Outcomes Associated With Adapting a Research-Supported Treatment for Children With Behavior Disorders.

Abstract:
Purpose
The aims of this study are to describe an adaptation process of a research-supported treatment (RST) for children with oppositional defiant disorder and to examine provider attitudes toward RSTs prior to and following this process.

Method
Providers from 14 agencies in New York State delivered the adapted RST, following training. Attitudes toward RSTs were measured by the Evidence-Based Practice Attitude Scale at baseline and posttest.

Results
Openness toward RSTs decreased from baseline to posttest. The majority of providers reported modifications to the structure and process of the intervention.

Discussion
To improve the uptake and usability of RSTs in practice, future research must further address adaptation processes and their relationships to attitudes toward RSTs.

adapting research-supported treatment
implementation
multiple family groups


Theory of electrophoretic focusing on an inverse electromigration dispersion profile.

Abstract: Electrophoretic focusing on an inverse electromigration dispersion (EMD) profile is based on a principle different from those of other electrophoretic separation methods. It has already proved its applicability in analytical practice by offering competitive separation performance and sensitivity and specific selectivity. It can be classified as an intermediate between field-driven and equilibrium gradient methods and is therefore interesting from the viewpoint of theory of separation methods. This work presents a comprehensive theoretical description of electrophoretic focusing on an inverse EMD profile comprising properties of the electrolyte system, formed gradients, and focused analyte zones. The separation properties are described in terms of resolution and peak capacity and their dependence on system and analyte properties is discussed from the viewpoint of how the counteracting phenomena of electromigration and dispersion are affected by electric current, voltage, and hydrodynamic and electroosmotic flow. The overall performance of the present method is shown to be comparable with other electrophoretic separation methods like zone electrophoresis or isoelectric focusing.

D004553:Electric Conductivity
D053841:Electroosmosis
D019075:Electrophoresis, Capillary
D057446:Hydrodynamics
D006863:Hydrogen-Ion Concentration
D007525:Isoelectric Focusing

Focusing
Electromigration dispersion
Separation methods
Electrophoresis theory


Adolescent elite athletes' cigarette smoking, use of snus, and alcohol.

Abstract: The purpose was to examine cigarette smoking, use of snus, alcohol, and performance-enhancing illicit drugs among adolescent elite athletes and controls, and possible gender and sport group differences. First-year students at 16 Norwegian Elite Sport High Schools (n = 677) and two randomly selected high schools (controls, n = 421) were invited to participate. Totally, 602 athletes (89%) and 354 (84%) controls completed the questionnaire. More controls than athletes were smoking, using snus, and drinking alcohol. Competing in team sports was associated with use of snus [odds ratio = 2.8, 95% confidence interval (CI) 1.6 to 4.7] and a similar percentage of male and female handball (22.2% vs 18.8%) and soccer players (15.7% vs 15.0%) reported using snus. For controls, not participating in organized sport was a predictor for smoking (odds ratio = 4.9, 95% CI 2.2 to 10.9). Female athletes were more prone to drink alcohol than males (46.3% vs 31.0%, P < 0.001). Only, 1.2% athletes and 2.8% controls reported use of performance-enhancing illicit drugs. In conclusion, use of legal drugs is less common among athletes, but this relationship depends on type of sport and competition level. The association between team sports and use of snus suggests that sport subcultures play a role.

drinking
non-athletes
performance
recreational drugs
smokeless tobacco


Integrated cardiopulmonary sonography: a useful tool for assessment of acute pulmonary edema in the intensive care unit.

Abstract:
OBJECTIVES
Bedside sonography has become a popular method of assessment of critically ill patients with shock and dyspnea. This study evaluated the usefulness of integrated cardiopulmonary sonography for assessment of acute pulmonary edema.

METHODS
A total of 128 intensive care unit (ICU) patients with acute pulmonary edema were randomly divided into 2 groups: a sonography group, which received standard treatment as well as cardiopulmonary sonography, and a control group, which received standard treatment only. All patients were treated according to the same therapeutic strategies and underwent chest radiography and central venous catheter placement. Serum myocardial injury marker levels and central venous/arterial blood gas parameters were measured 0, 24, and 72 hours after enrollment. The cumulative fluid infusion volume at 6, 12, 24, and 72 hours, the time to diagnosis of the pulmonary edema etiology by the attending physician, the lengths of ICU and hospital stays, and ICU mortality were recorded.

RESULTS
The sonography group had a shorter time to diagnosis and received a smaller fluid infusion volume than the control group. There were no significant differences in ICU mortality and lengths of ICU and hospital stays between the sonography and control groups. In patients with cardiogenic pulmonary edema, the sonography group had a significantly shorter ICU stay and a faster return to normal myocardial injury marker levels and perfusion parameters than the control group (P < .05).

CONCLUSIONS
Integrated cardiopulmonary sonography resulted in faster and better-informed clinical decision making, shortened the time to diagnosis of the pulmonary edema etiology, and decreased fluid use. However, the impact of this examination on prognoses requires further study. We propose that integrated cardiopulmonary sonography may be a useful bedside tool for treatment of ICU patients with acute pulmonary edema.

Wang|Xiao-Ting|XT| Liu|Da-Wei|DW| Zhang|Hong-Min|HM| Chai|Wen-Zhao|WZ|

sonography
acute pulmonary edema
etiology
critical care
point-of-care ultrasound
prognosis


Sequential numerical simulation of vascular remodeling and thrombosis in unconventional hybrid repair of ruptured middle aortic syndrome.

Abstract: Unconventional surgical procedures may be utilized in treating complicated middle aortic syndrome (MAS), the outcome and prognosis of which remain largely undetermined due to limited numbers and significant heterogeneity of this population. Using computational fluid dynamics (CFD) analysis, this study aimed to assess the dynamic changes of postoperative aortic flow in seeking to unveil the relationship between hemodynamics and vascular remodeling and thrombotic events. One patient with middle aortic syndrome complicated with aortic rupture was treated with hybrid repair of extra-anatomic bypass and fenestrated endovascular aortic repair. The patient was followed-up for 8 months by computational tomography angiography and Doppler ultrasound. Thoracoabdominal aortic blood flow and locations with ongoing thrombosis at 1, 3, and 6 months postoperatively were simulated and analyzed. Remodeling processes, including low wall shear-mediated constrictive remodeling of non-stented aorta, neointimal hyperplasia at suture lines, and minimal thrombosis at various locations, were evident. Meanwhile, abdominal blood flow was tri-phasic at 1 month after surgery, and was reversed and stabilized at 6 months. The distribution of newly formed thrombus vary at different follow-up stages, which were in line with the numerical simulation of thrombosis from different postoperative time points. CFD-based sequential monitoring is of promising value in capturing dynamic changes of vascular outcome.

Sun|Xiaoning|X| Ma|Tianxiang|T| Liu|Zhili|Z| Wu|Xiao|X| Zhang|Bo|B| Zhu|Shenling|S| Li|Fangda|F| Chen|Mengyin|M| Zheng|Yuehong|Y| Liu|Xiao|X|

D017545:Aortic Aneurysm, Thoracic
D057510:Endovascular Procedures
D006801:Humans
D016896:Treatment Outcome
D066253:Vascular Remodeling

Computational fluid dynamics
Endovascular procedures
Patient-specific modeling
Thrombus formation
Vascular grafting


Tissue-specific transcriptome profiling of Plutella xylostella third instar larval midgut.

Abstract: The larval midgut of diamondback moth, Plutella xylostella, is a dynamic tissue that interfaces with a diverse array of physiological and toxicological processes, including nutrient digestion and allocation, xenobiotic detoxification, innate and adaptive immune response, and pathogen defense. Despite its enormous agricultural importance, the genomic resources for P. xylostella are surprisingly scarce. In this study, a Bt resistant P. xylostella strain was subjected to the in-depth transcriptome analysis to identify genes and gene networks putatively involved in various physiological and toxicological processes in the P. xylostella larval midgut. Using Illumina deep sequencing, we obtained roughly 40 million reads containing approximately 3.6 gigabases of sequence data. De novo assembly generated 63,312 ESTs with an average read length of 416 bp, and approximately half of the P. xylostella sequences (45.4%, 28,768) showed similarity to the non-redundant database in GenBank with a cut-off E-value below 10(-5). Among them, 11,092 unigenes were assigned to one or multiple GO terms and 16,732 unigenes were assigned to 226 specific pathways. In-depth analysis identified genes putatively involved in insecticide resistance, nutrient digestion, and innate immune defense. Besides conventional detoxification enzymes and insecticide targets, novel genes, including 28 chymotrypsins and 53 ABC transporters, have been uncovered in the P. xylostella larval midgut transcriptome; which are potentially linked to the Bt toxicity and resistance. Furthermore, an unexpectedly high number of ESTs, including 46 serpins and 7 lysozymes, were predicted to be involved in the immune defense.As the first tissue-specific transcriptome analysis of P. xylostella, this study sheds light on the molecular understanding of insecticide resistance, especially Bt resistance in an agriculturally important insect pest, and lays the foundation for future functional genomics research. In addition, current sequencing effort greatly enriched the existing P. xylostella EST database, and makes RNAseq a viable option in the future genomic analysis.

Xie|Wen|W| Lei|Yanyuan|Y| Fu|Wei|W| Yang|Zhongxia|Z| Zhu|Xun|X| Guo|Zhaojiang|Z| Wu|Qingjun|Q| Wang|Shaoli|S| Xu|Baoyun|B| Zhou|Xuguo|X| Zhang|Youjun|Y|

D020133:Reverse Transcriptase Polymerase Chain Reaction

Plutella xylostella
midgut
insecticide resistance
Illumina sequencing
expressed sequence tag


Fluorescence properties of curcumin-loaded nanoparticles for cell tracking.

Abstract:
Background
Posttransplant cell tracking, via stem cell labeling, is a crucial strategy for monitoring and maximizing benefits of cell-based therapies. The structures and functionalities of polysaccharides, proteins, and lipids allow their utilization in nanotechnology systems.

Materials and methods
In the present study, we analyzed the potential benefit of curcumin-loaded nanoparticles (NPC) using Vero cells (in vitro) and NPC-labeled adipose-derived mesenchymal stem cells (NPC-ADMSCs) (in vivo) in myocardial infarction and sciatic nerve crush preclinical models. Thereafter, transplantation, histological examination, real time imaging, and assessment of tissue regeneration were done.

Results
Transplanted NPC-ADMSCs were clearly identified and revealed potential benefit when used in cell tracking.

Conclusion
This approach may have broad applications in modeling labeled transplanted cells and in developing improved stem cell therapeutic strategies.

de Souza|Carolina Maria Costa Oliveira|CMCO|

de Carvalho|Katherine Athayde Teixeira|KAT|

D045164:Mesenchymal Stem Cell Transplantation

mesenchymal stem cells
sciatic nerve crush
transplantation
cell marking
myocardium infarction


Role of stem cell therapies in treating chronic wounds: A systematic review.

Abstract:
BACKGROUND
The impairment of cutaneous wound healing results in chronic, non-healing wounds that are caused by altered wound environment oxygenation, tissue injury, and permissive microbial growth. Current modalities for the treatment of these wounds inadequately address the complex changes involved in chronic wound pathogenesis. Consequently, stem cell therapies have emerged as a potential therapeutic modality to promote cutaneous regeneration through trophic and paracrine activity.

AIM
To investigate current literature regarding use of stem cell therapies for the clinical treatment of chronic, non-healing wounds.

METHODS
PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus were queried with combinations of the search terms "mesenchymal stem cells," "adult stem cells," "embryonic stem cells," "erythroid precursor cells," "stem cell therapies," and "chronic wounds" in order to find relevant articles published between the years of 2000 and 2019 to review a 20-year experience. Reference lists from the articles were reviewed to identify additional pertinent articles. Retrieved manuscripts (reviews, case reports/series, retrospective/prospective studies, and clinical trials) were evaluated by the authors for their depiction of clinical stem cell therapy use. Data were extracted from the articles using a standardized collection tool.

RESULTS
A total of 43 articles describing the use of stem cell therapies for the treatment of chronic wounds were included in this review. While stem cell therapies have been explored in in vitro and in vivo applications in the past, recent efforts are geared towards assessing their clinical role. A review of the literature revealed that adipose-derived stem cells, bone marrow-derived stem cells, bone marrow-derived mononuclear cells, epidermally-derived mesenchymal stem cells, fibroblast stem cells, keratinocyte stem cells, placental mesenchymal stem cells, and umbilical cord mesenchymal stem cells have all been employed in the treatment of chronic wounds of various etiologies. Most recently, embryonic stem cells have emerged as a novel stem cell therapy with the capacity for multifaceted germ cell layer differentiation. With the capacity for self-renewal and differentiation, stem cells can enrich existing cell populations in chronic wounds in order to overcome barriers impeding the progression of wound healing. Further, stem cell therapies can be utilized to augment cell engraftment, signaling and activity, and resultant patient outcomes.

CONCLUSION
Assessing observed clinical outcomes, potential for stem cell use, and relevant therapeutic challenges allows wound care stakeholders to make informed decisions regarding optimal treatment approaches for their patients' chronic wounds.

Raghuram|Anjali C|AC|
Yu|Roy P|RP|
Lo|Andrea Y|AY|
Sung|Cynthia J|CJ|
Bircan|Melissa|M|
Thompson|Holly J|HJ|
Wong|Alex K|AK|

Stem cell therapies
Chronic wounds
Mesenchymal stem cells
Adult stem cells
Embryonic stem cells
Erythroid precursor cells


A Multichannel Strain Measurement Technique for Nanomodified Smart Cement-Based Sensors in Reinforced Concrete Structures.

Abstract: Nanomodified smart cement-based sensors are an emerging self-sensing technology for the structural health monitoring (SHM) of reinforced concrete (RC) structures. To date, several literature works demonstrated their strain-sensing capabilities, which make them suited for damage detection and localization. Despite the most recent technological improvements, a tailored measurement technique allowing feasible field implementations of smart cement-based sensors to concrete structures is still missing. In this regard, this paper proposes a multichannel measurement technique for retrieving strains from smart cement-based sensors embedded in RC structures using a distributed biphasic input. The experiments performed for its validation include the investigation on an RC beam with seven embedded sensors subjected to different types of static loading and a long-term monitoring application on an RC plate. Results demonstrate that the proposed technique is effective for retrieving time-stable simultaneous strain measurements from smart cement-based sensors, as well as for aiding the identification of the changes in their electrical outputs due to the influence of environmental effects variable over time. Accordingly, the proposed multichannel strain measurement technique represents a promising approach for performing feasible field implementations of smart cement-based sensors to concrete structures.

strain measurement
measurement techniques
smart cement-based sensors
reinforced concrete structures
structural health monitoring
carbon nanotubes
smart materials
smart structures


Handling Uncertainty in Cost-Effectiveness Analysis: Budget Impact and Risk Aversion.

Abstract: Methods to handle uncertainty in economic evaluation have gained much attention in the literature, and the cost-effectiveness acceptability curve (CEAC) is the most widely used method to summarise and present uncertainty associated with program costs and effects in cost-effectiveness analysis. Some researchers have emphasised the limitations of the CEAC for informing decision and policy makers, as the CEAC is insensitive to radial shifts of the joint distribution of incremental costs and effects in the North-East and South-West quadrants of the cost-effective plane (CEP). Furthermore, it has been pointed out that the CEAC does not incorporate risk-aversion in valuing uncertain costs and effects. In the present article, we show that the cost-effectiveness affordability curve (CEAFC) captures both dimensions of the joint distribution of incremental costs and effects on the CEP and is, therefore, sensitive to radial shifts of the joint distribution on the CEP. Furthermore, the CEAFC also informs about the budget impact of a new intervention, as it can be used to estimate the joint probability that an intervention is both affordable and cost-effective. Moreover, we show that the cost-effectiveness risk-aversion curve (CERAC) allows the analyst to incorporate different levels of risk-aversion into the analysis and can, therefore, be used to inform decision-makers who are risk-averse. We use data from a published cost-effectiveness model of palbociclib in addition to letrozole versus letrozole alone for the treatment of oestrogen-receptor positive, HER-2 negative, advanced breast cancer to demonstrate the differences between CEAC, CEAFC and CERAC, and show how these can jointly be used to inform decision and policy makers.

uncertainty
cost-effectiveness analysis
budget impact
economic evaluation
risk-aversion
health care costs
health outcomes


A Case of a Reversible Neurologic Adverse Reaction to Apixaban Confirmed by Re-Challenge.

Abstract: Post-marketing reporting of adverse drug events is essential for new medications, as pre-FDA approval studies lack sufficient subject numbers to detect signals for rare events. Prescriptions for the novel oral anticoagulant factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) have equaled or exceeded those for vitamin K antagonists in many clinical settings requiring chronic anticoagulation, and those of injectable heparins for deep vein thrombosis prophylaxis. We report the case of a 60-year-old woman followed for permanent atrial fibrillation who was prescribed apixaban. She rapidly developed worsening neurologic symptoms of imbalance and non-vertiginous dizziness preventing her from walking, headache, diplopia, and confusion/disorientation. Her symptoms began to resolve after stopping the drug, with return to baseline function within 72 h. Unbeknownst to her cardiology care team, the patient chose to re-challenge herself with apixaban at the same dose, producing identical symptoms and again total symptom resolution within 24 h of drug discontinuation. When seen by her physician, her physical examination was unchanged from her pre-treatment baseline. Symptoms did not recur when switched to rivaroxaban therapy.

Josyln|James A|JA|
Khattak|Furqan H|FH|
Geraci|Stephen A|SA|

Neurologic
Apixaban
Adverse drug reaction
DOAC
NOAC


Sqt1p is an eight-bladed WD40 protein.

Abstract: Ribosome biogenesis in eukaryotes is a complex and highly orchestrated process involving more than 200 accessory factors in addition to ribosomal RNAs and ribosomal proteins. Among the many factors involved, Sqt1p has been reported to specifically bind to uL16 and to act as a chaperone. The crystal structure of full-length Sqt1p from the yeast Saccharomyces cerevisiae has been solved at 3.35 Å resolution. A SAD experiment at the Se K edge and an S-SAD experiment on the same selenomethionine-substituted protein crystal allowed unambiguous positioning of the selenomethionine and Cys residues. On the basis of the atomic structure of Sqt1p, the potential residues involved in uL16 interaction were identified and tested.


Google AdWords and Facebook Ads for Recruitment of Pregnant Women into a Prospective Cohort Study With Long-Term Follow-Up.

Abstract: Objectives Several types of epidemiologic studies suffer from decreasing participation rates, resulting in potential selection bias and delay or termination of studies. We aimed to determine the feasibility of online methods for recruitment of pregnant women into a prospective cohort study. Methods In addition to traditional recruitment through prenatal care providers, we advertized participation in the PRegnancy and Infant DEvelopment (PRIDE) Study, an ongoing prospective cohort study with long-term follow-up in The Netherlands enrolling women in early pregnancy, through Google AdWords (30 days) and Facebook Ads (31 and 27 days) campaigns between September 2016 and January 2017. We calculated costs per eligible participant and compared demographics, health-related characteristics, and follow-up rates between participants recruited through online methods and prenatal care providers. Results During the study period, we recruited six women through AdWords (€54.28 per participant), 59 through Facebook (€10.17 per participant), and 327 through prenatal care providers (no valid cost estimate available). Facebook participants seemed to be younger (29.0 vs. 30.7 years), to have a higher body mass-index and/or low/intermediate education (27.0 vs. 24.0 kg/m2 and 41 vs. 25%, respectively), and to start prenatal care in secondary care more often (12 vs. 5%) than participants recruited through prenatal care providers. Item non-response and loss to follow-up rates were higher among women recruited online than among those recruited through prenatal care providers. Conclusion Google AdWords did not contribute substantially, but Facebook Ads may complement traditional recruitment methods of pregnant women into prospective cohort studies, despite challenges that may threaten internal validity.

van Gelder|Marleen M H J|MMHJ|http://orcid.org/0000-0003-4853-4434

Participant recruitment
Epidemiologic methods
Internet
PRIDE Study
Social media


Reducing the metabolic cost of walking with an ankle exoskeleton: interaction between actuation timing and power.

Abstract:
BACKGROUND
Powered ankle-foot exoskeletons can reduce the metabolic cost of human walking to below normal levels, but optimal assistance properties remain unclear. The purpose of this study was to test the effects of different assistance timing and power characteristics in an experiment with a tethered ankle-foot exoskeleton.

METHODS
Ten healthy female subjects walked on a treadmill with bilateral ankle-foot exoskeletons in 10 different assistance conditions. Artificial pneumatic muscles assisted plantarflexion during ankle push-off using one of four actuation onset timings (36, 42, 48 and 54% of the stride) and three power levels (average positive exoskeleton power over a stride, summed for both legs, of 0.2, 0.4 and 0.5 W∙kg-1). We compared metabolic rate, kinematics and electromyography (EMG) between conditions.

RESULTS
Optimal assistance was achieved with an onset of 42% stride and average power of 0.4 W∙kg-1, leading to 21% reduction in metabolic cost compared to walking with the exoskeleton deactivated and 12% reduction compared to normal walking without the exoskeleton. With suboptimal timing or power, the exoskeleton still reduced metabolic cost, but substantially less so. The relationship between timing, power and metabolic rate was well-characterized by a two-dimensional quadratic function. The assistive mechanisms leading to these improvements included reducing muscular activity in the ankle plantarflexors and assisting leg swing initiation.

CONCLUSIONS
These results emphasize the importance of optimizing exoskeleton actuation properties when assisting or augmenting human locomotion. Our optimal assistance onset timing and average power levels could be used for other exoskeletons to improve assistance and resulting benefits.

Galle|Samuel|S|0000-0002-1928-7764
Malcolm|Philippe|P|
Collins|Steven Hartley|SH|
De Clercq|Dirk|D|

Metabolic cost
Optimal assistance
Augmentation
Human locomotion
Lower-limb exoskeletons


A Case of Intraparenchymal Hepatic Hemorrhage Due to Ticagrelor Loading Treatment in an Elderly Patient With Acute Coronary Syndrome.

Abstract: Ticagrelor is a potent P2Y12 inhibitor that is increasingly used in acute coronary syndrome. Although drug-related intrahepatic hemorrhages have been reported with anticoagulant drugs, no case of intrahepatic hemorrhage due to ticagrelor has been encountered in the literature. With this case, we tried to explain that potent antiaggregant drugs may cause this rare bleeding complication. Although ticagrelor is used for rapid antiaggregation effect in acute coronary syndrome, de-escalation to clopidogrel treatment in elderly patients during the hospitalization period is a more reasonable option.

ticagrelor
elderly
acute coronary syndrome
de-escalation
intraparenchymal hemorrhage


G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status.

Abstract: Cancer cells often exhibit altered epigenetic signatures that can misregulate genes involved in processes such as transcription, proliferation, apoptosis and DNA repair. As regulation of chromatin structure is crucial for DNA repair processes, and both DNA repair and epigenetic controls are deregulated in many cancers, we speculated that simultaneously targeting both might provide new opportunities for cancer therapy. Here, we describe a focused screen that profiled small-molecule inhibitors targeting epigenetic regulators in combination with DNA double-strand break (DSB) inducing agents. We identify UNC0638, a catalytic inhibitor of histone lysine N-methyl-transferase G9a, as hypersensitising tumour cells to low doses of DSB-inducing agents without affecting the growth of the non-tumorigenic cells tested. Similar effects are also observed with another, structurally distinct, G9a inhibitor A-366. We also show that small-molecule inhibition of G9a or siRNA-mediated G9a depletion induces tumour cell death under low DNA damage conditions by impairing DSB repair in a p53 independent manner. Furthermore, we establish that G9a promotes DNA non-homologous end-joining in response to DSB-inducing genotoxic stress. This study thus highlights the potential for using G9a inhibitors as anti-cancer therapeutic agents in combination with DSB-inducing chemotherapeutic drugs such as etoposide.

D000971:Antineoplastic Combined Chemotherapy Protocols

UNC0638
Chemotherapeutics
Cancer epigenetics
Chemical probes
Non-homologous end joining


Impaired discrimination of a subanesthetic dose of ketamine in a maternal immune activation model of schizophrenia risk.

Abstract:
BACKGROUND
Animal models of psychiatric diseases suffer from a lack of reliable methods for accurate assessment of subjective internal states in nonhumans. This gap makes translation of results from animal models to patients particularly challenging.

AIMS/METHODS
Here, we used the drug-discrimination paradigm to allow rats that model a risk factor for schizophrenia (maternal immune activation, MIA) to report on the subjective internal state produced by a subanesthetic dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine.

RESULTS/OUTCOMES
The MIA rats' discrimination of ketamine was impaired relative to controls, both in the total number of rats that acquired and the asymptotic level of discrimination accuracy. This deficit was not due to a general inability to learn to discriminate an internal drug cue or internal state generally, as MIA rats were unimpaired in the learning and acquisition of a morphine drug discrimination and were as sensitive to the internal state of satiety as controls. Furthermore, the deficit was not due to a decreased sensitivity to the physiological effects of ketamine, as MIA rats showed increased ketamine-induced locomotor activity. Finally, impaired discrimination of ketamine was only seen at subanesthetic doses which functionally correspond to psychotomimetic doses in humans.

CONCLUSION
These data link changes in NMDA responses to the MIA model. Furthermore, they confirm the utility of the drug-discrimination paradigm for future inquiries into the subjective internal state produced in models of schizophrenia and other developmental diseases.

ketamine
Maternal immune activation
schizophrenia
rat
drug discrimination
NMDA receptors


MiR-452-5p promotes colorectal cancer progression by regulating an ERK/MAPK positive feedback loop.

Abstract:
BACKGROUND
MiR-452-5p plays an essential role in the development of a variety of tumors, but little is known about its biological function and mechanism in colorectal cancer (CRC).

METHODS
The expression levels of miR-452-5p in CRC tissues and cells were detected by real-time quantitative PCR (qRT-PCR). Besides, the biological effects of miR-452-5p on CRC were investigated by functional experiments in vitro and in vivo. Furthermore, bioinformatics analysis, dual-luciferase reporter assay, chromatin immunecipitation assay, western blotting and recovery experiments were implemented to investigate the underlying molecular mechanism.

RESULTS
The expression level of miR-452-5p was up-regulated in CRC tissues. MiR-452-5p promoted CRC cell proliferation, cell cycle transition and chemoresistance, and inhibited cell apoptosis. Moreover, miR-452-5p directly targeted PKN2 and DUSP6 and subsequently activated the ERK/MAPK signaling pathway, and it was transcriptionally regulated by c-Jun.

CONCLUSION
To conclude, miR-452-5p expression is up-regulated in CRC, which promotes the progression of CRC by activating the miR-452-5p-PKN2/DUSP6-c-Jun positive feedback loop. These findings indicate that miR-452-5p may act as a potential therapeutic target and clinical response biomarker for CRC.

Lin|Xin|X| Han|Lu|L| Gu|Chuncai|C| Lai|Yihong|Y| Lai|Qiuhua|Q| Li|Qingyuan|Q| He|Chengcheng|C| Meng|Yan|Y| Pan|Lei|L| Liu|Side|S| Li|Aimin|A|

D015972:Gene Expression Regulation, Neoplastic

D060888:Real-Time Polymerase Chain Reaction


Fracture repair requires TrkA signaling by skeletal sensory nerves.

Abstract: Bone is richly innervated by nerve growth factor-responsive (NGF-responsive) tropomyosin receptor kinase A-expressing (TrKa-expressing) sensory nerve fibers, which are required for osteochondral progenitor expansion during mammalian skeletal development. Aside from pain sensation, little is known regarding the role of sensory innervation in bone repair. Here, we characterized the reinnervation of tissue following experimental ulnar stress fracture and assessed the impact of loss of TrkA signaling in this process. Sequential histological data obtained in reporter mice subjected to fracture demonstrated a marked upregulation of NGF expression in periosteal stromal progenitors and fracture-associated macrophages. Sprouting and arborization of CGRP+TrkA+ sensory nerve fibers within the reactive periosteum in NGF-enriched cellular domains were evident at time points preceding periosteal vascularization, ossification, and mineralization. Temporal inhibition of TrkA catalytic activity by administration of 1NMPP1 to TrkAF592A mice significantly reduced the numbers of sensory fibers, blunted revascularization, and delayed ossification of the fracture callus. We observed similar deficiencies in nerve regrowth and fracture healing in a mouse model of peripheral neuropathy induced by paclitaxel treatment. Together, our studies demonstrate an essential role of TrkA signaling for stress fracture repair and implicate skeletal sensory nerves as an important upstream mediator of this repair process.

Li|Zhu|Z|
Meyers|Carolyn A|CA|
Chang|Leslie|L|
Lee|Seungyong|S|
Li|Zhi|Z|
Tomlinson|Ryan|R|
Hoke|Ahmet|A|
Clemens|Thomas L|TL|
James|Aaron W|AW|

D000818:Animals
D004195:Disease Models, Animal
D017102:Fracture Healing
D050723:Fractures, Bone
D015775:Fractures, Stress
D005727:Ganglia, Spinal
D017930:Genes, Reporter
D021621:Imaging, Three-Dimensional
D008297:Male
D051379:Mice
D008810:Mice, Inbred C57BL
D020932:Nerve Growth Factor
D010012:Osteogenesis
D010521:Periosteum
D020917:Receptor, trkA
D011984:Sensory Receptor Cells
D015398:Signal Transduction
D013234:Stem Cells
D019076:Transgenes
D055114:X-Ray Microtomography


Efficacy of imagery rescripting and imaginal exposure for nightmares: A randomized wait-list controlled trial.

Abstract: Nightmares can be effectively treated with cognitive-behavioral therapies. Though it remains elusive which therapeutic elements are responsible for the beneficial effects on nightmare symptoms, imagery rescripting (IR) and imaginal exposure (IE) are commonly identified as active treatment components of nightmare therapies. With this randomized controlled trial, we compared IR and IE as individual treatments to a wait-list (WL) condition to determine whether these particular therapeutic elements ameliorate nightmare symptoms. For this purpose, 104 patients with a primary DSM-5 diagnosis of nightmare disorder were randomly assigned to three weekly individual sessions of either IR or IE, or WL. Results showed that compared to WL, both interventions effectively reduced nightmare frequency (ΔdIR-WL = 0.74; ΔdIE-WL = 0.70) and distress (ΔdIR-WL = 0.98; ΔdIE-WL = 1.35) in a sample that predominantly consisted of idiopathic nightmare sufferers. The effects of IR and IE were comparable to those observed for other psychological nightmare treatments. Initial effects at post-treatment were sustained at 3- and 6-months follow-up, indicating that IR and IE both seem to be efficacious treatment components of nightmare therapies. Additional research is needed to directly compare IR and IE among both idiographic and posttraumatic nightmare sufferers with respect to treatment expectancy, acceptability, and effectiveness.

Kunze|Anna E|AE|
Arntz|Arnoud|A|
Morina|Nexhmedin|N|
Kindt|Merel|M|
Lancee|Jaap|J|

Imagery rescripting
Imaginal exposure
Nightmares
Nightmare disorder
Imagery rehearsal therapy
RCT


Synergistic anti-tumor effects of arsenic trioxide and blue LED irradiation on human osteosarcoma.

Abstract: Arsenic trioxide (ATO) has been well recognized as an anti-tumor agent for various human cancers. Recently, the blue light emitting diodes (LEDs)-based therapy has also been demonstrated to be potential therapeutic strategies for several cancers. However, the combination effects of ATO and blue LED on tumor suppression are still unclear. In this study, we determined whether combination of ATO and blue LED irradiation at 470 nm in wavelength exhibited superior anti-tumor activity in human osteosarcoma (OS). We observed that combination treatments of ATO and blue LED much more significantly decreased the percentages of proliferative cells, and increased apoptotic rate compared with any single treatments in U-2 OS cells. Furthermore, we found suppression of cell migration and invasion were much more pronounced in ATO plus blue LED treated group than single treated groups. Moreover, reactive oxygen species (ROS) assay and immunostaining of γ-H2A.X and p53 indicated that the combined treatments resulted in further markedly increases in ROS accumulation, DNA damage and p53 activity. Taken together, our study demonstrated synergistical anti-tumor effects of combined treatments of ATO and blue LED on human OS cells, which were associated with an increased ROS accumulation, DNA damaged mediated p53 activation.

Feng|Chao|C| Gong|Rui|R| Zheng|Qiuyan|Q| Yan|Gege|G| He|Mingyu|M| Lei|Hong|H| Li|Xingda|X| Zhang|Lai|L| Xu|Zihang|Z| Liu|Shenzhen|S| Yu|Meixi|M| Ma|Tianshuai|T| Gao|Manqi|M| Bamba|Djibril|D| Idiiatullina|Elina|E| Zagidullin|Naufal|N| Pavlov|Valentin|V| Xu|Chaoqian|C| Yuan|Ye|Y| Yang|Lei|L|

D017209:Apoptosis
D000077237:Arsenic Trioxide
D015153:Blotting, Western
D045744:Cell Line, Tumor
D002465:Cell Movement
D004249:DNA Damage
D006801:Humans
D020287:In Situ Nick-End Labeling
D012516:Osteosarcoma
D017382:Reactive Oxygen Species
D016159:Tumor Suppressor Protein p53

Blue LED irradiation
Arsenic trioxide (ATO)
Osteosarcoma (OS)
p53
DNA damage


Antioxidant defence system based oxidative stress mitigation through dietary jamun tree leaf in experimentally infected snubnose pompano, Trachinotus blochii.

Abstract: A 45-day feeding trial was conducted to evaluate the effect of dietary jamun tree leaf (JL) on the antioxidant defence system-based disease resistance in juveniles of Trachinotus blochii. The juveniles of snubnose pompano were distributed into four treatment groups in triplicates. Each treatment was fed with a diet containing either 0 (0JL), 0.5 (0.5JL), 1 (1JL) and 1.5% JL (1.5JL) in the feed. After feeding trial, the fishes were experimentally infected with Vibrio parahaemolyticus. The activities of oxidative stress enzymes such as superoxide dismutase and catalase were found to be increasing with increasing level of dietary JL incorporation, and the lower value was witnessed in control group in pre- and post-challenge. After challenge, the alanine and aspartate aminotransferase activities in all the treatments were significantly increased (P < 0.05) than the pre-challenge condition and exhibited reverse trend with the antioxidant enzymes. The alkaline and acid phosphatase activities were found higher in 1.5JL group and showed significant difference (P < 0.05) among the treatments. The respiratory burst activity and liver glycogen content showed an increasing trend as the level of inclusion of JL increased in the diet. The acetylcholinesterase activity was significantly plunged (P < 0.05) after experimental infection, and JL diet fed groups showed better activity. After experimental infection with V. parahaemolyticus, the highest relative percentage of survival was observed in 1JL and 1.5JL groups. Hence, dietary supplementation of jamun tree leaf at the level of 1% is adequate to reduce the oxidative stress and improved the innate immune status through antioxidant defence system.

Antioxidant defence system
Stress mitigation
Jamun tree leaf
Snubnose pompano
Relative percentage of survival


Transcription Factor EBF1 Over-Expression Suppresses Tumor Growth in vivo and in vitro via Modulation of the PNO1/p53 Pathway in Colorectal Cancer.

Abstract: Early B cell factor 1 (EBF1) has been identified as an upstream transcription factor of the potential oncogene PNO1 and is involved in the growth of colorectal cancer (CRC) cells. However, its expression, biological function, and underlying mechanism of action in most solid tumors remain largely unknown. We postulated that EBF1 has a role in the pathophysiology of CRC. Analysis of EBF1 mRNA expression in CRC tumor samples from several public databases and directly from banked tissues revealed that EBF1 mRNA expression is lower in CRC tissue compared to non-cancerous colorectal tissue. Survival analysis of multiple datasets revealed that low EBF1 expression was correlated with shorter overall survival, relapse-free survival, and event-free survival in CRC patients. Transduction of lentivirus encoding full length EBF1 followed by in vitro and in vivo assays demonstrated that EBF1 over-expression in CRC cell lines suppresses cell growth by inhibiting cell viability, cell survival, and induces cell cycle arrest and apoptosis. Mechanistic investigation indicated that EBF1 over-expression down-regulates PNO1 mRNA and protein expression, as well as transcriptional activity while up-regulating the expression of p53 and p21 proteins. These findings suggest that EBF1 is a novel potential tumor suppressor in CRC with prognostic value for the identification of patients at high-risk of relapse.

Shen|Zhiqing|Z|
Chen|Youqin|Y|
Li|Li|L|
Liu|Liya|L|
Peng|Meizhong|M|
Chen|Xiaoping|X|
Wu|Xiangyan|X|
Sferra|Thomas J|TJ|
Wu|Meizhu|M|
Lin|Xiaoying|X|
Cheng|Ying|Y|
Chu|Jianfeng|J|
Shen|Aling|A|
Peng|Jun|J|

EBF1
tumor growth
PNO1
p53 pathway
colorectal cancer
survival


Lignin from Micro- to Nanosize: Applications.

Abstract: Micro- and nanosize lignin has recently gained interest due to improved properties compared to standard lignin available today. As the second most abundant biopolymer after cellulose, lignin is readily available but used for rather low-value applications. This review focuses on the application of micro- and nanostructured lignin in final products or processes that all show potential for high added value. The fields of application are ranging from improvement of mechanical properties of polymer nanocomposites, bactericidal and antioxidant properties and impregnations to hollow lignin drug carriers for hydrophobic and hydrophilic substances. Also, a carbonization of lignin nanostructures can lead to high-value applications such as use in supercapacitors for energy storage. The properties of the final product depend on the surface properties of the nanomaterial and, therefore, on factors like the lignin source, extraction method, and production/precipitation methods, as discussed in this review.

D057927:Hydrophobic and Hydrophilic Interactions

lignin
nanocomposites
drug carrier
UV-blocker
antibacterial
biorefinery
microparticles
nanoparticles
reinforcing


Betaine and ascorbic acid modulate indoor behavior and some performance indicators of broiler chickens in response to hot-dry season.

Abstract: Heat stress causes lipid peroxidation in poultry, necessitating antioxidant administration. The experiment evaluated the modulating effects of betaine and ascorbic acid (AA) on indoor behavior and some performance parameters of broiler chickens during the hot-dry season. Experimental groups were: Group I (control) was daily given sterile water; Group II, betaine at 250 mg/kg; Group III, AA (50 mg/kg), and Group IV, betaine (250 mg/kg) + AA (50 mg/kg), orally for 42 days. The natural occurring dry-bulb temperature (28.0-37.0 °C), relative humidity (69.0-93.0%), and temperature-humidity index (27.9-36.1 °C) were predominantly outside the thermo-neutral zone for broiler chickens, indicating heat stress conditions. Scan test, used to assess the percentage of birds sitting/lying, panting, feeding, drinking and spreading wings, was performed at 06:00 h, 13:00 h and 18:00 h on each of days 35 and 42. Feed intakes (FD), water consumption (WC), body weight, average daily weight gain (ADG) and feed-to-gain ratio (FGR) were obtained. Betaine+AA reduced (P < 0.05) percentage of birds panting; AA decreased (P < 0.05) percentage of birds spreading wing, compared with control. Finisher phase: betaine and/or AA, decreased FGR, increased ADG (P < 0.05); betaine reduced (P < 0.01) FD compared with control. Grower phase: betaine, either alone or with AA, lowered FGR and FD (P < 0.01); AA reduced (P < 0.01) FD, compared with control. Starter phase: betaine and/or AA decreased WC (P < 0.05); AA lowered FGR, compared with controls. Betaine administration decreased (P < 0.05) FD at 4 week-old, but its administration, either alone or with AA, reduced WC at 1 week-old, compared with control. Overall, betaine and/or AA group lowered FGR compared with controls. In conclusion, administration of betaine and/or AA to broiler chickens modulated indoor behavior, some performance indicators and water consumption during the hot-dry season.

Egbuniwe|Ifeanyichukwu Chukwuemeka|IC|
Ayo|Joseph Olusegun|JO|
Ocheja|Ohiemi Benjamin|OB|

Betaine
Indoor behavior
Performance
Heat stress


Exploring the genomic and proteomic variations of SARS-CoV-2 spike glycoprotein: A computational biology approach.

Abstract: The newly identified SARS-CoV-2 has now been reported from around 185 countries with more than a million confirmed human cases including more than 120,000 deaths. The genomes of SARS-COV-2 strains isolated from different parts of the world are now available and the unique features of constituent genes and proteins need to be explored to understand the biology of the virus. Spike glycoprotein is one of the major targets to be explored because of its role during the entry of coronaviruses into host cells. We analyzed 320 whole-genome sequences and 320 spike protein sequences of SARS-CoV-2 using multiple sequence alignment. In this study, 483 unique variations have been identified among the genomes of SARS-CoV-2 including 25 nonsynonymous mutations and one deletion in the spike (S) protein. Among the 26 variations detected in S, 12 variations were located at the N-terminal domain (NTD) and 6 variations at the receptor-binding domain (RBD) which might alter the interaction of S protein with the host receptor angiotensin-converting enzyme 2 (ACE2). Besides, 22 amino acid insertions were identified in the spike protein of SARS-CoV-2 in comparison with that of SARS-CoV. Phylogenetic analyses of spike protein revealed that Bat coronavirus have a close evolutionary relationship with circulating SARS-CoV-2. The genetic variation analysis data presented in this study can help a better understanding of SARS-CoV-2 pathogenesis. Based on results reported herein, potential inhibitors against S protein can be designed by considering these variations and their impact on protein structure.

Lokman|Syed Mohammad|SM|
Rasheduzzaman|Md|M|
Salauddin|Asma|A|
Barua|Rocktim|R|
Tanzina|Afsana Yeasmin|AY|
Rumi|Meheadi Hasan|MH|
Hossain|Md Imran|MI|
Siddiki|A M A M Zonaed|AMAMZ|
Mannan|Adnan|A|
Hasan|Md Mahbub|MM|

D054730:Protein Interaction Domains and Motifs


Locked Nucleic Acid Gapmers and Conjugates Potently Silence ADAM33, an Asthma-Associated Metalloprotease with Nuclear-Localized mRNA.

Abstract: Two mechanisms dominate the clinical pipeline for oligonucleotide-based gene silencing, namely, the antisense approach that recruits RNase H to cleave target RNA and the RNAi approach that recruits the RISC complex to cleave target RNA. Multiple chemical designs can be used to elicit each pathway. We compare the silencing of the asthma susceptibility gene ADAM33 in MRC-5 lung fibroblasts using four classes of gene silencing agents, two that use each mechanism: traditional duplex small interfering RNAs (siRNAs), single-stranded small interfering RNAs (ss-siRNAs), locked nucleic acid (LNA) gapmer antisense oligonucleotides (ASOs), and novel hexadecyloxypropyl conjugates of the ASOs. Of these designs, the gapmer ASOs emerged as lead compounds for silencing ADAM33 expression: several gapmer ASOs showed subnanomolar potency when transfected with cationic lipid and low micromolar potency with no toxicity when delivered gymnotically. The preferential susceptibility of ADAM33 mRNA to silencing by RNase H may be related to the high degree of nuclear retention observed for this mRNA. Dynamic light scattering data showed that the hexadecyloxypropyl ASO conjugates self-assemble into clusters. These conjugates showed reduced potency relative to unconjugated ASOs unless the lipophilic tail was conjugated to the ASO using a biocleavable linkage. Finally, based on the lead ASOs from (human) MRC-5 cells, we developed a series of homologous ASOs targeting mouse Adam33 with excellent activity. Our work confirms that ASO-based gene silencing of ADAM33 is a useful tool for asthma research and therapy.

Pendergraff|Hannah M|HM|
Krishnamurthy|Pranathi Meda|PM|
Debacker|Alexandre J|AJ|
Moazami|Michael P|MP|
Sharma|Vivek K|VK|
Niitsoo|Liisa|L|
Yu|Yong|Y|
Tan|Yen Nee|YN|
Haitchi|Hans Michael|HM|
Watts|Jonathan K|JK|

ADAM33
gene silencing
antisense
siRNAs
nuclear RNA


Cancer cells activate damage-tolerant and error-prone DNA synthesis.

Abstract: Trans-lesion synthesis (TLS) is a DNA damage-tolerant and error-prone mode of DNA replication. Recent work shows that many cancer cells coopt an aberrantly expressed germ cell protein, melanoma antigen-A4 (MAGE-A4), to activate TLS. MAGE-A4-induced "pathological TLS" provides a potential mechanism through which neoplastic cells can tolerate intrinsic and therapeutic genotoxicity while acquiring mutability.

trans-lesion synthesis (TLS)
melanoma antigen-A4 (MAGE-A4)
Cancer-testes antigens (CTA)
DNA damage
RAD18
genome maintenance
mutagenesis


The impact of prophylactic dexamethasone on postoperative sore throat: an updated systematic review and meta-analysis.

Abstract:
Background/Aims
An updated systematic review and meta-analysis was conducted to assess the effect of prophylactic dexamethasone for tracheal intubation of general anesthesia on postoperative sore throat (POST).

Methods
Comprehensive literature search of databases for randomized controlled trials (RCTs), including Embase, PubMed, and Cochrane Library, which evaluate the effect of prophylactic dexamethasone on POST was conducted. RevMan 5.0 and STATA 12.0 software were used to perform meta-analyses.

Results
Fourteen RCTs totaling 1,837 patients were included for analysis. Compared with placebo, a significant reduction in the incidence of POST (OR 0.44, 95% CI 0.33-0.58, P<0.00001), hoarseness (OR 0.42, 95% CI 0.31-0.58, P<0.00001), and postoperative nausea and vomiting (PONV) (OR 0.06, 95% CI 0.03-0.14, P<0.00001) and a comparable incidence of cough (OR 0.59, 95% CI 0.19-1.89, P=0.38) was described in patients receiving dexamethasone, with or without concomitant drugs. Dexamethasone ≥0.2 mg/kg had a statistically greater impact on reducing the incidence of POST than dexamethasone 0.1-0.2 mg/kg, while dexamethasone ≤0.1 mg/kg did not. Dexamethasone was as effective as other drugs such as ondansetron, magnesium sulfate, ketamine gargle, betamethasone gel, and ketorolac for reducing POST (OR 0.70, 95% CI 0.46-1.07, P=0.10). Dexamethasone plus a different drug was more effective than dexamethasone alone for reducing the incidence of POST at 24 hours (OR 0.40, 95% CI 0.21-0.77, P=0.006). Compared with controls, a statistically higher blood glucose level was the only adverse event during the immediate postoperative period in patients receiving dexamethasone.

Conclusions
Intravenous dexamethasone ≥0.2 mg/kg within 30 minutes before or after induction of general anesthesia should be recommended as grade 1A evidence with safety and efficacy in reducing the incidence of POST, hoarseness, and PONV in patients without pregnancy, diabetes mellitus, or contraindications for corticosteroids.

Jiang|Yaofei|Y| Chen|Ruoxi|R| Xu|Suming|S| Li|Jiaxi|J| Yu|Fanqi|F| Kong|Lingdong|L| Sun|Yuhan|Y| Ye|Yuan|Y| Li|Yimin|Y| Yu|Mengqi|M| Wu|Jiaming|J|

dexamethasone
postoperative sore throat
systematic review
meta-analysis
corticosteroids


Genetic Features of Aflatoxin-Associated Hepatocellular Carcinoma.

Abstract:
BACKGROUND & AIMS
Dietary exposure to aflatoxin is an important risk factor for hepatocellular carcinoma (HCC). However, little is known about the genomic features and mutations of aflatoxin-associated HCCs compared with HCCs not associated with aflatoxin exposure. We investigated the genetic features of aflatoxin-associated HCC that can be used to differentiate them from HCCs not associated with this carcinogen.

METHODS
We obtained HCC tumor tissues and matched non-tumor liver tissues from 49 patients, collected from 1990 through 2016, at the Qidong Liver Cancer Hospital Institute in China-a high-risk region for aflatoxin exposure (38.2% of food samples test positive for aflatoxin contamination). Somatic variants were identified using GATK Best Practices Pipeline. We validated part of the mutations from whole-genome sequencing and whole-exome sequencing by Sanger sequencing. We also analyzed genomes of 1072 HCCs, obtained from 5 datasets from China, the United States, France, and Japan. Mutations in 49 aflatoxin-associated HCCs and 1072 HCCs from other regions were analyzed using the Wellcome Trust Sanger Institute mutational signatures framework with non-negative matrix factorization. The mutation landscape and mutational signatures from the aflatoxin-associated HCC and HCC samples from general population were compared. We identified genetic features of aflatoxin-associated HCC, and used these to identify aflatoxin-associated HCCs in datasets from other regions. Tumor samples were analyzed by immunohistochemistry to determine microvessel density and levels of CD34 and CD274 (PD-L1).

RESULTS
Aflatoxin-associated HCCs frequently contained C>A transversions, the sequence motif GCN, and strand bias. In addition to previously reported mutations in TP53, we found frequent mutations in the adhesion G protein-coupled receptor B1 gene (ADGRB1), which were associated with increased capillary density of tumor tissue. Aflatoxin-associated HCC tissues contained high-level potential mutation-associated neoantigens, and many infiltrating lymphocytes and tumors cells that expressed PD-L1, compared to HCCs not associated with aflatoxin. Of the HCCs from China, 9.8% contained the aflatoxin-associated genetic features, whereas 0.4%-3.5% of HCCs from other regions contained these genetic features.

CONCLUSIONS
We identified specific genetic and mutation features of HCCs associated with aflatoxin exposure, including mutations in ADGRB1, compared to HCCs from general populations. We associated these mutations with increased vascularization and expression of PD-L1 in HCC tissues. These findings might be used to identify patients with HCC due to aflatoxin exposure, and select therapies.

Zhang|Weilong|W| He|Huan|H| Zang|Mengya|M| Wu|Qifeng|Q| Zhao|Hong|H| Lu|Ling-Ling|LL| Ma|Peiqing|P| Zheng|Hongwei|H| Wang|Nengjin|N| Zhang|Ying|Y| He|Siyuan|S| Chen|Xiaoyan|X| Wu|Zhiyuan|Z| Wang|Xiaoyue|X| Cai|Jianqiang|J| Liu|Zhihua|Z| Sun|Zongtang|Z| Zeng|Yi-Xin|YX| Qu|Chunfeng|C| Jiao|Yuchen|Y|

Risk Factor
Liver Cancer
Aspergillus
Pathogenesis


A nationwide survey of hypertrophic pachymeningitis in Japan.

Abstract:
OBJECTIVES
To clarify the prevalence, frequent causes and distinct features of hypertrophic pachymeningitis (HP) according to background conditions in a nationwide survey in Japan.

METHODS
The study began with a preliminary survey to determine the approximate number of HP patients diagnosed from 1 January 2005 to 31 December 2009, and was followed by a questionnaire survey for clinical and laboratory findings. HP was defined as a condition with thickening of the cranial or spinal dura mater with inflammation, evidenced by MRI or histology.

RESULTS
Crude HP prevalence was 0.949/100 000 population. The mean age at onset was 58.3±15.8 years. Among 159 cases for whom detailed data were collated, antineutrophil cytoplasmic antibody (ANCA)-related HP was found in 54 cases (34.0%) and IgG4/multifocal fibrosclerosis (MFS)-related HP in 14 cases (8.8%). Seventy cases (44.0%) were classified as 'idiopathic' and 21 (13.2%) as 'others'. ANCA-related HP cases showed a female preponderance, a higher age of onset, and higher frequencies of otological symptoms and elevated systemic inflammatory biomarkers, but lower frequencies of diplopia compared with idiopathic HP. IgG4/MFS-related HP cases showed a marked male predominance; all had cranial HP while none had isolated spinal HP or decreased sensation.

CONCLUSIONS
HP is not extremely rare. ANCA-related HP is the most frequent form, followed by IgG4/MFS-related HP. Both forms have unique features, which may help to differentiate background causes.

Yonekawa|Tomomi|T| Murai|Hiroyuki|H| Utsuki|Satoshi|S| Matsushita|Takuya|T| Masaki|Katsuhisa|K| Isobe|Noriko|N| Yamasaki|Ryo|R| Yoshida|Mari|M| Kusunoki|Susumu|S| Sakata|Kiyomi|K| Fujii|Kiyotaka|K| Kira|Jun-ichi|J|

MRI
Bacteriology
Immunology
Infectious Diseases


Nicotine protects against manganese and iron-induced toxicity in SH-SY5Y cells: Implication for Parkinson's disease.

Abstract: Manganese (Mn) and iron (Fe) are trace elements that are essential for proper growth and physiological functions as both play critical role in a variety of enzymatic reactions. At high concentrations, however, they can be toxic and cause neurodegenerative disorders, particularly Parkinson-like syndromes. Nicotine, on the other hand, has been shown to have neuroprotective effects against various endogenous or exogenous toxins that selectively damage the dopaminergic cells. These cells include neuroblastoma-derived SH-SY5Y cells which express significant dopaminergic activity. However, practically no information on possible neuroprotective effects of nicotine against toxicity induced by trace elements is available. Therefore, in this study we investigated the effects of nicotine on toxicity induced by manganese or iron in these cells. Exposure of SH-SY5Y cells for 24 h to manganese (20 μM) or iron (20 μM) resulted in approximately 30% and 35% toxicity, respectively. Pretreatment with nicotine (1 μM) completely blocked the toxicities of Mn and Fe. The effects of nicotine, in turn, were blocked by selective nicotinic receptor antagonists. Thus, dihydro-beta erythroidine (DHBE), a selective alpha 4-beta 2 subtype antagonist and methyllycaconitine (MLA), a selective alpha7 antagonist, as well as mecamylamine, a non-selective nicotinic antagonist all dose-dependently blocked the protective effects of nicotine against both Mn and Fe. These findings provide further support for the potential utility of nicotine or nicotinic agonists in Parkinson's disease-like neurodegenerative disorders, including those that might be precipitated by trace elements, such as Fe and Mn. Moreover, both alpha4-beta2 and alpha7 nicotinic receptor subtypes appear to mediate the neuroprotective effects of nicotine against toxicity induced by these two trace metals.

Getachew|Bruk|B|
Csoka|Antonei B|AB|
Aschner|Michael|M|
Tizabi|Yousef|Y|

Nicotine
Manganese
Parkinson's disease
Iron
Neuroprotection
Nicotinic receptors
Cell culture
Neurotoxicity


A Novel Synchronous MAC Protocol for Wireless Sensor Networks with Performance Analysis.

Abstract: Synchronous medium access control (MAC) protocols are highly essential for wireless sensor networks (WSN) to support transmissions with energy saving, quality services, and throughput in industrial, commercial and healthcare applications. In this paper, a synchronous channel access mechanism is designed, where sensors can reserve the contention free data transmission slots in different available channels. To reduce the delay of data transmission among the nodes in the mesh topology, a linear programming problem (LPP) model is designed to select suitable relay nodes. Moreover, the performance of the proposed MAC is analyzed and our models are validated with simulation and analytical results. The results show that our proposed MAC protocol outperforms the IEEE 802.15.4e MAC mechanism in terms of throughput, reliability, delay, energy, packet drop rate and transmission success rate.

wireless sensor networks
performance analysis
mesh topology
IEEE 802.15.4e
DSME


Retrospective analysis of hospital admissions due to immune checkpoint inhibitor-induced immune-related adverse events (irAE).

Abstract:
AIM
Hospital admissions secondary to immune-related adverse events (irAE) arising from immune checkpoint inhibitors (ICI) are likely to increase with increasing use of this class of drug. We sought to determine the characteristics and outcomes of hospital admissions due to irAE.

METHODS
A retrospective analysis of patients treated with ICI at two tertiary hospitals in Queensland (Australia) was performed. Patients who received at least one dose of ICI for a nonhaematological malignancy between the 1st January 2016 and 1st January 2017 were included. All subsequent hospital admissions were analyzed.

RESULTS
A total of 140 patients were included, with the most common malignancies being non-small-cell-cell lung cancer (41%) and melanoma (18%), and most patients received anti-PD1 treatment (78%). A sum of 76 patients accounted for 116 admissions. Comparing admissions due to irAE and non-irAE, those admitted for irAE had a significantly longer duration on ICI prior to admission (173 vs 105 days, P = 0.04) but durations of admissions were similar (9.0 vs 8.5 days, P = 0.85). Fifteen patients (11% overall cohort) accounted for 18 admissions attributable to 16 separate irAE. irAE was not considered as a differential diagnosis on admission in 7 patients (38%). In those patients, commencement of corticosteroids was delayed (1.5 days, P = 0.01) but this did not translate into adverse outcomes such as prolonged admissions, prolonged steroid use or long-term complications. All patients with irAE were managed with high-dose corticosteroids. One death resulted from irAE (pneumonitis).

CONCLUSIONS
A sum of 11% patients receiving ICI required hospital admission for irAE. The relatively high rate of irAE as a missed differential diagnosis on admission suggests a need for improved cross-discipline awareness, education, and institutional management guidelines.

D064420:Drug-Related Side Effects and Adverse Reactions

admissions
immune checkpoint
immune-related adverse events
immunotherapy
inpatient


Spinal-epidural Abscess Presenting as an Acute Abdomen in a Child: A Case Report and Review of the Literature.

Abstract: Abdominal presentations in patients with spinal-epidural abscess (SEA) are not uncommon. However, it needs to be continually emphasized that the atypical presentations of these diseases could delay the timely diagnosis and consequently prompt management, which threatens spinal cord, leading to potential to paralysis or even death. We report a case of a young girl who presented with abdominal pain and fever. The diagnosis of SEA was unfortunately so delayed that the patient did not show any functional recovery postoperatively. This report aims to highlight the importance of high level of clinical suspicion to recognize an atypical presentation of the SEA. Moreover, the fully detailed history-taking and physical examination are of paramount importance. Spinal underlying pathologies should always be considered as a cause of abdominal pain, especially in children.

Fakhouri|Fakhr|F| Ghazal|Ahmad|A| Alnaeb|Hasnaa|H| Hezan|Rasha|R| Araj|Joudi|J|

Abdominal pain
delayed diagnosis
epidural abscess
exploratory laparotomy
misdiagnosis


A chicken bioreactor for efficient production of functional cytokines.

Abstract:
BACKGROUND
The global market for protein drugs has the highest compound annual growth rate of any pharmaceutical class but their availability, especially outside of the US market, is compromised by the high cost of manufacture and validation compared to traditional chemical drugs. Improvements in transgenic technologies allow valuable proteins to be produced by genetically-modified animals; several therapeutic proteins from such animal bioreactors are already on the market after successful clinical trials and regulatory approval. Chickens have lagged behind mammals in bioreactor development, despite a number of potential advantages, due to the historic difficulty in producing transgenic birds, but the production of therapeutic proteins in egg white of transgenic chickens would substantially lower costs across the entire production cycle compared to traditional cell culture-based production systems. This could lead to more affordable treatments and wider markets, including in developing countries and for animal health applications.

RESULTS
Here we report the efficient generation of new transgenic chicken lines to optimize protein production in eggs. As proof-of-concept, we describe the expression, purification and functional characterization of three pharmaceutical proteins, the human cytokine interferon α2a and two species-specific Fc fusions of the cytokine CSF1.

CONCLUSION
Our work optimizes and validates a transgenic chicken system for the cost-effective production of pure, high quality, biologically active protein for therapeutics and other applications.

Herron|Lissa R|LR|0000-0001-9961-4421
Pridans|Clare|C|
Turnbull|Matthew L|ML|
Smith|Nikki|N|
Lillico|Simon|S|
Sherman|Adrian|A|
Gilhooley|Hazel J|HJ|
Wear|Martin|M|
Kurian|Dominic|D|
Papadakos|Grigorios|G|
Digard|Paul|P|
Hume|David A|DA|
Gill|Andrew C|AC|
Sang|Helen M|HM|

Cytokines
Biologics
Animal biotechnology
Recombinant proteins
Transgenic animals


An analytical method to measure the contribution of clear synaptic and dense-core peri-synaptic vesicles to neurotransmitter release from synaptic terminals with two classes of secretory vesicles.

Abstract: Two types of secretory vesicles co-exist at some presynaptic terminals. Clear synaptic vesicles (CSV) release their contents at the synaptic active zone, upon single impulses, while dense-core vesicles (DCV) usually release their contents in the periphery of the terminal upon repetitive stimulation. Part of the transmitter released by DCV diffuses to produce paracrine effects, and part of it reaches the postsynaptic terminal, adding its effect to that of synaptic release. This article presents an analytical method to separate the contribution of CSV and DCV to the postsynaptic responses, based on the kinetics of postsynaptic currents (PSCs). Since stimulation with single presynaptic impulses usually triggers release only from CSV, the kinetics of the resulting PSC can be used as a template to model the postsynaptic response to release from CSV during stimulation trains, accounting for the variations in the amplitude of PSCs due to short-term synaptic plasticity. Subtraction of this model simulation to the total recorded PSC renders the response to DCV peri‑synaptic release, which has slower kinetics. The method can be further simplified by measuring only the amplitudes of the PSC peaks for synaptic release and the integral of the current for peri‑synaptic release.•The postsynaptic current in response to presynaptic release from clear synaptic vesicles is modeled using the kinetics of the PSC in response to single impulses.•The model synaptic response is subtracted from the total recorded PSC to obtain the response to peri‑synaptic release from dense-core vesicles.

Presynaptic terminal
Clear synaptic vesicles
Dense-core vesicles
Synaptic plasticity
Synaptic compartmentalization
Synaptic modeling


Ultrasound characteristics combined with gamma-glutamyl transpeptidase for diagnosis of biliary atresia in infants less than 30 days.

Abstract:
PURPOSE
To retrospectively assess the diagnostic performance of grey-scale ultrasound (US) characteristics and gamma-glutamyl transpeptidase (GGT) alone or combined in distinguishing biliary atresia (BA) from other cholestasis diseases in infants younger than 30 days.

MATERIALS AND METHODS
Between January 2012 and October 2020, the demographic characteristics, laboratory results and US characteristics of 35 BA and 52 non-BA infants younger than 30 days were retrospectively evaluated. Areas under the receiver operating characteristic curves (AUCs) were used to estimate the probability of predicting BA, which were compared by DeLong test.

RESULTS
The diagnostic performance of gallbladder classification in identifying BA was higher than that of fibrotic cord thickness (AUC 0.900 vs. 0.771, P = 0.03). With the cutoff level of 188 IU/L, serum GGT had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 77.1%, 69.2%, 62.8%, and 81.8%, respectively. Combined with gallbladder classification and GGT, the sensitivity, specificity, PPV, NPV and accuracy were 100.0%, 63.5%, 64.8%, 100.0% and 78.2%.

CONCLUSIONS
Gallbladder classification was more valuable than fibrotic cord thickness in the diagnosis of BA among infants less than 30 days. Combined with gallbladder classification and GGT, the sensitivity for the diagnosis of BA can reach 100.0%.

Wang|Guotao|G| Zhang|Nan|N| Zhang|Xiaoer|X| Zhou|Wenying|W| Xie|Xiaoyan|X| Zhou|Luyao|L|

Ultrasound
Gamma-glutamyl transpeptidase
Biliary atresia
Infants


Formation of oil-particle aggregates: Particle penetration and impact of particle properties and particle-to-oil concentration ratios.

Abstract: Oil droplets in marine environment interact with particles to form oil particle aggregates (OPA), and alters the transport and fate of oil. We investigated the impact of particles properties on the formation of OPAs. It was found that the distribution of 9 μm spherical silica (sand) particles on the oil droplet was more uniform than the 3 μm silica particles, and it is likely due to the inertia of the larger particles causing them to lodge into the droplet. Also, the OPAs of the 3 μm silica particles were much smaller than those of the 9 μm particles. For kaolinite particles that are rod-like of length around 10 μm, it was found that increasing the hydrophobicity of the particles from a contact angle (CA) of ~ 29o to 38o, increases the penetration of the particles in the oil through a projectile penetration mechanism, whereby the particle possesses sufficient inertia to penetrate into the oil. However, a further increase in hydrophbocitiy (CA ~ 57o) caused the particles to agglomerate together and avoid the oil droplets. The oil droplets got smaller with time probably due to the penetration of the particles in them. For an oil concentration of 500 mg/L, a particle concentration of 100 mg/L was incapable of fragmenting the oil droplets, but particle concentration of 500 mg/L fragmented the droplets similarly to a concentration of 1500 mg/L. This is due to the larger coverage of the droplet surface area by the particles and the subsequent weakening of its structural rigidity through the reduction of the oil-water interfacial tension. The study shows that the fate (e.g., after 24 h) of OPAs greatly depends on the type of sediments where the oil spilled (sand versus clay) and their concentration.

Ji|Wen|W| Boufadel|Michel|M| Zhao|Lin|L| Robinson|Brian|B| King|Thomas|T| Lee|Kenneth|K|

Oil particle aggregate
Hydrophobicity
Projectile penetration
Droplet size distribution
Microscale structure
Oil mass percentage


Management of spent shea waste: An instrumental characterization and valorization in clay bricks construction.

Abstract: This work studies the reuse of spent shea waste as an economic construction material in improving fired clay bricks manufacture aside providing a novel approach to ecofriendly managing its excessive generated from the shea agroindustry. For this purpose, the influence of spent shea waste addition on the chemical, mineralogical, molecular bonding and technological properties (i.e. compressive strength and water absorption) of the fired clay bricks were extensively investigated. The results indicated that the chemical, mineralogical, phase transformations, molecular bonding and thermal behavior of the produced bricks were practically unaffected by the addition of spent shea waste. However, spent shea waste addition increased the compressive strengths and water absorptions of the brick products. Potential performance benefits of reusing spent shea waste was improved fluxing agents, energy-contribution reaction, excellent porosifying effect, reduced thermal conductivity and enhanced compressive strengths of the brick products. This research has therefore provided compelling evidence that could create newfound route for the synergistic ecofriendly reuse of spent shea waste to enhance clay brick construction aside being a potential mainstream disposal option.

Adazabra|A N|AN|
Viruthagiri|G|G|
Shanmugam|N|N|

D000538:Aluminum Silicates
D000077215:Clay
D019245:Compressive Strength
D003252:Construction Materials
D059027:Recycling
D012037:Refuse Disposal
D013814:Thermal Conductivity

Spent shea waste
Clay bricks
Shea agroindustry
Waste management


FDG-PET/CT activity leads to the diagnosis of unsuspected TB: a retrospective study.

Abstract:
OBJECTIVE
Mycobacterium tuberculosis infection leads to latent or active tuberculosis (TB). Increased uptake on 18F-fluoro-2-deoxy-glucose-positron emission tomography/computed tomography (FDG-PET/CT) has been reported in the lungs and lymph nodes of individuals with recent infection and active TB, but not in individuals without known recent exposure or suggestive symptoms. We describe five patients with lung nodules not suspected to be due to TB in whom abnormalities on FDG-PET/CT scans ultimately were attributed to TB infection.

RESULTS
Patient records were searched using the words "positron emission tomography/computed tomography" and 24 codes for TB between 2004 and 2013. Patients with a diagnosis of TB and a PET/CT scan were included. Clinical and radiographic data were retrieved. PET/CT images were reviewed by an experienced radiologist. FDG-PET/CT scans revealed elevated FDG-uptake in lungs of five patients subsequently diagnosed with active (n = 3) or clinically inactive (n = 2) tuberculosis. Uptake magnitude was unrelated to disease activity. These findings suggest that tuberculosis latency may include periods of percolating inflammation of uncertain relationship to future disease risk.

D000072078:Positron Emission Tomography Computed Tomography

Latent
Imaging
Risk
Biomarkers
Subclinical TB


Complete genome sequence of Leuconostoc gelidum subsp. gasicomitatum KG16-1, isolated from vacuum-packaged vegetable sausages.

Abstract: Leuconostoc gelidum subsp. gasicomitatum is a predominant lactic acid bacterium (LAB) in spoilage microbial communities of different kinds of modified-atmosphere packaged (MAP) food products. So far, only one genome sequence of a poultry-originating type strain of this bacterium (LMG 18811(T)) has been available. In the current study, we present the completely sequenced and functionally annotated genome of strain KG16-1 isolated from a vegetable-based product. In addition, six other vegetable-associated strains were sequenced to study possible "niche" specificity suggested by recent multilocus sequence typing. The genome of strain KG16-1 consisted of one circular chromosome and three plasmids, which together contained 2,035 CDSs. The chromosome carried at least three prophage regions and one of the plasmids encoded a galactan degradation cluster, which might provide a survival advantage in plant-related environments. The genome comparison with LMG 18811(T) and six other vegetable strains suggests no major differences between the meat- and vegetable-associated strains that would explain their "niche" specificity. Finally, the comparison with the genomes of other leuconostocs highlights the distribution of functionally interesting genes across the L. gelidum strains and the genus Leuconostoc.

Andreevskaya|Margarita|M| Hultman|Jenni|J| Johansson|Per|P| Laine|Pia|P| Paulin|Lars|L| Auvinen|Petri|P| Björkroth|Johanna|J|


High density of cytotoxic T-lymphocytes is linked to tumoral PD-L1 expression regardless of the mismatch repair status in colorectal cancer.

Abstract:
BACKGROUND
Immune checkpoint-inhibitors targeting the PD-1/PD-L1 system are FDA approved in microsatellite instable (MSI) or mismatch repair deficient (dMMR) colorectal cancer (CRC). PD-L1 expression is tightly linked to features connected to immune checkpoint inhibitor response, but studies on large subsets of cancers analyzing the correlation between different status of MSI/dMMR, tumor infiltrating lymphocytes and PD-L1 expression are still lacking.

METHODS
More than 1800 CRC were analyzed for PD-L1 by immunohistochemistry in a tissue microarray format. Data were compared to MMR, the number of intratumoral CD8+ cytotoxic T-cells, and adverse clinico-pathological parameters. Different cutoff levels for defining PD-L1 positivity in tumor cells (1%, 5%, 10%, and 50%) yielded comparable results.

RESULTS
At a cutoff level of 5%, PD-L1 positivity was seen in 5.1% of tumors. PD-L1 was more often positive in dMMR (18.6%) than in MMR proficient (pMMR) cancers (4.1%; p < 0.0001). The number of intratumoral CD8+ lymphocytes was strikingly higher in PD-L1 positive (939.5 ± 118.2) than in PD-L1 negative cancers (310.5 ± 24.8). A higher number of intratumoral CD8+ lymphocytes was found in dMMR CRC (PD-L1 positive: 1999.7 ± 322.0; PD-L1 negative: 398.6 ± 128.0; p < 0.0001) compared to pMMR CRC (PD-L1 positive: 793.2 ± 124.8; PD-L1 negative: 297.2 ± 24.2; p < 0.0001). In dMMR and pMMR CRC, PD-L1 expression in tumor cells was unrelated to tumor stage, lymph node status or lymphatic/venous invasion. PD-L1 positivity in tumor associated immune cells was seen in 47.5% of cases and was significantly linked to high numbers of tumor infiltrating CD8+, low tumor stage, and absence of lymph node metastasis and lymphatic/venous invasion (p < 0.0001 each).

CONCLUSION
The data support the previously suggested fact that PD-L1 expression in tumor cells is driven by extensive cytotoxic T-cell infiltration in highly immunogenic dMMR and pMMR CRC. Frequent and intense PD-L1 expression in tumor cells of dMMR CRC may contribute to the high response rates of dMMR CRC to immune checkpoint-inhibitors.

Möller|Katharina|K|
Blessin|Niclas C|NC|
Höflmayer|Doris|D|
Büscheck|Franziska|F|
Luebke|Andreas M|AM|
Kluth|Martina|M|
Hube-Magg|Claudia|C|
Zalewski|Katarzyna|K|
Hinsch|Andrea|A|
Neipp|Michael|M|
Mofid|Hamid|H|
Lárusson|Hannes|H|
Daniels|Thies|T|
Isbert|Christoph|C|
Coerper|Stephan|S|
Ditterich|Daniel|D|
Rupprecht|Holger|H|
Goetz|Albert|A|
Bernreuther|Christian|C|
Sauter|Guido|G|
Uhlig|Ria|R|
Wilczak|Waldemar|W|
Simon|Ronald|R|
Steurer|Stefan|S|
Minner|Sarah|S|
Burandt|Eike|E|
Krech|Till|T|
Perez|Daniel|D|
Izbicki|Jakob R|JR|
Clauditz|Till S|TS|
Marx|Andreas H|AH|

D060890:B7-H1 Antigen
D015179:Colorectal Neoplasms
D053843:DNA Mismatch Repair
D006801:Humans
D053842:Microsatellite Instability
D013602:T-Lymphocytes, Cytotoxic

PD-L1
colorectal cancer
tissue microarray
CD8+ T-cell lymphocytes


Molecular Evolution of Alternative Oxidase Proteins: A Phylogenetic and Structure Modeling Approach.

Abstract: Alternative oxidases (AOXs) are mitochondrial cyanide-resistant membrane-bound metallo-proteins catalyzing the oxidation of ubiquinol and the reduction of oxygen to water bypassing two sites of proton pumping, thus dissipating a major part of redox energy into heat. Here, the structure of Arabidopsis thaliana AOX 1A has been modeled using the crystal structure of Trypanosoma brucei AOX as a template. Analysis of this model and multiple sequence alignment of members of the AOX family from all kingdoms of Life indicate that AOXs display a high degree of conservation of the catalytic core, which is formed by a four-α-helix bundle, hosting the di-iron catalytic site, and is flanked by two additional α-helices anchoring the protein to the membrane. Plant AOXs display a peculiar covalent dimerization mode due to the conservation in the N-terminal region of a Cys residue forming the inter-monomer disulfide bond. The multiple sequence alignment has also been used to infer a phylogenetic tree of AOXs whose analysis shows a polyphyletic origin for the AOXs found in Fungi and a monophyletic origin of the AOXs of Eubacteria, Mycetozoa, Euglenozoa, Metazoa, and Land Plants. This suggests that AOXs evolved from a common ancestral protein in each of these kingdoms. Within the Plant AOX clade, the AOXs of monocotyledon plants form two distinct clades which have unresolved relationships relative to the monophyletic clade of the AOXs of dicotyledonous plants. This reflects the sequence divergence of the N-terminal region, probably due to a low selective pressure for sequence conservation linked to the covalent homo-dimerization mode.

Pennisi|Rosa|R| Salvi|Daniele|D| Brandi|Valentina|V| Angelini|Riccardo|R| Ascenzi|Paolo|P| Polticelli|Fabio|F|

D000595:Amino Acid Sequence
D017360:Arabidopsis
D020134:Catalytic Domain
D017124:Conserved Sequence
D019143:Evolution, Molecular
D024101:Mitochondrial Proteins
D008958:Models, Molecular
D010084:Oxidation-Reduction
D010088:Oxidoreductases
D010802:Phylogeny
D010940:Plant Proteins
D010944:Plants
D011487:Protein Conformation
D016415:Sequence Alignment
D013329:Structure-Activity Relationship
D014346:Trypanosoma brucei brucei

Molecular evolution
Alternative oxidase
Molecular modeling
Phylogenetic analysis


François Leuret: the last moral therapist.

Abstract: By the 1840s French psychiatrists had abandoned Moral Treatment as an individual psychological therapy, as opposed to an institutional practice. One advocate of Moral Treatment, however, would not go along with this movement. In three books and several papers published between 1834 and 1846, François Leuret (1797-1851) advocated aggressive psychological treatment. Recent commentators have understandably concentrated on the controversies surrounding Leuret's practices. What such an approach has failed to make clear, however, is that Leuret had a complex, systematic psychological theory supporting his clinical judgements. In addition to reviewing the controversies that surrounded Leuret, this paper spells out Leuret's psychological theory and shows how he used this theory to think about the individual psychotherapy he provided for his patients.

François Leuret
moral treatment
psychotherapy
19th century
France
J.E.D. Esquirol
Philippe Pinel
psychiatry


The effect of concentration, reconstitution solution and pH on the stability of a remifentanil hydrochloride and propofol admixture for simultaneous co-infusion.

Abstract:
BACKGROUND
There are scenarios where pre-mixing and infusing analgesic and anaesthetic agents as a single intravenous (IV) solution is highly desirable; however, it is important to ensure the agents are compatible when mixed. As such, the long-term stability of a remifentanil-propofol mixture, and means of improving this, were assessed across a range of remifentanil concentrations, diluents, and time points.

METHODS
Remifentanil was reconstituted with ultrapure water, 0.9% saline, 20% saline, or 8.4% sodium bicarbonate solution (the latter two chosen for their pH characteristics, rather than their use in pharmaceutical reconstitution) and then mixed with propofol (1%) or further diluted with water to derive concentrations of 10-50 μg mL- 1. Remifentanil and propofol concentrations were determined initially and then periodically for up to 24 h using high performance liquid chromatography (HPLC). Mass spectrometry (MS) was used to detect degradation products in solutions containing 30 μg mL- 1 of remifentanil. Statistical analysis was performed using ANOVA and Student's t-test, with a significance value of 0.05.

RESULTS
Isolated remifentanil (pH < 4) and propofol (pH 7.35) did not degrade significantly when reconstituted with water or saline solution over 24 h, while remifentanil reconstituted with sodium bicarbonate degraded significantly (P < 0.001, pH 8.65). Mixing with propofol substantially increased the pH of the mixture and resulted in significant remifentanil degradation for all reconstitution solutions used, while propofol remained stable (pH 6.50). The amount of degradation product detected in samples containing isolated remifentanil and a mixture of the drugs was proportional to the remifentanil degradation observed.

CONCLUSIONS
Remifentanil stability is affected by both the reconstitution solution used and when mixed with propofol, with pH appearing to be a contributing factor to degradation. If the pH of the solution and concentration of remifentanil are correctly controlled, e.g. through the use of a more acidic diluent, an admixture of remifentanil and propofol may be useful clinically.

Henkel|Emily|E|0000-0002-7320-1378 Vella|Rebecca|R| Behan|Kieran|K| Austin|David|D| Kruger|Peter|P| Fenning|Andrew|A|

Remifentanil
Propofol
HPLC
Chemical stability
Drug-drug interaction(s)
Pharmaceutical preparations


The association between asymptomatic coronary artery disease and CHADS2 and CHA2 DS2 -VASc scores in patients with stroke.

Abstract:
BACKGROUND AND PURPOSE
CHADS2 and CHA2 DS2 -VASc scores are measurement tools that stratify thromboembolic risk in patients with non-valvular atrial fibrillation, and are predictive of cerebral atherosclerosis, fatal stroke and ischaemic heart disease. Patients with higher CHADS2 and CHA2 DS2 -VASc scores are more likely to have had an akinetic/hypokinetic left ventricular segment or a recent myocardial infarction, all of which are associated with coronary artery disease (CAD). Most of the CHADS2 score components are also risk factors for atherosclerosis. Thus, CHADS2 and CHA2 DS2 -VASc scores may be predictive of CAD.

METHODS
In all, 1733 consecutive patients with acute ischaemic stroke who underwent multi-slice computed tomography coronary angiography were enrolled. The association of CHADS2 and CHA2 DS2 -VASc scores with the presence and severity of CAD was investigated.

RESULTS
Of the 1733 patients, 1220 patients (70.4%) had any degree of CAD and 576 (33.3%) had significant CAD (≥ 50% stenosis in at least one coronary artery). As the CHADS2 and CHA2 DS2 -VASc scores increased, the presence of CAD also increased (P < 0.001). The severity of CAD was correlated with CHADS2 score (Spearman coefficient 0.229, P < 0.001) and CHA2 DS2 -VASc score (Spearman coefficient 0.261, P < 0.001). In multivariate analysis, after adjusting for confounding factors, CHADS2 and CHA2 DS2 -VASc scores ≥2 were independently associated with CAD. The CHA2 DS2 -VASc score was a better predictor of the presence of CAD than the CHADS2 score on area under the curve analysis.

CONCLUSION
CHADS2 and CHA2 DS2 -VASc scores were predictive of the presence and severity of CAD in patients with stroke. When a patient has high CHADS2 or CHA2 DS2 -VASc scores, physicians should consider coronary artery evaluation.

Cha|M-J|MJ|
Lee|H S|HS|
Kim|Y D|YD|
Nam|H S|HS|
Heo|J H|JH|

coronary artery disease
stroke
CHADS2 score
CHA2DS2-VAScscore


The avian W chromosome is a refugium for endogenous retroviruses with likely effects on female-biased mutational load and genetic incompatibilities.

Abstract: It is a broadly observed pattern that the non-recombining regions of sex-limited chromosomes (Y and W) accumulate more repeats than the rest of the genome, even in species like birds with a low genome-wide repeat content. Here, we show that in birds with highly heteromorphic sex chromosomes, the W chromosome has a transposable element (TE) density of greater than 55% compared to the genome-wide density of less than 10%, and contains over half of all full-length (thus potentially active) endogenous retroviruses (ERVs) of the entire genome. Using RNA-seq and protein mass spectrometry data, we were able to detect signatures of female-specific ERV expression. We hypothesize that the avian W chromosome acts as a refugium for active ERVs, probably leading to female-biased mutational load that may influence female physiology similar to the 'toxic-Y' effect in Drosophila males. Furthermore, Haldane's rule predicts that the heterogametic sex has reduced fertility in hybrids. We propose that the excess of W-linked active ERVs over the rest of the genome may be an additional explanatory variable for Haldane's rule, with consequences for genetic incompatibilities between species through TE/repressor mismatches in hybrids. Together, our results suggest that the sequence content of female-specific W chromosomes can have effects far beyond sex determination and gene dosage. This article is part of the theme issue 'Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part II)'.

Peona|Valentina|V|
Palacios-Gimenez|Octavio M|OM|
Blommaert|Julie|J|
Liu|Jing|J|
Haryoko|Tri|T|
Jønsson|Knud A|KA|
Irestedt|Martin|M|
Zhou|Qi|Q|
Jern|Patric|P|
Suh|Alexander|A|

W chromosome
sex chromosome
transposable element
Haldane's rule
endogenous retrovirus
transcriptome


Pseudotumor cerebri syndrome causing a terson like syndrome.

Abstract:
Purpose
Terson syndrome presents with retinal and vitreous hemorrhages in patients with a subarachnoid hemorrhage or after acutely elevated intracranial pressure. The source of this hemorrhage has been debated and may originate either from direct extension of intracranial hemorrhage or more likely from the peripapillary retinal vessels.

Observations
A 39-year-old woman presenting with nausea, vomiting, floaters and papilledema with normal neuroimaging was diagnosed ultimately with pseudotumor cerebri syndrome. She had a right vitreous hemorrhage and bilateral subretinal and intraretinal hemorrhages which were consistent with Terson like syndrome. Her symptoms resolved with acetazolamide over one month and the retinal and vitreous hemorrhages significantly improved over two months.

Conclusions and importance
This case with initial presentation of pseudotumor cerebri syndrome causing a Terson like syndrome may help elucidate the mechanism behind the etiology of these hemorrhages from leaking peripapillary vessels.

Pseudotumor cerebri syndrome
Terson syndrome
Vitreous Hemorrhage
Vitreous Hemorrhage
Papilledema
Idiopathic intracranial hypertension
Vitreous hemorrhage


Continuous Positive Airway Pressure Improves Quality of Life in Women with Obstructive Sleep Apnea. A Randomized Controlled Trial.

Abstract:
RATIONALE
Continuous positive airway pressure (CPAP) is the treatment of choice in patients with symptomatic obstructive sleep apnea (OSA). CPAP treatment improves quality of life (QoL) in men with OSA, but its role in women has not yet been assessed.

OBJECTIVES
To investigate the effect of CPAP on QoL in women with moderate to severe OSA.

METHODS
We conducted a multicenter, open-label randomized controlled trial in 307 consecutive women diagnosed with moderate to severe OSA (apnea-hypopnea index, ≥15) in 19 Spanish sleep units. Women were randomized to receive effective CPAP therapy (n = 151) or conservative treatment (n = 156) for 3 months. The primary endpoint was the change in QoL based on the Quebec Sleep Questionnaire. Secondary endpoints included changes in daytime sleepiness, mood state, anxiety, and depression. Data were analyzed on an intention-to-treat basis with adjustment for baseline values and other relevant clinical variables.

MEASUREMENTS AND MAIN RESULTS
The women in the study had a mean (SD) age of 57.1 (10.1) years and a mean (SD) Epworth Sleepiness Scale score of 9.8 (4.4), and 77.5% were postmenopausal. Compared with the control group, the CPAP group achieved a significantly greater improvement in all QoL domains of the Quebec Sleep Questionnaire (adjusted treatment effect between 0.53 and 1.33; P < 0.001 for all domains), daytime sleepiness (-2.92; P < 0.001), mood state (-4.24; P  = 0.012), anxiety (-0.89; P = 0.014), depression (-0.85; P = 0.016), and the physical component summary of the 12-item Short Form Health Survey (2.78; P = 0.003).

CONCLUSIONS
In women with moderate or severe OSA, 3 months of CPAP therapy improved QoL, mood state, anxiety and depressive symptoms, and daytime sleepiness compared with conservative treatment. Clinical trial registered with www.clinicaltrials.gov (NCT02047071).

D045422:Continuous Positive Airway Pressure

D006970:Disorders of Excessive Somnolence

continuous positive airway pressure
quality of life
women
obstructive sleep apnea
Quebec Sleep Questionnaire


Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09).

Abstract:
BACKGROUND
There is evidence linking metformin to improved prostate cancer (PCa)-related outcomes.

OBJECTIVE
To evaluate treatment with metformin in patients with castration-resistant PCa (CRPC) and the effect of the treatment on progression-free survival (PFS) and PSA doubling time (PSA DT).

DESIGN, SETTING, AND PARTICIPANTS
Forty-four men with progressive metastatic CRPC from 10 Swiss centers were included in this single-arm phase 2 trial between December 2010 and December 2011.

INTERVENTION
Patients received metformin 1000 mg twice daily until disease progression.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The primary end point was the absence of disease progression at 12 wk. Simon two-stage optimal design was applied. With a 5% significance level and 90% power, 44 patients were required to test PFS at 12 wk ≤ 15% (H0) compared with ≥ 35% (H1).

RESULTS AND LIMITATIONS
Thirty-six percent of patients were progression-free at 12 wk, 9.1% were progression-free at 24 wk, and in two patients a confirmed ≥ 50% prostate-specific antigen (PSA) decline was demonstrated. In 23 patients (52.3%) we observed a prolongation of PSA DT after starting metformin. The homeostatic model assessment index fell by 26% from baseline to 12 wk, indicating an improvement in insulin sensitivity. There was a significant change in insulin-like growth factor-1 and insulin-like growth factor binding protein 3 from baseline to 12 wk. Sample size and lack of a control arm are the limitations of this trial; analyses are therefore exploratory.

CONCLUSIONS
Treatment with metformin is safe in nondiabetic patients, and it yields objective PSA responses and may induce disease stabilization. The activity of metformin in PCa, along with its low cost, favorable toxicity profile, and positive effect on metabolic parameters, suggests that further investigation of metformin as therapy for patients with PCa is of interest.

PATIENT SUMMARY
In this trial we assessed the use of the diabetes mellitus drug metformin in patients with advanced prostate cancer. We found disease stabilization and prolongation of prostate-specific antigen doubling time in some patients as well as effects on metabolic parameters.

TRIAL REGISTRATION
This study is registered with ClinicalTrials.gov with the identifier NCT01243385.

PREVIOUS PRESENTATION
The study was presented at ESMO 2012 (abstract 1460).

Rothermundt|Christian|C|
Hayoz|Stefanie|S|
Templeton|Arnoud J|AJ|
Winterhalder|Ralph|R|
Strebel|Räto T|RT|
Bärtschi|Daniela|D|
Pollak|Michael|M|
Lui|Lillianne|L|
Endt|Kathrin|K|
Schiess|Ralph|R|
Rüschoff|Jan H|JH|
Cathomas|Richard|R|
Gillessen|Silke|S|

D018972:Insulin-Like Growth Factor Binding Protein 3

Metformin
Castration-resistant prostate cancer
Metabolic parameters


Risk of Hepatitis B Virus Reactivation in Rheumatoid Arthritis Patients Undergoing Tocilizumab-Containing Treatment.

Abstract:
BACKGROUND AND AIM
To investigate the risk of hepatitis B virus reactivation in patients undergoing long-term tocilizumab therapy for rheumatoid arthritis.

METHOD
From January 2011 through August 2019, a total of 97 patients were enrolled in this retrospective study. Clinical data, comedications, and the occurrence of HBV reactivation were recorded.

RESULTS
Seven patients were HBsAg+ (7.2%), 64 were HBsAg-/HBcAb+ (65.9%), and 26 were HBsAg-/HBcAb- (26.8%). The median disease follow-up time was 9 years. TCZ was administered for a median of 29 months. Four patients (4.1%) experienced HBV reactivation after tocilizumab therapy. Of the 7 HBsAg+ patients, 4 received antiviral prophylaxis and had no HBV reactivation; the remaining 3 patients did not receive antiviral prophylaxis, and all 3 (100%) experienced HBV reactivation and hepatitis flare-up. Hyperbilirubinemia occurred in 2 of these 3 patients, with mild prothrombin time prolongation in one. After salvage entecavir treatment, all patients had a favorable outcome. Of the 64 HBsAg-/HBcAb+ patients, only one became positive for serum HBV DNA (2.5 × 107 IU/mL) after 18 months of tocilizumab treatment (1.6%; 1/64). This patient was immediately treated with entecavir, which prevented hepatitis flare-up.

CONCLUSIONS
Tocilizumab is widely used in treating rheumatoid arthritis and has the potential to reduce the mortality rate among severe COVID-19 patients. However, HBV reactivation needs to be considered. HBsAg+ patients have a high risk of HBV reactivation, which could be prevented by antiviral prophylaxis. Although the risk of reactivation is low in HBsAg-/HBcAb+ patients, strict monitoring is necessary.

Kuo|Meng Hsuan|MH|
Tseng|Chih-Wei|CW|0000-0002-6951-4646
Lu|Ming-Chi|MC|
Tung|Chien-Hsueh|CH|
Tseng|Kuo-Chih|KC|
Huang|Kuang-Yung|KY|
Lee|Chi-Hui|CH|
Lai|Ning-Sheng|NS|

Rheumatoid arthritis
Tocilizumab
HBV reactivation
Hepatitis flare-up


A comparative evaluation of migration sedimentation method for sperm preparation.

Abstract: The effectiveness of semen preparation using the migration-sedimentation (MS) method was evaluated, and compared to density gradient centrifuge and swim-up combination (DGC+SU). Sperm selection using MS is based on motility, thus, deleterious effects for which centrifugation has been blamed, are believed to be avoided. Normozoospermic male patients who had more than 10% forward progressive motile sperm in their ejaculate were included in the study. Spermatozoa selected by two different methods were investigated and compared according to sperm motility, concentration, morphology, vitality, DNA fragmentation, and presence of persistent histones. The concentration and motility of sperm in the MS group was improved when compared to the DGC+SU group, but the difference between groups was not significant. The proportion of sperm with normal morphology was found to be 12.19 ± 6.45% vs. 10.67 ± 5.44%, vitality rate was 74.09 ± 16.65% vs. 70.45 ± 16.78%, DNA fragmentation rate was 3.91 ± 3.96%, vs. 2.95 ± 3.33%, presence of persistent histone proportion was 10.59 ± 13.40%, vs. 8.86 ± 7.89% in DGC+SU and MS groups respectively, without significance. The simple technique avoids centrifuge-based damage.

migration-sedimentation
Centrifugation
sperm selection
in vitro fertilization
infertility


Evaluation of antioxidant capacity of Chinese five-spice ingredients.

Abstract: Phenolic compounds in spices were reportedly found to possess high antioxidant capacities (AOCs), which may prevent or reduce risk of human diseases such as cardiovascular disease, cancer and diabetes. The potential AOC of Chinese five-spice powder (consist of Szechuan pepper, fennel seed, cinnamon, star anise and clove) with varying proportion of individual spice ingredients was investigated through four standard methods. Our results suggest that clove is the major contributor to the AOC of the five-spice powder whereas the other four ingredients contribute to the flavour. For example, the total phenolic content as well as ferric reducing antioxidant power (FRAP), Trolox equivalent antioxidant capacity (TEAC) and oxygen radical absorbance capacity (ORAC) values increased linearly with the clove percentage in five-spice powder. This observation opens the door to use clove in other spice mixtures to increase their AOC and flavour. Moreover, linear relationships were also observed between AOC and the total phenolic content of the 32 tested spice samples.

Bi|Xinyan|X|
Soong|Yean Yean|YY|
Lim|Siang Wee|SW|
Henry|Christiani Jeyakumar|CJ|

Antioxidant
Chinese five-spice powder
total phenolic content
FRAP
TEAC
ORAC