Synthesis and structure-activity relationship of teixobactin analogues via convergent Ser ligation

Publication date: Available online 29 April 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Kang Jin, Kathy Hiu Laam Po, Shengxi Wang, Jonathan Avraham Reuven, Chi Nga Wai, Ho Ting Lau, Ting Ho Chan, Sheng Chen, Xuechen Li
Convergent Ser/Thr ligation has been used to prepare a series of teixobactin analogues (28 in total) to establish a structure-activity relationship of teixobactin. Anti-bacterial evaluations of these synthetic analogues have revealed the critical amino acid residues and the sites tolerable of modifications. These studies will shed lights on the further development of teixobactin analogues with improved antibacterial activities.

Graphical abstract

http://ift.tt/2oL5PGF

A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066

Publication date: Available online 30 April 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Claudia De Fusco, Paul Brear, Jessica Iegre, Kathy Hadje Georgiou, Hannah F. Sore, Marko Hyvönen, David R. Spring
Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool. The work described herein shows potential for the development of a novel class of CK2 inhibitors.

Graphical abstract

http://ift.tt/2oLl1E1

Zinc Complex of Tryptophan Appended 1,4,7,10-Tetraazacyclododecane as Potential Anticancer Agent: Synthesis and Evaluation

Publication date: Available online 29 April 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Anupriya Adhikari, Neelam Kumari, Manish Adhikari, Nitin Kumar, Anjani K Tiwari, Abha Shukla, Anil K Mishra, Anupama Datta
With the rising incidences of cancer cases, the quest for new metal based anticancer drugs has led to extensive research in cancer biology. Zinc complexes of amino acid residue side chains are well recognized for hydrolysis of phosphodiester bond in DNA at faster rate. In the presented work, a Zn(II) complex of cyclen substituted with two L-tryptophan units, Zn(II)-Cyclen-(Trp)2 has been synthesized and evaluated for antiproliferative activity. Zn(II)-Cyclen-(Trp)2 was synthesized in ∼70% yield and its DNA binding potential was evaluated through QM/MM study which suggested good binding (G = -9.426) with B-DNA. The decrease in intensity of the positive and negative bands of CT-DNA at 278 nm and 240 nm, respectively demonstrated an effective unwinding of the DNA helix with loss of helicity. The complex was identified as an antiproliferative agent against U-87 MG cells with 5 fold increase in apoptosis with respect to control (2 h post incubation, IC50 25 µM). Electrophoresis and comet assay studies exhibited an increase in DNA breakage after treatment with complex while caspase-3/ β-actin cleavage established a caspase-3 dependent apoptosis pathway in U-87 MG cells after triggering DNA damage. In vivo tumor specificity of the developed ligand was validated after radiocomplexation with ^99mTc (>98% radiochemical yield and specific activity of 2.56 GBq/µmol). Avid tumor/muscle ratio of >6 was depicted in biodistribution and SPECT imaging studies in U-87 MG xenograft model nude mice.

Graphical abstract

http://ift.tt/2ptVcFH

Effect of replacing main-chain ureas with thiourea and guanidinium surrogates on the bactericidal activity of membrane active oligourea foldamers

Publication date: Available online 29 April 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Stéphanie Antunes, Jean-Philippe Corre, Guillain Mikaty, Céline Douat, Pierre L. Goossens, Gilles Guichard
Membrane-active foldamers have recently emerged as potential mimics of antimicrobial peptides (AMPs). Amphiphilic cationic helical N,N'-linked oligoureas are one such class of AMP mimics with activities in vitro against a broad range of bacteria including Bacillus anthracis, a Gram-positive sporulating bacillus and causing agent of anthrax. Here we have used site-selective chemical modifications of the oligourea backbone to gain additional insight into the relationship between structure and function and modulate anthracidal activity. A series of analogues in which urea linkages at selected positions are replaced by thiourea and guanidium surrogates have been prepared on solid support and tested against different bacterial forms of B. anthracis (germinated spores and encapsulated bacilli). Urea→thiourea and urea→guanidinium replacements close to the negative end of the helix dipole led to analogues with increased potency and selectivity for B. anthracis versus mammalian cells

Graphical abstract

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Synthesis and anticancer activity evaluation of novel aza-artemisinin derivatives

Publication date: Available online 30 April 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sampad Jana, Shabina Iram, Joice Thomas, Sandra Liekens, Wim Dehaen
Three series of aza-artemisinin derivatives were synthesized for studies of anticancer activity. The first series of compounds were prepared via copper(I)-catalyzed azide alkyne cycloaddition, so called "click reaction", starting from propargyl derivatives of 11-aza-artemisinin and various azides, whereas the second and third series of compounds were prepared by triazolization reaction starting from enolizable ketones and primary amines connected to artemisinin. In vitro studies of the 23 synthesized artemisinin derivatives unveiled that 9 compounds displayed antiproliferative activity in the low micromolar range, with 5d being the most promising compound showing 50% inhibition of Cem and HeLa cell growth at 0.92 and 1.2 µM, respectively.

Graphical abstract

http://ift.tt/2ptIFli

Lipase-catalyzed kinetic resolution as key step in the synthesis of enantiomerically pure σ ligands with 2-benzopyran structure

Publication date: Available online 30 April 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Inga Knappmann, Kirstin Lehmkuhl, Jens Köhler, Dirk Schepmann, Martin Giera, Franz Bracher, Bernhard Wünsch
In order to obtain enantiomerically pure σ1 receptor ligands with a 2-benzopyran scaffold an Oxa-Pictet-Spengler reaction with the enantiomerically pure 2-phenylethanol derivatives (R)-4 and (S)-4 was envisaged. The kinetic resolution of racemic alcohol (±)-4 using Amano Lipase PS-C II and isopropenyl acetate in tert-butyl methyl ether led to the (R)-configured alcohol (R)-4 in 42% yield with an enantiomeric excess of 99.6%. The (S)-configured alcohol (S)-4 was obtained by Amano Lipase PS-C II catalyzed hydrolysis of enantiomerically enriched acetate (S)-5 (76.9% ee) and provided (S)-4 in 26% yield and 99.7% ee. The absolute configuration of alcohol (R)-4 was determined by exciton coupled CD spectroscopy of the bis(bromobenzoate) (R)-7. The next important step for the synthesis of 2-benzopyrans 2 and 3 was the Oxa-Pictet-Spengler reaction of the enantiomerically pure alcohols (R)-4 and (S)-4 with piperidone ketal 8 and chloropropionaldehyde acetal 12. The conformationally restricted spirocyclic 2-benzopyrans 2 revealed higher σ1 affinity than the more flexible aminoethyl derivatives 3. The (R)- and (R,R)-configured enantiomers (R)-2 and (R,R)-3 represent the eutomers of this class of compounds with eudismic ratios of 4.8 (2b) and 4.5 (2c). High σ1/σ2 selectivity (>49) was found for the most potent σ1 ligands (R)-2b, (R)-2c, (R)-2d, and (S)-2d (Ki(σ1) 9-15 nM).

Graphical abstract

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Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11β hydroxysteroid dehydrogenase type 1 inhibitor

Publication date: Available online 29 April 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Linghang Zhuang, Colin M. Tice, Zhenrong Xu, Wei Zhao, Salvacion Cacatian, Yuan-Jie Ye, Suresh B. Singh, Peter Lindblom, Brian M. McKeever, Paula M. Krosky, Yi Zhao, Deepak Lala, Barbara A. Kruk, Shi Meng, Lamont Howard, Judith A. Johnson, Yuri Bukhtiyarov, Reshma Panemangalore, Joan Guo, Rong Guo, Frank Himmelsbach, Bradford Hamilton, Annette Schuler-Metz, Heike Schauerte, Richard Gregg, Gerard M. McGeehan, Katerina Leftheris, David A. Claremon
A potent, in vivo efficacious 11β hydroxysteroid dehydrogenase type 1 (11β HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11β HSD1 activity in human adipocytes with an IC50 of 4.3 nM and in primary human adipose tissue with an IC80 of 53 nM. Oral administration of 11j to cynomolgus monkey inhibited 11β HSD1 activity in adipose tissue. Compound 11j exhibited > 1000x selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.

Graphical abstract

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O-GlcNAc modification inhibits the calpain-mediated cleavage of α-synuclein

Publication date: Available online 29 April 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Paul M. Levine, Cesar A. De Leon, Ana Galesic, Aaron Balana, Nicholas P. Marotta, Yuka E. Lewis, Matthew R. Pratt
The major protein associated with Parkinson's disease (PD) is α-synuclein, as it can form toxic amyloid-aggregates that are a hallmark of many neurodegenerative diseases. α-Synuclein is a substrate for several different posttranslational modifications (PTMs) that have the potential to affect its biological functions and/or aggregation. However, the biophysical effects of many of these modifications remain to be established. One such modification is the addition of the monosaccharide N-acetyl-glucosamine, O-GlcNAc, which has been found on several α-synuclein serine and threonine residues in vivo. We have previously used synthetic protein chemistry to generate α-synuclein bearing two of these physiologically relevant O-GlcNAcylation events at threonine 72 and serine 87 and demonstrated that both of these modifications inhibit α-synuclein aggregation. Here, we use the same synthetic protein methodology to demonstrate that these same O-GlcNAc modifications also inhibit the cleavage of α-synuclein by the protease calpain. This further supports a role for O-GlcNAcylation in the modulation of α-synuclein biology, as proteolysis has been shown to potentially affect both protein aggregation and degradation.

Graphical abstract

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Optimal needle length for epinephrine prefilled syringe in children

Publication date: Available online 29 April 2017
Source:Annals of Allergy, Asthma & Immunology
Author(s): Wiparat Manuyakorn, Buntita Bamrungchaowkasem, Nichanan Ruangwattanapaisarn, Wasu Kamchaisatian, Suwat Benjaponpitak




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Successful management of hereditary angioedema during pregnancy in a patient with heterozygous MTHFR mutation

Publication date: Available online 29 April 2017
Source:Annals of Allergy, Asthma & Immunology
Author(s): Inmaculada Martinez Saguer, Carmen Escuriola Ettingshausen




http://ift.tt/2oUjbMi

Orofacial electromyographic correlates of induced verbal rumination

Publication date: Available online 30 April 2017
Source:Biological Psychology
Author(s): Ladislas Nalborczyk, Marcela Perrone-Bertolotti, Céline Baeyens, Romain Grandchamp, Mircea Polosan, Elsa Spinelli, Ernst H.W. Koster, Hélène Lœvenbruck
Rumination is predominantly experienced in the form of repetitive verbal thoughts. Verbal rumination is a particular case of inner speech. According to the Motor Simulation view, inner speech is a kind of motor action, recruiting the speech motor system. In this framework, we predicted an increase in speech muscle activity during rumination as compared to rest. We also predicted increased forehead activity, associated with anxiety during rumination. We measured electromyographic activity over the orbicularis oris superior and inferior, frontalis and flexor carpi radialis muscles. Results showed increased lip and forehead activity after rumination induction compared to an initial relaxed state, together with increased self-reported levels of rumination. Moreover, our data suggest that orofacial relaxation is more effective in reducing rumination than non-orofacial relaxation. Altogether, these results support the hypothesis that verbal rumination involves the speech motor system, and provide a promising psychophysiological index to assess the presence of verbal rumination.



http://ift.tt/2qkJBsd

Diagnostic potential of NETosis-derived products for disease activity, atherosclerosis and therapeutic effectiveness in Rheumatoid Arthritis patients

Publication date: Available online 29 April 2017
Source:Journal of Autoimmunity
Author(s): C. Pérez-Sánchez, P. Ruiz-Limón, M.A. Aguirre, Y. Jiménez-Gómez, I. Arias-de la Rosa, M.C. Ábalos-Aguilera, A. Rodriguez-Ariza, M.C. Castro-Villegas, R. Ortega-Castro, P. Segui, C. Martinez, R. Gonzalez-Conejero, S. Rodríguez-López, J.A. Gonzalez-Reyes, J.M. Villalba, E. Collantes-Estévez, A. Escudero, N. Barbarroja, Ch. López-Pedrera
Objectives1) To assess the association of NETosis and NETosis-derived products with the activity of the disease and the development of cardiovascular disease in RA; 2) To evaluate the involvement of NETosis on the effects of biologic therapies such as anti-TNF alpha (Infliximab) and anti-IL6R drugs (Tocilizumab).MethodsOne hundred and six RA patients and 40 healthy donors were evaluated for the occurrence of NETosis. Carotid-intimae media thickness was analyzed as early atherosclerosis marker. Inflammatory and oxidative stress mediators were quantified in plasma and neutrophils. Two additional cohorts of 75 RA patients, treated either with Infliximab (n = 55) or Tocilizumab (n = 20) for six months, were evaluated.ResultsNETosis was found increased in RA patients, beside myeloperoxidase and neutrophil elastase protein levels. Cell-free nucleosomes plasma levels were elevated, and strongly correlated with the activity of the disease and the positivity for autoantibodies, alongside inflammatory and oxidative profiles in plasma and neutrophils. Moreover, ROC analyses showed that cell-free nucleosomes levels could identify RA patients showing early atherosclerosis with high specificity.RA patients treated either with IFX or TCZ for six months exhibited decreased generation of NETs. Concomitantly, clinical parameters and serum markers of inflammation were found reduced. Mechanistic in vitro analyses showed that inhibition of NETs extrusion by either DNase, IFX or TCZ, further abridged the endothelial dysfunction and the activation of immune cells, thus influencing the global activity of the vascular system.ConclusionsNETosis-derived products may have diagnostic potential for disease activity and atherosclerosis, as well as for the assessment of therapeutic effectiveness in RA.



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NAD+ dependent deacetylase Sirtuin 5 rescues the innate inflammatory response of endotoxin tolerant macrophages by promoting acetylation of p65

Publication date: Available online 29 April 2017
Source:Journal of Autoimmunity
Author(s): Kewei Qin, Chaofeng Han, Hua Zhang, Tianliang Li, Nan Li, Xuetao Cao
The induction and persistence of a hypo-inflammatory and immunosuppressive state in severe sepsis is commonly associated with increased risks of secondary infections and mortality. Toll-like receptor (TLR)-triggered inflammatory response of macrophages/monocytes plays an important role in determining the outcome of hyper-inflammation during the acute phase and the hypo-inflammation during immunosuppressive phase of sepsis. However, the mechanisms for controlling hypo-inflammatory response in endotoxin tolerant macrophages remain to be fully understood. Considering that metabolic control of inflammation is an emerging field and the balance between AMP/ATP and oxidized NAD⁺/reduced NADH is associated with inflammation and metabolism, we analyzed the level of NAD⁺ in TLR-triggered innate inflammatory response, and found that the decreased level of NAD⁺ was significantly related to the increased inflammatory cytokine production both in vivo and in vitro. By screening the expression and function of NAD⁺ dependent type III deacetylase Sirtuin family members, we found that SIRT5 and SIRT1/2 had opposite expression patterns and functions in macrophages. SIRT5 deficiency decreased TLR-triggered inflammation in both acute and immunosuppressive phases of sepsis. Interestingly, cytoplasmic SIRT5 counteracted the inhibitory effects of SIRT2 and enhanced the innate inflammatory responses in macrophages and even in endotoxin-tolerant macrophages by promoting acetylation of p65 and activation of NF-κB pathway. Mechanistically, SIRT5 competed with SIRT2 to interact with NF-κB p65, in a deacetylase activity-independent way, to block the deacetylation of p65 by SIRT2, which consequently led to increased acetylation of p65 and the activation of NF-κB pathway and its downstream cytokines. Our study discovered the new functions of different Sirtuin members in sepsis, indicating that targeting of Sirtuin family members at different sepsis phases can be helpful to precisely control the progression of sepsis.



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No outcome disparities in patients with diffuse large B-cell lymphoma and a low socioeconomic status

Publication date: June 2017
Source:Cancer Epidemiology, Volume 48
Author(s): Karin Boslooper, Mels Hoogendoorn, Eric N. van Roon, Robby E. Kibbelaar, Huib Storm, Sjoerd Hovenga, Gerhard Woolthuis, Bas P. van Rees, Bart Klijs, Nic J.G.M. Veeger, Hanneke C. Kluin-Nelemans, Geertruida H. de Bock
IntroductionIn patients with diffuse large B-cell lymphoma (DLBCL) socioeconomic status (SES) is associated with outcome in several population-based studies. The aim of this study was to further investigate the existence of disparities in treatment and survival.MethodsA population-based cohort study was performed including 343 consecutive patients with DLBCL, diagnosed between 2005 and 2012, in the North-west of the Netherlands. SES was based on the socioeconomic position within the Netherlands by use of postal code and categorized as low, intermediate or high. With multivariable logistic regression and Cox proportional hazard models the association between SES and respectively treatment and overall survival (OS) was evaluated.ResultsTwo-third of patients was positioned in low SES. Irrespective of SES an equal proportion of patients received standard immunochemotherapy. SES was not a significant risk indicator for OS (intermediate versus low SES: hazard ratio (HR) 1.31 (95%CI 0.78–2.18); high versus low SES: HR 0.83 (95%CI 0.48–1.46)). The mortality risk remained significantly increased with higher age, advanced performance status, elevated LDH and presence of comorbidity.ConclusionWithin the setting of free access to health care, in this cohort of patients with DLBCL no disparities in treatment and survival were seen in those with lower SES.



http://ift.tt/2oKZnj1

Nonalcoholic fatty liver disease and mortality among cancer survivors

Publication date: June 2017
Source:Cancer Epidemiology, Volume 48
Author(s): Justin C. Brown, Michael O. Harhay, Meera N. Harhay
BackgroundNonalcoholic fatty liver disease (NAFLD) may foster a tumor microenvironment that promotes cancer recurrence and progression. We examined the relationship between NAFLD and mortality among a sample of cancer survivors.MethodsUltrasonography was used to assess hepatic steatosis, and standardized algorithms were used to define NAFLD. Study endpoints included all-cause, cancer-specific, and cardiovascular-specific mortality.ResultsAmong 387 cancer survivors, 17.6% had NAFLD. During a median of 17.9 years of follow up, we observed 196 deaths from all causes. In multivariable-adjusted regression models, NAFLD was associated with an increased risk of all-cause mortality [HR: 2.52, 95% CI: 1.47–4.34; P=0.001]. We observed 86 cancer-specific deaths. In multivariable-adjusted regression models, NAFLD was associated with an increased risk of cancer-specific mortality [HR: 3.21, 95% CI: 1.46–7.07; P=0.004]. We observed 46 cardiovascular-specific deaths. In multivariable-adjusted regression models, NAFLD was not associated with an increased risk of cardiovascular-specific mortality [HR: 1.04, 95% CI: 0.30–3.64, P=0.951].ConclusionNAFLD is associated with an increased risk of all-cause and cancer-specific mortality among cancer survivors. This novel observation warrants replication. Evaluating the efficacy of interventions, such as lifestyle modification through weight loss and exercise, to improve NAFLD in this population may be considered.



http://ift.tt/2qkpJ8B

Modulation of protein synthesis and degradation maintains proteostasis during yeast growth at different temperatures

Publication date: Available online 29 April 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Marta Benet, Ana Miguel, Fany Carrasco, Tianlu Li, Jordi Planells, Paula Alepuz, Vicente Tordera, José E. Pérez-Ortín
To understand how cells regulate each step in the flow of gene expression is one of the most fundamental goals in molecular biology. In this work, we have investigated several protein turnover-related steps in the context of gene expression regulation in response to changes in external temperature in model yeast Saccharomyces cerevisiae. We have found that the regulation of protein homeostasis is stricter than mRNA homeostasis. Although global translation and protein degradation rates are found to increase with temperature, the increase of the catalytic activity of ribosomes is higher than the global translation rate suggesting that yeast cells adapt the amount of translational machinery to the constraints imposed by kinetics in order to minimize energy costs. Even though the transcriptional machinery is subjected to the same constraints, we observed interesting differences between transcription and translation, which may be related to the different energy costs of the two processes as well as the differential functions of mRNAs and proteins.



http://ift.tt/2pibVNm

The Effect of Ventilating Tubes in Young Children with Recurrent Acute Otitis Media: an Update of the Literature

Abstract

Purpose of Review

Ventilating tube treatment (VT) is a common surgical procedure in preschool children. Twenty to fifty percent of children treated with VT suffer from recurrent acute otitis media (RAOM). The aim of this review is to update current knowledge on the topic.

Recent Findings

There is still controversy regarding the use of VT for children with RAOM. So far, only six randomized trials have been published. From the limited data pool, it seems that children with RAOM treated with VT experienced less time with acute otitis media and experienced less recurrence compared to controls. However, no difference in quality of life was found between subgroups in one trial.

Summary

Children with RAOM seem to benefit from VT on objective parameters, especially if middle ear effusion is present in between acute episodes. There is a need for more high quality evidence on the subjective domains such as disease severity and quality of life.

http://ift.tt/2qrjyPB

Guidelines for the Treatment of Acute Otitis Media: Why Are There Worldwide Differences?

Abstract

Purpose of Review

This study aims to review differences between acute otitis media (AOM) diagnosis and treatment guidelines from different countries, with regards to the aspects of diagnostic criteria and methods, supplementary tests, treatment options, recommended first-, second-, and third-line antibiotics, non-antibiotic treatment options, and preventive means and measures.

Recent Findings

Tympanic membrane (TM) bulging, opacity, and presence of middle ear fluid are the pillars for diagnosis, as marginal/uncertain cases are not accepted anymore. Guidelines from developed countries offer the use of pneumatic otoscopy and tympanometry to aid diagnosis. Withholding antibiotic therapy and a "watchful waiting" in mild-moderate cases are preferred in settings where follow-up visits are both possible and attainable, mostly in developed countries. While amoxicillin is mostly accepted as the first-line antibiotic therapy, options for second- and third-line antibiotics vary, according to local bacteriology and antimicrobial susceptibility data and costs. Other treatments, such as complementary and alternative medicine, steroids, or anti-histamines, are either rejected or ignored. Reduction of known risk factors and call for vaccinations (influenza, pneumococcal conjugate vaccine) are encouraged mostly in developed countries, where such immunizations have been implemented in National Immunization Programs.

Summary

Despite regional differences, AOM guidelines worldwide share common grounds on various matters concerning diagnosis and management: diagnosis based on TM findings observed on otoscopy and/or pneumatic otoscopy or tympanometry, "watchful waiting" approach in appropriate cases, oral analgesic treatment using ibuprofen/paracetamol, reduction of risk factors, and preventive measures to reduce AOM.

http://ift.tt/2oKL51Z

The Effect of Ventilating Tubes in Young Children with Recurrent Acute Otitis Media: an Update of the Literature

Abstract

Purpose of Review

Ventilating tube treatment (VT) is a common surgical procedure in preschool children. Twenty to fifty percent of children treated with VT suffer from recurrent acute otitis media (RAOM). The aim of this review is to update current knowledge on the topic.

Recent Findings

There is still controversy regarding the use of VT for children with RAOM. So far, only six randomized trials have been published. From the limited data pool, it seems that children with RAOM treated with VT experienced less time with acute otitis media and experienced less recurrence compared to controls. However, no difference in quality of life was found between subgroups in one trial.

Summary

Children with RAOM seem to benefit from VT on objective parameters, especially if middle ear effusion is present in between acute episodes. There is a need for more high quality evidence on the subjective domains such as disease severity and quality of life.

http://ift.tt/2qrjyPB

Guidelines for the Treatment of Acute Otitis Media: Why Are There Worldwide Differences?

Abstract

Purpose of Review

This study aims to review differences between acute otitis media (AOM) diagnosis and treatment guidelines from different countries, with regards to the aspects of diagnostic criteria and methods, supplementary tests, treatment options, recommended first-, second-, and third-line antibiotics, non-antibiotic treatment options, and preventive means and measures.

Recent Findings

Tympanic membrane (TM) bulging, opacity, and presence of middle ear fluid are the pillars for diagnosis, as marginal/uncertain cases are not accepted anymore. Guidelines from developed countries offer the use of pneumatic otoscopy and tympanometry to aid diagnosis. Withholding antibiotic therapy and a "watchful waiting" in mild-moderate cases are preferred in settings where follow-up visits are both possible and attainable, mostly in developed countries. While amoxicillin is mostly accepted as the first-line antibiotic therapy, options for second- and third-line antibiotics vary, according to local bacteriology and antimicrobial susceptibility data and costs. Other treatments, such as complementary and alternative medicine, steroids, or anti-histamines, are either rejected or ignored. Reduction of known risk factors and call for vaccinations (influenza, pneumococcal conjugate vaccine) are encouraged mostly in developed countries, where such immunizations have been implemented in National Immunization Programs.

Summary

Despite regional differences, AOM guidelines worldwide share common grounds on various matters concerning diagnosis and management: diagnosis based on TM findings observed on otoscopy and/or pneumatic otoscopy or tympanometry, "watchful waiting" approach in appropriate cases, oral analgesic treatment using ibuprofen/paracetamol, reduction of risk factors, and preventive measures to reduce AOM.

http://ift.tt/2oKL51Z

GPER1/GPR30 in the brain: Crosstalk with classical estrogen receptors and implications for behavior

Publication date: Available online 29 April 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Maria M. Hadjimarkou, Nandini Vasudevan
The GPER1/GPR30 is a membrane estrogen receptor (mER) that binds 17β-estradiol (17β-E) with high affinity and is thought to play a role in cancer progression and cardiovascular health. Though widespread in the central nervous system, less is known about this receptor's function in the brain. GPER1 has been shown to activate kinase cascades and calcium flux within cells rapidly, thus fitting in with the idea of being a mER that mediates non-genomic signaling by estrogens. Signaling from GPER1 has been shown to improve spatial memory, possibly via release of neurotransmitters and generation of new spines on neurons in the hippocampus. In addition, GPER1 activation contributes to behaviors that denote anxiety and to social behaviors such as social memory and lordosis behavior in mice. In the male hippocampus, GPER1 activation has also been shown to phosphorylate the classical intracellular estrogen receptor (ER)α, suggesting that crosstalk with ERα is important in the display of these behaviors, many of which are absent in ERα-null mice. In this review, we present a number of categories of such crosstalk, using examples from literature. The function of GPER1 as an ERα collaborator or as a mER in different tissues is relevant to understanding both normal physiology and abnormal pathology, mediated by estrogen signaling.



http://ift.tt/2qr5xkK

What New Research Says about Mitochondrial Function and Movement Disorders – An Update

Mitochondria are organelles present in all the cells in our body except red blood cells. These mitochondria are the units of the cell that are responsible for creating 90 percent of the energy we need to ...

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Comparing sprint and endurance training on anxiety, depression and its relation with brain-derived neurotrophic factor in rats

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Hossein TaheriChadorneshin, Sadegh Cheragh-Birjandi, Saeed Ramezani, Seyed-Hosein Abtahi-Eivary
Although the response of brain-derived neurotrophic factor (BDNF) has been shown to low intensity exercise training, but the effect of intensive exercise training is not clear. Also, there is insufficient information about relationship between BDNF and depression and anxiety following intensive exercise. This study aimed to investigate the effects of 6 weeks of intensive endurance training (ET) and sprint interval training (SIT) on brain BDNF and its relationship with anxiety and depression in Albino Wistar rats. Anxiety and depression of rats were measured by elevated plus maze (EPM) and tail suspension test (TST), respectively. All data were analyzed using one-way ANOVA and Pearson's correlation coefficient at P<0.05 level. Both SIT and ET regimens increased BDNF content in the brain, and the alterations made were greater following SIT than ET. Also, both SIT and ET regimens increased number of entries and the time spent in the open arm significantly in EPM, with a higher elevation following SIT than ET. In addition, both SIT and ET regimens decreased number and duration of immobility significantly in TST, with a higher reduction following SIT than ET. Furthermore, BDNF content correlated positively with number of entries and the time spent in the open arm in EPM and negatively with number and duration of immobility in TST. Collectively, sprint interval training regimen, rather than intensive endurance training regimen, is highly potential to improve anxiety and depression through a greater increase in BDNF contents in brain.



http://ift.tt/2oTRt21

Neural impact of low-level alcohol use on response inhibition: An fMRI investigation in young adults

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Taylor Hatchard, Ola Mioduszewski, Carley Fall, Aziza Byron-Alhassan, Peter Fried, Andra M. Smith
It is widely known that alcohol consumption adversely affects human health, particularly in the immature developing brains of adolescents and young adults, which may also have a long-lasting impact on executive functioning. The present study investigated the neural activity of 28 young adults from the Ottawa Prenatal Prospective Study (OPPS) using functional magnetic resonance imaging (fMRI). The purpose of this study was to discover the impact of regular low-level alcohol consumption on response inhibition as the participants performed a Go/No-Go task. Results indicated that, despite a lack of performance differences, young adults who use alcohol on a regular basis differ significantly from those who do not use alcohol regularly (if at all) with respect to their neural activity as the circuitry engaged in response inhibition is being challenged. Specifically, areas that showed significantly more activation in users compared to controls included the left hippocampus, parahippocampal gyrus, superior frontal gyrus, precentral gyrus, right superior parietal lobule, and the cerebellum. These results suggest that even in low amounts, regular consumption of alcohol may have a significant impact on neurophysiological functioning during response inhibition in the developing brain of youth.



http://ift.tt/2pwlVDq

Blockade of muscarinic acetylcholine receptors in the ventral tegmental area blocks the acquisition of reward-related learning

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): E. Galaj, R. Nisanov, R. Ranaldi
In the present study we investigated whether stimulation of muscarinic acetylcholine (mACh) receptors in the ventral tegmental area (VTA) plays a role in the acquisition of food-based conditioned approach learning. Rats were exposed to 3 (in Experiment 1) or 7 (in Experiment 2) conditioning sessions in which 30, randomly presented light (CS) presentations were paired with delivery of food pellets (US), followed by one session with no light or food and finally one CS-only test session with only light stimulus presentations. Bilateral microinjections of scopolamine (a mACh receptor antagonist) were made either prior to each conditioning session (Experiment 1; to test effects on acquisition) or prior to the CS-only test (Experiment 2; to test effects on performance of the learned response). Scopolamine produced a dose-related significant reduction in the acquisition of conditioned approach but had no effect on its performance. These results suggest that mACh receptor stimulation in the VTA plays a necessary role in the acquisition of reward-related learning.



http://ift.tt/2oTCoh4

The brain and the subjective experience of time. A voxel based symptom-lesion mapping study

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Luigi Trojano, Michelina Caccavale, Francesco De Bellis, Claudio Crisci
The aim of the study was to identify the anatomical bases involved in the subjective experience of time, by means of a voxel based symptom-lesion mapping (VLSM) study on patients with focal brain damage. Thirty-three patients (nineteen with right-hemisphere lesions −RBD, and fourteen with left lesion- LBD) and twenty-eight non-neurological controls (NNC) underwent the semi-structured QUEstionnaire for the Subjective experience of Time (QUEST) requiring retrospective and prospective judgements on self-relevant time intervals. All participants also completed tests to assess general cognitive functioning and two questionnaires to evaluate their emotional state. Both groups of brain-damaged patients achieved significantly different scores from NNC on the time performance, without differences between RBD and LBD. VLSM showed a cluster of voxels located in the right inferior parietal lobule significantly related to errors in the prospective items. The lesion subtraction analysis revealed two different patterns possibly associated with errors in the prospective items (the right inferior parietal cortex, rolandic operculum and posterior middle temporal gyrus) and in the retrospective items (superior middle temporal gyrus, white matter posterior to the insula).



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The OXTR gene, implicit learning and social processing: Does empathy evolve from perceptual skills for details?

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Martin Melchers, Christian Montag, Sebastian Markett, Nawael Niazy, Johanna Groß-Bölting, Jelena Zimmermann, Martin Reuter
Oxytocin is an important messenger in the brain that has been linked to a variety of social functions in pharmacological studies. Besides, functional genetic variations on the oxytocin receptor gene have been repeatedly associated with social processing and functioning. Despite this knowledge, there are very few studies investigating the mechanisms that may explain the link between oxytocin and social functions. In the endeavor to fill this gap in the literature, the current study searches for associations between the prominent rs2268498 polymorphism on the oxytocin receptor gene and participants' ability to perceive and store implicit social information, which is a fundamental function in social information processing. N=121 healthy participants were experimentally tested with an implicit learning paradigm, answered questionnaires assessing empathy and autistic traits, and were genotyped for the rs2268498 polymorphism. T-allele carriers (TT and TC genotypes) exhibited significantly better implicit learning performance than carriers of the CC-genotype, and learning performance was positively associated with self-reported empathy and negatively with self-reported autistic traits. Results indicate that differences in implicit perception and storing of environmental details while watching social interactions could be an important mechanism to explain the association between differences in endogenous oxytocin activity and social functioning.



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The influence of stress on neuroinflammation and alterations in brain structure and function in major depressive disorder

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Yong-Ku Kim, Eunsoo Won
Major depressive disorder (MDD) is a condition which has often been associated with chronic stress. The sympathetic nervous system is continuously activated without the normal counteraction of the parasympathetic nervous system under the influence of chronic stress. As a result, epinephrine and norepinephrine levels are increased, and acetylcholine levels are decreased, which in turn can increase the levels of pro-inflammatory cytokines. Peripheral inflammatory responses can access the brain, with neuroinflammation contributing to the increase in neurotoxic kynurenine pathway metabolites such as 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid, and decrease in neuroprotective metabolites such as kynurenic acid. Pro-inflammatory cytokines can also exert direct neurotoxic effects on specific brain regions. Previous imaging studies have reported associations between pro-inflammatory states and alterations in brain regions involved in emotional regulation, including the hippocampus, amygdala and anterior cingulate cortex. Alterations in structure and function of such brain areas due to the neurotoxic effects of increased inflammation may be associated with the pathophysiology of depression. This review focuses the influence of stress on neuroinflammation which may cause alterations in brain structure and function in MDD.



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The blockage of ventromedial hypothalamus CRF type 2 receptors impairs escape responses in the elevated T-maze

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Mariana S.C.F. Silva, Thaissa M.O. Souza, Bruno A. Pereira, Daniel A. Ribeiro, Isabel C. Céspedes, Jackson C. Bittencourt, Milena B. Viana
In a previous study, the administration of corticotrophin-releasing factor (CRF) into the dorsomedial hypothalamus (DMH), a region that modulates defensive reactions, was shown to facilitate elevated T-maze (ETM) avoidance responses, an anxiogenic-like effect. Intra-DMH administration of the CRF type 1 receptor (CRFR1) antagonist antalarmin induced anxiolytic-like effects and counteracted the anxiogenic effects of CRF. The present study further investigates the role played by CRF receptors of the medial hypothalamus in anxiety. For that, male wistar rats were treated with CRFR1 and CRFR2-modulating drugs in the DMH or VMH, another hypothalamic nucleus implicated with defensive and emotional behavior, and tested in the ETM for inhibitory avoidance and escape measurements. In clinical terms, these responses have been respectively related to generalized anxiety and panic disorder. All animals were tested in an open field, immediately after the ETM, for locomotor activity assessment. The results showed that intra-VMH CRF or antalarmin did not alter ETM avoidance or escape performance. Intra-VMH injection of the CRFR2 preferential antagonist antisauvagine-30 or of the selective CRFR2 antagonist astressin 2-B inhibited escape performance, a panicolytic-like effect, without altering avoidance reactions. The CRFR2 agonist urocortin-2 intra-VMH was by itself without effect but blocked the effects of astressin 2-B. None of the drugs administered into the DMH altered ETM measurements. Additionally, none of the compounds altered locomotor activity measurements. These results suggest that VMH CRFR2 modulate a defensive response associated with panic disorder and are of relevance to the better understanding of the neural mechanisms underlying this pathological condition.



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The effect of regulatory mode on procrastination: Bi-stable parahippocampus connectivity with dorsal anterior cingulate and anterior prefrontal cortex

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Chenyan Zhang, Yan Ni, Tingyong Feng
Previous research has elucidated that procrastination can be influenced by regulatory mode orientations. However, the neural mechanism of regulatory modes affecting procrastination is not well understood. To address this question, we employed resting-state functional magnetic resonance imaging (RS-fMRI) to test the influence of two regulatory modes (assessment and locomotion) on procrastination. The behavioral results showed that procrastination was positively correlated with assessment orientation but negatively correlated with locomotion orientation. Neuroimaging results indicated that the functional connectivity between parahippocampal cortex (PHC) and dorsal anterior cingulate (dACC) was negatively correlated with assessment scores, while the functional connectivity between anterior prefrontal cortex (aPFC) and parahippocampal cortex (PHC) was negatively correlated with locomotion scores. Critically, mediation analysis showed that the different effects of two distinct regulatory modes on procrastination were mediated by PHC-dACC and aPFC-PHC functional connectivity respectively. These results suggested that people's procrastination could be predicted by regulatory mode orientations, which is mediated by PHC connectivity with dACC and aPFC respectively. The present study extends our knowledge on procrastination and provides neural mechanism for understanding the link between regulatory mode orientations and procrastination.



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EMG biofeedback training in adult attention-deficit/hyperactivity disorder: An active (control) training?

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Beatrix Barth, Kerstin Mayer, Ute Strehl, Andreas J. Fallgatter, Ann-Christine Ehlis
ObjectiveThe present study aimed at revealing neurophysiological effects induced by electromyography (EMG) based biofeedback, considered as a semi-active control condition in neurofeedback studies, in adult attention-deficit/hyperactivity disorder (ADHD) patients.Methods20 adult ADHD patients trained their muscle activity in the left and right supraspinatus muscle over the course of 30 EMG biofeedback sessions. Changes induced by the EMG feedback were evaluated at a clinical and neurophysiological level; additionally, the relation between changes in EEG activity recorded at the vertex over the training course and changes of symptom severity over the treatment course were assessed in order to investigate the mechanisms underlying clinical effects of EMG biofeedback.ResultsParticipants showed significant behavioral improvements on a self-rating scale. There was a significant increase in alpha power, but no significant changes in the delta frequency range; changes in the theta and beta frequency range were not significant after adjustment for multiple comparisons. No statistically significant correlation was found between changes in EEG frequency bands and changes in ADHD symptoms.ConclusionsThe current results assessed by means of a single-electrode EEG constitute a starting point regarding a clearer understanding of mechanisms underlying clinical effects of EMG biofeedback. Although we did not reveal systematic effects induced by EMG feedback on brain activity it remains an open question whether EMG biofeedback induces changes in brain regions or parameters we did not gather in the present study (e.g. motor cortex).



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dl-3-n-butylphthalide promotes neuroplasticity and motor recovery in stroke rats

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Yefei Sun, Xi Cheng, Huibin Wang, Xiaopeng Mu, Yifan Liang, YuJia Luo, Huiling Qu, Chuansheng Zhao
Backgrounds and aimsRacemic l-3-n-butylphthalide (dl-NBP), is able to achieve a functional recovery in animal models of cerebral ischemia, vascular dementia, and Alzheimer's disease. In this study, we investigated the effect of dl-NBP on axonal growth, neurogenesis and behavioral performances in rats with cerebral ischemia.MethodsFocal cerebral ischemia in rats was produced by intracerebral injection of endothelin-1. Starting from postoperative day 7, the experimental rats were administered 70mg/kg dl-NBP by oral gavage for two weeks. Biotinylated dextran amine (BDA) was injected into the contralateral sensorimotor cortex on day 14 after ischemia to trace the sprouting of corticospinal tract (CST) fibers into the denervated cervical spinal cord. The expressions of Nogo-A, Nogo-R, Rho-A, and ROCK in the perilesional cortex, the expressions of BDA, PSD-95, and vGlut1 in the denervated spinal cord, 5-bromo-20-deoxyuridine (BrdU)/DCX-positive cells in the subventricular zone (SVZ) of the injured hemisphere were detected by immunofluorescence. The rats' behavioral abilities were measured on postoperative days 30–32 in the beam-walking, cylinder and sticky label tests.Resultsdl-NBP treatment significantly increased the number and length of crossing CST fibers, enhanced significantly the expression levels of synapse-associated proteins including PSD95 and VGlut-1 in the denervated cervical spinal cord, elevated the number of BrdU+/DCX+ cells in SVZ, and reduced markedly those of Rho-A+, ROCK+, Nogo-A+ and Nogo-R+ cells in perilesional cortex. In addition, dl-NBP improved the behavioral performance of the ischemic rats.Conclusiondl-NBP enhanced the behavioral recovery after cerebral ischemia in rats, possibly by increasing axonal growth and neurogenesis.



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Time-dependent sensitization of antipsychotic effect in adolescent male and female rats

Publication date: 15 June 2017
Source:Behavioural Brain Research, Volume 328
Author(s): Xiaojing Ding, Xiaonan Li, Qing Shu, Ruiyong Wu, Gang Hu, Ming Li
Many behavioral and biological effects of a psychoactive drug often undergo time-dependent change following even one single drug exposure. The present study examined whether one or two exposures of haloperidol, olanzapine or clozapine would also induce a time-dependent change in their behavioral effects in adolescent rats, and whether such a change vary between sexes. Adolescent Sprague-Dawley rats (<40days old) were first treated with one single injection of haloperidol (0.05 and 0.1mg/kg, sc), clozapine (10.0 and 20.0mg/kg, sc), 2 injections of olanzapine (1.0 and 2.0mg/kg, sc) or vehicle, and tested in a conditioned avoidance response (CAR) model or a PCP (3.20mg/kg, sc)-induced hyperlocomotion model to assess the drug's antipsychotic-like behavioral effects. One or three weeks later, rats were challenged with the drug and their avoidance responses and the PCP-induced hyperlocomotion were re-assessed. One-trial haloperidol and 2-trial olanzapine induced a sensitization, while 1-trial clozapine induced a tolerance effect. The 1-trial haloperidol sensitization was significantly higher at the 3-week time point than at 1-week point, especially in the females. Clozapine tolerance in the conditioned avoidance response model also exhibited the time-dependent increase in both sex groups. Olanzapine sensitization in the PCP model showed a time-dependent change in a sex-dependent fashion. Overall, the time-dependent antipsychotic sensitization and tolerance can be demonstrated in adolescent animals. Many pharmacological (e.g. specific drugs, drug doses), individual (e.g. male versus female) and environmental (e.g. specific behavioral models) factors play a role in the modulation of the strength of antipsychotic sensitization and tolerance.



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The lateral hypothalamus to lateral habenula projection, but not the ventral pallidum to lateral habenula projection, regulates voluntary ethanol consumption

Publication date: 15 June 2017
Source:Behavioural Brain Research, Volume 328
Author(s): Chandni Sheth, Teri M. Furlong, Kristen A. Keefe, Sharif A. Taha
The lateral habenula (LHb) is an epithalamic brain region implicated in aversive processing via negative modulation of midbrain dopamine (DA) and serotonin (5-HT) systems. Given the role of the LHb in inhibiting DA and 5-HT systems, it is thought to be involved in various psychiatric pathologies, including drug addiction. In support, it has been shown that LHb plays a critical role in cocaine- and ethanol-related behaviors, most likely by mediating drug-induced aversive conditioning. In our previous work, we showed that LHb lesions increased voluntary ethanol consumption and operant ethanol self-administration and blocked yohimbine-induced reinstatement of ethanol self-administration. LHb lesions also attenuated ethanol-induced conditioned taste aversion suggesting that a mechanism for the increased intake of ethanol may be reduced aversion learning. However, whether afferents to the LHb are required for mediating effects of the LHb on these behaviors remained to be investigated. Our present results show that lesioning the fiber bundle carrying afferent inputs to the LHb, the stria medullaris (SM), increases voluntary ethanol consumption, suggesting that afferent structures projecting to the LHb are important for mediating ethanol-directed behaviors. We then chose two afferent structures as the focus of our investigation. We specifically studied the role of the inputs from the lateral hypothalamus (LH) and ventral pallidum (VP) to the LHb in ethanol-directed behaviors. Our results show that the LH-LHb projection is necessary for regulating voluntary ethanol consumption. These results are an important first step towards understanding the functional role of afferents to LHb with regard to ethanol consumption.

Graphical abstract

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An online tool that provides access to evidence-based literature on dental restorations: www.crownorfill.com

Publication date: Available online 29 April 2017
Source:The Journal of Prosthetic Dentistry
Author(s): Kelvin I. Afrashtehfar, Faleh Tamimi




http://ift.tt/2qjVoaa

Void and gap evaluation using microcomputed tomography of different fiber post cementation techniques

Publication date: Available online 29 April 2017
Source:The Journal of Prosthetic Dentistry
Author(s): Eduardo A. Caceres, Camila S. Sampaio, Pablo J. Atria, Helora Moura, Marcelo Giannini, Paulo G. Coelho, Ronaldo Hirata
Statement of problemFew studies have investigated the voids and gaps produced during the cementation of fiber posts using different techniques.PurposeThe purpose of this study was to evaluate and quantify void and gap area formations of different fiber post cementation techniques using microcomputed tomography (μCT).Material and methodsStandardized endodontically treated acrylic resin roots (N=24) were divided into 4 groups (n=6) according to different fiber posts cemented with the resin cement (FB); fiber posts relined with composite resin followed by cementation (FBR); fiber posts cemented using an ultrasonic device (FBU); and fiber posts relined with composite resin and cemented using an ultrasonic device (FBRU). Each specimen was scanned twice using micro-computed tomography (μCT; empty root, followed by after fiber post cementation). Digital imaging and communications in medicine (DICOM) files were transferred into 3-dimensional (3D) reconstruction software for analysis. Void volume in the cementation system and gap area formation were evaluated; quantitative and qualitative analyses were performed. The data were analyzed using 2-way ANOVA and the Tukey honest significant difference post hoc test (α=.05).ResultsFBR showed a lower percentage of voids than obtained for FB (P<.05). Groups FB, FBU, and FBRU did not show significant difference in void formation (P>.05). No significant differences were found in gap area formations among the experimental groups (P>.05).ConclusionsThe use of a composite resin to reline the fiber post significantly decreased the void formation in the cementation procedure when no ultrasonic device was used. The use of an ultrasonic device did not decrease the percentage of void or gap formation for any technique evaluated.



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Evaluation of the marginal fit of CAD-CAM zirconia copings: Comparison of 2D and 3D measurement methods

Publication date: Available online 29 April 2017
Source:The Journal of Prosthetic Dentistry
Author(s): Philippe Boitelle, Laurent Tapie, Bernardin Mawussi, Olivier Fromentin
PurposeThe purpose of this in vitro study was to compare the marginal fit of zirconia copings by using 2 different measurement methods: a triple optical scan method and a silicone replica method.Material and methodsSixty zirconia copings fabricated by computer-aided design and computer-aided manufacture (CAD-CAM) systems were studied for the marginal fit. For the replica method, the thickness of the light-body silicone layer of the discrepancy was assessed using light microscopy and image analysis software. The triple-scan optical method was performed to obtain a digital three-dimensional map of the marginal fit and analyzed marginal fit measurement values. For each method, the reliability of the measurement was tested, and a nonparametric analysis was then performed to compare the marginal fit values as measured by the 2 evaluation methods (α=.05).ResultsIntraclass correlation coefficients and repeatability coefficients revealed good repeatability for both of the evaluation methods. However, the triple-scan method produced a smaller marginal fit than the replica method (P<.001) for the entire group studied.ConclusionsAlthough both methods showed good repeatability, the triple-scan method was more reliable.



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Prosthetic rehabilitation following lateral resection of the mandible with a long cantilever implant-supported fixed prosthesis: A 3-year clinical report

Publication date: Available online 29 April 2017
Source:The Journal of Prosthetic Dentistry
Author(s): Georgios Maroulakos, William W. Nagy, Ayman Ahmed, Ioli I. Artopoulou
This clinical report describes the prosthetic management of the surgical reconstruction of a patient after mandibular resection. Complete oral rehabilitation was achieved with a maxillary complete denture and a mandibular implant-supported fixed prosthesis with a custom titanium framework and a long unilateral cantilever.



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Waste heaps left by historical Zn-Pb ore mining are hotspots of species diversity of beech forest understory vegetation

Publication date: 1 December 2017
Source:Science of The Total Environment, Volumes 599–600
Author(s): Marcin W. Woch, Anna M. Stefanowicz, Małgorzata Stanek
Metalliferous mining and smelting industries are associated with very high levels of heavy metal(loid) contamination of the environment. Heavy metals have been proved to significantly influence the species diversity and composition of grassland communities, but little is known on their effects on forest understory vegetation.Therefore, the aim of this study was to investigate the effects of the presence of small heaps of waste rock left by historical Zn-Pb ore mining on understory vegetation. The heaps are scattered over vast areas of beech forests in southern Poland. Three types of study plots were established: (1) on waste heaps themselves, (2) in their vicinity (5–10m from the foot of the heaps, with no waste rock but potentially influenced by the heaps through drainage water), and (3) at least 100m from the foot of the heaps (pseudo-control). In all plots vegetation parameters, i.e., plant species number, cover and community composition, life forms and strategies, as well as basic soil properties were assessed. Although the heaps contained high concentrations of metals, namely Cd, Pb and Zn, they were characterised by higher cover and diversity of understory vegetation, including ancient forest and endangered species, in comparison to their surroundings. They were also characterised by the distinct species composition of their plant communities. This might have resulted from the beneficial influence of high pH and Ca content originating from waste rock composed of dolomite and calcite, as well as from increased habitat heterogeneity, e.g. soil skeleton and steeper slopes. Another important factor influencing the richness and composition of understory was tree cover, which relates to the light transmissibility of the canopy. Our study proved that the disturbance brought about by the former mining and processing of metal ores led to the formation of species-rich understory with high frequency and cover of naturally-valuable species.

Graphical abstract

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Trace element concentrations along a gradient of urban pressure in forest and lawn soils of the Paris region (France)

Publication date: 15 November 2017
Source:Science of The Total Environment, Volume 598
Author(s): Ludovic Foti, Florence Dubs, Jacques Gignoux, Jean-Christophe Lata, Thomas Z. Lerch, Jérôme Mathieu, François Nold, Naoise Nunan, Xavier Raynaud, Luc Abbadie, Sébastien Barot
The concentration, degree of contamination and pollution of 7 trace elements (TEs) along an urban pressure gradient were measured in 180 lawn and wood soils of the Paris region (France). Iron (Fe), a major element, was used as reference element. Copper (Cu), cadmium (Cd), lead (Pb) and zinc (Zn) were of anthropogenic origin, while arsenic (As), chromium (Cr) and nickel (Ni) were of natural origin. Road traffic was identified as the main source of anthropogenic TEs. In addition, the industrial activity of the Paris region, especially cement plants, was identified as secondary source of Cd. Soil characteristics (such as texture, organic carbon (OC) and total nitrogen (tot N) contents) tell the story of the soil origins and legacies along the urban pressure gradient and often can explain TE concentrations. The history of the land-use types was identified as a factor that allowed understanding the contamination and pollution by TEs. Urban wood soils were found to be more contaminated and polluted than urban lawns, probably because woods are much older than lawns and because of the legacy of the historical management of soils in the Paris region (Haussmann period). Lawn soils are similar to the fertile agricultural soils and relatively recently (mostly from the 1950s onwards) imported from the surrounding of Paris, so that they may be less influenced by urban conditions in terms of TE concentrations. Urban wood soils are heavily polluted by Cd, posing a high risk to the biological communities. The concentration of anthropogenic TEs increased from the rural to the urban areas, and the concentrations of most anthropogenic TEs in urban areas were equivalent to or above the regulatory reference values, raising the question of longer-term monitoring.

Graphical abstract

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A porous Zn-based metal-organic framework for pH and temperature dual-responsive controlled drug release

Publication date: 1 September 2017
Source:Microporous and Mesoporous Materials, Volume 249
Author(s): Wenxin Lin, Quan Hu, Ke Jiang, Yuanjing Cui, Yu Yang, Guodong Qian
A porous metal-organic framework Zn-TBDA (TBDA = 4′-(1H-tetrazol-5-yl) -[1,1′-biphenyl]-3,5-dicarboxylic acid) with one-dimensional channels has been synthesized from zinc ions and bifunctional ligands. The negligible cytotoxicity of Zn-TBDA is confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay and microscopy observation. The anticancer drug methotrexate (MTX) is loaded into Zn-TBDA successfully via in-situ encapsulation and the loading capability reaches about 12.59 wt% in resulting composite MTX-encapsulated Zn-TBDA. Under different physiological microenvironments, MTX-encapsulated Zn-TBDA exhibits sensitive pH and temperature dual-responsive release manners, revealing its practical value as a smart drug carrier with controlled release in certain site and improved therapeutic efficacy without any additional external fields.

Graphical abstract

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Body composition estimation in children and adolescents by bioelectrical impedance analysis: A systematic review

Publication date: Available online 29 April 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): João Antônio Chula de Castro, Tiago Rodrigues de Lima, Diego Augusto Santos Silva
BackgroundBioelectrical impedance analysis (BIA) has commonly been used to assess the body composition of children and adolescents. BIA validation studies have found distinct correlation values with reference methods.ObjectivesTo assess the reproducibility, correlation and mean differences in body composition estimated by BIA and reference methods, we systematically reviewed the literature in the pediatric population.MethodThe search for articles was conducted in March 2016 and was limited to articles published from 2005 to 2015 in the PubMed, Embase, EBSCO, Web of Science, Scopus and SciELO databases. Two reviewers independently performed data selection and extraction of studies that investigated the BIA validity, responsiveness, reliability and/or measurement error (reproducibility) to estimate body composition in children and adolescents with an average age ≤ 18 years.ResultsThe search produced 48 articles. Almost perfect reproducibility was found in the body fat percentage estimated by BIA, and there was almost perfect correlation between the BIA ratings and reference methods for fat mass and fat-free mass. Regarding component estimates, BIA underestimated the fat mass in both sexes.ConclusionsThe body fat percentage estimated by BIA exhibited almost perfect reproducibility. The fat mass and fat-free mass estimated by BIA correlated almost perfectly with the reference methods in both sexes. BIA underestimated the fat mass in both sexes.



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APOE ε4 allele elevates the expressions of inflammatory factors and promotes Alzheimer’s disease progression: a comparative study based on Han and She populations in the Wenzhou area

Publication date: Available online 29 April 2017
Source:Brain Research Bulletin
Author(s): Yin-Ying Fan, Qiao-Le Cai, Zhi-Yong Gao, Xue Lin, Qi Huang, Wei Tang, Jia-Hong Liu
ObjectiveThis study aimed to investigate the impact of apolipoprotein E 4 (APOE4) gene polymorphisms on the expressions of inflammatory factors and the progression of Alzheimer's disease (AD).MethodsA total of 185 AD patients (the case group, 130 cases from the Han ethnic group and 55 cases from the She ethnic group) and 190 healthy individuals (the control group, 130 cases from the Han ethnic group and 60 cases from the She ethnic group) were recruited for our study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was conducted to detect APOE4 genotype and allele frequency. Enzyme-linked immunosorbent assay (ELISA) was used to determine the expressions of inflammatory factors in plasma.ResultsIn both Han and She populations, the frequency of ε3/4 and ε4/4 genotypes and the ε4 allele was significantly higher in the case group than that in the control group. ε3/4 and ε4/4 genotypes and the ε4 allele were the risk factors for AD. In both Han and She populations, the ε2/4, ε3/4 and ε4/4 carriers showed increased levels of TNF-α, IL-6, and IL-1β when compared with the ε2/2 + ε2/3 + ε3/3 carriers. The TNF-α, IL-6, and IL-1β levels were higher in the ε4/4 carriers than those in the ε2/4 and ε3/4 carriers, and ε2/4, ε3/4 and ε4/4 carriers in the case group exhibited increased levels of TNF-α, IL-6, and IL-1β when compared with the control group (P <0.05). Logistic regression analysis indicated that the ε3/4 genotype and TNF-α, IL-6, and IL-1β levels were associated with the susceptibility to AD in the Han population, while ε3/4 and ε4/4 genotypes and TNF-α, IL-6, and IL-1β levels were related to the susceptibility to AD in the She population.ConclusionsThe APOE4 ε4 allele may enhance susceptibility to AD and promotes the expressions of inflammatory factors in AD.



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ShapeCut: Bayesian Surface Estimation Using Shape-Driven Graph

Publication date: Available online 29 April 2017
Source:Medical Image Analysis
Author(s): Gopalkrishna Veni, Shireen Y. Elhabian, Ross T. Whitaker
A variety of medical image segmentation problems present significant technical challenges, including heterogeneous pixel intensities, noisy/ill-defined boundaries and irregular shapes with high variability. The strategy of estimating optimal segmentations within a statistical framework that combines image data with priors on anatomical structures promises to address some of these technical challenges. However, methods that rely on local optimization techniques and/or local shape penalties (e.g., smoothness) have been proven to be inadequate for many difficult segmentation problems. These challenging segmentation problems can benefit from the inclusion of global shape priors within a maximum-a-posteriori estimation framework, which biases solutions toward an object class of interest. In this paper, we propose a maximum-a-posteriori formulation that relies on a generative image model by incorporating both local and global shape priors. The proposed method relies on graph cuts as well as a new shape parameters estimation that provides a global updates-based optimization strategy. We demonstrate our approach on synthetic datasets as well as on the left atrial wall segmentation from late-gadolinium enhancement MRI, which has been shown to be effective for identifying myocardial fibrosis in the diagnosis of atrial fibrillation. Experimental results prove the effectiveness of the proposed approach in terms of the average surface distance between extracted surfaces and the corresponding ground-truth, as well as the clinical efficacy of the method in the identification of fibrosis and scars in the atrial wall.

Graphical abstract

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Effect of confounding variables on hemodynamic response function estimation using averaging and deconvolution analysis: An event-related NIRS study

Publication date: 15 July 2017
Source:NeuroImage, Volume 155
Author(s): Ardalan Aarabi, Victoria Osharina, Fabrice Wallois
Slow and rapid event-related designs are used in fMRI and functional near-infrared spectroscopy (fNIRS) experiments to temporally characterize the brain hemodynamic response to discrete events. Conventional averaging (CA) and the deconvolution method (DM) are the two techniques commonly used to estimate the Hemodynamic Response Function (HRF) profile in event-related designs. In this study, we conducted a series of simulations using synthetic and real NIRS data to examine the effect of the main confounding factors, including event sequence timing parameters, different types of noise, signal-to-noise ratio (SNR), temporal autocorrelation and temporal filtering on the performance of these techniques in slow and rapid event-related designs. We also compared systematic errors in the estimates of the fitted HRF amplitude, latency and duration for both techniques. We further compared the performance of deconvolution methods based on Finite Impulse Response (FIR) basis functions and gamma basis sets.Our results demonstrate that DM was much less sensitive to confounding factors than CA. Event timing was the main parameter largely affecting the accuracy of CA. In slow event-related designs, deconvolution methods provided similar results to those obtained by CA. In rapid event-related designs, our results showed that DM outperformed CA for all SNR, especially above -5 dB regardless of the event sequence timing and the dynamics of background NIRS activity. Our results also show that periodic low-frequency systemic hemodynamic fluctuations as well as phase-locked noise can markedly obscure hemodynamic evoked responses. Temporal autocorrelation also affected the performance of both techniques by inducing distortions in the time profile of the estimated hemodynamic response with inflated t-statistics, especially at low SNRs. We also found that high-pass temporal filtering could substantially affect the performance of both techniques by removing the low-frequency components of HRF profiles.Our results emphasize the importance of characterization of event timing, background noise and SNR when estimating HRF profiles using CA and DM in event-related designs.



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The cortical spatiotemporal correlate of otolith stimulation: Vestibular evoked potentials by body translations

Publication date: 15 July 2017
Source:NeuroImage, Volume 155
Author(s): M. Ertl, M. Moser, R. Boegle, J. Conrad, P. zu Eulenburg, M. Dieterich
The vestibular organ senses linear and rotational acceleration of the head during active and passive motion. These signals are necessary for bipedal locomotion, navigation, the coordination of eye and head movements in 3D space. The temporal dynamics of vestibular processing in cortical structures have hardly been studied in humans, let alone with natural stimulation.The aim was to investigate the cortical vestibular network related to natural otolith stimulation using a hexapod motion platform. We conducted two experiments, 1. to estimate the sources of the vestibular evoked potentials (VestEPs) by means of distributed source localization (n=49), and 2. to reveal modulations of the VestEPs through the underlying acceleration intensity (n=24). For both experiments subjects were accelerated along the main axis (left/right, up/down, fore/aft) while the EEG was recorded.We were able to identify five VestEPs (P1, N1, P2, N2, P3) with latencies between 38 and 461 ms as well as an evoked beta-band response peaking with a latency of 68 ms in all subjects and for all acceleration directions. Source localization gave the cingulate sulcus visual (CSv) area and the opercular-insular region as the main origin of the evoked potentials. No lateralization effects due to handedness could be observed. In the second experiment, area CSv was shown to be integral in the processing of acceleration intensities as sensed by the otolith organs, hinting at its potential role in ego-motion detection. These robust VestEPs could be used to investigate the mechanisms of inter-regional interaction in the natural context of vestibular processing and multisensory integration.



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Predictive validity of cannabis consumption measures: Results from a national longitudinal study

Publication date: October 2017
Source:Addictive Behaviors, Volume 73
Author(s): Anne Buu, Yi-Han Hu, Sanjana Pampati, Brooke J. Arterberry, Hsien-Chang Lin
BackgroundValidating the utility of cannabis consumption measures for predicting later cannabis related symptomatology or progression to cannabis use disorder (CUD) is crucial for prevention and intervention work that may use consumption measures for quick screening. This study examined whether cannabis use quantity and frequency predicted CUD symptom counts, progression to onset of CUD, and persistence of CUD.MethodsData from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) at Wave 1 (2001–2002) and Wave 2 (2004–2005) were used to identify three risk samples: (1) current cannabis users at Wave 1 who were at risk for having CUD symptoms at Wave 2; (2) current users without lifetime CUD who were at risk for incident CUD; and (3) current users with past-year CUD who were at risk for persistent CUD. Logistic regression and zero-inflated Poisson models were used to examine the longitudinal effect of cannabis consumption on CUD outcomes.ResultsHigher frequency of cannabis use predicted lower likelihood of being symptom-free but it did not predict the severity of CUD symptomatology. Higher frequency of cannabis use also predicted higher likelihood of progression to onset of CUD and persistence of CUD. Cannabis use quantity, however, did not predict any of the developmental stages of CUD symptomatology examined in this study.ConclusionsThis study has provided a new piece of evidence to support the predictive validity of cannabis use frequency based on national longitudinal data. The result supports the common practice of including frequency items in cannabis screening tools.



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Development of a financially viable model for the management of mandibular fractures as day cases in a level 1 major trauma centre

There is a subgroup of patients with mandibular fractures who could safely and effectively be managed in an outpatient day-care unit. Suitability depends on medical, social, and operative factors, and identification of the correct criteria will govern management after that in the emergency department. Reduced use of beds would lead to less money being spent on emergency treatment, and increased capacity for elective surgery. The aims of this study were to identify a group of patients with mandibular fractures whose duration of operation and period of recovery would be suitable for treatment in the day-care unit, and to evaluate the potential financial benefits.

http://ift.tt/2qjCyA7

Use of couplers for vascular anastomoses in 601 free flaps for reconstruction of defects of the head and neck: technique and two-year retrospective clinical study

We describe our experience with the use of 854 couplers for venous or arterial anastomoses, or both, in 601 free flaps for reconstruction of defects of the head and neck. We reviewed 601 patients who had had free flaps (with the microvascular anastomoses being made with couplers in 519) between July 2013 and December 2015. Personal details, and clinical data including the site of the defect, the tumour excised, the types of flaps, the size of the couplers, the method of anastomosis (venous or arterial) in which the coupler was used, and postoperative complications were recorded.

http://ift.tt/2phvlC6

Successful management of hereditary angioedema during pregnancy in a patient with heterozygous MTHFR mutation

Hereditary angioedema (HAE) caused by C1-esterase inhibitor (C1-INH) deficiency is a rare, autosomal dominant disorder. Type 1 HAE makes up 85% of cases and is caused by reduced circulating levels of C1-INH, whereas type 2 HAE is caused by dysfunctional circulating C1-INH despite normal levels.1 Symptoms of type 1 and 2 HAE may include abdominal symptoms and episodes of swelling of the face, genitalia, extremities, urinary tract, and upper airways. Angioedema of the upper airways is life-threatening and can lead to death by asphyxiation.

http://ift.tt/2oKjZIs

Optimal needle length for epinephrine prefilled syringe in children

Patients with a history of anaphylaxis have a strong indication for the use of epinephrine auto-injectors (EAIs).1 However, EAIs are available in only 59.1% of countries according to a recent report from the World Allergy Organization.2 Appropriate EAI needle length for delivering epinephrine into intramuscular tissues has been studied in adults3–5 and children.6–8 EAIs also require a pressure trigger for delivery of epinephrine, which compresses the subcutaneous tissues and thus shortens the skin-to-muscle depth (STMD).

http://ift.tt/2oWKiXP

Successful management of hereditary angioedema during pregnancy in a patient with heterozygous MTHFR mutation

Hereditary angioedema (HAE) caused by C1-esterase inhibitor (C1-INH) deficiency is a rare, autosomal dominant disorder. Type 1 HAE makes up 85% of cases and is caused by reduced circulating levels of C1-INH, whereas type 2 HAE is caused by dysfunctional circulating C1-INH despite normal levels.1 Symptoms of type 1 and 2 HAE may include abdominal symptoms and episodes of swelling of the face, genitalia, extremities, urinary tract, and upper airways. Angioedema of the upper airways is life-threatening and can lead to death by asphyxiation.

http://ift.tt/2oKjZIs

Optimal needle length for epinephrine prefilled syringe in children

Patients with a history of anaphylaxis have a strong indication for the use of epinephrine auto-injectors (EAIs).1 However, EAIs are available in only 59.1% of countries according to a recent report from the World Allergy Organization.2 Appropriate EAI needle length for delivering epinephrine into intramuscular tissues has been studied in adults3–5 and children.6–8 EAIs also require a pressure trigger for delivery of epinephrine, which compresses the subcutaneous tissues and thus shortens the skin-to-muscle depth (STMD).

http://ift.tt/2oWKiXP

Haplotypes of the RANK and OPG genes are associated with chronic arthralgia in individuals with and without temporomandibular disorders

The aim of this study was to evaluate the association between genetic polymorphisms and the comorbid presence of chronic systemic arthralgia in patients with articular temporomandibular disorders (TMD). Subjects were evaluated for the presence of TMD and asked about the presence of chronic joint pain. Four groups were included in the study: articular TMD and systemic arthralgia (n=85), no articular TMD and systemic arthralgia (n=82), articular TMD and no systemic arthralgia (n=21), no articular TMD and no systemic arthralgia (control, n=72).

http://ift.tt/2psGKOb

Characterization of high-resolution Gradient Echo and Spin Echo EPI for fMRI in the human visual cortex at 7T

Publication date: July 2017
Source:Magnetic Resonance Imaging, Volume 40
Author(s): Catarina Rua, Mauro Costagli, Mark R. Symms, Laura Biagi, Graziella Donatelli, Mirco Cosottini, Alberto Del Guerra, Michela Tosetti
The increased signal-to-noise ratio (SNR) offered by functional Magnetic Resonance Imaging (fMRI) at 7T allows the acquisition of functional data at sub-millimetric spatial resolutions. However, simply reducing partial volume effects is not sufficient to precisely localize task-induced activation due to the indirect mechanisms that relate brain function and the changes in the measured signal.In this work T2* and T2 weighted Echo Planar Imaging (EPI) schemes based on Gradient Recalled Echo (GRE) and Spin Echo (SE) were evaluated in terms of temporal SNR, percent signal change, contrast to noise ratio (CNR), activation volume, and sensitivity and specificity to gray matter. Datasets were acquired during visual stimulation at in-plane resolutions ranging between 1.5×1.5mm² and 0.75×0.75mm² targeting the early visual cortex.While similar activation foci were obtained in all acquisitions, at in-plane resolutions of 1.0×1.0mm² and larger voxel sizes the T2 weighted contrast of SE-EPI allowed the identification of the activation site with better spatial accuracy. However, at sub-millimetric resolutions the decrease in temporal SNR significantly hampered the sensitivity and the extent of the activation site. On the other hand, high resolution T2* weighted data collected with GRE-EPI provided higher CNR and sensitivity, benefiting from the decreased physiological and partial volume effects. However, spurious activations originating from regions of blood drainage were still present in GRE data, and simple thresholding techniques were found to be inadequate for the removal of such contributions. The combination of 2-class and 3-class automated segmentations, performed directly in EPI space, allowed the selection of active voxels in gray matter. This approach could enable GRE-EPI to accurately map functional activity with satisfactory CNR and specificity to the true site of activation.



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A Neural Model of Mind Wandering

Publication date: Available online 28 April 2017
Source:Trends in Cognitive Sciences
Author(s): Matthias Mittner, Guy E. Hawkins, Wouter Boekel, Birte U. Forstmann




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Mixed Signals: On Separating Brain Signal from Noise

Publication date: Available online 28 April 2017
Source:Trends in Cognitive Sciences
Author(s): Lucina Q. Uddin
Accurate description of human brain function requires the separation of true neural signal from noise. Recent work examining spatial and temporal properties of whole-brain fMRI signals demonstrates how artifacts from a variety of sources can persist after rigorous processing, and highlights the lack of consensus on how to address this challenge.



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Advancing the Science of Dietary Patterns Research to Leverage a Complex Systems Approach

Publication date: Available online 29 April 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Jill Reedy, Susan M. Krebs-Smith, Ross A. Hammond, Erin Hennessy




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Semantic Word Category Processing in Semantic Dementia and Posterior Cortical Atrophy

Publication date: Available online 29 April 2017
Source:Cortex
Author(s): Zubaida Shebani, Karalyn Patterson, Peter J. Nestor, Lara Z. Diaz-de-Grenu, Kate Dawson, Friedemann Pulvermüller
There is general agreement that perisylvian language cortex plays a major role in lexical and semantic processing; but the contribution of additional, more widespread, brain areas in the processing of different semantic word categories remains controversial. We investigated word processing in two groups of patients whose neurodegenerative diseases preferentially affect specific parts of the brain, to determine whether their performance would vary as a function of semantic categories proposed to recruit those brain regions. Cohorts with (i) Semantic Dementia (SD), who have anterior temporal-lobe atrophy, and (ii) Posterior Cortical Atrophy (PCA), who have predominantly parieto-occipital atrophy, performed a lexical decision test on words from five different lexico-semantic categories: colour (e.g., yellow), form (oval), number (seven), spatial prepositions (under) and function words (also). Sets of pseudo-word foils matched the target words in length and bi-/tri-gram frequency. Word-frequency was matched between the two visual word categories (colour and form) and across the three other categories (number, prepositions, function words). Age-matched healthy individuals served as controls. Although broad word processing deficits were apparent in both patient groups, the deficit was strongest for colour words in SD and for spatial prepositions in PCA. The patterns of performance on the lexical decision task demonstrate (a) general lexicosemantic processing deficits in both groups, though more prominent in SD than in PCA, and (b) differential involvement of anterior-temporal and posterior-parietal cortex in the processing of specific semantic categories of words.



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