Cosmetics, Vol. 5, Pages 35: From Mice to Men: An Evolutionary Conserved Breakdown of the Epidermal Calcium Gradient and Its Impact on the Cornified Envelope

Cosmetics, Vol. 5, Pages 35: From Mice to Men: An Evolutionary Conserved Breakdown of the Epidermal Calcium Gradient and Its Impact on the Cornified Envelope

Cosmetics doi: 10.3390/cosmetics5020035

Authors: Maria Karolin Streubel Claudia Neuhofer Johannes Bischof Peter Steinbacher Elisabeth Russe Gottfried Wechselberger Klaus Richter Mark Rinnerthaler

In previous publications, we could establish that a hallmark of human skin aging is the breakdown of the epidermal calcium gradient. This redistribution of calcium has many implications, including a restructuring of the cornified envelope, a reduced epidermal barrier function, a change in lipid composition, a reduced skin hydration, and an increased skin pH. Especially the age-dependent change in the cornified envelope composition was solely studied in human foreskin samples. The aim of this study was to confirm that this effect is neither restricted to UV-protected skin area nor limited to a specific sex. In addition, we wanted to show that the collapse of the epidermal calcium gradient is not only a hallmark of human skin aging, but is also evolutionarily conserved in mammals. By using such techniques as IHC, Western blot analysis, and RT-PCR, we could demonstrate the following: (1) A change in the epidermal calcium gradient is in fact the most important sign of epidermal aging in mammals (as shown in female human eyelids and mouse skin samples of the external ear-shell); (2) The disturbed calcium homeostasis affects the expression and crosslinking of most cornified-envelope-specific genes such as loricrin and filaggrin. In this way, we could establish that the age-dependent altered composition of the cornified envelope is a typical sign of skin aging not only in humans, but in mice, too. This makes the mouse an important model organism to study these changes.

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Perioperative management of patients with cancer pain treated with opioids: a retrospective study

Abstract

Purpose

We retrospectively studied perioperative management of patients receiving opioid treatment for cancer pain to facilitate establishing a standard policy for our institute.

Methods

Subjects were patients who had been administered strong opioids for cancer pain and had undergone surgery with general anesthesia. We divided the patients into groups C and D. Group C was comprised of patients who had been administered their baseline opioids continuously during the perioperative period, and group D of those who had discontinued baseline opioid use during this period.

Results

We identified 70 evaluable patients, 36 in group C and 34 in group D. The intraoperative anesthesia courses were similar, being uneventful, in all cases. With respect to postoperative adverse effects within 24 h after awakening from anesthesia, severe adverse effects (additional administration of more than four analgesics and intense agitation) were significantly more frequent in group D than in group C (12 vs 1, respectively. p = 0.004). Univariate analysis revealed that baseline opioid discontinuation was the only factor associated with severe adverse effects [odds ratio 12.6, 95% confidence interval (1.49–105.8), p = 0.01].

Conclusion

Discontinuation of baseline opioid increased adverse effects in the early postoperative period, which were attributed to exacerbation of early postoperative pain.

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Retraction notice to "Graphene quantum dots decorated CdS doped graphene oxide sheets in dual action mode: as initiator and platform for designing of nimesulide imprinted polymer " [BIOS 89P1 (2017) 627-635]

Publication date: 30 August 2018
Source:Biosensors and Bioelectronics, Volume 114
Author(s): Santanu Patra, Ekta Roy, Raksha Choudhary, Ashutosh Tiwari, Rashmi Madhuri, Prashant K. Sharma




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Editorial Board

Publication date: 30 August 2018
Source:Biosensors and Bioelectronics, Volume 114





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Enzyme-free homogeneous electrochemical biosensor for DNA assay using toehold-triggered strand displacement reaction coupled with host-guest recognition of Fe3O4@SiO2@β-CD nanocomposites

Publication date: 30 August 2018
Source:Biosensors and Bioelectronics, Volume 114
Author(s): Jingjing Jiang, Xinyi Lin, Dong Ding, Guowang Diao
Taking advantages of the toehold-triggered strand displacement reaction (TSDR) and host-guest interaction of β-cyclodextrin (β-CD), a facile enzyme-free and homogeneous electrochemical sensing strategy was designed for the sensitive assay of target DNA using Fe3O4@SiO2@β-CD nanocomposites and ferrocene-labeled hairpin DNA (H-1) as the capture and electrochemical probes, respectively. Upon addition of target molecule, the initiated TSDR process induced the conformational change of H-1, and subsequently stimulated the dynamic assembly of assist probes (A-1 and A-2) to generate H-1:A-1:A-2 duplex along with the release of target sequence. The released target could drive the next TSDR recycling and finally result in the formation of numerous DNA duplex. After the molecular recognition of Fe3O4@SiO2@β-CD nanocomposites, a large number of duplex were easily separated from the supernatant solution under an external magnetic field, which led to a decreased H-1 concentration in residual solution, concomitant with a remarkable reduction of peak current. Under the optimized conditions, wide linear range (1–5000 pM), low detection limit (0.3 pM), desirable reproducibility, good selectivity, and satisfactory practical analysis were obtained by the combination of the superior recognition capability of β-CD, TSDR-induced signal amplification, and homogeneous electroanalytical method. The proposed detection strategy could offer a universal approach for the monitoring of various biological analytes via the rational design of probe sequences.



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Predictors, utilization patterns, and overall survival of patients undergoing metastasectomy for metastatic renal cell carcinoma in the era of targeted therapy

Publication date: Available online 5 June 2018
Source:European Journal of Surgical Oncology
Author(s): Maxine Sun, Christian P. Meyer, Jose A. Karam, Guillermo de Velasco, Steven L. Chang, Sumanta K. Pal, Quoc-Dien Trinh, Toni K. Choueiri
IntroductionMetastasectomy (MSX) is considered a treatment option in patients with metastatic renal cell carcinoma (mRCC) at diagnosis, but its role in the targeted therapy era is unclear. We sought to describe the utilization trends of MSX and survival outcomes in a large US cohort.Materials and MethodsUsing the National Cancer Database, we identified patients undergoing MSX for mRCC at diagnosis between 2006-2013. Linear regression methods estimated utilization trends, and hierarchical models identified independent predictors of MSX after adjusting for hospital clustering. Kaplan-Meier survival estimates and Cox proportional hazard models were used to evaluate overall survival according to treatment after propensity-score matching.ResultsOf 6994 mRCC patients, 1976 underwent MSX (28.3%). Those treated at academic facilities were more likely to undergo a MSX (OR: 1.57, 95% CI 1.20-2.06, p=0.001). In contrast, older patients (OR: 0.99, 95% CI: 0.98-1.00), black race (OR: 0.65, 95% CI: 0.51-0.82), higher pT stage (OR: 0.76, 95% CI: 0.65-0.89), and who received targeted therapy (OR: 0.72, 95% CI: 0.63-0.82, all p≤0.008) were less likely to undergo MSX. Overall, MSX patients had an improved survival compared to non-MSX patients (HR: 0.83, 95% CI: 0.77-0.90, p<0.001), as well as among patients treated with targeted therapy (HR: 0.77, 95% CI: 0.77-0.96, p=0.008).ConclusionsOur findings indicate that MSX-treated patients may benefit from an improved overall survival compared to non-MSX treated patients. Good patient selection and a proper risk stratification strategy are still very important considerations.



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Relationship between complications and long-term prognosis after total gastrectomy with splenectomy for proximal advanced gastric cancer

Publication date: Available online 5 June 2018
Source:European Journal of Surgical Oncology
Author(s): Bing Quan, Wen-Tao Yan, Jiong-Jie Yu, Feng Shen, Tian Yang




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Olfactory bulbus volume and olfactory sulcus depth in migraine patients: an MRI evaluation

Abstract

Objectives

To compare the measurements of olfactory bulb volume and olfactory sulcus depth in patients with migraine and a control group.

Methods

The study included the cranial MRI (1.5 T) images of 200 adults diagnosed with migraine and a control group of 100 subjects without migraine. The control group mainly consisted of the patients with non-migraneous headache. The measurements were obtained from coronal T2-weighted images for standard olfactory bulb (OB) volume and olfactory sulcus (OS) depth.

Results

The OB volume and OS depth values were lower in the migraine group than in the control group. In the migraine group, left OB volume of the males was significantly lower than those of the females. In both the migraine and control groups separately, the left-side OB volume values and the right side OS depth values were significantly greater than those of the contralateral side. There were positive correlations between right and left OB volume, and right and left OS depth values. No change was seen in OB volume and OS depth values according to gender. In older patients, a decrease was determined in the right and left OB volume, and the left-side OS depth values. There was a negative correlation between osmophobia and OB volume values. In migraine patients with osmophobia, the OB volume values were significantly decreased.

Conclusion

OB volume values were lower in migraine patients. When osmophobia was present, the OB volume was lower than that of the non-osmophobia migraine patients. Olfactory function monitoring with olfactory tests and olfactory volume monitoring on MRI can be recommended for all migraine patients to diagnose olfactory dysfunction earlier, especially those with osmophobia. Because their OB volume values were detected as lower than those of the migraine patients without osmophobia, it may be thought that blood flow changes and osmophobia may affect the olfactory bulb volume shrinkage in migraine patients.

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Water: From Pollution to Purification

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Polydrug use patterns, risk behavior and unmet healthcare need in a community-based sample of women who use cocaine, heroin or methamphetamine

Publication date: October 2018
Source:Addictive Behaviors, Volume 85
Author(s): Jennifer Lorvick, Erica N. Browne, Barrot H. Lambdin, Megan Comfort
BackgroundThe use of multiple illicit drugs (polydrug use) is associated with health-related harms and elevated risk of drug overdose. Polydrug use in common among women who use 'hard' drugs, such as cocaine, heroin or methamphetamine.MethodsQuantitative data collection was conducted with a community-recruited sample of 624 women who used heroin, methamphetamine or cocaine in Oakland, CA during 2014–2015. We conducted latent class analysis to classify polydrug use patterns. We assessed associations between classes of polydrug use and infectious disease risk behaviors, health care utilization and unmet health care need.ResultsWe identified four distinct classes of drug use: (1) predominantly crack (52% of women); (2) powder cocaine & non-heroin opioids (8%); (3) moderate polydrug use (25%); (4) heavy polydrug use (15%). Odds of sexual risk, injection drug use and unmet healthcare need were twice as high in the heavy polydrug use class as the predominantly crack class (p > 0.01 for each outcome). The rate of binge drinking (as days per month) was also significantly higher in the heavy polydrug class (p = 0.01). The moderate polydrug use class had higher odds of injection drug use and drug treatment participation, compared to the mainly crack class (p < 0.001 for each outcome). There were no differences between classes in health insurance or health care utilization.DiscussionReduction of polydrug use could be an effective harm reduction strategy to address sexual and injection risk among women. The use of both opioids and stimulants in three of the four classes suggests that multi-modal substance abuse treatment approaches may be most appropriate.



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Psychometric evaluation of the drinking refusal self-efficacy scale - revised with college students in the United States

Publication date: October 2018
Source:Addictive Behaviors, Volume 85
Author(s): Kray A. Scully, Richard S. Mohn, Michael B. Madson
Drinking refusal self-efficacy has recently emerged as a potential factor related to reduced alcohol consumption and alcohol-related negative consequences in college students. The Drinking Refusal Self-Efficacy Questionnaire-Revised (DRSEQ-R) has been commonly used to assess for drinking refusal self-efficacy. However, psychometric evaluation of the measure with college students from the United States is needed to enhance its research and clinical utility. The goal of the present study was to confirm the factor structure of the DRSEQ-R with a sample of traditional aged college students from the United States as well as assess the measurement invariance of the factor structure across sex and race and the measure's convergent validity with other common alcohol use measures. Traditional age college students (n = 1683, 73% women; 63% White, non-Hispanic) completed measures of drink refusal self-efficacy, protective behavioral strategies, weekly alcohol use, hazardous drinking, and alcohol-related negative consequences. Using exploratory factor analysis and multi-group confirmatory factor analyses, a three-factor structure was identified, but, unlike the DRSEQ-R, one item loaded onto the opportunistic relief factor instead of the social pressure factor. The proposed model registered more reliable internal consistencies across the subscales, was invariant across sex and race, and demonstrated acceptable convergent validity with other commonly used alcohol measures. The proposed model for the DRSE-R may be a more psychometrically sound way to assess for drinking refusal self-efficacy among college students in the United States. Implications, limitations, and future research directions are discussed.



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Watch the Clock, Not the Scale

Publication date: 5 June 2018
Source:Cell Metabolism, Volume 27, Issue 6
Author(s): Kelli L. Vaughan, Julie A. Mattison
The prevalence of diabetes is on the rise, leading to astronomical increases in healthcare costs. In this issue of Cell Metabolism, Sutton et al. (2018) report improved metabolic outcomes even without weight loss. The trick? Eat early and for only 6 hr of the day.

Teaser

The prevalence of diabetes is on the rise, leading to astronomical increases in healthcare costs. In this issue of Cell Metabolism, Sutton et al. (2018) report improved metabolic outcomes even without weight loss. The trick? Eat early and for only 6 hr of the day.


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Visualizing Fatty Acid Flux

Publication date: 5 June 2018
Source:Cell Metabolism, Volume 27, Issue 6
Author(s): Ulf Eriksson, Annelie Falkevall
In a recent issue of Cell Metabolism, He et al. (2018) describes a novel technique to visualize cardiac intravascular lipoprotein lipase-mediated processing of triglyceride-rich lipoproteins and then follow the flux of released fatty acids across the endothelium to the underlying cardiomyocytes at high spatial resolution. This allows for detailed analyses of this clearly complex process.

Teaser

In a recent issue of Cell Metabolism, He et al. (2018) describes a novel technique to visualize cardiac intravascular lipoprotein lipase-mediated processing of triglyceride-rich lipoproteins and then follow the flux of released fatty acids across the endothelium to the underlying cardiomyocytes at high spatial resolution. This allows for detailed analyses of this clearly complex process.


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Obesity Protects Cancer from Drugs Targeting Blood Vessels

Publication date: 5 June 2018
Source:Cell Metabolism, Volume 27, Issue 6
Author(s): Yihai Cao
Drugs that target angiogenesis are commonly used for treating various cancers, but their clinical benefits are limited. In a recent Science Translational Medicine article, Incio et al. (2018) provide mechanistic insight on the role of obesity in the development of anti-VEGF drug resistance in human patients and murine models of breast cancer.

Teaser

Drugs that target angiogenesis are commonly used for treating various cancers, but their clinical benefits are limited. In a recent Science Translational Medicine article, Incio et al. (2018) provide mechanistic insight on the role of obesity in the development of anti-VEGF drug resistance in human patients and murine models of breast cancer.


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OXPHOS Defects Due to mtDNA Mutations: Glutamine to the Rescue!

Publication date: 5 June 2018
Source:Cell Metabolism, Volume 27, Issue 6
Author(s): Christos Chinopoulos
Mutations in mtDNA associated with OXPHOS defects preclude energy harnessing by OXPHOS. The work of Chen et al. (2018) is previewed, reporting flux pathways of glutamine catabolism in mtDNA mutant cells yielding high-energy phosphates through substrate-level phosphorylation and the influence exerted by the severity of OXPHOS impairment.

Teaser

Mutations in mtDNA associated with OXPHOS defects preclude energy harnessing by OXPHOS. The work of Chen et al. is previewed, reporting flux pathways of glutamine catabolism in mtDNA mutant cells yielding high-energy phosphates through substrate-level phosphorylation and the influence exerted by the severity of OXPHOS impairment.


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Viral Vectors for Studying Brain Mechanisms that Control Energy Homeostasis

Publication date: 5 June 2018
Source:Cell Metabolism, Volume 27, Issue 6
Author(s): Giacomo Mancini, Tamas L. Horvath
Viral vectors have been shown to be potent and versatile tools for genome editing. In the present Minireview, we focus on lentiviruses and adeno-associated viruses as vectors and their use in the study of the hypothalamic circuits involved in the regulation of energy homeostasis.

Teaser

Genetically modified adeno-associated viruses represent an extremely useful technology for delivering genetically encoded tools into cells both in vitro and in vivo. Mancini and Horvath review essential techniques for the implementation of viral versatility and specificity to study brain circuits involved in the regulation of energy metabolism.


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Of Mice Not Men? Actions of Interleukin-6 on Glucose Tolerance

Publication date: 5 June 2018
Source:Cell Metabolism, Volume 27, Issue 6
Author(s): Emma R. McGlone, Tricia M. Tan
In mice, interleukin-6 (IL-6) improves glucose tolerance via stimulation of glucagon-like peptide 1 (GLP-1) secretion. In this issue of Cell Metabolism, Lang Lehrskov et al. (2018) demonstrate that IL-6 infusion has GLP-1-dependent and -independent actions with opposing effects on glucose tolerance, resulting in an overall improvement in healthy male volunteers but no improvement in male patients with diabetes.

Teaser

In mice, interleukin-6 (IL-6) improves glucose tolerance via stimulation of glucagon-like peptide 1 (GLP-1) secretion. In this issue of Cell Metabolism, Lang Lehrskov et al. (2018) demonstrate that IL-6 infusion has GLP-1-dependent and -independent actions with opposing effects on glucose tolerance, resulting in an overall improvement in healthy male volunteers but no improvement in male patients with diabetes.


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Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

Publication date: 5 June 2018
Source:Cell Metabolism, Volume 27, Issue 6
Author(s): Mark P. Mattson, Thiruma V. Arumugam
During aging, the cellular milieu of the brain exhibits tell-tale signs of compromised bioenergetics, impaired adaptive neuroplasticity and resilience, aberrant neuronal network activity, dysregulation of neuronal Ca²⁺ homeostasis, the accrual of oxidatively modified molecules and organelles, and inflammation. These alterations render the aging brain vulnerable to Alzheimer's and Parkinson's diseases and stroke. Emerging findings are revealing mechanisms by which sedentary overindulgent lifestyles accelerate brain aging, whereas lifestyles that include intermittent bioenergetic challenges (exercise, fasting, and intellectual challenges) foster healthy brain aging. Here we provide an overview of the cellular and molecular biology of brain aging, how those processes interface with disease-specific neurodegenerative pathways, and how metabolic states influence brain health.

Teaser

Mattson and Arumugam provide a comprehensive view of the cellular and molecular biology of brain aging and discuss how metabolic states influence brain health, including susceptibility to Alzheimer's and Parkinson's diseases and stroke. They consider how the sedentary lifestyle accelerates brain aging and discuss the potential for intermittent metabolic switching to counteract the process.


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Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota

Publication date: 5 June 2018
Source:Cell Metabolism, Volume 27, Issue 6
Author(s): Francesca Cignarella, Claudia Cantoni, Laura Ghezzi, Amber Salter, Yair Dorsett, Lei Chen, Daniel Phillips, George M. Weinstock, Luigi Fontana, Anne H. Cross, Yanjiao Zhou, Laura Piccio
Multiple sclerosis (MS) is more common in western countries with diet being a potential contributing factor. Here we show that intermittent fasting (IF) ameliorated clinical course and pathology of the MS model, experimental autoimmune encephalomyelitis (EAE). IF led to increased gut bacteria richness, enrichment of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families and enhanced antioxidative microbial metabolic pathways. IF altered T cells in the gut with a reduction of IL-17 producing T cells and an increase in regulatory T cells. Fecal microbiome transplantation from mice on IF ameliorated EAE in immunized recipient mice on a normal diet, suggesting that IF effects are at least partially mediated by the gut flora. In a pilot clinical trial in MS patients, intermittent energy restriction altered blood adipokines and the gut flora resembling protective changes observed in mice. In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome.

Graphical abstract

Teaser

Intermittent fasting confers protection in the multiple sclerosis animal model through effects on the gut microbiota; similar changes to the gut microbiota were observed in relapsing multiple sclerosis patients undergoing intermittent energy restriction.


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Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility

Publication date: 5 June 2018
Source:Cell Metabolism, Volume 27, Issue 6
Author(s): Martin Valdearcos, John D. Douglass, Megan M. Robblee, Mauricio D. Dorfman, Daniel R. Stifler, Mariko L. Bennett, Irene Gerritse, Rachael Fasnacht, Ben A. Barres, Joshua P. Thaler, Suneil K. Koliwad




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JAK/STAT3-Regulated Fatty Acid β-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance

Publication date: 5 June 2018
Source:Cell Metabolism, Volume 27, Issue 6
Author(s): Tianyi Wang, Johannes Francois Fahrmann, Heehyoung Lee, Yi-Jia Li, Satyendra C. Tripathi, Chanyu Yue, Chunyan Zhang, Veronica Lifshitz, Jieun Song, Yuan Yuan, George Somlo, Rahul Jandial, David Ann, Samir Hanash, Richard Jove, Hua Yu




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12,13-diHOME: An Exercise-Induced Lipokine that Increases Skeletal Muscle Fatty Acid Uptake

Publication date: 5 June 2018
Source:Cell Metabolism, Volume 27, Issue 6
Author(s): Kristin I. Stanford, Matthew D. Lynes, Hirokazu Takahashi, Lisa A. Baer, Peter J. Arts, Francis J. May, Adam C. Lehnig, Roeland J.W. Middelbeek, Jeffrey J. Richard, Kawai So, Emily Y. Chen, Fei Gao, Niven R. Narain, Giovanna Distefano, Vikram K. Shettigar, Michael F. Hirshman, Mark T. Ziolo, Michael A. Kiebish, Yu-Hua Tseng, Paul M. Coen, Laurie J. Goodyear




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Protein Kinase C-β Dictates B Cell Fate by Regulating Mitochondrial Remodeling, Metabolic Reprogramming, and Heme Biosynthesis

Publication date: Available online 5 June 2018
Source:Immunity
Author(s): Carlson Tsui, Nuria Martinez-Martin, Mauro Gaya, Paula Maldonado, Miriam Llorian, Nathalie M. Legrave, Merja Rossi, James I. MacRae, Angus J. Cameron, Peter J. Parker, Michael Leitges, Andreas Bruckbauer, Facundo D. Batista
PKCβ-null (Prkcb^−/−) mice are severely immunodeficient. Here we show that mice whose B cells lack PKCβ failed to form germinal centers and plasma cells, which undermined affinity maturation and antibody production in response to immunization. Moreover, these mice failed to develop plasma cells in response to viral infection. At the cellular level, we have shown that Prkcb^−/− B cells exhibited defective antigen polarization and mTORC1 signaling. While altered antigen polarization impaired antigen presentation and likely restricted the potential of GC development, defective mTORC1 signaling impaired metabolic reprogramming, mitochondrial remodeling, and heme biosynthesis in these cells, which altogether overwhelmingly opposed plasma cell differentiation. Taken together, our study reveals mechanistic insights into the function of PKCβ as a key regulator of B cell polarity and metabolic reprogramming that instructs B cell fate.

Graphical abstract

Teaser

Lymphocyte activation is associated with major changes in metabolism. Tsui and colleagues demonstrate that PKCβ promotes metabolic reprogramming to drive effector fate decision in B cells.


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A Single-Cell Transcriptomic Atlas of Thymus Organogenesis Resolves Cell Types and Developmental Maturation

Publication date: Available online 5 June 2018
Source:Immunity
Author(s): Eric M. Kernfeld, Ryan M.J. Genga, Kashfia Neherin, Margaret E. Magaletta, Ping Xu, René Maehr
Thymus development is critical to the adaptive immune system, yet a comprehensive transcriptional framework capturing thymus organogenesis at single-cell resolution is still needed. We applied single-cell RNA sequencing (RNA-seq) to capture 8 days of thymus development, perturbations of T cell receptor rearrangement, and in vitro organ cultures, producing profiles of 24,279 cells. We resolved transcriptional heterogeneity of developing lymphocytes, and genetic perturbation confirmed T cell identity of conventional and non-conventional lymphocytes. We characterized maturation dynamics of thymic epithelial cells in vivo, classified cell maturation state in a thymic organ culture, and revealed the intrinsic capacity of thymic epithelium to preserve transcriptional regularity despite exposure to exogenous retinoic acid. Finally, by integrating the cell atlas with human genome-wide association study (GWAS) data and autoimmune-disease-related genes, we implicated embryonic thymus-resident cells as possible participants in autoimmune disease etiologies. This resource provides a single-cell transcriptional framework for biological discovery and molecular analysis of thymus organogenesis.

Graphical abstract

Teaser

Studies of thymus development typically lack single-cell resolution, use indirect readouts, or target narrow cell subsets. Using single-cell RNA sequencing during thymus organogenesis, Kernfeld and Genga et al. reveal cellular heterogeneity, interrogate developmental dynamics by direct observation, and pinpoint cell-specific expression patterns in stromal and blood populations.


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Naive B Cells with High-Avidity Germline-Encoded Antigen Receptors Produce Persistent IgM+ and Transient IgG+ Memory B Cells

Publication date: Available online 5 June 2018
Source:Immunity
Author(s): Kathryn A. Pape, Robert W. Maul, Thamotharampillai Dileepan, Amanda Schmidt Paustian, Patricia J. Gearhart, Marc K. Jenkins
Although immune memory often lasts for life, this is not the case for certain vaccines in some individuals. We sought a mechanism for this phenomenon by studying B cell responses to phycoerythrin (PE). PE immunization of mouse strains with Igh^b immunoglobulin (Ig) variable heavy chain (VH) genes elicited affinity-matured switched Ig memory B cells that declined with time, while the comparable population from an Igh^a strain was numerically stable. Igh^b strains had larger numbers of PE-specific naive B cells and generated smaller germinal center responses and larger numbers of IgM memory cells than the Igh^a strain. The properties of PE-specific B cells in Igh^b mice correlated with usage of a single VH that afforded high-affinity PE binding in its germline form. These results suggest that some individuals may be genetically predisposed to generate non-canonical memory B cell responses to certain antigens because of avid antigen binding via germline-encoded VH elements.

Graphical abstract

Teaser

Immunity induced by certain vaccines declines over time. By studying B cell responses to phycoerythrin, Pape et al. find that memory B cells can be short-lived when generated from precursors that experience unusually strong early signals through their un-mutated antigen receptors.


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Miriam’s Journey to Sound

"It was one of the best days of my life," says Miriam Green in an emotionally charged voice. "I wish...

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Save the Date: Dr. Steven Zeitels to Speak at ORL Frontiers Next Month

Steven Marc Zeitels, MD, is the invited speaker for ORL Frontiers 2018, which will be held Saturday, June 23, at...

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Amber Luong, MD, PhD Recognized as Trailblazer

Amber Luong, MD, PhD, associate professor of otorhinolaryngology, has been recognized with the 2017 Helen F. Krause, MD Memorial Trailblazer...

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A Novel Missense Mutation in SLC5A5 Gene in a Sudanese Family with Congenital Hypothyroidism

Thyroid, Ahead of Print.


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Molecular targets of celastrol in cancer: Recent trends and advancements

Publication date: Available online 5 June 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Dharambir Kashyap, Ajay Sharma, Hardeep Singh Tuli, Katrin Sak, Tapan Mukherjee, Anupam Bishayee
Despite the advancement in the well-equipped and sophisticated laboratories and facilities, cancer remains to be a major cause of death worldwide. Consequently, further investigation of novel strategies need to be evolved. Since the last few decades, the utilization of phytochemicals is emerging against several human cancers, including lung, breast, colon carcinoma, lymphoma, and other hematological malignancies. Terpenoids are a category of therapeutically active phytochemicals that have been utilized against cancer, cardiovascular and neurodegenerative disorders. Particularly, celastrol, a pentacyclic terpenoid, is well-studied for its variety of pharmacological properties. It is well documented that celastrol can modulate a variety of signaling pathways. Celastrol's anti-proliferative role has been found to be associated with its pro-apoptotic (via protein kinase B), anti-angiogenic (via vascular endothelial growth factor and vascular endothelial growth factor receptor), anti-metastatic (via matrix metalloproteinases), and anti-inflammatory (via cytokines and chemokines) activities. This review describes various molecular mechanisms of celastrol for understanding the biology of cancer initiation, progression as well as designing efficacious therapeutic strategies.



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An investigation of some Schiff base derivatives as chemosensors for Zn(II): The performance characteristics and potential applications

Publication date: 5 October 2018
Source:Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, Volume 203
Author(s): Ece Ergun, Ümit Ergun, Özgür İleri, Muhammed Fatih Küçükmüzevir
The fluorescence properties of four simple Schiff bases (LH2, LDMH2, LH2^H and LDM^HH2) and their potential application as chemosensors for the detection of zinc ion in aqueous solution have been investigated. While LH2 and LDMH2 have displayed specific recognition to Zn(II), the reduced derivatives (LH2^H and LDM^HH2) of these ligands have shown no fluorescence response due to the lack of CN group. The Job plots, fluorescence titration experiments and ESI-MS results indicate the formation of 1:1 complexes between sensors and Zn(II). The analytic methods based on LH2 and LDMH2 as chemosensors have been proposed and optimized to detect Zn(II) ions in aqueous solution. The optimized methods have shown a good range of linearity, high precision, good accuracy and low detection limit. As an alternative to these methods, LH2 and LDMH2 have the capability to detect Zn(II) ions by naked eye under UV lamp. Moreover, LH2-Zn and LDMH2-Zn complexes have the ability to be a staining agent for identifying the radiation treatment of food by DNA comet assay.

Graphical abstract

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Structural diversity and luminescent sensing of three coordination polymers based on the hydrolysates of N,N′-bis(3,5-dicarboxylatophenyl)pyromelliticdi-imide)

Publication date: 5 November 2018
Source:Journal of Molecular Structure, Volume 1171
Author(s): Liming Fan, Jiang Wang, Li Zhao, Yujuan Zhang, Xiaoqing Wang, Tuoping Hu, Xiutang Zhang
Based on the hydrolysates of N,N′-bis(3,5-dicarboxylatophenyl)pyromelliticdi-imide) (H4L) and 1,3-bis(imidazol-1-ylmethyl)benzene (bimb), three coordination polymers, namely, {[Zn(BTC)0.5(bimb)]·4H2O}n (1), [Cu(BTC)0.5(bimb)]n (2), and {[Cd(AIP)(H2O)]·H2O}n (3), have been obtained under solvothermal conditions. The possible hydrolysis mechanism of H4L was investigated here. Structural analyses reveal that complex 1 is a 3D (4,4)-c {6⁴.8²}{6⁶}2-bbf net. Complex 2 displays a 2D 4-c {3².6².7²}-kgm sheet. While complex 3 exhibits a 3D (3,6)-c {4.6²}2{4².6¹⁰.8³}-rtl net based on binuclear {Cd2(COO)4} SBUs. Besides, luminescent sensing investigation indicated that 1 and 3 exhibit highly sensitive and selective sensing of chromate anions in aqueous solution.

Graphical abstract

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Characterization of polymer-coated CdSe/ZnS quantum dots and investigation of their behaviour in soil solution at relevant concentration by asymmetric flow field-flow fractionation – multi angle light scattering – inductively coupled plasma - mass spectrometry

Publication date: 22 October 2018
Source:Analytica Chimica Acta, Volume 1028
Author(s): Stéphane Faucher, Gaëlle Charron, Elias Lützen, Philippe Le Coustumer, Dirk Schaumlöffel, Yann Sivry, Gaëtane Lespes
A careful separation, identification and characterization of polymer-coated quantum dots (P-QDs) in complex media such as soil solution is the key point to understand their behaviour and to accurately predict their fate in the environment. In the present study, a synthesized CdSe/ZnS core/shell P-QDs suspension, proved to be stable for at least six months, was investigated with respect to P-QDs dimension, structure and elemental composition. Separation of P-QDs and size distribution determination were carried out by Asymmetric Flow Field-Flow Fractionation (AF4) - Multi Angle Light Scattering (MALS). AF4 and MALS were coupled to Inductively Coupled Plasma-Mass Spectrometry (ICPMS) as a selective and sensitive technique for the detection and the characterization of metallic and metalloid analytes. The exploration of element-specific data obtained by ICPMS after AF4 separation enabled the signal to be deconvoluted reliably. Thus, 3 classes of size populations were identified from the whole population of P-QDs. Additionally, a soil solution and a mix of P-QDs suspension with soil solution were characterized by the same method. This strategy enabled the P-QD population, which interacted with the soil solution, to be determined, this interaction leading either to an aggregation or dissolution of the P-QDs. Reproducibility and recovery of the size distributions and element concentrations were examined for each sample. Complementarily, Dynamic Light Scattering (DLS) and Scanning Transmission Electron Microscopy (STEM) were used jointly with AF4-MALS-ICPMS in order to demonstrate all potentialities of this coupling technique.

Graphical abstract

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Family-based treatment for transition age youth: parental self-efficacy and caregiver accommodation

Abstract

Background

Family-Based Treatment (FBT) is the first line of care in paediatric treatment while adult programs focus on individualized models of care. Transition age youth (TAY) with Anorexia Nervosa (AN) are in a unique life stage and between systems of care. As such, they and their caregivers may benefit from specialized, developmentally tailored models of treatment.

Methods

The primary purpose of this study was to assess if parental self-efficacy and caregiver accommodation changed in caregivers during the course of FBT-TAY for AN. The secondary aim was to determine if changes in parental self-efficacy and caregiver accommodation contributed to improvements in eating disorder behaviour and weight restoration in the transition age youth with AN. Twenty-six participants (ages 16–22) and 39 caregivers were recruited. Caregivers completed the Parents versus Anorexia Scale and Accommodation and Enabling Scale for Eating Disorders at baseline, end-of-treatment (EOT), and 3 months follow-up.

Results

Unbalanced repeated measures designs for parental self-efficacy and caregiver accommodation towards illness behaviours were conducted using generalized estimation equations. Parental self-efficacy increased from baseline to EOT, although not significantly (p = .398). Parental self-efficacy significantly increased from baseline to 3 months post-treatment (p = .002). Caregiver accommodation towards the illness significantly decreased from baseline to EOT (p = 0.0001), but not from baseline to 3 months post-treatment (p = 1.000). Stepwise ordinary least squares regression estimates of eating disorder behaviour and weight restoration did not show that changes in parental-self efficacy and caregiver accommodation predict eating disorder behaviour or weight restoration at EOT or 3 months post-treatment.

Conclusions

Our findings demonstrate, albeit preliminary at this stage, that FBT-TAY promotes positive increases in parental self-efficacy and assists caregivers in decreasing their accommodation to illness behaviours for transition age youth with AN. However, changes in the parental factors did not influence changes in eating and weight in the transition age youth.

https://ift.tt/2M0eb5m

3D heterogeneous islet organoid generation from human embryonic stem cells using a novel engineered hydrogel platform

Publication date: September 2018
Source:Biomaterials, Volume 177
Author(s): Joseph Candiello, Taraka Sai Pavan Grandhi, Saik Kia Goh, Vimal Vaidya, Maya Lemmon-Kishi, Kiarash Rahmani Eliato, Robert Ros, Prashant N. Kumta, Kaushal Rege, Ipsita Banerjee
Organoids, which exhibit spontaneous organ specific organization, function, and multi-cellular complexity, are in essence the in vitro reproduction of specific in vivo organ systems. Recent work has demonstrated human pluripotent stem cells (hPSCs) as a viable regenerative cell source for tissue-specific organoid engineering. This is especially relevant for engineering islet organoids, due to the recent advances in generating functional beta-like cells from human pluripotent stem cells. In this study, we report specific engineering of regenerative islet organoids of precise size and cellular heterogeneity, using a novel hydrogel system, Amikagel. Amikagel facilitated controlled and spontaneous aggregation of human embryonic stem cell derived pancreatic progenitor cells (hESC-PP) into robust homogeneous spheroids. This platform further allowed fine control over the integration of multiple cell populations to produce heterogeneous spheroids, which is a necessity for complex organoid engineering. Amikagel induced hESC-PP spheroid formation enhanced pancreatic islet-specific Pdx-1 and NKX6.1 gene and protein expression, while also increasing the percentage of committed population. hESC-PP spheroids were further induced towards mature beta-like cells which demonstrated increased Beta-cell specific INS1 gene and C-peptide protein expression along with functional insulin production in response to in vitro glucose challenge. Further integration of hESC-PP with biologically relevant supporting endothelial cells resulted in multicellular organoids which demonstrated spontaneous maturation towards islet-specific INS1 gene and C-peptide protein expression along with a significantly developed extracellular matrix support system. These findings establish Amikagel –facilitated platform ideal for islet organoid engineering.



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Transfection of gene regulation nanoparticles complexed with pDNA and shRNA controls multilineage differentiation of hMSCs

Publication date: September 2018
Source:Biomaterials, Volume 177
Author(s): Hye Jin Kim, Se Won Yi, Hyun Jyung Oh, Jung Sun Lee, Ji Sun Park, Keun-Hong Park
Overexpression and knockdown of specific proteins can control stem cell differentiation for therapeutic purposes. In this study, we fabricated RUNX2, SOX9, and C/EBPα plasmid DNAs (pDNAs) and ATF4-targeting shRNA (shATF4) to induce osteogenesis, chondrogenesis, and adipogenesis of human mesenchymal stem cells (hMSCs). The pDNAs and shATF4 were complexed with TRITC-gene regulation nanoparticles (GRN). Osteogenesis-related gene expression was reduced at early (12 h) and late (36 h) time points after co-delivery of shATF4 and SOX9 or C/EBPα pDNA, respectively, and osteogenesis was inhibited in these hMSCs. By contrast, osteogenesis-related genes were highly expressed upon co-delivery of RUNX2 and ATF4 pDNAs. DEX in GRN enhanced chondrogenic differentiation. Expression of osteogenesis-, chondrogenesis-, and adipogenesis-related genes was higher in hMSCs transfected with NPs complexed with RUNX2 and ATF4 pDNAs, shATF4 and SOX9 pDNA, and shATF4 and C/EBPα pDNA for 72 h than in control hMSCs, respectively. Moreover, delivery of these NPs also increased expression of osteogenesis-, chondrogenesis-, and adipogenesis-related proteins. These alterations in expression led to morphological changes, indicating that hMSCs differentiated into osteoblasts, chondrocytes, and adipose cells.



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Nanodiamonds as “artificial proteins”: Regulation of a cell signalling system using low nanomolar solutions of inorganic nanocrystals

Publication date: September 2018
Source:Biomaterials, Volume 176
Author(s): Lukas Balek, Marcela Buchtova, Michaela Kunova Bosakova, Miroslav Varecha, Silvie Foldynova-Trantirkova, Iva Gudernova, Iva Vesela, Jan Havlik, Jitka Neburkova, Stuart Turner, Mateusz Adam Krzyscik, Malgorzata Zakrzewska, Lars Klimaschewski, Peter Claus, Lukas Trantirek, Petr Cigler, Pavel Krejci
The blocking of specific protein-protein interactions using nanoparticles is an emerging alternative to small molecule-based therapeutic interventions. However, the nanoparticles designed as "artificial proteins" generally require modification of their surface with (bio)organic molecules and/or polymers to ensure their selectivity and specificity of action. Here, we show that nanosized diamond crystals (nanodiamonds, NDs) without any synthetically installed (bio)organic interface enable the specific and efficient targeting of the family of extracellular signalling molecules known as fibroblast growth factors (FGFs). We found that low nanomolar solutions of detonation NDs with positive ζ-potential strongly associate with multiple FGF ligands present at sub-nanomolar concentrations and effectively neutralize the effects of FGF signalling in cells without interfering with other growth factor systems and serum proteins unrelated to FGFs. We identified an evolutionarily conserved FGF recognition motif, ∼17 amino acids long, that contributes to the selectivity of the ND-FGF interaction. In addition, we inserted this motif into a de novo constructed chimeric protein, which significantly improved its interaction with NDs. We demonstrated that the interaction of NDs, as purely inorganic nanoparticles, with proteins can mitigate pathological FGF signalling and promote the restoration of cartilage growth in a mouse limb explant model. Based on our observations, we foresee that NDs may potentially be applied as nanotherapeutics to neutralize disease-related activities of FGFs in vivo.



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A “top-down” approach to actuate poly(amine-co-ester) terpolymers for potent and safe mRNA delivery

Publication date: September 2018
Source:Biomaterials, Volume 176
Author(s): Yuhang Jiang, Alice Gaudin, Junwei Zhang, Tushar Agarwal, Eric Song, Amy C. Kauffman, Gregory T. Tietjen, Yongheng Wang, Zhaozhong Jiang, Christopher J. Cheng, W. Mark Saltzman
Gene delivery is known to be a complicated multi-step biological process. It has been observed that subtle differences in the structure and properties of polymeric materials used for gene delivery can lead to dramatic differences in transfection efficiency. Therefore, screening of properties is pivotal to optimizing the polymer. So far, most polymeric materials are built in a "bottom-up" manner, i.e. synthesized from monomers that allow modification of polymer composition or structural factors. With this method, we previously synthesized and screened a library of biodegradable poly(amine-co-ester) (PACE) terpolymers for optimized DNA delivery. However, it can be tedious and time consuming to synthesize a polymer library for screening, particularly when small changes of a factor need to be tested, when multiple factors are involved, and when the effects of different factors are synergistic. In the present work, we evaluate the potential of PACE to deliver mRNA. After observing that mRNA transfection efficiency was highly dependent on both end group composition and molecular weight (MW) of PACE in a synergistic manner, we developed a "top-down" process we called actuation, to simultaneously vary these two factors. Some of the actuated PACE (aPACE) materials presented superior mRNA delivery properties compared to regular PACE, with up to a 10⁶-fold-increase in mRNA transfection efficiency in vitro. Moreover, when aPACE was used to deliver mRNA coding for erythropoietin (EPO) in vivo, it produced high levels of EPO in the blood for up to 48 h without inducing systemic toxicity. This polymer constitutes a new delivery vehicle for mRNA-based treatments that provides safe yet potent protein production.

Graphical abstract

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Molecular targets of celastrol in cancer: Recent trends and advancements

Publication date: Available online 5 June 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Dharambir Kashyap, Ajay Sharma, Hardeep Singh Tuli, Katrin Sak, Tapan Mukherjee, Anupam Bishayee
Despite the advancement in the well-equipped and sophisticated laboratories and facilities, cancer remains to be a major cause of death worldwide. Consequently, further investigation of novel strategies need to be evolved. Since the last few decades, the utilization of phytochemicals is emerging against several human cancers, including lung, breast, colon carcinoma, lymphoma, and other hematological malignancies. Terpenoids are a category of therapeutically active phytochemicals that have been utilized against cancer, cardiovascular and neurodegenerative disorders. Particularly, celastrol, a pentacyclic terpenoid, is well-studied for its variety of pharmacological properties. It is well documented that celastrol can modulate a variety of signaling pathways. Celastrol's anti-proliferative role has been found to be associated with its pro-apoptotic (via protein kinase B), anti-angiogenic (via vascular endothelial growth factor and vascular endothelial growth factor receptor), anti-metastatic (via matrix metalloproteinases), and anti-inflammatory (via cytokines and chemokines) activities. This review describes various molecular mechanisms of celastrol for understanding the biology of cancer initiation, progression as well as designing efficacious therapeutic strategies.



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Dendritic cells in inflammatory angiogenesis and lymphangiogenesis

Daniela Bosisio | Roberto Ronca | Valentina Salvi | Marco Presta | Silvano Sozzani

https://ift.tt/2sEUqY4

Contents Continued

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68





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Motor coordination and synaptic plasticity deficits are associated with increased cerebellar activity of NADPH oxidase, CAMKII, and PKC at preplaque stage in the TgCRND8 mouse model of Alzheimer's disease

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Roberto Russo, Fabio Cattaneo, Pellegrino Lippiello, Claudia Cristiano, Fabio Zurlo, Martina Castaldo, Carlo Irace, Tiziana Borsello, Rita Santamaria, Rosario Ammendola, Antonio Calignano, Maria Concetta Miniaci
Numerous studies indicate that the cerebellum undergoes structural and functional neurodegenerative changes in Alzheimer's disease. The purpose of this study was to examine the extent of cerebellar alterations at early, preplaque stage of the pathology in TgCRND8 mice through behavioral, electrophysiological, and molecular analysis. Balance beam test and foot-printing analysis revealed significant motor coordination and balance deficits in 2-month-old TgCRND8 mice compared to their littermates. Patch-clamp recordings performed on cerebellar slices of transgenic mice showed synaptic plasticity deficit and loss of noradrenergic modulation at parallel fiber-Purkinje cell synapse suggesting an early dysfunction of the cerebellar circuitry due to amyloid precursor protein overexpression. Finally, western blot analysis revealed an enhanced expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p47^phox and p67^phox as well as Ca²⁺/calmodulin-dependent protein kinase and protein kinase C alpha in the cerebellum of 2-month-old transgenic mice. Therefore, we propose the existence of self-sustaining feedback loop involving the formyl peptide receptor 2-reactive oxygen species-Ca²⁺/calmodulin-dependent protein kinase II-protein kinase C alpha pathway that may promote reactive oxygen species generation in the early stage of Alzheimer's disease and eventually contribute to the exacerbation of pathological phenotype.



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A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Binbin Wang, Suying Bao, Zhigang Zhang, Xueya Zhou, Jing Wang, Yanhui Fan, Yan Zhang, Yan Li, Luhua Chen, Yizhen Jia, Jiang Li, Miaoxin Li, Wenhua Zheng, Nan Mu, Liqiu Wang, Zhe Yu, Dana S.M. Wong, Yalun Zhang, Joseph Kwan, Henry Ka-Fung Mak, Amirthagowri Ambalavanan, Sirui Zhou, Wangwei Cai, Jin Zheng, Shishu Huang, Guy A. Rouleau, Wanling Yang, Ekaterina Rogaeva, Xu Ma, Peter St George-Hyslop, Leung Wing Chu, You-Qiang Song
Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. To identify rare genetic factors other than apolipoprotein E ɛ4 allele (ApoE ɛ4) contributing to the pathogenesis of late-onset AD (LOAD), we conducted a whole-exome analysis of 246 ApoE ɛ4-negative LOAD cases and 172 matched controls in Hong Kong Chinese population. LOAD patients showed a significantly higher burden of rare loss-of-function variants in genes related to immune function than healthy controls. Among the genes involved in immune function, we identified a rare stop-gain variant (p.Q48X) in mixed lineage kinase domain like pseudokinase (MLKL) gene present exclusively in 6 LOAD cases. MLKL is expressed in neurons, and the its expression levels in the p.Q48X carriers were significantly lower than that in age-matched wild-type controls. The ratio of Aβ42 to Aβ40 significantly increased in MLKL knockdown cells compared to scramble controls. MLKL loss-of-function mutation might contribute to late-onset ApoE ɛ4-negative AD in the Hong Kong Chinese population.



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Education amplifies brain atrophy effect on cognitive decline: implications for cognitive reserve

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Dan Mungas, Brandon Gavett, Evan Fletcher, Sarah Tomaszewski Farias, Charles DeCarli, Bruce Reed
Level of education is often regarded as a proxy for cognitive reserve in older adults. This implies that brain degeneration has a smaller effect on cognitive decline in those with more education, but this has not been directly tested in previous research. We examined how education, quantitative magnetic resonance imaging–based measurement of brain degeneration, and their interaction affect cognitive decline in diverse older adults spanning the spectrum from normal cognition to dementia. Gray matter atrophy was strongly related to cognitive decline. While education was not related to cognitive decline, brain atrophy had a stronger effect on cognitive decline in those with more education. Importantly, high education was associated with slower decline in individuals with lesser atrophy but with faster decline in those with greater atrophy. This moderation effect was observed in Hispanics (who had high heterogeneity of education) but not in African-Americans or Caucasians. These results suggest that education is an indicator of cognitive reserve in individuals with low levels of brain degeneration, but the protective effect of higher education is rapidly depleted as brain degeneration progresses.



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Targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Adeline S.L. Ng, Yi Jayne Tan, Zhao Yi, Moses Tandiono, Elaine Chew, Jacqueline Dominguez, Mabel Macas, Ebonne Ng, Shahul Hameed, Simon Ting, Eng King Tan, Jia Nee Foo, Nagaendran Kandiah
To identify genes associated with frontotemporal dementia (FTD) in South-East Asia, targeted exome sequencing and C9orf72 genotyping was performed in 198 subjects (52 patients with FTD and 146 healthy controls) who were screened for mutations in 12 FTD-associated genes. We detected a homozygous TREM2 R47C mutation in a patient with behavioral variant FTD without bone cysts or bone-associated phenotype. Two novel nonsense GRN mutations in 3 FTD patients from the Philippines were detected, but no known pathogenic mutations in other FTD-associated genes were found. In 45 subjects screened for C9orf72 repeat expansions, no pathogenic expansion (≥30 repeats) was identified, but there was a higher proportion of intermediate length (≥10–29 repeats) alleles in patients compared with controls (8/90 alleles, 8.9% vs. 9/164 alleles, 5.5%). Overall, we detected a mutation rate of 7.7% (4/52 patients) in our cohort. Given recent findings of enrichment of rare TREM2 variants (including R47C) in Alzheimer's disease, it is notable that we detected a homozygous TREM2 R47C carrier presenting with an FTD rather than an Alzheimer's disease phenotype.



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Longitudinal accrual of neocortical amyloid burden is associated with microstructural changes of the fornix in cognitively normal adults

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Zhuang Song, Michelle E. Farrell, Xi Chen, Denise C. Park
The fornix and parahippocampal cingulum are 2 major limbic tracts in the core memory network of the hippocampus. Although these fiber tracts are known to degrade with Alzheimer's disease (AD), little is known about their vulnerability in the asymptomatic phase of AD. In this longitudinal study of cognitively normal adults, we assessed amyloid-beta (Aβ) plaques using positron emission tomography and white matter microstructure using diffusion tensor imaging. We found that an increase of neocortical Aβ burden over time was associated with an increase of radial diffusivity in the fornix but not in the parahippocampal cingulum. The effect of increasing neocortical Aβ burden on the fornix remained significant after controlling for baseline measures, head motion, global brain atrophy, regional Aβ burden in the hippocampus, or microstructural changes in the global white matter. In addition, microstructural changes in the fornix were not associated with decline of episodic memory or other cognitive abilities. Our findings suggest that microstructural changes in the fornix may be an early sign in the asymptomatic phase of AD.



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Cover 2: Editorial Advisory Board

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68





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Upregulation of histone deacetylase 2 in laser capture nigral microglia in Parkinson's disease

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Yuyan Tan, Elaine Delvaux, Jennifer Nolz, Paul D. Coleman, Shengdi Chen, Diego Mastroeni
Histone deacetylase (HDAC) inhibitors have been widely reported to have considerable therapeutic potential in a host of neurodegenerative diseases. However, HDAC inhibitor selectivity and specificity in specific cell classes have been a source of much debate. To address the role of HDAC2 in specific cell classes, and in disease, we examined glial protein and mRNA levels in the substantia nigra (SN) of Parkinson's disease (PD) and normal controls (NCs) by immunohistochemistry and laser captured microdissection followed by quantitative real time polymerase chain reaction. Differential expression analysis in immunohistochemically defined laser capture microglia revealed significant upregulation of HDAC2 in the PD SN compared to NC subjects. Complementary in vivo evidence reveals significant upregulation of HDAC2 protein levels in PD SN microglia compared to NC subjects. Correspondingly, human immortalized telencephalic/mesencephalic microglial cells reveal significant upregulation of HDAC2 in the presence of the potent microglial activator lipopolysaccharide. These data provide evidence that selective inhibition of HDAC2 in PD SN microglia could be a promising approach to treat microglial-initiated nigral dopaminergic neuronal cell loss in PD.



https://ift.tt/2xIgDuh

Classifying Alzheimer's disease with brain imaging and genetic data using a neural network framework

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Kaida Ning, Bo Chen, Fengzhu Sun, Zachary Hobel, Lu Zhao, Will Matloff, Arthur W. Toga
A long-standing question is how to best use brain morphometric and genetic data to distinguish Alzheimer's disease (AD) patients from cognitively normal (CN) subjects and to predict those who will progress from mild cognitive impairment (MCI) to AD. Here, we use a neural network (NN) framework on both magnetic resonance imaging-derived quantitative structural brain measures and genetic data to address this question. We tested the effectiveness of NN models in classifying and predicting AD. We further performed a novel analysis of the NN model to gain insight into the most predictive imaging and genetics features and to identify possible interactions between features that affect AD risk. Data were obtained from the AD Neuroimaging Initiative cohort and included baseline structural MRI data and single nucleotide polymorphism (SNP) data for 138 AD patients, 225 CN subjects, and 358 MCI patients. We found that NN models with both brain and SNP features as predictors perform significantly better than models with either alone in classifying AD and CN subjects, with an area under the receiver operating characteristic curve (AUC) of 0.992, and in predicting the progression from MCI to AD (AUC=0.835). The most important predictors in the NN model were the left middle temporal gyrus volume, the left hippocampus volume, the right entorhinal cortex volume, and the APOE (a gene that encodes apolipoprotein E) ɛ4 risk allele. Furthermore, we identified interactions between the right parahippocampal gyrus and the right lateral occipital gyrus, the right banks of the superior temporal sulcus and the left posterior cingulate, and SNP rs10838725 and the left lateral occipital gyrus. Our work shows the ability of NN models to not only classify and predict AD occurrence but also to identify important AD risk factors and interactions among them.



https://ift.tt/2sAIB60

DNAJC12 mutation is rare in Chinese Han population with Parkinson's disease

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Yu Fan, Zhi-hua Yang, Fang Li, Xin-chao Hu, Yi-wei Yue, Jing Yang, Yu-tao Liu, Han Liu, Yan-lin Wang, Chang-he Shi, Yu-ming Xu
Recently, mutations of DNAJC12 gene were reported to be associated with early-onset parkinsonism, progressive neurodevelopmental delay, and dystonia in several unrelated pedigrees. This study aimed to evaluate DNAJC12 coding mutations in sporadic Chinese Han patients with Parkinson's disease (PD) and test whether an age-of-onset effect exists. Seven hundred two Chinese Han sporadic PD patients, including 181 early-onset PD and 521 late-onset PD, and 728 healthy controls were recruited. No documented disease-causing mutation of DNAJC12 was identified, but we found 7 single-nucleotide polymorphisms. Allele frequencies did not differ between all the PD patients and controls or between any 2 subgroups for all these single-nucleotide polymorphisms. Our study suggests that DNAJC12 mutation is not a risk factor of PD in Chinese Han population, and no age-of-onset effect was verified.



https://ift.tt/2xIgveh

Association analyses of variants of SIPA1L2, MIR4697, GCH1, VPS13C, and DDRGK1 with Parkinson's disease in East Asians

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Ming Zou, Rui Li, Jian-Yong Wang, Ke Wang, Ya-Nan Wang, Yang Li, Fei-Xue Ji, Sheng-Nan Sun, Shi-Shi Huang, Hui-Hui Fan, Chen-Ping Huang, Xiong Zhang, Jian-Hong Zhu
A recent large-scale European-originated genome-wide association data meta-analysis followed by a replication study identified 6 new risk loci for Parkinson's disease (PD), which include rs10797576/SIPA1L2, rs117896735/INPP5F, rs329648/MIR4697, rs11158026/GCH1, rs2414739/VPS13C, and rs8118008/DDRGK1. However, whether these new loci are associated with PD in Asian populations remain elusive. The INPP5F is nonpolymorphic in Asians. The present study aimed to understand the effects of the other 5 new loci in a Han Chinese population comprising 579 sporadic PD patients and 642 controls. Significant associations with PD were observed in the variants of SIPA1L2 (p = 0.001) and VPS13C (p = 0.007), where the T (odd ratio [OR] = 1.484, 95% confidence interval [CI] 1.186–1.858) and A (OR = 1.362, 95% CI 1.087–1.707) alleles serve as the risk alleles, respectively. The genotype distributions in the SIPA1L2 and VPS13C variants were also different between the patients and controls (p = 0.002 and p = 0.023, respectively). In contrast, no significant association with PD was found in the variants of MIR4697, GCH1, and DDRGK1 either in allele or genotype frequencies. Noteworthy, a followed meta-analysis of East Asian studies suggested an association of the GCH1 variant with PD (p = 0.04, OR 1.08, 95% CI 1.00–1.16), while the other results are in line with those of our cohort. In conclusion, our study together with meta-analyses demonstrates that the variants of SIPA1L2 and VPS13C, potentially GCH1, but not of MIR4697 and DDRGK1, are associated with PD susceptibility in East Asians.



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Genome-wide association identifies a novel locus for delirium risk

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Thomas H. McCoy, Kamber Hart, Amelia Pellegrini, Roy H. Perlis
We aimed to identify common genetic variations associated with delirium through genome-wide association testing in a hospital biobank. We applied a published electronic health record-based definition of delirium to identify cases of delirium, and control individuals with no history of delirium, from a biobank spanning 2 Boston academic medical centers. Among 6035 individuals of northern European ancestry, including 421 with a history of delirium, we used logistic regression to examine genome-wide association. We identified one locus spanning multiple genes, including 3 interleukin-related genes, associated with p = 1.41e-8, and 5 other independent loci with p < 5e-7. Our results do not support previously reported candidate gene associations in delirium. Identifying common-variant associations with delirium may provide insight into the mechanisms responsible for this complex and multifactorial outcome. Using standardized claims-based phenotypes in biobanks should allow the larger scale investigations required to confirm novel loci such as the one we identify.



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Mutation screening of the TIA1 gene in Chinese patients with amyotrophic lateral sclerosis/frontotemporal dementia

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): XiaoJing Gu, YongPing Chen, QianQian Wei, Bei Cao, RuWei Ou, XiaoQin Yuan, YanBin Hou, LingYu Zhang, Hui Liu, XuePing Chen, Hui-Fang Shang
Mutations in the low-complexity domain (LCD) of T-cell intracellular antigen-1 (TIA1) have been reported to be associated with amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) in the Caucasian population. In the present study, we aimed to screen mutations in the LCD (exon 11–13) of TIA1 and determine the mutation frequency in Chinese ALS/FTD patients. A total of 740 ALS patients, including 721 sporadic ALS (sALS), 19 familial ALS, 24 FTD patients, and 501 healthy controls, were directly sequenced. A novel variant p.S349P was found in a male sALS patient who presented with mild cognitive decline and a survival time of 1.23 years since onset. No mutation in the LCD of TIA1 was found in the familial ALS and FTD patients. The mutation frequency of TIA1 was 0.14% (1/721) in Chinese sALS patients, which suggests that TIA1 mutation is an uncommon genetic cause for ALS in the Chinese population.



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Cover 4: Contents

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68





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ECT: a new look at an old friend

Purpose of review Electroconvulsive therapy (ECT) as a treatment option in psychiatry is advancing day by day. This review discusses new advancements in ECT with regards to anesthetic variables, stimulus, and response variables along with their impact on clinical outcomes. Recent findings Anesthetic variables influence clinical efficacy and patient tolerance of ECT. Although etomidate or a ketamine–propofol combination may be the first choice for many clinicians, the search for ideal induction agent continues. Dexmedetomidine, remifentanil, or ketamine may aid in augmentation of ECT; however, they are not recommended routinely. A systematic procedure for hyperventilation of the patient has been shown to have clinical repercussions. Optimizing anesthesia-ECT time interval (ASTI) has a significant impact on the success of the procedure. BIS monitoring alone cannot be relied upon for timing stimulus. High-dose brief pulse right unilateral ECT represents an acceptable first-line form of treatment, though there is currently no 'gold standard'. Other stimulus variations such as focal electrically administered seizure therapy, individualized low-amplitude seizure therapy, magnetic seizure therapy, left unilateral and left anterior right temporal electrode placements are explored to reduce memory effects. EEG ictal indices may be relied upon for seizure adequacy, and therefore may be used to both guide treatment and predict the outcome of the procedure. Summary Modern ECT is streamlined by augmentation with drugs, hyperventilation, optimizing anesthesia-ECT time interval, and various stimulus parameters guided by seizure adequacy markers. Correspondence to Pavan Kumar Kadiyala, Assistant Professor, Department of Psychiatry, ASR Academy of Medical Sciences, Eluru, AP 534005, India. Tel: +919980731234; e-mail: drkadiyala2@gmail.com Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Do we really need an anesthesiologist for routine colonoscopy in American Society of Anesthesiologist 1 and 2 patients?

Purpose of review In an era where healthcare costs are being heavily scrutinized, every expenditure is reviewed for medical necessity. Multiple national gastroenterology societies have issued statements regarding whether an anesthesiologist is necessary for routine colonoscopies in American Society of Anesthesiologist (ASA) 1 and 2 patients. Recent findings A large percentage of patients are undergoing screening colonoscopy without any sedation at all, which would not require an independent practitioner to administer medications. Advances in technique and technology are making colonoscopies less stimulating. Advantages to administering sedation, including propofol, have been seen even when not administered under the direction of an anesthesiologist and complications seem to be rare. The additional cost of having monitored anesthesia care appears to be a driving factor in whether a patient receives it or not. Summary A large multiinstitutional randomized control trial would be necessary to rule out potential confounders and to determine whether there is a safety benefit or detriment to having anesthesiologist-directed care in the setting of routine colonoscopies in ASA 1 and 2 patients. Further discussion would be necessary regarding what the monetary value of that effect is if a small difference were to be detected. Correspondence to Jeffrey D. White, MD, Department of Anesthesiology, University of Florida College of Medicine, 1600 SW Archer Road, PO Box 100254, Gainesville, FL 32610, USA. Tel: +1 352 273 6575; e-mail: jwhite@anest.ufl.edu Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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An autophagy-targeting peptide to treat chronic inflammatory demyelinating polyneuropathies

Publication date: Available online 5 June 2018
Source:Journal of Autoimmunity
Author(s): Susana Brun, Nicolas Schall, Srinivasa Reddy Bonam, Kévin Bigaut, Ayikoe-Guy Mensah-Nyagan, Jérôme de Sèze, Sylviane Muller
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nerves evolving with diffuse sensory and motor symptoms. Although it is claimed that in neurodegenerative pathologies, a common feature is the failure of proteolytic systems to adequately eliminate aggregated or misfolded proteins, it has not been addressed whether autophagy, a central "clearance" system delivering damaged intracellular components to lysosomes, is affected in CIDP. The focus of the present investigation was therefore to determine if some defects exist in autophagy processes in this setting and if they can be corrected or minimized using an appropriate treatment targeting this survival pathway. Experiments were performed using a rat model mimicking human CIDP, also known as chronic experimental autoimmune neuritis (c-EAN), the disease establishment and development of which was followed at both the clinical and biological levels (indices of disease severity, histopathological alteration, cytokines and antibodies rates). Based on immunofluorescence and western immunoblotting experiments on sciatic nerves and spleen cells from c-EAN rats, we demonstrate that both, macroautophagy and chaperone-mediated autophagy (CMA), are significantly altered in non-neuronal cells of the peripheral nervous system. We show further that a 21-mer synthetic phosphopeptide called P140, known to target CMA and successfully used in pathological settings where CMA markers are overexpressed, considerably ameliorates the clinical and biological course of the disease in c-EAN rats. P140 displayed prophylactic and therapeutic effects, both in terms of disease intensity and chronicity, and preserved sciatic nerves from disease-related damages. Our findings uncover new disrupted molecular pathways in a c-EAN model and provide a proof-of-concept that targeting CMA might represent a promising therapeutic strategy for treating inflammatory neuropathies for which no disease-specific treatment is currently available.



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Nontuberculous mycobacteria in the environment of Hranice Abyss, the world’s deepest flooded cave (Hranice karst, Czech Republic)

Abstract

Nontuberculous mycobacteria (NTM) are widely distributed in the environment. On one hand, they are opportunistic pathogens for humans and animals, and on the other hand, they are effective in biodegradation of some persistent pollutants. Following the recently recorded large abundance of NTM in extreme geothermal environments, the aim of the study was to ascertain the occurrence of NTM in the extreme environment of the water zone of the Hranice Abyss (HA). The HA mineral water is acidic, with large concentrations of free CO₂, and bacterial slimes creating characteristic mucilaginous formations. Both culture and molecular methods were used to compare the mycobacterial diversity across the linked but distinct ecosystems of HA and the adjacent Zbrašov Aragonite Caves (ZAC) with consideration of their pathogenic relevance. Six slowly growing NTM species (M. arupense, M. avium, M. florentinum, M. gordonae, M. intracellulare) and two rapidly growing NTM species (M. mucogenicum, M. sediminis) were identified in the water and in the dry zones at both sites. Proteobacteria were dominant in all the samples from both the HA and the ZAC. The bacterial microbiomes of the HA mineral water and HA slime were similar, but both differed from the microbiome in the ZAC mineral water. Actinobacteria, a phylum containing mycobacteria, was identified in all the samples at low proportional abundance. The majority of the detected NTM species belong among environmental opportunistic pathogens.

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ATYPICAL LANGUAGE CHARACTERISTICS AND TRAJECTORIES IN CHILDREN WITH 22Q11.2 DELETION SYNDROME

Publication date: Available online 5 June 2018
Source:Journal of Communication Disorders
Author(s): Ellen Van Den Heuvel, Eric Manders, Ann Swillen, Inge Zink
Background22q11.2 deletion syndrome (22q11.2DS) is a genetic condition associated with a highly variable phenotypic expression. During childhood speech and language deficits are commonly observed. Findings of cross-sectional studies suggest syndrome-specific and changing language profiles, but a longitudinal approach to identify developmental changes is still lacking to date.AimsThe present study aimed to delineate language characteristics and trajectories by comparing the performance of Dutch-speaking school-aged children with 22q11.2DS (n = 18) to those of peers with idiopathic intellectual disability (IID, n  = 19) and to those of children with IID and comorbid autism spectrum disorder (IID + ASD, n = 23). The literature shows contradictory findings regarding language comprehension difficulties in children with 22q11.2DS, we focused on the receptive-expressive language discrepancy. Given their relative strength for verbal short-term memory (VSTM) tasks, a fine-grained error categorization was included to elucidate a possible influence of VSTM on the expressive language outcomes. Finally, we suggested that the inability of children with 22q11.2DS to use contextual information could interfere with morphosyntactic measures.MethodsAll groups (22q11.2DS, IID, and IID + ASD) were matched for nonverbal fluid reasoning (Gf) using the Analogies and Categories subtests of the Snijders-Oomen Nonverbal Intelligence Test or the Matrix Reasoning and Picture Concepts subtests of the Wechsler Preschool and Primary Scale of Intelligence. Several structural language skills were measured using the Clinical Evaluation of Language Fundamentals and Peabody Picture Vocabulary Test. The same instruments were re-administered after 18 to 24 months. A fine-grained error analysis of the Formulating and Recalling Sentences subtests, both measuring expressive syntax, explored factors contributing to expressive language deficits.ResultsIn children with 22q11.2DS the relative advantage of receptive over expressive language had decreased compared to children with IID. For children with 22q11.2DS, complex sentence comprehension remained very challenging over time. Expressive language skills seemed less limited compared to children with IID, and were accompanied by less VSTM difficulties. In children with 22q11.2DS and children with IID + ASD, variable patterns of strengths and weaknesses were demonstrated, resulting in subtle differences between these groups. Error analyses indicated disregard of content-contextual cues and use of vague and elliptic language as being typical for children with 22q11.2DS.ConclusionsWe recommend that in children with 22q11.2DS the impact of the receptive language impairment should be comprehensively examined and followed-up since it can have a negative effect on their social communication skills, adaptive functioning and academic achievement. Error analysis underscores that multiple measures should be used to evaluate the child's expressive language ability. Further research should focus on developmental trajectories of social communication skills and on the use of intervention strategies focusing on language comprehension and pragmatics in children with 22q11.2DS.



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Manejo de los carcinomas diferenciados de tiroides

Publication date: Available online 5 June 2018
Source:Acta Otorrinolaringológica Española
Author(s): Laura Fernández-Vañes, José Luis Llorente, Patricia García-Cabo, Marta Menéndez, Daniel Pedregal, Juan Pablo Rodrigo, Fernando López
Introducción y objetivosEl tratamiento principal de los carcinomas diferenciados de tiroides es la cirugía seguida de radioyodo. El propósito de este estudio es exponer nuestra experiencia en el manejo de estos tumores.Material y métodoSe presenta un estudio retrospectivo de los 55 pacientes intervenidos quirúrgicamente de un carcinoma diferenciado de tiroides en nuestro hospital entre los años 2007 y 2011.ResultadosLa edad media al diagnóstico fue de 49 años, con un predominio femenino (78% de los casos). El 78% de los pacientes se encontraban en fases iniciales (estadios i y ii). El diagnóstico histopatológico definitivo fue de carcinoma papilar en el 84% y folicular en el 16% restante. A todos, salvo a 2 pacientes (4%), se les realizó una tiroidectomía total, acompañada de linfadenectomía en el 58% de los casos. Un 9% de los pacientes presentó hipoparatiroidismo permanente y aunque un 18% sufrió parálisis recurrencial unilateral transitoria, un 40% de ellos se recuperó completamente a los 6 meses. Se administró radioyodo en el postoperatorio al 89% de los pacientes. Se produjo un 40% de recidivas, la mayor parte de las cuales (29% de los pacientes) se localizaron a nivel cervical. La supervivencia a los 5 años fue del 87%, siendo del 95% en el subtipo papilar y descendiendo al 56% en el folicular (p=0,001).Discusión/conclusionesLos carcinomas diferenciados de tiroides son tumores con un pronóstico excelente tras un tratamiento quirúrgico adecuado previa valoración preoperatoria exhaustiva y seguimiento postoperatorio estricto debido a las tasas significativas de recidiva.Introduction and objectivesRadioiodine is the principal treatment for differentiated thyroid carcinomas. The aim of this study is to present our experience in the management of these tumours.Material and methodWe present a retrospective study of 55 patients operated for differentiated thyroid carcinoma in our hospital between 2007 and 2011.ResultsThe mean age at time of diagnosis was 49 years, and females predominated (78% of cases). Seventy eight percent of the patients were in the initial stages (stages i and ii). The definitive histopathological diagnosis was papillary carcinoma in 84% and follicular carcinoma in the remaining 16%. All of the patients, with the exception of 2 (4%), underwent total thyroidectomy, with lymphadenectomy in 58% of cases. Nine percent of the patients had permanent hypoparathyroidism and although 18% suffered transitory unilateral paralysis, 40% of these female patients had completely recovered after 6 months. Eighty-nine percent of the patients were given radioiodine postoperatively. There was a recurrence rate of 40% most of which was at cervical level (29% of the patients). Survival at 5 years was 87%, 95% of the papillary subtype, falling to 56% of the follicular subtype (P=.001).Discussion/conclusionsThe prognosis for differentiated thyroid carcinomas is excellent after appropriate surgical treatment, thorough preoperative assessment,and strict postoperative follow-up due to the significant recurrence rates.



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Olfactory dysfunction out of season in seasonal allergic rhinitis

Olfactory dysfunction (OD) is one of the major symptoms caused by seasonal allergic rhinitis (AR).1 It has been reported that in allergic rhinitis, inflammatory cells infiltrate the olfactory mucosa.2 Moll et al.3 showed that the extra-seasonal score in the 1-butanol threshold test of patients with grass pollen allergy was lower than that of control subjects. It was also reported that all patients had normal olfactory function (OF) prior to the season.1 It is therefore unclear whether OD persists out of pollen season in patients with seasonal AR, especially in patients who do not complain of OD.

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Novel Approaches to Block Complement

The complement system may contribute in many ways to transplant injury, being a promising target for specific therapeutic interventions. There is evidence that the monoclonal anti-C5 antibody eculizumab is effective in the prevention and treatment of early antibody-mediated rejection (ABMR), but terminal complement blockade might be of limited efficiency in chronic rejection. Given the diversity of immunological events triggered by activation steps upstream to C5, in particular, opsonin and anaphylatoxin formation through C3 cleavage, one may argue that, in the specific context of ABMR, inhibition of antibody-triggered classical pathway (CP) activation might be beneficial. Strategies to interfere with key CP component C1 are currently under clinical evaluation and include the therapeutic use of purified C1-inhibitor, which, besides targeting the integrity and function of the C1 complex, also affects components of the lectin pathway, the contact system, the coagulation cascade or surface molecules mediating leukocyte-endothelial interactions. In addition, a monoclonal anti-C1s antibody (BIVV009) has now entered clinical evaluation and was shown to effectively block antibody-triggered CP activation in rejecting kidney allografts. Moreover, modified apheresis techniques for preferential removal of macromolecules, including C1q, may allow for efficient complement depletion, in addition to antibody removal. The availability of effective strategies to interfere with the CP, as well as innovative approaches targeting other pathways, some of them already being tested in clinical trials, will help us figure out how complement contributes to acute and chronic graft injury, and hopefully provide us with new ways to more efficiently counteract rejection. Correspondence: Georg A. Böhmig, Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria, Phone: +43-1-40400-43630, Fax: +43-1-40400-39304, E-mail: georg.boehmig@meduniwien.ac.at Author's specific contribution G.A.B. participated in the conception, writing and revision of the paper F.E. participated in the conception, writing and revision of the paper M.W. participated in the conception, writing and revision of the paper L.R. participated in the conception, writing and revision of the paper Disclosure G.A.B. received research support (unrestricted grants) from Fresenius Medical Care, Bad Homburg, Germany, and True North Therapeutics, Inc., South San Francisco, CA, USA. F.E., M.W. and L.R. declare no conflicts of interest. Funding None Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Procurement of Extended Vascularized Skin Flaps from The Donor Enables Hand Transplantation in Severe Upper Extremity Burns: An Anatomical Study.

Background: Hand transplantation in patients with severe upper extremity burns can be associated with an increased risk of exposure of vessels, tendons and nerves because of extensive skin and soft tissue deficit. This study evaluated how to reliably transfer additional extended skin flaps with a standard hand allograft. Methods: Twenty-five upper extremities were used. Sixteen were injected with latex to map the perforating branches of the brachial (BA), superior ulnar collateral (SUCA), radial (RA), ulnar (UA) and posterior interosseous (PIA) arteries. Nine hand allografts were procured, injected with blue ink through the BA to assess the perfusion of the skin flaps and then mock transplanted. Results: Sizable perforators from the BA, SUCA, RA, UA and PIA were used to augment the vascularization of the skin flaps. The average stained area of the medial arm flap was between 85.7% and 93.9%. The stained area of the volar forearm flap was the smallest when based on perforators within 6 cm from the wrist crease (51.22%). The dorsal forearm flap showed the least amount of staining (34.7 %- 46.1%). The average time to repair tendons, nerves and vessels was longer when a single volar forearm-arm flap was harvested (171.6 minutes). Harvest of the allograft associated with a distally based forearm flap and islanded arm flap was the fastest (181.6±17.55 minutes). Conclusions: Extended skin flaps, based on perforators of the main axial vessels, can be reliably transplanted with a standard hand allograft based on the brachial or axillary vascular pedicle. Financial Disclosure Statement: The authors have no conflict of interest to disclose. Presented at EURAPS Research Council meeting, 2017 in Pisa, Italy and at Plastic Surgery the Meeting (ASPS), 2017 in Orlando, Florida. Acknowledgment: The authors would like to acknowledge Pierpaolo Marchetti, PhD for the statistical analysis and Ashley Healy for meticulous proofreading and editing the paper. Corresponding Author: Antonio Rampazzo, MD, PhD, Plastic Surgery Department,, Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk A60-522, Cleveland, OH, USA. E-mail: ©2018American Society of Plastic Surgeons

https://ift.tt/2sAynTa

“Functional Outcomes of Late Post-Traumatic Enophthalmos Correction”

Title: Functional Outcomes of Late Post- Traumatic Enophthalmos Correction Background: Post-traumatic enophthalmos has debilitating functional consequences resulting in restriction of ocular motility and diplopia. Surgical correction aims to restore the globe position and ultimately improve function. This study evaluates the functional outcome of post-traumatic enophthalmos repair. Methods: Patients included in this study had post-traumatic enophthalmos and diplopia requiring enophthalmos repair. Diplopia was graded from 0 (no diplopia) to 4 (constant diplopia) based on the Functional Diplopia Grading Scale. Limitations of eye movements were recorded in the vertical, horizontal and torsional directions. Data were gathered prospectively at pre-operative assessment, post enophthalmos repair, and final follow up. Results: Between 2002 and 2014, 41 patients fulfilled inclusion criteria. Substantial functional improvement, defined as a decrease of ≥ 1 grade of diplopia, was achieved in 65.9% of patients (27 out of 41) after all surgical interventions. Patients with residual diplopia (34/41) after enophthalmos surgery were managed with secondary strabismus surgery (10/34) and or prism glasses (4/34). After all interventions, vertical restrictions improved from μ=-1.95 (σ=1.13) to μ=-1.06 (σ=0.98). Horizontal restrictions improved from μ=-0.88 (σ=0.62) to μ=0.59 (σ=0.6). Adequate clinical correction of enophthalmos to within 2 mm of contralateral globe was achieved in 37 of 41. Conclusions: This is the largest case series evaluating functional outcomes of patients undergoing post-traumatic delayed enophthalmos repair. A multidisciplinary care approach resulted in improved globe position, eye movement, and improvement of diplopia. Further studies with larger sample sizes are needed to better understand and treat this important and challenging problem. Financial Disclosure Statement: The authors have nothing to disclosure. No funding was received for this article. Presentations: Orlando, Florida USA. October 2017. American Society of Plastic Surgeons, The Meeting. A summary of results of this research were presented. Victoria, British Columbia Canada. June 2015. National Canadian Society of Plastic Surgeons. Preliminary data from this research was presented. Conflict of Interest statement: There are no identified conflicts of interest identified by any authors involved in this research. Statement of Human and Animal Rights: Human rights were protected in this research and care has been taken to eliminate identifying aspects of the patient and their case in keeping with policies for ethics and research. Statement of Informed Consent: The patient presented in this case report has consented to being involved in this research and informed consent was obtained for the described procedure. Statement of Funding: There was no financial or grant support of this research. Corresponding author: Mark McRae MD, FRCS(C), Assistant Professor, McMaster University, 50 Charlton Avenue East Rm G845, Hamilton, Ontario, Canada. amcraem2@mcmaster.ca ©2018American Society of Plastic Surgeons

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Utilization of Routine Pathology Evaluation of Non-Malignant Lesions in Hand Surgery – A National Study

Background: Most lesions of the upper extremity are common and benign, and many have questioned the need for routine pathology evaluation of these specimens. We aim to examine the national utilization of routine pathology examination of non-malignant hand lesions to help guide healthcare policy and practice patterns. Methods: We used a national level Marketscan database to form a cohort of adult patients who underwent excision of non-malignant upper extremity lesions. We calculated the rate of submission for each surgical procedure and separately for each diagnosis. We also investigated demographic and clinical characteristics associated with the submission of surgical specimens using a multivariable logistic regression model. We calculated total cost of routine pathology evaluation. Results: The final study cohort included 222,947 patients and 182,962 specimens from 153,518 cases. The mean rate of submission was 69%. Older age, Northeast region, and high comorbidity scores showed significant correlation with the odds of having a specimen submitted for pathology evaluation. Excision of primary wrist ganglion was the most performed procedure, and benign lesions over 4.0cm in size were most frequently submitted for pathology. The mean cost of routine pathology exam was $133 per specimen and annual expenditure of $5 million. Conclusions: The routine pathology examination of benign hand lesions is utilized frequently while providing limited clinical benefit at a cost. To increase efficiency and improve quality of care, surgeons should be aware of the low value of routine pathology evaluation and be more selective for cases for which diagnostic testing will change management. Funding: Funding for this work was supported by a Midcareer Investigator Award (2 K24-AR053120-06) to Dr. Kevin Chung from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. Acknowledgements: We thank Melissa Shauver, MPH for her contribution in proofreading the manuscript. Corresponding Author: Kevin C. Chung, MD, MS, Section of Plastic Surgery, The University of Michigan Health System, 1500 E. Medical Center Drive , 2130 Taubman Center, SPC 5340, Ann Arbor, MI 48109-5340, Phone: 734-936-5885, Fax: 734-763-5354, E-mail: kecchung@med.umich.edu ©2018American Society of Plastic Surgeons

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New Strategies for Remnant Ear Treatment in Lobule-Type Microtia Reconstruction

Background: Numerous modifications have been successfully applied in microtia reconstruction over the past several decades, and lobular transposition has become a routine technique in a two-stage operation. However, it is still a demanding challenge to manipulate the remnant ear with various quantities or positions in lobule-type microtia. The authors demonstrate the relevant details of treating remnant tissue in different conditions. Methods: A total of 390 lobule-type microtia patients underwent autogenous costal cartilage auricular reconstruction between 2010 and 2015. Because the quantity or position of the remnant ear varies from patient to patient, corresponding tactics need to be taken into consideration for appropriate treatment. Four possible scenarios of remnant ear shape have been described, and relevant strategies for each were introduced. Results: Favorable reconstructed auricles with aesthetic natural earlobes have been produced; the location of the reconstructed ear is symmetric to the contralateral ear. It provides a harmonized framework and periphery tissue for the integrity of the contour of the constructed auricle. Conclusions: Proper utilization of the remnant ear as well as framework fabrication and skin flap dissection are critical factors to attain a satisfactory contour of the auricle in microtia reconstruction. Our technique made it possible to construct a cosmetically refined ear with harmonious integrity. Financial disclosure: None of the authors has a financial interest to declare in relation to the content of this article. ACKNOWLEDGMENT: The authors thank Dr. Françoise Firmin, M.D., Ph.D., Dr. Cheng Wang M.D., Dr. Chunxiao Cui M.D., Ph.D., Dr. Tianya Li M.D., Ph.D. and Dr. Wei Chen M.D., Ph.D. for contributing to the work. Corresponding Author: Dr. Ruhong Zhang M.D., Ph.D., Professor in the Department of Plastic and Reconstructive Surgery, Shanghai 9 th People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639, Zhi Zao Ju Rd., Shanghai, China. 200011, Phone: 86-21-23271699-5122(EXT.) Fax: 86-21-63136856, Email: zhangruhong@163.com ©2018American Society of Plastic Surgeons

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Surgical management and outcomes of Pierre Robin Sequence: a comparison of mandibular distraction osteogenesis and tongue-lip adhesion

There is a paucity of primary literature directly comparing tongue-lip adhesion (TLA) versus mandibular distraction osteogenesis (MDO) in surgical treatment of patients with Pierre Robin Sequence (PRS). This study comprehensively reviews the literature to evaluate and compare the effectiveness of MDO and TLA in improving airway and feeding outcomes. A search was performed using the MEDLINE (PubMed interface) and Embase databases for publications between 1960 through June 2017. English-language, original studies involving MDO or TLA in treatment of PRS subjects were included. Extracted data included prevention of tracheostomy (primary airway outcome) and ability to feed exclusively by mouth (primary feeding outcome). Sixty-seven studies total were included in the review. Ninety-five percent (657/693) of subjects treated with MDO avoided tracheostomy. Eighty-nine percent (289/323) of subjects treated with TLA avoided tracheostomy. Eighty-seven percent (323/370) of subjects treated with MDO achieved full oral feeds at latest follow-up. Seventy percent (110/157) of subjects treated with TLA achieved full oral feeds at latest follow up. The rate of second intervention for recurrent obstruction ranged from 4 to 6% in MDO studies, compared to range of 22 to 45% in TLA studies. Variability of patient selection, surgical techniques, outcomes measurement methods, and follow up length across studies precluded meta-analysis of the data. Both MDO and TLA are effective alternatives to tracheostomy for patients who fail conservative management, improve feeding and promote weight gain. MDO may be superior to TLA in long-term resolution of airway obstruction and avoidance of gastrostomy, but is associated with notable complications. Disclosure: None of the authors listed have any conflicts of interest to report. Authorship: All listed authors 1) contributed to conception and design, acquisition of data, or analysis and interpretation of data; 2) drafted the article or revised it critically; 3) gave final approval of the version to be published; 4) agreed to be accountable for all aspects of the work. Conflicts of Interest: The authors report no relevant financial disclosures related to this current work. IRB: This study does not contain primary data involving human subjects at the Children's Hospital of Philadelphia and so did not undergo Institutional Review Board review. Corresponding Author: Dr. Scott P. Bartlett, Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, The University of Pennsylvania, Colket Translational Research Building, 9th Floor, Philadelphia, PA 19104; E-mail: bartletts@email.chop.edu ©2018American Society of Plastic Surgeons

https://ift.tt/2sBpkBB

Serum Squamous Cell Carcinoma Antigen in Psoriasis: A Potential Quantitative Biomarker for Disease Severity

Background: An objective and quantitative method to evaluate psoriasis severity is important for practice and research in the precision care of psoriasis. Objectives: We aimed to explore serum biomarkers quantitatively in association with disease severity and treatment response in psoriasis patients, with serum squamous cell carcinoma antigen (SCCA) evaluated in this pilot study. Methods: 15 psoriasis patients were treated with adalimumab. At different visits before and after treatment, quantitative body surface area (qBSA) was obtained from standardized digital body images of the patients, and the psoriasis area severity index (PASI) was also monitored. SCCA were detected by using microparticle enzyme immunoassay. The serum biomarkers were also tested in healthy volunteers as normal controls. Receiver-operating characteristic (ROC) curve analysis was used to explore the optimal cutoff point of SCCA to differentiate mild and moderate-to-severe psoriasis. Results: The serum SCCA level in the psoriasis group was significantly higher (p #x3c; 0.05) than in the normal control group. After treatment, the serum SCCA levels were significantly decreased (p #x3c; 0.05). The SCCA level was well correlated with PASI and qBSA. In ROC analysis, when taking PASI = 10 or qBSA = 10% as the threshold, an optimal cutoff point of SCCA was found at 2.0 ng/mL with the highest Youden index. Conclusion: Serum SCCA might be a useful quantitative biomarker for psoriasis disease severity.
Dermatology

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