bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two-Weekly High-Dose-Rate Brachytherapy Boost After External Beam Radiotherapy for Localized Prostate Cancer: Long-Term Outcome and Toxicity Analysis
Authors: Tamihardja Jörg , Lutyj Paul , Kraft Johannes , Lisowski Dominik , Weick Stefan , Flentje Michael , Polat Bülent 
Published: December 2021

PurposeEvaluation of clinical outcome of two-weekly high-dose-rate brachytherapy boost after external beam radiotherapy (EBRT) for localized prostate cancer.Methods338 patients with localized prostate cancer receiving definitive EBRT followed by a two-weekly high-dose-rate brachytherapy boost (HDR-BT boost) in the period of 2002 to 2019 were analyzed. EBRT, delivered in 46 Gy (DMean) in conventional fractionation, was followed by two fractions HDR-BT boost with 9 Gy (D90%) two and four weeks after EBRT. Androgen deprivation therapy (ADT) was added in 176 (52.1%) patients. Genitourinary (GU)/gastrointestinal (GI) toxicity was evaluated utilizing the Common Toxicity Criteria for Adverse Events (version 5.0) and biochemical failure was defined according to the Phoenix definition.ResultsMedian follow-up was 101.8 months. 15 (4.4%)/115 (34.0%)/208 (61.5%) patients had low-/intermediate-/high-risk cancer according to the D`Amico risk classification. Estimated 5-year and 10-year biochemical relapse-free survival (bRFS) was 84.7% and 75.9% for all patients. The estimated 5-year bRFS was 93.3%, 93.4% and 79.5% for low-, intermediate- and high-risk disease, respectively. The estimated 10-year freedom from distant metastasis (FFM) and overall survival (OS) rates were 86.5% and 70.0%. Cumulative 5-year late GU toxicity and late GI toxicity grade ≥ 2 was observed in 19.3% and 5.0% of the patients, respectively. Cumulative 5-year late grade 3 GU/GI toxicity occurred in 3.6%/0.3%.ConclusionsTwo-weekly HDR-BT boost after EBRT for localized prostate cancer showed an excellent toxicity profile with low GU/GI toxicity rates and effective long-term biochemical control.
Human Milk-Based or Bovine Milk-Based Fortifiers Differentially Impact the Development of the Gut Microbiota of Preterm Infants
Authors: Aguilar-Lopez Miriam , Wetzel Christine , MacDonald Alissa , Ho Thao T. B. , Donovan Sharon M. 
Published: December 2021

Background: Preterm infants are exposed to different dietary inputs during their hospitalization in the neonatal intensive care unit (NICU). These include human milk (HM), with a human milk-based (HMF) or a bovine milk-based (BMF) fortifier, or formula. Milk consumption and the type of fortification will cause changes in the gut microbiota structure of preterm infants. This study aimed to characterize the gut microbiota of PT infant according to the type of feeding and the type of HM fortification and its possible association with infant's growth.Methods: Ninety-seven infants born ≤33 wks of gestation or &lt;1,500 g were followed during the hospitalization period in the NICU after birth until discharge. Clinical and dietary information was collected, including mode of delivery, pregnancy complications, mechanical ventilation, use of antibiotics, weight, and type and amount of milk consumed. To characterize the gut microbiota composition, weekly stool samples were collected from study participants. The V3–V4 region of the 16S rRNA bacterial gene was Sequenced using Illumina MiSeq technology.Results: After birth, black maternal race, corrected gestational age (GA) and exposure to pregnancy complications, had a significant effect on gut microbial diversity and the abundance of Enterococcus, Veillonella, Bifidobacterium, Enterobacter, and Bacteroides. Over the course of hospitalization, corrected GA and exposure to chorioamnionitis remained to have an effect on gut microbial composition. Two different enterotypes were found in the gut microbiota of preterm infants. One enriched in Escherichia-Shigella, and another enriched in uncharacterized Enterobacteriaceae, Klebsiella and Clostridium sensu stricto 1. Overall, HM and fortification with HMF were the most common feeding strategies. When consuming BMF, PT infants had higher growth rates than those consuming HMF. Milk and type of fortification were significantly associated with the abundance of Clostridium sensu stricto 1, Bifidobacterium and Lactobacillus.Conclusions: This observational study shows the significant association between milk consumption and the exposure to HMF or BMF fortification in the fecal microbiota composition of preterm infants. Additionally, these results show the effect of other perinatal factors in the establishment and development of PT infant's gut microbiota.
A Novel Homozygous Variant of TMEM231 in a Case With Hypoplasia of the Cerebellar Vermis and Polydactyly
Authors: Wang Tao , Liu Yu-Xing , Luo Fang-Mei , Dong Yi , Li Ya-Li , Fan Liang-Liang 
Published: December 2021

Background: Transmembrane protein 231 (TMEM231) is a component of the B9 complex that participates in the formation of the diffusion barrier between the cilia and plasma membrane. Mutations in TMEM231 gene may contribute to the Joubert syndrome (JBTS) or Meckel–Gruber syndrome (MKS). However, reports on JBTS or MKS caused by TMEM231 mutations are comparatively rare.Method: We describe a Chinese fetus with unexplained hypoplasia of the cerebellar vermis and polydactyly, detected by ultrasound imaging. The fetus was primarily diagnosed with JBTS/MKS. The parents of this fetus were non-consanguineous and healthy. Whole-exome sequencing (WES) and bioinformatics strategies were employed to explore the genetic lesion of this family.Results: An unknown missense variant (c.19C&gt;T;p.R7W) of TMEM231 gene was detected. The variant was predicted as pathogenic and was absent in our 200 healthy controls.Conclusion: WES was employed to explore the genetic lesion of a fetus with unexplained hypoplasia of the cerebellar vermis and polydactyly. A novel variant in TMEM231 gene was identified. Our study not only provided data for genetic counseling and prenatal diagnosis to this family but also broadened the spectrum of TMEM231 mutations.
Transarterial Embolization in Neonatal Kasabach–Merritt Syndrome
Authors: Wang Yinghao , Wang Song , Wang Lili , Bi Shaohua , Zhang Jian , Zha Ping , Dai Liying 
Published: December 2021

Background: Kasabach–Merritt syndrome (KMS) is characterized by large hemangiomas and persistent thrombocytopenia, which may result in visceral hemorrhage and disseminated intravascular coagulation. This study aimed to evaluate the value of transarterial embolization (TAE) in neonatal KMS patients.Patients and Methods: The clinical course of 11 neonates with KMS who underwent TAE in the Department of Neonatology, Anhui Provincal Children's Hospital, Anhui Medical University, China, were reviewed retrospectively.Results: Eleven neonates with KMS (nine male and two female) were admitted to our hospital between the age of 1 h and 6 days. All were born with progressively enlarged hemangiomas and persistent thrombocytopenia. The largest lesion had its maximum size reached at 15 × 8 × 8 cm. Eight patients had cutaneous hemangiomas (1 right face, one oropharynx, one left upper arm, two back, one left lumbar, one right lower leg, and one right thigh), and three patients had liver hemangiomas. All 11 patients underwent TAE. Nine patients underwent two TAEs, and two patients underwent only one embolization procedure. They all obtained &gt;80% devascularization of their lesions without a major complication. The platelet count increased at 2–5 days after treatment and reached normal count and coagulation profile at 18–28 days after the TAE.Conclusions: TAE is a safe and effective alternative therapy for neonatal KMS patients.
Study on the Chemical Constituents and Anti-Migraine Activity of Supercritical CO2 Extracts of Zanthoxylum schinifolium
Authors: Yuan Ruifang , Shi Yunzhen , Zhang Jinming , Hu Qi , Wei Xichuan , Luo Chuanhong , Wu Yi , Yang Jinhui , Yang Ming , Wang Fang , Zheng Chuan , Zhang Dingkun 
Published: December 2021

Background:Zanthoxylum schinifolium is a common herbal medicine in Southwest China. It is also a condiment commonly used in many families. In Chinese folk medicine, Z. schinifolium is considered to have the effect of relieving migraine, but there is no modern evidence on its anti-migraine mechanism.Objective: The aim of this study was to investigate the chemical constituents of the supercritical carbon dioxide extracts of Z. schinifolium (CO2-ZSE) and its effects on migraine animals.Materials and Methods: Supercritical CO2 extraction technology was applied to extract the dried fruit of Z. schinifolium, and the chemical components were determined by gas chromatography–mass spectrometry (GC-MS). Two migraine animal models were established by subcutaneous injection of nitroglycerin (NTG) and reserpine, respectively, to further evaluate the therapeutic effect of CO2-ZSE and explore its mechanism. On the basis of the experimental results, the therapeutic effects of linalool in different dosages and different ways of administration on NTG-induced migraine rats have been further investigated.Results: About 125 peaks were detected in CO2-ZSE, and the relative content of linalool was 74.16%. CO2-ZSE decreased the number of head-scratching significantly and the levels of serum nitric oxide (NO), endothelin-1 (ET-1), calcitonin gene–related peptide (CGRP), interleukin-1β (IL-1β), nuclear factor kappa B (NF-κB) p65, and inhibitor of kappa B alpha (IκBα), and increased the level of 5-hydroxytryptamine (5-HT). Linalool has the potential to reduce the frequency of scratching the head and the expressions of NO, ET-1, and CGRP in NTG-induced migraine rats.Conclusion: CO2-ZSE has a definite therapeutic effect on migraine by affecting the expression of vasomotor factors and the inflammatory pathway. Linalool has been proven to be the main effective substance against migraine. These findings provide scientific basis for the development of effective and simple migraine therapy.
Phytomedicine in Disease Management: In-Silico Analysis of the Binding Affinity of Artesunate and Azadirachtin for Malaria Treatment
Authors: Okoh Michael P. , Singla Rajeev K. , Madu Chijioke , Soremekun Opeyemi , Adejoh Johnson , Alli Lukman A. , Shen Bairong 
Published: December 2021

In the rural communities of sub-Saharan African (sSA) countries, malaria is being managed using phytocompounds. Artesunate is reported to inhibit Gephyrin E, a central, multi-domain scaffolding protein of inhibitory post-synapses. Neem plant and its metabolites like azadirachtin are being indicated for management of malaria by traditional healers. The present study was aimed to cheminformatically analyse the binding potential of artesunate and azadirachtin with various reactive moieties of Gephyrin E, to reduce malaria scourge. With molecular dynamics (MD), binding free energy estimation and binding affinity of artesunate and azadirachtin to Gephyrin E was done. GRIP docking was done to study the interactions of these test ligands with Gephyrin E (6FGC). MD simulation gave insights to structural changes upon binding of artesunate and azadirachtin in the ligand-binding pocket of Gephyrin E. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) were calculated. From the estimation, azadirachtin had a total binding energy of −36.97 kcal/mol; artesunate had a binding energy of −35.73 kcal/mol. The GRIP docking results provided a clearer evidence that artesunate has comparatively better binding affinity to Gephyrin E than azadirachtin, and the critical binding sites (in activity order) were cavity 3, 2, 8, and 6 for artesunate while for azadirachtin, it was cavity 6, 3, 8, and 2. The GRIP docking provided detailed interactions at the atomic levels, providing evidence; both compounds have chances to overcome the drug resistance problem, albeit higher for artesunate. Our findings added another piece of evidence that azadirachtin may be effective as an anti-malarial agent. The results herein may provide impetus for more studies into bioactive components of plant origin towards the effective management of malaria disease phenotype.
Examining Sex Differences in Conditioned Place Preference or Aversion to Methamphetamine in Adolescent and Adult Mice
Authors: Cullity Ellen R. , Guerin Alexandre A. , Perry Christina J. , Kim Jee Hyun 
Published: December 2021

Adolescence marks a particularly vulnerable period to developing substance use disorders. Human and rodent studies suggest that hypersensitivity to reward may contribute towards such vulnerability when adolescents are exposed to casual drug use. Methamphetamine is a popular illicit substance used by male and female youths. However, age- and sex-specific research in methamphetamine is scarce. The present study therefore aimed to examine potential sex differences in methamphetamine-conditioned place preference in adolescent and adult mice. Mice (n = 16–24/group) were conditioned to methamphetamine (0.1 mg/kg). We observed that regardless of age, females were more hyperactive compared to males. Individually normalized score against baseline preference indicated that on average, adolescents formed stronger preference compared to adults in both sexes. This suggests that adolescents are more sensitive to the rewarding effects of methamphetamine compared to adults. Surprisingly, individual data showed that some mice formed a conditioned place aversion instead of preference, with females less likely to form an aversion compared to males. These results suggest that adolescents may be hypersensitive to methamphetamine’s rewarding effects. In addition, female resistance to the aversive effects of methamphetamine may relate to the sex-specific findings in humans, including quicker transition to regular methamphetamine use observed in females compared to males.
Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity
Authors: Zhang Yudi , Fu Yuping , Jiang Tiannan , Liu Binghua , Sun Hongke , Zhang Ying , Fan Boyuan , Li Xiaoli , Qin Xinghua , Zheng Qiangsun 
Published: December 2021

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical setting. Its pathogenesis was associated with metabolic disorder, especially defective fatty acids oxidation (FAO). However, whether promoting FAO could prevent AF occurrence and development remains elusive. In this study, we established a mouse model of obesity-related AF through high-fat diet (HFD) feeding, and used l-carnitine (LCA, 150 mg/kg⋅BW/d), an endogenous cofactor of carnitine palmitoyl-transferase-1B (CPT1B; the rate-limiting enzyme of FAO) to investigate whether FAO promotion can attenuate the AF susceptibility in obesity. All mice underwent electrophysiological assessment for atrial vulnerability, and echocardiography, histology and molecular evaluation for AF substrates and underlying mechanisms, which were further validated by pharmacological experiments in vitro. HFD-induced obese mice increased AF vulnerability and exhibited apparent atrial structural remodeling, including left atrial dilation, cardiomyocyte hypertrophy, connexin-43 remodeling and fibrosis. Pathologically, HFD apparently leads to defective cardiac FAO and subsequent lipotoxicity, thereby evoking a set of pathological reactions including oxidative stress, DNA damage, inflammation, and insulin resistance. Enhancing FAO via LCA attenuated lipotoxicity and lipotoxicity-induced pathological changes in the atria of obese mice, resulting in restored structural remodeling and ameliorated AF susceptibility. Mechanistically, LCA activated AMPK/PGC1α signaling both in vivo and in vitro, and pharmacological inhibition of AMPK via Compound C attenuated LCA-induced cardio-protection in palmitate-treated primary atrial cardiomyocytes. Taken together, our results demonstrated that FAO promotion via LCA attenuated obesity-mediated AF and structural remodeling by activating AMPK signaling and alleviating atrial lipotoxicity. Thus, enhancing FAO may be a potential therapeutic target for AF.
Anti-Osteogenic Effect of Danshensu in Ankylosing Spondylitis: An in Vitro Study Based on Integrated Network Pharmacology
Authors: Li Jiaxiao , Chen Zexin , Liao Hongbo , Zhong Yanting , Hua Junying , Su Miaoling , Li Jiahao , Xu Jinrong , Cui Liao , Cui Yang 
Published: December 2021

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by abnormal bone metabolism, with few effective treatments available. Danshensu [3-(3,4-dihydroxy-phenyl) lactic acid) is a bioactive compound from traditional Chinese medicine with a variety of pharmacologic effects. In the present study, we investigated the pharmacologic effect and molecular mechanism of Danshensu in AS. Potential targets of Danshensu were identified in four drugs-genes databases; and potential pharmacologic target genes in AS were identified in three diseases-genes databases. Differentially expressed genes related to AS were obtained from the Gene Expression Omnibus database. Overlapping targets of Danshensu and AS were determined and a disease–active ingredient–target interaction network was constructed with Cytoscape software. Enrichment analyses of the common targets were performed using Bioconductor. To test the validity of the constructed network, an in vitro model was established by treating osteoblasts from newborn rats with low concentrations of tumor necrosis factor (TNF)-α. Then, the in vitro model and AS fibroblasts were treated with Danshensu (1–10 μM). Osteogenesis was evaluated by alkaline phosphatase staining and activity assay, alizarin red staining, quantitative PCR, and western blotting. We identified 2944 AS-related genes and 406 Danshensu targets, including 47 that were common to both datasets. The main signaling pathways associated with the targets were the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways. A low concentration of TNF-α (0.01 ng/ml) promoted the differentiation of osteoblasts; this was inhibited by Danshensu, which had the same effect on AS fibroblasts but had the opposite effect on normal osteoblasts. Danshensu also decreased the phosphorylation of JNK and ERK in AS fibroblasts. There results provide evidence that Danshensu exerts an anti-osteogenic effect via suppression of JNK and ERK signaling, highlighting its therapeutic potential for the treatment of AS.
Effect of Anti-Inflammatory and Antimicrobial Cosupplementations on Sepsis Prevention in Critically Ill Trauma Patients at High Risk for Sepsis
Authors: Kamel Noha A. , Soliman Moetaza M. , Abo-Zeid Maha A. , Shaaban Mona I. 
Published: December 2021

Background: Sepsis development in patients with trauma is associated with bad prognosis. This study investigated the effect of immunomodulatory interventions in major trauma patients at high risk for sepsis.Methods: In a randomized, double-blinded, controlled design, severe trauma patients were stratified by leukocyte anti-sedimentation rate (LAR) test into high risk (HR) and low risk (LR) for sepsis. The HR patients were randomly allocated into intravenous vitamin C plus vitamin B1 (HR-CB), intramuscular vitamin D plus oral Lactobacillus probiotics (HR-DP), or control (HR-C) groups. The clinical trial was registered at clinicaltrials.gov (https://clinicaltrials.gov/show/NCT04216459).Outcomes: The primary outcome was Acute Physiologic Assessment and Chronic Health Evaluation score II (APACHE II) score. Secondary outcomes included sepsis incidence, changes in Sequential Organ Failure Assessment (SOFA) score, and serum monocyte chemoattractant protein-1 (MCP-1) on day 6 from baseline, 28-day mortality, intensive care unit (ICU), and hospital discharge.Results: The HR-DP, HR-CB, and LR groups showed a significantly lower incidence of sepsis development (20%, 20%, and 16%, respectively, versus 60% in the HR-C group, p-value = 0.004). The three groups also showed a significant improvement in APACHE II and SOFA scores. Besides, MCP-1 levels were significantly decreased in HR-DP and HR-CB groups compared to the HR-C group (p-value ≤ 0.05). Significantly decreased mortality (10% and 16% versus 60% in the HR-C group) and increased ICU discharge (95% and 84% versus 45% in the HR-C group) were observed in HR-CB and LR groups (p-value = 0.001).Conclusion: Both combinations of interventions improved APACHE II scores and reduced sepsis incidence in trauma patients. The LAR combined with injury severity score were good sepsis predictors.
Response of Bone Metabolism Markers to Ice Swimming in Regular Practitioners
Authors: Mu Shuai , Xia Yang , Wu Qijun , Ji Chao , Dai Huixu , Zhang Ming , Jiao Jiao , Shi Feng , Liu Shengye , Wang Guangbin , Shen Tao , Tian Ye , Yang Liqing , Fu Qin , Zhao Yuhong 
Published: December 2021

Objective: Both exercise and cold exposure cause physiological stress and they often occur in combination. However, the effects of exercise during severe cold on variation in bone metabolism in humans have remained elusive. The aim of this study was to investigate the variations in circulating bone metabolism markers after ice swimming (IS).Methods: Eighty-seven women and men aged 42–84 years old were recruited to perform regular IS activities. Serum parathyroid hormone (PTH), total calcium (Ca2+), total phosphorus (Pi), total magnesium (Mg2+), N-terminal osteocalcin (N-MID), total propeptide of procollagen 1 (TPINP), and C-terminal telopeptide of type 1 collagen (β-CTX) were measured 30 min before and 30 min after IS. Bone mineral content (BMC) and bone mineral density (BMD) were assessed at lumbar spine 1–4 (L1–L4) and femoral neck (FN). The IS habits were obtained from questionnaires and the 10-year probability of osteoporotic fracture was calculated using the FRAX® tool with and without a BMD value of the FN.Results: There were significant increases in PTH (median, 40.120–51.540 pg/mL), Ca2+ (median, 2.330–2.400 mmol/L), and Pi (median, 1.100–1.340 mmol/L) and significant decreases in TPINP (median, 38.190–36.610 ng/mL) and β-CTX (median, 0.185–0.171 ng/mL), while there was a trend for increased serum Mg2+ (P = 0.058) but no significant change in N-MID (P = 0.933) after IS in all subjects. The increases in the proportions of cases of hyperparathyroidemia, hypercalcemia, and hyperphosphatemia in those performing IS were statistically significant. The baseline levels and the changes of bone metabolism markers had associations with osteoporosis and bone status, but these may be age and sex dependent. Finally, there were significant correlations among the bone metabolism markers.Conclusion: IS caused significant alterations in bone metabolic markers, specifically, increases in PTH, Ca2+ and Pi should raise concerns about potential cardiovascular health risks in severe cold exercise. Additionally, a divergence between PTH elevation and a decline in bone turnover, which shown a special change of bone metabolism after IS and may suggest potential therapeutic implications of cold exercise in PTH and bone metabolic disorders.