phagolysosomal acidification. PPE18‐mediated inhibition of MHC class II antigen presentation caused poorer activation of CD4 T cells. Mice infected with M. smegmatis expressing PPE18 exhibited reduced maturation and activation of B cells and had decreased Mycobacteria‐specific antibody titers. Thus M. tuberculosis probably utilizes PPE18 to inhibit MHC class II antigen presentation causing poorer activation of adaptive immune responses. This study may be useful in understanding host–pathogen interaction and open up directions of designing novel therapeutics targeting PPE18 to tackle this nefarious pathogen.
Design of home load management system for load rationing in Pakistan
Authors: Butt Muhammad Bilal , Dilshad Saad , Abas Naeem , Rauf Shoaib , Saleem Muhammad Shoaib
Published: October 2020

The fast‐growing electricity demand in Pakistan and other developing countries has posed a severe challenge to electricity distribution systems. Indeed, most of the utility companies have to follow a trend of load shedding to face this difficulty. Load shedding is the “art” of managing the load demand by shedding loads in critical situations where the demand is higher than the total generation to avoid system failure. Although electricity utilities are suggesting consumers reduce the load during peak hours in their monthly bills, the consumers are not willing or aware of this. It is clear how tedious and tiresome it is to remind the customers what the peak hours are, and manually switch off/on the heavy load during peak and off‐peak hours. The estimated cost of the system is around 43$ and 28$ with and without Global System for Mobile Communications module for message notification. Moreover, the distribution feeder has a specific capacity to bear the load in peak hours after this is automatically shut down the whole feeder. In this paper, the simulation analysis of a single‐family house is performed for automatic load reduction during peak hours in Proteus software. A hardware prototype is then designed and applied so as to validate the proposed control system. The results show that the proposed scheme allows for an efficient peak shaving during peak hours. For some typical domestic and commercial consumers, the financial benefits are also calculated. It is concluded that the payback period of this device is almost 1 month if it reduces 50% of load during the 4‐hour peak time. The proposed system may be implemented as a single additional tool/span is already available energy meters and may quickly be adopted by electric utilities of developing countries to avoid the load shedding trend.
Binder‐Assisted Dispersion of Agglomerated Carbon Nanotubes for Efficiently Establishing Conductive Networks in Cathodes of Li‐Ion Batteries
Authors: Zhang Mengxuan , Ning Guoqing , Xiao Zhihua
Published: October 2020

Carbon nanotubes (CNTs) are a promising conductive additive for Li‐ion batteries. However, good dispersion of agglomerated CNTs (ACNTs) still remains challenge. Herein, a binder‐assisted dispersion of ACNTs is demonstrated to efficiently construct a homogeneous conductive network in LiFePO4 cathodes. The addition of polyvinylidene fluoride (PVDF) significantly reduces the size of ACNT agglomerates, which leads to better dispersion of ACNTs in N‐methyl‐pyrrolidone. The LiFePO4 electrodes with conductive networks constructed from PVDF–ACNT suspensions exhibit superior electrode performance, as compared to those using the commercial CNT slurry.
Performance analysis of randomized arbitration interframe space tuning algorithm for enhanced distributed channel access in IEEE 802.11p based vehicular network
Authors: Antony Justin Gopinath , Balasubramanian Nithya
Published: October 2020

The Internet of Vehicle (IoV) aims to provide efficient vehicular communication by enhancing connectivity and user safety. IEEE 802.11p, a medium access control protocol, plays a vital role in the IoV protocol stack, which uses the enhanced distributed channel access (EDCA) method for channel contention. To deal with safety and nonsafety vehicular applications, EDCA adopts four access categories (AC), and each AC manages the channel access based on the priority of packets along with the contention window size and arbitration interframe spacing number (AIFSN). However, these contention parameters are fixed for each AC, and it does not account the real‐time network traffic. Hence, the fine‐tuning of AIFSN values and maintaining strict priority are challenging tasks for the highly dynamic vehicular network. To address these issues, this article proposes a novel probabilistic approach, namely, the randomized AIFSN tuning (RAT) algorithm for EDCA. It updates AIFSN value for every retransmission based on the vehicle density and contention intensity by preserving the strict priority behavior of the AC queues. A three‐dimensional Markov model is developed to analyze the proposed algorithm in terms of collision probability and throughput. The proposed RAT algorithm is simulated using the NS3 network simulator along with simulations for urban mobility (SUMO) for the real‐time traffic, and results are compared with other related algorithms in terms of packet loss, goodput, packet delivery ratio, and delay of each AC queue. These results reveal that the proposed RAT algorithm outperforms related algorithms under varying vehicle density.
Potential pest invasion risk posed by international sweet cherry trade
Authors: Lu Guocai , Zhao Zihua , Pan Xubin
Published: October 2020

Trade has long been considered a potent pathway throughout the global spread of alien species, while related links between them remain poorly tested at a global scale. We therefore took sweet cherry, an emerging commercial fresh fruit, as a case study to explore the international trade patterns and its impact on global pest transfer. We used data on annual bilateral trade volume between countries from 1961 to 2016 (from FAOSTAT) and the current occurrence of sweet cherry pests per country (from CABI). The international sweet cherry trade was highly concentrated, especially in Europe with obvious intracontinental self‐selling. Cluster analysis and nonmetric multidimensional scaling divided the 66 producing countries into five groupings on pest compositional similarities, for which both the short geographical distance and trade pattern above‐mentioned might be responsible. Meanwhile, the country‐level pest species richness increased linearly with the log of production and proportionally over‐represented in specific countries with large import volumes. Overall, ongoing regional and global cooperation for most trading countries should be promoted to improve international regulations, and to maximize the benefits of pest records in terms of facilitating trade and reducing invasion risks of alien species. This is particularly essential for China, who has already granted sweet cherry market permits to 10 main producing countries. Of those, all but three were in the same grouping as China which poses the greatest risk for pest introduction and establishment.
Research constituents, intellectual structure, and collaboration pattern in the Journal of Forecasting: A bibliometric analysis
Authors: Baker H. Kent , Kumar Satish , Pattnaik Debidutta
Published: October 2020

This study provides a retrospective of the Journal of Forecasting (JoF) between 1982 and 2019. Evidence shows a considerable increase in JoF's productivity and influence since 1982. For example, a JoF article, on average, receives more than 18 citations, and contributions from 65 nations appear in the journal. All articles have a forecasting implication, but JoF encourages a wide range of contexts recently featuring value‐at‐risk and financial econometrics. Factors with a positive association with JoF citations include the number of references, article length, article age, special issue, and number of authors.
PARP inhibition in prostate cancer
Authors: Nientiedt Cathleen , Duensing Anette , Zschäbitz Stefanie , Jäger Dirk , Hohenfellner Markus , Stenzinger Albrecht , Duensing Stefan
Published: October 2020

Defects in DNA damage repair genes are more common in prostate cancer than previously thought. These alterations provide an opportunity for precision oncology approaches and a number of studies have now shown that PARP inhibitors can have significant antitumor activity in men with DNA damage repair‐deficient metastatic castration‐resistant prostate cancer. This review summarizes the key clinical trials related to the use of PARP inhibitors in prostate cancer. Besides clinical outcomes, toxicity, and PARP inhibitor resistance, the role of different DNA repair genes in the response to PARP inhibition will be discussed.
Spectrally Selective Absorbers/Emitters for Solar Steam Generation and Radiative Cooling‐Enabled Atmospheric Water Harvesting
Authors: Li Yang , Lin Chongjia , Huang Jingyuan , Chi Cheng , Huang Baoling
Published: October 2020

Renewable energy harvesting from the sun and outer space have aroused significant interest over the past decades due to their great potential in addressing the energy crisis. Furthermore, the harvested renewable energy has benefited another global challenge, water scarcity. Both solar steam generation and passive radiative cooling‐enabled atmospheric water harvesting are promising technologies that produce freshwater in green and sustainable ways. Spectral control is extremely important to achieve high efficiency in the two complementary systems based on absorbing/emitting light in a specific wavelength range. For this reason, a broad variety of solar absorbers and IR emitters with great spectral selectivity have been developed. Although operating in different spectral regions, solar selective absorbers and IR selective emitters share similar design strategies. At this stage, it is urgent and necessary to review their progress and figure out their common optical characteristics. Herein, the fundamental mechanisms and recent progress in solar selective absorbers and IR selective emitters are summarized, and their applications in water production are reported. This review aims to identify the importance of selective absorbers/emitters and inspire more research works on selective absorbers/emitters through the summary of advances and the establishment of the connection between solar absorbers and IR emitters.
Lower Cretaceous clastic dykes in southern Tibet: Characteristics and palaeogeographic significance
Authors: Guo Huifang , Chen Xi , Yao Hanwei , Han Kaibo , Garzanti Eduardo , Liu Xuan , Fan Hanhan
Published: October 2020

A clastic dyke is a stratigraphically vertical, wall‐like body of clastic material that fills open fissures across strata, and may provide important information on regional depositional processes and tectonic activity. Clastic dyke swarms composed of greyish to brown, fine‐ to medium‐grained lithic‐rich volcaniclastic sandstone are widely exposed in the lower Aptian shales in the Gucuo and Wölong areas of the Tethyan Himalaya in southern Tibet, where they are distributed along a series of normal faults. The length and width of clastic dykes range from 5 to 50 m and from 20 to 150 cm, respectively. The U–Pb age spectra of zircon grains contained in clastic dykes are similar to those in Lower Cretaceous sandstones exposed in the studied areas (i.e., Wölong volcaniclastics) and display a youngest peak at 124.3± 2 Ma. Petrographic analyses show that the underlying strata and dykes contain more volcanic lithic fragments and less feldspar grains than the overlying strata, indicating that the dykes were derived from underlying strata and injected upward along faults. Their formation may be explained by a fault‐induced clastic‐dyke model: normal faults provided conduits for clastic material injected from the underlying unlithified sandstones which were undergoing refluidization owing to over‐pressure. We infer that the liquefaction of underlying strata was induced by earthquakes associated with the extensive magmatic activities and regional extension that affected the Indian passive margin of Neotethys during the Early Cretaceous.
A real‐world efficacy and safety analysis of combined carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed/refractory multiple myeloma
Authors: Rocchi Serena , Tacchetti Paola , Pantani Lucia , Mancuso Katia , Rizzello Ilaria , di Giovanni Bezzi Chiara , Scalese Marco , Dozza Luca , Marzocchi Giulia , Martello Marina , Barilà Gregorio , Antonioli Elisabetta , Staderini Michela , Buda Gabriele , Petrini Mario , Cea Michele , Quaresima Micol , Furlan Anna , Bonalumi Angela , Cavo Michele , Zamagni Elena
Published: October 2020

Carfilzomib–lenalidomide–dexamethasone (KRd) has been approved for the treatment of relapsed/refractory multiple myeloma (RRMM). We conducted a retrospective analysis of 197 RRMM patients (pts) between January 2016 and March 2018 in six Italian hematologic centers, with the aim to evaluate efficacy and safety of KRd in real‐life. At KRd initiation 27% carried high risk cytogenetic abnormalities (HRCA) [del17p and/or t(4;14) and/or t(14;16)], median number of prior lines of therapy was 2 (1–8), nearly all pts (96%) received prior bortezomib (18% refractory) while 45% were exposed to lenalidomide (R; 22% refractory). At the median of 12.5 months, 52% of the pts had discontinued treatment, mainly (66%) for progression. Main grade 3–4 adverse events were neutropenia (21%), infections (11%), and hypertension (6%). Overall, the response rate was 88%. The median progression‐free survival (PFS) was 19.8 months and 1‐year overall survival (OS) rate was 80.6%. By subgroup analysis, extended PFS and OS were observed for pts who received ≤2 prior lines of therapy (HR = 0.42, p < 0.001 and HR = 0.35, p = 0.001, respectively), not refractory to prior R (HR = 0.37, p < 0.001, and HR = 0.47, p = 0.024), without HRCA (HR = 0.33, p = 0.005 and HR = 0.26, p = 0.016) and achieving ≥ very good partial response (VGPR; HR = 0.17, p < 0.001 and HR = 0.18, p < 0.001). In conclusion, KRd demonstrated to be effective in RRMM pts treated in real‐world setting, without new safety concerns. Better survival outcomes emerged for pts with ≤2 prior lines of therapy, achieving at least a VGPR, and without HRCA.
What has single‐cell RNA sequencing revealed about microglial neuroimmunology?
Authors: Kubick Norwin , Henckell Flournoy Patrick C. , Klimovich Pavel , Manda Gina , Mickael Michel‐Edwar
Published: October 2020

The use of single‐cell RNA sequencing (scRNA‐seq) in microglial research is increasing rapidly. The basic workflow of this approach consists of isolating single cells, followed by sequencing. scRNA‐seq is capable of examining microglial heterogeneity on a cellular level. However, the results gained from applying this technique suffer from discrepancies due to differences between applied methods characteristics such as the number of cells sequenced and the depth of sequencing. This review aims to shed more light on the recent developments that happened in this field and how they are related to the methods used. To do that, we track the progress and limitations of various scRNA‐seq methods currently available. The review then summarizes the current knowledge gained using scRNA‐seq in the field of microglia, including novel subpopulations associated with function and development under homeostasis as well during several pathological conditions such as Alzheimer, lipopolysaccharide response, and HIV in relation to the methods employed. Our review points out that despite major developments found using this technique, current scRNA‐seq methods suffer from high cost, low yields, and nonstandardization of generated data. Additional development of scRNA‐seq methods will raise our awareness of microglia's heterogeneity and plasticity under healthy and pathological conditions.
Single probe diffuse reflectance spectroscopy to assess the effect of sarcopoterium spinosum treatment on the cerebral tissue properties of ApoE knockout mouse
Authors: Shemesh David , Rozenberg Konstantin , Rosenzweig Tovit , Abookasis David
Published: October 2020

In this work, diffuse near‐infrared light reflectance spectroscopy based on a single optical probe, contains central single collection fiber surrounded by a circular array of illumination fibers, was used to quantify cerebral tissue properties in ApoE knockout mice following Sarcopoterium spinosum treatment. Sarcopoterium spinosum, also known as Thorny burnet, is a Mediterranean plant widely used as a traditional therapy for the treatment of a variety of pathologies, primarily type 2 diabetes mellitus (T2D). While it's efficacy in the treatment of T2D, and of other components of metabolic syndrome, have already been validated by us, the aim of this study was to investigate the effects of Sarcopoterium spinosum extract (SSE) on dyslipidemia and vascular functions. We utilized ApoE deficient mice (ApoE−/−, Atherosclerosis‐prone apolipoprotein E‐deficient), who have a severe impairment in plasma lipoprotein clearance and thus develop alterations in blood lipid profile and are highly susceptible to atherogenic plaque formation. A total of 34 male mice were divided into five groups representing various genetic, dietary, and treatment configurations. Optical measurements were used to assess changes in diffused reflectance spectra, optical properties (absorption and scattering), and cerebral tissue chromophore contents. Specifically, significant improvement in cerebral hemoglobin level was observed in ApoE KO mice, fed an artherogenic diet (ATD), upon SSE treatment. Biochemical and histological analyses of ApoE−/−ATD mice showed elevated body weight and a high level of blood triglycerides, free fatty acids and cholesterol. In contrast, in SSE treated mice improvement was observed, suggesting beneficial effects of SSE. In ApoE−/−ATD mice group a higher levels of deoxyhemoglobin was monitored indicating that the rate of oxygen release to the tissue is low. This was supported by decrease in oxygen saturation. It was also shown a reduction in water content in the brain of ApoE KO. Mice fed with the atherogenic diet demonstrated increased water content as compared to STD‐fed ApoE KO mice, while SSE administration reversed the effect of the diet. To our knowledge, no such study has been reported before.
Fabrication and characterization of Ag‐ and Ga‐doped mesoporous glass‐coated scaffolds based on natural marine sponges with improved mechanical properties
Authors: Ciraldo Francesca E. , Arango‐Ospina Marcela , Goldmann Wolfgang H. , Beltrán Ana M. , Detsch Rainer , Gruenewald Alina , Roether J. A. , Boccaccini Aldo R.
Published: October 2020

Natural marine sponges were used as sacrificial template for the fabrication of bioactive glass‐based scaffolds. After sintering at 1050°C, the resulting samples were additionally coated with a silicate solution containing biologically active ions (Ag and Ga), well‐known for their antibacterial properties. The produced scaffolds were characterized by superior mechanical properties (maximum compressive strength of 4 MPa) and total porosity of ~80% in comparison to standard scaffolds made by using PU foam templates. Direct cell culture tests performed on the uncoated and coated samples showed positive results in terms of adhesion, proliferation, and differentiation of MC3T3‐E1 cells. Moreover, vascular endothelial growth factor (VEGF) secretion from cells in contact with scaffold dissolution products was measured after 7 and 10 days of incubation, showing promising angiogenic results for bone tissue engineering applications. The antibacterial potential of the produced samples was assessed by performing agar diffusion tests against both Gram‐positive and Gram‐negative bacteria.
PARK7 enhances antioxidative‐stress processes of BMSCs via the ERK1/2 pathway
Authors: Zhang Fei , Peng Wuxun , Zhang Jian , Wang Lei , Dong Wentao , Zheng Yinggang , Wang Zhenwen , Xie Zhihong , Wang Tao , Wang Chuan , Yan Yanglin
Published: October 2020

Oxidative stresss in the microenvironment surrounding lesions induces apoptosis of transplanted bone‐marrow‐derived mesenchymal stem cells (BMSCs). Hence, there is an urgent need for improving antioxidative‐stress processes of transplanted BMSCs to further promote their survival. The present study reports the role and mechanism of Parkinson's disease protein 7 (PARK7) in enhancing antioxidative activity in BMSCs. We used a PARK7 lentivirus to transfect BMSCs to up‐ or downregulate PARK7, and then used H2O2 to simulate oxidative stress in BMSCs in vitro. Overexpression of PARK7 effectively reduced reactive oxygen species and malondialdehyde, protected mitochondrial membrane potential, and resisted oxidative‐stress‐induced apoptosis of BMSCs, but the expression of PARK7 was downregulated, these results were reversed. At the same time, we also found that overexpression of PARK7 increased extracellular‐regulated protein kinase 1/2 (ERK1/2) phosphorylation and nuclear translocation, as well as upregulated Elk1 phosphorylation and superoxide dismutase (SOD) expression. In contrast, when U0126 was used to block the ERK1/2 pathway, ERK1/2 and Elk1 phosphorylation levels were downregulated, ERK1/2 nuclear translocation and SOD content were significantly reduced, and PARK7‐overexperssion‐induced antioxidative activity was completely blocked. Collectively, our results suggest that PARK7 overexpression increased antioxidative‐stress processes and survival of BMSCs subjected to H2O2 via activating the ERK1/2 signaling pathway. Our findings may guide the development of a PARK7‐specific strategy for improving the transplantation efficacy of BMSCs.
Unusual Distribution Kinetics of Gadoxetate in Healthy Human Subjects Genotyped for OATP1B1: Application of Population Analysis and a Minimal Physiological‐Based Pharmacokinetic Model
Authors: Weiss Michael , Siegmund Werner
Published: October 2020

Gadoxetate (Gd‐EOB‐DTPA) is a hepatobiliary‐specific contrast agent for magnetic resonance imaging. Using a minimal physiological‐based pharmacokinetic (PBPK) model, it has been shown for the first time, that the rapid initial decline of plasma concentration after intravenous injection is the result of an uptake into hepatocytes rather than of a distribution into the extravascular extracellular space. About 50% of the steady‐state distribution volume is related to hepatic uptake. The hepatic extraction ratio and hepatic clearance estimated based on the liver model as a part of the PBPK model were in accordance with literature data. The same holds for the predicted time course of the amount of gadoxetate in liver parenchyma. In elucidating the impact of OATP1B1 genotype (*1a/*1a and *15/*15) on the pharmacokinetics of gadoxetate, we found that tissue uptake and back‐transfer rates were significantly reduced, whereas the hepatic sinusoidal efflux rate was significantly increased in carriers of the *15/*15 haplotype compared with those of the *1a/*1a (wild type). The model is potentially useful for determining hepatic kinetic parameters and distribution properties of drugs.
Usefulness of lactate dehydrogenase in differentiating abnormal cervical lymphadenopathy
Authors: Kamiya Naoko , Ishikawa Yukiko , Takeshima Taro , Sagara Yuka , Yamamoto Sayaka , Naka Mieno Makiko , Kotani Kazuhiko , Matsumura Masami
Published: October 2020

Background

Cervical lymphadenopathy is commonly seen in general practice, and its etiology is diverse. Establishing the diagnostic strategy for lymphadenopathy would be desirable to avoid overlooking neoplasms or other critical conditions. This study aims to identify the useful laboratory parameters for cervical lymphadenopathy that require clinical observation or intervention.

Methods

The participants were outpatients presenting cervical swelling or cervical lymph node (LN) pain who consulted the General Internal Medicine department from 2010 to 2016. We evaluated the characteristics, physical findings, and laboratory parameters with final diagnoses by multivariate logistic regression analysis. We categorized the final diagnoses as “Clinical Intervention Required Group (CIRG)” including necrotizing lymphadenitis, hematologic neoplasms, metastatic lymphadenopathy, tuberculous lymphadenitis, bacterial infectious diseases, infectious mononucleosis, autoimmune diseases, and other abnormal conditions or “No‐CIRG” not requiring further clinical observation or intervention.

Results

We evaluated 409 participants, with 130 (31.8%) diagnosed as belonging to the CIRG. There was an association between CIRG and various parameters: age ≥60 years old (adjusted odds ratio [AOR], 2.70; 95% confidence interval [CI], 1.48‐4.90), having a referral (AOR, 1.83; 95% CI, 1.12‐3.00), diameter of LN ≥ 2 cm (AOR, 1.91; 95% CI, 1.05‐3.48), fixed LNs (AOR, 2.74; 95% CI, 1.02‐7.37), and lactate dehydrogenase (LD) ≥400 U/L (AOR, 3.78; 95% CI, 1.46‐9.77). Eighty‐two percent of LD ≥ 400 cases in the CIRG were infectious mononucleosis or necrotizing lymphadenitis.

Conclusions

Besides the clinical indicators reported previously, we may apply an elevated LD level as a useful indicator of cervical lymphadenopathy that requires further clinical observation or intervention.
Effect of cigarette smoke extract on the intestinal microenvironment of ulcerative colitis tissue
Authors: Cannon Aoife , Clarke Niamh , MacCarthy Finbar , Dunne Cara , Kevans David , Mahmud Nasir , Lysaght Joanne , O'Sullivan Jacintha
Published: October 2020

Background and Aim

Ulcerative colitis (UC) is an autoimmune disease characterized by inflammation in the gastrointestinal tract. The severity of UC is higher in nonsmokers than smokers; however, the biological mechanisms controlling this effect remain unknown. The aim of this study was to examine the effect of cigarette smoke extract (CSE) on inflamed and noninflamed colonic tissue from UC patients and to determine if inflammatory mediators, transcription factors, and T cell phenotypes are altered by CSE.

Methods

Blood and colonic biopsies were obtained from UC patients undergoing endoscopy. Biopsies were cultured in the presence or absence of CSE. Multiplex enzyme‐linked immunosorbent assay (ELISA) measured secreted levels of inflammatory mediators. Nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) and Hypoxia‐inducible factor 1‐alpha (HIF‐1α) expression were measured by DNA‐binding ELISA. T cell phenotypes were assessed by flow cytometry in matched blood and biopsies.

Results

Secreted levels of interleukin 2 (IL‐2), interleukin 6 (IL‐6), tumor necrosis factor ‐ alpha (TNF‐α), chemokine (C‐C motif) ligand 2 (CCL2), and interleukin 10 (IL‐10) were significantly (all P < 0.05) decreased following treatment with CSE. This effect was specific to inflamed tissue and was not observed in noninflamed tissue. CSE did not alter the expression of NF‐κB or HIF‐1α. Assessment of T cell phenotypes in blood and tissue revealed that there were significantly more activated and exhausted T cells in the colonic tissue compared to matched blood. These profiles were not altered following CSE treatment.

Conclusion

These data suggest that observed effects of CSE in reducing inflammatory mediators ex vivo are specific to inflamed colonic tissue but are not due to the activation of NF‐κB or HIF‐1α and are not caused by alterations in subpopulations of T cells in these UC tissues.
Synthesis of 3‐cyano‐2‐pyridone derivative and its utility in the synthesis of some heterocyclic compounds with expecting antimicrobial activity
Authors: EL‐Hashash Maher A. , Shaban Safaa S. , Ali Rania S.
Published: October 2020

New 2‐pyridone derivatives bearing p‐methoxyphenyl and p‐bromophenyl substituents at C‐4 and C‐6 were prepared smoothly by the one‐pot reaction in high yield, and in a comparatively short time, it reacted with phosphorous oxychloride to produce the corresponding chloro compound. The latter was reacted with several nitrogen nucleophiles such as sodium azide, hydrazine, acetohydrazide, and benzohydrazide to give tetrazolo, hydrazino, and triazolo derivatives, respectively. The reaction of hydrazino derivative with cyclopentanone, furan‐2‐carbaldehyde afforded the corresponding hydrazone derivatives. Cyclocondensation of the latter compounds with thioglycolic acid afforded the nicotinamide derivatives. 2‐Pyridone reacted with ethyl chloroacetate to afford chloroacetate and ethyl acetate derivatives. Ethyl acetate‐derivative reacted with hydrazine hydrate and gave the acetohydrazide derivative, it was condensed with p‐anisaldehyde and gave the 4‐methoxybenzylidene acetohydrazide derivative. Also, 2‐pyridone reacted with chloroacetic acid and or benzoyl chloride, afforded the benzoate derivative and 2‐((6‐(4‐bromophenyl)‐3‐cyano‐4‐(4‐methoxyphenyl) pyridin‐2‐yl) oxy) acetic acid, respectively. Structures of the products were confirmed using spectroscopic data and elemental analyses. Antibacterial activity of the synthesized compounds was evaluated against Escherichia coli and Staphylococcus aureus.
Different glycoforms of alpha-1-acid glycoprotein contribute to its functional alterations in platelets and neutrophils
Authors: Sumanth Mosale Seetharam , Jacob Shancy P , Abhilasha Kandahalli Venkataranganayaka , Manne Bhanu Kanth , Basrur Venkatesha , Lehoux Sylvain , Campbell Robert A , Yost Christian C , McIntyre Thomas M , Cummings Richard D , Weyrich Andrew S , Rondina Matthew T , Marathe Gopal K
Published: October 2020

Alpha-1-acid glycoprotein (AGP-1) is a positive acute phase glycoprotein with uncertain functions. Serum AGP-1 (sAGP-1) is primarily derived from hepatocytes and circulates as 12–20 different glycoforms. We isolated a glycoform secreted from platelet-activating factor (PAF)-stimulated human neutrophils (nAGP-1). Its peptide sequence was identical to hepatocyte-derived sAGP-1, but nAGP-1 differed from sAGP-1 in its chromatographic behavior, electrophoretic mobility, and pattern of glycosylation. The function of these 2 glycoforms also differed. sAGP-1 activated neutrophil adhesion, migration, and neutrophil extracellular traps (NETosis) involving myeloperoxidase, peptidylarginine deiminase 4, and phosphorylation of ERK in a dose-dependent fashion, whereas nAGP-1 was ineffective as an agonist for these events. Furthermore, sAGP-1, but not nAGP-1, inhibited LPS-stimulated NETosis. Interestingly, nAGP-1 inhibited sAGP-1-stimulated neutrophil NETosis. The discordant effect of the differentially glycosylated AGP-1 glycoforms was also observed in platelets where neither of the AGP-1 glycoforms alone stimulated aggregation of washed human platelets, but sAGP-1, and not nAGP-1, inhibited aggregation induced by PAF or ADP, but not by thrombin. These functional effects of sAGP-1 correlated with intracellular cAMP accumulation and phosphorylation of the protein kinase A substrate vasodilator-stimulated phosphoprotein and reduction of Akt, ERK, and p38 phosphorylation. Thus, the sAGP-1 glycoform limits platelet reactivity, whereas nAGP-1 glycoform also limits proinflammatory actions of sAGP-1. These studies identify new functions for this acute phase glycoprotein and demonstrate that the glycosylation of AGP-1 controls its effects on 2 critical cells of acute inflammation.
Clinical features and antibody response of patients from a COVID‐19 treatment hospital in Wuhan, China
Authors: Chen Yong , Ke Yuehua , Liu Xiong , Wang Zhihua , Jia Ruizhong , Liu Wei , Yang Chaojie , Jia Leili , Wang Yong , Han Li , Xia Xinyi , Zhang Sibing , Wang Changjun
Published: October 2020

Coronavirus disease 2019 (COVID‐19) has rapidly evolved into a global pandemic. A total of 1578 patients admitted into a newly built hospital specialized for COVID‐19 treatment in Wuhan, China, were enrolled. Clinical features and the levels of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) immunoglobulin (Ig)M and IgG were analyzed. In total, 1532 patients (97.2%) were identified as laboratory‐confirmed cases. Seventy‐seven patients were identified as asymptomatic carriers (n = 64) or SARS‐CoV‐2 RNA positive before symptom onset (n = 13). The positive rates of SARS‐CoV‐2 IgM and IgG were 80.4% and 96.8%, respectively. The median of IgM and IgG titers were 37.0A U/ml (interquartile range [IQR]: 13.4–81.1 AU/ml) and 156.9 AU/ml (IQR: 102.8–183.3 AU/ml), respectively. The IgM and IgG levels of asymptomatic patients (median titers, 8.3 AU/ml and 100.3 AU/ml) were much lower than those in symptomatic patients (median titers, 38.0 AU/ml and 158.2 AU/ml). A much lower IgG level was observed in critically ill patients 42–60 days after symptom onset. There were 153 patients with viral RNA shedding after IgG detection. These patients had a higher proportion of critical illness during hospitalization (p < .001) and a longer hospital stay (p < .001) compared to patients with viral clearance after IgG detection. Coronary heart disease (odds ratio [OR], 1.89 [95% confidence interval [CI], 1.11–3.24]; p = .020), and intensive care unit admission (OR, 2.47 [95% CI, 1.31–4.66]; p = .005) were independent risk factors associated with viral RNA shedding after IgG detection. Symptomatic patients produced more antibodies than asymptomatic patients. The patients who had SARS‐CoV‐2 RNA shedding after developing IgG were more likely to be sicker patients.
Adipose tissue stem cells in peripheral nerve regeneration—In vitro and in vivo
Authors: Rhode Sophie Charlotte , Beier Justus Patrick , Ruhl Tim
Published: October 2020

After peripheral nerve injury, Schwann cells (SCs) are crucially involved in several steps of the subsequent regenerative processes, such as the Wallerian degeneration. They promote lysis and phagocytosis of myelin, secrete numbers of neurotrophic factors and cytokines, and recruit macrophages for a biological debridement. However, nerve injuries with a defect size of >1 cm do not show proper tissue regeneration and require a surgical nerve gap reconstruction. To find a sufficient alternative to the current gold standard—the autologous nerve transplant—several cell‐based therapies have been developed and were experimentally investigated. One approach aims on the use of adipose tissue stem cells (ASCs). These are multipotent mesenchymal stromal cells that can differentiate into multiple phenotypes along the mesodermal lineage, such as osteoblasts, chondrocytes, and myocytes. Furthermore, ASCs also possess neurotrophic features, that is, they secrete neurotrophic factors like the nerve growth factor, brain‐derived neurotrophic factor, neurotrophin‐3, ciliary neurotrophic factor, glial cell‐derived neurotrophic factor, and artemin. They can also differentiate into the so‐called Schwann cell‐like cells (SCLCs). These cells share features with naturally occurring SCs, as they also promote nerve regeneration in the periphery. This review gives a comprehensive overview of the use of ASCs in peripheral nerve regeneration and peripheral nerve tissue engineering both in vitro and in vivo. While the sustainability of differentiation of ASCs to SCLCs in vivo is still questionable, ASCs used with different nerve conduits, such as hydrogels or silk fibers, have been shown to promote nerve regeneration.
Impact of occlusive material and cochlea‐carotid artery relation on eustachian tube occlusion in subtotal petrosectomy
Authors: Lyutenski Stefan , El‐Saied Sabri , Schwab Burkard
Published: October 2020

Objective

To evaluate the success rate of eustachian tube (ET) occlusion in subtotal petrosectomy relative to the occlusive material used and to the varying protympanum anatomy, by means of standardized alignment of the cochlea‐carotid artery relation on computed tomography images.

Patients and methods

All cases of subtotal petrosectomy carried out by the same surgeon at a tertiary care referral center were retrospectively evaluated. Only cases with available computed tomography prior to second stage cochlear or middle ear implantation were included. The occlusive material was either muscle tissue or oxidized regenerated cellulose in combination with bone wax. On 3D multiplanar image reconstruction, the varying topographic interrelation of the cochlea and the petrous carotid artery was measured and categorized into two groups: detachment or overlapping.

Results

In 9 (31%) of the 29 included cases there was insufficient occlusion of the ET. In none of these cases was an infection of the fat filling in the obliterated cavity observed during the implantation procedure on second stage (average 10 months interval). The failure rate of both occlusion materials was almost the same (using muscle tissue, in 4 (33.3%) of 12 or oxidized regenerated cellulose, in 5 (29.4%) of 17 cases). It was also similar for both materials in each of the anatomic variation groups.

Conclusions

An incomplete occlusion of the ET alone does not appear to lead to an infection of the obliterated cavity. Autologous muscle tissue and oxidized regenerated cellulose had similar rates of ET occlusion failure. The topographical variance of the protympanum appears to have no direct influence on the success of the ET occlusion.
Single‐surgeon parotidectomy outcomes in an academic center experience during a 15‐year period
Authors: Deschler Daniel G. , Kozin Elliott D. , Kanumuri Vivek , Devore Elliana , Shapiro Chandler , Koen Nicholas , Sethi Rosh K.V.
Published: October 2020

Objective

As large single‐surgeon series in the literature are lacking, we sought to review a single‐surgeon's experience with parotidectomy in an academic center, with a focused analysis of pathology, technique, and facial nerve (FN) weakness. Benchmark values for complications and operative times with routine trainee involvement and without continuous FN monitoring are offered.

Materials and Methods

All patients who underwent parotidectomy, performed by D. G. D., for benign and malignant disease between January 2004 and December 2018 at an academic center were reviewed.

Results

A total of 924 parotidectomies, with adequate evaluatable data were identified. The majority of patients had benign tumors (70.9%). Partial/superficial parotidectomy was the most common approach (65.7%). Selective FN branch sacrifice was rare (12.3%), but significantly more common among patients with malignant pathology (33.8% vs 3.5% for benign, P < .0001). Among patients with intact FN, post‐operative short‐ and long‐term FN weaknesses were rare (6.5% and 1.7%, respectively). These rates were lower among patients with benign tumors (5.4% and 1.3%). Partial/superficial parotidectomy for benign tumors was associated with a low rate of short‐ and long‐term FN weaknesses (2.7% and 0.9%). Mean OR time was 185 minutes.

Conclusion

This is the largest single‐surgeon series on parotidectomy, spanning 15 years. We demonstrate excellent long‐ and short‐term FN paresis rates with acceptable operative times without regular use of continuous FN monitoring and with routine trainee involvement. These findings may provide valuable insight into parotid tumor pathology, FN outcomes, and feasibility and expectations of performing parotidectomy in an academic setting.

Level of Evidence

4.
Stress corrosion cracking of copper in swollen bentonite simulating nuclear waste disposal environment
Authors: Fujimoto Shinji , Tsuchiya Hiroaki , Ogawa Soma , Iida Yoshihisa , Taniguchi Naoki
Published: October 2020

Stress corrosion cracking (SCC) of pure copper in bentonite clay was examined using a slow strain rate test (SSRT). Bentonite was swollen with pure water or aqueous solutions containing NH3 of 5 and 10 mM. Thick corrosion films and particulate deposits were formed on the copper surface after the SSRT. Typical tarnish rupture‐type SCC occurred on pure copper in swollen bentonite with and without NH3. The crack propagation rate was enhanced by NH3. It is confirmed that a thick oxide layer was formed on copper during plastic deformation, resulting in tarnish crack‐type SCC. Many particulate deposits observed on the surface were formed due to the rapid dissolution of Cu2+ ions to form porous CuO at local deformed sites, regardless of the SCC occurrence.
Flavonoids as antiobesity agents: A review
Authors: Rufino Ana T. , Costa Vera M. , Carvalho Félix , Fernandes Eduarda
Published: October 2020

Obesity is a global health problem that affects all age groups in both developing and developed countries. In recent years, the prevalence of overweight and obesity has reached pandemic levels, resulting in a dramatic increase in the incidence of various comorbidities, such as cardiovascular diseases, type 2 diabetes, and cancer, consequently leading to massive health and socioeconomic burdens. Together with lifestyle changes, antiobesity pharmacotherapy is gaining momentum as an adjunctive treatment. However, the available pharmacological approaches have limited use owing to either significant adverse effects or low efficacy. Over the years, natural products have been an important source of lead compounds for drug discovery. Among these, flavonoids are associated with important biological effects and health‐promoting activities. In this review, we discuss the modulatory effects of flavonoids on obesity and their potential mechanisms of action. The literature strongly suggests that most common flavonoids demonstrate a pronounced effect on obesity as shown by their ability to lower body weight, fat mass, and plasma triglycerides/cholesterol, both in in vitro and in vivo models. The impact of flavonoids on obesity can be observed through different mechanisms: reducing food intake and fat absorption, increasing energy expenditure, modulating lipid metabolism, or regulating gut microbiota profile. A better understanding of the known antiobesity mechanisms of flavonoids will enable their potential use to treat this medical condition. Therefore, this review focuses on the putative biological mechanisms through which flavonoids may prevent or treat obesity and highlights new perspectives on future pharmacological use.
Structure elucidation of a new triterpene from Inonotus obliquus
Authors: Park Sangmin , Shin Hyeji , Park Dawon , Kim Hyunwoo , Byun Youngjoo , Lee Ki Yong
Published: October 2020

Ethyl acetate (EtOAc) fraction of the Inonotus obliquus (Hymenochaetaceae) significantly inhibited nitric oxide production in lipopolysaccharide (LPS)–induced murine BV2 microglial cells. A new triterpene, characterized as inonotusol H (1), was isolated from the EtOAc fraction using the bioactivity‐guided fractionation together with four known triterpenes, inotodiol (2), trametenolic acid (3), inonotsutriols A (4), and inonotusol A (5). Among them, Compounds 2–4 significantly reduced LPS‐induced nitric oxide production to 4.5 ± 0.8%, 47.4 ± 4.4%, and 2.8 ± 1.7%, respectively, at a concentration of 30 μM.