bluuebunny/crossref_metadata_2025 huggingface dataset:
A Hormetic Spatiotemporal Photosystem II Response Mechanism of Salvia to Excess Zinc Exposure
Authors: Moustakas Michael , Dobrikova Anelia , Sperdouli Ilektra , Hanć Anetta , Adamakis Ioannis-Dimosthenis S. , Moustaka Julietta , Apostolova Emilia
Published: September 2022

Exposure of Salvia sclarea plants to excess Zn for 8 days resulted in increased Ca, Fe, Mn, and Zn concentrations, but decreased Mg, in the aboveground tissues. The significant increase in the aboveground tissues of Mn, which is vital in the oxygen-evolving complex (OEC) of photosystem II (PSII), contributed to the higher efficiency of the OEC, and together with the increased Fe, which has a fundamental role as a component of the enzymes involved in the electron transport process, resulted in an increased electron transport rate (ETR). The decreased Mg content in the aboveground tissues contributed to decreased chlorophyll content that reduced excess absorption of sunlight and operated to improve PSII photochemistry (ΦPSII), decreasing excess energy at PSII and lowering the degree of photoinhibition, as judged from the increased maximum efficiency of PSII photochemistry (Fv/Fm). The molecular mechanism by which Zn-treated leaves displayed an improved PSII photochemistry was the increased fraction of open PSII reaction centers (qp) and, mainly, the increased efficiency of the reaction centers (Fv′/Fm′) that enhanced ETR. Elemental bioimaging of Zn and Ca by laser ablation–inductively coupled plasma–mass spectrometry (LA–ICP–MS) revealed their co-localization in the mid-leaf veins. The high Zn concentration was located in the mid-leaf-vein area, while mesophyll cells accumulated small amounts of Zn, thus resembling a spatiotemporal heterogenous response and suggesting an adaptive strategy. These findings contribute to our understanding of how exposure to excess Zn triggered a hormetic response of PSII photochemistry. Exposure of aromatic and medicinal plants to excess Zn in hydroponics can be regarded as an economical approach to ameliorate the deficiency of Fe and Zn, which are essential micronutrients for human health.
Compound Heterozygosis in AADC Deficiency and Its Complex Phenotype in Terms of AADC Protein Population
Authors: Bisello Giovanni , Bertoldi Mariarita
Published: September 2022

Aromatic amino acid decarboxylase (AADC) deficiency is a rare monogenic disease due to mutations in the ddc gene producing AADC, a homodimeric pyridoxal 5′-phosphate-dependent enzyme. The disorder is often fatal in the first decade and is characterized by profound motor impairments and developmental delay. In the last two years, there has been a net rise in the number of patients and variants identified, maybe also pushed by the ongoing gene therapy trials. The majority of the identified genotypes are compound heterozygous (about 70%). Efforts are underway to reach early diagnosis, find possible new markers/new fast methods, and predict clinical outcome. However, no clear correlation of genotype-to-phenotype exists to date. Nevertheless, for homozygous patients, reliable results have been obtained using genetic methods combined with available computational tools on crystal structures corroborated by biochemical investigations on recombinant homodimeric AADC variants that have been obtained and characterized in solution. For these variants, the molecular basis for the defect has been suggested and validated, since it correlates quite well with mildness/severity of the homozygous phenotype. Instead, prediction for compound heterozygous patients is more difficult since complementation effects could happen. Here, by analyzing the existing literature on compound heterozygosity in AADC deficiency and other genetic disorders, we highlight that, in order to assess pathogenicity, the measurement of activity of the AADC heterodimeric variant should be integrated by bioinformatic, structural, and functional data on the whole protein constellation theoretically present in such patients. A wider discussion on symptomatic heterozygosity in AADC deficiency is also presented.
Update on Extracellular Vesicle-Based Vaccines and Therapeutics to Combat COVID-19
Authors: Mustajab Tamanna , Kwamboka Moriasi Sheba , Choi Da Ae , Kang Dae Wook , Kim Junho , Han Kyu Ri , Han Yujin , Lee Sorim , Song Dajung , Chwae Yong-Joon
Published: September 2022

The COVID-19 pandemic has had a deep impact on people worldwide since late 2019 when SARS-CoV-2 was first identified in Wuhan, China. In addition to its effect on public health, it has affected humans in various aspects of life, including social, economic, cultural, and political. It is also true that researchers have made vigorous efforts to overcome COVID-19 throughout the world, but they still have a long way to go. Accordingly, innumerable therapeutics and vaccine candidates have been studied for their efficacies and have been tried clinically in a very short span of time. For example, the versatility of extracellular vesicles, which are membrane-bound particles released from all types of cells, have recently been highlighted in terms of their effectiveness, biocompatibility, and safety in the fight against COVID-19. Thus, here, we tried to explain the use of extracellular vesicles as therapeutics and for the development of vaccines against COVID-19. Along with the mechanisms and a comprehensive background of their application in trapping the coronavirus or controlling the cytokine storm, we also discuss the obstacles to the clinical use of extracellular vesicles and how these could be resolved in the future.
Antiviral Drugs Screening for Swine Acute Diarrhea Syndrome Coronavirus
Authors: Chen Yangzhen , You Yecheng , Wang Shuqi , Jiang Lin , Tian Lili , Zhu Shaozhou , An Xiaoping , Song Lihua , Tong Yigang , Fan Huahao
Published: September 2022

Coronaviruses as possible cross-species viruses have caused several epidemics. The ongoing emergency of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has posed severe threats to the global economy and public health, which has generated great concerns about zoonotic viruses. Swine acute diarrhea syndrome coronavirus (SADS-CoV), an alpha-coronavirus, was responsible for mass piglet deaths, resulting in unprecedented economic losses, and no approved drugs or vaccines are currently available for SADS-CoV infection. Given its potential ability to cause cross-species infection, it is essential to develop specific antiviral drugs and vaccines against SADS-CoV. Drug screening was performed on a total of 3523 compound-containing drug libraries as a strategy of existing medications repurposing. We identified five compounds (gemcitabine, mycophenolate mofetil, mycophenolic acid, methylene blue and cepharanthine) exhibiting inhibitory effects against SADS-CoV in a dose-dependent manner. Cepharanthine and methylene blue were confirmed to block viral entry, and gemcitabine, mycophenolate mofetil, mycophenolic acid and methylene blue could inhibit viral replication after SADS-CoV entry. This is the first report on SADS-CoV drug screening, and we found five compounds from drug libraries to be potential anti-SADS-CoV drugs, supporting the development of antiviral drugs for a possible outbreak of SADS-CoV in the future.
Renal Corin Is Essential for Normal Blood Pressure and Sodium Homeostasis
Authors: Zhou Tiantian , Zhang Shengnan , Du Chunyu , Wang Kun , Gu Xiabing , Sun Shijin , Zhang Xianrui , Niu Yayan , Wang Can , Liu Meng , Dong Ningzheng , Wu Qingyu
Published: September 2022

Atrial natriuretic peptide (ANP)-mediated natriuresis is known as a cardiac endocrine function in sodium and body fluid homeostasis. Corin is a protease essential for ANP activation. Here, we studied the role of renal corin in regulating salt excretion and blood pressure. We created corin conditional knockout (cKO), in which the Corin gene was selectively disrupted in the kidney (kcKO) or heart (hcKO). We examined the blood pressure, urinary Na+ and Cl− excretion, and cardiac hypertrophy in wild-type, corin global KO, kcKO, and hcKO mice fed normal- and high-salt diets. We found that on a normal-salt diet (0.3% NaCl), corin kcKO and hcKO mice had increased blood pressure, indicating that both renal and cardiac corin is necessary for normal blood pressure in mice. On a high-salt diet (4% NaCl), reduced urinary Na+ and Cl− excretion, increased body weight, salt-exacerbated hypertension, and cardiac hypertrophy were observed in corin kcKO mice. In contrast, impaired urinary Na+ and Cl− excretion and salt-exacerbated hypertension were not observed in corin hcKO mice. These results indicated that renal corin function is important in enhancing natriuresis upon high salt intakes and that this function cannot be compensated by the cardiac corin function in mice.
O-GlcNAcylation in Renal (Patho)Physiology
Authors: Silva-Aguiar Rodrigo P. , Peruchetti Diogo B. , Pinheiro Ana Acacia S. , Caruso-Neves Celso , Dias Wagner B.
Published: September 2022

Kidneys maintain internal milieu homeostasis through a well-regulated manipulation of body fluid composition. This task is performed by the correlation between structure and function in the nephron. Kidney diseases are chronic conditions impacting healthcare programs globally, and despite efforts, therapeutic options for its treatment are limited. The development of chronic degenerative diseases is associated with changes in protein O-GlcNAcylation, a post-translation modification involved in the regulation of diverse cell function. O-GlcNAcylation is regulated by the enzymatic balance between O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) which add and remove GlcNAc residues on target proteins, respectively. Furthermore, the hexosamine biosynthetic pathway provides the substrate for protein O-GlcNAcylation. Beyond its physiological role, several reports indicate the participation of protein O-GlcNAcylation in cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the impact of protein O-GlcNAcylation on physiological renal function, disease conditions, and possible future directions in the field.
Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing: A Clinic-Based, Observational Study
Authors: Yang Liu , Xie Fei , Liu Chang , Zhao Jin , Hu Taobo , Wu Jinbo , Zhao Xiaotao , Wang Shu
Published: September 2022

Breast cancer (BC) is associated with hereditary components, and some deleterious germline variants have been regarded as effective therapeutic targets. We conducted a clinic-based, observational study to better understand the distribution of deleterious germline variants and assess any clinicopathological predictors related to the variants among Chinese BC patients using a 32 cancer-related genes next-generation sequencing panel. Between November 2020 and February 2022, a total of 700 BC patients were recruited, and 13.1% (92/700) of them carried deleterious germline variants in 15 cancer-related genes, including 37 (37/700, 5.3%) in BRCA2, 29 (29/700, 4.1%) in BRCA1, 8 (8/700, 1.1%) in PALB2, 4 (4/700, 0.6%) in NBN, 3 (3/700, 0.4%) in MRE11A, 3 (3/700, 0.4%) in TP53 and 12 (12/700, 1.7%) in other genes. There were 28 novel variants detected: 5 in BRCA1, 14 in BRCA2, and 9 in non-BRCA1/2 genes. The variants in panel genes, HRR (homologous recombination repair)-related genes, and BRCA1/2 were significantly associated with the following clinicopathological factors: age at the initial diagnosis of BC, family history of any cancer, molecular subtype, Ki-67 index, and hereditary risk. In conclusion, we further expanded the spectrum of germline deleterious variants in Chinese BC patients, and the clinicopathological predictors of variants were identified to facilitate clinical genetic testing and counseling for appropriate individuals.
Bmal1 Regulates Prostate Growth via Cell-Cycle Modulation
Authors: Ueda Masakatsu , Kono Jin , Sengiku Atsushi , Nagumo Yoshiyuki , Mathis Bryan J. , Shimba Shigeki , Taketo Makoto Mark , Kobayashi Takashi , Ogawa Osamu , Negoro Hiromitsu
Published: September 2022

The circadian clock system exists in most organs and regulates diverse physiological processes, including growth. Here, we used a prostate-specific Bmal1-knockout mouse model (pBmal1 KO: PbsnCre+; Bmal1fx/fx) and immortalized human prostate cells (RWPE-1 and WPMY-1) to elucidate the role of the peripheral prostate clock on prostate growth. Bmal1 KO resulted in significantly decreased ventral and dorsolateral lobes with less Ki-67-positive epithelial cells than the controls. Next, the cap analysis of gene expression revealed that genes associated with cell cycles were differentially expressed in the pBmal1 KO prostate. Cdkn1a (coding p21) was diurnally expressed in the control mouse prostate, a rhythm which was disturbed in pBmal1 KO. Meanwhile, the knockdown of BMAL1 in epithelial RWPE-1 and stromal WPMY-1 cell lines decreased proliferation. Furthermore, RWPE-1 BMAL1 knockdown increased G0/G1-phase cell numbers but reduced S-phase numbers. These findings indicate that core clock gene Bmal1 is involved in prostate growth via the modulation of the cell cycle and provide a rationale for further research to link the pathogenesis of benign prostatic hyperplasia or cancer with the circadian clock.
Targeting Signaling Pathway Downstream of RIG-I/MAVS in the CNS Stimulates Production of Endogenous Type I IFN and Suppresses EAE
Authors: Kronborg Hansen Anne K. , Dubik Magdalena , Marczynska Joanna , Ojha Bhavya , Nistal-Villán Estanislao , González Aseguinolaza Gloria , Arengoth Dina S. , Owens Trevor , Khorooshi Reza
Published: September 2022

Type I interferons (IFN), including IFNβ, play a protective role in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Type I IFNs are induced by the stimulation of innate signaling, including via cytoplasmic RIG-I-like receptors. In the present study, we investigated the potential effect of a chimeric protein containing the key domain of RIG-I signaling in the production of CNS endogenous IFNβ and asked whether this would exert a therapeutic effect against EAE. We intrathecally administered an adeno-associated virus vector (AAV) encoding a fusion protein comprising RIG-I 2CARD domains (C) and the first 200 amino acids of mitochondrial antiviral-signaling protein (MAVS) (M) (AAV-CM). In vivo imaging in IFNβ/luciferase reporter mice revealed that a single intrathecal injection of AAV-CM resulted in dose-dependent and sustained IFNβ expression within the CNS. IFNβ expression was significantly increased for 7 days. Immunofluorescent staining in IFNβ-YFP reporter mice revealed extraparenchymal CD45+ cells, choroid plexus, and astrocytes as sources of IFNβ. Moreover, intrathecal administration of AAV-CM at the onset of EAE induced the suppression of EAE, which was IFN-I-dependent. These findings suggest that accessing the signaling pathway downstream of RIG-I represents a promising therapeutic strategy for inflammatory CNS diseases, such as MS.
β-Klotho Promotes the Development of Intrauterine Adhesions via the PI3K/AKT Signaling Pathway
Authors: Guo Zizhen , Wang Yuqing , Wen Xiaoyang , Xu Xinxin , Yan Lei
Published: September 2022

Intrauterine adhesion (IUA) refers to injury to the basal layer of the endometrium, which can be caused by various factors. It is often accompanied by clinical symptoms such as abnormal menstruation, infertility, recurrent abortion, and periodic abdominal pain. In recent years, a number of studies have reported the effects of β-Klotho (KLB) on the occurrence and development of human tumors and fibrotic diseases, but its relationship with endometrial fibroblasts and endometrial fibrosis has not been elucidated. In this study, we compared the expression of KLB in endometrial stromal cells (ESCs) from patients with IUA and normal controls. We constructed animal and cell models of IUA and conducted expression verification and functional experiments on KLB. We found that the expression of KLB was significantly increased in the ESCs of IUA patients and rat models compared with the controls. The overexpression of KLB could promote the proliferation and fibrosis of ESCs. In addition, the overexpression of KLB activated the PI3K/AKT signaling pathway in ESCs. Our study shows that KLB protein is highly expressed in the ESCs of patients with IUA and can enhance stromal cell proliferation and cell fibrosis by activating the PI3K/AKT pathway, thus promoting the development of IUA.
Carvedilol Selectively Stimulates βArrestin2-Dependent SERCA2a Activity in Cardiomyocytes to Augment Contractility
Authors: Maning Jennifer , Desimine Victoria L. , Pollard Celina M. , Ghandour Jennifer , Lymperopoulos Anastasios
Published: September 2022

Heart failure (HF) carries the highest mortality in the western world and β-blockers [β-adrenergic receptor (AR) antagonists] are part of the cornerstone pharmacotherapy for post-myocardial infarction (MI) chronic HF. Cardiac β1AR-activated βarrestin2, a G protein-coupled receptor (GPCR) adapter protein, promotes Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a SUMO (small ubiquitin-like modifier)-ylation and activity, thereby directly increasing cardiac contractility. Given that certain β-blockers, such as carvedilol and metoprolol, can activate βarrestins and/or SERCA2a in the heart, we investigated the effects of these two agents on cardiac βarrestin2-dependent SERCA2a SUMOylation and activity. We found that carvedilol, but not metoprolol, acutely induces βarrestin2 interaction with SERCA2a in H9c2 cardiomyocytes and in neonatal rat ventricular myocytes (NRVMs), resulting in enhanced SERCA2a SUMOylation. However, this translates into enhanced SERCA2a activity only in the presence of the β2AR-selective inverse agonist ICI 118,551 (ICI), indicating an opposing effect of carvedilol-occupied β2AR subtype on carvedilol-occupied β1AR-stimulated, βarrestin2-dependent SERCA2a activation. In addition, the amplitude of fractional shortening of NRVMs, transfected to overexpress βarrestin2, is acutely enhanced by carvedilol, again in the presence of ICI only. In contrast, metoprolol was without effect on NRVMs’ shortening amplitude irrespective of ICI co-treatment. Importantly, the pro-contractile effect of carvedilol was also observed in human induced pluripotent stem cell (hIPSC)-derived cardiac myocytes (CMs) overexpressing βarrestin2, and, in fact, it was present even without concomitant ICI treatment of human CMs. Metoprolol with or without concomitant ICI did not affect contractility of human CMs, either. In conclusion, carvedilol, but not metoprolol, stimulates βarrestin2-mediated SERCA2a SUMOylation and activity through the β1AR in cardiac myocytes, translating into direct positive inotropy. However, this unique βarrestin2-dependent pro-contractile effect of carvedilol may be opposed or masked by carvedilol-bound β2AR subtype signaling.
Improving Both the Thermostability and Catalytic Efficiency of Phospholipase D from Moritella sp. JT01 through Disulfide Bond Engineering Strategy
Authors: Li Lilang , Mao Xuejing , Deng Fuli , Wang Yonghua , Wang Fanghua
Published: September 2022

Mining of Phospholipase D (PLD) with high activity and stability has attracted strong interest for investigation. A novel PLD from marine Moritella sp. JT01 (MsPLD) was biochemically and structurally characterized in our previous study; however, the short half-life time (t1/2) under its optimum reaction temperature seriously hampered its further applications. Herein, the disulfide bond engineering strategy was applied to improve its thermostability. Compared with wild-type MsPLD, mutant S148C-T206C/D225C-A328C with the addition of two disulfide bonds exhibited a 3.1-fold t1/2 at 35 °C and a 5.7 °C increase in melting temperature (Tm). Unexpectedly, its specific activity and catalytic efficiency (kcat/Km) also increased by 22.7% and 36.5%, respectively. The enhanced activity might be attributed to an increase in the activation entropy by displacing more water molecules by the transition state. The results of molecular dynamics simulations (MD) revealed that the introduction of double disulfide bonds rigidified the global structure of the mutant, which might cause the enhanced thermostability. Finally, the synthesis capacity of the mutant to synthesize phosphatidic acid (PA) was evaluated. The conversion rate of PA reached about 80% after 6 h reaction with wild-type MsPLD but reached 78% after 2 h with mutant S148C-T206C/D225C-A328C, which significantly reduced the time needed for the reaction to reach equilibrium. The present results pave the way for further application of MsPLD in the food and pharmaceutical industries.
Knock-Out of the Five Lysyl-Oxidase Family Genes Enables Identification of Lysyl-Oxidase Pro-Enzyme Regulated Genes
Authors: Liburkin-Dan Tatyana , Nir-Zvi Inbal , Razon Hila , Kessler Ofra , Neufeld Gera
Published: September 2022

The five lysyl-oxidase genes share similar enzymatic activities and contribute to tumor progression. We have knocked out the five lysyl-oxidase genes in MDA-MB-231 breast cancer cells using CRISPR/Cas9 in order to identify genes that are regulated by LOX but not by other lysyl-oxidases and in order to study such genes in more mechanistic detail in the future. Re-expression of the full-length cDNA encoding LOX identified four genes whose expression was downregulated in the knock-out cells and rescued following LOX re-expression but not re-expression of other lysyl-oxidases. These were the AGR2, STOX2, DNAJB11 and DNAJC3 genes. AGR2 and STOX2 were previously identified as promoters of tumor progression. In addition, we identified several genes that were not downregulated in the knock-out cells but were strongly upregulated following LOX or LOXL3 re-expression. Some of these, such as the DERL3 gene, also promote tumor progression. There was very little proteolytic processing of the re-expressed LOX pro-enzyme in the MDA-MB-231 cells, while in the HEK293 cells, the LOX pro-enzyme was efficiently cleaved. We introduced point mutations into the known BMP-1 and ADAMTS2/14 cleavage sites of LOX. The BMP-1 mutant was secreted but not cleaved, while the LOX double mutant dmutLOX was not cleaved or secreted. However, even in the presence of the irreversible LOX inhibitor β-aminoproprionitrile (BAPN), these point-mutated LOX variants induced the expression of these genes, suggesting that the LOX pro-enzyme has hitherto unrecognized biological functions.
Moderate Aerobic Exercise Regulates Follicular Dysfunction by Initiating Brain-Derived Neurotrophic Factor (BDNF)-Mediated Anti-Apoptotic Signaling Pathways in Polycystic Ovary Syndrome
Authors: Zhang Yaling , Chen Dejian , Wang Daojuan , Wang Lei , Weng Yajing , Wang Hongwei , Wu Xiaoke , Wang Yong
Published: September 2022

Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women. Moderate aerobic exercise intervention is considered an initial treatment strategy for managing PCOS. Brain-derived neurotrophic factor (BDNF) is an important molecular mediator and a beneficial response to exercise. We aimed to investigate the expression pattern and underlying molecular mechanisms of this neurotrophic factor during follicle development in ovarian tissues. The PCOS model was established by subcutaneous injection of 60 mg/kg dehydroepiandrosterone (DHEA) into the neck of Sprague Dawley rats for 35 consecutive days. PCOS rats then received aerobic exercise for 8 weeks. Body/ovarian weight and peripheral serum hormone levels were observed. Immunohistochemistry combined with Western blot analysis and fluorescence quantitative polymerase chain reaction were used to detect the changes in BDNF-TrkB/p75NTR pathway, apoptosis, and inflammatory factors. We show that moderate aerobic exercise not only reverses the PCOS phenotype but also activates the BDNF-TrkB pathway and initiates downstream targets. p-TrkB upregulates and phosphorylates phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) to inhibit apoptosis. In addition, aerobic exercise therapy reduces the high expression of p75NTR in the ovarian tissue of PCOS rats and initiates the anti-apoptotic effect from the downstream pathway of NF-κB/JNK. Our in vitro results state that treatment with BDNF ameliorated dihydrotestosterone (DHT)-induced granulosa cells (GCs) apoptosis by provoking p-TrkB activation and upregulating the PI3K/AKT pathway. The present study suggests that moderate aerobic exercise regulates follicular dysfunction in PCOS-like rats. One possible mechanism is to initiate the BDNF-mediated anti-apoptotic signaling pathway.
Impact of Different KDIGO Criteria on Clinical Outcomes for Early Identification of Acute Kidney Injury after Non-Cardiac Surgery
Authors: Fu Jingwen , Kosaka Junko , Morimatsu Hiroshi
Published: September 2022

The Kidney Disease Improving Global Outcomes (KDIGO) guidelines are currently used in acute kidney injury (AKI) diagnosis and include both serum creatinine (SCR) and urine output (UO) criteria. Currently, many AKI-related studies have inconsistently defined AKI, which possibly affects the comparison of their results. Therefore, we hypothesized that the different criteria in the KDIGO guidelines vary in measuring the incidence of AKI and its association with clinical outcomes. We retrospectively analyzed that data of patients admitted to the intensive care unit after non-cardiac surgery in 2019. Three different criteria used to define AKI were included: UOmean, mean UO < 0.5 mL/kg/h over time; UOcont, hourly UO < 0.5 mL/kg/h over time; or SCR, KDIGO guidelines SCR criteria. A total of 777 patients were included, and the incidence of UOmean-AKI was 33.1%, the incidence of UOcont-AKI was 7.9%, and the incidence of SCR-AKI was 2.0%. There were differences in the length of ICU stay and hospital stay between AKI and non-AKI patients under different criteria. We found differences in the incidence and clinical outcomes of AKI after non-cardiac surgery when using different KDIGO criteria.
Use of Neuronavigation and Augmented Reality in Transsphenoidal Pituitary Adenoma Surgery
Authors: Bopp Miriam H. A. , Saß Benjamin , Pojskić Mirza , Corr Felix , Grimm Dustin , Kemmling André , Nimsky Christopher
Published: September 2022

The aim of this study was to report on the clinical experience with microscope-based augmented reality (AR) in transsphenoidal surgery compared to the classical microscope-based approach. AR support was established using the head-up displays of the operating microscope, with navigation based on fiducial-/surface- or automatic intraoperative computed tomography (iCT)-based registration. In a consecutive single surgeon series of 165 transsphenoidal procedures, 81 patients underwent surgery without AR support and 84 patients underwent surgery with AR support. AR was integrated straightforwardly within the workflow. ICT-based registration increased AR accuracy significantly (target registration error, TRE, 0.76 ± 0.33 mm) compared to the landmark-based approach (TRE 1.85 ± 1.02 mm). The application of low-dose iCT protocols led to a significant reduction in applied effective dosage being comparable to a single chest radiograph. No major vascular or neurological complications occurred. No difference in surgical time was seen, time to set-up patient registration prolonged intraoperative preparation time on average by twelve minutes (32.33 ± 13.35 vs. 44.13 ± 13.67 min), but seems justifiable by the fact that AR greatly and reliably facilitated surgical orientation and increased surgeon comfort and patient safety, not only in patients who had previous transsphenoidal surgery but also in cases with anatomical variants. Automatic intraoperative imaging-based registration is recommended.
Quality of Life in the Postpartum Recovery of Women Who Practice Hypopressive Exercise: Randomized Clinical Trial
Authors: Sanchez-Garcia Juan Carlos , Aguilar-Cordero María José , Montiel-Troya Maria , Marín-Jiménez Ana Eugenia , Cortes-Martin Jonathan , Rodriguez-Blanque Raquel
Published: September 2022

Background: Practicing physical exercise is a way of maintaining a healthy lifestyle and it has been demonstrated to provide benefits and improve quality of life after labour. Aim: The objective of this study is to determine if performing a moderate hypopressive exercise program after childbirth improves the HRQoL of women. Materials and Methods: A 12-week randomized clinical trial was carried out. The women in the exercise group followed a training program based on the hypopressive method, which comprises postural and respiratory exercises of moderate intensity. We used the SF-36v2 questionnaire to assess the Health-Related Quality of Life in women. Results: We found statistically significant differences (p < 0.05) in general health components, vitality, emotional role, and mental health in the sample group of exercise group of women, who obtained a higher score. We found statistically significant differences in all aspects between the groups. The interaction between time and group affect in general health components, vitality, emotional role and the score of mental components. In all of them, the score was higher at the end of the programme and in the exercise group. Conclusions: The training program with hypopressive physical exercise improves the quality of life after childbirth. According to the guidelines recommended by the ACOG, the hypopressive method is valid for the improvement of HRQoL in women who perform this method at 16 weeks of delivery. Further studies are recommended to start such exercises one week after delivery in postpartum women.
Deep Learning for the Automatic Segmentation of Extracranial Venous Malformations of the Head and Neck from MR Images Using 3D U-Net
Authors: Ryu Jeong Yeop , Hong Hyun Ki , Cho Hyun Geun , Lee Joon Seok , Yoo Byeong Cheol , Choi Min Hyeok , Chung Ho Yun
Published: September 2022

Background: It is difficult to characterize extracranial venous malformations (VMs) of the head and neck region from magnetic resonance imaging (MRI) manually and one at a time. We attempted to perform the automatic segmentation of lesions from MRI of extracranial VMs using a convolutional neural network as a deep learning tool. Methods: T2-weighted MRI from 53 patients with extracranial VMs in the head and neck region was used for annotations. Preprocessing management was performed before training. Three-dimensional U-Net was used as a segmentation model. Dice similarity coefficients were evaluated along with other indicators. Results: Dice similarity coefficients in 3D U-Net were found to be 99.75% in the training set and 60.62% in the test set. The models showed overfitting, which can be resolved with a larger number of objects, i.e., MRI VM images. Conclusions: Our pilot study showed sufficient potential for the automatic segmentation of extracranial VMs through deep learning using MR images from VM patients. The overfitting phenomenon observed will be resolved with a larger number of MRI VM images.
Mechanisms and Neuroimaging Patterns of Hypereosinophilia-Related Ischemic Stroke: A Narrative Review through Three Cases
Authors: Cioclu Maria Cristina , Cavallieri Francesco , Napoli Manuela , Moratti Claudio , Pascarella Rosario , Valzania Franco , Zedde Marialuisa
Published: September 2022

Background: Hypereosinophilic syndromes (HES) are a group of relatively rare disorders in which neurological manifestations, including ischemic stroke, are common. The hypothesized pathophysiological mechanisms are hypercoagulability, cardioembolism (mainly mediated by myocardial involvement) and damage to the endothelium. A variable ischemic pattern has been described, including an association of territorial and border zone ischemic stroke. Methods: Three patients who presented to our department with acute stroke were selected aiming to show these three different mechanisms inferred from the stroke pattern on brain Magnetic Resonance Imaging (MRI) and to simultaneously illustrate the three main causes of HES. Results and Discussion: The first patient is a 55-year-old man with an abrupt onset of aphasia due to an acute ischemic stroke involving the left parietal lobule and the angular gyrus; recent lab test had shown hypereosinophilia. An extensive workup excluded primary and secondary causes of hypereosinophilia so a diagnosis of idiopathic hypereosinophilia was done and he was treated with high doses of steroids. The second patient had severe hypereosinophilia and developed multiple small, scattered ischemic lesions, mainly in border zone zones. The history of severe asthma and recurrent sinusitis supported the diagnosis of EGPA (Eosinophilic Granulomatosis with Polyangiitis); considering the severe clinical conditions and the presumptive role of hypereosinophilia in determining her symptoms, steroid treatment was promptly started, with good clinical response. The third patient also presented with multiple metachronous ischemic lesions, both in cortical and border zone distribution and marked eosinophilia; the diagnostic work-up found an ovarian cancer. She was treated with steroids and then underwent surgery and adjuvant chemotherapy. Conclusions: HES should be considered in stroke etiological evaluation, although it is a rare disorder, and border zones pattern without large artery steno-occlusion on neuroimaging may help to raise the suspicion in the neurovascular diagnostic pathway. A thorough research of the sources of hypereosinophilia should be performed to select the appropriate therapy.
Mid-Term Results of Fenestrated Endovascular Repair after Prior Open Aortic Reconstruction
Authors: Marques de Marino Pablo , Abu Jiries Melad , Tesinsky Pavel , Ibraheem Anas , Katsargyris Athanasios , Verhoeven Eric L.
Published: September 2022

This study aims to assess the mid-term results of fenestrated endovascular aneurysm repair (FEVAR) for the treatment of proximal aortic pathology after previous open surgical repair (OSR). All patients with a previous history of OSR of an abdominal aortic aneurysm undergoing a FEVAR procedure between October 2010 and November 2021 were included. The endpoints of the study were technical success, mortality, target vessel patency and reinterventions during follow-up. Thirty-five patients (34 male, mean age 72.9 ± 7 years) were included. The median interval from the primary surgery to the FEVAR procedure was 136 months (range 47–261). The indication for treatment was a para-anastomotic aneurysm in 18 (51%) patients and a true aneurysm due to progression of disease in 17 (49%) patients. Technical success was achieved in 33 (94%) patients. There was one (3%) early death due to postoperative bleeding from a renal artery. Estimated survival at 12, 24 and 36 months was 89.1% ± 6%, 84.4% ± 7.3% and 84.4% ± 7.3%, respectively. There was no aneurysm-related mortality. One (3%) target vessel occluded during follow-up and three (9%) patients underwent late reinterventions. In conclusion, FEVAR is a safe and effective alternative for the endovascular treatment of para-anastomotic aneurysms/pseudoaneurysms after OSR showing high technical success, low mortality and morbidity, and good mid-term outcomes.
Influence of Risk Factors on Exercise Tolerance in Patients after Myocardial Infarction—Early Cardiac Rehabilitation in Poland
Authors: Bryndal Aleksandra , Glowinski Sebastian , Grochulska Agnieszka
Published: September 2022

(1) Background: Prognosis in patients with cardiovascular diseases is significantly influenced by lifestyle and the control of risk factors. Patients after myocardial infarction require special care and promptly introduced cardiac rehabilitation. The primary aim of this study was to identify risk factors and their influence on exercise tolerance before and after cardiac rehabilitation (CR) provided under the Coordinated Specialist Care Programme—Infarct (CSC-Infarct). (2) Methods: The study was carried out at the Cardiac Rehabilitation Centre of Slupsk Specialist Hospital on a group of 112 patients aged 35–87 (62.78 ± 10.09 years) after myocardial infarction (MI), participating in CSC-Infarct. An exercise test (treadmill ECG test), the 6 min walk test (6MWT), echocardiography, blood test (total cholesterol, HDL, LDL, TG), measurement of diastolic pressure ratio (DPr), waist-to-hip ratio (WHR), and BMI were performed in participants on the first and last day of CR. Rating of perceived exertion was assessed with Borg’s scale. (3) Results: The overweight variable had the strongest effect on the increased value of initial: HR rest, HR max, and HR 1 min after exercise compared to subjects with normal BMI. DPr values before and after CR were also higher in overweight patients. Scores of 6MWT were higher in smokers compared to non-smokers. The final MET value was significantly higher in non-diabetic subjects. Hyperlipidaemia was associated with a higher initial HR max and initial HR 1 min after exercise. DPr before CR was also higher. The initial and final MET values were lower in hypertensive patients. Borg’s rating of perceived exertion measured after the final exercise test was also higher in hypertensive patients. Hypertension influenced the initial and final 6MWT scores, which were significantly higher in normotensive patients. (4) Conclusions: CR within CSC-infarction in patients after myocardial infarction improves exercise tolerance. Exercise tolerance in post-MI patients with concomitant risk factors is lower compared to post-MI patients without risk factors.
Genome Sequencing and Transcriptome Profiling in Twins Discordant for Mayer-Rokitansky-Küster-Hauser Syndrome
Authors: Buchert Rebecca , Schenk Elisabeth , Hentrich Thomas , Weber Nico , Rall Katharina , Sturm Marc , Kohlbacher Oliver , Koch André , Riess Olaf , Brucker Sara Y. , Schulze-Hentrich Julia M.
Published: September 2022

To identify potential genetic causes for Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), we analyzed blood and rudimentary uterine tissue of 5 MRKH discordant monozygotic twin pairs. Assuming that a variant solely identified in the affected twin or affected tissue could cause the phenotype, we identified a mosaic variant in ACTR3B with high allele frequency in the affected tissue, low allele frequency in the blood of the affected twin, and almost absent in blood of the unaffected twin. Focusing on MRKH candidate genes, we detected a pathogenic variant in GREB1L in one twin pair and their unaffected mother showing a reduced phenotypic penetrance. Furthermore, two variants of unknown clinical significance in PAX8 and WNT9B were identified. In addition, we conducted transcriptome analysis of affected tissue and observed perturbations largely similar to those in sporadic cases. These shared transcriptional changes were enriched for terms associated with estrogen and its receptors pointing at a role of estrogen in MRKH pathology. Our genome sequencing approach of blood and uterine tissue of discordant twins is the most extensive study performed on twins discordant for MRKH so far. As no clear pathogenic differences were detected, research to evaluate other regulatory layers are required to better understand the complex etiology of MRKH.
Influence of Occupation on the Prevalence of Spinal Pain among Physiotherapists and Nurses
Authors: Bryndal Aleksandra , Glowinski Sebastian , Grochulska Agnieszka
Published: September 2022

(1) Background: Neck pain (NP) and low back pain (LBP) are common musculoskeletal disorders, one of the major causes of disability globally. The aim of the study was to determine the influence of medical occupation (physiotherapist and nurse) on the prevalence of spinal pain, functional status and degree of disability. (2) Methods: a total of 544 people (462 females (84.9%) and 82 males (15.1%)), licensed to practice as a physiotherapist (n1 = 240 (44.1%)) or nurse (n2 = 304 (55.9%)) in Poland completed a special questionnaire designed by the authors of the study, and were assessed using the Neck Disability Index (NDI, Polish language version) and Revised Oswestry Disability Index (ODI, Polish language version). (3) Results: Compared to physiotherapists, nurses were older, shorter, had higher BMI, and longer work experience. In the whole study group, 30.2% of subjects reported NP, 17.7% reported thoracic pain (ThP) and 80.5% reported LBP. During working life, 90.9% of physiotherapists and 97.7% of nurses experienced spinal pain. Pain intensity measured with Visual Analogue Scale (VAS) was higher among nurses (mean 5.37) than among physiotherapists (mean 4.64). Nurses had a higher degree of disability caused by LBP and NP measured with ODI and NDI compared to physiotherapists. (4) Conclusions: Excessive strain of the spine associated with occupational activities has a strong impact on the intensity and frequency of spinal pain episodes. Physiotherapists and nurses mainly suffer from low back pain. Pain scores measured with VAS are higher in nurses than in physiotherapists.
Analysis of Visual Risk Factors of Anterior Cruciate Ligament Injury of Knee Joint
Authors: Chen Zhong , Li Yuheng , Zhang Yichi , Zhang Zhengzheng , Wang Jingsong , Deng Xinghao , Liu Chengxiao , Chen Na , Jiang Chuan , Li Weiping , Song Bin
Published: September 2022

This study aimed to explore whether the defect of visual function is a risk factor of knee anterior cruciate ligament (ACL) sports injury and to provide a theoretical basis for the primary prevention of ACL sports injury. This cross-sectional study included 392 participants divided into two groups: the sports injury group (287 with sports injury of knee) and the control group (105 healthy volunteers). Participants in the sports injury group were further divided into the ACL-Intact group (133) and the ACL-Deficient group (154). Participants in the sports injury group received a questionnaire about the conditions of their injury (including injury action, site condition, weather, contact) and a visual examination by synoptophore (including binocular vision, subjective and objective oblique angle, visual fusion range, stereoacuity). Participants in the control group only received the visual examination. In the end, we found that low visual fusion range (p = 0.003) and injury action, especially quick turn (p = 0.001), sudden stop (p < 0.001) and jump (p = 0.001), are the major risk factors for ACL injury in the analysis of the integrated data. In addition, athletes with low vision fusion range have increased risk of ACL sports injury when they make a sudden stop on wooden floor, plastic floor or cement floor on cloudy days (OR = 13.208). Visual factors, especially low fusion range, significantly increase the risk of ACL sports injury.
The Prognostic Value of Pre-Treatment Circulating Biomarkers of Systemic Inflammation (CRP, dNLR, YKL-40, and IL-6) in Vulnerable Older Patients with Metastatic Colorectal Cancer Receiving Palliative Chemotherapy—The Randomized NORDIC9-Study
Authors: Liposits Gabor , Skuladottir Halla , Ryg Jesper , Winther Stine Brændegaard , Möller Sören , Hofsli Eva , Shah Carl-Henrik , Poulsen Laurids Østergaard , Berglund Åke , Qvortrup Camilla , Osterlund Pia , Johansen Julia S. , Glimelius Bengt , Sorbye Halfdan , Pfeiffer Per
Published: September 2022

Appropriate patient selection for palliative chemotherapy is crucial in patients with metastatic colorectal cancer (mCRC). We investigated the prognostic value of C-reactive protein (CRP), derived neutrophil-to-lymphocyte ratio (dNLR), Interleukin (IL)-6, and YKL-40 on progression-free survival (PFS) and overall survival (OS) in the NORDIC9 cohort. The randomized NORDIC9-study included patients ≥70 years with mCRC not candidates for standard full-dose combination chemotherapy. Participants received either full-dose S1 (Teysuno) or a dose-reduced S1 plus oxaliplatin. Blood samples were collected at baseline and biomarkers were dichotomized according to standard cut-offs. Multivariable analyses adjusted for age, sex, ECOG performance status, and treatment allocation; furthermore, C-statistics were estimated. In total, 160 patients with a median age of 78 years (IQR: 76–81) were included between 2015 and 2017. All investigated biomarkers were significantly elevated in patients with either weight loss, ≥3 metastatic sites, or primary tumor in situ. In multivariable analyses, all markers showed significant association with OS; the highest HR was observed for CRP (HR = 3.40, 95%CI: 2.20–5.26, p < 0.001). Regarding PFS, statistically significant differences were found for CRP and IL-6, but not for dNLR and YKL-40. Applying C-statistics, CRP indicated a good prognostic model for OS (AUC = 0.72, 95%CI: 0.67–0.76). CRP is an easily available biomarker, which may support therapeutic decision-making in vulnerable older patients with mCRC.
Research Trends and Hotspots of Retinal Optical Coherence Tomography: A 31-Year Bibliometric Analysis
Authors: Lin Aidi , Mai Xiaoting , Lin Tian , Jiang Zehua , Wang Zhenmao , Chen Lijia , Chen Haoyu
Published: September 2022

The emergence of optical coherence tomography (OCT) over the past three decades has sparked great interest in retinal research. However, a comprehensive analysis of the trends and hotspots in retinal OCT research is currently lacking. We searched the publications on retinal OCT in the Web of Science database from 1991 to 2021 and performed the co-occurrence keyword analysis and co-cited reference network using bibliometric tools. A total of 25,175 publications were included. There has been a progressive increase in the number of publications. The keyword co-occurrence network revealed five clusters of hotspots: (1) thickness measurements; (2) therapies for macular degeneration and macular edema; (3) degenerative retinal diseases; (4) OCT angiography (OCTA); and (5) vitrectomy for macular hole and epiretinal membrane. The co-citation analysis displayed 26 highly credible clusters (S = 0.9387) with a well-structured network (Q = 0.879). The major trends of research were: (1) thickness measurements; (2) therapies for macular degeneration and macular edema; and (3) OCTA. Recent emerging frontiers showed a growing interest in OCTA, vessel density, choriocapillaris, central serous chorioretinopathy, Alzheimer’s disease, and deep learning. This review summarized 31 years of retinal OCT research, shedding light on the hotspots, main themes, and emerging frontiers to assist in future research.
Current and Future Insights for Optimizing Antithrombotic Therapy to Reduce the Burden of Cardiovascular Ischemic Events in Patients with Acute Coronary Syndrome
Authors: Selvarajah Abi , Tavenier Anne H. , Fabris Enrico , van Leeuwen Maarten A. H. , Hermanides Renicus S.
Published: September 2022

The pharmacological treatment strategies for acute coronary syndrome (ACS) in recent years are constantly evolving to develop more potent antithrombotic agents, as reflected by the introduction of more novel P2Y12 receptor inhibitors and anticoagulants to reduce the ischemic risk among ACS patients. Despite the substantial improvements in the current antithrombotic regimen, a noticeable number of ACS patients continue to experience ischemic events. Providing effective ischemic risk reduction while balancing bleeding risk remains a clinical challenge. This updated review discusses the currently approved and widely used antithrombotic agents and explores newer antithrombotic treatment strategies under development for the initial phase of ACS.