Sphingosine-1-phosphate inhibits IL-1-induced expression of C-C motif ligand 5 via c-Fos-dependent suppression of IFN-β amplification loop.

Abstract: The neuroinflammation associated with multiple sclerosis involves activation of astrocytes that secrete and respond to inflammatory mediators such as IL-1. IL-1 stimulates expression of many chemokines, including C-C motif ligand (CCL) 5, that recruit immune cells, but it also stimulates sphingosine kinase-1, an enzyme that generates sphingosine-1-phosphate (S1P), a bioactive lipid mediator essential for inflammation. We found that whereas S1P promotes IL-1-induced expression of IL-6, it inhibits IL-1-induced CCL5 expression in astrocytes. This inhibition is mediated by the S1P receptor (S1PR)-2 via an inhibitory G-dependent mechanism. Consistent with this surprising finding, infiltration of macrophages into sites of inflammation increased significantly in S1PR2(-/-) animals. However, activation of NF-κB, IFN regulatory factor-1, and MAPKs, all of which regulate CCL5 expression in response to IL-1, was not diminished by the S1P in astrocytes. Instead, S1PR2 stimulated inositol 1,4,5-trisphosphate-dependent Ca(++) release and Elk-1 phosphorylation and enhanced c-Fos expression. In our study, IL-1 induced the IFNβ production that supports CCL5 expression. An intriguing finding was that S1P induced c-Fos-inhibited CCL5 directly and also indirectly through inhibition of the IFN-β amplification loop. We propose that in addition to S1PR1, which promotes inflammation, S1PR2 mediates opposing inhibitory functions that limit CCL5 expression and diminish the recruitment of immune cells.

Yester|Jessie W|JW|
Bryan|Lauren|L|
Waters|Michael R|MR|
Mierzenski|Bartosz|B|
Biswas|Debolina D|DD|
Gupta|Angela S|AS|
Bhardwaj|Reetika|R|
Surace|Michael J|MJ|
Eltit|Jose M|JM|
Milstien|Sheldon|S|
Spiegel|Sarah|S|
Kordula|Tomasz|T|


Atomistic Insight into Glide-Driven Phase Transformations in Layered Oxides for Sodium-Ion Batteries: A Case Study on Na xVO2.

Abstract: Among high-capacity, low-cost cathode contenders for Na-ion batteries, layered transition-metal oxides are particularly promising materials. Yet there is a strong need to improve their long-term stability and capacity retention due to unwanted phase transitions occurring during sodium insertion and extraction cycles. Here, using density functional theory calculations and thoroughly examining P ↔ O transitions in Na xVO2 as a case study, we provide atomic-level understanding into the glide-driven processes in these compounds. In particular, we rationalize the commonly observed effect of high Na contents on preventing gliding processes at low states of charge. And we identify the beneficial impact of Na ions at face-shared prismatic sites in P-type phases to specifically hinder P → O transitions. We put forward that the gained new insights can help to focus and guide the current research efforts to design layered transition-metal oxides with enhanced long-term stability for practical applications.

Na-ion batteries
phase transition
density functional theory
layered materials
positive electrodes
sodium-layered transition-metal oxides


Enacting global health in the nursing classroom.

Abstract: Globalization presents nurses with the challenges and an ethical responsibility of being competent caregivers within a global society. The link between globalization and global health, and the contributions nursing can make to the global health environment are described in the delivery of a new required course for undergraduate nursing students in a four year degree program. Innovative approaches for the delivery of this course are described, which even though living locally, can encourage nursing students to think globally. The need for nursing programs to acknowledge the shared responsibilities for examining global health challenges is now part of our reality in many countries.

Global health
Global social justice
Undergraduate nursing education


Behavioral responses to encounter of fishing boats in wandering albatrosses.

Abstract: Animals are attracted to human food subsidies worldwide. The behavioral response of individuals to these resources is rarely described in detail, beyond chances of encounters. Seabirds for instance scavenge in large numbers at fishing boats, triggering crucial conservation issues, but how the response to boats varies across encounters is poorly known. Here we examine the behavioral response of wandering albatrosses (Diomedea exulans), equipped with GPS tags, to longline fishing boats operating near their colony for which we had access to vessel monitoring system data. We distinguish between encounters (flying within 30 km of a boat) and attendance behavior (sitting on the sea within 3 km of a boat), and examine factors affecting each. In particular, we test hypotheses that the response to encountered boats should vary with sex and age in this long-lived dimorphic species. Among the 60% trips that encountered boats at least once, 80% of them contained attendance (but attendance followed only 60% of each single encounter). Birds were more attracted and remained attending longer when boats were hauling lines, despite the measures enforced by this fleet to limit food availability during operations. Sex and age of birds had low influence on the response to boats, except the year when fewer boats came fishing in the area, and younger birds were attending further from boats compared to older birds. Net mass gain of birds was similar across sex and not affected by time spent attending boats. Our results indicate albatrosses extensively attend this fishery, with no clear advantages, questioning impacts on foraging time budgets. Factors responsible for sex foraging segregation at larger scale seem not to operate at this fleet near the colony and are not consistent with predictions of optimal foraging theory on potential individual dominance asymmetries. This approach complements studies of large-scale overlap of animals with human subsidies.

Collet|Julien|J|
Patrick|Samantha C|SC|
Weimerskirch|Henri|H|

seabirds
vessel monitoring system
fisheries
competition
foraging decisions
movement ecology


2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

Abstract: To develop response criteria for juvenile dermatomyositis (DM). We analysed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural history data and a conjoint analysis survey. They were further validated using data from the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis (RIM) trial. At a consensus conference, experts considered 14 top candidate criteria based on their performance characteristics and clinical face validity, using nominal group technique. Consensus was reached for a conjoint analysis-based continuous model with a total improvement score of 0-100, using absolute per cent change in core set measures of minimal (≥30), moderate (≥45), and major (≥70) improvement. The same criteria were chosen for adult DM/polymyositis, with differing thresholds for improvement. The sensitivity and specificity were 89% and 91-98% for minimal improvement, 92-94% and 94-99% for moderate improvement, and 91-98% and 85-86% for major improvement, respectively, in juvenile DM patient cohorts using the IMACS and PRINTO core set measures. These criteria were validated in the PRINTO trial for differentiating between treatment arms for minimal and moderate improvement (p=0.009-0.057) and in the RIM trial for significantly differentiating the physician's rating for improvement (p<0.006). The response criteria for juvenile DM consisted of a conjoint analysis-based model using a continuous improvement score based on absolute per cent change in core set measures, with thresholds for minimal, moderate, and major improvement.

D016032:Randomized Controlled Trials as Topic


The association between child maltreatment and adult poverty - A systematic review of longitudinal research.

Abstract: Child maltreatment is a global problem affecting millions of children and is associated with an array of cumulative negative outcomes later in life, including unemployment and financial difficulties. Although establishing child maltreatment as a causal mechanism for adult economic outcomes is fraught with difficulty, understanding the relationship between the two is essential to reducing such inequality. This paper presents findings from a systematic review of longitudinal research examining experiences of child maltreatment and economic outcomes in adulthood. A systematic search of seven databases found twelve eligible retrospective and prospective cohort studies. From the available evidence, there was a relatively clear relationship between 'child maltreatment' and poorer economic outcomes such as reduced income, unemployment, lower level of job skill and fewer assets, over and above the influence of family of origin socio-economic status. Despite an extremely limited evidence base, neglect had a consistent relationship with a number of long-term economic outcomes, while physical abuse has a more consistent relationship with income and employment. Studies examining sexual abuse found less of an association with income and employment, although they did find a relationship other outcomes such as sickness absence, assets, welfare receipt and financial insecurity. Nonetheless, all twelve studies showed some association between at least one maltreatment type and at least one economic measure. The task for future research is to clarify the relationship between specific maltreatment types and specific economic outcomes, taking account of how this may be influenced by gender and life course stage.

Bunting|Lisa|L| Davidson|Gavin|G| McCartan|Claire|C| Hanratty|Jennifer|J| Bywaters|Paul|P| Mason|Will|W| Steils|Nicole|N|

Child maltreatment
Poverty
Systematic review
Longitudinal
Adult economic outcomes
Childhood adversity
Welfare inequalities


Athletic identity and self-esteem among active and retired Paralympic athletes.

Abstract: Athletic identity (AI) has been suggested as a variable that can have an impact on the psychological health of the athletes upon retirement. The aim of this study was to provide more insight on the transition out of elite sport by assessing and comparing the extent of AI and self-esteem in an active group (AG) and a retired group (RG) of Paralympic athletes. Perceived stress and depressive symptoms were additionally assessed in the AG and RG, respectively. A non-probability sampling method was used to recruit active and retired Paralympic athletes (AG, n = 43; RG, n = 41, where 35 retired voluntarily and 6 retired involuntarily) with visual or physical impairments, from Dutch-, English-, Portuguese- and Spanish-speaking countries. Participants completed an electronic survey with questionnaires to assess the study variables mentioned above. Descriptive analysis, comparisons (Mann-Whitney U test and t-test) and Spearman's correlation coefficient were performed for the statistical analysis. Scores of AI were significantly lower in the RG (44.6 ± 9.6) compared to the AG (49.4 ± 8.9); t(82) = 2.36, p = .021, d = 0.51. No differences in self-esteem were found between RG and AG; however, within the RG, athletes who involuntarily retired (21 ± 7.1) had significantly lower self-esteem scores than those who retired voluntarily (25.2 ± 4.2); t(39) = 2.04, p = .049, d = 0.73. In conclusion, free choice upon retirement can positively influence the athletes' self-esteem, whereas a strong AI may negatively influence the retirement process, as it was positively correlated with depressive symptoms (ρ = .409, p = .008). These findings can have practical implications for sport psychologists to better support their athletes.

Marin-Urquiza|Adriana|A|
Ferreira|José Pedro|JP|
Van Biesen|Debbie|D|

self-esteem
retirement
Disability sport
emotional problems
transition out of sport


Shexiang Baoxin Pill, a Proprietary Multi-Constituent Chinese Medicine, Prevents Locomotor and Cognitive Impairment Caused by Brain Ischemia and Reperfusion Injury in Rats: A Potential Therapy for Neuropsychiatric Sequelae of Stroke.

Abstract: Ischemic stroke is a common type of cerebrovascular event and also the leading cause of disability. Post-stroke cognitive impairment occurs frequently in stroke survivors. Shexiang Baoxin Pill (SBP) is a proprietary Chinese medicine, initially used to treat cardiovascular diseases. Herein, we aim to explore the effects of SBP on oxygen glucose deprivation and reoxygenation (OGD/R) in neuronal cells (CATH.a) and cerebral ischemia/reperfusion injury induced post-stroke cognitive impairment in middle cerebral artery occlusion (MCAO) rat model. MCAO rats received two doses of oral SBP treatment (28 or 56 mg/kg) after 1 h of operation and once daily for 2 weeks continuously. Behavioral tests, immunoblotting, and immunofluorescence were examined after 14 days. Current data suggest that SBP enhanced cell viability and downregulated apoptosis via activating the PI3K/Akt signaling pathway in CATH. a cells. Furthermore, 14 days of SBP treatment promoted the recovery of learning and locomotor function in the MCAO rats. SBP up-regulated the expression of p-Akt, p-GSK3β, as well as the expression of NMDAR1, PSD-95, and AMPAR. Also, SBP down-regulated the expression of p-CaMKII. These results indicated that long-term SBP treatment might be a potential option for cognitive impairment induced by the ischemic stroke.

Qin|Zong-Shi|ZS|
Zheng|Yu|Y|
Zhou|Xi-Dan|XD|
Shi|Dong-Dong|DD|
Cheng|Dan|D|
Shek|Chun Shum|CS|
Zhan|Chang-Sen|CS|
Zhang|Zhang-Jin|ZJ|

shexiang baoxin pill
ischemic stroke
middle cerebral artery occlusion
locomotor ability
post stroke cognitive impairment


Perisylvian GABA levels in schizophrenia and bipolar disorder.

Abstract: The aim of this study is to measure GABA levels of perisylvian cortices in schizophrenia and bipolar disorder patients, using proton magnetic resonance spectroscopy (1H-MRS). Patients with schizophrenia (n=25), bipolar I disorder (BD-I; n=28) and bipolar II disorder (BD-II; n=20) were compared with healthy controls (n=30). 1H-MRS data was acquired using a Siemens 3T whole body scanner to quantify right and left perisylvian structures' (including superior temporal lobes) GABA levels. Right perisylvian GABA values differed significantly between groups [χ2=9.62, df: 3, p=0.022]. GABA levels were significantly higher in the schizophrenia group compared with the healthy control group (p=0.002). Furthermore, Chlorpromazine equivalent doses of antipsychotics correlated with right hemisphere GABA levels (r2=0.68, p=0.006, n=33). GABA levels are elevated in the right hemisphere in patients with schizophrenia in comparison to bipolar disorder and healthy controls. The balance between excitatory and inhibitory controls over the cortical circuits may have direct relationship with GABAergic functions in auditory cortices. In addition, GABA levels may be altered by brain regions of interest, psychotropic medications, and clinical stage in schizophrenia and bipolar disorder.

Atagün|Murat İlhan|Mİ|
Şıkoğlu|Elif Muazzez|EM|
Soykan|Çağlar|Ç|
Serdar Süleyman|Can|C|
Ulusoy-Kaymak|Semra|S|
Çayköylü|Ali|A|
Algın|Oktay|O|
Phillips|Mary Louise|ML|
Öngür|Dost|D|
Moore|Constance Mary|CM|

D066244:Proton Magnetic Resonance Spectroscopy

GABA
Schizophrenia
Bipolar disorder
Magnetic resonance spectroscopy
Auditory cortex


COVID-19 Infection and Neurological Complications: Present Findings and Future Predictions.

Abstract: The present outbreak caused by SARS-CoV-2, an influenza virus with neurotropic potential, presents with neurological manifestations in a large proportion of the affected individuals. Disorders of the central and peripheral nervous system are all present, while stroke, ataxia, seizures, and depressed level of consciousness are more common in severely affected patients. People with these severe complications are most likely elderly with medical comorbidities, especially hypertension and other vascular risk factors. However, postinfectious complications are also expected. Neurological disorders as sequelae of influenza viruses have been repeatedly documented in the past and include symptoms, signs, and diseases occurring during the acute phase and, not rarely, during follow-up. Postinfectious neurological complications are the result of the activation of immune mechanisms and can explain the insurgence of immune-mediated diseases, including the Guillain-Barré syndrome and other diseases of the central and peripheral nervous system that in the past occurred as complications of viral infections and occasionally with vaccines. For these reasons, the present outbreak calls for the introduction of surveillance systems to monitor changes in the frequency of several immune-mediated neurological diseases. These changes will determine a reorganization of the measures apt to describe the interaction between the virus, the environment, and the host in areas of different dimensions, from local communities to regions with several millions of inhabitants. The public health system, mainly primary care, needs to be strengthened to ensure that research and development efforts are directed toward right needs and directions. To cope with the present pandemic, better collaboration is required between international organizations along with more research funding, and tools in order to detect, treat, and prevent future epidemics.

Beghi|Ettore|E| Feigin|Valery|V| Caso|Valeria|V| Santalucia|Paola|P| Logroscino|Giancarlo|G|

Infection
Outbreak
Neurological disorders
Coronavirus


Brain Asymmetry Detection and Machine Learning Classification for Diagnosis of Early Dementia.

Abstract: Early identification of degenerative processes in the human brain is considered essential for providing proper care and treatment. This may involve detecting structural and functional cerebral changes such as changes in the degree of asymmetry between the left and right hemispheres. Changes can be detected by computational algorithms and used for the early diagnosis of dementia and its stages (amnestic early mild cognitive impairment (EMCI), Alzheimer's Disease (AD)), and can help to monitor the progress of the disease. In this vein, the paper proposes a data processing pipeline that can be implemented on commodity hardware. It uses features of brain asymmetries, extracted from MRI of the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, for the analysis of structural changes, and machine learning classification of the pathology. The experiments provide promising results, distinguishing between subjects with normal cognition (NC) and patients with early or progressive dementia. Supervised machine learning algorithms and convolutional neural networks tested are reaching an accuracy of 92.5% and 75.0% for NC vs. EMCI, and 93.0% and 90.5% for NC vs. AD, respectively. The proposed pipeline offers a promising low-cost alternative for the classification of dementia and can be potentially useful to other brain degenerative disorders that are accompanied by changes in the brain asymmetries.

brain asymmetry
asymmetry detection
dementia
SVM
brain MRI
deep learning
machine learning methods


Retinal lesions induce fast intrinsic cortical plasticity in adult mouse visual system.

Abstract: Neuronal activity plays an important role in the development and structural-functional maintenance of the brain as well as in its life-long plastic response to changes in sensory stimulation. We characterized the impact of unilateral 15° laser lesions in the temporal lower visual field of the retina, on visually driven neuronal activity in the afferent visual pathway of adult mice using in situ hybridization for the activity reporter gene zif268. In the first days post-lesion, we detected a discrete zone of reduced zif268 expression in the contralateral hemisphere, spanning the border between the monocular segment of the primary visual cortex (V1) with extrastriate visual area V2M. We could not detect a clear lesion projection zone (LPZ) in areas lateral to V1 whereas medial to V2M, agranular and granular retrosplenial cortex showed decreased zif268 levels over their full extent. All affected areas displayed a return to normal zif268 levels, and this was faster in higher order visual areas than in V1. The lesion did, however, induce a permanent LPZ in the retinorecipient layers of the superior colliculus. We identified a retinotopy-based intrinsic capacity of adult mouse visual cortex to recover from restricted vision loss, with recovery speed reflecting the areal cortical magnification factor. Our observations predict incomplete visual field representations for areas lateral to V1 vs. lack of retinotopic organization for areas medial to V2M. The validation of this mouse model paves the way for future interrogations of cortical region- and cell-type-specific contributions to functional recovery, up to microcircuit level.

Smolders|Katrien|K|
Vreysen|Samme|S|
Laramée|Marie-Eve|ME|
Cuyvers|Annemie|A|
Hu|Tjing-Tjing|TT|
Van Brussel|Leen|L|
Eysel|Ulf T|UT|
Nys|Julie|J|
Arckens|Lutgarde|L|

superior colliculus
immediate early gene
molecular activity
visual cortex plasticity


New Insights on the Role of the pLMST6 Plasmid in Listeria monocytogenes Biocide Tolerance and Virulence.

Abstract: Listeria monocytogenes the causative agent of listeriosis is an important public health concern and food safety challenge. Increased tolerance of this bacterium to benzalkonium chloride (BC), an antibacterial agent widely used in industrial settings, is a growing issue. Plasmid pLMST6 harboring the gene of the multidrug efflux pump protein EmrC has been recently linked to enhanced BC tolerance and meningitis due to L. monocytogenes ST6 strains. In this study, occurrence and contribution of this plasmid to BC tolerance was examined using PCR, plasmid curing and transformation, RT-qPCR and proteome analysis, respectively. Furthermore, the substrate specificity of the pLMST6 associated EmrC efflux pump and the impact of the plasmid on L. monocytogenes virulence were investigated. pLMST6 was detected in 7 (1.6%) of 439 L. monocytogenes strains isolated from different sources. A phenotypic role of this plasmid in conferring increased BC tolerance was confirmed by showing that plasmid cure increases BC susceptibility whereas plasmid complementation and transformation increased BC tolerance in different L. monocytogenes genetic backgrounds and L. innocua. RT-qPCR showed that BC stress exposure strongly induces the expression of mRNAs associated with pLMST6 genes for EmrC and a TetR transcription regulator. A full proteome analysis in a plasmid harboring L. monocytogenes strain revealed that the pLMST6 encoded putative TetR family transcription regulator protein is the most upregulated protein in response to BC stress exposure. An investigation into the EmrC efflux pump's substrate spectrum showed that while pLMST6 confers increased tolerance to other quaternary ammonium compounds (QACs) based disinfectants it has no impact on the sensitivity of L. monocytogenes to non-QAC disinfectants as well as on antibiotics such as ampicillin, tetracycline and gentamicin. A reduction in the survival of zebrafish embryos infected with pLMST6 plasmid harboring L. monocytogenes strains was observed when compared with plasmid cured variants of the same strains suggesting that some pLMST6 harbored genes might contribute to increased virulence capacity. Overall these results confirm the phenotypic contribution of pLMST6 plasmid in promoting and dissemination of BC tolerance in L. monocytogenes as well as provide new insights on different molecular levels of pLMST6 associated genes in response to BC stress.

Kropac|Alexandra C|AC|
Eshwar|Athmanya K|AK|
Stephan|Roger|R|
Tasara|Taurai|T|

pLMST6
plasmid
Listeria monocytogenes
biocide
benzalkonium chloride
emrC
quaternary ammonium compound


Macroporous natural capsules extracted from Phoenix dactylifera L. spore and their application in oral drugs delivery.

Abstract: Macroporous natural sporopollenin exine capsules (SEC) were extracted from date palm (Phoenix dactylifera L.) and coated by natural polymer composite (carboxymethyl cellulose with epichlorohydrin). The polymer coated exine capsules (PCEC) were used in in-vitro investigations for controlled delivery of paracetamol. SEC, PCEC, and drugs loaded capsules (PCEC-PAR) were characterized by scanning electron microscope (SEM), surface area (BET), Fourier-transform infrared (FT-IR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The length of SEC was found to be 20-20.5 μm, and the pore sized was 50-135 nm, as measured using SEM. The studies revealed that maximum loading of the drug was at pH 6.0 (97.2%, with 50 mg mL(-1)). The results indicate that by increasing the pH from 1.4 to 7.4, the cumulative release rates of paracetamol in physiological buffer solution (PBS) is more than two times as in simulated gastric fluid (SGF). In addition, the in-vitro toxicity of PCEC against Caco-2 cells was tested by the 3-[4,5-dimethylthiazole-2-yl]-2,5 diphenyltetrazolium bromide (MTT) assay, and the results revealed that PCEC are biocompatible materials. The overall results encourage further studies on the clinical use of PCEC as drug carriers.

Alshehri|Saad M|SM|
Al-Lohedan|Hamad A|HA|
Al-Farraj|Eida|E|
Alhokbany|Norah|N|
Chaudhary|Anis Ahmad|AA|
Ahamad|Tansir|T|

Drugs delivery
Sporopollenin
Paracetamol
X-ray diffraction
FTIR


Green Revolution research saved an estimated 18 to 27 million hectares from being brought into agricultural production.

Abstract: New estimates of the impacts of germplasm improvement in the major staple crops between 1965 and 2004 on global land-cover change are presented, based on simulations carried out using a global economic model (Global Trade Analysis Project Agro-Ecological Zone), a multicommodity, multiregional computable general equilibrium model linked to a global spatially explicit database on land use. We estimate the impact of removing the gains in cereal productivity attributed to the widespread adoption of improved varieties in developing countries. Here, several different effects--higher yields, lower prices, higher land rents, and trade effects--have been incorporated in a single model of the impact of Green Revolution research (and subsequent advances in yields from crop germplasm improvement) on land-cover change. Our results generally support the Borlaug hypothesis that increases in cereal yields as a result of widespread adoption of improved crop germplasm have saved natural ecosystems from being converted to agriculture. However, this relationship is complex, and the net effect is of a much smaller magnitude than Borlaug proposed. We estimate that the total crop area in 2004 would have been between 17.9 and 26.7 million hectares larger in a world that had not benefited from crop germplasm improvement since 1965. Of these hectares, 12.0-17.7 million would have been in developing countries, displacing pastures and resulting in an estimated 2 million hectares of additional deforestation. However, the negative impacts of higher food prices on poverty and hunger under this scenario would likely have dwarfed the welfare effects of agricultural expansion.

Stevenson|James R|JR|
Villoria|Nelson|N|
Byerlee|Derek|D|
Kelley|Timothy|T|
Maredia|Mywish|M|

agricultural productivity
land-use change


Improvement in patient-reported outcomes in Chinese adults after bariatric surgery: 1-year follow-up of a prospective cohort.

Abstract:
BACKGROUND
Impaired health-related quality of life is commonly observed in patients with obesity who are scheduled for bariatric surgery. However, bariatric surgery tends to improve quality of life physically, with no final conclusion regarding mental domains.

OBJECTIVE
To assess changes of patient-reported outcomes in terms of health-related quality of life, depression, anxiety status, and physical activity (PA) after bariatric surgery among patients with obesity.

SETTINGS
Queen Mary Hospital, Tung Wah Hospital, and United Christian Hospital, Hong Kong SAR; a longitudinal study.

METHODS
A multicenter, prospective, observational cohort study was conducted in Hong Kong between 2017 and 2018. Follow-up interviews at 1, 3, 6, and 12 months postoperatively were administrated via telephone. Short Form-12 Health Survey Version 2, Euroqol 5-dimension-5-level, and Impact of Weight on Quality of Life-Lite were used to assess health-related quality of life. Scores of anxiety and depression were evaluated by Hospital Anxiety and Depression Scale. Walking, moderate, and vigorous metabolic equivalent tasks and PA levels were measured by International Physical Activity Questionnaire-Short Form. Demographic and clinical characteristics, including age, sex, body mass index, and preexisting co-morbidities at baseline were collected. Comparisons of scores were made between baseline and 12 months using paired t test or McNemar test.

RESULTS
A total of 25 patients who have received bariatric surgery (laparoscopic sleeve gastrectomy: 96%; laparoscopic gastric bypass: 4%) and 25 control patients matched using propensity scores derived by baseline covariates were involved. Significant improvements were observed in health-related quality of life regarding physical functioning (P < .001), role physical (P = .013), bodily pain (P = .011), general health (P < .011), vitality (P = .029), social functioning (P = .017), and physical composite summary (P < .001) of Short Form-12 Health Survey Version 2 from baseline to follow-up 12 months after surgery. Scores of physical composite summary, mental composite summary, and Short Form-6 D of surgical patients all had an overall upward trend during observation compared with those in the control group. All domains in Impact of Weight on Quality of Life-Lite were significantly higher at 12 months compared with baseline (P = .001 in sexual life domain, P < .001 in other domains). Patients experienced a decrease in depression score of Hospital Anxiety and Depression Scale 12 months after bariatric surgery (P = .026), while anxiety score was not found to differ from baseline (P = .164). No significant differences in total metabolic equivalent tasks (P = .224) and PA levels (P = .180) between baseline and 12-month follow-up were found.

CONCLUSION
After 12 months of follow-up, increase in physical quality of life, reduction in depression status and less impairment caused by weight were observed, without significant changes in anxiety score and postoperative PA.

Wei|Yihui|Y|
Wu|Tingting|T|
Tong|Daniel K H|DKH|
Law|Betty T T|BTT|
Leung|David K W|DKW|
Lam|Cindy L K|CLK|
Wong|Carlos K H|CKH|

D000071066:Patient Reported Outcome Measures

Patient-reported outcomes
Chinese
Bariatric surgery
Quality of life
Obesity
Depression
Physical activity


Lower neural value signaling in the prefrontal cortex is related to childhood family income and depressive symptomatology during adolescence.

Abstract: Lower family income during childhood is related to increased rates of adolescent depression, though the underlying mechanisms are poorly understood. Evidence suggests that individuals with depression demonstrate hypoactivation in brain regions involved in reward learning and decision-making processes (e.g., portions of the prefrontal cortex). Separately, lower family income has been associated with neural alterations in similar regions. Motivated by this research, we examined associations between family income, depression, and brain activity during a reward learning and decision-making fMRI task in a sample of adolescents (full n = 94; usable n = 78; mean age = 15.2 years). We focused on brain activity for: 1) expected value (EV), the learned subjective value of an object, and 2) prediction error, the difference between EV and the actual outcome received. Regions of interest related to reward learning were examined in connection to childhood family income and parent-reported adolescent depressive symptoms. As hypothesized, lower activity in the subgenual anterior cingulate (sACC) for EV in response to approach stimuli was associated with lower childhood family income, as well as greater symptoms of depression measured one-year after the neuroimaging session. These results are consistent with the hypothesis that lower early family income leads to disruptions in reward and decision-making brain circuitry, contributing to adolescent depression.

Palacios-Barrios|Esther E|EE|
Hanson|Jamie L|JL|
Barry|Kelly R|KR|
Albert|W Dustin|WD|
White|Stuart F|SF|
Skinner|Ann T|AT|
Dodge|Kenneth A|KA|
Lansford|Jennifer E|JE|

Prefrontal cortex
Adolescent depression
Reward learning
Decision-making
Child poverty
Socioeconomic status


Glucocorticoid-induced osteoporosis: from clinical trials to clinical practice.

Abstract: Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis. To date, six large randomized controlled clinical trials on the efficacy of pharmaceutical treatment in GIOP have been conducted. All of these studies have focused predominately on bone mineral density outcomes, and none of them have been statistically powered to address fracture endpoints. The purpose of this review is to highlight differences in the design and results within these large randomized GIOP clinical trials, and how these differences might affect clinical decisions. Differences between studies in trial design, populations studied, and variable efficacy impact the comparability and generalizability of these findings, and ultimately should affect practitioners' behavior. We review the clinical trials that provide the best quality evidence on comparative efficacy and safety of GIOP treatments. We also propose suggestions on the design of future GIOP clinical trials with attention to improved generalizability, and, ideally, study designs that might achieve fracture outcomes.

glucocorticoid-induced osteoporosis
bone
fracture
review
randomized clinical trials


Comparison of analgesic efficacy of paracetamol and tramadol for pain relief in active labor.

Abstract:
STUDY OBJECTIVE
To evaluate the efficacy and safety profile of paracetamol in comparison with tramadol for pain relief during active labor.

DESIGN
Prospective, randomized, double-blind study.

SETTING
Maternity Wing of the Postgraduate Institute of Medical Education and Research, Chandigarh.

PATIENT
Sixty laboring, primiparous, full-term parturients with uncomplicated, singleton pregnancy in spontaneous labor and cervical dilatation of 3-5 cm.

INTERVENTION
Parturients were randomized into 2 groups to receive either 1 mg/kg of tramadol intramuscularly (group T; n = 29) or 1 g of paracetamol intravenously (group P; n = 30). Same doses of the drugs were repeated after 4 hours of initial dose.

MEASUREMENT
Primary outcome of the study was to assess the analgesic efficacy of the 2 drugs as measured by visual analog scale (VAS) score. Secondary outcome recorded was duration of labor, presence of any maternal, or fetal adverse events during the study.

RESULTS
Both the groups showed comparable VAS scores at all times of observation. Lower mean VAS scores were reported in both the groups till 120 minutes only. The duration of first stage of labor was shorter in group P (248.00 ± 98.171 vs 340.63 ± 111.592 minutes; P = .003). The duration of second stage of labor was comparable between the 2 groups. Higher incidence of maternal side effects such as nausea/vomiting and sedation was associated with the use of tramadol. Neonatal outcome was comparable.

CONCLUSION
Intravenous paracetamol provides comparable analgesia as intramuscular tramadol during active labor.

Kaur Makkar|Jeetinder|J|
Jain|Kajal|K|
Bhatia|Nidhi|N|
Jain|Vanita|V|
Mal Mithrawal|Sanwar|S|

Paracetamol
Tramadol
Active labor
Side effects
Analgesia


Green methodology based on dispersive liquid-liquid microextraction and micellar electrokinetic chromatography for 5-nitroimidazole analysis in water samples.

Abstract: Dispersive liquid-liquid microextraction has been proposed as an extraction technique combined with micellar electrokinetic chromatography (MEKC) for the analysis of eight 5-nitroimidazole compounds, including some metabolites, in water samples. Determination has been carried out using a diode array detector, employing 20 mM sodium phosphate and 150 mM SDS as separation buffer. Separation has taken place under a voltage of 25 kV and a temperature of 20°C. Samples were prepared in a buffer without micelles and they were hydrodynamically injected at 50 mbar for 25 s, producing a sweeping effect on the analytes for increasing sensitivity. Different factors involved in the dispersive liquid-liquid microextraction procedure were optimized, such as sample pH, nature, and volume of extraction and dispersive solvents in the mixture, percentage of NaCl added to sample and shaking time after the injection of the extraction and dispersive solvents. The method was characterized for water samples, achieving detection limits lower than 2.4 μg/L. Trueness was checked in river, tap, and bottled water. Dispersive liquid-liquid microextraction combined with MEKC constitutes an easy, cheap, and green alternative for 5-nitroimidazole analysis in environmental water samples.

Hernández-Mesa|Maykel|M|
Cruces-Blanco|Carmen|C|
García-Campaña|Ana M|AM|

D020374:Chromatography, Micellar Electrokinetic Capillary


Bone Marrow Stem Cells-Seeded Polyethylene Terephthalate Scaffold in Repair and Regeneration of Rabbit Achilles Tendon.

Abstract: The objective of this study was to evaluate the effect of bone marrow stem cells (BMSCs)-seeded polyethylene terephthalate (PET) scaffold for Achilles tendon repair in a rabbit model. The allogeneic BMSCs were seeded onto the PET scaffold and cultured in vitro for 14 days. Sixteen mature New Zealand rabbits underwent surgery to establish a 2-cm Achilles tendon defect model. The BMSCs-seeded PET scaffold was implanted into the defect of one limb (BMSCs-PET group), while the PET scaffold without BMSCs was implanted into the defect of contralateral limb as the control (PET group). All rabbits were sacrificed at 6 and 12 weeks after surgery. At 12 weeks after surgery, macroscopic and histological results showed formation of tendon-like tissues, and the structure was more mature in the BMSCs-PET group. Immunohistochemical analysis and real-time polymerase chain reaction (RT-PCR) demonstrated that the collagen I and collagen III were significantly higher in the BMSCs-PET group compared with those in the PET group. Mechanically, both the failure load and the average stiffness were significantly higher in the BMSCs-PET group than those in the PET group. In conclusion, BMSCs-seeded PET scaffold could effectively facilitate the healing process after being implanted in a rabbit Achilles tendon defect model.

D000125:Achilles Tendon
D000818:Animals
D001696:Biomechanical Phenomena
D001854:Bone Marrow Cells
D002478:Cells, Cultured
D011093:Polyethylene Terephthalates
D011817:Rabbits
D012038:Regeneration
D033581:Stem Cell Transplantation
D013234:Stem Cells
D023822:Tissue Engineering
D054457:Tissue Scaffolds
D014945:Wound Healing

Polyethylene terephthalate
Scaffold
Regeneration
Achilles tendon
Bone marrow stem cell


Sodium Hypochlorite and a Preparation Containing Glycocholic Acid and Surfactants Have a Synergistic Action on Organic Tissue Dissolution In Vitro.

Abstract:
INTRODUCTION
The aim of this study was to evaluate porcine palatal mucosa dissolution by sodium hypochlorite (NaOCl) with or without an auxiliary dissolving agent containing glycocholic acid and a mixture of surfactants (Keratobacter [KB]; Saint Joseph DID, Valencia, Spain).

METHODS
One hundred forty samples were obtained from porcine palatal mucosa and weighed using a high-precision balance. The samples were randomly divided into 4 experimental groups (n = 35) based on the test solution used: distilled water (the negative control), CanalPro NaOCl 6% (Coltene Whaledent, Altstätten, Switzerland), KB, and a 9:1 vol/vol mixture of NaOCl with KB (NaOCl + KB). After 5, 10, 15, and 20 minutes of immersion in the solutions at 27°C ± 1°C, the samples were weighted by a blinded assessor. The intergroup weight at the different time points was statistically analyzed using the analysis of variance test with the Bonferroni posttest.

RESULTS
All test groups presented with tissue dissolution although complete dissolution did not occur in any sample. The largest percent in weight reduction occurred between time points (t) = 0 minutes and t = 5 minutes for the NaOCl + KB group (22.5%) followed by KB (18.5%) for the same time period. NaOCl presented with similar tissue dissolution activity during the different time points, ranging from 7.8% (t = 10 minutes-t = 15 minutes) to 6.8% (t = 15 minutes-t = 20 minutes). Significant weight differences were found among the different experimental groups after 5, 10, and 15 minutes of incubation, with the only exception being KB versus NaOCl + KB. No significant differences were found when comparing the test groups at t = 20 minutes.

CONCLUSIONS
The addition of KB to NaOCl increased porcine palatal mucosa dissolution in vitro.

Peña López|Alejandro|A|
Conde|Antonio J|AJ|
Estevez|Roberto|R|
Valencia de Pablo|Oliver|O|
Rossi-Fedele|Giampiero|G|
Cisneros|Rafael|R|

D000818:Animals
D004357:Drug Synergism
D006000:Glycocholic Acid
D066298:In Vitro Techniques
D009061:Mouth Mucosa
D010159:Palate
D012388:Root Canal Irrigants
D012973:Sodium Hypochlorite
D013501:Surface-Active Agents
D013552:Swine

sodium hypochlorite
glycocholic acid
surfactant
dissolution
Dental pulp


A Cardiology Handbook App to Improve Medical Education for Internal Medicine Residents: Development and Usability Study.

Abstract:
BACKGROUND
At most institutions, internal medicine residents struggle with balancing clinical duties and learning opportunities, particularly during busy cardiology ward rotations. To improve learning experiences for residents, we helped develop a cardiology handbook app to supplement cardiology education.

OBJECTIVE
The aim of this study was to report the development, implementation, and preliminary impact of the Krannert Cardiology Handbook app on graduate medical education.

METHODS
In June 2017, 122 residents at Indiana University were invited to download the digital handbook in the Krannert app. The Krannert app featured a total of 13 chapters written by cardiology fellows and faculty at Indiana University. Residents were surveyed on their self-reported improvement in cardiology knowledge and level of satisfaction after using the Krannert app. Residents were also surveyed regarding their preference for a digital handbook app versus a paper handbook.

RESULTS
Of the 122 residents, 38 trainees (31.1%) participated in survey evaluations. Among all respondents, 31 app users (82%) reported that the app helped improve their cardiology knowledge base. The app had an overall favorable response.

CONCLUSIONS
The Krannert app shows promise in augmenting clinical education in cardiology with mobile learning. Future work includes adding new topics, updating the content, and comparing the app to other learning modalities.

cardiology
internal medicine
mobile learning
medical reference app


Health-related quality of life of people with multimorbidity at a community-based, interprofessional student-assisted clinic: Implications for assessment and intervention.

Abstract: Objective This study examined the relationship between the number of comorbidities and health-related quality of life (HRQoL) and between select physical conditions and HRQoL. Differences in HRQoL in comparison to a normative sample were also examined. Method A cross-sectional study among people with multimorbidity ( n = 401) attending a community-based, interdisciplinary health clinic was conducted. HRQoL was measured using the eight dimensions of the SF-36. Multiple linear regression and t-tests were used to analyse the data. Results A downward trend in HRQoL continued from 2 to 14 concurrent comorbidities. Patients with a higher number of comorbidities reported greater deficits in HRQoL, when age, gender, education and perceived social support were controlled for (beta = -0.11 to -0.31). The impact of the number of comorbidities was greatest for the bodily pain dimension of the SF-36 (beta = -0.31). Deficits were greatest for people with gastrointestinal conditions and back pain or sciatica. Moderate to large deficits in HRQoL compared to a normative population were found (Cohen's d = 0.54-1.16). Discussion Understanding associations between the number and type of physical comorbidities and HRQoL may assist clinical services to design broad but targeted interventions to optimize HRQoL in this group of people.

Tyack|Zephanie|Z|0000-0003-3376-5731 Kuys|Suzanne|S| Cornwell|Petrea|P| Frakes|Kerrie-Anne|KA| McPhail|Steven|S|

Health-related quality of life
multimorbidity
chronic disease
complex chronic conditions
multimorbidity epidemiology


Efficacy of theory-based interventions for young people with type 1 diabetes: a systematic review and meta-analysis.

Abstract:
PURPOSE
Theory-based behaviour change interventions have been recommended to improve outcomes for young people with type 1 diabetes. However, theory has exclusively been considered in a simplistic all-or-none fashion. We therefore (1) examined the nature and extent of explicit theory use in published interventions involving young people with type 1 diabetes and (2) the relationship between how theory is used and intervention outcomes.

METHODS
We conducted systematic searches for randomized controlled trials (RCTs) published between 1999 and 2012. We used a detailed structured framework to code how theory was used and meta-analytic techniques to examine the relationships between theory use and intervention efficacy.

RESULTS
We identified 34 articles comprising 27 RCTs. Thirty per cent (k = 8) did not use theory in any of the ways assessed. Where present, the most common use of theory was providing evidence that a targeted theoretical construct predicted behaviour (k = 15; 56%). Trials that used theory to some extent had marginally larger pooled effect sizes for both medical and psychological outcomes than those that did not. However, in meta-regression models, use of theory did not significantly predict intervention outcomes.

CONCLUSIONS
Theory is under-utilized in intervention development for young people with type 1 diabetes. When employed, theory appears to be advantageous, but not necessarily predictive of intervention success. We argue that greater emphasis is needed on choosing appropriate theory, which should then become central to the process of intervention development. Statement of contribution What is already known on this subject? Interventions for young people with type 1 diabetes that explicitly cite a theoretical basis may be more effective than those that do not. Recommendations have been made for theory to be central to the intervention development process in this area. What does this study add? Theory use in recent interventions for young people with type 1 diabetes is extremely limited. Larger positive medical and psychological outcomes are observed in interventions making some use of theory. Greater use of theory does not necessarily guarantee intervention success.

Ayling|Kieran|K| Brierley|Samantha|S| Johnson|Barbara|B| Heller|Simon|S| Eiser|Christine|C|

interventions
young people
diabetes
behaviour change
theory


Toward a Unified View of Cognitive and Biochemical Activity: Meditation and Linguistic Self-Reconstructing May Lead to Inflammation and Oxidative Stress Improvement.

Abstract: Stress appears to be the basis of many diseases, especially myocardial infarction. Events are not objectively "stressful" but what is central is how the individual structures the experience he is facing: the thoughts he produces about an event put him under stress. This cognitive process could be revealed by language (words and structure). We followed 90 patients with ischemic heart disease and 30 healthy volunteers, after having taught them the Relaxation Response (RR) as part of a 4-day Rational-Emotional-Education intervention. We analyzed with the Linguistic Inquiry and Word Count software the words that the subjects used across the study following the progression of blood galectin-3 (inflammation marker) and malondialdehyde (oxidative stress marker). During the follow-up, we confirmed an acute and chronic decrease in the markers of inflammation and oxidative stress already highlighted in our previous studies together with a significant change in the use of language by the subjects of the RR groups. Our results and the precise design of our study would seem to suggest the existence of an intimate relationship and regulatory action by cognitive processes (recognizable by the type of language used) on some molecular processes in the human body.

Dal Lin|Carlo|C|0000-0003-1406-6281
Brugnolo|Laura|L|
Marinova|Mariela|M|
Plebani|Mario|M|
Iliceto|Sabino|S|
Tona|Francesco|F|0000-0003-4828-7875
Vitiello|Giuseppe|G|0000-0002-5710-7904

cognition
meditation
stress
language
relaxation response
Rational–Emotional–Education
dissipative quantum model of brain


A novel method to determine the minimum number of sequences required for reliable microbial community analysis.

Abstract: Although high-throughput sequencing is an efficient approach to study the structure of microbial communities in detail, it is still impossible to enumerate all individuals using this method. Therefore, it is a common strategy to generate sampling datasets that are representative of the assemblages. However, the representativeness of these sampling datasets has never been assessed. In this study, we developed a method to determine the minimum number sequences that are required to be analyzed to obtain a reliable description of microbial community structure. First, a set of datasets from microbial communities were constructed by in silico sampling at different depths. Second, the correlation equation between dissimilarity of the sampling datasets and sampling depths was fitted, and thereby the minimum number of 16S rRNA gene sequences was predicted. Finally, we verified the method using empirical data of microbiota from a laboratory mesocosm. Our method showed that at least 5,528,079 sequences were required to reliably characterize microbial communities inhabiting the mesocosms. However, if only dominant OTUs (>1%) were considered, thousands of sequences were enough. This promising method provides a criterion to ensure sequencing sufficiency when analyzing the structure of natural microbial communities.

Ni|Jiajia|J| Li|Xiaojing|X| He|Zhili|Z| Xu|Meiying|M|

Minimum number of sequences
Microbial community
High-throughput sequencing
Community structure
Sequencing depth


CAST: Its molecular structure and phosphorylation-dependent regulation of presynaptic plasticity.

Abstract: Our brain functions rely on sophisticated communication between synapses in the nervous system. Most synapses utilize a specialized submembranous structure, the so-called 'active zone', for the efficient transmission of chemical signals. The presynaptic active zone plays pivotal roles in the precise regulation of neurotransmitter release from the nerve terminals in a temporally and spatially coordinated manner. During the last two decades, several active zone-specific proteins have been isolated and characterized, including Bassoon, Piccolo/Aczonin, RIM, Munc13-1, ELKS, and CAST. The CAST/ELKS family is capable of potent direct interactions with other active zone proteins, forming a large protein complex that seems to be a molecular basis for electron density in the presynaptic active zone. The molecular details of the integrity of the active zone been well studied, however, we are just beginning to understanding its physiological significance in higher brain functions such as learning and memory, emotion, and consciousness. Focusing on the CAST/ELKS protein family, this review describes their biochemical properties, physiological functions in brain areas such as the hippocampus, and the significance of CAST phosphorylation in presynaptic short-term plasticity.

D048868:Adaptor Proteins, Signal Transducing

CAST
active zones
RIM
ELKS
SAD
synaptic plasticity
synaptic vesicles


Do Medical Students in Their Fifth Year of Undergraduate Training Differ in Their Suitability to Become a "Good Doctor" Depending on Their Admission Criteria? A Pilot Study.

Abstract:
Background
In Germany, the pre-university grade point average (pu-GPA) has to be the main criterion for medical school applicant selection. This is also mandatory in the university-specific selection procedures (Auswahlverfahren der Hochschulen [AdH]). The admission framework has now been reworked following a judgement by the German Federal Constitutional Court. From 2020, more students will be admitted based solely on the pu-GPA and at least two selection criteria independent of the pu-GPA have to be considered in the AdH. However, the question whether an AdH (the core of the AdH at Lübeck Medical School [LMS], Germany, is a 30-mins panel interview led by two faculty members and one student) leads to better doctors as compared to pu-GPA-based selection, remains unanswered.

Objective
To compare students selected based either on their pu-GPA alone ("pu-GPA-students") or based on the result of the AdH at LMS ("AdH-students") regarding their suitability to become a good doctor.

Design
We conducted a cross-sectional observational pilot study at LMS. Students were judged regarding their overall suitability to become a good doctor by their supervising general practitioners after a two-week internship in their last year of theoretical medical education. The scores were matched to the selection procedure and compared between the pu-GPA-students and AdH-students.

Results
In all, 79% of the AdH-students were rated as "absolutely suitable" for the medical profession, as compared to 42% of the pu-GPA-students (p = 0.01, odds ratio 5.17, 95% confidence interval = 1.41, 18.99). We did not find any association between gender or age and the suitability rating.

Conclusion
Despite the small sample size, our results indicate that it could be favourable to select medical students not only based on their pu-GPA but also using additional selection criteria.

medical students
students selection
medical education
educational assessment


EEG background features that predict outcome in term neonates with hypoxic ischaemic encephalopathy: A structured review.

Abstract:
OBJECTIVES
Hypoxic ischaemic encephalopathy is a significant cause of mortality and morbidity in the term infant. Electroencephalography (EEG) is a useful tool in the assessment of newborns with HIE. This systematic review of published literature identifies those background features of EEG in term neonates with HIE that best predict neurodevelopmental outcome.

METHODS
A literature search was conducted using the PubMed, EMBASE and CINAHL databases from January 1960 to April 2014. Studies included in the review described recorded EEG background features, neurodevelopmental outcomes at a minimum age of 12 months and were published in English. Pooled sensitivities and specificities of EEG background features were calculated and meta-analyses were performed for each background feature.

RESULTS
Of the 860 articles generated by the initial search strategy, 52 studies were identified as potentially relevant. Twenty-one studies were excluded as they did not distinguish between different abnormal background features, leaving 31 studies from which data were extracted for the meta-analysis. The most promising neonatal EEG features are: burst suppression (sensitivity 0.87 [95% CI (0.78-0.92)]; specificity 0.82 [95% CI (0.72-0.88)]), low voltage (sensitivity 0.92 [95% CI (0.72-0.97)]; specificity 0.99 [95% CI (0.88-1.0)]), and flat trace (sensitivity 0.78 [95% CI (0.58-0.91)]; specificity 0.99 [95% CI (0.88-1.0)]).

CONCLUSION
Burst suppression, low voltage and flat trace in the EEG of term neonates with HIE most accurately predict long term neurodevelopmental outcome.

SIGNIFICANCE
This structured review and meta-analysis provides quality evidence of the background EEG features that best predict neurodevelopmental outcome.

Awal|Md Abdul|MA|
Lai|Melissa M|MM|
Azemi|Ghasem|G|
Boashash|Boualem|B|
Colditz|Paul B|PB|

EEG
Background features
Structured review
Newborn
HIE
Neurodevelopmental outcome
Meta-analysis
Hypothermia


A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial☆.

Abstract:
BACKGROUND
Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC.

PATIENTS AND METHODS
The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146).

RESULTS
A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable.

CONCLUSIONS
In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.

Park|S H|SH|
Lim|D H|DH|
Sohn|T S|TS|
Lee|J|J|
Zang|D Y|DY|
Kim|S T|ST|
Kang|J H|JH|
Oh|S Y|SY|
Hwang|I G|IG|
Ji|J H|JH|
Shin|D B|DB|
Yu|J I|JI|
Kim|K-M|KM|
An|J Y|JY|
Choi|M G|MG|
Lee|J H|JH|
Kim|S|S|
Hong|J Y|JY|
Park|J O|JO|
Park|Y S|YS|
Lim|H Y|HY|
Bae|J M|JM|
Kang|W K|WK|
|||

D000971:Antineoplastic Combined Chemotherapy Protocols

gastric cancer
adjuvant chemotherapy
radiotherapy


Current Status of CAR T Cell Therapy for Leukemias.

Abstract: Chimeric antigen receptor (CAR) T-cell therapy has become the standard of care for children and young adults with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), and it is a highly promising therapy under investigation for adults with relapsed disease. Despite having potentially life-threatening toxicities, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, the benefits of CAR T-cell therapy far outweigh these risks, particularly as increased experience and improved supportive care measures are mitigating these toxicities. CAR T cells can result in complete remission for significant proportion of patients with relapsed and refractory B-ALL and permit them to proceed to potentially curative allogeneic hematopoietic stem cell transplantation (allo-HSCT). CAR T cells may also be curative by themselves. Herein lie the greatest challenges and questions for clinical investigators, specifically, how are CAR T cells best employed and how do we overcome mechanisms of resistance to them? The primary clinical question is the timing and even the necessity of allo-HSCT. Relative to resistance, we know that target antigen loss, specifically CD19, is a major contributor to resistance. However, current investigations of alternative targets, such CD22, and CAR T cells expressing dual targeting antigen receptors have demonstrated encouraging initial results and provide a high degree of optimism that the efficacy and the broader application of CAR T-cell therapy will gradually increase in B-ALL. That optimism is not as high and the challenges are increased for the application of CAR T cells in T-cell leukemias and acute myeloid leukemia due to the relative lack of suitable leukemia surface targets that are not also expressed on normal hematopoietic progenitors. Despite these significant challenges, considerable research is being conducted into the development of CAR T cells for these diseases utilizing unique technologies, which may be applicable to other diseases.

Harris|Katherine|K|
LaBelle|James L|JL|
Bishop|Michael R|MR|

CAR T cells
Leukemia
Acute lymphoblastic leukemia
Toxicities
Mechanisms of resistance
Immunotherapy


Day-surgery percutaneous nephrolithotomy: a high-volume center retrospective experience.

Abstract:
PURPOSE
Percutaneous nephrolithotomy (PCNL) is traditionally performed on an inpatient basis. We determine the safety and outcome of day-surgery PCNL by experienced surgeon hands.

PATIENTS AND METHODS
A protocol for day-surgery PCNL was undertaken. A retrospective analysis of all 86 cases of planned day-surgery PCNL accomplished by an experienced surgeon who followed this protocol between May 2017 and March 2019 was performed. Patient demographics, operative data, complications, and readmission rates were recorded. Day-surgery PCNL was defined as discharge of patients either the same day or within 24 h after surgery.

RESULTS
The average stone burden was 361.1 mm2 and 70 (81.4%) of patients had multiple stones or staghorn stones. 82 (95.4%) patients achieved same-day discharge or received overnight observation prior to discharge, and 4 patients (4.6%) required full admission (longer than 24 h). The readmission rate was 2.3% (2 patients). The postoperative complications occurred in 10 (11.6%) patients, including 7, 2, 2 of grade I, II, III complications. The average operation time was 64 min and the hemoglobin drop was 15.7 ± 16.9 g/L. The established tracts size ranged from 16 to 22Fr. The stone clearance rate was 90.7%. The tubeless without nephrostomy tube was performed in 60.5%. Eight cases were performed by multiple-tracts PCNL with 2-4 tracts, with only two case required full admission.

CONCLUSION
Experienced surgeons who performed day-surgery PCNL experience excellent patient outcomes in appropriately selected patients. Most complications can be treated conservatively and only a few required intervention or readmission.

Wu|Xiangkun|X| Zhao|Zhijian|Z| Sun|Hongling|H| Cai|Chao|C| Li|Zhilin|Z| Cheng|Donglong|D| Zhu|Huacai|H| Zeng|Guohua|G| Liu|Yongda|Y|

Percutaneous nephrolithotomy
Outcomes
Day-surgery PCNL
Staghorn stone
Multiple tracts


Common gastrointestinal parasites of indigenous camels (Camelus dromedarius) with traditional husbandry management (free-ranging system) in central deserts of Iran.

Abstract: Gastrointestinal parasites of domesticated animals, especially in animals with traditional husbandry management cause reduction in production and performance of them. Aim of our study was to determine prevalence of gastrointestinal parasites in indigenous camels, with traditional husbandry management that have no direct contact with other livestock. This study was carried out between Kerman and Yazd provinces of Iran, midsummer 2011. Fecal samples of 100 randomly selected camels of all age and sex, collected directly from their rectum. The fecal samples were examined by direct smear, simple flotation technique, centrifugal sedimentation technique, and McMaster egg counting technique and fecal culture to identification and determine the burden of parasites in different age groups. Nematode eggs and Eimeria oocysts were found (64 %) and (24 %) in fecal samples respectively. Parasite eggs that observed in camel feces were belong to Nematodirus spp. (52 %), Trichostrongyle type eggs (49 %), Haemonchus spp. (38 %), Trichuris spp. (14 %) Marshallagia spp. (10 %) and Eimeria cameli (24 %), the age of infected camels with helminthic infections was significantly higher than non-infected camels (p < 0.05), there was also a significant correlation between age and severity of coccidiosis (p < 0.05). Camel calves and camels below 5 years old were more infected with the Eimeria sp. than older ones. This study revealed gastrointestinal parasites is a major problem of indigenous camels with traditional husbandry, so parasite control programs must be established for increasing the productivity of this useful animal and industrial system for breeding camels recommended to increase productivity of them, especially where harsh climatic condition affected other livestock.

Radfar|Mohammad Hossein|MH|
Aminzadeh Gowhari|Mansour|M|

Gastrointestinal parasites
Indigenous camels
Iran
Prevalence


Human health risk assessment of triclosan in land-applied biosolids.

Abstract: Triclosan (5-chloro-2-[2,4-dichlorophenoxy]-phenol) is an antimicrobial agent found in a variety of pharmaceutical and personal care products. Numerous studies have examined the occurrence and environmental fate of triclosan in wastewater, biosolids, biosolids-amended soils, and plants and organisms exposed to biosolid-amended soils. Triclosan has a propensity to adhere to organic carbon in biosolids and biosolid-amended soils. Land application of biosolids containing triclosan has the potential to contribute to multiple direct and indirect human health exposure pathways. To estimate exposures and human health risks from biosolid-borne triclosan, a risk assessment was conducted in general accordance with the methodology incorporated into the US Environmental Protection Agency's Part 503 biosolids rule. Human health exposures to biosolid-borne triclosan were estimated on the basis of published empirical data or modeled using upper-end environmental partitioning estimates. Similarly, a range of published triclosan human health toxicity values was evaluated. Margins of safety were estimated for 10 direct and indirect exposure pathways, both individually and combined. The present risk assessment found large margins of safety (>1000 to >100 000) for potential exposures to all pathways, even under the most conservative exposure and toxicity assumptions considered. The human health exposures and risks from biosolid-borne triclosan are concluded to be de minimis. Environ Toxicol Chem 2016;35:2358-2367. © 2016 SETAC.

Verslycke|Tim|T|
Mayfield|David B|DB|
Tabony|Jade A|JA|
Capdevielle|Marie|M|
Slezak|Brian|B|

Risk assessment
Triclosan
Biosolids
Antimicrobials
Personal care products


Structural, Evolutionary, and Functional Analysis of the Protein O-Mannosyltransferase Family in Pathogenic Fungi.

Abstract: Protein O-mannosyltransferases (Pmts) comprise a group of proteins that add mannoses to substrate proteins at the endoplasmic reticulum. This post-translational modification is important for the faithful transfer of nascent glycoproteins throughout the secretory pathway. Most fungi genomes encode three O-mannosyltransferases, usually named Pmt1, Pmt2, and Pmt4. In pathogenic fungi, Pmts, especially Pmt4, are key factors for virulence. Although the importance of Pmts for fungal pathogenesis is well established in a wide range of pathogens, questions remain regarding certain features of Pmts. For example, why does the single deletion of each pmt gene have an asymmetrical impact on host colonization? Here, we analyse the origin of Pmts in fungi and review the most important phenotypes associated with Pmt mutants in pathogenic fungi. Hence, we highlight the enormous relevance of these glycotransferases for fungal pathogenic development.

pathogens
Pmt
Ustilago maydis
appressorium
glycosylation


In vitro antimicrobial activities of animal-used quinoxaline 1,4-di-N-oxides against mycobacteria, mycoplasma and fungi.

Abstract:
BACKGROUND
The quinoxaline 1,4-di-N-oxides (QdNOs) were known as potent antibacterial agents. For the purpose of evaluating the bioactivity of existing animal-used QdNOs drugs against representative pathogenic microorganism, the representative drugs of quinoxalines including cyadox, mequindox, quinocetone and their metabolites were submitted to the in vitro evaluation for antituberculosis, antimycoplasma, antifungal and antiviral activities.

RESULTS
In antituberculosis assays, the prototype compounds were active (MIC = 4 ~ 8 μg/mL) against Mycobacterium tuberculosis H37Rv and M. bovis. Combined antimicrobial susceptibility test indicated that cyadox, mequindox and quinocetone combined with rifampicin had additive effect against M. tuberculosis complex with Fractional Inhibitory Concentration Index (FIC) of 0.75. Results of antifungal assays showed that quinocetone was active against Microsporum canis with MIC of 8 μg/mL. Antimycoplasma screening showed a generally good activity of quinocetone against Mycoplasma gallisepticum and Mycoplasma hyopneumoniae, with MIC between 8 and 16 μg/mL. As shown from the combined antimicrobial susceptibility test, cyadox, mequindox and quinocetone combined with tetracycline had additive effect against Mycoplasma gallisepticum with FIC of 0.75. These compounds were also submitted to antiviral assay against infectious bursal disease virus, porcine reproductive and respiratory syndrome virus, porcine parvovirus and classical swine fever virus. The results obtained showed that these QdNOs and their metabolites have no inhibitory activity against these viruses in vitro.

CONCLUSIONS
QdNOs exhibit antimicrobial activities against mycobacteria, mycoplasma and fungi. This study gives new insight in further application of QdNOs and offers a way to promote the healthcare of animal husbandry.

Zhao|Yan|Y| Cheng|Guyue|G| Hao|Haihong|H| Pan|Yuanhu|Y| Liu|Zhenli|Z| Dai|Menghong|M| Yuan|Zonghui|Z|


Spontaneous limb movements and posturing secondary to acute basilar artery occlusion: a potentially devastating seizure mimic.

Abstract: Basilar artery occlusion is a devastating but treatable form of ischaemic stroke with high morbidity and mortality rates. The diagnosis is often challenging due to considerable heterogeneity of clinical signs and symptoms. We report a case of an acute basilar artery occlusion presenting with decreased level of consciousness associated with rhythmic tonic movements of the four extremities, mimicking seizure activity. The patient was treated with intravenous thrombolysis and subsequently gained good recovery. Awareness of this entity is required to recognise this potentially treatable, but otherwise devastating seizure mimic.

Wilson|L K|LK|
Benavente|O R|OR|
Woolfenden|A R|AR|
Asdaghi|N|N|


Physiologically Relevant In Vitro-In Vivo Correlation (IVIVC) Approach for Sildenafil with Site-Dependent Dissolution.

Abstract: This study aimed to establish a physiologically relevant in vitro-in vivo correlation (IVIVC) model reflecting site-dependent dissolution kinetics for sildenafil based on population-pharmacokinetic (POP-PK) modeling. An immediate release (IR, 20 mg) and three sustained release (SR, 60 mg) sildenafil tablets were prepared by wet granulation method. In vitro dissolutions were determined by the paddle method at pH 1.2, 4.5, and 6.8 media. The in vivo pharmacokinetics were assessed after oral administration of the prepared IR and SR formulations to Beagle dogs (n = 12). The dissolution of sildenafil from SR formulations was incomplete at pH 6.8, which was not observed at pH 1.2 and pH 4.5. The relative bioavailability was reduced with the decrease of the dissolution rate. Moreover, secondary peaks were observed in the plasma concentration-time curves, which may result from site-dependent dissolution. Thus, a POP-PK model was developed to reflect the site-dependent dissolution by separately describing the dissolution and absorption processes, which allowed for estimation of the in vivo dissolution of sildenafil. Finally, an IVIVC was established and validated by correlating the in vitro and in vivo dissolution rates. The present approach may be applied to establish IVIVC for various drugs with complex dissolution kinetics for the development of new formulations.

in vitro-in vivo correlation
sildenafil
site-dependent dissolution
pharmacokinetics
population pharmacokinetic modeling


Proline cis-trans isomerization is influenced by local lysine acetylation-deacetylation.

Abstract: Acetylation of lysine residues has several characterised functions in chromatin. These include neutralization of the lysine's positive charge to directly influence histone tail-DNA/internucleosomal interactions or indirect effects via bromodomain-containing effector proteins. Recently, we described a novel function of lysine acetylation to influence proline isomerization and thus local protein conformation. We found that acetylation of lysine 14 in the histone H3 N-terminal tail (H3K14ac), an intrinsically disordered domain, increased the proportion of neighbouring proline 16 (H3P16) in the trans conformation. This conformation of the tail was associated with reduced tri-methylation on histone H3 lysine 4 (H3K4me3) due to both decreased methylation by the Set1 methyltransferase (with the me3-specific subunit Spp1) and increased demethylation by the demethylase Jhd2. Interestingly, H3K4me3 on individual genes was differentially affected by substitution of H3K14 or H3P16, with ribosomal protein genes losing the least H3K4me3 and environmental stress-induced genes losing the most.

proline cis-trans isomerization
lysine acetylation
histone H3
Saccharomyces cerevisiae
intrinsically disordered regions
post-translational modifications
protein structure


Geophilomorpha from Alborz Mountains and a checklist of Chilopoda from Iran.

Abstract: This study presents an updated checklist of centipedes (Chilopoda) from Iran based on a review of the literature and recently examined specimens of Geophilomorpha collected from many sites in the Alborz Mountains. The centipedes of Iran comprise 48 species, of which 17 species have so far only been reported from Iran. Many species are known from a single locality, and only from specimens of a single sex. Species of the geophilomorph genera Clinopodes and Strigamia are here reported from Iran for the first time. The checklist includes all published geographical distribution data from Iran and a comparison with the centipede fauna of neighboring countries using the Jaccard index. The Iranian centipede fauna is still scantily known and further investigations are expected to contribute substantially, especially because of the diverse physiography of the country.

Zarei|Roghaieh|R| Rahimian|Hassan|H| Mirmonsef|Hassan|H| Bonato|Lucio|L|

west Asia, Middle East, Iran fauna, Chilopoda


An exploratory study examining factors underpinning postural instability in older adults with idiopathic neck pain.

Abstract: There is limited understanding of potential mechanisms underpinning postural control deficits in people with neck pain. This study examined several characteristics that might explain impaired postural stability in a group of older adults with neck pain, and compared the results in this cohort with that of asymptomatic controls. In this cross-sectional study we compared physical activity, lower limb motor and sensory function, vestibular and visual function, falls efficacy and dizziness handicap in 84 older adults with (n=35, age 69.6±6.3) and without (n=49, age 69.4±4.7) idiopathic neck-pain. Additionally, dynamic balance was assessed using the dynamic gait index (DGI) and standard and wavelet analysis of static balance was computed after data capture. Physical activity levels, lower limb motor and sensory function, vestibular function and visual contrast sensitivity were not different between groups (p>0.05). The neck-pain group demonstrated higher falls efficacy (p=0.01), greater levels of dizziness handicap (p<0.01), and higher CoP velocity measures in the moderate (1.56-6.25Hz) and low (0.39-1.56Hz) frequency bandwidths. Our results suggest that neck-pain induced postural control deficits in older adults may not be associated with the physical activity levels, lower limb motor and sensory function, or vestibular and visual function. Inferring from wavelet analysis results, we speculated that sensory re-weighting may have occurred to compensate for the deficits in neck proprioception. Further research is warranted to determine neck specific mechanisms underpinning postural control dysfunction in neck pain.

Quek|June|J|
Treleaven|Julia|J|
Clark|Ross A|RA|
Brauer|Sandra G|SG|

Older adults
Neck pain
Physical activity
Balance
Sensorimotor


Perceived utility and relevance of intern well-being sessions.

Abstract:
BACKGROUND/AIM
We conducted a pilot project assessing the perceived utility and relevance of well-being sessions provided to interns at a large regional teaching hospital in Australia, with the aim of promoting intern well-being and fostering a nurturing and supportive learning and work hospital culture.

METHODS
Our intervention involved two separate 60-min lectures covering well-being topics and skills to approximately 50 interns within protected teaching time, along with emailed well-being resources. Participants were emailed an online survey asking questions about value and novelty of the sessions, and work satisfaction and stress, as well as open comments. A request for an additional interview to explore responses in more depth was included.

RESULTS
Fifty interns attended at least one of the sessions and 35 participated in the survey, six to an additional interview. Survey and interview data showed that the majority of interns perceived the sessions as valuable, relevant and useful and felt that ongoing sessions would benefit junior medical officers in future years. Feedback highlighted the importance of providing future sessions in person, incorporating an interactive approach and emphasised that work site factors and medical culture play a large causative role in their stress.

CONCLUSIONS
We conclude that well-being sessions are acceptable and useful to interns and should be incorporated into hospital teaching curricula, and evaluated. However, these programmes are unlikely to change the high stress experienced unless external and systemic stressors are addressed by all stakeholders.

junior medical officer health and well-being


Immunohistochemical profile of normal mesothelium and histiocytic/methothelial hyperplasia: a case report.

Abstract: Immunohistochemical profiles of normal mesothelium and histiocytic/mesothelial hyperplasia (HMH) are unknown. A 19-year-old man was treated by thoracoscopic resection of bullae of left lung. Histologically, there were cell proliferative foci composed of round cells without significant atypia (histiocyte, mesothelium and T-lymphocytes). The cell proliferative foci were patch-like, and no invasive features were seen. Because it is composed of histiocytes, mesothelium, and T-lymphocytes, the diagnosis was HMH. Immunohistochemically, cell components of HMH showed the following immunoreactions: calrenitin 3+, D2-40 3+, pancytokeratin AE1/3 3+, pancytokeratin CAM5.2 3+, cytokeratin (CK) 34βE12 1+, CK5/6 1+, CK7 1+, CK8 3+, CK 14 1+, CK18 2+, CK19 2+, p53 10%, Ki67 20%, CD68 3+, CD45 2+, CD45 RO 2+, vimentin 3+, Ber-EP4 -, CK20 -, EMA -, desmin -, CEA -, CA19-9 -, TTF-1 -, S100 protein -, αsmooth muscle actin -, CD34 -, CD20 -, chromogranin -, synaptophysin -, NSE -, CDX2 -, CD56 -, HER2 -, MUC1 -, MUC2 -, MUC5AC -, and MUC6 -. The normal mesothelium showed the following immunoprofile: calrenitin 3+, D2-40 3+, pancytokeratin AE1/3 3+, pancytokeratin CAM5.2 3+, CK34βE12 3+, CK5/6 2+, CK7 2+, CK8 3+, CK 14 -, CK18 3+, CK19 2+, vimentin 1+, p53 -, Ki67 1%, CD68 -, CD45 -, CD45 RO -, Ber-EP4 -, CK20 -, EMA -, desmin -, CEA -, CA19-9 -, TTF-1 -, S100 protein -, α-smooth muscle actin -, CD34 -, chromogranin -, synaptophysin -, NSE -, CDX2 -, CD56 -, HER2 -, MUC1 -, MUC2 -, MUC5AC -, and MUC6 -. These findings indicate that the immunoprolfile of mesothelium in HMH was immunohistochemically very similar to that of normal mesothelium except for CD68, p53 protein, Ki-67 labeling, CD45 and CD45 RO. These indicate that the HMH was reactive phenomenon and HMH is composed of hyperplastic mesothelium, histiocytes and T-lymphocytes. The immunoprofile of normal mesothelium provide basic knowledge of mesothelial pathology.

immunohistochemical profile
Mesothelium
histiocytic methothelial hyperplasia


Structure-dependent inhibitory effects of synthetic cannabinoids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and skin tumour promotion in mice.

Abstract:
OBJECTIVES
Whether and how synthetic cannabinoids affect inflammation and carcinogenesis has not been well studied. The present study was thus conducted to assess effects of synthetic cannabinoids on inflammation and carcinogenesis in vivo in mice.

METHODS
Twenty-three analogues of synthetic cannabinoids were isolated from, and identified as adulterants in, illegal drugs distributed in the Tokyo metropolitan area, and were examined for their inhibitory effects on the induction of oedema in mouse ears by 12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, selected cannabinoids, JWH-018, -122 and -210, were studied for their effects on carcinogenesis induced in mouse skin initiated with 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by TPA.

KEY FINDINGS
Among cannabinoids, naphthoylindoles mostly exhibited superior inhibitory effects against TPA-induced ear oedema and, especially, JWH-018, -122 and -210 showed potent activity with 50% inhibitory dose (ID50) values of 168, 346 and 542 nm, respectively (an activity corresponding to that of indometacin (ID50 = 908 nm)). Furthermore these three compounds also markedly suppressed the tumour-promoting activity of TPA.

CONCLUSIONS
This is the first report indicating the structure-activity relationships for the anti-inflammatory activity of synthetic cannabinoids on TPA-induced inflammation in mice. Naphthoylindoles, JWH-018, -122 and -210, had the most potent anti-inflammatory activity and also markedly inhibited tumour promotion by TPA in the two-stage mouse skin carcinogenesis model. The present results suggest that synthetic cannabinoids, such as JWH-018, -122 and -210, may be used as cancer chemopreventive agents in the future.

synthetic cannabinoids
12-O-tetradecanoylphorbol-13-acetate
anti-inflammatory effect
anti-tumour-promoting agent
two-stage carcinogenesis


In vitro evaluation of the hyaluronic acid/alginate composite powder for topical haemostasis and wound healing.

Abstract: The use of haemostatic agents can provide life-saving treatment for patients who suffer from massive bleeding in both prehospital and intraoperative conditions. However, there are still urgent demands for novel haemostatic materials that exhibit better haemostatic activity, biocompatibility, and biodegradability than existing products. In the present study, we aim to evaluate the feasibility of new wound dressing, RapidClot, for treating uncontrolled haemorrhage through a series of in vitro assessments to determine the swelling ratio, clotting time, enzymatic degradation, haemolytic activity, cytotoxicity, cell proliferation, and migration. The results indicated that the RapidClot revealed better water adsorption capacity and shorter blood clotting time (132.7 seconds) than two commercially available haemostatic agents Celox (378.7 seconds) and WoundSeal (705.3 seconds). Additionally, the RapidClot dressing exhibited a similar level of degradability in the presence of hyaluronidase and lysozyme as that of Celox, whereas negligible degradation of WoundSeal was obtained. Although both Celox and RapidClot revealed a similar level in cell viability (above than 90%) against NIH/3 T3 fibroblasts, improved cell proliferation and migration could be obtained in RapidClot. Taking together, our results demonstrated that RapidClot could possess a great potential for serving as an efficient healing dressing with haemorrhage control ability.

biodegradation
fibroblast
haemorrhage control
cytocompatibility
haemostatic powder


Organ Biodistribution of Radiolabelled γδ T Cells Following Liposomal Alendronate Administration in Different Mouse Tumour Models.

Abstract: Vγ9Vδ2 T cell immunotherapy has been shown to be effective in delaying tumour growth in both pre-clinical and clinical studies. It has been pointed out the importance of the ability of cells to accumulate within tumours and the association with therapeutic efficacy in clinical studies of adoptive T cell transfer. We have previously reported that alendronate liposomes (L-ALD) increase the efficacy of this therapy after localised or systemic injection of γδ T cells in mice, inoculated with ovarian, melanoma, pancreatic or experimental lung metastasis tumour models, respectively. This study aimed to examine the organ biodistribution and tumour uptake of human γδ T cells in subcutaneous (SC), intraperitoneal (IP) or experimental metastatic lung tumours, established in NOD-SCID gamma (NSG) mice using the melanoma cell line A375Pβ6.luc. pre-injected with L-ALD. Overall, small variations in blood profiles and organ biodistribution of γδ T cells among the different tumour models were observed. Exceptionally, IP-tumour and experimental metastatic lung-tumour bearing mice pre-injected with L-ALD showed a significant decrease in liver accumulation, and highest uptake of γδ T cells in lungs and tumour-bearing lungs, respectively. Lower γδ T cell count was found in the SC and IP tumours.

Wang|Julie T-W|JT|
Hodgins|Naomi O|NO|
Al-Jamal|Wafa' T|WT|
Maher|John|J|
Sosabowski|Jane K|JK|
Al-Jamal|Khuloud T|KT|

γδ T cells
liposomes
adoptive immunotherapy
bisphosphonates
nitrogen-containing bisphosphonates


Safety and Tolerability of Glucagon-Like Peptide-1 Receptor Agonists Utilizing Data from the Exenatide Clinical Trial Development Program.

Abstract: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated benefits for patients with type 2 diabetes including A1C reduction and weight loss with minimal risk of hypoglycemia. This article provides an evidence-based update of safety and tolerability considerations for the clinical use of GLP-1RAs as a class, with a specific detailed review of data from the exenatide clinical trial development program, which has the longest history and availability of safety and tolerability data as the first-approved GLP-1RA. Specific areas covered include comparative risk of hypoglycemia, as well as pancreatic, thyroid, and cardiovascular safety data; clinical guidance regarding current safety and tolerability data is also reviewed.

Peng|Hui|H|
Want|Laura L|LL|
Aroda|Vanita R|VR|

Safety
Exenatide
Pancreatitis
Cardiovascular
GLP-1 receptor agonists
Incretin


Adrenergic β receptor activation in the basolateral amygdala, which is intracellular Zn2+-dependent, rescues amyloid β1-42-induced attenuation of dentate gyrus LTP.

Abstract: On the basis of the evidence that the basolateral amygdala (BLA) modulates hippocampal memory processes via synaptic plasticity, here we report that adrenergic β receptor activation in the BLA rescues amyloid β1-42 (Aβ1-42)-induced attenuation of long-term potentiation (LTP) at perforant pathway-dentate granule cell (DGC) synapses. When 500 μM isoproterenol (2 μl), an adrenergic β receptor agonist, was injected into the BLA 20 min before LTP induction, LTP was enhanced. Isoproterenol-mediated enhancement of LTP was blocked by co-injection with 100 μM ZnAF-2DA, an intracellular Zn2+ chelator, suggesting that intracellular Zn2+ is required for the intracellular signaling cascade after adrenergic β receptor activation in the BLA. Aβ1-42-induced attenuation of LTP, which was induced by Aβ1-42 injection into the dentate gyrus 60 min before LTP induction, was rescued by isoproterenol injection into the BLA 20 min before LTP induction, but not by 500 μM phenylephrine (2 μl), an adrenergic α1 receptor agonist, injection into the BLA, which did not enhance LTP unlike the case of isoproterenol injection. Interestingly, Aβ1-42-induced attenuation of LTP was also rescued by 100 μM isoproterenol injection into the BLA 20 min before LTP induction, which did not enhance LTP. The present study demonstrates that adrenergic β receptor activation in the BLA, which is linked with intracellular Zn2+ signaling, rescues Aβ1-42-induced attenuation of dentate gyrus LTP. It is likely that adrenergic β receptor activation in the BLA is a strategy for rescuing Aβ1-42-induced cognitive decline that is associated with hippocampal synaptic plasticity.

Tamano|Haruna|H|
Kubota|Mitsuyasu|M|
Fujise|Yuki|Y|
Shimaya|Ryota|R|
Itoh|Ryusei|R|
Suzuki|Miki|M|
Adlard|Paul A|PA|
Bush|Ashley I|AI|
Takeda|Atsushi|A|

Amygdala
Dentate gyrus LTP
Isoproterenol
Amyloid β(1-42)
Zinc


Iterative joint classifier and domain adaptation for visual transfer learning.

Abstract: Current available supervised classifiers cannot generalize across various domains due to distribution mismatch among them. Domain adaptation and transfer learning algorithms are proposed to tackle domain shift problem that originates from different data collection conditions. In this paper, we propose a transfer learning framework called iterative joint classifier and domain adaptation for visual transfer learning (ICDAV), which utilizes the balanced maximum mean discrepancy to better transfer knowledge across domains. Also, for learning a robust classifier against domain shift, a set of graph manifold regularizer and modified joint probability maximum mean discrepancy are simultaneously exploited to capture the domain structures and adapt the distribution of projected samples during the model learning process. Variety of experiments on several public datasets indicates that our approach achieves remarkable performance on visual domain adaptation and transfer learning tasks.

Domain adaptation
Transfer learning
Manifold regularization
Visual classification


L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor.

Abstract: Blood pressure is regulated by extrinsic factors including noradrenaline, the sympathetic neurotransmitter that controls cardiovascular functions through adrenergic receptors. However, the fine-tuning system of noradrenaline signaling is relatively unknown. We here show that l-3,4-dihydroxyphenylalanine (L-DOPA), a precursor of catecholamines, sensitizes the vascular adrenergic receptor alpha1 (ADRA1) through activation of L-DOPA receptor GPR143. In WT mice, intravenous infusion of the ADRA1 agonist phenylephrine induced a transient elevation of blood pressure. This response was attenuated in Gpr143 gene-deficient (Gpr143-/y) mice. Specific knockout of Gpr143 in vascular smooth muscle cells (VSMCs) also showed a similar phenotype, indicating that L-DOPA directly modulates ADRA1 signaling in the VSMCs. L-DOPA at nanomolar concentrations alone produced no effect on the VSMCs, but it enhanced phenylephrine-induced vasoconstriction and intracellular Ca2+ responses. Phenylephrine also augmented the phosphorylation of extracellular signal-regulated kinases in cultured VSMCs from WT but not Gpr143-/y mice. In WT mice, blood pressure increased during the transition from light-rest to dark-active phases. This elevation was not observed in Gpr143-/y mice. Taken together, our findings provide evidence for L-DOPA/GPR143 signaling that exerts precursor control of sympathetic neurotransmission through sensitizing vascular ADRA1.

Masukawa|Daiki|D|
Koga|Motokazu|M|
Sezaki|Anna|A|
Nakao|Yuka|Y|
Kamikubo|Yuji|Y|
Hashimoto|Tatsuo|T|
Okuyama-Oki|Yuki|Y|
Aladeokin|Aderemi Caleb|AC|
Nakamura|Fumio|F|
Yokoyama|Utako|U|
Wakui|Hiromichi|H|
Ichinose|Hiroshi|H|
Sakurai|Takashi|T|
Umemura|Satoshi|S|
Tamura|Koichi|K|
Ishikawa|Yoshihiro|Y|
Goshima|Yoshio|Y|

D048049:Extracellular Signal-Regulated MAP Kinases

Cell Biology
Pharmacology
Vascular Biology


Biomimetic Iron Complex Achieves TET Enzyme Reactivity*.

Abstract: The epigenetic marker 5-methyl-2'-deoxycytidine (5mdC) is the most prevalent modification to DNA. It is removed inter alia via an active demethylation pathway: oxidation by Ten-Eleven Translocation 5-methyl cytosine dioxygenase (TET) and subsequent removal via base excision repair or direct demodification. Recently, we have shown that the synthetic iron(IV)-oxo complex [FeIV (O)(Py5 Me2 H)]2+ (1) can serve as a biomimetic model for TET by oxidizing the nucleobase 5-methyl cytosine (5mC) to its natural metabolites. In this work, we demonstrate that nucleosides and even short oligonucleotide strands can also serve as substrates, using a range of HPLC and MS techniques. We found that the 5-position of 5mC is oxidized preferably by 1, with side reactions occurring only at the strand ends of the used oligonucleotides. A detailed study of the reactivity of 1 towards nucleosides confirms our results; that oxidation of the anomeric center (1') is the most common side reaction.

Schmidl|David|D|
Jonasson|Niko S W|NSW|
Korytiaková|Eva|E|
Carell|Thomas|T|
Daumann|Lena J|LJ|0000-0003-2197-136X

TET enzymes
5-methyl cytosine
iron(IV)-oxo
DNA methylation
bioinorganic chemistry
enzyme models


Interdialytic Weight Gain Effects on Hemoglobin Concentration and Cardiovascular Events.

Abstract:
Introduction
Although predialysis hemoglobin concentration is affected by interdialytic weight gain (IDWG), the interaction between these parameters is not well understood.

Methods
Using data from the Japanese Dialysis Outcomes and Practice Pattern Study phases 1-5, we analyzed patients who underwent maintenance hemodialysis. The exposure variable was hemoglobin concentration, and the effect modifier was IDWG at baseline. These 2 categorical variables were then combined and analyzed. The primary outcome was major adverse cardiovascular events (MACEs). Hazard ratios were estimated using a Cox model for the association between exposure and MACEs after adjusting for potential confounders. We examined additive interactions between hemoglobin concentration and IDWG by calculating the relative excess risk due to interaction, which is defined as a departure from the additivity of effects.

Results
A total of 8234 patients were enrolled. During a median follow-up of 2.1 years, 1062 (12.9%) patients developed MACEs. In IDWG categories of <6%, adjusted hazard ratios for MACEs tended to be lower as hemoglobin concentration increased. In IDWG categories of ≥6%, point estimation of MACEs with hemoglobin concentration of ≥11.0 g/dl-<12.0 g/dl was higher than that with hemoglobin concentration of ≥10.0 g/dl-<11.0 g/dl. The relative excess risk due to interaction was 0.22 (95% confidence interval 0.02-0.42) between IDWG category of ≥6% and hemoglobin categories of ≥11.0 g/dl-<12.0 g/dl, indicating a synergistic interaction.

Conclusions
The association between hemoglobin concentration and MACEs differed across IDWG. Consideration should be given to the upper limit of hemoglobin concentration in patients with high IDWG.

Hara|Takashi|T| Kimachi|Miho|M| Akizawa|Tadao|T| Fukuhara|Shunichi|S| Yamamoto|Yosuke|Y|

interdialytic weight gain
hemoglobin
predialysis
interaction
hemodialysis
major adverse cardiovascular events


High-throughput sequencing of microbial eukaryotes in Lake Baikal reveals ecologically differentiated communities and novel evolutionary radiations.

Abstract: We performed high-throughput 18S rDNA V9 region sequencing analyses of microeukaryote (protist) communities at seven sites with depths ranging from 0 to 1450 m in the southern part of Lake Baikal. We show that microeukaryotic diversity differed according to water column depth and sediment depth. Chrysophytes and perkinsids were diverse in subsurface samples, novel radiations of petalomonads and Ichthyobodo relatives were found in benthic samples, and a broad range of divergent OTUs were detected in deep subbenthic samples. Members of clades usually associated with marine habitats were also detected, including syndineans for the first time in freshwater systems. Fungal- and cercozoan-specific c. 1200 bp amplicon clone libraries also revealed many novel lineages in both planktonic and sediment samples at all depths, a novel radiation of aphelids in shallower benthic samples, and partitioning of sarcomonad lineages in shallow vs deep benthic samples. Putative parasitic lineages accounted for 12.4% of overall reads, including a novel radiation of Ichthyobodo (fish parasite) relatives. Micrometazoans were also analysed, including crustaceans, rotifers and nematodes. The deepest (>1000 m) subsurface sediment samples harboured some highly divergent sequence types, including heterotrophic flagellates, parasites, putative metazoans and sequences likely representing organisms originating from higher up in the water column.

Yi|Zhenzhen|Z| Berney|Cedric|C| Hartikainen|Hanna|H| Mahamdallie|Shazia|S| Gardner|Michelle|M| Boenigk|Jens|J| Cavalier-Smith|Thomas|T| Bass|David|D|

Lake Baikal
18S rDNA
microeukaryote
depth
Cercozoa
fungi