bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgery Performed Under Propofol Anesthesia Induces Cognitive Impairment and Amyloid Pathology in ApoE4 Knock-In Mouse Model
Authors: Kim Jong-Ho , Jung Harry , Lee Yeonkyeong , Sohn Jong-Hee
Published: April 2021

Background: Postoperative cognitive dysfunction (POCD) following anesthesia and surgery is a common and severe complication, especially in elderly patients. A pre-existing cognitive impairment may impart susceptibility to further cognitive dysfunction; the mechanism remains unclear. We hypothesized that the specific impacts of anesthesia and surgery on individuals with preclinical Alzheimer’s disease (AD) may render them more susceptible to an increase in the risk of cognitive impairment. The aim of this study was to compare the cognitive impairment between normal adult mice and those with preclinical AD after propofol anesthesia and surgery.

Methods: We performed abdominal surgery in cognitively pre-symptomatic, 5-month-old male mice with sporadic AD (apolipoprotein E4 allele, ApoE4-KI) and age-matched (C57BL/6J) controls. Propofol anesthesia (170 mg/kg) was induced via retro-orbital injection over 2 h. Morris water maze (MWM) and Y-maze tests were conducted 2 days before and 2, 4, and 7 days after surgery. The mean escape latencies and spontaneous alternation percentages were the major outcomes. Neuronal apoptosis in hippocampal sections was evaluated using the terminal dUTP nick-end labeling (TUNEL) assay. Hippocampal amyloid beta (Aβ) levels were assessed via quantitative immunohistochemistry (IHC).

Results: The control mice exhibited increased mean escape latencies of MWM at postoperative 2 and 4, but not at day 7; ApoE4-KI mice exhibited such increases at postoperative days 2, 4 and 7. Significant differences between ApoE4-KI and control mice in terms of the mean escape latencies were evident at days 2 and 7 (both P < 0.05). However, performance on a non-hippocampal memory tasks (Y-maze test) did not differ. More TUNEL-positive neurons were evident in the hippocampal CA3 region of ApoE4-KI mice at postoperative days 2 and 4, but not at day 7 compared to the control group (both P < 0.05). IHC revealed significantly elevated Aβ deposition in the hippocampal CA3 region of ApoE4-KI mice at postoperative days 4 and 7 compared to control mice (both P < 0.05).

Conclusions: Propofol anesthesia followed by surgery induced persistent changes in cognition, and pathological hippocampal changes in pre-symptomatic, but vulnerable AD mice. It would be appropriate to explore whether preclinical AD patients are more vulnerable to POCD development.
Comparative Study of Specific Loss Power and Transverse Relaxivity of Spinel Ferrite Nanoensembles Coated With Chitosan and Polyethylene Glycol
Authors: Hoque S. Manjura , Islam M. Khairul , Hoq Amitra , Haque M. Manjurul , Maritim Samuel , Coman Daniel , Hyder Fahmeed
Published: April 2021

We synthesized spinel ferrite nanoensembles (MnFe2O4, CoFe2O4, and Fe3O4) using the chemical co-precipitation method and characterized their physical, chemical, and magnetic properties by X-ray diffraction (XRD), transmission electron microscopy (TEM), physical properties measurement system (PPMS), Mössbauer spectroscopy, Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS) and Raman spectroscopy. Their relaxation properties and potential for hyperthermia therapy were determined using nuclear magnetic resonance (NMR) and cell viability assay, respectively. XRD and TEM data confirmed that the particle core sizes were 6–9 nm before coating while their sizes increased to 10–14 nm and 14–20 nm after coating with chitosan and polyethylene glycol (PEG), respectively. Mössbauer spectroscopy showed superparamagnetic behavior for MnFe2O4 nanoparticles and ferrimagnetic behavior for the CoFe2O4 and Fe3O4 nanoparticles. A detailed studies of MH loops of all three ferrites before and after coating showed surface functionalization by a large reduction of coercivity and anisotropy. The successful coating was further confirmed by the peak shifts in the FTIR spectra of the particles whereas Raman spectra of coated ferrites also displayed the characteristic absorption patterns and suppression of the ferrite peaks suggesting successful coating. The induced heating profile of the nanoparticles in stable suspension was tested with a radio frequency magnetic field of 76 mT and a frequency of 400 kHz. High mortality (>98%) of 9 L gliosarcoma cancer cells by hyperthermia suggested that these nanoparticles could be used for cancer therapy. Transverse relaxivities (r2) determined by NMR for chitosan-coated MnFe2O4, CoFe2O4, and Fe3O4 nanoparticles were 297 (±22), 353 (±26), and 345 (±13), mM−1S−1, while for PEG-coated nanoparticles are 165 (±22), 146 (±14), and 159 (±07) mM−1S−1, respectively. Overall these spinel ferrite nanoensembles show great promise for cancer theranostics research applications.
Stem Cell Neurodevelopmental Solutions for Restorative Treatments of the Human Trunk and Spine
Authors: Olmsted Zachary T. , Paluh Janet L.
Published: April 2021

The ability to reliably repair spinal cord injuries (SCI) will be one of the greatest human achievements realized in regenerative medicine. Until recently, the cellular path to this goal has been challenging. However, as detailed developmental principles are revealed in mouse and human models, their application in the stem cell community brings trunk and spine embryology into efforts to advance human regenerative medicine. New models of posterior embryo development identify neuromesodermal progenitors (NMPs) as a major bifurcation point in generating the spinal cord and somites and is leading to production of cell types with the full range of axial identities critical for repair of trunk and spine disorders. This is coupled with organoid technologies including assembloids, circuitoids, and gastruloids. We describe a paradigm for applying developmental principles towards the goal of cell-based restorative therapies to enable reproducible and effective near-term clinical interventions.
Blind Visualization of Task-Related Networks From Visual Oddball Simultaneous EEG-fMRI Data: Spectral or Spatiospectral Model?
Authors: Labounek René , Wu Zhuolin , Bridwell David A. , Brázdil Milan , Jan Jiří , Nestrašil Igor
Published: April 2021

Various disease conditions can alter EEG event-related responses and fMRI-BOLD signals. We hypothesized that event-related responses and their clinical alterations are imprinted in the EEG spectral domain as event-related (spatio)spectral patterns (ERSPat). We tested four EEG-fMRI fusion models utilizing EEG power spectra fluctuations (i.e., absolute spectral model - ASM; relative spectral model - RSM; absolute spatiospectral model - ASSM; and relative spatiospectral model - RSSM) for fully automated and blind visualization of task-related neural networks. Two (spatio)spectral patterns (high δ4 band and low β1 band) demonstrated significant negative linear relationship (pFWE < 0.05) to the frequent stimulus and three patterns (two low δ2 and δ3 bands, and narrow θ1 band) demonstrated significant positive relationship (p < 0.05) to the target stimulus. These patterns were identified as ERSPats. EEG-fMRI F-map of each δ4 model showed strong engagement of insula, cuneus, precuneus, basal ganglia, sensory-motor, motor and dorsal part of fronto-parietal control (FPCN) networks with fast HRF peak and noticeable trough. ASM and RSSM emphasized spatial statistics, and the relative power amplified the relationship to the frequent stimulus. For the δ4 model, we detected a reduced HRF peak amplitude and a magnified HRF trough amplitude in the frontal part of the FPCN, default mode network (DMN) and in the frontal white matter. The frequent-related β1 patterns visualized less significant and distinct suprathreshold spatial associations. Each θ1 model showed strong involvement of lateralized left-sided sensory-motor and motor networks with simultaneous basal ganglia co-activations and reduced HRF peak and amplified HRF trough in the frontal part of the FPCN and DMN. The ASM θ1 model preserved target-related EEG-fMRI associations in the dorsal part of the FPCN. For δ4, β1, and θ1 bands, all models provided high local F-statistics in expected regions. The most robust EEG-fMRI associations were observed for ASM and RSSM.
Short-Term Immobilization Promotes a Rapid Loss of Motor Evoked Potentials and Strength That Is Not Rescued by rTMS Treatment
Authors: Gaffney Christopher J. , Drinkwater Amber , Joshi Shalmali D. , O'Hanlon Brandon , Robinson Abbie , Sands Kayle-Anne , Slade Kate , Braithwaite Jason J. , Nuttall Helen E.
Published: April 2021

Short-term limb immobilization results in skeletal muscle decline, but the underlying mechanisms are incompletely understood. This study aimed to determine the neurophysiologic basis of immobilization-induced skeletal muscle decline, and whether repetitive Transcranial Magnetic Stimulation (rTMS) could prevent any decline. Twenty-four healthy young males (20 ± 0.5 years) underwent unilateral limb immobilization for 72 h. Subjects were randomized between daily rTMS (n = 12) using six 20 Hz pulse trains of 1.5 s duration with a 60 s inter-train-interval delivered at 90% resting Motor Threshold (rMT), or Sham rTMS (n = 12) throughout immobilization. Maximal grip strength, EMG activity, arm volume, and composition were determined at 0 and 72 h. Motor Evoked Potentials (MEPs) were determined daily throughout immobilization to index motor excitability. Immobilization induced a significant reduction in motor excitability across time (−30% at 72 h; p < 0.05). The rTMS intervention increased motor excitability at 0 h (+13%, p < 0.05). Despite daily rTMS treatment, there was still a significant reduction in motor excitability (−33% at 72 h, p < 0.05), loss in EMG activity (−23.5% at 72 h; p < 0.05), and a loss of maximal grip strength (−22%, p < 0.001) after immobilization. Interestingly, the increase in biceps (Sham vs. rTMS) (+0.8 vs. +0.1 mm, p < 0.01) and posterior forearm (+0.3 vs. +0.0 mm, p < 0.05) skinfold thickness with immobilization in Sham treatment was not observed following rTMS treatment. Reduced MEPs drive the loss of strength with immobilization. Repetitive Transcranial Magnetic Stimulation cannot prevent this loss of strength but further investigation and optimization of neuroplasticity protocols may have therapeutic benefit.
Comparisons Between Frontline Therapy and a Combination of Eltrombopag Plus Immunosuppression Therapy and Human Leukocyte Antigen-Haploidentical Hematopoietic Stem Cell Transplantation in Patients With Severe Aplastic Anemia: A Systematic Review
Authors: Yang Yuan , Ji Jiang , Tang Zengwei , Han Bing
Published: April 2021

Background and Aims: This study aimed at comparing the efficacy and safety of eltrombopag (EPAG) plus immunosuppressive therapies (ISTs) and haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the frontline treatment for severe aplastic anemia (SAA) patients.

Methods: Four electronic databases and Clinicaltrials.gov were comprehensively searched from January 2010 to August 2020. Studies that aimed at evaluating the efficacy and safety of EPAG+IST or haplo-HSCT in SAA patients were included. One-/2-year overall survival (OS), complete response (CR), and overall response rates (ORRs) were indirectly compared between EPAG+IST and haplo-HSCT.

Results: A total of 447 patients involved in 10 cohort studies were found to be eligible for this study. A narrative synthesis was performed due to lack of data directly comparing the outcome of EPAG+IST and haplo-HSCT. Consistent with the analysis results in the whole population, subgroup analyses in the age-matched population showed that there was no significant difference in ORR between EPAG+IST and haplo-HSCT groups. However, the CR rate was lower in the EPAG+IST group when compared with the haplo-HSCT group. The incidence rate of clonal evolution/SAA relapse ranged at 8–14 and 19–31% in the EPAG+IST group but not reported in the haplo-HSCT group. The incidence rate for acute graft vs. host disease (aGVHD) and chronic graft vs. host disease (cGVHD) ranged at 52–57 and 12–67%, respectively, for the haplo-HSCT group. The main causes of deaths were infections in the EPAG+IST group, and GVHD and infections in the haplo-HSCT group.

Conclusion: EPAG+IST has a comparable ORR and 1-/2-year OS but lower CR rate when indirectly compared with haplo-HSCT in the frontline treatment of patients with SAA. Patients treated with haplo-HSCT may exhibit a high incidence of GVHD, whereas patients treated with EPAG+IST may experience more relapses or clone evolution.
Prognostic Models for Patients With Gleason Score 9 Prostate Cancer: A Population-Based Study
Authors: Qiu Jianhui , Cai Desheng , Wang Zixin , Zhou Jingcheng , Gong Yanqing , Cai Lin , Gong Kan
Published: April 2021

Purpose: Gleason score (GS) system is one of the most widely used histological grading methods for prostate cancer (PCa) all over the world. GS can be obtained by adding the primary Gleason pattern (GP) and secondary GP. Different proportions of GP 4 and GP 5 in prostate specimens can both lead to GS 9. In this study, we explored whether GP 5 + 4 or GP 4 + 5 was associated with different prognoses among patients with GS 9 PCa.

Materials and methods: A retrospective population-based study was conducted on 10,124 subjects diagnosed with GS 9 PCa between 2004 and 2009 from the Surveillance, Epidemiology, and End Results program. A 1:1 propensity-score matching (PSM) was performed to balance the baseline characteristics between the GP 4 + 5 and 5 + 4 groups and to compare the prognoses between the two groups. Cox regression analysis and Fine-Gray competing risk regression models were adopted to screen the covariates significantly associated with all-cause mortality (ACM) and cancer-specific mortality (CAM).

Results: GP 5 + 4 was associated with higher risks of ACM and CSM before or after PSM than GP 4 + 5. In the original cohort, there were eight independent predictors for ACM, which were age at diagnosis, race, AJCC NM stage, PSA levels, treatments, GP, and marital status, confirmed by the Cox analysis; and nine independent predictors for CSM, which were age at diagnosis, race, AJCC TNM stage, PSA levels, treatments, GP, and marital status, confirmed by the competing-risk model.

Conclusion: GP 5 + 4 was associated with a poorer overall survival and cancer-specific survival compared with GP 4 + 5.
Small Cell Lung Cancer Transformation as a Resistance Mechanism to Osimertinib in Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma: Case Report and Literature Review
Authors: Leonetti Alessandro , Minari Roberta , Mazzaschi Giulia , Gnetti Letizia , La Monica Silvia , Alfieri Roberta , Campanini Nicoletta , Verzè Michela , Olivani Andrea , Ventura Luigi , Tiseo Marcello
Published: April 2021

Introduction: Small cell lung cancer (SCLC) transformation represents a mechanism of resistance to osimertinib in EGFR-mutated lung adenocarcinoma, which dramatically impacts patients' prognosis due to high refractoriness to conventional treatments.

Case Description: We present the case of a patient who developed a SCLC phenotypic transformation as resistance mechanism to second-line osimertinib for T790M-positive EGFR-mutated NSCLC. Our patient received platinum–etoposide doublet following SCLC switch and achieved a modest clinical benefit which lasted 4 months. NGS and IHC analyses for p53 and Rb were performed on subsequent liver biopsies, revealing baseline TP53 mutation and complete absence of p53 and Rb expression. Primary cell cultures were established following a liver biopsy at the time of SCLC transformation, and drug sensitivity assays showed meaningful cell growth inhibition when osimertinib was added to platinum–etoposide compared with control (p < 0.05). A review of the current literature regarding SCLC transformation after failure of osimertinib was performed.

Conclusions: Based on retrospective data available to date, platinum–etoposide chemotherapy is the preferred treatment choice in the occurrence of SCLC transformation after osimertinib failure. The extension of osimertinib in combination with chemotherapy in the occurrence of SCLC transformation as resistance mechanism to osimertinib is a matter of debate. The combination of osimertinib and platinum–etoposide was effective in inhibiting cell growth in our primary cell cultures. Clinical studies are needed to further explore this combination in the occurrence of SCLC transformation as a resistance mechanism to osimertinib.
Biological Roles and Therapeutic Applications of IDH2 Mutations in Human Cancer
Authors: Guo Jinxiu , Zhang Ruyue , Yang Zhe , Duan Zhenfeng , Yin Detao , Zhou Yubing
Published: April 2021

Isocitrate dehydrogenase (IDH) is a key metabolic enzyme catalyzing the interconversion of isocitrate to α-ketoglutarate (α-KG). Mutations in IDH lead to loss of normal enzymatic activity and gain of neomorphic activity that irreversibly converts α-KG to 2-hydroxyglutarate (2-HG), which can competitively inhibit a-KG-dependent enzymes, subsequently induces cell metabolic reprograming, inhibits cell differentiation, and initiates cell tumorigenesis. Encouragingly, this phenomenon can be reversed by specific small molecule inhibitors of IDH mutation. At present, small molecular inhibitors of IDH1 and IDH2 mutant have been developed, and promising progress has been made in preclinical and clinical development, showing encouraging results in patients with IDH2 mutant cancers. This review will focus on the biological roles of IDH2 mutation in tumorigenesis, and provide a proof-of-principle for the development and application of IDH2 mutant inhibitors for human cancer treatment.
Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon
Authors: Darrigues Emilie , Elberson Benjamin W. , De Loose Annick , Lee Madison P. , Green Ebonye , Benton Ashley M. , Sink Ladye G. , Scott Hayden , Gokden Murat , Day John D. , Rodriguez Analiz
Published: April 2021

Neuro-oncology biobanks are critical for the implementation of a precision medicine program. In this perspective, we review our first year experience of a brain tumor biobank with integrated next generation sequencing. From our experience, we describe the critical role of the neurosurgeon in diagnosis, research, and precision medicine efforts. In the first year of implementation of the biobank, 117 patients (Female: 62; Male: 55) had 125 brain tumor surgeries. 75% of patients had tumors biobanked, and 16% were of minority race/ethnicity. Tumors biobanked were as follows: diffuse gliomas (45%), brain metastases (29%), meningioma (21%), and other (5%). Among biobanked patients, 100% also had next generation sequencing. Eleven patients qualified for targeted therapy based on identification of actionable gene mutations. One patient with a hereditary cancer predisposition syndrome was also identified. An iterative quality improvement process was implemented to streamline the workflow between the operating room, pathology, and the research laboratory. Dedicated tumor bank personnel in the department of neurosurgery greatly improved standard operating procedure. Intraoperative selection and processing of tumor tissue by the neurosurgeon was integral to increasing success with cell culture assays. Currently, our institutional protocol integrates standard histopathological diagnosis, next generation sequencing, and functional assays on surgical specimens to develop precision medicine protocols for our patients. This perspective reviews the critical role of neurosurgeons in brain tumor biobank implementation and success as well as future directions for enhancing precision medicine efforts.
Mapping of Cervical and Upper Mediastinal Lymph Node Recurrence for Guiding Clinical Target Delineation of Postoperative Radiotherapy in Thoracic Esophageal Squamous Cell Carcinoma
Authors: Wang Yichun , Ye Dongmei , Kang Mei , Zhu Liyang , Yang Mingwei , Jiang Jun , Xia Wanli , Kang Ningning , Chen Xiangcun , Wang Jie , Wang Fan
Published: April 2021

Background

The lower neck and upper mediastinum are the major regions for postoperative radiotherapy (PORT) in thoracic esophageal squamous cell carcinoma (TESCC). However, there is no uniform standard regarding the delineation of nodal clinical target volume (CTVnd). This study aimed to map the recurrent lymph nodes in the cervical and upper mediastinal regions and explore a reasonable CTVnd for PORT in TESCC.

Methods

We retrospectively reviewed patients in our hospital with first cervical and/or upper mediastinal lymph node recurrence (LNR) after upfront esophagectomy. All of these recurrent lymph nodes were plotted on template computed tomography (CT) images with reference to surrounding structures. The recurrence frequency at different stations was investigated and the anatomic distribution of recurrent lymph nodes was analyzed.

Results

A total of 119 patients with 215 recurrent lymph nodes were identified. There were 47 (39.5%) patients with cervical LNR and 102 (85.7%) patients with upper mediastinal LNR. The high-risk regions were station 101L/R, station 104L/R, station 106recL/R, station 105 and station 106pre for upper TESCC and station 104L/R, station 106recL/R, station 105, station 106pre and station 106tbL for middle and lower TESCCs. LNR in the external group of station 104L/R was not common, and LNR was not found in the narrow spaces where the trachea was in close contact with the innominate artery, aortic arch and mediastinal pleura. LNR below the level of the cephalic margin of the superior vena cava was also not common for upper TESCC.

Conclusions

The CTVnd of PORT in the cervical and upper mediastinal regions should cover station 101L/R, station 104L/R, station 106recL/R, station 105 and station 106pre for upper TESCC and station 104L/R, station 106recL/R, station 105, station 106pre and station 106tbL for middle and lower TESCCs. Based on our results, we proposed a useful atlas for guiding the delineation of CTVnd in TESCC.
Identification of a Rare Exon 19 Skipping Mutation in ALMS1 Gene in Alström Syndrome Patients From Two Unrelated Saudi Families
Authors: Saadah Omar I. , Banaganapalli Babajan , Kamal Naglaa M. , Sahly Ahmed N. , Alsufyani Hadeel A. , Mohammed Arif , Ahmad Aftab , Nasser Khalidah Khalid , Al-Aama Jumana Y. , Shaik Noor Ahmad , Elango Ramu
Published: April 2021

Background: Alström syndrome (AS) is a very rare childhood disorder characterized by cardiomyopathy, progressive hearing loss and blindness. Inherited genetic variants of ALMS1 gene are the known molecular cause of this disease. The objective of this study was to characterize the genetic basis and understand the genotype–phenotype relationship in Saudi AS patients.

Methods: Clinical phenotyping and whole-exome sequencing (WES) analysis were performed on six AS patients belonging to two unrelated consanguineous Saudi families. Sanger sequencing was performed to determine the mode of inheritance of ALMS1 variant in first-degree family relatives and also to ensure its rare prevalence in 100 healthy population controls.

Results: We identified that Alström patients from both the families were sharing a very rare ALMS1, 3′-splice site acceptor (c.11873−2 A>T) variant, which skips entire exon-19 and shortens the protein by 80 amino acids. This disease variant was inherited by AS patients in autosomal recessive mode and is not yet reported in any population-specific genetic databases. AS patients carrying this mutation showed heterogeneity in clinical presentations. Computational analysis of the mutant centroid structure of ALMS1 mRNA revealed that exon-19 skipping enlarges the hairpin loop and decreases the free energy, eventually affecting its folding pattern, stability, and function. Hence, we propose c.11873–2A as an AS causative potential founder mutation in Saudi Arabia because it is found in two families lacking a common lineage.

Conclusions: We conclude that WES analysis potentially helps in clinical phenotyping, early diagnosis, and better clinical management of Alström patients showing variable clinical expressivity.
Therapeutic Potentials of Antiviral Plants Used in Traditional African Medicine With COVID-19 in Focus: A Nigerian Perspective
Authors: Attah Alfred Francis , Fagbemi Adeshola Adebayo , Olubiyi Olujide , Dada-Adegbola Hannah , Oluwadotun Akinseinde , Elujoba Anthony , Babalola Chinedum Peace
Published: April 2021

The coronavirus disease 2019 (COVID-19) pandemic is caused by an infectious novel strain of coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which was earlier referred to as 2019-nCoV. The respiratory disease is the most consequential global public health crisis of the 21st century whose level of negative impact increasingly experienced globally has not been recorded since World War II. Up till now, there has been no specific globally authorized antiviral drug, vaccines, supplement or herbal remedy available for the treatment of this lethal disease except preventive measures, supportive care and non-specific treatment options adopted in different countries via divergent approaches to halt the pandemic. However, many of these interventions have been documented to show some level of success particularly the Traditional Chinese Medicine while there is paucity of well reported studies on the impact of the widely embraced Traditional African Medicines (TAM) adopted so far for the prevention, management and treatment of COVID-19. We carried out a detailed review of publicly available data, information and claims on the potentials of indigenous plants used in Sub-Saharan Africa as antiviral remedies with potentials for the prevention and management of COVID-19. In this review, we have provided a holistic report on evidence-based antiviral and promising anti-SARS-CoV-2 properties of African medicinal plants based onin silicoevidence,in vitro assaysandin vivoexperiments alongside the available data on their mechanistic pharmacology. In addition, we have unveiled knowledge gaps, provided an update on the effort of African Scientific community toward demystifying the dreadful SARS-CoV-2 micro-enemy of man and have documented popular anti-COVID-19 herbal claims emanating from the continent for the management of COVID-19 while the risk potentials of herb-drug interaction of antiviral phytomedicines when used in combination with orthodox drugs have also been highlighted. This review exercise may lend enough credence to the potential value of African medicinal plants as possible leads in anti-COVID-19 drug discovery through research and development.
Danshen (Salvia miltiorrhiza) on the Global Market: What Are the Implications for Products’ Quality?
Authors: Kum Ka Yui , Kirchhof Rainer , Luick Rainer , Heinrich Michael
Published: April 2021

Background: Danshen (Radix et rhizoma Salviae miltiorrhizae; Salvia miltiorrhiza Bunge, Lamiaceae) is commonly used in Asia, including China, Japan, and Korea with markets in America and Europe growing substantially. It is included in multiple pharmacopeias and salvianolic acid B and tanshinone IIA are used as quality markers. However, on the markets, substitutes and different processing methods often are a concern. a concern regarding patients’ safety and expected outcomes.

Aims: This study aims at understanding the quality of Danshen-derived products on the market, and the relationship between the chemistry, biological activity and the processing and storage methods.

Methods: For heavy metal analysis, inductively coupled plasma optical emission spectrometry was used. High performance thin-layer chromatography and proton nuclear magnetic resonance coupled with principal component analysis were used to understand the variation of metabolite composition. MTT assay and LPS induced NO production assay were used to evaluate the cytotoxicity effect and anti-inflammatory activity, respectively.

Result and Discussion: Six out of sixty samples exceed the limits of cadmium according to the Chinese or United States Pharmacopoeia. Arsenic, lead and copper contents are all below pharmacopoeial thresholds. With more complex processing procedure, the risk of heavy metal contamination increases, especially with arsenic and cadmium. The metabolite compositions show a variability linked to processing and storage methods. Authenticated samples and Vietnamese primary samples contain higher salvianolic acid B, and their chemical compositions are more consistent compared to Chinese online store samples. Overall, a significant chemical variation can be observed in Danshen products directly linked to processing and storage method. In the MTT assay, fourteen samples show cytotoxicity while seven samples increase the proliferation of RAW264.7. In the LPS induced NO production of RAW 264.7, only seven samples show significant inhibitory effects.

Conclusion: This is the first interdisciplinary investigation focusing on understanding the current market and the quality of Danshen. The quality of Danshen products on the high street are inferior to the authenticated samples. The results of the bioassays selected is not useful to differentiate the quality and composition according to the current definition in the pharmacopoeias. Overall, this approach highlights the tremendous variability of the products linked to processing and the need for more systematic and stringent quality assurance.
Novel Regulatory Factors and Small-Molecule Inhibitors of FGFR4 in Cancer
Authors: Liu Yanan , Wang Canwei , Li Jifa , Zhu Jiandong , Zhao Chengguang , Xu Huanhai
Published: April 2021

Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase receptor that is a member of the fibroblast growth factor receptor family and is stimulated by highly regulated ligand binding. Excessive expression of the receptor and its ligand, especially FGF19, occurs in many types of cancer. Abnormal FGFR4 production explains these cancer formations, and therefore, this receptor has emerged as a potential target for inhibiting cancer development. This review discusses the diverse mechanisms of oncogenic activation of FGFR4 and highlights some currently available inhibitors targeting FGFR4.
Lentivirus-Carried microRNA-195 Rescues Memory Deficits of Alzheimer’s Disease Transgenic Mouse by Attenuating the Generation of Amyloid Plaques
Authors: Su Dan , Chai Yani , Yang Junkai , Wang Xuqiao , Liu Ying , Ma Jing , Tang Xin , Mishra Chandan , Chandra Shah Ram , Yue Weidong , Ai Jing
Published: April 2021

Although lots of new drugs are developed to treat Alzheimer’s disease (AD), many clinical trials of monotherapy have failed to affect disease progression or symptoms compared with placebo. Recently, scientists believe that combination treatment is more promising than monotherapy. Previous studies found that microRNA-195 (miR-195) was down-regulated in the hippocampi and cortices of chronic brain hypoperfusion (CBH) rats and ApoE4(+/+) mice, and up-regulation of miR-195 can improve the declined cognitive function of ApoE4(+/+) mice and CBH rats by targeting multi-genes that are related to AD pathology, including amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) genes. However, whether the gain-of-function of miR-195 could improve the impaired learning and memory ability of APP/PS1 transgenic mouse has not been reported. In this study, we stereotaxically injected lentiviral-carried miR-195 into the bilateral hippocampus of 4-month-old (4M) APP/PS1 mice. Morris water maze (MWM) was performed to detect the effect of miR-195 on the cognitive function of APP/PS1 mice after 1M, 2M, and 3M treatment. Western blot was used to detect the expression of APP, BACE1, and AT8. Aβ plagues were quantitatively assessed by immunofluorescence technique. We found that the declined cognitive phenotype of APP/PS1 mice occurred at the age of 6M, not at the age of 5M. And treatment of Lv-pre-miR-195 to APP/PS1 mice for 1M did not achieve any changes. Although Lv-pre-miR-195 treatment for 2M improved the declined learning ability of APP/PS1 mice, it did not affect the memory functions. However, Lv-pre-miR-195 treatment in APP/PS1 mice for 3M can effectively improve both the learning and memory ability of APP/PS1 mice at the age of 7M. Further studies demonstrated that gain-of-function of miR-195 by Lv-pre-miR-195 injection could inhibit the increased APP and AT8 expression of APP/PS1 mice but did not affect BACE1 level that was not changed in both hippocampus and cortex. By counting the number of Aβ plaques of different sizes, we found that Lv-pre-miR-195 treatment mainly reduced the number of Aβ plaques of less than 20 μm, but did not affect the number of Aβ plaques of greater than 50 μm. Taken together, the gain-of -function of miR-195 in the hippocampus can improve the cognition of APP/PS1 mice, probably by blocking the formation of Aβ plagues rather than clearing those that have already formed Aβ plagues.
Natural-Derived Polysaccharides From Plants, Mushrooms, and Seaweeds for the Treatment of Inflammatory Bowel Disease
Authors: Li Cailan , Wu Guosong , Zhao Hualang , Dong Na , Wu Bowen , Chen Yujia , Lu Qiang
Published: April 2021

Inflammatory bowel disease (IBD) is a chronic inflammatory disease impairing the gastrointestinal tract, and its incidence and prevalence have been increasing over time worldwide. IBD greatly reduces peoples' quality of life and results in several life-threatening complications, including polyp, toxic colonic dilatation, intestinal perforation, gastrointestinal bleeding, and cancerization. The current therapies for IBD mainly include drugs for noncritical patients and operation for critical patients. However, continuous use of these drugs causes serious side effects and increased drug resistance, and the demand of effective and affordable drugs with minimal side effects for IBD sufferers is urgent. Natural-derived polysaccharides are becoming a research hotspot for their therapeutic effects on IBD. This study focuses on the research progress of various natural polysaccharides from plants, seaweeds, and mushrooms for the treatment of IBD during recent 20 years. Regulation of oxidative stress, inflammatory status, gut microbiota, and immune system and protection of the intestinal epithelial barrier function are the underlying mechanisms for the natural-derived polysaccharides to treat IBD. The excellent efficacy and safety of polysaccharides make them promising candidates for IBD therapy.
Ultrasonographic Evaluation of Intestinal Fibrosis and Inflammation in Crohn’s Disease. The State of the Art
Authors: Ferretti Francesca , Cannatelli Rosanna , Ardizzone Sandro , Maier Jeanette A. , Maconi Giovanni
Published: April 2021

The evaluation of the degree of inflammation and fibrosis, intrinsic elements in intestinal wall damage of Crohn’s disease, is essential to individuate the extent of the lesions and the presence of strictures. This information will contribute to the choice of the appropriate therapeutic approach, the prediction of the response to therapy and the course of the disease. The accurate evaluation of the extent and severity of inflammation and/or fibrosis in Crohn’s disease currently requires histopathological analysis of the intestinal wall. However, in clinical practice and research, transmural assessment of the intestinal wall with cross sectional imaging is increasingly used for this purpose. The B-mode ultrasonograhic characteristics of the intestinal wall, the assessment of its vascularization by color Doppler and I.V. contrast agents, and the evaluation of the mechanical and elastic properties by sonoelastography, may provide useful and accurate information on the severity and extent of inflammation and intestinal fibrosis in Crohn’s disease. The purpose of this review is to provide an update on current sonographic methods to discriminate inflammation and fibrosis in Crohn’s disease.
A Retrospective Cohort Study on the Clinical Course of Patients With Moderate-Type COVID-19
Authors: Liao Xiaohua , Lv Xin , Song Cheng , Jiang Mao , He Ronglin , Han Yuanyuan , Li Mengyu , Zhang Yan , Jiang Yupeng , Meng Jie
Published: April 2021

Background: A large number of people contracted moderate-type COVID-19 around the world. However, to our knowledge no studies have covered the clinical course of patients with moderate-type COVID-19. This study describes the clinical course of moderate-type patients with COVID-19 from Wuhan City and Yiyang City, and explores factors relevant to the length of hospitalization and symptoms relief.

Methods: The study analyzed the clinical course of 107 moderate-type patients with COVID-19 from the outbreak area (Wuhan) and the imported area (Yiyang), and used automatic linear modeling and multivariate linear regression analysis to explore the factors relevant to the length of hospitalization and symptoms relief. Furthermore, we created a scoring system to value the length of hospitalization and symptoms relief.

Results: Lymphopenia, elevated C-reactive protein, increased LDH, bilateral lung GGO (ground glass opacity), and lung consolidation were more likely to appear in ordinary inpatients with moderate-type COVID-19 from Wuhan (P < 0.05), compared to infected medical staff from Wuhan and ordinary inpatients with moderate-type COVID-19 from Yiyang. Meanwhile, the length of hospitalization and symptoms relief was longer in ordinary patients with moderate-type COVID-19 from Wuhan (P < 0.05). Onset of symptoms to admission, ESR, leucocytes count, and bilateral lung GGO were linearly related to the length of hospitalization (P < 0.05); onset of symptoms to admission, leucocytes count, bilateral lung GGO, and lung consolidation were linearly related to the length of symptoms relief (P < 0.05). By using the scoring system, we found that the time of hospitalization and symptoms relief lengthened as the scores increased.

Conclusions: This study described the clinical course of patients with moderate-type COVID-19, and found that ordinary patients with moderate-type COVID-19 in outbreak areas were more serious and needed stronger treatment and longer treatment time. Onset of symptoms to admission, ESR, leucocytes count, and bilateral lung GGO can be effective predictors of the length of hospitalization. And onset of symptoms to admission, leucocytes count, bilateral lung GGO, and lung consolidation can be effective predictors of the amount of time until symptoms relief. Most importantly, we have created a scoring system, which could contribute to the diagnosis and treatment of COVID-19.
Impact of COVID-19 on the Mental Health of Healthcare Workers: A Cross-Sectional Study From Pakistan
Authors: Hayat Khezar , Arshed Muhammad , Fiaz Iqra , Afreen Urooj , Khan Faiz Ullah , Khan Tahir Abbas , Kadirhaz Muhtar , Shukar Sundus , Saeed Azwa , Gill Muhammad Rouf , Fang Yu
Published: April 2021

Background: The novel coronavirus (COVID-19) pandemic has significantly increased the rate of mortality and morbidity worldwide due to its rapid transmission rate. The mental health status of individuals could have a negative impact attributed to this global situation. Therefore, this study was intended to explore the symptoms of depression and anxiety among healthcare workers (HCWs) of Pakistan during the ongoing COVID-19 pandemic.

Methods: A cross-sectional survey was undertaken by administering a web-based questionnaire between May and June 2020. Two tools, including the Patient Health Questionnaire (PHQ9) and Generalized Anxiety Disorder-7 (GAD-7), were employed to measure anxiety and depression symptoms among HCWs. The data analyses were carried out using descriptive statistics, Man Whitney, and Kruskal Wallis tests.

Results: Of 1094 HCWs who participated in this online survey, 742 (67.8%) were physicians, followed by nurses (n = 277, 25.3%) and pharmacists (n = 75, 6.9%). The survey respondents had a median depression and anxiety score of 5.00 (7.00–3.00) and 8.00 (11.00–5.00), respectively. A considerable number of HCWs (82.2%) utilized online psychological resources to deal with their psychological distress. Female HCWs, nurses, frontline HCWs, and HCWs aged 30–49 years were more likely to suffer from depression and anxiety (p < 0.05).

Conclusion: During the recent ongoing pandemic of COVID-19, there is a mild level of symptoms of depression and anxiety among HCWs. Our findings call for urgent psychological interventions for vulnerable groups of Pakistani HCWs.
Feeling Valued and Adding Value: A Participatory Action Research Project on Co-creating Practices of Social Inclusion in Kindergartens and Communities
Authors: Heimburg Dina von , Langås Susanne Vollan , Ytterhus Borgunn
Published: April 2021

Background:Contemporary public health problems connect to the social determinants of health, with a growing recognition of social inclusion as imperative to sustainable development. In this quest for social inclusion, early childhood and families are of particular interest. Although co-creation is suggested as viable path to support well-being, less is known how social inclusion might be co-created in practice. The aim of this study was to explore how Participatory Action Research (PAR) can be a tool for transformative practices in a local community, pointing to kindergartens as meeting places for recognizing social inclusion as a common value in early childhood.

Methods:A qualitative PAR study was embedded in a Norwegian municipality as an integrated part of their local public health work. The study involved a wide range of participants and stakeholders in three kindergartens and the wider community. Together, we explored potentials for co-creating social inclusion to achieve well-being through cycles of transformative actions and reflections. Reflexive thematic analysis was applied to generate patterns and themes in the data.

Results:The participants formulated and took on ownership to an inclusive agenda through the PAR-process. Acts of inclusion was framed by an intersection between political aims of achieving health and well-being for all and public value co-creation unfolding at the level of the place, in the context of the Norwegian welfare regime. To feel valued and adding value was seen as important aspects for social inclusion. Four themes were generated from analysis; (1) Co-creating a shared vision of inclusive communities, (2) Becoming aware and empowered through caring, sharing and collaboration, (3) Places and spaces of inclusiveness in kindergartens and beyond, and (4) Valuing and practicing inclusion, and signs of transformative change.

Conclusions:Through the PAR process, parents, kindergartens employees, community members and policy makers appear to have opened a creative toolbox for inclusive and transformational change through formulating and co-creating inclusion and well-being as public values. The results suggest that local actors might support adaptive social systems to taking on relational responsibility for inclusive processes and outcomes in the pursuit of well-being for all.
The Impacts of Flattening Fiscal Reform on Health Expenditure in China
Authors: Hao Jun , Tang Chengxiang , Zhu Junli , Jiang Jiayi
Published: April 2021

Introduction:A number of provinces have implemented a fiscal reform of flattening government since the first decade of this century in China. This study aims to quantitatively analyze the influences of this government fiscal reform on county-level health expenditure. We also bring forward policy suggestions for improving county-level fiscal system and healthcare delivery.

Methods:We collected a novel longitudinal county-level data from 2003 to 2010, including counties' socioeconomic data, fiscal revenue, and health expenditure. Jilin Province, Hebei Province, and Anhui Province were selected as representative samples for this policy evaluation. The study employed a time-varying difference-in-difference model specification to investigate the impacts of flattening fiscal reform on health expenditure.

Results:The analyses find that the fiscal system reforms of the three provinces have a significantly positive impact on the health expenditure of county-level governments. However, we find no policy effects on the proportion of health expenditure to fiscal expenditure of county-level governments. The estimation results are robust after controlling several background variables.

Conclusion:The results yield important policy insights that public finance and its reform significantly impacts health expenditures in China. The government may still need to strengthen the transfer payment system to guarantee the social welfare provision in healthcare.
The Biomechanical Characteristics of the Strongman Yoke Walk
Authors: Hindle Benjamin R. , Lorimer Anna , Winwood Paul , Brimm Daniel , Keogh Justin W. L.
Published: April 2021

The yoke walk is a popular strongman exercise where athletes carry a heavily loaded frame balanced across the back of their shoulders over a set distance as quickly as possible. The aim of this study was to use ecologically realistic training loads and carry distances to (1) establish the preliminary biomechanical characteristics of the yoke walk; (2) identify any biomechanical differences between male and female athletes performing the yoke walk; and (3) determine spatiotemporal and kinematic differences between stages (intervals) of the yoke walk. Kinematic and spatiotemporal measures of hip and knee joint angle, and mean velocity, stride length, stride rate and stance duration of each 5 m interval were taken whilst 19 strongman athletes performed three sets of a 20 m yoke walk at 85% of their pre-determined 20 m yoke walk one repetition maximum. The yoke walk was characterised by flexion of the hip and slight to neutral flexion of the knee at heel strike, slight to neutral extension of the hip and flexion of the knee at toe-off and moderate hip and knee range of motion (ROM), with high stride rate and stance duration, and short stride length. Between-interval comparisons revealed increased stride length, stride rate and lower limb ROM, and decreased stance duration at greater velocity. Although no main between-sex differences were observed, two-way interactions revealed female athletes exhibited greater knee extension at toe-off and reduced hip ROM during the initial (0–5 m) when compared with the final three intervals (5–20 m), and covered a greater distance before reaching maximal normalised stride length than males. The findings from this study may better inform strongman coaches, athletes and strength and conditioning coaches with the biomechanical knowledge to: provide athletes with recommendation on how to perform the yoke walk based on the technique used by experienced strongman athletes; better prescribe exercises to target training adaptations required for improved yoke walk performance; and better coach the yoke walk as a training tool for non-strongman athletes.