A Case of T-cell Lymphoprliferative Disorder Associated with Hypereosinophilia with Excellent Response to Mycophenolate Mofetil

Publication date: Available online 1 February 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Amr Hanbali, Marwan Shaheen, Feras Alfraih, Wafa Al-Otaibi, Riad El Fakih, Tarek Owaidah, Syed Ahmed
Hypereosinophilic syndrome (HES) is a group of rare blood disorders characterized by a persistent elevation of blood eosinophil count ⩾1.5 × 10⁹/L and clinical manifestations attributable to eosinophilia or tissue hypereosinophilia. Lymphocytic variant of HES (HES-L) is a known subtype according to World Health Organization classification. It is well documented in the literature that patients with HES-L are predisposed to develop T-cell lymphoma. We report a case of T-cell lymphoproliferation associated with hypereosinophilia, which has been successfully treated with mycophenolate mofetil, with resolution of skin lesions and normalization of eosinophil count and immunoglobulin E level. We believe this is a clinically relevant case since this is a rare disease with little known knowledge on its best treatment modality.



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Synovial Sarcoma of the Hard Palate: The Third Case in the Medical Literature

Publication date: Available online 1 February 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Aseel Doubi, Motaz Doubi, Nabil Al Zaher, Asma Tulbah




http://ift.tt/2k1BBJ6

Diagnosis of Variant RARA Translocation Using Standard Dual-Color Dual-Fusion PML/RARA FISH probes: An Illustrative Report

Publication date: Available online 1 February 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Manish K. Singh, Mayur Parihar, Neeraj Arora, D.K. Mishra, Saurabh J. Bhave, Mammen Chandy
Acute promyelocytic leukemia (APML) with variant RARa translocations comprises 1–2% of APML cases. However, the diagnosis of these cases is challenging as the routine practice includes fluorescence in situ hybridization (FISH) reverse transcription polymerase chain reaction targeting the PML and RARA genes to detect PML/RARA fusions. Here, we report a case highlighting the importance of atypical FISH signal patterns in standard dual-color dual-fusion PML/RARa FISH analysis complimented by karyotyping to detect these variant RARA translocations.



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Study of CD4+, CD8+, and Natural Killer Cells (CD16+, CD56+) in Children with Immune Thrombocytopenic Purpura

Publication date: Available online 1 February 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Farida Hussein El-Rashedy, Mahmoud Ahmed El-Hawy, Mohamed Ahmed Helwa, Sameh Said Abd-Allah
Objective/BackgroundTo assess the percentage of CD4⁺, CD8⁺, and natural killer cells (CD16⁺, CD56⁺) in children with immune thrombocytopenic purpura (ITP) at presentation and study their impact on disease chronicity.MethodsThis case–control study was conducted at the Pediatric Hematology and Oncology Unit, Menoufia University Hospital (tertiary care center in Egypt). The study was held on 30 children presenting with ITP; they were followed-up and classified into two groups: 15 children with acute ITP; and 15 children with chronic ITP. Patients were compared to a group of 15 healthy children of matched age and sex. Measurements of CD4⁺, CD8⁺, and natural killer cells (CD16⁺, CD56⁺) by flow cytometry were assessed and compared in these groups.ResultsCD4⁺ and CD4⁺/CD8⁺ were significantly lower in acute and chronic patients than the control group (p < .05 and p < .001, respectively), with no significant difference between acute and chronic patients (p > .05). However, CD8⁺ was significantly higher in acute and chronic patients than the control group (p < .05), with no significant difference between acute and chronic patients (p > .05). Natural killer cell percent was significantly lower in acute patients than the control group (p < .001), with no significant difference between chronic and control groups (p > .05).ConclusionITP is associated with immunity dysfunction denoted by the increase in cytotoxic T lymphocytes and the decrease in natural killer cells.



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Relapse of Hodgkin Lymphoma after Autologous Transplantation: Time to Rethink Treatment?

Publication date: Available online 1 February 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Yogesh Jethava, Guru Subramanian Guru Murthy, Mehdi Hamadani
Relapse of Hodgkin lymphoma after autologous hematopoietic cell transplantation (autologous HCT) is a major therapeutic challenge. Its management, at least in younger patients, traditionally involves salvage chemotherapy aiming to achieve disease remission followed by consolidation with allogeneic hematopoietic cell transplantation (allogeneic HCT) in eligible patients. The efficacy of salvage therapy is variable and newer combination chemotherapy regimens have improved the outcomes. Factors such as shorter time to relapse after autologous HCT and poor performance status have been identified as predictors of poor outcome. Newer agents such as immunoconjugate brentuximab vedotin, checkpoint inhibitors (e.g., pembrolizumab, nivolumab), lenalidomide, and everolimus are available for the treatment of patients relapsing after autologous HCT. With the availability of reduced intensity conditioning allogeneic HCT, more patients are eligible for this therapy with lesser toxicity and better efficacy due to graft versus lymphoma effects. Alternative donor sources such as haploidentical stem cell transplantation and umbilical cord blood transplantation are expanding this procedure to patients without HLA-matched donors. However, strategies aimed at reduction of disease relapse after reduced intensity conditioning allogeneic HCT are needed to improve the outcomes of this treatment. This review summarizes the current data on salvage chemotherapy and HCT strategies used to treat patients with relapsed Hodgkin lymphoma after prior autologous HCT.



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Prognosis Biomarkers Evaluation in Chronic Lymphocytic Leukemia

Publication date: Available online 1 February 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Lorena Caixeta Gomes, Fernanda Cristina Gontijo Evangelista, Lirlândia Pires de Sousa, Sergio Schusterschitz da Silva Araujo, Maria das Graças Carvalho, Adriano de Paula Sabino
Objective/BackgroundFrom clinical and biological points of view, chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by a progressive accumulation of lymphocytes in the peripheral blood, bone marrow, and lymphoid organs. New prognostic markers in CLL may be useful to clinicians for predicting outcome and in clinical decision-making. The aim of this study was to evaluate the potential prognostic value of the apoptotic/survival-controlling proteins and protein tyrosine kinase ZAP-70 gene expression in CLL patients and control individuals, correlating such findings with patients' clinical data.MethodsFifty-three patients diagnosed with CLL attending the hematology service of a clinical hospital, and 24 healthy individuals with no history of leukemia (Control group) were enrolled in this study. Analyses of apoptotic/survival-controlling proteins were performed by western blot and ZAP-70 gene expression was evaluated by real-time polymerase chain reaction.ResultsSignificant differences were observed for the p-p38, Mcl-1 long, and Mcl-1 short proteins when patients were compared with CLL and controls. A positive correlation between the results for Mcl-1 short and Mcl-1 long and lymphocyte count was observed, corroborating the hypothesis of an imbalance between proteins of cell survival pathways/apoptosis in CLL.ConclusionZAP-70 gene expression was not detected as a discriminant biomarker in these CLL patients. An imbalance between apoptosis-related proteins was observed in the present study, corroborating the hypothesis of increased survival of lymphocytes in CLL patients.



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Glomangiopericytoma (Hemangiopericytoma) of the Maxillary Sinus and Sinonasal Tract

Publication date: Available online 1 February 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Samaher Al Saad, Razan Al Hadlaq, Nabil Al-Zaher
Glomangiopericytoma of the sinonasal tract (formerly known as hemangiopericytoma) is a rare soft tissue tumor with a perivascular myoid phenotype. It accounts for 1 percent of all vascular tumors. Herein, it is our pleasure to report that in 2006, we, Head & Neck Surgeons at King Faisal Specialist Hospital & Research Center in Riyadh, Saudi Arabia, had the opportunity to contribute to the curative management of a 22-year-old patient, a registered nurse who presented with a 6-month history of recurrent minor spontaneous epistaxis and her clinical, radiological and histopathological assessment confirmed that this was due to a left maxillary glomangiopericytoma. The patient underwent angioembolization followed by left maxillectomy. The patient has been followed up closely until a local recurrence had been discovered and was managed with local surgical resection and adjuvant radiotherapy. Since then, the patient has been free from her malignant disease and is following up regularly with no evidence of metastasis or recurrence.



http://ift.tt/2k1z55P

Munich anatomy and the distribution of bodies from the Stadelheim execution site during National Socialism

Publication date: Available online 2 February 2017
Source:Annals of Anatomy - Anatomischer Anzeiger
Author(s): Mathias Schütz, Jens Waschke, Georg Marckmann, Florian Steger
During the reign of National Socialism (NS) anatomical institutes regularly received bodies of executed prisoners in steadily increasing numbers. After 1939, the execution site at Stadelheim prison in Munich supplied not only Munich Anatomical Institute but also the institutes in Erlangen, Innsbruck and Würzburg. Due to the disappearance of the Munich body journals, the exact dimension and procedure of body procurement from Stadelheim remained unknown for 70 years. After consultation of a wide range of sources, including rediscovered fragments of the body journals, it is now possible to give an almost comprehensive account of the developments. This article deals with the attempts at recovering information on body procurement from Stadelheim prison during the NS period, having already indicated the significance of Munich Anatomical Institute in organizing the distribution of bodies. Thereafter, it addresses the number and distinct groups of Stadelheim prisoners, executed and delivered to the four anatomical institutes, the differences in the handling of their bodies, and the extent to which in particular the Munich Anatomical Institute profited from the massive increase in executions. Finally, it unveils the role of the Munich Anatomical Institute in distributing those bodies among the anatomical institutes during the Second World War, making it not only the main beneficiary but also the interim center of this process.



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A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now

Publication date: Available online 2 February 2017
Source:Cancer Treatment Reviews
Author(s): Joaquin Bellmunt, Thomas Powles, Nicholas J. Vogelzang
The treatment of bladder cancer has evolved over time to encompass not only the traditional modalities of chemotherapy and surgery, but has been particularly impacted by the use of immunotherapy. The first immunotherapy was the live, attenuated bacterial Bacillus Calmette–Guérin vaccine, which has been the standard of care non-muscle-invasive bladder cancer since 1990. Modern immunotherapy has focused on inhibitors of checkpoint proteins, which are molecules that impede immune function, thereby allowing tumor cells to grow and proliferate unregulated. Several checkpoint targets (programmed death ligand-1 [PD-L1] programmed cell death protien-1 [PD-1], and cytotoxic T-lymphocyte associated protein 4 [CTLA4]) have received the most attention in the treatment of bladder cancer, and have inhibitor agents either approved or in late-stage development. This review describes the most recent data on agents that inhibit PD-L1, found on the surface of tumor cells, and PD-1 found on activated T and B cells and macrophages. Atezolizumab is the only member of this class currently approved for the treatment of bladder cancer, but nivolumab, pembrolizumab, durvalumab, and avelumab all have positive results for this indication, and approvals are anticipated in the near future. The checkpoint inhibitors offer an effective alternative for patients for whom previously there were few options for durable responses, including those who are ineligible for cisplatin-based regimens or who are at risk of significant toxicity. Research is ongoing to further categorize responses, define ideal patient populations, and investigate combinations of checkpoint inhibitors to address multiple pathways in immune system functioning.



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Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: a network meta-analysis

Publication date: Available online 2 February 2017
Source:Cancer Treatment Reviews
Author(s): Sandro Pasquali, Vanna Chiarion-Sileni, Carlo Riccardo Rossi, Simone Mocellin
BackgroundImmune checkpoint inhibitors and targeted therapies, two new class of drugs for treatment of metastatic melanoma, have not been compared in randomized controlled trials (RCT). We quantitatively summarized the evidence and compared immune and targeted therapies in terms of both efficacy and toxicity.MethodsA comprehensive search for RCTs of immune checkpoint inhibitors and targeted therapies was conducted to August 2016. Using a network meta-analysis approach, treatments were compared with each other and ranked based on their effectiveness (as measured by the impact on progression-free survival [PFS]) and acceptability (the inverse of high grade toxicity).ResultsTwelve RCTs enrolling 6,207 patients were included. Network meta-analysis generated 15 comparisons. Combined BRAF and MEK inhibitors were associated with longer PFS as compared to anti-CTLA4 (HR: 0.22; 95% confidence interval [CI]: 0.12-0.41) and anti-PD1 antibodies alone (HR: 0.38; CI: 0.20-0.72). However, anti-PD1 monoclonal antibodies were less toxic than anti-CTLA4 monoclonal antibodies (RR: 0.65; CI:0.40-0.78) and their combination significantly increased toxicity compared to either single agent anti-CTLA4 (RR: 2.06; CI: 1.45-2.93) or anti-PD1 monoclonal antibodies (RR: 3.67; CI: 2.27-5.96). Consistently, ranking analysis suggested that the combination of targeted therapies is the most effective strategy, whereas single agent anti-PD1 antibodies have the best acceptability. The GRADE level of evidence quality for these findings was moderate to low.ConclusionsThe simultaneous inhibition of BRAF and MEK appears the most effective treatment for melanomas harboring BRAF V600 mutation, although anti-PD1 antibodies appear to be less toxic. Further research is needed to increase the quality of evidence.



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Breast PET/MR Imaging

Publication date: Available online 1 February 2017
Source:Radiologic Clinics of North America
Author(s): Amy Melsaether, Linda Moy

Teaser

Breast and whole-body PET/MR imaging is being used to detect local and metastatic disease and is being investigated for potential imaging biomarkers, which may eventually help personalize treatments and prognoses. This article provides and overview of breast and whole-body PET/MR exam techniques, summarizes PET and MR breast imaging for lesion detection, outlines investigations into multi-parametric breast PET/MR, looks at breast PET/MR in the setting of neo-adjuvant chemotherapy, and reviews the pros and cons of whole-body PET/MR in the setting of metastatic or suspected metastatic breast cancer.


http://ift.tt/2k17Fge

Attentional bias to alcohol stimuli predicts elevated cue-induced craving in young adult social drinkers

Publication date: July 2017
Source:Addictive Behaviors, Volume 70
Author(s): Linda Manchery, Devorah E. Yarmush, Peter Luehring-Jones, Joel Erblich
Considerable evidence has identified biased cognitive processing of alcohol-related stimuli as an important factor in the maintenance of alcohol-seeking and relapse among individuals suffering from alcohol use-disorders (AUDs). In addition, a large body of research has demonstrated that exposure to alcohol cues can elicit powerful alcohol cravings. Little is known, however, about the possible relationship between attentional bias and cue-induced cravings, and even less is known about these processes in social drinkers without a personal history of AUDs. The goal of this study was to examine the possibility that attentional biases toward alcohol-related stimuli would predict elevated cue-induced alcohol craving in this population. Young adult social drinkers (N=30, Mean age=22.8±1.9, 61% female) recruited from an urban university population completed a visual dot probe task in which they were presented with alcohol and neutral stimulus pictures that were immediately followed by a visual probe replacing one of the pictures. Attentional bias was measured by calculating reaction times to probes that replaced alcohol stimuli vs. neutral stimuli. Participants then completed a classic alcohol cue-exposure task and reported cravings immediately before and after alcohol and neutral cue-exposures. Not surprisingly, exposure to alcohol cues elicited significant cravings. Consistent with the study hypothesis, larger attentional biases toward alcohol stimuli predicted higher levels of alcohol craving. Findings demonstrate that heightened attention to alcohol stimuli can significantly impact motivation to consume in healthy young adults, and suggest a possible pathway linking cognitive processes early in the drinking trajectory to the later development of AUDs.



http://ift.tt/2kuLC52

Financial strain and cognitive-based smoking processes: The explanatory role of depressive symptoms among adult daily smokers

Publication date: July 2017
Source:Addictive Behaviors, Volume 70
Author(s): Zuzuky Robles, Sahar Anjum, Lorra Garey, Brooke Y. Kauffman, Rubén Rodríguez-Cano, Kirsten J. Langdon, Clayton Neighbors, Lorraine R. Reitzel, Michael J. Zvolensky
Little work has focused on the underlying mechanisms that may link financial strain and smoking processes. The current study tested the hypothesis that financial strain would exert an indirect effect on cognitive-based smoking processes via depressive symptoms. Three clinically significant dependent variables linked to the maintenance of smoking were evaluated: negative affect reduction motives, negative mood abstinence expectancies, and perceived barriers for quitting. Participants included 102 adult daily smokers (Mage=33.0years, SD=13.60; 35.3% female) recruited from the community to participate in a self-guided (unaided; no psychological or pharmacological intervention) smoking cessation study. Results indicated that depressive symptoms explain, in part, the relation between financial strain and smoking motives for negative affect reduction, negative mood abstinence expectancies, and perceived barriers for quitting. Results indicate that smoking interventions for individuals with high levels of financial strain may potentially benefit from the addition of therapeutic tactics aimed at reducing depression.



http://ift.tt/2jIktHz

Prevalence and harm perceptions of hookah smoking among U.S. adults, 2014–2015

Publication date: June 2017
Source:Addictive Behaviors, Volume 69
Author(s): Ban A Majeed, Kymberle L Sterling, Scott R Weaver, Terry F Pechacek, Michel P Eriksen
This study aimed to determine the prevalence and factors associated with hookah smoking and perceptions of harm among U.S. adults. Data were pooled from the Tobacco Products and Risk Perceptions Surveys conducted separately in the summers of 2014 and 2015, among a probability sample selected from an online research panel. Descriptive, logistic regression, and multinomial logistic regression analyses were conducted. In 2014/2015, prevalence of ever and past 30-day hookah smoking among U.S. adults were 15.8% (95% C.I.: 15.0%, 16.7%) and 1.5% (95% C.I.: 1.2%, 1.8%), respectively. Adults who used other alternative tobacco products had a higher odds of hookah smoking than those who did not. Adults with some college education (AOR, 1.53) and with a college degree or more (AOR, 2.21), those identified as non-Hispanic other (AOR, 1.38) were more likely to be ever hookah smokers. Being a young adult (AOR, 2.7), college-educated (AOR, 2.3), never smoker (AOR, 2.1), and an ever hookah smoker (AOR, 2.8) were associated with lower perceptions of harm. Findings suggest that young college students are at higher risk of smoking hookah and that hookah smoking is more prevalent among individuals who use other tobacco products, such as little cigars and cigarillos, traditional cigars, and e-cigarettes, indicating a distinct group of users of alternative tobacco products. Regarding potential harm of hookah, the study highlights a knowledge gap and misperception especially among young, college-educated, and never smokers. Public health interventions should target these subpopulations to provide them with accurate information on hookah smoking.



http://ift.tt/2kuR5sx

Genetics of early onset Parkinson’s disease in Finland: exome sequencing and genome-wide association study

Publication date: Available online 2 February 2017
Source:Neurobiology of Aging
Author(s): A. Siitonen, M.A. Nalls, D. Hernández, J.R. Gibbs, J. Ding, P. Ylikotila, C. Edsall, A. Singleton, K. Majamaa
Several genes and risk factors are associated with Parkinson's disease (PD). Although many of the genetic markers belong to a common pathway, a unifying pathogenetic mechanism is yet to be found. Also, missing heritability analyses have estimated that only part of the genetic influence contributing to PD has been found. Here, we carried out whole-exome sequencing (WES) on 438 Finnish patients with early-onset PD. We also re-analyzed previous data from genome-wide association studies (GWAS) on the same cohort. Variants in the CEL gene/locus were associated with PD in both GWAS and WES analysis. Exome-wide gene-based association tests also identified the MPHOSPH10, TAS2R19 and SERPINA1 genes in the discovery dataset (p<2.5E-6). MPHOSPH10 had estimated odds ratio (OR) of 1.53 and the rs141620200 variant in SERPINA1 had OR of 1.27. We identified several candidate genes, but further investigation is required in order to determine the role of these genes in PD.



http://ift.tt/2l1IbQd

A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy

Publication date: Available online 2 February 2017
Source:Cancer Cell
Author(s): Isabelle K. Vila, Yixin Yao, Goeun Kim, Weiya Xia, Hyejin Kim, Sun-Joong Kim, Mi-Kyung Park, James P. Hwang, Enrique González-Billalabeitia, Mien-Chie Hung, Su Jung Song, Min Sup Song
UBE2O is localized in the 17q25 locus, which is known to be amplified in human cancers, but its role in tumorigenesis remains undefined. Here we show that Ube2o deletion in MMTV-PyVT or TRAMP mice profoundly impairs tumor initiation, growth, and metastasis, while switching off the metabolic reprogramming of tumor cells. Mechanistically, UBE2O specifically targets AMPKα2 for ubiquitination and degradation, and thereby promotes activation of the mTOR-HIF1α pathway. Notably, inactivation of AMPKα2, but not AMPKα1, abrogates the tumor attenuation caused by UBE2O loss, while treatment with rapamycin or inhibition of HIF1α ablates UBE2O-dependent tumor biology. Finally, pharmacological blockade of UBE2O inhibits tumorigenesis through the restoration of AMPKα2, suggesting the UBE2O-AMPKα2 axis as a potential cancer therapeutic target.

Graphical abstract

Teaser

Vila et al. show that UBE2O, which is overexpressed in many human cancers, targets AMPKα2 for ubiquitination and degradation, and thereby promotes activation of the mTOR-HIF1α pathway. Genetic deletion or pharmacological blockade of UBE2O inhibits tumorigenesis through the restoration of AMPKα2.


http://ift.tt/2kxBzMk

Bone mineral density and bone metabolic markers’ status in children with neurofibromatosis type 1

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


http://ift.tt/2l1ukZU

A minimum stochastic model evaluating the interplay between population density and drift for species coexistence

Publication date: February 2017
Source:Acta Oecologica, Volume 79
Author(s): Rafael Dettogni Guariento, Adriano Caliman
Despite the general acknowledgment of the role of niche and stochastic process in community dynamics, the role of species relative abundances according to both perspectives may have different effects regarding coexistence patterns. In this study, we explore a minimum probabilistic stochastic model to determine the relationship of populations relative and total abundances with species chances to outcompete each other and their persistence in time (i.e., unstable coexistence). Our model is focused on the effects drift (i.e., random sampling of recruitment) under different scenarios of selection (i.e., fitness differences between species). Our results show that taking into account the stochasticity in demographic properties and conservation of individuals in closed communities (zero-sum assumption), initial population abundance can strongly influence species chances to outcompete each other, despite fitness inequalities between populations, and also, influence the period of coexistence of these species in a particular time interval. Systems carrying capacity can have an important role in species coexistence by exacerbating fitness inequalities and affecting the size of the period of coexistence. Overall, the simple stochastic formulation used in this study demonstrated that populations initial abundances could act as an equalizing mechanism, reducing fitness inequalities, which can favor species coexistence and even make less fitted species to be more likely to outcompete better-fitted species, and thus to dominate ecological communities in the absence of niche mechanisms. Although our model is restricted to a pair of interacting species, and overall conclusions are already predicted by the Neutral Theory of Biodiversity, our main objective was to derive a model that can explicitly show the functional relationship between population densities and community mono-dominance odds. Overall, our study provides a straightforward understanding of how a stochastic process (i.e., drift) may affect the expected outcome based on species selection (i.e., fitness inequalities among species) and the resulting outcome regarding unstable coexistence among species.



http://ift.tt/2kmyrkc

Angiogenesis regulation by nanocarriers bearing RNA interference

Publication date: Available online 2 February 2017
Source:Advanced Drug Delivery Reviews
Author(s): Paula Ofek, Galia Tiram, Ronit Satchi-Fainaro
Since the approval of bevacizumab as antiangiogenic therapy in 2004 by the FDA, an array of angiogenesis inhibitors have been developed and approved. However, results were disappointing with regards to their therapeutic efficacy. RNA interference approaches offer the possibility of rational design with high specificity, lacking in many current drug treatments for various diseases including cancer. However, in vivo delivery issues still represent a significant obstacle for widespread clinical applications. In the current review, we summarize the advances in the last decade in the field of angiogenesis-targeted RNA interference approaches, with special emphasis on oncology applications. We present pro-angiogenic and anti-angiogenic factors as potential targets, experimental evidence and clinical trials data on angiogenesis regulation by RNA interference. Consequent challenges and opportunities are discussed.

Graphical abstract

http://ift.tt/2jBNLwd

Beyond Cell Division: the Ecological Roles of Autolysins in Oral Biofilm Communities

Abstract

Purpose of Review

The goal of this review is to address the complicated nature of autolysins found among oral bacteria and the roles they play within the oral biofilm. The various functions of autolysins are discussed, as well as the regulation of autolysins and overall contribution to biofilms and the oral environment.

Recent Findings

With their many functions, bacterial autolysins can be understood as contributing to both cell physiology and population dynamics within the oral environment. Cell division, peptidoglycan turnover/remodeling, fratricide, and programmed cell death are all influenced, if not controlled, by autolysins. The release of nutrients and DNA as functional byproducts of lysins can alter the biofilm by affecting the growth and overall genetic makeup of the diverse bacteria.

Summary

Autolysins and their various functions contribute to biofilm formation, horizontal gene transfer, and the overall health of the oral cavity.

http://ift.tt/2k53Wkm

Photobiomodulation laser and pulsed electrical field increase the viability of the musculocutaneous flap in diabetic rats

Abstract

The purpose of this study is to investigate the effect of pulsed electrical field (PEF) and photobiomodulation laser (PBM) on the viability of the TRAM flap in diabetic rats. Fifty Wistar rats were divided into five homogeneous groups: Group 1—control; Group 2—diabetics; Group 3—diabetics + PEF; Group 4—diabetic + laser 660 nm, 10 J/cm², 0.27 J; Group 5—diabetic + laser 660 nm, 140 J/cm², 3.9 J. The percentage of necrotic area was evaluated using software Image J®. The peripheral circulation of the flap was evaluated by infrared thermography FLIR T450sc (FLIR® Systems—Oregon USA). The thickness of the epidermis (haematoxylin-eosin), mast cell (toluidine blue), leukocytes, vascular endothelial growth factor, fibroblast and newly formed blood vessels were evaluated. For the statistical analysis, the Kruskal-Wallis test was applied followed by Dunn and ANOVA test followed by Tukey with critical level of 5% (p < 0.05). The PEF reduced the area of necrosis, decreased the leukocytes, increased the mast cells, increased the thickness of epidermis and increased newly formed blood vessels when it was compared to the untreated diabetic group of animals. Laser 660 nm, fluence 140 J/cm² (3.9 J) showed better results than the 10 J/cm² (0.27 J) related to reduction of the area of necrosis and the number of leukocytes, increased mast cells, increased thickness of the epidermis, increased vascular endothelial growth factor, increased fibroblast growth factor and increase of newly formed blood vessels in diabetic animals. The laser and pulsed electrical field increase the viability of the musculocutaneous flap in diabetic rats.

http://ift.tt/2k5c9Fn

Understanding and predicting fracture risk in acromegaly

http://ift.tt/2ktVsEu

Receptor tyrosine kinase-like orphan receptor 1 (ROR-1): An emerging target for diagnosis and therapy of chronic lymphocytic leukemia

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Leili Aghebati-Maleki, Mahdi Shabani, Behzad Baradaran, Morteza Motallebnezhad, Jafar Majidi, Mehdi Yousefi
Chronic lymphocytic leukemia (CLL) is characterized by reposition of malignant B cells in the blood, bone marrow, spleen and lymph nodes. It remains the most common leukemia in the Western world. Within the recent years, major breakthroughs have been made to prolong the survival and improve the health of patients. Despite these advances, CLL is still recognized as a disease without definitive cure. New treatment approaches, based on unique targets and novel drugs, are highly desired for CLL therapy. The Identification and subsequent targeting of molecules that are overexpressed uniquely in malignant cells not normal ones play critical roles in the success of anticancer therapeutic strategies. In this regard, ROR family proteins are known as a subgroup of protein kinases which have gained huge popularity in the scientific community for the diagnosis and treatment of different cancer types. ROR1 as an antigen exclusively expressed on the surface of tumor cells can be a target for immunotherapy. ROR-1 targeting using different approaches such as siRNA, tyrosine kinase inhibitors, cell therapy and antibody induces tumor growth suppression in cancer cells. In the current review, we aim to present an overview of the efforts and scientific achievements in targeting ROR family, particularly ROR-1, for the diagnosis and treatment of chronic lymphocytic leukemia (CLL).



http://ift.tt/2kx7bS9

The role of IL17B-IL17RB signaling pathway in breast cancer

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Vahideh Alinejad, Sanam Dolati, Morteza Motallebnezhad, Mehdi Yousefi
Breast cancer is the most important cause of death in women globally. Though, improved survival is due to the developments in the screening techniques, initial diagnosis, and advances in treatments. Numerous factors contributed in the progression of breast cancer, such as inflammation. The most significant factor involved in the inflammatory process, is T helper 17 (Th17) cells. Th17 cells have an exceptional role in many of inflammatory diseases like psoriasis, rheumatoid arthritis, and breast cancer through production of proinflammatory cytokine (IL17). As the collected indication recommends a possible relevance between chronic inflammation and cancer tumorigenesis, it appears that this cytokine can stimulate the tumorigenesis of breast tumor cells. The IL17 family consist of 6 protein members, among them IL17B and its receptor, and IL17RB signaling pathway plays a key role in development and progression of breast cancer, and targeting this signaling pathway or its specific downstream mediators by a chemotherapy drug and small interfering RNA interference is a potentially novel therapeutic pathway for inhibition of this disease. This comprehensive review details the recognition of activity, signaling, and the roles of IL17B-IL17RB in breast cancer have caused to determination of new therapeutic mechanisms with the purpose of introduction this system and the regulation of its signaling pathway.



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Quality of Adjuvant Endocrine Therapy Delivery for Breast Cancer Care

This cohort study investigates temporal patterns and factors associated with the receipt of adjuvant endocrine therapy in women with breast cancer in the National Cancer Database.

http://ift.tt/2k4vvKo

Lung Cancer Screening With Low-Dose Computed Tomography

This study examines whether low-dose computed tomography screening for lung cancer increased following the United States Preventive Services Task Force recommendations.

http://ift.tt/2l0Mds3

Error in Methods Section

There were several words missing from the first sentence of the Methods section of the Research Letter titled "Increase in Prostate Cancer Distant Metastases at Diagnosis in the United States," by Hu et al. The sentence should have read "Using the most recent Surveillance, Epidemiology, and End Results (SEER) release, we identified 1 107 111 men 40 years or older diagnosed with pathologically confirmed prostate cancer and 545 399 from 2004 to 2013." The article has been corrected online.

http://ift.tt/2k4ywuk

Population-Attributable Risk Proportion of Clinical Risk Factors for Breast Cancer

This population-based, case-control, cohort study uses data from the Breast Cancer Surveillance Consortium to assess risk factors associated with breast cancer in premenopausal and postmenopausal women.

http://ift.tt/2l0LWoN

Myeloid Neoplasm After Therapy for Autoimmune Disease

This case-control study assesses the association of cytotoxic, anti-inflammatory, and immunomodulating agents with the risk for developing myeloid neoplasms among patients with autoimmune disease.

http://ift.tt/2k4wo60

Human-Machine Collaboration in Cancer Treatment

This Viepoint examines the implementation and possible benefits of human-machine collaboration in treating patients with cancer.

http://ift.tt/2k4pIVw

Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review

Abstract

Background

The management of acne in adult females is problematic, with many having a history of treatment failure and some having a predisposition to androgen excess. Alternatives to oral antibiotics and combined oral contraceptives (COCs) are required.

Objective

Our aim was to conduct a hybrid systematic review of the evidence for benefits and potential harms of oral spironolactone in the management of acne in adult females.

Methods

The review was conducted according to a previously published protocol. Three reviewers independently selected relevant studies from the search results, extracted data, assessed the risk of bias, and rated the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Results

Ten randomized controlled trials (RCTs) and 21 case series were retrieved. All trials were assessed as being at a 'high risk' of bias, and the quality of evidence was rated as low or very low for all outcomes. Apart from one crossover trial that demonstrated statistical superiority of a 200 mg daily dose versus inflamed lesions compared with placebo, data from the remaining trials were unhelpful in establishing the degree of efficacy of lower doses versus active comparators or placebo. Menstrual side effects were significantly more common with the 200 mg dose; frequency could be significantly reduced by concomitant use of a COC. Pooling of results for serum potassium supported the recent recommendation that routine monitoring is not required in this patient population.

Conclusion

This systematic review of RCTs and case series identified evidence of limited quality to underpin the expert endorsement of spironolactone at the doses typically used (≤100 mg/day) in everyday clinical practice.

http://ift.tt/2kY42Zn

System Identification of Velocity Mechanomyogram Measured with a Capacitor Microphone for Muscle Stiffness Estimation

Publication date: Available online 1 February 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Takanori Uchiyama, Taiki Tomoshige
A mechanomyogram (MMG) measured with a displacement sensor (displacement MMG) can provide a better estimation of longitudinal muscle stiffness than that measured with an acceleration sensor (acceleration MMG), but the displacement MMG cannot provide transverse muscle stiffness. We propose a method to estimate both longitudinal and transverse muscle stiffness from a velocity MMG using a system identification technique. The aims of this study are to show the advantages of the proposed method. The velocity MMG was measured using a capacitor microphone and a differential circuit, and the MMG, evoked by electrical stimulation, of the tibialis anterior muscle was measured five times in seven healthy young male volunteers. The evoked MMG system was identified using the singular value decomposition method and was approximated with a fourth-order model, which provides two undamped natural frequencies corresponding to the longitudinal and transverse muscle stiffness. The fluctuation of the undamped natural frequencies estimated from the velocity MMG was significantly smaller than that from the acceleration MMG. There was no significant difference between the fluctuations of the undamped natural frequencies estimated from the velocity MMG and that from the displacement MMG. The proposed method using the velocity MMG is thus more advantageous for muscle stiffness estimation.



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Mn2+ doped-CdTe/ZnS modified fluorescence nanosensor for detection of glucose

Publication date: June 2017
Source:Sensors and Actuators B: Chemical, Volume 245
Author(s): Sandeep K. Vaishanav, Jyoti Korram, Rekha Nagwanshi, Kallol K. Ghosh, Manmohan L. Satnami
Quantitative detection of glucose is an important issue in food industry, various biotechnological processes and medication of metabolic disorders. Herein, we have reported a detection method based on Mn²⁺-doped-CdTe/ZnS modified nanosensor for rapid and sensitive detection of glucose levels in human biological fluids i.e. blood and urine. In this strategy Mn²⁺-doped CdTe/ZnS quantum dots (QDs) were designed for the direct measurement of glucose. The fluorescence (FL) of Mn²⁺-doped CdTe/ZnS QDs was sensitive to hydrogen peroxide (H2O2). The catalytic oxidation of glucose by glucose oxidase (GOx) produces H2O2 that extensively quenched the FL of QDs. Experimental results showed that the decrease of the QDs FL was proportional to the concentration of glucose within the range of 0.1nM–10μM with the detection limit of 0.1nM under the optimized experimental conditions. Glucose in blood and urine samples was effectively detected by this strategy. The comparison with commercialized glucose meter indicated that this proposed glucose assay system is not only simple, sensitive, but also reliable and suitable for practical application. The high sensitivity, versatility, portability, high-throughput and low cost of this glucose sensor implied its potential in point-of-care clinical diagnosis of diabetes and other fields.

Graphical abstract

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Water–n-BuOH solvothermal synthesis of ZnAl–LDHs with different morphologies and its calcined product in efficient dyes removal

Publication date: 15 May 2017
Source:Journal of Colloid and Interface Science, Volume 494
Author(s): Gailing Huang, Yingying Sun, Chencong Zhao, Yifei Zhao, Zhaoyuan Song, Junli Chen, Shulan Ma, Junping Du, Zhigang Yin
In this study, water–n-BuOH mixed solvents were used to synthesize the ZnAl–layered double hydroxides (ZnAl–LDHs) via hydrothermal method. The XRD, FT-IR, SEM, ICP and CHN analyses revealed that the type of intercalated anions, the layer Zn/Al ratios, and morphologies of the LDHs depended on the ratio of V(water)/V(n-BuOH) in the mixed solvents. When the ratio of V(water)/V(n-BuOH) is 3 or 0.3, the as-prepared LDHs had 3D "silk flowers" (ZnAl–LDH–3) or "Sedimentary rock" morphology (ZnAl–LDH–0.3). Adsorption properties of dyes on calcined LDHs were studied. Compared with ZnAl–LDO–0.3 and ZnAl–LDO–w (calcined from the LDHs obtained in pure water), ZnAl–LDO–3 showed much better adsorption efficiency for anionic dyes thanks to its much larger BET-specific surface area. The sorption kinetics for dyes was appropriately described by the pseudo–second–order model and sorption isotherms can be fitted more satisfactorily by the Langmuir model. With the increasing concentrations of dyes from 10mg/L to 400mg/L, the maximum absorption capacities of ZnAl–LDO–3 were 1540mg/g (2.21mmol/g) for congo red, 1153mg/g (3.52mmol/g) for methyl orange and 390mg/g (0.63mmol/g) for active red (X-3B), respectively. The adsorption dyes onto the external surface is still the main mechanism for LDO adsorbents. The ZnAl–LDO–3 was a potential adsorbent for dyeing wastewater treatment.

Graphical abstract

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Neutrophil perversion in demyelinating autoimmune diseases: Mechanisms to medicine

Publication date: Available online 2 February 2017
Source:Autoimmunity Reviews
Author(s): Courtney S. Casserly, Julia C. Nantes, Ryder F. Whittaker Hawkins, Luc Vallières
Neutrophils are essential to a healthy life, yet pose a threat if improperly controlled. Neutrophil perversion is well documented in a variety of inflammatory disorders (e.g. arthritis, lupus, psoriasis), but is only beginning to be demystified in autoimmune demyelination, the most common cause of neurological disability in young adults. Using the animal model experimental autoimmune encephalomyelitis (EAE), several molecules that help neutrophils invade the central nervous system (CNS) have been identified. Mechanisms by which neutrophils may contribute to demyelination have also been proposed (e.g. secretion of endothelial/leukocytic modulators, antigen presentation to T cells, myelin degradation and phagocytosis). In human, neutrophils are seen in the CNS of people with neuromyelitis optica spectrum disorder and other severe variants of autoimmune demyelinating diseases. At the time of autopsy for multiple sclerosis (MS) — often many years after its onset — neutrophils appear to have escaped the scene of the crime. However, new clues implicate neutrophils in MS relapses and progression. This warrants further investigating 1) the differential importance of neutrophils among demyelinating diseases, 2) the largely unknown effects of current MS therapies on neutrophils, and 3) the potential of neutrophil proteins as clinical biomarkers or therapeutic targets.



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Autoimmune hepatitis and occult HCV infection: A prospective single-centre clinical study

Publication date: Available online 1 February 2017
Source:Autoimmunity Reviews
Author(s): Roee Dvir, Giuseppe Andrea Sautto, Nicasio Mancini, Sara Racca, Roberta Antonia Diotti, Massimo Clementi, Massimo Memoli




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Management of Venetoclax-Posaconazole Interaction in Acute Myeloid Leukemia Patients: Evaluation of Dose Adjustments

Publication date: Available online 1 February 2017
Source:Clinical Therapeutics
Author(s): Suresh K. Agarwal, Courtney D. DiNardo, Jalaja Potluri, Martin Dunbar, Hagop M. Kantarjian, Rod A. Humerickhouse, Shekman L. Wong, Rajeev M. Menon, Marina Y. Konopleva, Ahmed Hamed Salem
PurposeThe effect of posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor and commonly used antifungal agent, on the pharmacokinetic properties of venetoclax, a CYP3A substrate, was evaluated in patients with acute myeloid leukemia to determine the dose adjustments needed to manage this potential interaction.MethodsTwelve patients received 20- to 200-mg ramp-up treatment with oral venetoclax and 20 mg/m² of intravenous decitabine on days 1 through 5, followed by 400 mg of venetoclax alone on days 6 through 20. On days 21 through 28, patients received 300 mg of posaconazole plus reduced doses of venetoclax (50 or 100 mg) to account for expected increases in venetoclax plasma concentrations. Blood samples were collected before dosing and up to 24 hours after the venetoclax dose on days 20 and 28.FindingsCompared with a venetoclax dose of 400 mg when administered alone (day 20), coadministration of venetoclax at a 50-mg dose with multiple doses of posaconazole increased mean venetoclax Cmax and AUC0–24 by 53% and 76%, respectively, whereas coadministration of venetoclax at a 100-mg dose with posaconazole increased mean venetoclax Cmax and AUC0–24 by 93% and 155%, respectively. When adjusted for different doses and nonlinearity, posaconazole was estimated to increase venetoclax Cmax and AUC0–24 by 7.1- and 8.8-fold, respectively. Both the 50- and 100-mg venetoclax doses administered with posaconazole were well tolerated.ImplicationsThe results are consistent with inhibition of CYP3A-mediated metabolism of venetoclax. Posaconazole can be used for antifungal prophylaxis in patients with acute myeloid leukemia receiving venetoclax after reducing the venetoclax dose by at least 75%. ClinicalTrials.gov identifier: NCT02203773.



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Monthly Oral Ibandronate Reduces Bone Loss in Korean Women With Rheumatoid Arthritis and Osteopenia Receiving Long-term Glucocorticoids: A 48-week Double-blinded Randomized Placebo-controlled Investigator-initiated Trial

Publication date: Available online 1 February 2017
Source:Clinical Therapeutics
Author(s): Kichul Shin, Sung-Hwan Park, Won Park, Han Joo Baek, Yun Jong Lee, Seong Wook Kang, Jung-Yoon Choe, Wan-Hee Yoo, Yong-Beom Park, Jung-Soo Song, Seung-Geun Lee, Bin Yoo, Dae-Hyun Yoo, Yeong Wook Song
PurposeOur aim was to investigate the efficacy of monthly oral ibandronate in Korean women with rheumatoid arthritis and reduced bone mineral density (BMD) receiving long-term glucocorticoids.MethodsPatients (n = 167 women) were randomly assigned (1:1) to receive ibandronate 150 mg or placebo every 4 weeks. Patients had taken glucocorticoid (equivalent of daily prednisolone ≥5 mg) for 3 or more consecutive months before enrollment, and had a lumbar spine 1 to 4 (L1–L4) T-score of < −1.0 and ≥ −2.5. Both groups were provided with daily calcium carbonate and cholecalciferol. The primary end point was the L1 to L4 BMD percent changes at 48 weeks compared with baseline.FindingsBaseline characteristics were comparable between the 2 groups. BMD percent changes in L1 to L4 at 48 weeks were significantly different between the ibandronate versus the placebo group (+3.7% [5.1%] vs −1.9% [4.4%], respectively; P < 0.0001). BMD percent changes at 48 weeks in femur neck and total hip also had similar results (P = 0.0073 and P = 0.0031, respectively). Decrease of serum type 1 collagen C-terminal telopeptide was significant at both 24 and 48 weeks in the ibandronate group. There was no incident of fragility fracture in both groups during the study period. Safety profiles, including adverse events, were comparable between the 2 groups.ImplicationsMonthly oral ibandronate for 48 weeks is well tolerated and effective in reducing bone mineral loss in women with rheumatoid arthritis on long-term glucocorticoid therapy. Longer follow-up studies are needed to investigate the benefit of ibandronate on fracture rate reduction in this subset of patients. ClinicalTrials.gov identifier: NCT01287533.



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More Efficient Compliance with European Medicines Agency and Food and Drug Administration Regulations for Pediatric Oncology Drug Development: Problems and Solutions

Publication date: Available online 1 February 2017
Source:Clinical Therapeutics
Author(s): Christopher-Paul Milne
5w?>The morbidity and mortality toll of pediatric cancer affects the public health of children worldwide, but despite the gains in the fight against cancer, more progress needs to take place against this disease, which is a leading cause of death and chronic disability in children. In response, leading regulatory authorities in the developed world have been ratcheting up their efforts to induce the private sector to expand their research and development focus during drug development for adult cancers to include children. In mid-May 2016, the Center for the Study of Drug Development at Tufts University held a roundtable workshop on pediatric oncology to explore how companies could maximize the efficiency of pediatric assessment of adult cancer indications while minimizing resource expenditures to comply with regulatory requirements under the European Medicines Agency and the U.S. Food and Drug Administration. Although worldwide a child is diagnosed with cancer every 3 minutes, pediatric cancer is a rare disease, and trial participants are hard to come by. Thus, the market hardly sustains research and development expenses, advances in pharmacogenomics are not reaching down the age scale, and even in the public sector, basic research funding for pediatric cancer pales in comparison to the amount spent on cancer overall. The goal of the roundtable was to acknowledge these problems, and more importantly, to raise the level of awareness of potential solutions, including: more efficient use of the data hierarchy of informative events in clinical trials; new innovative clinical trial platforms for rapid assessment of new drugs in children; new developments in formulation technology; and optimization of speed in pediatric drug development through a multi-stakeholder network collaboration separate from the adult development plan.



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New Drugs for Rare Diseases in Children

Publication date: Available online 1 February 2017
Source:Clinical Therapeutics
Author(s): Klaus Rose
PurposeUnited States (US) Pediatric Legislation (PL) was introduced in 1997 to improve children's health. The European Union PL (EUPL) has been in force since 2007. Both PLs facilitate additional pediatric research on primarily adult drugs. The EUPL declares that the forces of the market are not sufficient for children. Without a pediatric investigation plan, new drugs can no longer be registered with the European Union. New ways on how to facilitate drug development for rare pediatric diseases are being proposed.MethodsUS PL, EUPL, and implications of modern labels for medical decision making are discussed.FindingsModern drug labels constituted a step from eminence-based towards data-based medical decision making. However, approval by regulatory authorities did not replace knowledge transfer in medicine, which continued in university education, through conferences, consensus papers, and so on. Children were successfully treated with off-label drugs in pediatric oncology and in many other diseases. Describing children as "therapeutic orphans" reflected an overestimation of drug labels and an underestimation of nonregulatory systematic clinical testing. Therapeutic breakthroughs have occurred, for example, in acute myelogenous leukemia and cystic fibrosis. Rare diseases need new innovative drugs and therapeutic concepts for further breakthroughs.ImplicationsThe focus of PL on additional pediatric measures for predominantly adult new drugs reflects a tunnel view. Similar to the introduction of modern pharmaceutical legislation that triggered comparable laws in most countries worldwide after 1962, we currently need new worldwide steps to reward innovative treatment concepts for rare diseases—not against, but through the market. Created by philanthropy, parents, and other supporters, new therapeutic concepts should be rewarded upon meeting regulatory milestones. This market is limited today. It needs not only a boost by pioneers, but also acceptance, welcome, and re-thinking about drug development in academia, politics, and by the general public.



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The clinical effectiveness of individual behaviour change interventions to reduce risky sexual behaviour after a negative human immunodeficiency virus test in men who have sex with men: systematic and realist reviews and intervention development.

Behaviour change interventions can reduce HIV-risk-related behaviour but their UK applicability is uncertain. A candidate intervention was developed for UK use but would need testing in a trial.

http://ift.tt/2k099Y7

Benefits and Harms of Treating Blood Pressure in Older Adults: A Systematic Review and Meta-analysis [Internet].

Hypertension is a very common chronic illness in the United States and among Veterans. Use of antihypertensive medications can lower the risk of cardiovascular disease, cerebrovascular disease, renal disease, and death. The most beneficial blood pressure targets for patients of specific age groups, however, has been a topic of some debate and controversy, stemming from concerns that the ratio of benefit to harm of a given blood pressure level may vary with age. In 2014, the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (previously JNC-FG8, referred to in this report as JNC-BP) published new guidelines for the treatment of hypertension, as well as a new treatment goal for older individuals (over age 60) for systolic blood pressure (SBP) of

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Factors that influence variation in clinical decision-making about thrombolysis in the treatment of acute ischaemic stroke: results of a discrete choice experiment.

The study found several patient and clinician factors were associated with clinical decision-making about the offer of thrombolysis in the treatment of acute ischaemic stroke. For instance, clinicians were more likely to treat patients aged 85 years than patients aged 68 years; they were also more likely to offer thrombolysis to patients with severe stroke than to those with mild stroke. There was also evidence of significant heterogeneity among clinicians on some patient factors. The discrete choice experiment meant that only a subset of factors could be explored; those not explored require further research.

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Alexithymia and Plaque Psoriasis: Preliminary Investigation in a Clinical Sample of 250 Patients

Background/Aims: Psoriasis as a dermatological disorder has complex effects on mental health and the psychological status of the patient. Many authors proposed that assessing how psoriasis affects a patient's life is better than a body surface area measurement for delineating psoriasis severity. Alexithymia is a personality dimension characterized by difficulty identifying feelings, difficulty describing feelings, and externally oriented thinking observed in many clinical conditions, especially in psychosomatic disorders. This study aimed to determine the prevalence of alexithymia in patients with plaque psoriasis compared with healthy participants, while taking into consideration demographic and clinical variables. Methods: We enrolled 250 patients with chronic plaque psoriasis, naïve to any systemic treatment, and 215 healthy individuals. The 20-item Toronto Alexithymia Scale (TAS-20) was used to assess alexithymia. Data analysis was done. Results: The mean TAS score was 53.5 (±15.3) for the patient group and 45.1 (±10.8) for controls (p Conclusion: This study suggests that the assessment of alexithymia should be a part of the comprehensive care of patients with moderate to severe psoriasis. For this purpose, the TAS-20 is a useful and simple tool to be used in daily clinical practice.
Dermatology

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Study of Pembrolizumab (MK-3475) or Placebo With Chemoradiation in Participants With Locally Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-412/KEYNOTE-412)

Condition:   Head and Neck Neoplasms
Interventions:   Biological: Pembrolizumab;   Drug: Placebo;   Drug: Cisplatin;   Radiation: Accelerated Fractionation (AFX) Radiotherapy;   Radiation: Standard Fractionation (SFX) Radiotherapy
Sponsor:   Merck Sharp & Dohme Corp.
Not yet recruiting - verified February 2017

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Gain-of-function STAT1 mutations are associated with intracranial aneurysms

Publication date: Available online 2 February 2017
Source:Clinical Immunology
Author(s): Mete Dadak, Roland Jacobs, Jelena Skuljec, Adan Chari Jirmo, Özlem Yildiz, Frank Donnerstag, Niklas Thomas Baerlecken, Reinhold Ernst Schmidt, Heinrich Lanfermann, Thomas Skripuletz, Philipp Schwenkenbecher, Christoph Kleinschnitz, Hayrettin Tumani, Martin Stangel, Refik Pul
Chronic mucocutaneous candidiasis, characterized by persistent or recurrent fungal infections, represents the clinical hallmark in gain-of-function (GOF) signal transducer and activator of transcription 1 (STAT1) mutation carriers. Several cases of intracranial aneurysms have been reported in patients with GOF STAT1 mutation but the paucity of reported cases likely suggested this association still as serendipity. In order to endorse this association, we link the development of intracranial aneurysms with STAT1 GOF mutation by presenting the two different cases of a patient and her mother, and demonstrate upregulated phosphorylated STAT4 and IL-12 receptor β1 upon stimulation in patient's blood cells. We also detected increased transforming growth factor (TGF)-β type 2 receptor expression, particularly in CD14⁺ cells, and a slightly higher phosphorylation rate of SMAD3. In addition, the mother of the patient developed disseminated bacille Calmette-Guérin disease after vaccination, speculating that GOF STAT1 mutations may confer a predisposition to weakly virulent mycobacteria.



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Anti-BlyS antibody reduces the immune reaction against enzyme and enhances the efficacy of enzyme replacement therapy in Fabry disease model mice

Publication date: Available online 2 February 2017
Source:Clinical Immunology
Author(s): Yohei Sato, Hiroyuki Ida, Toya Ohashi
Formation of antibodies against a therapeutic enzyme is an important complication during enzyme replacement therapy (ERT) for lysosomal storage diseases. Fabry disease (FD) is caused by a deficiency of alpha-galactosidase (GLA), which results in the accumulation of globotriaosylceramide (GL-3). We have shown immune tolerance induction (ITI) during ERT in FD model mice by using an anti-B lymphocyte stimulator (anti-BlyS) antibody (belimumab). A single dose of the anti-BlyS antibody temporarily lowered the percentage of B cells and IgG antibody titer against recombinant human GLA. Administration of a low maintenance dose of the anti-BlyS antibody suppressed the B cell population and immunotolerance was induced in 20% of mice, but antibody formation could not be prevented. We then increased the maintenance dose of the anti-BlyS antibody and immunotolerance was induced in 50% of mice. Therapeutic enzyme distribution and clearance of GL-3 were also enhanced by a high maintenance dose of the anti-BlyS antibody.



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A novel mutation in TAP1 gene leading to MHC class I deficiency: Report of two cases and review of the literature

Publication date: Available online 2 February 2017
Source:Clinical Immunology
Author(s): Damla Hanalioglu, Deniz Cagdas Ayvaz, Tuba Turul Ozgur, Mirjam van der Burg, Ozden Sanal, Ilhan Tezcan
Major histocompatibility complex (MHC) class I deficiency syndrome is a rare primary immunodeficiency caused by mutations in the peptide transporter complex associated with antigen presentation (TAP) gene which plays a crucial role in intracellular peptide antigen presentation. A few cases have been reported to date. Recurrent sinopulmonary infections and skin ulcers are main characteristics of the syndrome. Here we report two siblings diagnosed with TAP1 deficiency syndrome associated only with recurrent sinopulmonary infections with the description of a novel mutation leading to a premature stop codon in TAP1 gene and review of the relevant literature. Both of the siblings had recurrent sinopulmonary infections since childhood, responded to antibiotherapy well, neither of them had hospitalization history because of infections. One had chronic hepatitis B infection which may possibly be related to TAP1 gene defect.



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Contribution of MAML1 in esophageal squamous cell carcinoma tumorigenesis

Publication date: Available online 1 February 2017
Source:Annals of Diagnostic Pathology
Author(s): Mahnaz Hashemi Bidokhti, Mohammad Mahdi Forghanifard, Noorieh Sharifi, Soodabeh Abbasi Sani, Mohammad Reza Abbaszadegan
BackgroundNotch signaling pathway is involved in different cellular and developmental processes including cell proliferation, differentiation and apoptosis. Mastermind like1 (MAML1) is a critical key transcription coactivator of this pathway. In this study, we aimed to examine MAML1 protein expression in esophageal squamous cell carcinoma (ESCC) and reveal its association with clinicopathological variables of the patients.MethodsTumoral and their margin normal tissues from 56 ESCC patients were recruited for protein expression analysis using immunohistochemistry (IHC). Furthermore, MAML1 expression was analyzed in ESCC cell line KYSE-30 using immunocytochemistry.ResultsOverexpression of MAML1 was detected in 59% of tumor samples. It was significantly associated with different indices of poor prognosis including depth of tumor invasion (P=0.026), grade of tumor differentiation (P=0.002), stage of tumor progression (P=0.004) and sex (P=0.027).ConclusionBeside the appearing evidences explaining MAML1 role in different cellular processes and its deviations in different malignancies and also based on its correlation with different clinicopathological variables of ESCC, MAML1 can be proposed as potentially novel molecular marker for ESCC progression and tumorigenesis as well as therapeutic target to inhibit and reverse progression and development of the disease.



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Retroperitoneal lymphangioleiomyoma with lymph node involvement: A pathologic-radiologic correlation of a rare form of myomelanocytic tumor

Publication date: Available online 1 February 2017
Source:Annals of Diagnostic Pathology
Author(s): Amrou Abdelkader, Cesar A. Lam, Kaushik S. Shahir, Kathleen Christians, Saul M. Suster
Lymphangioleiomyomatosis (LAM) is a rare and slowly progressive disorder that usually arises in the lung, affects exclusively women in their childbearing years, and typically presents with progressive dyspnea on exertion and pneumothorax. Infrequently, extra-pulmonary LAM can occur in the retroperitoneum, uterine wall, mediastinum and intraperitoneal lymph nodes. Histologically, LAM is characterized by a proliferation of perivascular epithelioid cells (PEC) that express markers for both melanocytes and smooth muscle cells.We report a case of a peripancreatic retroperitoneal mass that was incidentally discovered on magnetic resonance image (MRI) scan of a 38-year-old female. The morphologic findings and the immunohistochemical staining were consistent with a lymphangioleiomyoma. The radiologic and pathologic correlation along with differential diagnosis of this rare entity is discussed.



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Patterns of care in adjuvant therapy for resected oral cavity squamous cell cancer in the elderly

Publication date: Available online 2 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Erqi L. Pollom, Alexander L. Chin, Nancy Y. Lee, C. Jillian Tsai
PurposeTo characterize the patterns of care and potential barriers to access to care for elderly oral cavity cancer patients in the adjuvant setting.Methods and MaterialsWe performed a retrospective cohort study using the National Cancer Data Base, and identified patients with resected oral cavity squamous cell carcinoma diagnosed between 2004 and 2012, who survived for at least 3 months after surgery. We used logistic regression models to assess the association between age (<70, 70-79, and ≥80 years) and the receipt of adjuvant therapy within 3 months of surgery. We additionally assessed the association between patient and tumor characteristics and the receipt of adjuvant therapy among those ≥70-years-old.ResultsA total of 25,829 patients were included in the study. Compared to those <70-years-old, older patients were more likely to have no neck dissection or fewer lymph nodes dissected, and were less likely to receive adjuvant therapy than younger patients. Of our cohort, 11,361 patients (44%) had pathologic T3/T4 or N2/N3 disease, and 4,185 patients (16%) had extracapsular nodal extension (ECE) or positive surgical margins. In multivariate analyses controlling for comorbidity and demographic characteristics, older age was independently associated with lower odds of receiving adjuvant radiation in the T3/T4 or N2/N3 subgroup and adjuvant chemoradiation in the positive ECE or positive surgical margin subgroup. Among elderly patients, both greater patient distance from reporting facility and older age were associated with lower odds of receiving both adjuvant radiation (0.66, 95% CI 0.55-0.81) and chemoradiation (0.56, 95% CI 0.40-0.79).ConclusionsIn a national hospital-based cohort of oral cavity cancer patients, elderly patients were less likely to receive adjuvant radiation or chemoradiation. Greater patient distance from reporting facility, in addition to older age, was associated with lower odds of receiving both adjuvant radiation and adjuvant chemoradiation.

Teaser

We compared patterns of adjuvant therapy in different patient age groups (<70, 70-79, and ≥80 years) with resected oral cavity squamous cell carcinoma using the National Cancer Data Base. Older patients were less likely to receive adjuvant therapy, even among those with pathologic T3/T4 or N2/N3 disease, extracapsular nodal extension, or positive margins. Both greater distance from reporting facility and older age were associated with lower odds of receiving adjuvant therapy.


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Clinical implementation of a model-based in vivo dose verification system for SBRT-VMAT treatments using the EPID

Publication date: Available online 2 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Peter M. McCowan, Ganiyu Asuni, Eric Van Uytven, Timothy VanBeek, Boyd M.C. McCurdy, Shaun K. Loewen, Naseer Ahmed, Bashir Bashir, James B. Butler, Amitava Chowdhury, Arbind Dubey, Ahmet Leylek, Maged Nashed
PurposeElectronic portal imaging devices (EPIDs) are available on all modern linear accelerators. A system has been developed that uses on-treatment EPID images to reconstruct the in vivo dose delivered to the patient. We report findings from our in vivo dosimetry program implemented for all SBRT patients over a 31 month period, and discuss the value and challenges of utilizing in vivo EPID dosimetry clinically.MethodsFrom December 2013 to July 2016, 117 SBRT-VMAT patients (100 lung, 15 spine, and 2 liver) underwent 602 EPID-based in vivo dose verification events. A developed model-based dose reconstruction algorithm calculates the 3D dose distribution to the patient by back-projecting the primary fluence measured by the EPID during treatment. The EPID frame-averaging was optimized in June 2015. For each treatment, a 3%/3mm gamma (γ) comparison between our EPID derived dose and the Eclipse AcurosXB predicted dose to the planning target volume (PTV) and the ≥20% isodose volume were performed. Alert-levels were defined as γ pass-rates <85% (lung and liver) and <80% (spine). Investigations were carried out for all fractions exceeding the alert-level and were classified as: EPID-related, algorithmic, patient setup, anatomical change, or unknown/unidentified errors.ResultsThe percentages of fractions exceeding the alert levels were 22.6% for lung before frame-average optimization and 8.0% for lung, 20.0% for spine, and 10.0% for liver after frame-average optimization. Overall, mean PTV γ pass-rates were 90.7% ± 9.2%, 87.0% ± 9.3%, and 91.2% ± 3.4% for the lung, spine, and liver patients respectively.ConclusionsResults from the clinical implementation of our model-based in vivo dose verification method using on-treatment EPID images is reported. The method is demonstrated to be valuable for routine clinical use for verifying delivered dose as well as detecting errors.

Teaser

The results of a 31 month clinical implementation of our model-based, 3D patient in vivo dose verification system for all fractions of SBRT-VMAT treatments are given. Alert-levels based on 3D γ pass-rates in the PTV and ≥20% dose volumes were used. Flagged fractions were investigated to determine the cause of the discrepancy.


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New urea-modified paper substrate for enhanced analytical performance of negative ion mode paper spray mass spectrometry

Publication date: 1 May 2017
Source:Talanta, Volume 166
Author(s): Jingjing Liu, Yan He, Shuo Chen, Ming Ma, Shouzuo Yao, Bo Chen
Electrospray ionization mass spectrometry (ESI-MS) analysis in the negative ion mode is adversely affected by ionization suppression caused by electrical discharge and the presence of salts. Paper spray mass spectrometry (PS-MS) also suffers from the above phenomenon, being built on principles similar to those of ESI. Herein, we report the use of a paper substrate modified by 1-[3-(trimethoxysilyl)propyl]urea to improve the sensitivity of quantitative PS-MS analysis in the negative ion mode. The obtained results demonstrated that the urea modified paper substrate can effectively bind anions and highly polar compounds in the sample solution, decreasing competitive ionization in the negative ion mode of PS-MS and significantly reducing the signal intensity of Cl⁻ adducts. In addition, the analyte responses were also significantly improved owing to the decreased electrical discharge observed for the less polar surface to decrease electrical discharge. Compared to non-modified PS-MS, urea-modified PS-MS exhibits a much higher sensitivity, showing 2−109 times improved signal-to-noise ratio (S/N). In real sample analysis, the limits of detection (LODs) of salicylic acid in urine and terpene lactones in Ginkgo biloba extract (EGb) were improved 10-fold and 2–40-fold, respectively, compared to that of non-modified PS-MS.

Graphical abstract

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Stable isotope labeling assisted liquid chromatography–tandem mass spectrometry for the analysis of perfluorinated carboxylic acids in serum samples

Publication date: 1 May 2017
Source:Talanta, Volume 166
Author(s): Shijuan Zhang, Zhongyin Ji, Zhiwei Sun, Mingshuang Li, Cuncun Sheng, Mingbo Yue, Yanxin Yu, Guang Chen, Jinmao You
A new stable isotope labeling (SIL) reagent pair, 10-methyl-acridone-2-sulfonohydrazide (MASH) and its deuterated counterpart d3-MASH was synthesized and successfully applied to the analysis of perfluorinated carboxylic acids (PFCAs) in serum samples. The limits of detection (LODs) were in the range of 0.07–0.42μg/L, and the limits of quantitation (LOQs) were in the range of 0.25–1.38μg/L. Besides ionization enhancing effect, MASH also showed excellent fluorescence property. Therefore, the mass spectrometer operation cost was greatly lowered by carrying out parameter optimization experiments on HPLC which is easier to operate and maintain. The SIL strategy was confirmed to be effective in reducing matrix effect. The developed multiple-reaction monitoring (MRM) condition of PFCAs was also suitable for other carboxylic acid due to the introduction of MASH which is more prone to fragmentation than the analytes. With the MRM conditions obtained from PFCAs, fatty acids were also found in serum samples. This feature made the proposed method show powerful potential in the identification of acidic compounds in complex samples in the absence of corresponding standard.

Graphical abstract

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Revealing the location of semen, vaginal fluid and urine in stained evidence through near infrared chemical imaging

Publication date: 1 May 2017
Source:Talanta, Volume 166
Author(s): Félix Zapata, Fernando E. Ortega-Ojeda, Carmen García-Ruiz
Crime scene investigation (CSI) requires the ultimate available technology for a rapid, non-destructive, and accurate detection of a wide variety of evidence including invisible stains of bodily fluids. Particularly crucial is the discrimination of semen in stained evidence from sexual abuse cases. This is because those evidence have high odds of containing the DNA from the aggressor. To this aim, we demonstrated the potential of near infrared hyperspectral imaging (NIR-HSI) to make visible stains of semen, vaginal fluid, and urine on fabrics, which lays the bases to face the challenging visualization and discrimination of semen within bodily fluids mixtures. Combining the NIR-HSI data and simple chemometric techniques such as principal component analysis and classical least squares regression, we have revealed the location of semen, vaginal fluid and urine in bodily fluids stained evidence.

Graphical abstract

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Preparation and evaluation of magnetic core-shell mesoporous molecularly imprinted polymers for selective adsorption of tetrabromobisphenol S

Publication date: 1 May 2017
Source:Talanta, Volume 166
Author(s): Xuemei Wang, Pengfei Huang, Xiaomin Ma, Huan Wang, Xiaoquan Lu, Xinzhen Du
Novel magnetic mesoporous molecularly imprinted polymers (MMIPs) with core-shell structure were prepared by simple surface molecular imprinting polymerization using tetrabromobisphenol-S (TBBPS) as the template. The MMIPs-TBBPS were characterized by fourier-transform infrared spectrometry (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 adsorption-desorption transmission, and vibrating sample magnetometry. The resultant MMIPs-TBBPS were successfully applied magnetic solid-phase extraction (MSPE) coupled with HPLC determination of TBBPS in spiked real water samples with recoveries of 77.8–88.9%. The adsorption experiments showed that the binding capacity of MMIPs-TBBPS to TBBPS and six structural analogs were significantly higher than that of the magnetic nonimprinted polymers (MNIPs). Meanwhile, the MMIPs-TBBPS possessed rapid binding affinity, excellent magnetic response, specific selectivity and high adsorption capacity toward TBBPS with a maximum adsorption capacity of 1626.8µgg⁻¹. The analytical results indicate that the MMIPs-TBBPS are promising materials for selective separation and fast enrichment of TBBPS from complicated enviromental samples.

Graphical abstract

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Microstructural and kinetic investigation on the suppression of grain growth in nanocrystalline copper by the dispersion of silicon carbide nanoparticles

Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): M.R. Akbarpour, M. Farvizi, H.S. Kim
In this paper, the thermal stability and grain growth kinetics of nanocrystalline Cu, reinforced with SiC nanoparticles and obtained using a mechanical milling process, were investigated during isothermal annealing. The presence of the nanoparticles in the nanocrystalline copper matrix resulted in a significant decrease in grain growth, the formation of partially textured microstructure and twin boundaries at higher temperatures, and an increase in the volume fraction of recrystallized grains, as estimated by grain orientation spread, in comparison to unreinforced Cu during annealing. The lower volume fraction of recrystallized grains at higher temperatures was attributed to dynamic recovery. Normal grain growth was observed in the annealing range of 400–600°C, and significant abnormal grain growth was observed at higher temperatures. An analysis of the grain growth kinetics in the temperature range of 400–600°C revealed a time exponent of n≈3.6 and activation energy of ≈34kJmol⁻¹, based on the parabolic equation. The calculated activation energy for grain growth in the SiC dispersion strengthened Cu was found to be less than that of nanocrystalline Cu. The low activation energy and high thermal stability were attributed to high lattice strain and the retarding effect of nanoparticles by the Zener mechanism.

Graphical abstract

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In situ deformation analysis of Mg in multilayer Mg-steel structures

Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): Alireza Sadeghi, Junya Inoue, Nobuhiko Kyokuta, Toshihiko Koseki
The deformation modes of Mg in a steel-Mg-steel multilayer composite were studied by step-by-step deformation and EBSD for the same region at 0, 20 and 30% deformation. Texture evolution was characterized using pole figures. The results indicate that the basal texture intensity significantly increases up to 20% deformation. However, from 20% to 30% deformation, activity of prismatic slip increases and the intensity of the overall basal texture is reduced. Shear stress and Schmid factor analysis of the multilayer system showed the probability of prismatic slip increases up to 35% by increasing the stress ratio up to 0.4 and decreases afterwards.

Graphical abstract

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J-integral for spallation of protective layer subjected to metal dusting corrosion

Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): Xiaobin Yang, Yiu-Wing Mai
The failure of high temperature alloys exposed to a carburizing gas atmosphere due to metal dusting corrosion was studied. A coupled model of the solid subjected to mechano-diffusional stresses was developed. For an interface crack between the protective film and the alloy substrate under an applied diffusion stress, the J-integral for film spallation was determined. The effects of interface crack length, film thickness and film mechanical properties on the J-integral (that is, the energy release rate) for spallation were investigated. Finally, comparisons of calculated J-integral values and experimental results are given and discussed.

Graphical abstract

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Effect of Cr and Al additions on the development of interphase-precipitated carbides strengthened dual-phase Ti-bearing steels

Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): Shao-Pu Tsai, Te-Cheng Su, Jer-Ren Yang, Chih-Yuan Chen, Yuan-Tsung Wang, Ching-Yuan Huang
The development of Ti-Cr-bearing hot-rolled dual-phase steel with an excellent combination of mechanical properties (yield strength of 655MPa, ultimate tensile strength of 911MPa, and elongation of 30%) has been achieved. Due to the significant strengthening obtained from interphase-precipitated nanometer-sized carbides in ferrite, this dual-phase steel has yield ratio of about 0.72, which is much higher than that of conventional dual-phase steels. Isothermal transformations on a dilatometer have been performed to investigate the effect of Cr and Al additions on austenite-to-ferrite transformation in Ti-based steels. It was found that an addition of 0.6wt.% Cr obviously retards the transformation rate of ferrite, as compared with an addition of 0.1wt.% Al. The results from dilatometry and transmission electron microscopy revealed that due to the lower transformation rate in Ti-Cr-bearing steel, a much higher density of nanometer-sized interphase-precipitated carbides in ferrite occurred during the isothermal holding at 650°C, leading to a significant increase in the strength of ferrite.

Graphical abstract

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The Preventive Effect of Coffee Compounds on Dermatitis and Epidermal Pigmentation after Ultraviolet Irradiation in Mice

Background: Ultraviolet (UV) irradiation is well known to promote inflammation and pigmentation of skin. UVB mainly affects dermatitis and pigmentation. Coffee contains a number of polyphenols, such as caffeic acid (CA) and chlorogenic acid (CGA) but their in vivo bioactivity for photobiology remains unclear. Methods: C57BL/6j male mice were irradiated with UVB (1.0 kJ/m²/day) for 3 days. Five days after the final session of UVB irradiation, the dorsal skin, ear epidermis, and blood samples were analyzed to investigate the inflammatory factors, melanogenesis factors and related hormones. Results: After the oral administration of CA (100 mg/day) or CGA (100 mg/day) for 8 days, only CA was found to inhibit dermatitis and pigmentation. The pathway by which CA inhibits dermatitis is related to the mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)1/2/cAMP response element binding protein (CREB) pathway. Otherwise, the pathway by which CA inhibits pigmentation is related to the activation of the β-endorphin-μ-opioid receptor and suppresses the cAMP-microphthalmia-associated transcription factor (MITF) pathway. Conclusion: It is suggested that the oral administration of CA prevented dermatitis and pigmentation after UVB irradiation in mice.
Skin Pharmacol Physiol 2017;30:24-35

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Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior

Publication date: 14 April 2017
Source:Behavioural Brain Research, Volume 323
Author(s): Brian A. Lloyd, Holly S. Hake, Takayuki Ishiwata, Caroline E. Farmer, Esteban C. Loetz, Monika Fleshner, Sondra T. Bland, Benjamin N. Greenwood
Exercise can enhance learning and memory and produce resistance against stress-related psychiatric disorders such as depression and anxiety. In rats, these beneficial effects of exercise occur regardless of exercise controllability: both voluntary and forced wheel running produce stress-protective effects. The mechanisms underlying these beneficial effects of exercise remain unknown. The mammalian target of rapamycin (mTOR) is a translation regulator important for cell growth, proliferation, and survival. mTOR has been implicated in enhancing learning and memory as well as antidepressant effects. Moreover, mTOR is sensitive to exercise signals such as metabolic factors. The effects of exercise on mTOR signaling, however, remain unknown. The goal of the present study was to test the hypothesis that exercise, regardless of controllability, increases levels of phosphorylated mTOR (p-mTOR) in brain regions important for learning and emotional behavior. Rats were exposed to 6 weeks of either sedentary (locked wheel), voluntary, or forced wheel running conditions. At 6 weeks, rats were sacrificed during peak running and levels of p-mTOR were measured using immunohistochemistry. Overall, both voluntary and forced exercise increased p-mTOR-positive neurons in the medial prefrontal cortex, striatum, hippocampus, hypothalamus, and amygdala compared to locked wheel controls. Exercise, regardless of controllability, also increased numbers of p-mTOR-positive glia in the striatum, hippocampus, and amygdala. For both neurons and glia, the largest increase in p-mTOR positive cells was observed after voluntary running, with forced exercise causing a more modest increase. Interestingly, voluntary exercise preferentially increased p-mTOR in astrocytes (GFAP+), while forced running increased p-mTOR in microglia (CD11+) in the inferior dentate gyrus. Results suggest that mTOR signaling is sensitive to exercise, but subtle differences exist depending on exercise controllability. Increases in mTOR signaling could contribute to the beneficial effects of exercise on cognitive function and mental health.



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Cognitive deficit in hippocampal-dependent tasks in Werner syndrome mouse model

Publication date: 14 April 2017
Source:Behavioural Brain Research, Volume 323
Author(s): Khaoula Rekik, Bernard Francés, Philippe Valet, Cédric Dray, Cédrick Florian
Mammalian aging is often characterized by metabolic disturbances, cognitive declines and DNA repairs deficiency, but the underlying molecular mechanisms are still not well understood. Alterations in DNA repair can significantly exacerbate aging. Mammalian neuronal cells which accumulate unrepaired DNA damage over time could potentially lead to brain functions disorders. Focusing on the ATP-dependent RecQ-type DNA helicase, an enzyme involved in repair of double strand DNA, a mouse model of Werner syndrome (WS) had been proposed as a model of accelerated aging. Until now, no study has investigated the impact of this premature aging syndrome on learning and memory. Spatial memory and cognitive flexibility are particularly affected by the aging process in both men and rodents. Studies have shown that aged mice exhibited similar performance than young adult mice on non-hippocampus dependent memory whereas their performances were decreased in hippocampus-dependent tasks. In this study, we have submitted 3, 5 and 8 month-old WS mice to several behavioral paradigms to evaluate hippocampus-dependent (spatial object location, Morris water maze and fear conditioning) and non hippocampus-dependent (object recognition) memories. No effect on the locomotion activity and anxiety level has been observed in adult WS mice. Interestingly, the 8 month-old WS mice exhibit long-term memory impairment similar to aged mice, suggesting that adult WS mice do develop some aspects of cognitive aging.



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Effects of adolescent methamphetamine and nicotine exposure on behavioral performance and MAP-2 immunoreactivity in the nucleus accumbens of adolescent mice

Publication date: 14 April 2017
Source:Behavioural Brain Research, Volume 323
Author(s): Jordan M. Buck, Alysse S. Morris, Sydney J. Weber, Jacob Raber, Jessica A. Siegel
The neurotoxic effects of methamphetamine (MA) exposure in the developing and adult brain can lead to behavioral alterations and cognitive deficits in adults. Previous increases in the rates of adolescent MA use necessitate that we understand the behavioral and cognitive effects of MA exposure during adolescence on the adolescent brain. Adolescents using MA exhibit high rates of nicotine (NIC) use, but the effects of concurrent MA and NIC in the adolescent brain have not been examined, and it is unknown if NIC mediates any of the effects of MA in the adolescent. In this study, the long-term effects of a neurotoxic dose of MA with or without NIC exposure during early adolescence (postnatal day 30–31) were examined later in adolescence (postnatal day 41–50) in male C57BL/6J mice. Effects on behavioral performance in the open field, Porsolt forced swim test, and conditioned place preference test, and cognitive performance in the novel object recognition test and Morris water maze were assessed. Additionally, the effects of MA and/or NIC on levels of microtubule associated-2 (MAP-2) protein in the nucleus accumbens and plasma corticosterone were examined. MA and NIC exposure during early adolescence separately decreased anxiety-like behavior in the open field test, which was not seen following co-administration of MA/NIC. There was no significant effect of early adolescent MA and/or NIC exposure on the intensity of MAP-2 immunoreactivity in the nucleus accumbens or on plasma corticosterone levels. These results show that early adolescent MA and NIC exposure separately decrease anxiety-like behavior in the open field, and that concurrent MA and NIC exposure does not induce the same behavioral change as either drug alone.



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Intra-fraction respiratory motion and baseline drift during breast Helical Tomotherapy

Publication date: January 2017
Source:Radiotherapy and Oncology, Volume 122, Issue 1
Author(s): Rosalinda Ricotti, Delia Ciardo, Giovanni Fattori, Maria Cristina Leonardi, Anna Morra, Samantha Dicuonzo, Damaris Patricia Rojas, Floriana Pansini, Raffaella Cambria, Federica Cattani, Chiara Gianoli, Chiara Spinelli, Marco Riboldi, Guido Baroni, Roberto Orecchia, Barbara Alicja Jereczek-Fossa
Background and purposeTo investigate the intra-fraction breast motion during long-lasting treatments of breast cancer with Helical Tomotherapy by means of an optical tracking system.Materials and methodsA set of seven radio-transparent passive markers was placed on the thoraco-abdominal surface of twenty breast cancer patients and tracked by an infrared tracking system. A continuous non-invasive monitoring of intra-fraction motion from patient setup verification and correction to the end of radiation delivery was thus obtained. The measured displacements were analysed in terms of cyclic respiratory motion and slow baseline drift.ResultsThe average monitoring time per patient was 15.57min. The breathing amplitude of the chest was less than 2mm, on average, along all anatomical directions. The baseline drift of the body led to more significant setup uncertainties than the respiratory motion. The main intra-fraction baseline drifts were in posterior and inferior directions and occurred within the first eight minutes of monitoring. Considering the intra-fraction motion only, the resultant clinical-to-planning target volume safety margins are highly patient-specific and largely anisotropic.ConclusionThe non-respiratory motion occurring during prolonged treatments induces notable uncertainties. Non-invasive continuous monitoring of patient setup variations including baseline drifts is recommended in order to minimize dosimetric deviations, which might jeopardize the therapeutic ratio between target coverage and the sparing of organs at risk.



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Editorial Board

Publication date: January 2017
Source:Radiotherapy and Oncology, Volume 122, Issue 1





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Contents

Publication date: January 2017
Source:Radiotherapy and Oncology, Volume 122, Issue 1





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Pediatric Sepsis Biomarker Risk Model-II: Redefining the Pediatric Sepsis Biomarker Risk Model with Septic Shock Phenotype

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Ryan Anne Murphy




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Editorial Board

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2





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Activity-Related Symptom Exacerbations After Pediatric Concussion

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Christian David Magallanes




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Issue Highlights

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2





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Contents

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2





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Observed Long-Term Mortality after 18,000 Person-Years among Survivors in a Large Regional Drowning Registry

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Chelsea McCullough




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Partial Contents of Volume 52, Number 3

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2





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Cecal Perforation Associated with Clostridium difficile Infection: A Case Report

Publication date: Available online 2 February 2017
Source:The Journal of Emergency Medicine
Author(s): Sarah Kyuragi Luthe, Ryota Sato
BackgroundVarious complications are reported with Clostridium difficile infection (CDI), including fulminant CDI. Fulminant CDI is an underappreciated life-threatening condition associated with complications such as toxic megacolon and bowel perforation.Case ReportA 79-year-old woman presented to the Emergency Department with altered mental status. She was admitted and conservatively treated for a left thalamic hemorrhage. While hospitalized, she developed watery diarrhea due to Clostridium difficile. Although metronidazole was initiated, she developed altered mental status and septic shock. Abdominal x-ray study and computed tomography revealed a significantly dilatated colon and a massive pneumoperitoneum. She underwent subtotal colectomy with a 14-day course of intravenous meropenem.Why Should an Emergency Physician Be Aware of This?This case suggests that we must be aware of the complications that CDI may present and adequately consider surgical management because early diagnosis and surgical treatment is critical to reduce the mortality of fulminant CDI.



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Quantifying the Risk of Spinal Injury in Motor Vehicle Collisions According to Ambulatory Status: A Prospective Analytical Study

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Christopher Eric McCoy, Angelica Loza-Gomez, James Lee Puckett, Samantha Costantini, Patrick Penalosa, Craig Anderson, Carl Schultz
BackgroundThe association between ambulation at the scene of a motor vehicle collision (MVC) and spinal injury has never been quantified.ObjectiveTo evaluate the association between ambulation and spinal injury in patients involved in a MVC.MethodsProspective analytical-observational cohort study. Inclusion: patients sustaining traumatic injury in a MVC. Exclusion: < 18 years old, pregnancy. Primary outcome: spinal injury defined as injury to the cervical, thoracic, or lumbar spinal cord, bones, or ligaments. Secondary outcome: Injury resulting in neurological deficit, need for surgery, or death. A generalized linear model was used to evaluate the association between outcome and predictor variables. Risk ratios [RR] were reported with a point estimate and 95% confidence interval (CI). A two-tailed alpha of < 0.05 was the threshold for statistical significance.ResultsThere were 704 patients analyzed. Nonambulatory patients were 2.29 times more likely to sustain a spinal injury, compared to ambulatory patients (RR 2.29, 95% CI 1.34–3.91). Patients ≥ 65 years of age were 3.27 times more likely to sustain a spinal injury (RR 3.27, 95% CI 1.66–6.45). Patients with a Glasgow Coma Scale score ≤ 8 were 4.93 times more likely to sustain a spinal injury (RR 4.93, 95% CI 1.86–13.10).ConclusionIn this prospective analytical-observational study evaluating the association between ambulatory status and spinal injury in patients involved in MVCs, we observed that those patients who were nonambulatory were more than two times as likely to have a spinal injury compared to those patients who were ambulatory at the scene.



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Bystander Cricothyroidotomy with Household Devices- A Fresh Cadaveric Feasibility Study

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Ryan Anne Murphy




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Short ECG Segments Predict Defibrillation Outcome Using Quantitative Waveform Measures

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Christian David Magallanes




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Ventricular Fibrillation Waveform Measures and the Etiology of Cardiac Arrest

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Kimberly Hill




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American Academy of Emergency Medicine

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2





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Combination of Initial Neurologic Examination, Quantitative Brain Imaging and Electroencephalography to Predict Outcome After Cardiac Arrest

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Ryan Anne Murphy




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Public Opinion Regarding Whether Speaking With Patients About Firearms Is Appropriate: Results of a National Survey

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Chelsea McCullough




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Dynamic Prediction of Patient Outcomes During Ongoing Cardiopulmonary Resuscitation

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Chelsea McCullough




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Factors Associated with Failure of Emergency Department Management in Children with Acute Moderate or Severe Asthma: A Prospective, Multicenter, Cohort Study

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Christian David Magallanes




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Early Identification of Patients With Out-of-Hospital Cardiac Arrest With No Chance of Survival and Consideration for Organ Donation

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Kimberly Hill




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The Postcardiac Arrest Consult Team: Impact on Hospital Care Processes for Out-of-Hospital Cardiac Arrest Patients

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Kimberly Hill




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Hepatic Artery Rupture in a Young Man with Abdominal Pain and a Testicular Mass

Publication date: February 2017
Source:The Journal of Emergency Medicine, Volume 52, Issue 2
Author(s): Kevin S. Barlotta, David Page
BackgroundMale patients presenting to the emergency department (ED) with abdominal pain accompanied by a testicular mass should be evaluated for the presence of hernia, epididymitis, orchitis, and testicular torsion. When a patient presents with an asymptomatic testicular nodule or mass, the emergency physician should consider testicular carcinoma, a diagnosis that typically warrants no more than prompt urologic outpatient referral.Case ReportWe present a case involving a young male whose presenting complaint was abdominal pain. Despite his reluctance to initially discuss any genitourinary (GU) complaints, careful questioning and thorough examination revealed a large left testicular mass. Despite having a benign abdomen, the patient experienced a rapid clinical deterioration in the ED after a previously undiagnosed metastatic lesion to his liver eroded into his hepatic artery.Why Should an Emergency Physician Be Aware of This?This case highlights the importance of performing a GU examination in all patients presenting with abdominal pain and discusses a rare presentation of a relatively common male condition. We also discuss the prioritization of emergent interventions and diagnostic studies specific to this case.



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Agnosic vision is like peripheral vision, which is limited by crowding

Publication date: Available online 1 February 2017
Source:Cortex
Author(s): Francesca Strappini, Denis G. Pelli, Enrico Di Pace, Marialuisa Martelli
Visual agnosia is a neuropsychological impairment of visual object recognition despite near-normal acuity and visual fields. A century of research has provided only a rudimentary account of the functional damage underlying this deficit. We find that the object-recognition ability of agnosic patients viewing an object directly is like that of normally-sighted observers viewing it indirectly, with peripheral vision. Thus, agnosic vision is like peripheral vision. We obtained 14 visual-object-recognition tests that are commonly used for diagnosis of visual agnosia. Our "standard" normal observer took these tests at various eccentricities in his periphery. Analyzing the published data of 32 apperceptive agnosia patients and a group of 14 Posterior Cortical Atrophy (PCA) patients on these tests, we find that each patient's pattern of object recognition deficits is well characterized by one number, the equivalent eccentricity at which our standard observer's peripheral vision is like the central vision of the agnosic patient. In other words, each agnosic patient's equivalent eccentricity is conserved across tests. Across patients, equivalent eccentricity ranges from 4 to 40 deg, which rates severity of the visual deficit.In normal peripheral vision, the required size to perceive a simple image (e.g. an isolated letter) is limited by acuity, and that for a complex image (e.g. a face or a word) is limited by crowding. In crowding, adjacent simple objects appear unrecognizably jumbled unless their spacing exceeds the crowding distance, which grows linearly with eccentricity. Besides conservation of equivalent eccentricity across object-recognition tests, we also find conservation, from eccentricity to agnosia, of the relative susceptibility of recognition of ten visual tests. These findings show that agnosic vision is like eccentric vision.Whence crowding? Peripheral vision, strabismic amblyopia, and possibly apperceptive agnosia are all limited by crowding, making it urgent to know what drives crowding. Acuity does not (Song et al., 2014), but neural density might: neurons per deg² in the crowding-relevant cortical area.



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