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

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



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Editors / Publication Information

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





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

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



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

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



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

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



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

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



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

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



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

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



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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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



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Immune development and environment: lessons from Amish and Hutterite children

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



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

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

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

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



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

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



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Frontmatter

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

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Standard body mass index reference data of prepubescent diabetic Egyptian children

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

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

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

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

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

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

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

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

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

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

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

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

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

http://ift.tt/2x631ac

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

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

http://ift.tt/2vFkHWR

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

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

http://ift.tt/2x673j1

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

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

http://ift.tt/2vFJEBb

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

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

http://ift.tt/2x5Mpzo

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

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

http://ift.tt/2vFVnj9

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

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

http://ift.tt/2x5QXWH

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

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

http://ift.tt/2vFxVme

Sirolimus in the treatment of three infants with diffuse congenital hyperinsulinism

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

http://ift.tt/2x64PQn

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

Abstract

Objective

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

Methods

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

Results

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

Conclusions

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

http://ift.tt/2woFwGX

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

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



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Postcrania of the most primitive euprimate and implications for primate origins

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



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Benefits of flu vaccination for persons with diabetes mellitus: A review

Publication date: 12 September 2017
Source:Vaccine, Volume 35, Issue 38
Author(s): M. Goeijenbier, T.T. van Sloten, L. Slobbe, C. Mathieu, P. van Genderen, Walter E.P. Beyer, Albert D.M.E. Osterhaus
Diabetes mellitus imposes a significant and increasing burden on society, with major consequences for human health, welfare and the economy worldwide. Persons with diabetes mellitus are at increased risk of developing severe complications after influenza virus infection and guidelines advise vaccination. The present evidence for influenza vaccine effectiveness in persons with diabetes mellitus is mainly based on observational studies with clinical endpoints like hospitalization and death, indicating a beneficial reduction of morbidity and mortality. Further supportive evidence comes from serological studies, in which persons with diabetes mellitus usually develop similar antibody levels after vaccination as healthy people. Observational studies may be prone to selection bias, and serological studies may not completely mirror vaccine effectiveness in the field. Although more controlled trials in persons with diabetes mellitus with laboratory-confirmed, influenza-specific outcomes would be desirable to better estimate the effect of vaccination, the currently available data justify routine influenza vaccination in persons with diabetes mellitus. As in this risk group, the use of influenza vaccine is far below target worldwide, efforts should be made to increase vaccination coverage.



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Adjuvant HPV vaccination for anal cancer prevention in HIV-positive men who have sex with men: The time is now

Publication date: 12 September 2017
Source:Vaccine, Volume 35, Issue 38
Author(s): Ashish A. Deshmukh, Scott B. Cantor, Elisabeth Fenwick, Elizabeth Y. Chiao, Alan G. Nyitray, Elizabeth A. Stier, Stephen E. Goldstone, Timothy Wilkin, Jagpreet Chhatwal
ImportanceOutcomes of treating high-grade squamous intraepithelial lesions (HSIL), a precursor to anal cancer, remain uncertain. Emerging evidence shows that post HSIL treatment adjuvant quadrivalent human papillomavirus (qHPV) vaccination improves the effectiveness of treatment. However, no recommendations exist regarding the use of qHPV vaccine as an adjuvant form of therapy. Our objective was to determine whether post-treatment adjuvant vaccination should be adopted in HIV-infected MSM (individuals at highest risk for anal cancer) on the basis of cost-effectiveness determined using existing evidence or whether future research is needed.MethodsWe developed a Markov (state-transition) cohort model to assess the cost-effectiveness of post-treatment adjuvant HPV vaccination of 27years or older HIV-infected MSM. We first estimated cost-effectiveness and then performed value-of-information (VOI) analysis to determine whether future research is required by estimating the expected value of perfect information (EVPI). We also estimated expected value of partial perfect information (EVPPI) to determine what new evidences should have highest priority.ResultsWith the incremental cost-effectiveness ratio (ICER) of $71,937/QALY, "treatment plus vaccination" was the most cost-effective HSIL management strategy using the willingness-to-pay threshold of 100,000/QALY. We found that population-level EVPI for conducting future clinical research evaluating HSIL management approaches was US$12 million (range $6–$20 million). The EVPPI associated with adjuvant qHPV vaccination efficacy estimated in terms of hazards of decreasing HSIL recurrence was $0 implying that additional data from a future study evaluating efficacy of adjuvant qHPV vaccination will not change our policy conclusion that "treatment plus vaccination" was cost-effective. Both the ICER and EVPI were sensitive to HSIL treatment compliance.ConclusionPost-treatment adjuvant qHPV vaccination in HIV-infected MSM aged 27 or above is likely to be cost-effective. Use of adjuvant qHPV vaccination could be considered as a potential strategy to reduce rising anal cancer burden among these high-risk individuals.



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Extracting general practice data for timely vaccine coverage estimates: The England experience

Publication date: 12 September 2017
Source:Vaccine, Volume 35, Issue 38
Author(s): Michael Edelstein, Tim Crocker-Buque, Camille Tsang, Odette Eugenio, Tim Hopson, Richard Pebody, Mary Ramsay, Joanne M White
In England, primary care providers use standardised coding systems to record health events such as vaccination as well as patient characteristics. This information can be automatically extracted to estimate coverage for vaccine programmes delivered through primary care, in the general population as well as in specific geographical, ethnic, age or clinical groups. This system provides timely vaccine coverage estimates as well as the flexibility to extract tailored data in order to directly inform a continuously evolving national vaccine programme. It is however limited by the quality and completeness of clinical coding in primary care. A centralised, individual-level register would however improve data quality, completeness and reliability and remains the gold standard.



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Editorial Board/Aims and Scope

Publication date: 12 September 2017
Source:Vaccine, Volume 35, Issue 38





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A suicidal strain of Listeria monocytogenes is effective as a DNA vaccine delivery system for oral administration

Publication date: 12 September 2017
Source:Vaccine, Volume 35, Issue 38
Author(s): Shubhra Sinha, Cheng-Yi Kuo, Joan K. Ho, Paul J. White, Jalal A. Jazayeri, Colin W. Pouton
In this study we determined the in vivo activity of model ovalbumin vaccines delivered by direct intramuscular delivery of plasmid DNA or oral delivery using a recombinant suicidal Listeria monocytogenes strain (rsΔ2). In a previous report we described how rsΔ2 is capable of delivering luciferase, as protein or DNA, in vitro, into non-dividing intestinal epithelial cells (Kuo et al., 2009). This is achieved by engineering a dual expression shuttle vector, pDuLX-Luc, that replicates in E. coli and rsΔ2 and drives gene expression from the Listeria promoter (Phly) as well as the eukaryotic cytomegalovirus promoter (CMV), thereby delivering both protein and plasmid DNA to the cell cytoplasm. For the current in vivo study rsΔ2 containing pDuLX-OVA was used to deliver both ovalbumin protein and the mammalian expression plasmid by the oral route. Controls were used to investigate the activity of this system versus positive and negative controls, as well as quantifying activity against direct intramuscular injection of expression plasmids. Oral administration of rsΔ2(pDuLX-OVA) produced significant titres of antibody and was effective at inducing targeted T-cell lysis (approximately 30% lysis relative to an experimental positive control, intravenous OVA-coated splenocytes+lipopolysaccharide). Intramuscular injection of plasmids pDuLX-OVA or p3L-OVA (which lacks the prokaryotic promoter) also produced significant CTL-mediated cell lysis. The delivery of the negative control rsΔ2 (pDuLX-Luc) confirmed that the observed activity was induced specifically by the ovalbumin vaccination. The data suggest that the oral activity of rsΔ2(pDuLX-OVA) is explained by delivery of OVA protein, expressed in rsΔ2 from the prokaryotic promoter present in pDuLX-OVA, but transfection of mammalian cells in vivo may also play a role. Antibody titres were also produced by oral delivery (in rsΔ2) of the p3L-OVA plasmid in which does not include a prokaryotic promoter.



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Raw starch microparticles have immunostimulant activity in mice vaccinated with BCG and challenged with Mycobacterium tuberculosis

Publication date: 12 September 2017
Source:Vaccine, Volume 35, Issue 38
Author(s): Silvia Moreno-Mendieta, Jorge Barrios-Payán, Dulce Mata-Espinosa, Sergio Sánchez, Rogelio Hernández-Pando, Romina Rodríguez-Sanoja
The main challenge for vaccine development or improvement is the lack of safe adjuvants or immunostimulants that induce protective immune responses and can be used for mucosal immunization, which is a highly desirable strategy for vaccination against infectious diseases acquired by oral or intranasal routes. One promising alternative is the use of biodegradable and biocompatible polymeric microparticles. Recently, we developed an immobilization and delivery system with starch microparticles (SMPs) and a starch-binding domain (SBDtag) suitable for the mucosal administration of antigens and the induction of antigen-specific immune responses. Here, we explore the immunostimulant and reinforcing potential of the system using BALB/c mice with progressive pulmonary tuberculosis (PPT). The heat shock protein alpha-crystallin from Mycobacterium tuberculosis immobilized on SMPs (µAcr-SBDtag) or SMPs alone were administered nasally as boosters to BCG-vaccinated mice without any extra adjuvant. The mice were challenged intratracheally with either moderately virulent or highly virulent M. tuberculosis strains. Our results showed that the administration of either the immobilized antigen or SMPs asa booster for the BCG vaccination induced a significant reduction of bacterial loads in the lungs of mice, even more than in mice that received the BCG vaccination alone. Since no difference was observed in pulmonary bacillary burdens between the two reinforced groups, the obtained effect was most likely primarily caused by the starch. As determined by histological study, the administration of boosters did not contribute to the progress of pneumonia, which diminishes the safety concerns related to the administration of SMPs intranasally. Taken together, our findings suggest that this system may be considered asa new carbohydrate-based adjuvant suitable for mucosal vaccines against tuberculosis and other infectious diseases, and more generally, they highlight the potential of particulate α-glucans as immune response modifiers.



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A synthetic human cytomegalovirus pp65-IE1 fusion antigen efficiently induces and expands virus specific T cells

Publication date: 12 September 2017
Source:Vaccine, Volume 35, Issue 38
Author(s): Ellen K. Link, Christine Brandmüller, Yasemin Suezer, Stefanie Ameres, Asisa Volz, Andreas Moosmann, Gerd Sutter, Michael H. Lehmann
Infection with human cytomegalovirus (HCMV) can cause severe complications in newborns and immunocompromised patients, and a prophylactic or therapeutic vaccine against HCMV is not available. Here, we generated a HCMV vaccine candidate fulfilling the regulatory requirements for GMP-compliant production and clinical testing. A novel synthetic fusion gene consisting of the coding sequences of HCMV pp65 and IE1 having a deleted nuclear localization sequence and STAT2 binding domain was introduced into the genome of the attenuated vaccinia virus strain MVA. This recombinant MVA, MVA-syn65_IE1, allowed for the production of a stable ∼120kDa syn65_IE1 fusion protein upon tissue culture infection. MVA-syn65_IE1 infected CD40-activated B cells activated and expanded pp65- and IE1-specific T cells derived from HCMV-seropositive donors to at least equal levels as control recombinant MVA expressing single genes for pp65 or IE1. Additionally, we show that MVA-syn65_IE1 induced HCMV pp65- and IE1-epitope specific T cells in HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice. Thus, MVA-syn65_IE1 represents a promising vaccine candidate against HCMV and constitutes a basis for the generation of a multivalent vaccine targeting relevant pathogens in immunocompromised patients.



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A protein chimera including PspA in fusion with PotD is protective against invasive pneumococcal infection and reduces nasopharyngeal colonization in mice

Publication date: 12 September 2017
Source:Vaccine, Volume 35, Issue 38
Author(s): T.R. Converso, C. Goulart, M. Darrieux, L.C.C. Leite
Despite the success of the available polysaccharide-based vaccines against Streptococcus pneumoniae in preventing invasive diseases, this bacterium remains a major cause of death in many parts of the world. New vaccine strategies are needed in order to increase protection. Thus, the utilization of fusion proteins is being investigated as an alternative to the current formulations. In the present work, we demonstrate that a chimeric protein, composed of PspA and PotD in fusion is able to maintain the protective characteristics of both parental proteins, providing protection against systemic infection while reducing nasal colonization. The hybrid was not able to improve the response against invasive disease elicited by PspA alone, but the inclusion of PotD was able to reduce colonization, an effect never observed using subcutaneous immunization with PspA. The mechanisms underlying the protective efficacy of the rPspA-PotD hybrid protein were investigated, revealing the production of antibodies with an increased binding capacity to pneumococcal strains of diverse serotypes and genetic backgrounds, enhanced opsonophagocytosis, and secretion of IL-17 by splenocytes. These findings reinforce the use of chimeric proteins based on surface antigens as an effective strategy against pneumococcal infections.



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Plasma cell and serum antibody responses to influenza vaccine in preterm and full-term infants

Publication date: 12 September 2017
Source:Vaccine, Volume 35, Issue 38
Author(s): Carl T. D'Angio, Claire P. Wyman, Ravi S. Misra, Jessica L. Halliley, Hongyue Wang, Julianne E. Hunn, Caitlin M. Fallone, F. Eun-Hyung Lee
BackgroundPreterm (PT) infants are at greater risk for severe influenza infection and experience decrements in long-term antibody responses to vaccines. This may related to defects in antibody secreting cell (ASC) generation.ObjectiveTo investigate the relationships among the frequencies of influenza-specific antibody secreting cells, ASC numbers and subsets, and antibody responses to influenza vaccines (IV) among PT and full-term (FT) infants.Design/methodsWe enrolled 11 former PT (≤32weeks′ gestation, ≤1500 g′ birth weight) and 11FT infants, 6–17months of age, receiving their first influenza immunizations. Infants received two doses of inactivated trivalent (T)IV or quadrivalent (Q)IV during the 2012–2013 and 2013–2014 influenza seasons, respectively, at 0 and 28days, and blood was drawn at 0, 10, 35, and 56days and 9months. Vaccine-specific antibody was measured by hemagglutination inhibition (HAI) at 0 and 56days and 9months, vaccine-specific ASC numbers by enzyme linked immunospot (ELISPOT) at 10 and 35days, and ASC subsets by flow cytometry at 0, 10 and 35days.ResultsPT infants had post-vaccine HAI titers to all 4 vaccine strains at least equal to FT infants at 56days and 9months after beginning immunization. Influenza-specific ASC ELISPOT responses at 35days were higher among PT than FT infants (median 100 v. 30 per 10⁶ PBMC, p=0.04). ASC numbers at 35days were positively correlated with serum HAI titers at 56days (ρ=0.50–0.80). There were no statistical differences between PT and FT infants in the frequency of five ASC subsets and no specific ASC subset correlated with durability of serum antibody titers.ConclusionsInfluenza-specific ASC numbers in both FT and PT infants correlated with peak antibody titers, but ASC subsets did not correlate with durability of antibody response.



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Side effects of radiotherapy in breast cancer patients

Abstract

Aim

Breast cancer is the most common cancer type among women necessitating adjuvant radiotherapy. As the Internet has become a major source of information for cancer patients, this study aimed to evaluate the quality of websites giving information on side effects of radiotherapy for breast cancer patients.

Methods

A patients' search for the English terms "breast cancer – radiotherapy – side effects" and the corresponding German terms "Brustkrebs – Strahlentherapie – Nebenwirkungen" was carried out twice (5 months apart) using the search engine Google. The first 30 search results each were evaluated using the validated 16-question DISCERN Plus instrument, the Health on the Net Code of Conduct (HONcode) certification and the Journal of the American Medical Association (JAMA) benchmark criteria. The overall quality (DISCERN score) of the retrieved websites was further compared to queries via Bing and Yahoo search engines.

Results

The DISCERN score showed a great range, with the majority of websites ranking fair to poor. Significantly superior results were found for English websites, particularly for webpages run by hospitals/universities and nongovernmental organizations (NGO), when compared to the respective German categories. In general, only a minority of websites met all JAMA benchmarks and was HONcode certified (both languages). We did not determine a relevant temporal change in website ranking among the top ten search hits, while significant variation occurred thereafter. Mean overall DISCERN score was similar between the various search engines.

Conclusion

The Internet can give breast cancer patients seeking information on side effects of radiotherapy an overview. However, based on the currently low overall quality of websites and the lack of transparency for the average layperson, we emphasize the value of personal contact with the treating radio-oncologist in order to integrate and interpret the information found online.

http://ift.tt/2wiohZB

TSH oscillations in young patients with type 1 diabetes may be due to glycemic variability

Abstract

Purpose

A relationship between thyroid dysfunction and diabetes mellitus has been described by several authors but the role of glycemic variability is still unclear. We planned the present study to evaluate the influence of glycemic variability on thyroid hormones and TSH concentrations in patients with type 1 diabetes mellitus (T1DM).

Methods

Seventy-seven young patients with T1DM were enrolled and evaluated for basal glucose concentrations, HbA1c, thyroid hormones and TSH concentrations. Glucose variability was investigated by considering the standard deviation of blood glucose readings and by calculating the mean amplitude of glycemic excursions and continuous overlapping net glycemic action (CONGA). The low (LBGI) and high (HBGI) blood glucose indices were also calculated. The correlations between TSH, thyroid hormones, glycemia and HbA1c were studied in patients and in controls, whereas those between TSH, thyroid hormones and indices of glucose variability only in patients.

Results

No correlations were observed in T1DM patients between free thyroid hormones and glycemic values, HbA1c and indices of glucose variability, while an inverse correlation was observed between TSH levels and glycemic values (r = −0.27; p = 0.01), CONGA index (r = −0.35; p = 0.001) and HBGI (r = −0.28; p = 0.01) but not with HbA1c (r = −0.1; p = 0.47).

Conclusions

Our results suggest a direct action of glycemic excursions on TSH secretion, regardless of variations of thyroid hormone concentrations. Thus, the evaluation of thyroid function through the assay of TSH concentrations in these patients should be made, if possible, by multiple samples on patients in euglycemic state to avoid underestimation or overestimation of thyroid dysfunction due to a wrong diagnosis of euthyroidism or dysthyroidism with consequent inappropriate choice of therapeutic options.

http://ift.tt/2vrVG5p

Treatment outcomes after reduction of the target volume of intensity-modulated radiotherapy following induction chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: A prospective, multi-center, randomized clinical trial

Publication date: Available online 29 August 2017
Source:Radiotherapy and Oncology
Author(s): Hongru Yang, Xin Chen, Sheng Lin, Jinfeng Rong, Mi Yang, Qinglian Wen, Changling Shang, Lijia He, Peirong Ren, Shan Xu, Jianwen Zhang, Qiaoli Liu, Haowen Pang, Xiangxiang Shi, Juan Fan, Xiaoyang Sun, Daiyuan Ma, Bangxian Tan, Tao Zhang, Ling Zhang, Defeng Hu, Xiaobo Du, Yu Zhang, Shiming Wen, Xinping Zhang, Jingbo Wu
PurposeTo investigate whether reducing the target volume of intensity-modulated radiotherapy (IMRT) after induction chemotherapy (IC) improves the quality of life (QOL) in locoregionally advanced nasopharyngeal carcinoma (NPC) without decreasing the local control and survival rate.Patients and methodsA total number of 212 NPC patients staged as III–IVb were randomly assigned to group A (n=97) or group B (n=115) in this prospective clinical trial. All patients received IC followed by cisplatin concurrent with IMRT. IMRT was planned using the images of pre-IC in group A and post-IC in group B.ResultsThe dose received by normal tissues in group B was lower than that of group A (P<0.05). The recovery of the dry mouth symptoms in group B was significantly improved than group B. The quality of life (QOL) scores in group B were higher than group A. With a median follow-up of 35months, the 1-year estimated overall survival (OS), progression-free survival (PFS), locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS) in group A versus group B were 97.9% vs 97.3%, 90.7% vs 92,2%, 99.0% vs 98.2%, 91.8% vs 94.8%. The 2-year OS, PFS, LRFFS, DMFS in group A versus group B were 93.7% vs 92.9%, 83.4% vs 84.3%, 96.8% vs 95.5%, 86.5% vs 89.5%. The 3-year OS, PFS, LRFFS, DMFS in group A versus group B were 82.3% vs 87%, 74.7% vs 83.4%, 91.8 vs 93.9%, 81.3% vs 88.6%, respectively.ConclusionReducing the IMRT target volume after IC did not reduce the local control and survival rate in locoregionally advanced NPC but the doses received by normal tissues were decreased, and the QOL scores were improved.



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Life years lost attributable to late effects after radiotherapy for early stage Hodgkin lymphoma: The impact of proton therapy and/or deep inspiration breath hold

Publication date: Available online 30 August 2017
Source:Radiotherapy and Oncology
Author(s): Laura Ann Rechner, Maja Vestmø Maraldo, Ivan Richter Vogelius, Xiaorong Ronald Zhu, Bouthaina Shbib Dabaja, Nils Patrik Brodin, Peter Meidahl Petersen, Lena Specht, Marianne Camille Aznar
Background and purposeDue to the long life expectancy after treatment, the risk of late effects after radiotherapy (RT) is of particular importance for patients with Hodgkin lymphoma (HL). Both deep inspiration breath hold (DIBH) and proton therapy have been shown to reduce the dose to normal tissues for mediastinal HL, but the impact of these techniques in combination is unknown. The purpose of this study was to compare the life years lost (LYL) attributable to late effects after RT for mediastinal HL using intensity modulated radiation therapy (IMRT) in free breathing (FB) and DIBH, and proton therapy in FB and DIBH.Materials and methodsPlans for each technique were created for 22 patients with HL. Doses were extracted and the risk of late effects and LYL were estimated.ResultsWe found that the use of DIBH, proton therapy, and the combination significantly reduced the LYL compared to IMRT in FB. The lowest LYL was found for proton therapy in DIBH. However, when IMRT in DIBH was compared to proton therapy in FB, no significant difference was found.ConclusionsPatient-specific plan comparisons should be used to select the optimal technique when comparing IMRT in DIBH and proton therapy in FB.



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Editorial Board

Publication date: 1 September 2017
Source:American Journal of Infection Control, Volume 45, Issue 9





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APIC Masthead

Publication date: 1 September 2017
Source:American Journal of Infection Control, Volume 45, Issue 9





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Information for Readers

Publication date: 1 September 2017
Source:American Journal of Infection Control, Volume 45, Issue 9





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Erratum

Publication date: 1 September 2017
Source:American Journal of Infection Control, Volume 45, Issue 9





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Information for Authors

Publication date: 1 September 2017
Source:American Journal of Infection Control, Volume 45, Issue 9





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APIC education online

Publication date: 1 September 2017
Source:American Journal of Infection Control, Volume 45, Issue 9





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Table of Contents

Publication date: 1 September 2017
Source:American Journal of Infection Control, Volume 45, Issue 9





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Exploring inappropriate certified nursing assistant glove use in long-term care

Publication date: 1 September 2017
Source:American Journal of Infection Control, Volume 45, Issue 9
Author(s): Deborah Patterson Burdsall, Sue E. Gardner, Thomas Cox, Marin Schweizer, Kennith R. Culp, Victoria M. Steelman, Loreen A. Herwaldt
BackgroundCertified Nursing Assistants (CNAs) frequently wear gloves when they care for patients in standard precautions. If CNAs use gloves inappropriately, they may spread pathogens to patients and the environment, potentially leading to health care–associated infections (HAIs).MethodsUsing a descriptive structured observational design, we examined the degree of inappropriate health care personnel glove use in a random sample of 74 CNAs performing toileting and perineal care at 1 long-term care facility.ResultsDuring the 74 patient care events, CNAs wore gloves for 80.2% (1,774/2,213) of the touch points, failing to change gloves at 66.4% (225/339) of glove change points. CNAs changed gloves a median of 2.0 times per patient care event. A median of 1.0 change occurred at a change point. CNAs failed to change their gloves at a glove change point a median of 2.5 times per patient care event. Most (61/74; 82.4%) patient care events had >1 contaminated touch point. Over 44% (782/1,774) of the gloved touch points were defined as contaminated for a median of 8.0 contaminated glove touch points per patient care event. All contaminated touches were with gloved hands (P < .001).ConclusionsInappropriate glove use was frequently observed in this study. Contaminated gloves may be a significant cause of cross-contamination of pathogens in health care environments. Future research studies should evaluate strategies to improve glove use to reduce HAIs.



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Destruction of Clostridium difficile spores colitis using acidic electrolyzed water

Publication date: 1 September 2017
Source:American Journal of Infection Control, Volume 45, Issue 9
Author(s): Linda Tkhawkho, Karen Jackson, Orna Nitzan, Avi Peretz




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Can improving patient hand hygiene impact Clostridium difficile infection events at an academic medical center?

Publication date: 1 September 2017
Source:American Journal of Infection Control, Volume 45, Issue 9
Author(s): Marian Pokrywka, Michele Buraczewski, Debra Frank, Heather Dixon, Juliet Ferrelli, Kathleen Shutt, Mohamed Yassin
BackgroundHand hygiene plays an important role in the prevention of Clostridium difficile (CD) infection (CDI). Patient hand hygiene (PHH) may be a potentially underused preventative measure for CDI. Patient mobility and acuity along with a lack of education present obstacles to PHH for the hospitalized patient. Surveys of patients at our institution showed a need for increased PHH opportunities. The objective of this study was to increase PHH and to examine if PHH affected CDI at our hospital.MethodsA biphasic, quasi-experimental study was performed to increase PHH through education for staff and to provide education, assistance, and opportunities to the patient for hand cleaning. PHH practice was assessed by patient surveys and analyzed by χ² test. PHH effect on CDI was determined by following health care facility–onset CD laboratory–identified events data analyzed by National Healthcare Safety Network standardized infection ratios (SIRs).ResultsPHH opportunities improved significantly (P < .0001) after staff and patient education. CD SIRs deceased significantly for 6 months (P ≤ .05) after the PHH intervention.ConclusionsPHH opportunities can be increased by providing education and opportunities for patients to clean their hands. PHH should be considered a relevant preventative measure for CDI in hospitalized patients.



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Trends in the use of laboratory tests for the diagnosis of Clostridium difficile infection and association with incidence rates in Quebec, Canada, 2010-2014

Publication date: 1 September 2017
Source:American Journal of Infection Control, Volume 45, Issue 9
Author(s): C. Bogaty, S. Lévesque, C. Garenc, C. Frenette, D. Bolduc, L.-A. Galarneau, C. Lalancette, V. Loo, C. Tremblay, M. Trudeau, J. Vachon, M. Dionne, J. Villeneuve, J. Longtin, Y. Longtin
BackgroundSeveral Clostridium difficile infection (CDI) surveillance programs do not specify laboratory strategies to use. We investigated the evolution in testing strategies used across Quebec, Canada, and its association with incidence rates.MethodsCross-sectional study of 95 hospitals by surveys conducted in 2010 and in 2013-2014. The association between testing strategies and institutional CDI incidence rates was analyzed via multivariate Poisson regressions.ResultsThe most common assays in 2014 were toxin A/B enzyme immunoassays (EIAs) (61 institutions, 64%), glutamate dehydrogenase (GDH) EIAs (51 institutions, 53.7%), and nucleic acid amplification tests (NAATs) (34 institutions, 35.8%). The most frequent algorithm was a single-step NAAT (20 institutions, 21%). Between 2010 and 2014, 35 institutions (37%) modified their algorithm. Institutions detecting toxigenic C difficile instead of C difficile toxin increased from 14 to 37 (P < .001). Institutions detecting toxigenic C difficile had higher CDI rates (7.9 vs 6.6 per 10,000 patient days; P = .01). Institutions using single-step NAATs, GDH plus toxigenic cultures, and GDH plus cytotoxicity assays had higher CDI rates than those using an EIA-based algorithm (P < .05).ConclusionsLaboratory detection of CDI has changed since 2010. There is an association between diagnostic algorithms and CDI incidence. Mitigation strategies are warranted.



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A Study of Apatinib and Tegafur Gimeracil Oteracil in Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Condition:   Head and Neck Squamous Cell Carcinoma
Interventions:   Drug: Apatinib Mesylate Tablets;   Drug: Tegafur Gimeracil Oteracil Potassium Capsules
Sponsor:   Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University
Not yet recruiting - verified August 2017

http://ift.tt/2vrihix

Assessing Impact of CCO's PSO & PC Pathway in Ambulatory HNC Clinics

Conditions:   Head and Neck Cancer;   Psychosocial Care;   Supportive Care;   Psychosocial Intervention
Intervention:   Other: PSOPC pathway approach
Sponsor:   Sunnybrook Health Sciences Centre
Not yet recruiting - verified August 2017

http://ift.tt/2gq0ilG

Nivolumab + Chemoradiation in Stage II-IVB Nasopharyngeal Carcinoma

Condition:   Nasopharyngeal Carcinoma
Interventions:   Drug: Nivolumab;   Drug: Cisplatin;   Radiation: Radiation Therapy
Sponsors:   University of California, San Francisco;   National University Cancer Institute, Singapore;   Bristol-Myers Squibb
Not yet recruiting - verified August 2017

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Is quadriceps H-reflex excitability a risk factor for patellofemoral pain?

Publication date: October 2017
Source:Medical Hypotheses, Volume 108
Author(s): Marcella Ferraz Pazzinatto, Danilo de Oliveira Silva, Evangelos Pappas, Fernando Henrique Magalhães, Fábio Mícolis de Azevedo
Patellofemoral pain (PFP) is one of the most common conditions in orthopedic practice while recent evidence has suggested that it may be a predisposing factor to patellofemoral osteoarthritis. In addition to biomechanical alterations associated with the pathomechanisms underlying PFP, the investigation of neurophysiological alterations has provided novel information in the understanding of the pathophysiology of PFP. For instance, women with PFP present lower amplitude of the vastus medialis (VM) H-reflexes compared to pain-free controls, which suggests that the excitability of spinal reflexes might be a promising tool for discriminating woman with PFP in clinical practice. However, the cross-sectional design of the current research does not inform whether the reduced excitability predisposes to or is the consequence of PFP. Therefore, two hypotheses can be raised: (1) the reduction in excitability of the α-motoneurons is a risk factor for PFP; Or, (2) the reduction in H-reflex excitability is a consequence of PFP due to pain. If the former hypothesis is proven correct, it may help in the early identification of individuals with PFP. If the latter, it may help understand the reduced excitability as a consequence of the long-term pain, which may be interfering in the recovery of individuals with PFP in a long-term basis. In addition, exploring such hypotheses may have direct rehabilitative and prevention implications for PFP and its putative progression to knee osteoarthritis.



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Editorial board

Publication date: November 2017
Source:Biomaterials, Volume 144





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Vascular scaffolds with enhanced antioxidant activity inhibit graft calcification

Publication date: November 2017
Source:Biomaterials, Volume 144
Author(s): Bin Jiang, Rachel Suen, Jiao-Jing Wang, Zheng J. Zhang, Jason A. Wertheim, Guillermo A. Ameer
There is a need for off-the-shelf, small-diameter vascular grafts that are safe and exhibit high long-term patency. Decellularized tissues can potentially be used as vascular grafts; however, thrombogenic and unpredictable remodeling properties such as intimal hyperplasia and calcification are concerns that hinder their clinical use. The objective of this study was to investigate the long-term function and remodeling of extracellular matrix (ECM)-based vascular grafts composited with antioxidant poly(1, 8-octamethylene-citrate-co-cysteine) (POCC) with or without immobilized heparin. Rat aortas were decellularized to create the following vascular grafts: 1) ECM hybridized with POCC (Poly-ECM), 2) Poly-ECM subsequently functionalized with heparin (Poly-ECM-Hep), and 3) non-modified vascular ECM. Grafts were evaluated as interposition grafts in the abdominal aorta of adult rats at three months. All grafts displayed antioxidant activity, were patent, and exhibited minimal intramural cell infiltration with varying degrees of calcification. Areas of calcification co-localized with osteochondrogenic differentiation of vascular smooth muscle cells, lipid peroxidation, oxidized DNA damage, and cell apoptosis, suggesting an important role for oxidative stress in the calcification of grafts. The extent of calcification within grafts was inversely proportional to their antioxidant activity: Poly-ECM-Hep > ECM > Poly-ECM. The incorporation of antioxidants into vascular grafts may be a viable strategy to inhibit degenerative changes.

Graphical abstract

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Europium-doped mesoporous silica nanosphere as an immune-modulating osteogenesis/angiogenesis agent

Publication date: November 2017
Source:Biomaterials, Volume 144
Author(s): Mengchao Shi, Lunguo Xia, Zetao Chen, Fang Lv, Huiying Zhu, Fei Wei, Shengwei Han, Jiang Chang, Yin Xiao, Chengtie Wu
Although much research has gone into the design of nanomaterials, inflammatory response still impedes the capacity of nanomaterial-induced tissue regeneration. In-situ incorporation of nutrient elements in silica-based biomaterials has emerged as a new option to endow the nanomaterials modulating biological reactions. In this work, europium-doped mesoporous silica nanospheres (Eu-MSNs) were successfully synthesized via a one-pot method. The nanospheres (size of 280–300 nm) possess uniformly spherical morphology and mesoporous structure, and well distributed Eu elements. The nanospheres show distinct fluorescent property at 615 nm for potential bio-labeling. Noticeably, the Eu-MSNs stimulate pro-inflammatory response of macrophages and induce a modulated immune microenvironment, which further activates the osteogenic differentiation of bone marrow stromal cells (BMSCs) as well as angiogenic activity of human umbilical vein endothelial cells (HUVECs). During the process, osteogenesis-related genes (e.g. ALP, OCN, OPN and COL-I) of BMSCs, and angiogenesis-related genes (e.g. CD31, MMP9, VEGFR1/2, and PDGFRα/β) of HUVECs were significantly upregulated by Eu-MSNs modulating immune environment of macrophages. The in vivo study further demonstrated that the Eu-MSNs could not only stimulate osteogenesis by accelerating the new bone formation at critical-sized cranial defect site, but also support the blood vessel formation as well as collagen deposition and re-epithelialization at chronic skin wound sites, showing an improved angiogenesis activity when comparing with MSNs alone. Given the easy handling characteristics and extensive application potential, the results suggest that Eu-MSNs could be used as immunity-modulated osteogenesis/angiogenesis agent for skin and bone regeneration.

Graphical abstract

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The role of insulin growth factor-1 on the vascular regenerative effect of MAA coated disks and macrophage-endothelial cell crosstalk

Publication date: November 2017
Source:Biomaterials, Volume 144
Author(s): Ilana Talior-Volodarsky, Redouan Mahou, David Zhang, Michael Sefton
The IGF-1 signaling pathway and IGF-1-dependent macrophage/endothelial cell crosstalk was found to be critical features of the vascular regenerative effect displayed by implanted methacrylic acid –co-isodecyl acrylate (MAA-co-IDA; 40% MAA) coated disks in CD1 mice. Inhibition of IGF-1 signaling using AG1024 an IGF1-R tyrosine kinase inhibitor abrogated vessel formation 14 days after disk implantation in a subcutaneous pocket. Explanted tissue had increased arginase 1 expression and reduced iNOS expression consistent with the greater shift from "M1" ("pro-inflammatory") macrophages to "M2" ("pro-angiogenic") macrophages for MAA coated disks relative to control MM (methyl methacrylate-co-IDA) disks; the latter did not generate a vascular response and the polarization shift was muted with AG1024. In vitro, medium conditioned by macrophages (both human dTHP1 cells and mouse bone marrow derived macrophages) had elevated IGF-1 mRNA and protein levels, while the cells had reduced IGF1-R but elevated IGFBP-3 mRNA levels. These cells also had reduced iNOS and elevated Arg1 expression, consistent with the in vivo polarization results, including the inhibitory effects of AG1024. On the other hand, HUVEC exposed to dTHP1 conditioned medium migrated and proliferated faster suggesting that the primary target of the macrophage released IGF-1 was endothelial cells. Although further investigation is warranted, IGF-1 appears to be a key feature underpinning the observed vascularization. Why MAA based materials have this effect remains to be defined, however.



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Design of a nanocomposite substrate inducing adult stem cell assembly and progression toward an Epiblast-like or Primitive Endoderm-like phenotype via mechanotransduction

Publication date: November 2017
Source:Biomaterials, Volume 144
Author(s): Francesco Morena, Ilaria Armentano, Pia Montanucci, Chiara Argentati, Elena Fortunati, Simona Montesano, Ilaria Bicchi, Teresa Pescara, Ilaria Pennoni, Samantha Mattioli, Luigi Torre, Loredana Latterini, Carla Emiliani, Giuseppe Basta, Riccardo Calafiore, Josè Maria Kenny, Sabata Martino
This work shows that the active interaction between human umbilical cord matrix stem cells and Poly (l-lactide)acid (PLLA) and PLLA/Multi Walled Carbon Nanotubes (MWCNTs) nanocomposite films results in the stem cell assembly as a spheroid conformation and affects the stem cell fate transition.We demonstrated that spheroids directly respond to a tunable surface and the bulk properties (electric, dielectric and thermal) of plain and nanocomposite PLLA films by triggering a mechanotransduction axis. This stepwise process starts from tethering of the cells' focal adhesion proteins to the surface, together with the adherens junctions between cells. Both complexes transmit traction forces to F-Actin stress fibres that link Filamin-A and Myosin-IIA proteins, generating a biological scaffold, with increased stiffening conformation from PLLA to PLLA/MWCNTs, and enable the nucleoskeleton proteins to boost chromatin reprogramming processes. Herein, the opposite expression of NANOG and GATA6 transcription factors, together with other lineage specification related proteins, steer spheroids toward an Epiblast-like or Primitive Endoderm-like lineage commitment, depending on the absence or presence of 1 wt% MWCNTs, respectively.This work represents a pioneering effort to create a stem cell/material interface that can model the stem cell fate transition under growth culture conditions.

Graphical abstract

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Reactive oxygen species-responsive polymeric nanoparticles for alleviating sepsis-induced acute liver injury in mice

Publication date: November 2017
Source:Biomaterials, Volume 144
Author(s): Gan Chen, Hongzhang Deng, Xiang Song, Mingzi Lu, Lian Zhao, Sha Xia, Guoxing You, Jingxiang Zhao, Yulong Zhang, Anjie Dong, Hong Zhou
Sepsis-associated acute liver injury contributes to the pathogenesis of multiple organ dysfunction syndrome and is associated with increased mortality. Currently, no specific therapeutics for sepsis-associated liver injury are available. With excess levels of reactive oxygen species (ROS) being implicated as key players in sepsis-induced liver injury, we hypothesize that ROS-responsive nanoparticles (NPs) formed via the self-assembly of diblock copolymers of poly(ethylene glycol) (PEG) and poly(propylene sulfide) (PPS) may function as an effective drug delivery system for alleviating sepsis-induced liver injury by preferentially releasing drug molecules at the disease site. However, there are no reports available on the biocompatibility and effect of PEG-b-PPS-NPs in vivo. Herein, this platform was tested for delivering the promising antioxidant therapeutic molecule melatonin (Mel), which currently has limited therapeutic efficacy because of its poor pharmacokinetic properties. The mPEG-b-PPS-NPs efficiently encapsulated Mel using the oil-in-water emulsion technique and provided sustained, on-demand release that was modulated in vitro by the hydrogen peroxide concentration. Animal studies using a mouse model of sepsis-induced acute liver injury revealed that Mel-loaded mPEG-b-PPS-NPs are biocompatible and much more efficacious than an equivalent amount of free drug in attenuating oxidative stress, the inflammatory response, and subsequent liver injury. Accordingly, this work indicates that mPEG-b-PPS-NPs show potential as an ROS-mediated on-demand drug delivery system for improving Mel bioavailability and treating oxidative stress-associated diseases such as sepsis-induced acute liver injury.



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Prodrug-embedded angiogenic vessel-targeting nanoparticle: A positive feedback amplifier in hypoxia-induced chemo-photo therapy

Publication date: November 2017
Source:Biomaterials, Volume 144
Author(s): Dongbo Guo, Shuting Xu, Nan Wang, Huangyong Jiang, Yu Huang, Xin Jin, Bai Xue, Chuan Zhang, Xinyuan Zhu
Photodynamic therapy (PDT) induced hypoxia can significantly upregulate the expression of vascular endothelial growth factor (VEGF) at the tumor-stromal interface, resulting in a promoted angiogenesis. Thus, an angiogenesis vessel-targeting nanoparticle (AVT-NP) consisting of photosensitizer, angiogenic vessel-targeting peptide, and bioreductive prodrug is developed for a chemo-photo synergistic cancer therapy, with which anti-cancer effect is achieved first by PDT and immediately followed with hypoxia-activated cytotoxic free radicals. With targeting capability, the AVT-NPs can effectively accumulate at the tumor site due to the promoted angiogenesis in response to PDT-induced hypoxia. The more nanoparticles delivered to the tumor tissue, the higher efficacy of PDT can be achieved, resulting in a more severe hypoxia and increased angiogenesis. Therefore, the prodrug embedded AVT-NP functions as a positive feedback amplifier in the combinational chemo-photo treatment and indeed achieves an enhanced anti-tumor effect in both in vitro and in vivo studies.

Graphical abstract

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Interaction of Zap70 and CXCR4 receptor at lamellipodia that determines the directionality during Jurkat T cells chemotaxis

Publication date: October 2017
Source:Molecular Immunology, Volume 90
Author(s): Chia-Yun Wu, Yi-Ying Tsai, Sheng-Yi Chen, Yu-Ping Lin, Jyh-Wei Shin, Chia-Ching Wu, Bei-Chang Yang
Directional migration of T-lymphocytes is a key process during immune activation and is tightly regulated both temporally and spatially. The initial cell membrane protrusion at a particular site is critical for determining the direction of cell migration. In this study, we found that ZAP-70 protein appeared not only at the margin of the spreading areas of polarized Jurkat T cells but also formed clusters near the center of the cell body on a fibronectin plate. Specifically, some pZAP-70 was located at the lamellipodia/filopodia and was closely associated with the most extended membrane contact. To visualize the dynamic distribution of ZAP-70 on migrating Jurkat T cells, we generated a fluorescent ZAP-70-EGFP fusion protein (hZAP70G). Expression of the hZAP70G in P116 cells, a ZAP-70 defective Jurkat derivative, restored its chemotactic migration toward SDF-1, adhesion to fibronectin matrix, and integrin activation. In addition, the distribution of hZAP70G protein is associated with changes in cell shape, specifically the membrane protrusion step, forming filopodia/lamellipodia and a retracting uropod. Furthermore, SDF-1 stimulated the formation of ZAP-70 and CXCR4 complex. CXCR4 was observed mainly at the leading edge of migrating cell. The localization of ZAP-70 at the very front edge of protruding lamellipodia was close to CXCR4 and a part of them were overlapped. Collectively, our data describe the critical early step of directional cell movement toward SDF-1 that ZAP-70 is recruited to the CXCR4 at the leading edge of membrane and consequently modulates lamellipodia/filopodia formation and integrin activation.



http://ift.tt/2vJDS0K

Cirtical role for Salmonella effector SopB in regulating inflammasome activation

Publication date: October 2017
Source:Molecular Immunology, Volume 90
Author(s): Gui-Qiu Hu, Pei-Xuan Song, Wei Chen, Shuai Qi, Shui-Xing Yu, Chong-Tao Du, Xu-Ming Deng, Hong-Sheng Ouyang, Yong-Jun Yang
ObjectiveSalmonella is known to evolve many mechanisms to avoid or delay inflammasome activation which remain largely unknown. In this study, we investigated whether the SopB protein critical to bacteria virulence capacity was an effector that involved in the regulation of inflammasome activation.MethodsBMDMs from NLRC4-, NLRP3-, caspase-1/-11-, IFI16- and AIM2-deficient mice were pretreated with LPS, and subsequently stimulated with a series of SopB-related strains of Salmonella, inflammasome induced cell death, IL-1β secretion, cleaved caspase-1 production and ASC speckle formation were detected.ResultsWe found that SopB could inhibit host IL-1β secretion, caspase-1 activation and inflammasome induced cell death using a series of SopB-related strains of Salmonella; however the reduction of IL-1β secretion was not dependent on sensor that contain PYD domain, such as NLRP3, AIM2 or IFI16, but dependent on NLRC4. Notably, SopB specifically prevented ASC oligomerization and the enzymatic activity of SopB was responsible for the inflammasome inhibition. Furthermore, inhibition of Akt signaling induced enhanced inflammasome activation.ConclusionsThese results revealed a novel role in inhibition of NLRC4 inflammasome for Salmonella effector SopB.



http://ift.tt/2vrHHfK

Role of neuropilin-2 in the immune system

Publication date: October 2017
Source:Molecular Immunology, Volume 90
Author(s): S. Schellenburg, A. Schulz, D.M. Poitz, M.H. Muders
Neuropilins (NRPs) are single transmembrane receptors with short cytoplasmic tails and are dependent on receptors like VEGF receptors or Plexins for signal transduction. NRPs are known to be important in angiogenesis, lymphangiogenesis, and axon guidance. The Neuropilin-family consists of two members, Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2). They are up to 44 % homologous and conserved in all vertebrates. High levels of NRP2 are found on immune cells. Current research is very limited regarding the functions of NRP2 on these cells. Recent evidence suggests that NRP2 is important for migration, antigen presentation, phagocytosis and cell–cell contact within the immune system. Additionally, posttranslational NRP2 modifications like polysialylation are crucial for the function of some immune cells. This review is an overview about expression and functions of NRP2 in the immune system.



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The circular RNA of peripheral blood mononuclear cells: Hsa_circ_0005836 as a new diagnostic biomarker and therapeutic target of active pulmonary tuberculosis

Publication date: October 2017
Source:Molecular Immunology, Volume 90
Author(s): Ze-Gang Zhuang, Jun-Ai Zhang, Hou-Long Luo, Gan-Bin Liu, Yuan-Bin Lu, Nan-Hai Ge, Bi-Ying Zheng, Rui Xi Li, Chen Chen, Xin Wang, Yu-Qing Liu, Feng-Hui Liu, Yong Zhou, Xiao-Zhen Cai, Zheng W. Chen, Jun-Fa Xu
It has been reported that circular RNA (circRNA) is associated with human cancer. However, few studies have been reported in active pulmonary tuberculosis (APTB). The global circRNA expression was detected in the peripheral blood mononuclear cells (PBMCs) of APTB patients (n=5) and health controls (HC) (n=5) by using high-throughput sequencing. According to the systematical bioinformatics analysis, the basic content of circRNAs and their fold changes in the two groups were calculated. We selected 6 significant differentially expressed circRNAs, hsa_circ_0005836, hsa_circ_0009128, hsa_circ_0003519, hsa_circ_0023956, hsa_circ_0078768, and hsa_circ_0088452 and validated the expression in PBMCs from APTB (n=10) and HC (n=10) by real-time quantitative reverse transcription-polymerase chain reactions (qRT-PCRs). Further, the verification of these specific circRNAs (hsa_circ_0005836 and hsa_circ_0009128) between APTB (n=34) and HC (n=30) in PBMCs was also conducted by qRT-PCRs. The RNA-seq data showed the significant differential expression of the 523 circRNAs between the APTB and HC groups (199 circRNAs were significantly up-regulated and 324 circRNAs were down-regulated). Hsa_circ_0005836 and hsa_circ_0009128 expression was significantly down-regulated in the PBMCs of APTB (P<0.05) in the samples of APTB compared to HC in our study. The gene ontology based enrichment analysis of the circRNA-miRNA-mRNAs network showed that cellular catabolic process (P=7.10E-08), regulation of metabolic process (P=2.10E-06), catalytic activity (P=3.67E-08), protein binding (P=1.71E-07), cell part (P=3.46E-06), intracellular part (P=1.71E-07), and intracellular (P=3.67E-08) were recognized in the comparisons between APTB and HC. Based on KEGG analysis, HTLV-I infection, regulation of actin cytoskeleton, neurotrophin signaling pathway and mTOR signaling pathway were relevant during tuberculosis bacillus infection. We found for the first time that hsa_circ_0005836 and hsa_circ_0009128 were significantly down-regulated in the PBMCs of APTB compared with HC. Our findings indicate hsa_circ_0005836 might serve as a novel potential biomarker for TB infection.



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Elevated intrathymic sphingosine-1-phosphate promotes thymus involution during sepsis

Publication date: October 2017
Source:Molecular Immunology, Volume 90
Author(s): Laura Kuchler, Lisa K. Sha, Annika K. Giegerich, Tilo Knape, Carlo Angioni, Nerea Ferreirós, Martina V. Schmidt, Andreas Weigert, Bernhard Brüne, Andreas von Knethen
Sepsis mouse models revealed thymus atrophy, characterised by decreased thymus weight and loss of thymocytes due to apoptosis. Mice suffered from lymphopenia, a lack of T cells in the periphery, which attenuates their ability to fight against recurring and secondary infections during sepsis progression. Key players in thymus atrophy are IL-6, which is directly involved in thymus involution, and the sphingosine-1-phosphate − sphingosine-1-phosphate receptor 1 signaling, influencing thymocytes emigration. In healthy individuals a sphingosine-1-phosphate (S1P) gradient from lymphoid organs to the circulatory system serves as signal for mature T cell egress. In the present study we investigated, whether inhibition of S1P generation improves thymus involution. In sepsis, induced by cecal ligation and puncture (CLP), S1P in the thymus increased, while it decreased in serum, thus disrupting the naturally occurring S1P gradient. As a potential source of S1P we identified increased numbers of apoptotic cells in the thymic cortex of septic mice. Pharmacological inhibition of the S1P generating sphingosine kinases, by 4- [[4-(4-Chlorophenyl)-2-thiazolyl]amino]phenol (SK I–II), administered directly following CLP, prevented thymus atrophy. This was reflected by lymphocytosis, diminished apoptosis, decreased IL-6 expression, and an unaltered thymus weight. In addition SK I-II-treatment preserved the S1P balance and prevented S1P-dependent internalization of the sphingosine-1-phosphate receptor 1. Our data suggest that inhibition of sphingosine kinase and thus, S1P generation during sepsis restores thymic T cell egress, which might improve septic outcome.



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Interaction of extremophilic archaeal viruses with human and mouse complement system and viral biodistribution in mice

Publication date: October 2017
Source:Molecular Immunology, Volume 90
Author(s): Linping Wu, Kristine Buch Uldahl, Fangfang Chen, Halli Benasutti, Deborah Logvinski, Vivian Vu, Nirmal K. Banda, Xu Peng, Dmitri Simberg, Seyed Moein Moghimi
Archaeal viruses offer exceptional biophysical properties for modification and exploration of their potential in bionanotechnology, bioengineering and nanotherapeutic developments. However, the interaction of archaeal viruses with elements of the innate immune system has not been explored, which is a necessary prerequisite if their potential for biomedical applications to be realized. Here we show complement activation through lectin (via direct binding of MBL/MASPs) and alternative pathways by two extremophilic archaeal viruses (Sulfolobus monocaudavirus 1 and Sulfolobus spindle-shaped virus 2) in human serum. We further show some differences in initiation of complement activation pathways between these viruses. Since, Sulfolobus monocaudavirus 1 was capable of directly triggering the alternative pathway, we also demonstrate that the complement regulator factor H has no affinity for the viral surface, but factor H deposition is purely C3-dependent. This suggests that unlike some virulent pathogens Sulfolobus monocaudavirus 1 does not acquire factor H for protection. Complement activation with Sulfolobus monocaudavirus 1 also proceeds in murine sera through MBL-A/C as well as factor D-dependent manner, but C3 deficiency has no overall effect on viral clearance by organs of the reticuloendothelial system on intravenous injection. However, splenic deposition was significantly higher in C3 knockout animals compared with the corresponding wild type mice. We discuss the potential application of these viruses in biomedicine in relation to their complement activating properties.



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

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

Graphical abstract

Teaser

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


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