Paths to Open Access: An update from Acta Materialia, Inc.

Publication date: 15 September 2017
Source:Acta Biomaterialia, Volume 60
Author(s): Christopher A. Schuh, Kazuhiro Hono, William R. Wagner, Baptiste Gault, Joseph D'Angelo, George T. Gray




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Rheological characterization of human brain tissue

Publication date: 15 September 2017
Source:Acta Biomaterialia, Volume 60
Author(s): S. Budday, G. Sommer, J. Haybaeck, P. Steinmann, G.A. Holzapfel, E. Kuhl
The rheology of ultrasoft materials like the human brain is highly sensitive to regional and temporal variations and to the type of loading. While recent experiments have shaped our understanding of the time-independent, hyperelastic response of human brain tissue, its time-dependent behavior under various loading conditions remains insufficiently understood. Here we combine cyclic and relaxation testing under multiple loading conditions, shear, compression, and tension, to understand the rheology of four different regions of the human brain, the cortex, the basal ganglia, the corona radiata, and the corpus callosum. We establish a family of finite viscoelastic Ogden-type models and calibrate their parameters simultaneously for all loading conditions. We show that the model with only one viscoelastic mode and a constant viscosity captures the essential features of brain tissue: nonlinearity, pre-conditioning, hysteresis, and tension-compression asymmetry. With stiffnesses and time constants of μ∞=0.7kPa, μ1=2.0kPa, and τ1=9.7s in the gray matter cortex and μ∞=0.3kPa, μ1=0.9kPa and τ1=14.9s in the white matter corona radiata combined with negative parameters α∞ and α1, this five-parameter model naturally accounts for pre-conditioning and tissue softening. Increasing the number of viscoelastic modes improves the agreement between model and experiment, especially across the entire relaxation regime. Strikingly, two cycles of pre-conditioning decrease the gray matter stiffness by up to a factor three, while the white matter stiffness remains almost identical. These new insights allow us to better understand the rheology of different brain regions under mixed loading conditions. Our family of finite viscoelastic Ogden-type models for human brain tissue is simple to integrate into standard nonlinear finite element packages. Our simultaneous parameter identification of multiple loading modes can inform computational simulations under physiological conditions, especially at low to moderate strain rates. Understanding the rheology of the human brain will allow us to more accurately model the behavior of the brain during development and disease and predict outcomes of neurosurgical procedures.Statement of SignificanceWhile recent experiments have shaped our understanding of the time-independent, hyperelastic response of human brain tissue, its time-dependent behavior at finite strains and under various loading conditions remains insufficiently understood. In this manuscript, we characterize the rheology of human brain tissue through a family of finite viscoelastic Ogdentype models and identify their parameters for multiple loading modes in four different regions of the brain. We show that even the simplest model of this family, with only one viscoelastic mode and five material parameters, naturally captures the essential features of brain tissue: its characteristic nonlinearity, pre-conditioning, hysteresis, and tension-compression asymmetry. For the first time, we simultaneously identify a single parameter set for shear, compression, tension, shear relaxation, and compression relaxation loading. This parameter set is significant for computational simulations under physiological conditions, where loading is naturally of mixed mode nature. Understanding the rheology of the human brain will help us predict neurosurgical procedures, inform brain injury criteria, and improve the design of protective devices.

Graphical abstract

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Exploring the role of peptides in polymer-based gene delivery

Publication date: 15 September 2017
Source:Acta Biomaterialia, Volume 60
Author(s): Yanping Sun, Zhen Yang, Chunxi Wang, Tianzhi Yang, Cuifang Cai, Xiaoyun Zhao, Li Yang, Pingtian Ding
Polymers are widely studied as non-viral gene vectors because of their strong DNA binding ability, capacity to carry large payload, flexibility of chemical modifications, low immunogenicity, and facile processes for manufacturing. However, high cytotoxicity and low transfection efficiency substantially restrict their application in clinical trials. Incorporating functional peptides is a promising approach to address these issues. Peptides demonstrate various functions in polymer-based gene delivery systems, such as targeting to specific cells, breaching membrane barriers, facilitating DNA condensation and release, and lowering cytotoxicity. In this review, we systematically summarize the role of peptides in polymer-based gene delivery, and elaborate how to rationally design polymer-peptide based gene delivery vectors.Statement of SignificancePolymers are widely studied as non-viral gene vectors, but suffer from high cytotoxicity and low transfection efficiency. Incorporating short, bioactive peptides into polymer-based gene delivery systems can address this issue. Peptides demonstrate various functions in polymer-based gene delivery systems, such as targeting to specific cells, breaching membrane barriers, facilitating DNA condensation and release, and lowering cytotoxicity. In this review, we highlight the peptides' roles in polymer-based gene delivery, and elaborate how to utilize various functional peptides to enhance the transfection efficiency of polymers. The optimized peptide-polymer vectors should be able to alter their structures and functions according to biological microenvironments and utilize inherent intracellular pathways of cells, and consequently overcome the barriers during gene delivery to enhance transfection efficiency.

Graphical abstract

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Editorial Board

Publication date: 15 September 2017
Source:Acta Biomaterialia, Volume 60





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Burden of rare variants in ALS genes influences survival in familial and sporadic ALS

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58
Author(s): Shirley Yin-Yu Pang, Jacob Shujui Hsu, Kay-Cheong Teo, Yan Li, Michelle H.W. Kung, Kathryn S.E. Cheah, Danny Chan, Kenneth M.C. Cheung, Miaoxin Li, Pak-Chung Sham, Shu-Leong Ho
Genetic variants are implicated in the development of amyotrophic lateral sclerosis (ALS), but it is unclear whether the burden of rare variants in ALS genes has an effect on survival. We performed whole genome sequencing on 8 familial ALS (FALS) patients with superoxide dismutase 1 (SOD1) mutation and whole exome sequencing on 46 sporadic ALS (SALS) patients living in Hong Kong and found that 67% had at least 1 rare variant in the exons of 40 ALS genes; 22% had 2 or more. Patients with 2 or more rare variants had lower probability of survival than patients with 0 or 1 variant (p = 0.001). After adjusting for other factors, each additional rare variant increased the risk of respiratory failure or death by 60% (p = 0.0098). The presence of the rare variant was associated with the risk of ALS (Odds ratio 1.91, 95% confidence interval 1.03–3.61, p = 0.03), and ALS patients had higher rare variant burden than controls (MB, p = 0.004). Our findings support an oligogenic basis with the burden of rare variants affecting the development and survival of ALS.



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Mutations in TYROBP are not a common cause of dementia in a Turkish cohort

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58
Author(s): Lee Darwent, Susana Carmona, Ebba Lohmann, Gamze Guven, Celia Kun-Rodrigues, Basar Bilgic, Hasmet Hanagasi, Hakan Gurvit, Nihan Erginel-Unaltuna, Meltem Pak, John Hardy, Andrew Singleton, Jose Brás, Rita Guerreiro
Mutations in TYROBP and TREM2 have been shown to cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. Recently, variants in TREM2 were also associated with frontotemporal dementia and Alzheimer's disease. Given the functional proximity between these 2 genes, we investigated the genetic variation of TYROBP in a Turkish cohort of 103 dementia patients. No mutations or copy number variants predicted to be pathogenic were identified. These results indicate that mutations in TYROBP are not a common cause of dementia in this Turkish cohort.



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Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss

Publication date: November 2017
Source:Neurobiology of Aging, Volume 59
Author(s): Ann M. Laszczyk, Stephanie Fox-Quick, Hai T. Vo, Dailey Nettles, Phyllis C. Pugh, Linda Overstreet-Wadiche, Gwendalyn D. King
Although the absence of the age-regulating klotho protein causes klotho-deficient mice to rapidly develop cognitive impairment and increasing klotho enhances hippocampal-dependent memory, the cellular effects of klotho that mediate hippocampal-dependent memory function are unknown. Here, we show premature aging of the klotho-deficient hippocampal neurogenic niche as evidenced by reduced numbers of neural stem cells, decreased proliferation, and impaired maturation of immature neurons. Klotho-deficient neurospheres show reduced proliferation and size that is rescued by supplementation with shed klotho protein. Conversely, 6-month-old klotho-overexpressing mice exhibit increased numbers of neural stem cells, increased proliferation, and more immature neurons with enhanced dendritic arborization. Protection from normal age-related loss of object location memory with klotho overexpression and loss of spatial memory when klotho is reduced by even half suggests direct, local effects of the protein. Together, these data show that klotho is a novel regulator of postnatal neurogenesis affecting neural stem cell proliferation and maturation sufficient to impact hippocampal-dependent spatial memory function.



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Alzheimer's-related cortical atrophy is associated with postoperative delirium severity in persons without dementia

Publication date: November 2017
Source:Neurobiology of Aging, Volume 59
Author(s): Annie M. Racine, Tamara G. Fong, Thomas G. Travison, Richard N. Jones, Yun Gou, Sarinnapha M. Vasunilashorn, Edward R. Marcantonio, David C. Alsop, Sharon K. Inouye, Bradford C. Dickerson
Patients with dementia due to Alzheimer's disease (AD) have increased risk of developing delirium. This study investigated the relationship between a magnetic resonance imaging (MRI)–derived biomarker associated with preclinical AD and postoperative delirium. Participants were older adults (≥70 years) without dementia who underwent preoperative MRI and elective surgery. Delirium incidence and severity were evaluated daily during hospitalization. Cortical thickness was averaged across a published set of a priori brain regions to derive a measure known as the "AD signature." Logistic and linear regression was used, respectively, to test whether the AD signature was associated with delirium incidence in the entire sample (N = 145) or with the severity of delirium among those who developed delirium (N = 32). Thinner cortex in the AD signature did not predict incidence of delirium (odds ratio = 1.15, p = 0.38) but was associated with greater delirium severity among those who developed delirium (b = −1.2, p = 0.014). These results suggest that thinner cortices, perhaps reflecting underlying neurodegeneration due to preclinical AD, may serve as a vulnerability factor that increases severity once delirium occurs.

Graphical abstract

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Editorial Advisory Board

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58





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Screening for TMEM230 mutations in young-onset Parkinson's disease

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58
Author(s): Dongrui Ma, Jia Nee Foo, Ebonne Yulin Ng, Yi Zhao, Jian-Jun Liu, Eng King Tan
TMEM230 gene mutations have been reported to be linked with Parkinson's disease (PD) recently. To investigate the prevalence of this gene in southeastern Chinese patients with PD, whole exome sequencing was performed in young-onset and familial PD patients and healthy controls in our Asian population. One heterozygous missense p.Phe121Ser mutation was detected in a healthy 76-year-old control subject and no other TMEM230 mutations were found in PD patients and controls. These data suggest that TMEM230 mutation might be a rare cause of Chinese familial and sporadic PD patients and a larger sample size will be needed to evaluate the association of TMEM230 polymorphic variants with PD.



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Contents Continued

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58





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Presenilin 1 mutation decreases both calcium and contractile responses in cerebral arteries

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58
Author(s): Xavier Toussay, Jean-Luc Morel, Nathalie Biendon, Lolita Rotureau, François-Pierre Legeron, Marie-Charlotte Boutonnet, Yoon H. Cho, Nathalie Macrez
Mutations or upregulation in presenilin 1 (PS1) gene are found in familial early-onset Alzheimer's disease or sporadic late-onset Alzheimer's disease, respectively. PS1 has been essentially studied in neurons and its mutation was shown to alter intracellular calcium (Ca²⁺) signals. Here, we showed that PS1 is expressed in smooth muscle cells (SMCs) of mouse cerebral arteries, and we assessed the effects of the deletion of exon 9 of PS1 (PS1dE9) on Ca²⁺ signals and contractile responses of vascular SMC. Agonist-induced contraction of cerebral vessels was significantly decreased in PS1dE9 both in vivo and ex vivo. Spontaneous activity of Ca²⁺ sparks through ryanodine-sensitive channels (RyR) was unchanged, whereas the RyR-mediated Ca²⁺-release activated by caffeine was shorter in PS1dE9 SMC when compared with control. Moreover, PS1dE9 mutation decreased the caffeine-activated capacitive Ca²⁺ entry, and inhibitors of SERCA pumps reversed the effects of PS1dE9 on Ca²⁺ signals. PS1dE9 mutation also leads to the increased expression of SERCA3, phospholamban, and RyR3. These results show that PS1 plays a crucial role in the cerebrovascular system and the vascular reactivity is decreased through altered Ca²⁺ signals in PS1dE9 mutant mice.



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Multivariate analyses of peripheral blood leukocyte transcripts distinguish Alzheimer's, Parkinson's, control, and those at risk for developing Alzheimer's

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58
Author(s): Elaine Delvaux, Diego Mastroeni, Jennifer Nolz, Nienwen Chow, Marwan Sabbagh, Richard J. Caselli, Eric M. Reiman, Frederick J. Marshall, Paul D. Coleman
The need for a reliable, simple, and inexpensive blood test for Alzheimer's disease (AD) suitable for use in a primary care setting is widely recognized. This has led to a large number of publications describing blood tests for AD, which have, for the most part, not been replicable. We have chosen to examine transcripts expressed by the cellular, leukocyte compartment of blood. We have used hypothesis-based cDNA arrays and quantitative PCR to quantify the expression of selected sets of genes followed by multivariate analyses in multiple independent samples. Rather than a single study with no replicates, we chose an experimental design in which there were multiple replicates using different platforms and different sample populations. We have divided 177 blood samples and 27 brain samples into multiple replicates to demonstrate the ability to distinguish early clinical AD (Clinical Dementia Rating scale 0.5), Parkinson's disease (PD), and cognitively unimpaired APOE4 homozygotes, as well as to determine persons at risk for future cognitive impairment with significant accuracy. We assess our methods in a training/test set and also show that the variables we use distinguish AD, PD, and control brain. Importantly, we describe the variability of the weights assigned to individual transcripts in multivariate analyses in repeated studies and suggest that the variability we describe may be the cause of inability to repeat many earlier studies. Our data constitute a proof of principle that multivariate analysis of the transcriptome related to cell stress and inflammation of peripheral blood leukocytes has significant potential as a minimally invasive and inexpensive diagnostic tool for diagnosis and early detection of risk for AD.



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Association of anti-inflammatory cytokine IL10 polymorphisms with motoric cognitive risk syndrome in an Ashkenazi Jewish population

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58
Author(s): Sanish Sathyan, Nir Barzilai, Gil Atzmon, Sofiya Milman, Emmeline Ayers, Joe Verghese
Motoric cognitive risk (MCR) syndrome is a newly described predementia syndrome characterized by the presence of cognitive complaints and slow gait, which is associated with increased risk of conversion to dementia. The underlying biological mechanisms for MCR have not yet been established. Neuroinflammation mediated through cytokines plays a pivotal role in the pathogenesis of dementia. Hence, our objective was to prospectively examine whether variations in cytokine genes (CRP, IFNG, IL1A, IL1B, IL4, IL6, IL10, IL18, TNF, and IL12A) play a role in MCR incidence in 530 community-dwelling Ashkenazi Jewish adults aged 65 years and older without MCR or dementia at baseline enrolled in the LonGenity study. Over a median follow-up of 2.99 years, 70 participants developed MCR. Single nucleotide polymorphisms (SNPs) in the transcriptional regulatory regions of cytokine IL10, rs1800896 (hazard ratio adjusted for age, gender, and education, aHR: 1.667; 95% CI: 1.198–2.321) and rs3024498 (aHR: 1.926; 95% CI: 1.315–2.822), were associated with incident MCR. Functional analysis using in silico approaches indicated associated SNP rs3024498 "C" allele being the local expression quantitative trait locus. Associated alleles of both the SNPs, rs1800896 and rs3024498, were implicated with overexpression of IL10 gene. None of the variants in the neuroinflammatory pathway studied were associated with incident mild cognitive impairment syndrome. These observations support a role for the IL10 gene in dementia pathogenesis by increasing risk of developing MCR in older adults.



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Cognitive and motor functioning in elderly glucocerebrosidase mutation carriers

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58
Author(s): Eileen E. Moran, Cuiling Wang, Mindy Katz, Laurie Ozelius, Alison Schwartz, Jelena Pavlovic, Roberto A. Ortega, Richard B. Lipton, Molly E. Zimmerman, Rachel Saunders-Pullman
Mutations in the glucocerebrosidase (GBA) gene are a strong genetic risk factor for the development of Parkinson's disease and dementia with Lewy Bodies. However the penetrance of GBA mutations is low for these diseases in heterozygous carriers. The aim of this study was to examine the relationship between mutation status and cognitive and motor functioning in a sample of community-dwelling older adults. Using linear mixed effects models, we examined the effect of heterozygous mutation status on 736 community-dwelling older adults (≥70 years) without dementia or Parkinson's disease assessed over an average of 6 years, 28 of whom had a single GBA mutation (primarily N370S). Verbal memory was measured using the picture version of the Free and Cued Selective Reminding Test, and carriers showed significantly (p < 0.05) greater decline in verbal memory over time. There was no difference in motor function or any other cognitive domain. Taken together, these results suggest an effect, but an overall limited burden, of harboring a single GBA mutation in aging mutation carriers.



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Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58
Author(s): Elisa Teyssou, Laura Chartier, Maria-Del-Mar Amador, Roselina Lam, Géraldine Lautrette, Marie Nicol, Selma Machat, Sandra Da Barroca, Carine Moigneu, Mathilde Mairey, Thierry Larmonier, Safaa Saker, Christelle Dussert, Sylvie Forlani, Bertrand Fontaine, Danielle Seilhean, Delphine Bohl, Séverine Boillée, Vincent Meininger, Philippe Couratier, François Salachas, Giovanni Stevanin, Stéphanie Millecamps
Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser, P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S; and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2 in familial motor neuron diseases including ALS and spastic paraplegia (SP). A novel missense mutation (c.1462G>A, p.Ala488Thr, A488T) adjacent to this hotspot UBQLN2 domain was identified in a sporadic case of ALS. These mutations are conserved in mammals, are absent from ExAC and gnomAD browsers, and are predicted to be deleterious by SIFT in silico analysis. Patient lymphoblasts carrying a UBQLN2 mutation showed absence of ubiquilin-2 accumulation, disrupted binding with HSP70, and impaired autophagic pathway. Our results confirm the role of PXX repeat in ALS pathogenesis, show that UBQLN2-linked disease can manifest like a SP phenotype, evidence a highly reduced disease penetrance in females carrying UBQLN2 mutations, which is important information for genetic counseling, and underline the pivotal role of ubiquilin-2 in proteolysis regulation pathways.



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Corrigendum to “Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer’s disease” [Neurobiol. Aging 58 (2017) 1–13]

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58
Author(s): Ramon Velazquez, An Tran, Egide Ishimwe, Larry Denner, Nikhil Dave, Salvatore Oddo, Kelly T. Dineley




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Contents

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58





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Melasma Treatment With Combined Chemical Peels and Novel Topical Agent Containing an Anti-estrogen and a Vascular Endothelial Growth Factor Inhibitor.

No abstract available

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The Next Turf War for Botulinum Toxin?.

No abstract available

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Triple Combination Therapy for Pincer Nail Deformity: Surgical Matricectomy, Thioglycolic Acid, and Anticonvex Sutures.

BACKGROUND: Pincer nail deformity (PND) is characterized by an excessive transverse curvature of the nail plate that increases along the longitudinal axis of the nail. Although many conservative and surgical techniques have been used in clinical practice, an established consensus for the correction of PND has not been present yet. OBJECTIVE: Aim of the technique described in this article is to provide to restore the suitable nail-matrix system curvature by a simplified and quick approach, which could be seen as a synthesis of conservative and surgical treatments described in the literature. METHODS AND MATERIALS: Nineteen cases of pincer nail of the great toe in 14 patients were analyzed. After softening nail plate with 5% thioglycolic acid solution for at least half an hour, surgical bilateral matricectomy and 2 anticonvex sutures with 1-0 polypropylene were performed to ensure proper nail plate shape. Besides demographic data, visual analog scale (VAS) score for pain, width index, height index, patient and surgeon satisfaction scores, operation time, and the day of painless return to the daily activities were investigated. RESULTS: A statistical significance was observed in VAS score for pain, width, and height indices between preoperative and postoperative values. CONCLUSION: This report gives acceptable outcomes with a combination of surgery and conservative treatments. (C) 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.

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Correlation Between Original Biopsy Pathology and Mohs Intraoperative Pathology.

BACKGROUND: The pathology observed on initial biopsy specimens for nonmelanoma skin cancer (NMSC), specifically the tumor subtype, weighs heavily into the selection of the treatment modality. Recognizing aggressive features on intraoperative Mohs micrographic surgery (MMS) frozen sections that were not indicated on initial biopsy reports is not uncommon. To date, there is limited data describing this discrepancy. OBJECTIVE: To investigate the frequency and nature of incongruity between the pathology seen in initial biopsies and intraoperative Mohs sections, providing information that will potentially impact skin cancer treatment and biopsy recommendations. METHODS: Retrospective chart review of cases of NMSC referred for MMS at the authors' institution over a 1-year period, recording changes between tumor subtypes observed at biopsy and those observed during MMS. RESULTS: Cases (50.5%) (n = 163) changed aggressiveness. Of these, 33% (n = 108) were more aggressive, whereas 17% (n = 55) were less aggressive. CONCLUSION: A substantial discrepancy was observed between preoperative biopsy and intraoperative pathology, including a significant portion tumors that became more aggressive. These results suggest that treatment modalities without margin control may not provide adequate treatment for a considerable number of NMSC based on preoperative tumor type alone. (C) 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.

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Polyalkylimide and Invasive Growth of Basal Cell Carcinoma of the Skin.

No abstract available

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A Comparison of Objective Assessment Data for the United States and International Medical Graduates in a General Surgery Residency

Publication date: Available online 30 August 2017
Source:Journal of Surgical Education
Author(s): Francisco Cardenas Lara, Nimesh D. Naik, T.K. Pandian, Becca L. Gas, Suzanne Strubel, Rachel Cadeliña, Stephanie F. Heller, David R. Farley
ObjectiveTo compare objective assessment scores between international medical graduates (IMGs) and United States Medical Graduates. Scores of residents who completed a preliminary year, who later matched into a categorical position, were compared to those who matched directly into a categorical position at the Mayo Clinic, Rochester.DesignPostgraduate year (PGY) 1 to 5 residents participate in a biannual multistation, OSCE-style assessment event as part of our surgical training program. Assessment data were, retrospectively, reviewed and analyzed from 2008 to 2016 for PGY-1 and from 2013 to 2016 for PGY 2 to 5 categorical residents.SettingAcademic medical center.ParticipantsCategorical PGY 1 to 5 General Surgery (GS) residents at Mayo Clinic Rochester, MN.ResultsA total of 86 GS residents were identified. Twenty-one residents (1 United States Medical Graduates [USMG] and 20 IMGs) completed a preliminary GS year, before matching into a categorical position and 68 (58 USMGs and 10 IMGs) residents, who matched directly into a categorical position, were compared. Mean scores (%) for the summer and winter multistation assessments were higher for PGY-1 trainees with a preliminary year than those without (summer: 59 vs. 37, p < 0.001; winter: 69 vs. 61, p = 0.05). Summer and winter PGY-2 scores followed the same pattern (74 vs. 64, p < 0.01; 85 vs. 71, p < 0.01). For the PGY 3 to 5 assessments, differences in scores between these groups were not observed. IMGs and USMGs scored equivalently on all assessments. Overall, junior residents showed greater score improvement between tests than their senior colleagues (mean score increase: PGY 1-2 = 18 vs. PGY 3-5 = 3, p < 0.001).ConclusionsResidents with a previous preliminary GS year at our institution scored higher on initial assessments compared to trainees with no prior GS training at our institution. The scoring advantage of an added preliminary year decreased as trainees progressed through residency.



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Evaluating the Use of Cleft Lip and Palate 3D-Printed Models as a Teaching Aid

Publication date: Available online 30 August 2017
Source:Journal of Surgical Education
Author(s): Ahmad B. AlAli, Michelle F. Griffin, Wenceslao M. Calonge, Peter E. Butler
ObjectiveVisualization tools are essential for effective medical education, to aid students understanding of complex anatomical systems. Three dimensional (3D) printed models are showing a wide-reaching potential in the field of medical education, to aid the interpretation of 2D imaging. This study investigates the use of 3D-printed models in educational seminars on cleft lip and palate, by comparing integrated "hands-on" student seminars, with 2D presentation seminar methods.SettingCleft lip and palate models were manufactured using 3D-printing technology at the medical school.ParticipantsSixty-seven students from two medical schools participated in the study.DesignThe students were randomly allocated to 2 groups. Knowledge was compared between the groups using a multiple-choice question test before and after the teaching intervention. Group 1 was the control group with a PowerPoint presentation-based educational seminar and group 2 was the test group, with the same PowerPoint presentation, but with the addition of a physical demonstration using 3D-printed models of unilateral and bilateral cleft lips and palate.ResultsThe level of knowledge gained was established using a preseminar and postseminar assessment, in 2 different institutions, where the addition of the 3D-printed model resulted in a significant improvement in the mean percentage of knowledge gained (44.65% test group; 32.16%; control group; p = 0.038). Student experience was assessed using a postseminar survey, where students felt the 3D-printed model significantly improved the learning experience (p = 0.005) and their visualization (p = 0.001).ConclusionsThis study highlights the benefits of the use of 3D-printed models as visualization tools in medical education and the potential of 3D-printing technology to become a standard and effective tool in the interpretation of 2D imaging.



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Should Oral Corticosteroids Be Used to Treat Demyelinating Optic Neuritis?.

No abstract available

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Graphene nanoribbon/FePt bimetallic nanoparticles/uric acid as a novel magnetic sensing layer of screen printed electrode for sensitive determination of ampyra

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Pegah Hashemi, Hasan Bagheri, Abbas Afkhami, Salimeh Amidi, Tayyebeh Madrakian
A novel electrochemical sensor for sensitive determination of ampyra (Am) based on graphene nanoribbons modified by iron-platinum bimetallic nanoparticles and uric acid (SPCE/FePtGNR/UA) dropped on the screen-printed carbon electrode (SPCE) surface and magnetically captured onto an SPCE working electrode surface is reported in the present work. The modified nanocomposite and sensing layer was characterized by different techniques, including cyclic voltammetry (CV), linear sweep voltammetry (LSV), electrochemical impedance spectroscopy (EIS), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR) and X-ray powdered diffraction (XRD). Am determination by conventional electrochemical methods is not possible, because of its high redox overpotential. Therefore, the differential pulse voltammetry (DPV) signals of UA were used as a redox probe for indirect electrochemical determination of Am. The limit of detection (LOD) and linear concentration range were obtained as 0.028 and 0.08–9.0µmolL⁻¹ (3Sb/m = 3), respectively. The feasibility of the proposed method was examined by the detection of Am in biological and pharmaceutical samples with satisfactory results. The constructed electrochemical sensor was applied for fast, simple and sensitive detection of Am in real environments.

Graphical abstract

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Accurate and sensitive fluorescence detection of DNA based on G-quadruplex hairpin DNA

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Yi Liu, Rong Liao, Huan Wang, Hang Gong, Chunyan Chen, Xiaoming Chen, Changqun Cai
A facile and cost-effective fluorescence biosensor is constructed for the accurate and sensitive determination of DNA. The G-quadruplex-forming sequence in hairpin DNA sequence (H1) is originally locked. When target DNA is present, the hairpin structure of H1 can be unfolded and part of H1 hybridized with the target DNA to form a double-stranded DNA and a G-quadruplex. The hairpin DNA sequence (H2) hybridizes with the unfolded H1 and displaces the target DNA. Finally, the displaced target DNA again hybridizes with the H1 and initiates cycle amplification. Thus, the numerous G-quadruplexs at the H1 ends are formed, resulting in the fluorescent enhancement after binding with N-methyl mesoporphyrin IX (NMM). Lower background signal improves the accuracy of assay. The enzyme-free method can detect down to 40pM and a linear range of 3 orders of magnitude. Moreover, this strategy has an ability to discriminate the target DNA from even single-base mismatched or other sequence. The proposed method has potential applications in DNA-based molecular diagnostics.

Graphical abstract

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Full validation of a method for the determination of drugs of abuse in non-mineralized dental biofilm using liquid chromatography-tandem mass spectrometry and application to postmortem samples

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Kerstin Henkel, Markus J. Altenburger, Volker Auwärter, Merja A. Neukamm
Alternative matrices play a major role in postmortem forensic toxicology, especially if common matrices (like body fluids or hair) are not available. Incorporation of illicit and medicinal drugs into non-mineralized dental biofilm (plaque) seems likely but has not been investigated so far. Analysis of plaque could therefore extend the spectrum of potentially used matrices in postmortem toxicology. For this reason, a rapid, simple and sensitive method for the extraction, determination and quantification of ten drugs of abuse from plaque using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and fully validated. Amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA), 3,4-methylenedioxyamphetamine (MDA), cocaine, benzoylecgonine, morphine, codeine and 6-acetylmorphine were extracted from 2mg of dried and powdered plaque via ultrasonication with acetonitrile. The extracts were analyzed on a triple-quadrupole linear ion trap mass spectrometer in scheduled multiple reaction monitoring mode (sMRM). The method was fully validated and proved accurate, precise, selective and specific with satisfactory linearity within the calibrated ranges. The lower limit of quantification was 10–15pgmg⁻¹ for all compounds except for MDA (100pgmg⁻¹) and amphetamine (200pgmg⁻¹). The method has been successfully applied to three authentic postmortem samples with known drug history. Amphetamine, MDMA, cocaine, benzoylecgonine, morphine and codeine could be detected in these cases in concentrations ranging from 18pgmg⁻¹ for cocaine to 1400pgmg⁻¹ for amphetamine.

Graphical abstract

http://ift.tt/2vLIxzi

A novel colorimetric and ratiometric fluorescent probe for visualizing SO2 derivatives in environment and living cells

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Zhuo Ye, Chong Duan, Ruilong Sheng, Junchao Xu, Hongying Wang, Lintao Zeng
Monitoring sulfur dioxide (SO2) derivatives in environment is of great significance due to their harmful effects to the environment and human health. In this study, a fluorescent probe (CZBT) for SO2 derivatives was prepared from 9-ethyl-9H-carbazole-3,6-dicarboxaldehyde and 2-methyl-benzothiazolium, which displayed a noticeable color change from yellow to colorless along with a remarkable fluorescence change from yellow to blue in response to HSO3⁻. The probe could quantitatively determine the concentration of HSO3⁻ with excellent selectivity, high sensitivity and low limit of detection. ¹H NMR and HR-MS spectra demonstrated that a selective 1, 4-nucleophilic addition occurred on the bridge double bond in CZBT. The probe was successfully used to determine the SO2 derivatives in several real water samples with good recovery. Furthermore, the probe was employed for monitoring the level of intracellular HSO3⁻ in HeLa (human cervical cancer) cells by fluorescence imaging. These results indicated that CZBT has a good capability for monitoring SO2 derivatives in environment and living cells.

Graphical abstract

http://ift.tt/2vKUw02

Rapid and sensitive serum glucose determination using chemical labeling coupled with black phosphorus-assisted laser desorption/ionization time-of-flight mass spectrometry

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Qing Wang, Lei Yu, Chu-Bo Qi, Jun Ding, Xiao-Mei He, Ren-Qi Wang, Yu-Qi Feng
Monitoring the concentration of blood glucose in patients is a key component of good medical diagnoses. Therefore, developing an accurate, rapid and sensitive strategy for monitoring blood glucose is of vital importance. We proposed a strategy for serum glucose determination combining 2-(4-boronobenzyl) isoquinolin-2-ium bromide chemical labeling with black phosphorus assisted laser desorption ionization-time of flight mass spectrometry (CL-BP/ALDI-TOF MS). The entire analytical process consisted of 1min of protein precipitation and 3min of chemical labeling in a microwave oven prior to the BP/ALDI-TOF MS analysis. The analysis can be completed in 5min with high throughput and extremely low sample consumption. Good linearity for glucose was obtained with a correlation coefficient (R) of 0.9986. The limit of detection (LOD) and limit of quantification (LOQ) were 11.5 fmol and 37.5 fmol, respectively. Satisfied reproducibility and reliability were gained by evaluation of the intra- and inter-day precisions with relative standard deviations (RSDs) less than 7.2% and relative recoveries ranging from 87.1% to 108.1%, respectively. The proposed strategy was also applied for the analysis of endogenous glucose in various serum samples and the results were consistent with those obtained using the hexokinase method in a clinical laboratory. Considering the results, the proposed CL-BP/ALDI-TOF MS strategy has proven to be reliable, fast, and sensitive for quantitative analysis of serum glucose.

Graphical abstract

http://ift.tt/2vKUvJw

Coupling dispersive liquid-liquid microextraction to inductively coupled plasma atomic emission spectrometry: An oxymoron?

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): David Martínez, Daniel Torregrosa, Guillermo Grindlay, Luis Gras, Juan Mora
Coupling dispersive liquid-liquid micro-extraction (DLLME) to inductively coupled plasma atomic emission spectrometry (ICP-AES) is usually troublesome due to the limited plasma tolerance to the organic solvents usually employed for metal extraction. This work explores different coupling strategies allowing the multi-element determination by ICP-AES of the solutions obtained after DLLME procedures. To this end, three of the most common extractant solvents in DLLME procedures (1-undecanol, 1-butyl-3-methyl-imidazolium hexafluorophosphate and chloroform) have been selected to face most of the main problems reported in DLLME-ICP-AES coupling (i.e., those arising from the high solvent viscosity and volatility). Results demonstrate that DLLME can be successfully coupled to ICP-AES after a careful optimization of the experimental conditions. Thus, elemental analysis in 1-undecanol and 1-butyl-3-methyl-imidazolium hexafluorophosphate extracts can be achieved by ICP-AES after a simple dilution step with methanol (1:0.5). Chloroform can be directly introduced into the plasma with minimum changes in the ICP-AES configuration usually employed when operating with aqueous solutions. Diluted inorganic acid solutions (1% w w⁻¹ either nitric or hydrochloric acids) have been successfully tested for the first time as a carrier for the introduction of organic extractants in ICP-AES. The coupling strategies proposed have been successfully applied to the multi-element analysis (Al, Cu, Fe, Mn, Ni and Zn) of different water samples (i.e. marine, tap and river) by DLLME-ICP-AES.

Graphical abstract

http://ift.tt/2wRMSpA

Towards highly selective detection using metal nanoparticles: A case of silver triangular nanoplates and chlorine

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Vladimir V. Apyari, Marina O. Gorbunova, Anastasiya V. Shevchenko, Aleksei A. Furletov, Pavel A. Volkov, Alexey V. Garshev, Stanislava G. Dmitrienko, Yury A. Zolotov
The article describes a novel approach towards improving selectivity of volatile compounds detection using metal nanoparticles. It is based on combination of sensitive optical detection using convenient nanoparticle-modified paper test strips and dynamic gas extraction improving selectivity to volatile compounds. A simple and inexpensive setup allowing for realization of this combination is described. Analytical prospects of the approach are shown by the example of chlorine determination in highly salted aqueous solutions using silver triangular nanoplates and digital colorimetry. The limit of detection is equal to 0.03mgL⁻¹ and the determination range is 0.1–2mgL⁻¹. This determination can be successfully carried out in solutions containing at least 2·10⁵ greater molar amounts of Na⁺, K⁺, Zn²⁺, Cl^–, SO4^2–, and H2PO4^– with no sample pretreatment. The approach seems to be compatible with different types of nanoparticles with respect to detection of various analytes, thus having good opportunities for further development.

Graphical abstract

http://ift.tt/2vKBB5A

Redesigning flow injection after 40 years of development: Flow programming

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Jaromir (Jarda) Ruzicka
Automation of reagent based assays, by means of Flow Injection (FI), is based on sample processing, in which a sample flows continuously towards and through a detector for quantification of the target analyte. The Achilles heel of this methodology, the legacy of Auto Analyzer®, is continuous reagent consumption, and continuous generation of chemical waste. However, flow programming, assisted by recent advances in precise pumping, combined with the lab-on-valve technique, allows the FI manifold to be designed around a single confluence point through which sample and reagents are sequentially directed by means of a series of flow reversals. This approach results in sample/reagent mixing analogous to the traditional FI, reduces sample and reagent consumption, and uses the stop flow technique for enhancement of the yield of chemical reactions. The feasibility of programmable Flow Injection (pFI) is documented by example of commonly used spectrophotometric assays of, phosphate, nitrate, nitrite and glucose. Experimental details and additional information are available in online tutorial http://ift.tt/2vKL2lf

Graphical abstract

http://ift.tt/2vL5TF6

Expanded uncertainty associated with determination of isotope enrichment factors: Comparison of two point calculation and Rayleigh-plot

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Maxime Julien, Alexis Gilbert, Keita Yamada, Richard J. Robins, Patrick Höhener, Naohiro Yoshida, Gérald S. Remaud
The enrichment factor (ε) is a common way to express Isotope Effects (IEs) associated with a phenomenon. Many studies determine ε using a Rayleigh-plot, which needs multiple data points. More recent articles describe an alternative method using the Rayleigh equation that allows the determination of ε using only one experimental point, but this method is often subject to controversy. However, a calculation method using two points (one experimental point and one at t0) should lead to the same results because the calculation is derived from the Rayleigh equation. But, it is frequently asked "what is the valid domain of use of this two point calculation?" The primary aim of the present work is a systematic comparison of results obtained with these two methodologies and the determination of the conditions required for the valid calculation of ε. In order to evaluate the efficiency of the two approaches, the expanded uncertainty (U) associated with determining ε has been calculated using experimental data from three published articles. The second objective of the present work is to describe how to determine the expanded uncertainty (U) associated with determining ε. Comparative methodologies using both Rayleigh-plot and two point calculation are detailed and it is clearly demonstrated that calculation of ε using a single data point can give the same result as a Rayleigh-plot provided one strict condition is respected: that the experimental value is measured at a small fraction of unreacted substrate (f<30%). This study will help stable isotope users to present their results in a more rigorous expression: ε±U and therefore to define better the significance of an experimental results prior interpretation.Capsule: Enrichment factor can be determined through two different methods and the calculation of associated expanded uncertainty allows checking its significance.

Graphical abstract

http://ift.tt/2xLwDqF

Dihydropyridine-derived BODIPY probe for detecting exogenous and endogenous nitric oxide in mitochondria

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Chang Gao, Lan Lin, Wan Sun, Zheng-Li Tan, Jun-Ru Huang, Lan He, Zhong-Lin Lu
A mitochondria-targetable probe Mito-DHP for nitric oxide (NO) was designed and synthesized by introducing dihydropyridine and triphenylphosphonium (TPP) moieties into boron dipyrromethene (BODIPY) dye. Mito-DHP was able to effectively detect nitric oxide through the aromatization of dihydropyridine to fluorescent pyridine product under oxygen-free conditions. The probe Mito-DHP showed high selectivity to NO over a number of reactive oxygen/nitrogen species (ROS/RNS) as well as high sensitivity (detection limit at 25nM), pH stability and bio-compatibility. Furthermore, Mito-DHP proved to target mitochondria specifically and to visualize both exogenous and endogenous NO in real time.

Graphical abstract

http://ift.tt/2vKYh5m

Hierarchical oxygen-implanted MoS2 nanoparticle decorated graphene for the non-enzymatic electrochemical sensing of hydrogen peroxide in alkaline media

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Yudong Xue, Govindhan Maduraiveeran, Mingyong Wang, Shili Zheng, Yi Zhang, Wei Jin
Owing to the extensive applications of hydrogen peroxide (H2O2) in biological, environmental and chemical engineering, it is of great importance to investigate sensitive and selective sensing platform towards the detection of H2O2. Herein, oxygen-implanted MoS2 nanoparticles decorated graphene nanocomposite is synthesized via a facile one-pot solvothermal method for the sensitive detection of H2O2 in alkaline media. The structure and morphology of the MoS2/graphene nanocomposites were systematically characterized, showing that Mo-O bonds are formed and oxygen is implanted into the crystal structure in the nanocomposite. As a result, the MoS2/graphene composite exhibited enhanced electron transfer kinetics and excellent electro-reduction performance towards H2O2 in alkaline media. Under optimum conditions, the fabricated sensor demonstrated a wide linear response towards H2O2 in the range of 0.25–16mM with a low detection limit of 0.12μM and high sensitivity of 269.7μAmM⁻¹cm⁻². Besides, the constructed sensor presented a good selectivity to H2O2 with the presence of other interfering species. Therefore, the proposed sensor was successfully applied for the detection and determination of H2O2 in real sample, indicating great potential for the practical applications.

Graphical abstract

http://ift.tt/2vKwl1O

Applicability of the direct injection liquid chromatographic tandem mass spectrometric analytical approach to the sub-ngL−1 determination of perfluoro-alkyl acids in waste, surface, ground and drinking water samples

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Lorenzo Ciofi, Lapo Renai, Daniele Rossini, Claudia Ancillotti, Alida Falai, Donatella Fibbi, Maria Concetta Bruzzoniti, José Juan Santana-Rodriguez, Serena Orlandini, Massimo Del Bubba
The applicability of a direct injection UHPLC-MS/MS method for the analysis of several perfluoroalkyl acids (PFAAs) in a wide range of water matrices was investigated. The method is based on the direct injection of 100µL of centrifuged water sample, without any other sample treatment. Very good method detection limits (0.014–0.44ngL⁻¹) and excellent intra and inter-day precision (RSD% values in the range 1.8–4.4% and 2.7–5.7%, respectively) were achieved, with a total analysis time of 20min per sample. A high number of samples – i.e. 8 drinking waters (DW), 12 ground waters (GW), 13 surface waters (SW), 8 influents and 11 effluents of wastewater treatment plants (WWTPIN and WWTPOUT) were processed and the extent of matrix effect (ME) was calculated, highlighting the strong prevalence of |ME| < 20%. The occurrence of |ME| > 50% was occasionally observed only for perfluorooctanesulphonic and perfluorodecanoic acids. Linear discriminant analysis highlighted the great contribution of the sample origin (i.e. DW, GW, SW, WWTPIN and WWTPOUT) to the ME. Partial least square regression (PLS) and leave-one-out cross-validation were performed in order to interpret and predict the signal suppression or enhancement phenomena as a function of physicochemical parameters of water samples (i.e. conductivity, hardness and chemical oxygen demand) and background chromatographic area. The PLS approach resulted only in an approximate screening, due to the low prediction power of the PLS models. However, for most analytes in most samples, the fitted and cross-validated values were such as to correctly distinguish between | ME | higher than 20% or below this limit. PFAAs in the aforementioned water samples were quantified by means of the standard addition method, highlighting their occurrence mainly in WWTP influents and effluents, at concentrations as high as one hundred of µgL⁻¹.

Graphical abstract

http://ift.tt/2vL2sOR

Disordered photonics coupled with embedded nano-Au plasmonics inducing efficient photocurrent enhancement

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Jing Li, Junling Wang, Zhihui Dai, Hongbo Li
Spatial order used to be considered as a benefit for photonics; but recently the study of disorder has broken into people's horizons for its strong random scattering of light. In this work, disordered photonics coupled with plasmonics for efficiently enhanced photocurrent was first investigated using Au-ZnO nanowire array as a model. The embedded Au-ZnO nanowire array was facilely prepared using a template-free electrodeposition method. On the optimal plasmonic substrate, the photocurrent of disorder-enhanced Au-ZnO nanowire array is about 20-fold that of ZnO nanowire array. Both the plasmonic effect of Au NPs such as localized surface plasmons, surface plasmon polarizations and the disorder-enhanced photonics in the hybrid structure are available to improve the photoelectric conversion efficiency by enhancing the trapping of the simulated sunlight and the collection of charge carriers. Herein, disordered photonics was coupled with plasmonics to explain for the enhanced photocurrent. This work also provided a facile fabricating avenue for plasmonic noble metal embedded in semiconductor devices.

Graphical abstract

http://ift.tt/2wjLASL

FRET on lateral flow test strip to enhance sensitivity for detecting cancer biomarker

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Jidong Wang, Fengjing Cao, Songliang He, Yong Xia, Xinyu Liu, Wenxiao Jiang, Yangyang Yu, Huisheng Zhang, Wenwen Chen
Fluorescence resonance energy transfer (FRET) between fluorescein isothiocyanate (FITC) and gold nanoparticles (Au NPs) is introduced in the lateral flow strip to detect cancer biomarker CEA with the color and fluorescence dual-readout. Anti-CEA monoclonal antibody coated Au NPs were on the conjugate pad and FITC labelled antibody (FITC-Ab) for CEA was coated on the test line. All the reagents were general in the lateral flow strip or commercially available and no new materials or technique were involved, which make our proposal a more universal method and easier to operate. With the addition of CEA on the sample pad, anti-CEA monoclonal antibody coated Au NPs-CEA-FITC-Ab complex formed on the test line, leading to a megascopic red line and simultaneous quenched fluorescence of FITC via FRET. The visual limit of detection (LOD) through distinguishing red color change was 10ng/mL and the LOD by differentiating fluorescence intensity was 0.1ng/mL, which was two orders of magnitude lower than that without considering fluorescence in the strip. And the linear range changed from 10–80ng/mL to 5–80ng/mL with the analysis of fluorescence change. Meanwhile, the feasibility of our method applied in real clinical samples was also confirmed.

Graphical abstract

http://ift.tt/2wkcUQV

Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1

Publication date: Available online 30 August 2017
Source:Cell Stem Cell
Author(s): Fengyin Li, Bing He, Xiaoke Ma, Shuyang Yu, Rupali R. Bhave, Steven R. Lentz, Kai Tan, Monica L. Guzman, Chen Zhao, Hai-Hui Xue
Effective treatment of chronic myelogenous leukemia (CML) largely depends on the eradication of CML leukemic stem cells (LSCs). We recently showed that CML LSCs depend on Tcf1 and Lef1 factors for self-renewal. Using a connectivity map, we identified prostaglandin E1 (PGE1) as a small molecule that partly elicited the gene expression changes in LSCs caused by Tcf1/Lef1 deficiency. Although it has little impact on normal hematopoiesis, we found that PGE1 treatment impaired the persistence and activity of LSCs in a pre-clinical murine CML model and a xenograft model of transplanted CML patient CD34⁺ stem/progenitor cells. Mechanistically, PGE1 acted on the EP4 receptor and repressed Fosb and Fos AP-1 factors in a β-catenin-independent manner. Misoprostol, an FDA-approved EP4 agonist, conferred similar protection against CML. These findings suggest that activation of this PGE1-EP4 pathway specifically targets CML LSCs and that the combination of PGE1/misoprostol with conventional tyrosine-kinase inhibitors could provide effective therapy for CML.

Graphical abstract

Teaser

Xue and colleagues show that prostaglandin E1 (PGE1) inhibits the activity and self-renewal of human CML leukemic stem cells. Combination of PGE1 or an agonist for its receptor EP4 with conventional tyrosine kinase inhibitor treatment can effectively target CML leukemic stem cells and reduce leukemia growth.


http://ift.tt/2iIvpcT

Modelling iron mismanagement in neurodegenerative disease in vitro: paradigms, pitfalls, possibilities & practical considerations

Publication date: Available online 30 August 2017
Source:Progress in Neurobiology
Author(s): Sinead Healy, Jill M. McMahon, Una FitzGerald
Although aberrant metabolism and deposition of iron has been associated with aging and neurodegeneration, the contribution of iron to neuropathology is unclear. Well-designed model systems that are suited to studying the putative pathological effect of iron are likely to be essential if such unresolved details are to be clarified. In this review, we have evaluated the utility and effectiveness of the reductionist in vitro platform to study the molecular mechanisms putatively underlying iron perturbations of neurodegenerative disease. The expression and function of iron metabolism proteins in glia and neurons and the extent to which this iron regulatory system is replicated in in vitro models has been comprehensively described followed by an appraisal of the inherent suitability of different in vitro and ex vivo models that have been, or might be, used for iron loading. Next, we have identified and critiqued the relevant experimental parameters that have been used in in vitro iron loading experiments, including the choice of iron reagent, relevant iron loading concentrations and supplementation with serum or ascorbate, and propose optimal iron loading conditions. Finally, we have provided a synthesis of the differential iron accumulation and toxicity in glia and neurons from reported iron loading paradigms. In summary, this review has amalgamated the findings and paradigms of the published reports modelling iron loading in monocultures, discussed the limitations and discrepancies of such work to critically propose a robust, relevant and reliable model of iron loading to be used for future investigations.



http://ift.tt/2vLjhcd

Can less be more? Open trial of a stepped care approach for child and adolescent anxiety disorders

Publication date: October 2017
Source:Journal of Anxiety Disorders, Volume 51
Author(s): Jeremy W. Pettit, Yasmin Rey, Michele Bechor, Raquel Melendez, Daniella Vaclavik, Victor Buitron, Yair Bar-Haim, Daniel S. Pine, Wendy K. Silverman
This open trial presents a stepped care treatment approach for youths with anxiety disorders. In Step 1, 124 youths (65 girls; M age=9.7years) participated in a low intensity computer administered attention bias modification (ABM) protocol. Statistically significant reductions in youth anxiety severity were found following Step 1. Youths and parents were then given the option to not continue with further treatment or step up to a higher intensity cognitive behavioral therapy (CBT) protocol (Step 2). Of 112 youths who completed Step 1, 67 (59.8%) discontinued treatment and 45 (40.2%) stepped up. Co-occurring ADHD and higher anxiety severity at baseline were significantly associated with the decision to step up. Of those youths who completed Step 2, additional statistically significant reductions in youth anxiety severity were found. Across the entire protocol, 68.6% of youths were rated as either very much improved or much improved on the Clinical Global Impressions-Improvement scale. In a hypothetical comparison in which all youths received CBT alone, the stepped care protocol resulted in approximately 50% less time in treatment sessions. These findings support the promise of initiating youth anxiety disorder treatment with low intensity treatment and then stepping up to higher intensity treatment as needed.



http://ift.tt/2vGpDe0

Editors / Publication Information

Publication date: 1 November 2017
Source:Appetite, Volume 118





http://ift.tt/2vGxMim

Stress-induced eating and the relaxation response as a potential antidote: A review and hypothesis

Publication date: 1 November 2017
Source:Appetite, Volume 118
Author(s): Tasmiah Masih, James A. Dimmock, Elissa S. Epel, Kym J. Guelfi
There is an accumulating body of evidence to indicate that stress leads to the consumption of unhealthy, energy-dense, palatable food, potentially contributing to the alarming global prevalence of chronic diseases, including obesity. However, comparatively little research has been devoted to addressing how best to remedy this growing problem. We provide an overview of the influence of stress on dietary intake, and then explore the novel, yet simple, possibility that regular elicitation of the relaxation response may effectively reduce stress-induced eating via both physiological neuroendocrine and reward pathways and psychological pathways involving emotion regulation, and habitual coping. If shown to be effective, the regular practice of relaxation may provide a convenient, cost efficient, patient-centered therapeutic practice to assist in the prevention of unhealthy weight gain and other negative consequences of unhealthy food intake.



http://ift.tt/2x6xuF6

Eating and health behaviors in vegans compared to omnivores: Dispelling common myths

Publication date: 1 November 2017
Source:Appetite, Volume 118
Author(s): Sydney Heiss, Jaime A. Coffino, Julia M. Hormes
Studies comparing eating behaviors in individuals avoiding meat and other animal products to omnivores have produced largely inconclusive findings, in part due to a failure to obtain sufficiently large samples of vegan participants to make meaningful comparisons. This study examined eating and health behaviors in a large community sample of dietary vegans ("vegans"), compared to omnivores. Participants (n = 578, 80.4% female) completed an online questionnaire assessing a range of eating- and other health-related attitudes and behaviors. Vegans (62.0%, n = 358) and omnivores (38.1%, n = 220) were comparable in terms of demographics. Vegans scored significantly lower than omnivores the Eating Disorder Examination - Questionnaire (multivariate p < 0.001), a measure of pathological eating behavior. They also were more likely to consider themselves "healthy" (p < 0.001) and to prepare food at home (p < 0.001). Vegans more frequently consumed fruits, vegetables, nuts, beans and grains (all p < 0.001), and less frequently consumed caffeinated soft drinks (p < 0.001). There were no significant differences between vegans and omnivores on measures of eating styles, body mass index, smoking or exercise behaviors, or problems related to alcohol consumption. Effect sizes for comparisons on eating-related measures were generally small, with ηp2 ranging from <0.01 to 0.05; the size of effects for comparisons on measures of other health behaviors ranged from small to medium (Φ = 0.09 to 0.33 and ηp2 < 0.01 to 0.42). Taken together, findings suggest that ultimately, vegans do not differ much from omnivores in their eating attitudes and behaviors, and when they do, differences indicate slightly healthier attitudes and behaviors towards food. Similarly, vegans closely resembled omnivores in non-eating related health behaviors.



http://ift.tt/2vG60Tq

An historical perspective on variety in United States dining based on menus

Publication date: 1 November 2017
Source:Appetite, Volume 118
Author(s): Herbert L. Meiselman
While food variety continues to be of major interest to those studying eating and health, research has been mainly limited to laboratory research of simple meals. This paper seeks to enlarge the scope of eating research by examining the food offered in the earliest menus in United States restaurants and hotels of the early and mid-19th c, when restaurants began. This reveals a very large variety in what food was offered. The paper discusses why variety has declined in the US and probably elsewhere, including changes in the customer, changes in food service, changes of food availability, and the industrialization of the food supply. Menu analysis offers another approach to studying dietary variety across cultures and across time.



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Squamoid Morules in the Pseudoinvasive Foci of Colonic Polyp Morphologically Mimic Invasive Carcinoma

Publication date: Available online 30 August 2017
Source:Human Pathology
Author(s): Hee Eun Lee, Vishal S. Chandan, Chung-Ta Lee, Tsung-Teh Wu
Colorectal adenomas can show focal squamous differentiation or squamoid morules. We describe histologic findings of squamoid morules in the pseudoinvasive foci of colorectal polyps mimicking invasive carcinoma. Five colonic polyps with squamoid morules in the pseudoinvasive foci were collected. Histologic review and immunostains for cytokeratin (CK) 5/6, p63, synaptophysin, and chromogranin were performed on cases with squamoid morules. Forty-seven consecutive colorectal polyps with pseudoinvasion, none of which showed squamoid morules by histology review, and their clinicopathologic features were compared with the cases containing squamoid morules. Cases with squamoid morules more frequently occurred in younger patients (P=.047) and located in right colon (P=.027) than those without squamoid morules. Diagnosis of the polyps included tubular/tubulovillous adenoma with low-grade (with squamoid morules, n=3; vs without squamoid morules, n=29) or high-grade dysplasia (n=2 vs n=15) and sessile serrated adenoma (none vs n=3). Squamoid morules formed nodules protruding into the lumen of glandular structure or partially replaced adenomatous glands without forming a discrete nodule. They also presented as solid nests showing a well-formed morular structure around the bottom of adenomatous glands or myxoinflammatory stroma. Importantly, squamoid morules often formed a pseudocribriform or solid nest sitting in the stroma of pseudoinvasive foci. All cases (n=4) showed CK5/6 positivity and p63 negativity in squamoid morules. Three and 1 of 4 cases showed focal positivity for synaptophysin and chromogranin, respectively, in squamoid morules. Squamoid morules in colonic adenomatous polyps can mimic invasive carcinoma when present in the pseudoinvasive foci. Pathologists should be aware of its presence.



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Multicentric visceral epithelioid hemangioendothelioma, with extremity dermal deposits, unusual late recurrence on the nasal bridge and TFE3 gene rearrangement

Publication date: Available online 30 August 2017
Source:Human Pathology
Author(s): Khin Thway, Thomas Mentzel, Conal M Perrett, Eduardo Calonje
Epithelioid hemangioendothelioma (EHE) is a malignant neoplasm with vascular differentiation that most frequently occurs within soft tissues, bone, lung and liver. It is histologically typified by epithelioid or spindle cells present singly or in cords or clusters, many with cytoplasmic vacuoles that can contain intraluminal erythrocytes (in keeping with primitive vascular differentiation), within myxohyaline or sclerotic matrix. Up to 50% present with synchronous lesions as multifocal disease. The WWTR1–CAMTA1 fusion has been demonstrated in EHEs at a variety of sites and is considered to represent its genetic hallmark. We describe a case of EHE in a patient who initially presented with multiple liver and pulmonary deposits, was found to have a soft tissue lesion in the foot, and then presented with further lesions on the nasal bridge and the arm approximately six years after initial presentation. Interestingly, the case showed diffuse CAMTA1 expression but negative TFE3 immunohistochemically, but in contrast showed TFE3 gene rearrangement with fluorescence in situ hybridization but no evidence of WWTR1-CAMTA1 translocation. The clinical behavior of EHE is unpredictable, and this case highlights unusual anatomic, immunohistochemical and molecular cytogenetic findings. Characterization of the genetics of EHE is important as targeted therapies towards products of the specific WWTR1–CAMTA1 gene fusion may have an impact in the near future.



http://ift.tt/2wTIiqJ

1α,25-Dihydroxyvitamin D3 promotes osteogenesis by promoting Wnt signaling pathway

Publication date: Available online 30 August 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Yi Xiong, Yixin Zhang, Na Xin, Ying Yuan, Qin Zhang, Ping Gong, Yingying Wu
Diabetes mellitus (DM) remarkably affects bone metabolism and causes multiple skeletal disorders, which are associated with the increased oxidative stress that activates Forkhead family of transcription factors (FoxOs). 1α,25-Dihydroxy vitamin D3 (1,25(OH)2D3), the hormonally active form of vitamin D, plays a potential role in the prevention of glucose tolerance. However, its mechanism of action in high glucose-induced energy disorders remains unclear. In vitro study shows that 1,25(OH)2D3 promotes osteogenesis in high glucose-induced oxidative stress mainly results from increased osteoblasts proliferation and decreased apoptosis. Cells treated with 1,25(OH)2D3 exhibit an increased osteogenic differentiation capacity and an elevated level of osteogenic phenotype (i.e. alkaline phosphatase, collagen 1, osteocalcin, and osteopontin). We also found that the effect of 1,25(OH)2D3 on osteogenesis is achieved by FoxO1 inactivation and nuclear exclusion through PI3K/Akt pathway in a time- and dose-dependent manner. Moreover, the diversion of β-catenin from FoxO1- to Wnt/TCF4-mediated transcription was indirectly promoted by the inactivation of FoxO1. These data together reveals that the activated Wnt/β-catenin signaling is involved in the regulatory action of 1,25(OH)2D3 on osteogenesis in oxidative stress. This study also provides a novel understanding of the effect of 1,25(OH)2D3 on skeleton in oxidative stress condition.



http://ift.tt/2vtlEFi

G6PD plays a neuroprotective role in brain ischemia through promoting pentose phosphate pathway

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): Lijuan Cao, Dingmei Zhang, Jieyu Chen, Yuan-Yuan Qin, Rui Sheng, Xing Feng, Zhong Chen, Yuqiang Ding, Mei Li, Zheng-Hong Qin
TIGAR-regulated pentose phosphate pathway (PPP) plays a critical role in the neuronal survival during cerebral ischemia/reperfusion. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme in PPP and thus, we hypothesized that it plays an essential role in anti-oxidative defense through producing NADPH. The present study investigated the regulation and the role of G6PD in ischemia/reperfusion-induced neuronal injury with in vivo and in vitro models of ischemic stroke. The results showed that the levels of G6PD mRNA and protein were increased after ischemia/reperfusion. In vivo, lentivirus-mediated G6PD overexpression in mice markedly reduced neuronal damage after ischemia/reperfusion insult, while lentivirus-mediated G6PD knockdown exacerbated it. In vitro, overexpression of G6PD in cultured primary neurons decreased neuronal injury under oxygen and glucose deprivation/reoxygenation (OGD/R) condition, whereas knockdown of G6PD aggravated it. Overexpression of G6PD increased levels of NADPH and reduced form of glutathione (rGSH), and ameliorated ROS-induced macromolecular damage. On the contrary, knockdown of G6PD executed the opposite effects in mice and in primary neurons. Supplementation of exogenous NADPH alleviated the detrimental effects of G6PD knockdown, whereas further enhanced the beneficial effects of G6PD overexpression in ischemic injury. Therefore, our results suggest that G6PD protects ischemic brain injury through increasing PPP. Thus G6PD may be considered as potential therapeutic target for treatment of ischemic brain injury.

Graphical abstract

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Peroxiredoxin-2 plays a pivotal role as multimodal cytoprotector in the early phase of pulmonary hypertension

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): Enrica Federti, Alessandro Matté, Alessandra Ghigo, Immacolata Andolfo, Cimino James, Angela Siciliano, Christophe Leboeuf, Anne Janin, Francesco Manna, Soo Young Choi, Achille Iolascon, Elisabetta Beneduce, Davide Melisi, Dae Won Kim, Sonia Levi, Lucia De Franceschi
Pulmonary-artery-hypertension (PAH) is a life-threatening and highly invalidating chronic disorder. Chronic oxidation contributes to lung damage and disease progression. Peroxiredoxin-2 (Prx2) is a typical 2-cysteine (Cys) peroxiredoxin but its role on lung homeostasis is yet to be fully defined. Here, we showed that Prx2^-/- mice displayed chronic lung inflammatory disease associated with (i) abnormal pulmonary vascular dysfunction; and (ii) increased markers of extracellular-matrix remodeling. Hypoxia was used to induce PAH. We focused on the early phase PAH to dissect the role of Prx2 in generation of PAH. Hypoxic Prx2^-/-mice showed (i) amplified inflammatory response combined with cytokine storm; (ii) vascular activation and dysfunction; (iii) increased PDGF-B lung levels, as marker of extracellular-matrix deposition and remodeling; and (iv) ER stress with activation of UPR system and autophagy. Rescue experiments with in vivo the administration of fused-recombinant-PEP-Prx2 show a reduction in pulmonary inflammatory vasculopathy and in ER stress with down-regulation of autophagy. Thus, we propose Prx2 plays a pivotal role in the early stage of PAH as multimodal cytoprotector, targeting oxidation, inflammatory vasculopathy and ER stress with inhibition of autophagy. Collectively, our data indicate that Prx2 is able to interrupt the hypoxia induced vicious cycle involving oxidation-inflammation-autophagy in the pathogenesis of PAH.

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NADPH oxidases as drug targets and biomarkers in neurodegenerative diseases: What is the evidence?

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): Silvia Sorce, Roland Stocker, Tamara Seredenina, Rikard Holmdahl, Adriano Aguzzi, Adriano Chio, Antoine Depaulis, Freddy Heitz, Peter Olofsson, Tomas Olsson, Venceslas Duveau, Despina Sanoudou, Sara Skosgater, Antonia Vlahou, Dominique Wasquel, Karl-Heinz Krause, Vincent Jaquet
Neurodegenerative disease are frequently characterized by microglia activation and/or leukocyte infiltration in the parenchyma of the central nervous system and at the molecular level by increased oxidative modifications of proteins, lipids and nucleic acids. NADPH oxidases (NOX) emerged as a novel promising class of pharmacological targets for the treatment of neurodegeneration due to their role in oxidant generation and presumably in regulating microglia activation. The unique function of NOX is the generation of superoxide anion (O2^•–) and hydrogen peroxide (H2O2). However in the context of neuroinflammation, they present paradoxical features since O2^•–/H2O2 generated by NOX and/or secondary reactive oxygen species (ROS) derived from O2^•–/H2O2 can either lead to neuronal oxidative damage or resolution of inflammation. The role of NOX enzymes has been investigated in many models of neurodegenerative diseases by using either genetic or pharmacological approaches. In the present review we provide a critical assessment of recent findings related to the role of NOX in the CNS as well as how the field has advanced over the last 5 years. In particular, we focus on the data derived from the work of a consortium (Neurinox) funded by the European Commission's Programme 7 (FP7). We discuss the evidence gathered from animal models and human samples linking NOX expression/activity with neuroinflammation in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Creutzfeldt–Jakob disease as well as autoimmune demyelinating diseases like multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP). We address the possibility to use measurement of the activity of the NOX2 isoform in blood samples as biomarker of disease severity and treatment efficacy in neurodegenerative disease. Finally we clarify key controversial aspects in the field of NOX, such as NOX cellular expression in the brain, measurement of NOX activity, impact of genetic deletion of NOX in animal models of neurodegeneration and specificity of NOX inhibitors.

Graphical abstract

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Ellagic acid antagonizes Bnip3-mediated mitochondrial injury and necrotic cell death of cardiac myocytes

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): Abhinav Dhingra, Rahul Jayas, Pegah Afshar, Matthew Guberman, Graham Maddaford, Johnathan Gerstein, Brooke Lieberman, Hilary Nepon, Victoria Margulets, Rimpy Dhingra, Lorrie A. Kirshenbaum
The Bcl-2 protein Bnip3 is crucial for provoking oxidative injury to mitochondria following anthracycline treatment or ischemia-reperfusion injury. Herein, we investigate the effects of the polyphenolic compound ellagic acid (EA) on Bnip3 mediated mitochondrial injury and necrotic cell death in cardiac myocytes. In contrast to vehicle treated cardiomyocytes, Bnip3 was highly enriched in mitochondrial fractions of cardiac myocytes treated with the anthracycline doxorubicin or in cells subjected to hypoxia (HPX). Mitochondrial associated Bnip3 was accompanied by mPTP opening and loss of ∆Ψm. The dynamin related fission protein Drp-1 was phosphorylated (Drp1⁶¹⁶) and coincided with excessive mitochondrial fragmentation, mitophagy and necrosis in cardiac myocytes treated with doxorubicin or subjected to hypoxia. Moreover, knock-down of Bnip3 was sufficient to prevent mitochondrial fission and doxorubicin-induced cell death supporting the involvement of Bnip3 in doxorubicin cardiotoxity. Interestingly, mitochondrial associated Bnip3 in cells treated with doxorubicin was markedly reduced by EA. This resulted in significantly less mitochondrial fission and cell death. Notably, EA similarly suppressed mitochondrial injury and cell death induced by hypoxia or Bnip3 over-expression. Herein, we identify a novel signaling axis that operationally links EA and Bnip3 for suppression of cardiac cell death. We provide compelling new evidence that EA suppresses mitochondrial injury and necrotic cell death of cardiac myocytes by functionally abrogating Bnip3 activity. Hence, by suppressing mitochondrial injury induced by Bnip3, EA may provide a therapeutic advantage in reducing oxidative injury and cardiac dysfunction in cancer patients undergoing anthracycline treatment or individuals with ischemic cardiac stress.

Graphical abstract

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Advanced glycation end products receptor RAGE controls myocardial dysfunction and oxidative stress in high-fat fed mice by sustaining mitochondrial dynamics and autophagy-lysosome pathway

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): Yichi Yu, Lei Wang, Florian Delguste, Arthur Durand, Axel Guilbaud, Clementine Rousselin, Ann Marie Schmidt, Frédéric Tessier, Eric Boulanger, Remi Neviere
Oxidative stress and mitochondrial dysfunction are recognized as major contributors of cardiovascular damage in diabetes and high fat diet (HFD) fed mice. Blockade of receptor for advanced glycation end products (RAGE) attenuates vascular oxidative stress and development of atherosclerosis. We tested whether HFD-induced myocardial dysfunction would be reversed in RAGE deficiency mice, in association with changes in oxidative stress damage, mitochondrial respiration, mitochondrial fission and autophagy-lysosomal pathway. Cardiac antioxidant capacity was upregulated in RAGE⁻/⁻ mice under normal diet as evidenced by increased superoxide dismutase and sirtuin mRNA expressions. Mitochondrial fragmentation and mitochondrial fission protein Drp1 and Fis1 expressions were increased in RAGE⁻/⁻ mice. Autophagy-related protein expressions and cathepsin-L activity were increased in RAGE⁻/⁻ mice suggesting sustained autophagy-lysosomal flux. HFD induced mitochondrial respiration defects, cardiac contractile dysfunction, disrupted mitochondrial dynamics and autophagy inhibition, which were partially prevented in RAGE⁻/⁻ mice. Our results suggest that cardioprotection against HFD in RAGE⁻/⁻ mice include reactivation of autophagy, as inhibition of autophagic flux by chloroquine fully abrogated beneficial myocardial effects and its stimulation by rapamycin improved myocardial function in HFD wild type mice. As mitochondrial fission is necessary to mitophagy, increased fragmentation of mitochondrial network in HFD RAGE⁻/⁻ mice may have facilitated removal of damaged mitochondria leading to better mitochondrial quality control. In conclusion, modulation of RAGE pathway may improve mitochondrial damage and myocardial dysfunction in HFD mice. Attenuation of cardiac oxidative stress and maintenance of healthy mitochondria population ensuring adequate energy supply may be involved in myocardial protection against HFD.

Graphical abstract

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Hydrogen sulfide-producing cystathionine γ-lyase is critical in the progression of kidney fibrosis

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): Sang Jun Han, Mi Ra Noh, Jung-Min Jung, Isao Ishii, Jeongsoo Yoo, Jee In Kim, Kwon Moo Park
Cystathionine γ-lyase (CSE), the last key enzyme of the transsulfuration pathway, is involved in the production of hydrogen sulfide (H2S) and glutathione (GSH), which regulate redox balance and act as important antioxidant molecules. Impairment of the H2S- and GSH-mediated antioxidant system is associated with the progression of chronic kidney disease (CKD), characterized by kidney fibrosis and dysfunction. Here, we evaluated the role of CSE in the progression of kidney fibrosis after unilateral ureteral obstruction (UUO) using mice deficient in the Cse gene. UUO of wild-type mice reduced the expression of H2S-producing enzymes, CSE, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase in the obstructed kidneys, resulting in decreased H2S and GSH levels. Cse gene deletion lowered H2S and GSH levels in the kidneys. Deleting the Cse gene exacerbated the decrease in H2S and GSH levels and increase in superoxide formation and oxidative damage to proteins, lipids, and DNA in the kidneys after UUO, which were accompanied by greater kidney fibrosis, deposition of extracellular matrixes, expression of α-smooth muscle actin, tubular damage, and infiltration of inflammatory cells. Furthermore, Cse gene deletion exacerbated mitochondrial fragmentation and apoptosis of renal tubule cells after UUO. The data provided herein constitute in vivo evidence that Cse deficiency impairs renal the H2S- and GSH-producing activity and exacerbates UUO-induced kidney fibrosis. These data propose a novel therapeutic approach against CKD by regulating CSE and the transsulfuration pathway.

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Dimercapto-1-propanesulfonic acid (DMPS) induces metaphase II mouse oocyte deterioration

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): Sarah R. Aldhaheri, Roohi Jeelani, Hamid-Reza Kohan-Ghadr, Sana N. Khan, Sasha Mikhael, Christina Washington, Robert T. Morris, Husam M. Abu-Soud
In light of the recent lead contamination of the water in Flint, Michigan and its potential adverse outcomes, much research and media attention has turned towards the safety profile of commonly used chelators. Dimercapto-1-propanesulfonic acid (DMPS) typically used in the treatment of lead, mercury and arsenic poisoning also displays a high affinity towards transition metals such as zinc and copper, essential for biological functioning. It is given in series of dosages (0.2–0.4g/day) over a long period, and has the ability to enter cells. In this work, we investigated the mechanism through which increasing concentrations of DMPS alter oocyte quality as judged by changes in microtubule morphology (MT) and chromosomal alignment (CH) of metaphase II mice oocyte. The oocytes were directly exposed to increasing concentration of DMPS (10, 25, 50, 100 and 300μM) for four hours (time of peak plasma concentration after administration) and reactive oxygen species (mainly hydroxyl radical and superoxide) and zinc content were measured. This data showed DMPS plays an important role in deterioration of oocyte quality through a mechanism involving zinc deficiency and enhancement of reactive oxygen species a major contributor to oocyte damage. Our current work, for the first time, demonstrates the possibility of DMPS to negatively impact fertility. This finding can not only help in counseling reproductive age patients undergoing such treatment but also in the development of potential therapies to alleviate oxidative damage and preserve fertility in people receiving heavy metal chelators.

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There Is an Inclusion for That: Material Properties of Protein Granules Provide a Platform for Building Diverse Cellular Functions

Publication date: Available online 29 August 2017
Source:Trends in Biochemical Sciences
Author(s): Daniel Kaganovich
Proteins perform a staggering variety of functions in the cell. Traditionally, protein function was thought to be hard-wired into the folded structure and conformational dynamics of each protein molecule. Recent work describes a new mode of protein functionality driven by the collective behavior of many different proteins; most of which lack a defined structure. These proteins form clusters or granules in which unstructured polypeptides interact transiently. Nonspecific multivalent interactions drive the formation of phase-separated structures resembling aggregates. This type of functional aggregate granule can be thought of as a single supermolecular functional entity that derives function from its unique material properties. In this review we examine the emerging idea of protein granules as a new functional and structural unit of cellular organization.



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Immune development and environment: lessons from Amish and Hutterite children

Publication date: October 2017
Source:Current Opinion in Immunology, Volume 48
Author(s): Carole Ober, Anne I Sperling, Erika von Mutius, Donata Vercelli
Children who grow up in traditional farm environments are protected from developing asthma and allergy. This 'farm effect' can be largely explained by the child's early life contact with farm animals, in particular cows, and their microbes. Our studies in Amish and Hutterite school children living on farms in the U.S. have further demonstrated that this protection is mediated through innate immune pathways. Although very similar with respect to ancestry and many lifestyle factors that are associated with asthma risk, Amish and Hutterites follow farming practices that are associated with profound differences in the levels of house dust endotoxin, in the prevalence of asthma and atopy among school children, and in the proportions, phenotypes, and functions of immune cells from these children. In this review, we will consider our studies in Amish and Hutterites children in the context of the many previous studies in European farm children and discuss how these studies have advanced our understanding of the asthma-protective 'farm effect'.



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3D MR fingerprinting with accelerated stack-of-spirals and hybrid sliding-window and GRAPPA reconstruction

Publication date: 15 November 2017
Source:NeuroImage, Volume 162
Author(s): Congyu Liao, Berkin Bilgic, Mary Kate Manhard, Bo Zhao, Xiaozhi Cao, Jianhui Zhong, Lawrence L. Wald, Kawin Setsompop
PurposeWhole-brain high-resolution quantitative imaging is extremely encoding intensive, and its rapid and robust acquisition remains a challenge. Here we present a 3D MR fingerprinting (MRF) acquisition with a hybrid sliding-window (SW) and GRAPPA reconstruction strategy to obtain high-resolution T1, T2 and proton density (PD) maps with whole brain coverage in a clinically feasible timeframe.Methods3D MRF data were acquired using a highly under-sampled stack-of-spirals trajectory with a steady-state precession (FISP) sequence. For data reconstruction, kx-ky under-sampling was mitigated using SW combination along the temporal axis. Non-uniform fast Fourier transform (NUFFT) was then applied to create Cartesian k-space data that are fully-sampled in the in-plane direction, and Cartesian GRAPPA was performed to resolve kz under-sampling to create an alias-free SW dataset. T1, T2 and PD maps were then obtained using dictionary matching.ResultsPhantom study demonstrated that the proposed 3D-MRF acquisition/reconstruction method is able to produce quantitative maps that are consistent with conventional quantification techniques. Retrospectively under-sampled in vivo acquisition revealed that SW + GRAPPA substantially improves quantification accuracy over the current state-of-the-art accelerated 3D MRF. Prospectively under-sampled in vivo study showed that whole brain T1, T2 and PD maps with 1 mm³ resolution could be obtained in 7.5 min.Conclusions3D MRF stack-of-spirals acquisition with hybrid SW + GRAPPA reconstruction may provide a feasible approach for rapid, high-resolution quantitative whole-brain imaging.

Graphical abstract

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Neurophysiological evidence for enhanced tactile acuity in early blindness in some but not all haptic tasks

Publication date: 15 November 2017
Source:NeuroImage, Volume 162
Author(s): Ane Gurtubay-Antolin, Antoni Rodríguez-Fornells
Previous research assessing the presence of enhanced tactile skills in early-blind (EB) population obtained conflicting results. Most of the studies relied on behavioral measures with which different mechanisms leading to the same outcome go unnoticed. Moreover, the scarce electrophysiological research that has been conducted focused exclusively on the processing of microgeometric properties. To clarify the extent of superior tactile abilities in EBs using high-density multichannel electrophysiological recordings, the present study compared the electrophysiological correlates of EBs and sighted controls (CON) in two tactile discrimination tasks that targeted microgeometric (texture) and macrogeometric (shape) properties. After a restricted exploration (haptic glance), participants judged whether a touched stimulus corresponded to an expected stimulus whose name had been previously presented aurally. In the texture discrimination task, differences between groups emerged at ∼75 ms (early perceptual processing stages) whereas we found no between-group differences during shape discrimination. Furthermore, for the first time, we were able to determine the latency at which EBs started to discriminate micro- (EB: 170 ms; CON: 230 ms) and macrogeometric (EB: 250 ms; CON: 270 ms) properties. Altogether, the results suggest different electrophysiological signatures during texture (but not shape) discrimination in EBs, possibly due to cortical reorganization in occipital areas and their increased connectivity with S1.



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Functional subdivisions of the hypothalamus using areal parcellation and their signal changes related to glucose metabolism

Publication date: 15 November 2017
Source:NeuroImage, Volume 162
Author(s): Takahiro Osada, Ruriko Suzuki, Akitoshi Ogawa, Masaki Tanaka, Masaaki Hori, Shigeki Aoki, Yoshifumi Tamura, Hirotaka Watada, Ryuzo Kawamori, Seiki Konishi
The hypothalamus consists of numerous nuclei, and is regarded as the highest center for various autonomic functions. Although each hypothalamic nucleus implements a distinct function, it remains difficult to investigate the human hypothalamus at the nucleus level. In the present high-resolution functional MRI study, we utilized areal parcellation to discriminate individual nuclei in the human hypothalamus based on areal profiles of resting-state functional connectivity. The areal parcellation detected ten foci that were expected to represent hypothalamic nuclei, and the locations of the foci were consistent with those of the hypothalamic nuclei identified in previous histological studies. Regions of interest (ROI) analyses revealed contrasting brain activity changes following glucose ingestion: decrease in the ventromedial hypothalamic nucleus and increase in the lateral hypothalamic area in parallel with blood glucose increase. Moreover, decreased brain activity in the arcuate nucleus predicted future elevation of blood insulin during the first 10 min after glucose ingestion. These results suggest that the hypothalamic nuclei can putatively be determined using areal parcellation, and that the ROI analysis of the human hypothalamic nuclei is useful for future scientific and clinical investigations into the autonomic functions.



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Frontmatter

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: i-iii

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Standard body mass index reference data of prepubescent diabetic Egyptian children

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 909-915

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Frequency and risk factors of depression in type 1 diabetes in a developing country

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 917-922

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Association of obesity and health related quality of life in Iranian children and adolescents: the Weight Disorders Survey of the CASPIAN-IV study

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 923-929

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Association between urinary phthalates and metabolic abnormalities in obese Thai children and adolescents

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 931-938

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A pilot study of the effect of human breast milk on urinary metabolome analysis in infants

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 939-946

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Assessment of the correlation between the atherogenic index of plasma and cardiometabolic risk factors in children and adolescents: might it be superior to the TG/HDL-C ratio?

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 947-955

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Cardiovascular and metabolic risk in pediatric patients with congenital adrenal hyperplasia due to 21 hydroxylase deficiency

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 957-966

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Application of povidone-iodine at delivery significantly increases maternal urinary iodine but not neonatal thyrotropin in an area with iodine sufficiency

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 967-972

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Influence of topical iodine-containing antiseptics used during delivery on recall rate of congenital hypothyroidism screening program

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 973-978

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Applying targeted next generation sequencing to dried blood spot specimens from suspicious cases identified by tandem mass spectrometry-based newborn screening

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 979-988

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Initial patient choice of a growth hormone device improves child and adolescent adherence to and therapeutic effects of growth hormone replacement therapy

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 989-993

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An occult ectopic parathyroid adenoma in a pediatric patient: a case report and management algorithm

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 995-999

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Fetal goitrous hypothyroidism treated by intra-amniotic levothyroxine administration: case report and review of the literature

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 1001-1005

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Carotid intima media thickness in a girl with sitosterolemia carrying a homozygous mutation in the ABCG5 gene

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 1007-1011

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Sirolimus in the treatment of three infants with diffuse congenital hyperinsulinism

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Volume: 30
Issue: 9
Pages: 1013-1017

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Use of low-dose radioiodine ablation for Graves’ orbitopathy: results of a pilot, perspective study in a small series of patients

Abstract

Objective

Elimination of thyroid antigens by total thyroid ablation (TTA), namely, thyroidectomy followed by radioiodine, may be beneficial for Graves' Orbitopathy (GO). TTA is usually performed with a ¹³¹I dose of 30 mCi. In Italy, this dose must be followed by a 24-h protected hospitalization, with increase in the waiting lists. In contrast, a 15 mCi dose can be given without hospitalization and with lower costs. Here, we investigated whether a lower dose of radioiodine can be used to ablate thyroid remnants in patients with GO, after thyroidectomy.

Methods

The study was performed in two small groups of consecutive thyroidectomized patients (six patients per group) with Graves' hyperthyroidism and GO. Patients underwent ablation with either 15 or 30 mCi of ¹³¹I following treatment with recombinant human TSH (rhTSH). The primary outcome was rhTSH-stimulated serum thyroglobulin (Tg) at 6 months. The secondary outcome was baseline Tg at 6 months.

Results

Baseline Tg and rhTSH-stimulated Tg after at 6 months did not differ between two groups, suggesting a similar extent of ablation. rhTSH-stimulated Tg was reduced significantly compared with rhTSH-stimulated Tg at ablation in both groups. GO outcome following treatment with intravenous glucocorticoids did not differ between the two groups.

Conclusions

Our findings may provide a preliminary basis for the use of a 15 mCi dose of radioiodine upon rhTSH stimulation in thyroidectomized patients with Graves' hyperthyroidism and GO.

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The evolution of the platyrrhine talus: A comparative analysis of the phenetic affinities of the Miocene platyrrhines with their modern relatives

Publication date: October 2017
Source:Journal of Human Evolution, Volume 111
Author(s): Thomas A. Püschel, Justin T. Gladman, René Bobe, William I. Sellers
Platyrrhines are a diverse group of primates that presently occupy a broad range of tropical-equatorial environments in the Americas. However, most of the fossil platyrrhine species of the early Miocene have been found at middle and high latitudes. Although the fossil record of New World monkeys has improved considerably over the past several years, it is still difficult to trace the origin of major modern clades. One of the most commonly preserved anatomical structures of early platyrrhines is the talus. This work provides an analysis of the phenetic affinities of extant platyrrhine tali and their Miocene counterparts through geometric morphometrics and a series of phylogenetic comparative analyses. Geometric morphometrics was used to quantify talar shape affinities, while locomotor mode percentages (LMPs) were used to test if talar shape is associated with locomotion. Comparative analyses were used to test if there was convergence in talar morphology, as well as different models that could explain the evolution of talar shape and size in platyrrhines. Body mass predictions for the fossil sample were also computed using the available articular surfaces. The results showed that most analyzed fossils exhibit a generalized morphology that is similar to some 'generalist' modern species. It was found that talar shape covaries with LMPs, thus allowing the inference of locomotion from talar morphology. The results further suggest that talar shape diversification can be explained by invoking a model of shifts in adaptive peak to three optima representing a phylogenetic hypothesis in which each platyrrhine family occupied a separate adaptive peak. The analyses indicate that platyrrhine talar centroid size diversification was characterized by an early differentiation related to a multidimensional niche model. Finally, the ancestral platyrrhine condition was reconstructed as a medium-sized, generalized, arboreal, quadruped.



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Postcrania of the most primitive euprimate and implications for primate origins

Publication date: October 2017
Source:Journal of Human Evolution, Volume 111
Author(s): Doug M. Boyer, Séverine Toussaint, Marc Godinot
The fossil record of early primates is largely comprised of dentitions. While teeth can indicate phylogenetic relationships and dietary preferences, they say little about hypotheses pertaining to the positional behavior or substrate preference of the ancestral crown primate. Here we report the discovery of a talus bone of the dentally primitive fossil euprimate Donrussellia provincialis. Our comparisons and analyses indicate that this talus is more primitive than that of other euprimates. It lacks features exclusive to strepsirrhines, like a large medial tibial facet and a sloping fibular facet. It also lacks the medially positioned flexor-fibularis groove of extant haplorhines. In these respects, the talus of D. provincialis comes surprisingly close to that of the pen-tailed treeshrew, Ptilocercus lowii, and extinct plesiadapiforms for which tali are known. However, it differs from P. lowii and is more like other early euprimates in exhibiting an expanded posterior trochlear shelf and deep talar body. In overall form, the bone approximates more leaping reliant euprimates. The phylogenetically basal signal from the new fossil is confirmed with cladistic analyses of two different character matrices, which place D. provincialis as the most basal strepsirrhine when the new tarsal data are included. Interpreting our results in the context of other recent discoveries, we conclude that the lineage leading to the ancestral euprimate had already become somewhat leaping specialized, while certain specializations for the small branch niche came after crown primates began to radiate.



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