bluuebunny/crossref_metadata_2025 huggingface dataset:
The Redox-Active Tyrosine Is Essential for Proton Pumping in Cytochrome c Oxidase
Authors: Blomberg Margareta R. A.
Published: April 2021

Cellular respiration involves electron transport via a number of enzyme complexes to the terminal Cytochrome c oxidase (CcO), in which molecular oxygen is reduced to water. The free energy released in the reduction process is used to establish a transmembrane electrochemical gradient, via two processes, both corresponding to charge transport across the membrane in which the enzymes are embedded. First, the reduction chemistry occurring in the active site of CcO is electrogenic, which means that the electrons and protons are delivered from opposite sides of the membrane. Second, the exergonic chemistry is coupled to translocation of protons across the entire membrane, referred to as proton pumping. In the largest subfamily of the CcO enzymes, the A-family, one proton is pumped for every electron needed for the chemistry, making the energy conservation particularly efficient. In the present study, hybrid density functional calculations are performed on a model of the A-family CcOs. The calculations show that the redox-active tyrosine, conserved in all types of CcOs, plays an essential role for the energy conservation. Based on the calculations a reaction mechanism is suggested involving a tyrosyl radical (possibly mixed with tyrosinate character) in all reduction steps. The result is that the free energy released in each reduction step is large enough to allow proton pumping in all reduction steps without prohibitively high barriers when the gradient is present. Furthermore, the unprotonated tyrosine provides a mechanism for coupling the uptake of two protons per electron in every reduction step, i.e. for a secure proton pumping.
Synthesis Candidates Herbicide Through Optimization Quinclorac Containing 3-Methyl-1H-pyrazol-5-yl
Authors: Luo Dingfeng , Bai Haodong , Zhou Xiaomao , Wu Lamei , Zhang Chengjia , Wu Zhongchi , Li Zuren , Bai Lianyang
Published: April 2021

To enhance quinclorac potency, twenty-five derivatives were synthesized containing 3-methyl-1H-pyrazol-5-yl by intermediate derivatization methods (IDMs). These compounds were confirmed by melting point (mp), 1HNMR, 13CNMR, and HRMS. The compound 1,3-dimethyl-1H-pyrazol-5-yl 3,7-dichloroquinoline-8-carboxylate (10a) was determined by X-ray diffraction. The activity of these compounds substituent on the phenyl was: electron-drawing group > neutral group > donor-drawing group, the results was like that of substituted benzyl group on pyrazole. The herbicidal activity assays showed that compounds 1-(2-fluorophenyl)-3-methyl-1H-pyrazol-5-yl 3,7-dichloroquinoline-8-carboxylate (8l, EC50 = 10.53 g/ha) and 10a (EC50 = 10.37 g/ha) had an excellent inhibition effect on barnyard grass in greenhouse experiment. Greenhouse safety experiment of rice exhibited almost no difference in plant height and fresh weight treated 10a at stage 1∼2-leaf of rice after 14 days but 8l had a detrimental effect. Two season field assays showed 10a herbicidal activity on barnyard grass at 150 g/ha as equal as 300 g/ha quinclorac in fields in 2019 and 2020. The study demonstrated that 10a could be further researched as a potential herbicide to control barnyard grass in fields.
Evidence-Based Design Principles for Spanish Pronunciation Teaching
Authors: Colantoni Laura , Escudero Paola , Marrero-Aguiar Victoria , Steele Jeffrey
Published: April 2021

In spite of the considerable body of pedagogical and experimental research providing clear insights into best practices for pronunciation instruction, there exists relatively little implementation of such practices in pedagogical materials including textbooks. This is particularly true for target languages other than English. With the goal of assisting instructors wishing to build effective evidence-based instructional practices, we outline a set of key principles relevant to pronunciation teaching in general, illustrated here via Spanish in particular, drawing on previous pedagogical research as well as methods and findings from experimental (applied) linguistics. With the overall goal of enabling learners to move toward greater intelligibility, these principles include the importance of perceptual training from the onset of learning, a strong prosodic component, the use of contextualized activities, and a focus on segmental and prosodic phenomena with a high functional load as well as those that are shared across target language varieties. These principles are then illustrated with innovative perception and production exercises for beginner, university-level learners of Spanish. We conclude with a discussion of ways in which the pedagogical principles exposed here can be extended beyond the production of individual activities to the design of a broader pronunciation curriculum.
Emerging Role of Caveolin-1 in GLP-1 Action
Authors: Puddu Alessandra , Maggi Davide
Published: April 2021

Glucagon-like peptide-1 (GLP-1) is a gut hormone mainly produced in the intestinal epithelial endocrine L cells, involved in maintaining glucose homeostasis. The use of GLP-1 analogous and dipeptidyl peptidase-IV (DPP-IV) inhibitors is well-established in Type 2 Diabetes. The efficacy of these therapies is related to the activation of GLP-1 receptor (GLP-1R), which is widely expressed in several tissues. Therefore, GLP-1 is of great clinical interest not only for its actions at the level of the beta cells, but also for the extra-pancreatic effects. Activation of GLP-1R results in intracellular signaling that is regulated by availability of downstream molecules and receptor internalization. It has been shown that GLP-1R co-localizes with caveolin-1, the main component of caveolae, small invagination of the plasma membrane, which are involved in controlling receptor activity by assembling signaling complexes and regulating receptor trafficking. The aim of this review is to outline the important role of caveolin-1 in mediating biological effects of GLP-1 and its analogous.
Draft Genomes and Comparative Analysis of Seven Mangrove Rhizosphere-Associated Fungi Isolated From Kandelia obovata and Acanthus ilicifolius
Authors: Shi Chengcheng , Chen Jianwei , Ge Qijin , Sun Jiahui , Guo Wenjie , Wang Jie , Peng Ling , Xu Qiwu , Fan Guangyi , Zhang Wenwei , Liu Xin
Published: April 2021

Mangroves are one of the most productive and biologically diverse ecosystems, with unique plants, animals, and microorganisms adapted to the harsh coastal environments. Although fungi are widely distributed in the mangrove ecosystem and they are playing an important role in the decomposition of organic matter, their genomic profiles are still poorly understood. In this study, we isolated seven Ascomycota fungi (Westerdykella dispersa F012, Trichoderma lixii F014, Aspergillus tubingensis F023, Penicillium brefeldianum F032, Neoroussoella solani F033, Talaromyces fuscoviridis F034, and Arthrinium marii F035) from rhizospheres of two mangroves of Kandelia obovata and Acanthus ilicifolius. We sequenced and assembled the whole genome of these fungi, resulting in size ranging from 29 to 48 Mb, while contig N50 from 112 to 833 Kb. We generated six novel fungi genomes except A. tubingensis, and the gene completeness and genome completeness of all seven genomes are higher than 94%. Comparing with non-mangrove fungi, we found Carbohydrate-Binding Modules (CBM32), a subfamily of carbohydrate active enzymes, only detected in two mangrove fungi. Another two subfamilies, Glycoside Hydrolases (GH6) and Polysaccharide Lyases (PL4), were significantly different in gene copy number between K. obovata and A. ilicifolius rhizospheres (P-value 0.041 for GH6, 0.047 for PL4). These findings may indicate an important influence of mangrove environments or hosts on the ability of decomposition in rhizosphere fungi. Secondary metabolite biosynthesis gene clusters were detected and we found the mangrove fungi averagely contain 18 Type I Polyketide (t1pks) synthase, which was significantly higher than 13 in non-mangrove fungi (P-value 0.048), suggesting their potential roles in producing bioactive compounds that important for fungi development and ecology. We reported seven mangrove-associated fungal genomes in this study and compared their carbohydrate active enzymes and secondary metabolites (SM) genes with those of non-mangrove fungi, and the results suggest that there are differences in genetic information among fungi in different habitats.
Potential Prospective Biomarkers for Non-small Cell Lung Cancer: Mini-Chromosome Maintenance Proteins
Authors: Huang Chen , Lei Chuqi , Pan Boyu , Fang Senbiao , Chen Yubao , Cao Wenfeng , Liu Liren
Published: April 2021

Minichromosome maintenance proteins (MCMs) are considered to be essential factors coupling DNA replication to both cell cycle progression and checkpoint regulation. Previous studies have shown that dysregulation of MCMs are implicated in tumorigenesis of lung cancer. However, the distinct expression/mutation patterns and prognostic values of MCMs in lung cancer have yet to be systematically elucidated. In the present study, we analyzed the transcriptional levels, mutations, and prognostic value of MCM1-10 in non-small cell lung cancer (NSCLC) patients using multiple bioinformatics tools, including ONCOMINE, GEPIA, Kaplan–Meier Plotter, cBioPortal, and GESA. The analysis results from GEPIA dataset showed that MCM2/4/10 was significantly high expressed in both lung adenocarcinoma (LUAD) and squamous cell lung carcinomas (LUSCs). Meanwhile, the expression levels of MCM2/4/6/7/8 were associated with advanced tumor stages. Subsequent survival analysis using the Kaplan–Meier Plotter indicated that high expression levels of MCM1/2/3/4/5/6/7/8/10 were associated with worse overall survival (OS), while high expression level of MCM9 predicted better OS in these patients. Furthermore, we experimentally validated overexpression of MCM2 and MCM4 in NSCLC, thus the results from this study support a view that they may serve as potential prospective biomarkers to identify high-risk subgroups of NSCLC patients.
Case Report: Expanding Clinical, Immunological and Genetic Findings in Sideroblastic Anemia With Immunodeficiency, Fevers and Development Delay (SIFD) Syndrome
Authors: Mendonca Leonardo Oliveira , Prado Alex Isidoro , Costa Izelda Maria Carvalho , Bandeira Marcia , Dyer Rafael , Barros Samar Freschi , Khöler Karen Francine , Fonseca Luiz Augusto Marcondes , Kalil Jorge , Castro Fabio Morato , Toledo-Barros Myrthes Anna Maragna
Published: April 2021

Since the first description of the syndrome of sideroblastic anemia with immunodeficiency, fevers and development delay (SIFD), clinical pictures lacking both neurological and hematological manifestations have been reported. Moreover, prominent skin involvement, such as with relapsing erythema nodosum, is not a common finding. Up to this moment, no genotype and phenotype correlation could be done, but mild phenotypes seem to be located in the N or C part. B-cell deficiency is a hallmark of SIFD syndrome, and multiple others immunological defects have been reported, but not high levels of double negative T cells. Here we report a Brazilian patient with a novel phenotype of SFID syndrome, carrying multiple immune defects and harboring a novel mutation on TRNT1 gene.
Protective Effect of Intestinal Helminthiasis Against Tuberculosis Progression Is Abrogated by Intermittent Food Deprivation
Authors: Garrido-Amaro Cristina , Cardona Paula , Gassó Diana , Arias Lilibeth , Velarde Roser , Tvarijonativiciute Asta , Serrano Emmanuel , Cardona Pere-Joan
Published: April 2021

Background

Tuberculosis (TB) is still a major challenge for humankind. Because regions with the highest incidence also have a high prevalence of helminthiasis and nutritional scarcity, we wanted to understand the impact of these on TB progression.

Methods

We have developed an experimental murine model for active TB in C3HeB/FeJ, coinfected with Trichuris muris and Heligmosomoides polygyrus nematodes, and exposed to an environmental mycobacterium (M. manresensis) and intermittent fasting. Cause-effect relationships among these factors were explored with Partial Least Squares Path modelling (PLSPM).

Results

Previous parasitization had a major anti-inflammatory effect and reduced systemic levels of ADA, haptoglobin, local pulmonary levels of IL-1β, IL-6, TNF-α, CXCL-1, CXCL-5 and IL-10. Oral administration of heat-killed M. manresensis resulted in a similar outcome. Both interventions diminished pulmonary pathology and bacillary load, but intermittent food deprivation reduced this protective effect increasing stress and inflammation. The PLSPM revealed nematodes might have protective effects against TB progression.

Conclusions

Significantly higher cortisol levels in food-deprivation groups showed it is a stressful condition, which might explain its deleterious effect. This highlights the impact of food security on TB eradication policies and the need to prioritize food supply over deworming activities.
SARS-CoV-2 Spike Targets USP33-IRF9 Axis via Exosomal miR-148a to Activate Human Microglia
Authors: Mishra Ritu , Banerjea Akhil C.
Published: April 2021

SARS-CoV-2, the novel coronavirus infection has consistently shown an association with neurological anomalies in patients, in addition to its usual respiratory distress syndrome. Multi-organ dysfunctions including neurological sequelae during COVID-19 persist even after declining viral load. We propose that SARS-CoV-2 gene product, Spike, is able to modify the host exosomal cargo, which gets transported to distant uninfected tissues and organs and can initiate a catastrophic immune cascade within Central Nervous System (CNS). SARS-CoV-2 Spike transfected cells release a significant amount of exosomes loaded with microRNAs such as miR-148a and miR-590. microRNAs gets internalized by human microglia and suppress target gene expression of USP33 (Ubiquitin Specific peptidase 33) and downstream IRF9 levels. Cellular levels of USP33 regulate the turnover time of IRF9 via deubiquitylation. Our results also demonstrate that absorption of modified exosomes effectively regulate the major pro-inflammatory gene expression profile of TNFα, NF-κB and IFN-β. These results uncover a bystander pathway of SARS-CoV-2 mediated CNS damage through hyperactivation of human microglia. Our results also attempt to explain the extra-pulmonary dysfunctions observed in COVID-19 cases when active replication of virus is not supported. Since Spike gene and mRNAs have been extensively picked up for vaccine development; the knowledge of host immune response against spike gene and protein holds a great significance. Our study therefore provides novel and relevant insights regarding the impact of Spike gene on shuttling of host microRNAs via exosomes to trigger the neuroinflammation.
Liver Fibrosis in Non-alcoholic Fatty Liver Disease: From Liver Biopsy to Non-invasive Biomarkers in Diagnosis and Treatment
Authors: Heyens Leen J. M. , Busschots Dana , Koek Ger H. , Robaeys Geert , Francque Sven
Published: April 2021

An increasing percentage of people have or are at risk to develop non-alcoholic fatty liver disease (NAFLD) worldwide. NAFLD comprises different stadia going from isolated steatosis to non-alcoholic steatohepatitis (NASH). NASH is a chronic state of liver inflammation that leads to the transformation of hepatic stellate cells to myofibroblasts. These cells produce extra-cellular matrix that results in liver fibrosis. In a normal situation, fibrogenesis is a wound healing process that preserves tissue integrity. However, sustained and progressive fibrosis can become pathogenic. This process takes many years and is often asymptomatic. Therefore, patients usually present themselves with end-stage liver disease e.g., liver cirrhosis, decompensated liver disease or even hepatocellular carcinoma. Fibrosis has also been identified as the most important predictor of prognosis in patients with NAFLD. Currently, only a minority of patients with liver fibrosis are identified to be at risk and hence referred for treatment. This is not only because the disease is largely asymptomatic, but also due to the fact that currently liver biopsy is still the golden standard for accurate detection of liver fibrosis. However, performing a liver biopsy harbors some risks and requires resources and expertise, hence is not applicable in every clinical setting and is unsuitable for screening. Consequently, different non-invasive diagnostic tools, mainly based on analysis of blood or other specimens or based on imaging have been developed or are in development. In this review, we will first give an overview of the pathogenic mechanisms of the evolution from isolated steatosis to fibrosis. This serves as the basis for the subsequent discussion of the current and future diagnostic biomarkers and anti-fibrotic drugs.
Management of SARS-CoV-2 Infection: Key Focus in Macrolides Efficacy for COVID-19
Authors: Batiha Gaber El-Saber , Zayed Marwa A. , Awad Aya A. , Shaheen Hazem M. , Mustapha Suleiman , Herrera-Calderon Oscar , Pagnossa Jorge Pamplona , Algammal Abdelazeem M. , Zahoor Muhammad , Adhikari Achyut , Pandey Ishan , Elazab Sara T. , Rengasamy Kannan R. R. , Cruz-Martins Natália , Hetta Helal F.
Published: April 2021

Macrolides (e.g., erythromycin, fidaxomicin, clarithromycin, and azithromycin) are a class of bacteriostatic antibiotics commonly employed in medicine against various gram-positive and atypical bacterial species mostly related to respiratory tract infections, besides they possess anti-inflammatory and immunomodulatory effects. Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome of coronavirus 2 (SARS-CoV-2). It was first detected in Wuhan, Hubei, China, in December 2019 and resulted in a continuing pandemic. Macrolides have been extensively researched as broad adjunctive therapy for COVID-19 due to its immunostimulant abilities. Among such class of drugs, azithromycin is described as azalide and is well-known for its ability to decrease the production of pro-inflammatory cytokines, including matrix metalloproteinases, tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8. In fact, a report recently published highlighted the effectiveness of combining azithromycin and hydroxychloroquine for COVID-19 treatment. Indeed, it has been underlined that azithromycin quickly prevents SARS-CoV-2 infection by raising the levels of both interferons and interferon-stimulated proteins at the same time which reduces the virus replication and release. In this sense, the current review aims to evaluate the applications of macrolides for the treatment of COVID-19.
The Seeds of Doubt: Finding Seeds in Intriguing Places
Authors: Grillo Federica , Campora Michela , Cornara Laura , Cascini Alberta , Pigozzi Simona , Migliora Paola , Sarocchi Francesca , Mastracci Luca
Published: April 2021

Introduction: Seeds may be found in gastrointestinal tissue samples, and their multifaceted appearance may be challenging. The aim is to report a rough incidence of pathology samples which show seeds, specify the most frequent sample types and show an iconography of the most commonly identified seeds.

Materials and Methods: Between 2017 and 2020, all gastrointestinal pathology cases in which seeds/seed parts were found, were collected and seed type described by referencing a seed image library.

Results: Fifty cases with complete seeds/seed parts were collected: 16 colonic resections for colorectal cancer and diverticulosis, 13 appendiceal resections for appendicitis, 1 gastric resection. Fifteen cases were found in polypectomy specimens and 5 cases in colorectal endoscopic biopsies. Most frequent seed types were tomato, kiwi, blueberry, and blackberry seeds.

Conclusion: Seeds may be found in up to 4% of specimens; their recognition may be useful to exclude parasitic infections as well as in forensic sciences.
Microbial Transformation of neo-Clerodane Diterpenoid, Scutebarbatine F, by Streptomyces sp. CPCC 205437
Authors: Zhang Dewu , Tao Xiaoyu , Gu Guowei , Wang Yujia , Zhao Wenxia , Zhao Wuli , Ren Yan , Dai Shengjun , Yu Liyan
Published: April 2021

Biotransformation of the neo-clerodane diterpene, scutebarbatine F (1), by Streptomyces sp. CPCC 205437 was investigated for the first time, which led to the isolation of nine new metabolites, scutebarbatine F1–F9 (2–10). Their structures were determined by extensive high-resolution electrospray ionization mass spectrometry (HRESIMS) and NMR data analyses. The reactions that occurred included hydroxylation, acetylation, and deacetylation. Compounds 2–4 and 8–10 possess 18-OAc fragment, which were the first examples of 13-spiro neo-clerodanes with 18-OAc group. Compounds 7–10 were the first report of 13-spiro neo-clerodanes with 2-OH. Compounds 1–10 were biologically evaluated for the cytotoxic, antiviral, and antibacterial activities. Compounds 5, 7, and 9 exhibited cytotoxic activities against H460 cancer cell line with inhibitory ratios of 46.0, 42.2, and 51.1%, respectively, at 0.3 μM. Compound 5 displayed a significant anti-influenza A virus activity with inhibitory ratio of 54.8% at 20 μM, close to the positive control, ribavirin.
Exercise Training-Increased FBXO32 and FOXO1 in a Gender-Dependent Manner in Mild Cognitively Impaired African Americans: GEMS-1 Study
Authors: Bedada Fikru B. , Ntekim Oyonumo E. , Nwulia Evaristus O. , Fungwe Thomas V. , Nadarajah Sheeba Raaj , Obisesan Thomas O.
Published: April 2021

The ubiquitin proteasome system (UPS) and FOXOs transcription factors play a pivotal role in cellular clearance and minimizing the accumulation of Aβ in neurodegeneration (ND). In African Americans (AAs) with mild cognitive impairment (MCI), the role of components of UPS and FOXOs; and whether they are amenable to exercise effects is unknown. We hypothesized that exercise can enhance cellular clearance systems during aging and ND by increasing expressions of FBXO32 and FOXO1. To test this hypothesis, we used TaqMan gene expression analysis in peripheral blood (PB) to investigate the component of UPS and FOXOs; and provide mechanistic insight at baseline, during exercise, and in both genders. At baseline, levels of FBXO32 were higher in women than in men. In our attempt to discern gender-specific exercise-related changes, we observed that levels of FBXO32 increased in men but not in women. Similarly, levels of FOXO1 increased in men only. These data suggest that a graded dose of FBXO32 and FOXO1 may be beneficial when PB cells carrying FBXO32 and FOXO1 summon into the brain in response to Alzheimer’s disease (AD) perturbation (docking station PB cells). Our observation is consistent with emerging studies that exercise allows the trafficking of blood factors. Given the significance of FBXO32 and FOXO1 to ND and associated muscle integrity, our findings may explain, at least in part, the benefits of exercise on memory, associated gait, and balance perturbation acknowledged to herald the emergence of MCI.
Drug Delivery With Carbon-Based Nanomaterials as Versatile Nanocarriers: Progress and Prospects
Authors: Debnath Sujit Kumar , Srivastava Rohit
Published: April 2021

With growing interest, a large number of researches have been conducted on carbon-based nanomaterials (CBNs). However, their uses are limited due to comprehensive potential environmental and human health effects. It is often confusing for researchers to make an informed choice regarding the versatile carbon-based nanocarrier system and its potential applications. This review has highlighted emerging applications and cutting-edge progress of CBNs in drug delivery. Some critical factors like enzymatic degradation, surface modification, biological interactions, and bio-corona have been discussed here. These factors will help to fabricate CBNs for effective drug delivery. This review also addresses recent advancements in carbon-based target specific and release controlled drug delivery to improve disease treatment. The scientific community has turned their research efforts into the development of novel production methods of CBNs to make their production more attractive to the industrial sector. Due to the nanosize and diversified physical properties, these CBNs have demonstrated distinct biological interaction. Thus long-term preclinical toxicity study is recommended before finally translating to clinical application.
Whole-Brain Mapping the Direct Inputs of Dorsal and Ventral CA1 Projection Neurons
Authors: Tao Sijue , Wang Yihang , Peng Jundan , Zhao Yang , He Xiaobin , Yu Xuefeng , Liu Qing , Jin Sen , Xu Fuqiang
Published: April 2021

The CA1, an important subregion of the hippocampus, is anatomically and functionally heterogeneous in the dorsal and ventral hippocampus. Here, to dissect the distinctions between the dorsal (dCA1) and ventral CA1 (vCA1) in anatomical connections, we systematically analyzed the direct inputs to dCA1 and vCA1 projection neurons (PNs) with the rabies virus-mediated retrograde trans-monosynaptic tracing system in Thy1-Cre mice. Our mapping results revealed that the input proportions and distributions of dCA1 and vCA1 PNs varied significantly. Inside the hippocampal region, dCA1 and vCA1 PNs shared the same upstream brain regions, but with distinctive distribution patterns along the rostrocaudal axis. The intrahippocampal inputs to the dCA1 and vCA1 exhibited opposite trends, decreasing and increasing gradually along the dorsoventral axis, respectively. For extrahippocampal inputs, dCA1 and vCA1 shared some monosynaptic projections from certain regions such as pallidum, striatum, hypothalamus, and thalamus. However, vCA1, not dCA1, received innervations from the subregions of olfactory areas and amygdala nuclei. Characterization of the direct input networks of dCA1 and vCA1 PNs may provide a structural basis to understand the differential functions of dCA1 and vCA1.
Validating Automated Segmentation Tools in the Assessment of Caudate Atrophy in Huntington’s Disease
Authors: Mansoor Nina M. , Vanniyasingam Tishok , Malone Ian , Hobbs Nicola Z. , Rees Elin , Durr Alexandra , Roos Raymund A. C. , Landwehrmeyer Bernhard , Tabrizi Sarah J. , Johnson Eileanoir B. , Scahill Rachael I.
Published: April 2021

Background: Neuroimaging shows considerable promise in generating sensitive and objective outcome measures for therapeutic trials across a range of neurodegenerative conditions. For volumetric measures the current gold standard is manual delineation, which is unfeasible for samples sizes required for large clinical trials.

Methods: Using a cohort of early Huntington’s disease (HD) patients (n = 46) and controls (n = 35), we compared the performance of four automated segmentation tools (FIRST, FreeSurfer, STEPS, MALP-EM) with manual delineation for generating cross-sectional caudate volume, a region known to be vulnerable in HD. We then examined the effect of each of these baseline regions on the ability to detect change over 15 months using the established longitudinal Caudate Boundary Shift Integral (cBSI) method, an automated longitudinal pipeline requiring a baseline caudate region as an input.

Results: All tools, except Freesurfer, generated significantly smaller caudate volumes than the manually derived regions. Jaccard indices showed poorer levels of overlap between each automated segmentation and manual delineation in the HD patients compared with controls. Nevertheless, each method was able to demonstrate significant group differences in volume (p < 0.001). STEPS performed best qualitatively as well as quantitively in the baseline analysis. Caudate atrophy measures generated by the cBSI using automated baseline regions were largely consistent with those derived from a manually segmented baseline, with STEPS providing the most robust cBSI values across both control and HD groups.

Conclusions: Atrophy measures from the cBSI were relatively robust to differences in baseline segmentation technique, suggesting that fully automated pipelines could be used to generate outcome measures for clinical trials.
Early Orthostatic Exercise by Head-Up Tilt With Stepping vs. Standard Care After Severe Traumatic Brain Injury Is Feasible
Authors: Riberholt Christian Gunge , Olsen Markus Harboe , Søndergaard Christian Baastrup , Gluud Christian , Ovesen Christian , Jakobsen Janus Christian , Mehlsen Jesper , Møller Kirsten
Published: April 2021

Background:Intensive rehabilitation of patients after severe traumatic brain injury aims to improve functional outcome. The effect of initiating rehabilitation in the early phase, in the form of head-up mobilization, is unclear.

Objective:To assess whether early mobilization is feasible and safe in patients with traumatic brain injury admitted to a neurointensive care unit.

Methods:This was a randomized parallel-group clinical trial, including patients with severe traumatic brain injury (Glasgow coma scale <11 and admission to the neurointensive care unit). The intervention consisted of daily mobilization on a tilt-table for 4 weeks. The control group received standard care. Outcomes were the number of included participants relative to all patients with traumatic brain injury who were approached for inclusion, the number of conducted mobilization sessions relative to all planned sessions, as well as adverse events and reactions. Information on clinical outcome was collected for exploratory purposes.

Results:Thirty-eight participants were included (19 in each group), corresponding to 76% of all approached patients [95% confidence interval (CI) 63–86%]. In the intervention group, 74% [95% CI 52–89%] of planned sessions were carried out. There was no difference in the number of adverse events, serious adverse events, or adverse reactions between the groups.

Conclusions:Early head-up mobilization is feasible in patients with severe traumatic brain injury. Larger randomized clinical trials are needed to explore potential benefits and harms of such an intervention.

Clinical Trial Registration:[ClinicalTrials.gov], identifier [NCT02924649]. Registered on 3rd October 2016.
Natalizumab Pharmacokinetics and -Dynamics and Serum Neurofilament in Patients With Multiple Sclerosis
Authors: Proschmann Undine , Inojosa Hernan , Akgün Katja , Ziemssen Tjalf
Published: April 2021

Background: Natalizumab (NAT) is a high-efficacy treatment for relapsing remitting multiple sclerosis (RRMS). However, it is associated with an increased risk of progressive multifocal leukoencephalopathy that sometimes requires treatment cessation with a risk of returning disease activity. The aim of this study was to characterize the pharmacokinetics and -dynamics as well as neurodestruction marker serum neurofilament light chain (sNfL) in patients with RRMS and secondary progressive MS (SPMS) stopping NAT in correlation to clinical data.

Methods: In this study, 50 RRMS and 9 SPMS patients after NAT cessation were included. Five RRMS patients on NAT treatment holiday were evaluated. Clinical and radiological disease activity were systemically assessed by frequent exams after NAT stop. Free NAT concentration, cell bound NAT, α4-integrin expression and α4-integrin-receptor saturation as well as immune cell frequencies were measured for up to 4 months after NAT withdrawal. Additionally, sNfL levels were observed up to 12 months in RRMS and up to 4 months in SPMS patients.

Results: NAT cessation was associated with a return of disease activity in 38% of the RRMS and 33% of the SPMS patients within 12 and 7 months, respectively. Concentration of free and cell bound NAT as well as α4-integrin-receptor saturation decreased in the RRMS and SPMS patients whereas α4-integrin expression increased over time. NAT induced increase of lymphocytes and its subsets normalized and a non-significant drop of NK and Th17 T-cells counts could be detected. All RRMS patients showed physiological sNfL levels <8pg/ml 1 month after last NAT infusion. During follow-up period sNfL levels peaked up to 16-fold and were linked to return of disease activity in 19 of the 37 RRMS patients. Treatment holiday was also associated with a return of disease activity in 4 of 5 patients and with an increase of sNfL at an individual level.

Conclusions: We demonstrate the reversibility of NAT pharmacodynamic and -kinetic markers. sNfL levels are associated with the recurrence of disease activity and can also serve as an early marker to predict present before onset of clinical or radiological disease activity on the individual level.
BPPV: Comparison of the SémontPLUS With the Sémont Maneuver: A Prospective Randomized Trial
Authors: Strupp Michael , Goldschagg Nicolina , Vinck Anne-Sophie , Bayer Otmar , Vandenbroeck Sebastian , Salerni Lorenzo , Hennig Anita , Obrist Dominik , Mandalà Marco
Published: April 2021

Objective: To compare the efficacy of the Sémont maneuver (SM) with the new “SémontPLUS maneuver” (SM+) in patients with posterior canal BPPV canalolithiasis (pcBPPVcan).

Methods and Patients: In a prospective trinational (Germany, Italy, and Belgium) randomized trial, patients with pcBPPVcan were randomly assigned to SM or SM+; SM+ means overextension of the head by 60+° below earth horizontal line during the movement of the patient toward the affected side. The first maneuver was done by the physician, and the subsequent maneuvers by the patients 9 times/day on their own. Each morning the patient documented whether vertigo could be induced. The primary endpoints were: “How long (in days) does it take until no attacks can be induced?” and “What is the efficacy of a single SM/SM+?”

Results: In the 194 patients analyzed (96 SM, 98 SM+), it took 2 days (median, range 1–21 days, mean 3.6 days) for recovery with SM and 1 day (median, range 1-8 days, mean 1.8 days) with SM+ (p = 0.001, Mann-Whitney U-test). There was no difference in the second primary endpoint (chi2-test, p = 0.39).

Interpretation: This prospective trial shows that SM+ is more effective than SM when repeated therapeutic maneuvers are performed but not when a single maneuver is performed. It also supports the hypothesis of the biophysical model: overextension of the head during step 2 brings the clot of otoconia beyond the vertex of the canal, which increases the effectivity.

Classification of Evidence: This study provides Class I evidence that SM+ is superior to SM for multiple treatment maneuvers of pcBPPVcan.
Case Report: Ninjin'yoeito May Improve Quality of Life After Hospitalization for Acute Illness in Patients With Frailty
Authors: Kashima Masayuki
Published: April 2021

Introduction: Frail patients are susceptible to a large number of diseases, and frailty particularly is known to develop after acute illness. No conventional drugs are known to prevent such exacerbation after acute illness. However, traditional Japanese medicine, Kampo, is thought to confer efficacious energy and nutritional supplements and serve to improve malaise after acute illness. Ninjin'yoeito is a representative Kampo medicine for such situation.

Cases: We describe three frail patients hospitalized for acute illness who started taking ninjin'yoeito at the time of discharge.

Case 1: An 87-year-old man admitted with acute prostatitis complicated by hypertension and chronic obstructive pulmonary disease (COPD). His 36-Item Short Form Health Survey (SF-36) score, which is representative of total quality of life and comprises eight components, showed consistent improvements after 4 and 12 weeks of ninjin'yoeito administration, especially for body pain (BP; scores from 41 to 51 and 100, respectively), social function (SF; 50, 100, 100), and mental health (MH; 75, 75, 90).

Case 2: A 65-year-old man admitted with urinary tract infection complicated by primary sclerosing cholangitis and COPD. All SF-36 component scores showed improvement 12 weeks later: physical function (PF; 70–95), role physical (RP; 75–100), BP (72–84), general health (GH; 45–52), vitality (VT; 37.5–75), SF 75–100, role emotional (RE; 75–100), and MH (70–90).

Case 3: An 80-year-old man admitted for pneumonia complicated with hypertension. SF-36 score was improved 4 weeks later for RP (68.8–100), BP (52–61), GH (52–72), VT (43.8–62.5), SF (37.5–100), and RE (58.3–91.7).

Conclusion: Patients with frailty often have a worsened SF-36 score after discharge following acute illness, but the score may be improved by taking ninjin'yoeito.
Radiomic Analysis to Predict Outcome in Recurrent Glioblastoma Based on Multi-Center MR Imaging From the Prospective DIRECTOR Trial
Authors: Vils Alex , Bogowicz Marta , Tanadini-Lang Stephanie , Vuong Diem , Saltybaeva Natalia , Kraft Johannes , Wirsching Hans-Georg , Gramatzki Dorothee , Wick Wolfgang , Rushing Elisabeth , Reifenberger Guido , Guckenberger Matthias , Weller Michael , Andratschke Nicolaus
Published: April 2021

Background

Based on promising results from radiomic approaches to predict O6-methylguanine DNA methyltransferase promoter methylation status (MGMT status) and clinical outcome in patients with newly diagnosed glioblastoma, the current study aimed to evaluate radiomics in recurrent glioblastoma patients.

Methods

Pre-treatment MR-imaging data of 69 patients enrolled into the DIRECTOR trial in recurrent glioblastoma served as a training cohort, and 49 independent patients formed an external validation cohort. Contrast-enhancing tumor and peritumoral volumes were segmented on MR images. 180 radiomic features were extracted after application of two MR intensity normalization techniques: fixed number of bins and linear rescaling. Radiomic feature selection was performed via principal component analysis, and multivariable models were trained to predict MGMT status, progression-free survival from first salvage therapy, referred to herein as PFS2, and overall survival (OS). The prognostic power of models was quantified with concordance index (CI) for survival data and area under receiver operating characteristic curve (AUC) for the MGMT status.

Results

We established and validated a radiomic model to predict MGMT status using linear intensity interpolation and considering features extracted from gadolinium-enhanced T1-weighted MRI (training AUC = 0.670, validation AUC = 0.673). Additionally, models predicting PFS2 and OS were found for the training cohort but were not confirmed in our validation cohort.

Conclusions

A radiomic model for prediction of MGMT promoter methylation status from tumor texture features in patients with recurrent glioblastoma was successfully established, providing a non-invasive approach to anticipate patient’s response to chemotherapy if biopsy cannot be performed. The radiomic approach to predict PFS2 and OS failed.
Case Report: Late-Presenting Congenital Diaphragmatic Hernia With Tension Gastrothorax
Authors: Anekar Aabha A. , Nanjundachar Sumana , Desai Dhaneshgouda , Lakhani Jafferali , Kabbur Prakash M.
Published: April 2021

A congenital diaphragmatic hernia (CDH) occurs when the abdominal contents protrude into the thoracic cavity through an opening in the diaphragm. The main pathology lies in the maldevelopment or defective fusion of the pleuroperitoneal membranes. Delayed diagnosis in later childhood as in the index case reported here can lead to life-threatening complications such as tension gastrothorax and gastric volvulus. Such life-threatening conditions should be managed emergently avoiding misdiagnoses and untoward harm to the patient. We report a pediatric case of an 8-year-old boy who presented with respiratory distress, chest pain, and non-bilious vomiting. He was initially diagnosed with tension pneumothorax, and the chest x-ray was interpreted as hydropneumothorax. A chest tube placement was planned but was withheld due to excessive vomiting. A nasogastric (NG) tube was placed, and a barium-filled radiograph showed an intrathoracic presence of the stomach. A diagnosis of a congenital diaphragmatic hernia with tension gastrothorax was made. The posterolateral (Bochdalek) diaphragmatic hernia was repaired successfully. This case report highlights the importance of including a late-presenting CDH in the differential diagnoses of pediatric patients who present with respiratory distress, chest pain, non-bilious vomiting, and radiological findings suggestive of tension pneumothorax.
Case Report: White Colored Stool: An Early Sign of Cystic Fibrosis in Infants
Authors: Guo Jing , He Rong , Mao Zhi-qin
Published: April 2021

A 2-month-old male infant presented with white colored stools 1 month after birth. There was no jaundice of the skin, mucous membrane, or sclera; his liver was enlarged (4 cm below the ribs), and his liver function tests showed slightly elevated total bilirubin (TB), direct bilirubin (DB), and total bile acid (TBA). An abdominal doppler ultrasound showed no signs of biliary atresia. Genetic testing revealed a CFTR hemizygous mutation site (c.223C>T) in exon 3 and exon 2–3 heterozygous deletion mutation. The infant's stool turned yellow after oral administration of pancreatic tablets. Finally, the infant was diagnosed with cystic fibrosis (CF). Review of literature revealed five children (including the infant in this case study) with CF who presented with white stool. All five children had anemia, four had edema and hypoproteinemia, five had changes in stool color (it was pistachio-green color in two patients, pale colored in one, acholic stool in one, and white stool in one), two had cholestasis, one infant had delayed meconium discharge, and three children had delayed growth and hepatomegaly. Two children had an abnormal sweat test, one had a F508del compound heterozygous mutation, and one had three mutation sites (C.214G>G/A, P.A72T; C.650A>A/G, P.E217G, and C.3406G>G/A, P. A1136T), which was a compound heterozygous mutation. So, CF could be included in the differential diagnosis of infants with white stool. Genetic testing could confirm an early diagnosis of CF. Pancreatic replacement therapy has been shown to be beneficial for improving the digestive function.
Pharmacological Evaluation of Safoof-e-Pathar Phori- A Polyherbal Unani Formulation for Urolithiasis
Authors: Ahmad Wasim , Khan Mohammad Ahmed , Ashraf Kamran , Ahmad Ayaz , Daud Ali Mohammad , Ansari Mohd Nazam , Kamal YT , Wahab Shadma , Zaidi SM Arif , Mujeeb Mohd. , Ahmad Sayeed
Published: April 2021

Safoof-e-Pathar phori (SPP) is an Unani poly-herbomineral formulation, which has for a long time been used as a medicine due to its antiurolithiatic activity, as per the Unani Pharmacopoeia. This powder formulation is prepared using six different plant/mineral constituents. In this study, we explored the antiurolithiatic and antioxidant potentials of SPP (at 700 and 1,000 mg/kg) in albino Wistar rats with urolithiasis induced by 0.75% ethylene glycol (EG) and 1% ammonium chloride (AC). Long-term oral toxicity studies were performed according to the Organization for Economic Co-operation and Development (OECD) guidelines for 90 days at an oral dose of 700 mg/kg of SPP. The EG urolithiatic toxicant group had significantly higher levels of urinary calcium, serum creatinine, blood urea, and tissue lipid peroxidation and significantly (p< 0.001 vs control) lower levels of urinary sodium and potassium than the normal control group. Histopathological examination revealed the presence of refractile crystals in the tubular epithelial cell and damage to proximal tubular epithelium in the toxicant group but not in the SPP treatment groups. Treatment of SPP at 700 and 1,000 mg/kg significantly (p< 0.001 vs toxicant) lowered urinary calcium, serum creatinine, blood urea, and lipid peroxidation in urolithiatic rats, 21 days after induction of urolithiasis compared to the toxicant group. A long-term oral toxicity study revealed the normal growth of animals without any significant change in hematological, hepatic, and renal parameters; there was no evidence of abnormal histology of the heart, kidney, liver, spleen, or stomach tissues. These results suggest the usefulness of SPP as an antiurolithiatic and an antioxidant agent, and long-term daily oral consumption of SPP was found to be safe in albino Wistar rats for up to 3 months. Thus, SPP may be safe for clinical use as an antiurolithiatic formulation.
IR-61 Improves Voiding Function via Mitochondrial Protection in Diabetic Rats
Authors: Wang Jianwu , Dai Linyong , Yue Xiaofeng , Shen Chongxing , Li Tong , Long Lei , Zhi Yi , Wang Yawei , Shen Gufang , Shi Chunmeng , Liu Yunsheng , Fang Qiang , Li Weibing
Published: April 2021

Diabetic bladder dysfunction (DBD) afflicts nearly half of diabetic patients, but effective treatment is lacking. In this study, IR-61, a novel heptamethine cyanine dye with potential antioxidant effects, was investigated to determine whether it can alleviate DBD. Rats were intraperitoneally injected with IR-61 or vehicle after diabetes was induced with streptozotocin. Before evaluating the effects of IR-61 in improving DBD by filling cystometry, we detected its distribution in tissues and subcellular organelles by confocal fluorescence imaging. Near infrared (NIR) imaging showed that IR-61 could accumulate at high levels in the bladders of diabetic rats, and confocal images demonstrated that it was mainly taken up by bladder smooth muscle cells (BSMCs) and localized in mitochondria. Then, filling cystometry illustrated that IR-61 significantly improved the bladder function of diabetic rats. The histomorphometry results showed that IR-61 effectively mitigated the pathological changes in bladder smooth muscle (BSM) in diabetic rats. Furthermore, IR-61 remarkably reduced the number of apoptotic BSMCs and the unfavorable expression of proteins related to the mitochondrial apoptotic pathway (Bcl-2, BAX, Cytochrome C, and cleaved Caspase-9) in diabetic rats. Moreover, the frozen section staining and transmission electron microscopy results proved that IR-61 significantly reduced the reactive oxygen species (ROS) levels and prevented the mitochondrial mass and morphology damage in the BSM of diabetic rats. In addition, IR-61 upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its associated antioxidant proteins in the BSM of diabetic rats. Together, these results indicate that IR-61 can improve the voiding function of rats with DBD by protecting the mitochondria of BSMCs from oxidative stress, which is possibly mediated through the activation of the Nrf2 pathway.