Development of guidelines for giving community presentations about eating disorders: a Delphi study

Abstract

Background

Concerns exist around how to talk about eating disorders (EDs) due to evidence that suggests discussing ED symptoms and behaviours may cause or worsen symptoms in vulnerable people. Using expert consensus, we developed a set of guidelines for giving safe community presentations about EDs.

Methods

Participants with professional ED expertise, and people with lived experience of an ED, were recruited for a Delphi study. N = 26 panel members rated 367 statements for both a) inclusion in guidelines, and b) their potential to be helpful (increase knowledge, reduce stigma) or harmful (increase stigma, cause/worsen ED symptoms). After each round of the study, statements were classified as endorsed, re-rate, or not endorsed.

Results

208 statements were endorsed by the panel over three rounds. 13 statements were strongly endorsed in the first round, with both people with lived experience and professionals agreeing it is important for presentations to include information on etiology of EDs and to promote help-seeking. Several statements had a high level of disagreement between those with lived experience and professionals, including the idea that presentations should suggest dieting is likely to result in weight gain.

Discussion

The experts were able to develop consensus on a wide range of issues. Panel members, particularly people with lived experience, were sensitive to aspects of presentations that may be harmful to an audience. The guidelines fill an important gap in the literature and provide guidance to those educating the public about EDs; they should, however, be further evaluated to test their efficacy.

http://ift.tt/2z7Fowb

AHNS Series: Do you know your guidelines? Guideline recommendations for head and neck cancer of unknown primary site

Abstract

This article reviews the clinical practice guidelines for head and neck oncology focusing on the management of head and neck cancers of unknown primary (CUP). The primary purpose of this series is to raise awareness of the current guidelines in head and neck oncology by reviewing the recommendations and the evidence supporting such recommendations, particularly those published by the National Comprehensive Cancer Network (NCCN). We review the importance of a thorough history and physical examination, the impact of the American Joint Committee on Cancer (AJCC) eighth edition changes and the importance of immunohistochemistry, the timing and type of imaging, the role of panendoscopy and tonsillectomy (palatine and lingual), and the role of surgery, radiation, and chemotherapy in the primary management of these tumors.

http://ift.tt/2zn3nf0

Clinical diagnosis and treatment outcomes for parapharyngeal space schwannomas: A single-institution review of 21 cases

Abstract

Background

Because the incidence of schwannoma arising from the parapharyngeal space (PPS) is very low, no studies have analyzed extirpation methods and postoperative neurological complications exclusively in PPS schwannomas.

Methods

The preoperative diagnosis and clinical outcomes of surgical treatment in 21 patients with PPS schwannoma who underwent surgery were investigated.

Results

Neurological deficit of the involved nerve developed in all patients regardless of the extirpation method used. However, the incidence of first bite syndrome in sympathetic chain schwannoma was significantly lower after intracapsular enucleation (40%) than after total resection (100%; P = .045). Furthermore, the incidence of postoperative complications unrelated to the involved nerve was lower after intracapsular enucleation (0%) than after total resection (42.9%; P = .055).

Conclusion

Although postoperative neurological deficit of the involved nerve was unavoidable in PPS schwannoma, intracapsular enucleation could be beneficial by reducing its severity and the incidence of complications unrelated to the involved nerve.

http://ift.tt/2mNnBIL

AHNS Series: Do you know your guidelines? Guideline recommendations for head and neck cancer of unknown primary site

Abstract

This article reviews the clinical practice guidelines for head and neck oncology focusing on the management of head and neck cancers of unknown primary (CUP). The primary purpose of this series is to raise awareness of the current guidelines in head and neck oncology by reviewing the recommendations and the evidence supporting such recommendations, particularly those published by the National Comprehensive Cancer Network (NCCN). We review the importance of a thorough history and physical examination, the impact of the American Joint Committee on Cancer (AJCC) eighth edition changes and the importance of immunohistochemistry, the timing and type of imaging, the role of panendoscopy and tonsillectomy (palatine and lingual), and the role of surgery, radiation, and chemotherapy in the primary management of these tumors.

http://ift.tt/2zn3nf0

Clinical diagnosis and treatment outcomes for parapharyngeal space schwannomas: A single-institution review of 21 cases

Abstract

Background

Because the incidence of schwannoma arising from the parapharyngeal space (PPS) is very low, no studies have analyzed extirpation methods and postoperative neurological complications exclusively in PPS schwannomas.

Methods

The preoperative diagnosis and clinical outcomes of surgical treatment in 21 patients with PPS schwannoma who underwent surgery were investigated.

Results

Neurological deficit of the involved nerve developed in all patients regardless of the extirpation method used. However, the incidence of first bite syndrome in sympathetic chain schwannoma was significantly lower after intracapsular enucleation (40%) than after total resection (100%; P = .045). Furthermore, the incidence of postoperative complications unrelated to the involved nerve was lower after intracapsular enucleation (0%) than after total resection (42.9%; P = .055).

Conclusion

Although postoperative neurological deficit of the involved nerve was unavoidable in PPS schwannoma, intracapsular enucleation could be beneficial by reducing its severity and the incidence of complications unrelated to the involved nerve.

http://ift.tt/2mNnBIL

Effects of implant length and 3D bone-to-implant contact on initial stabilities of dental implant: a microcomputed tomography study

Abstract

Background

The influences of potential bone-to-implant contact (BIC) area (pBICA), BIC area (BICA), and three dimensional (3D) BIC percentage (3D BIC%; defined as BICA divided by pBICA) in relation to the implant length on initial implant stability were studied. Correlations between these parameters were also evaluated.

Methods

Implants with lengths of 8.5, 10, 11.5, and 13 mm were placed in artificial bone specimens to measure three indexes of the initial implant stability: insertion torque value (ITV), Periotest value (PTV), and implant stability quotient (ISQ). The implants and bone specimens were also scanned by microcomputed tomography, and the obtained images were imported into Mimics software to reconstruct the 3D models and calculate the parameters of 3D bone-to-implant contact including pBICA, BICA, and 3D BIC%. The Kruskal-Wallis test, Wilcoxon rank-sum test with Bonferroni adjustment, and Spearman correlations were applied for statistical and correlation analyses.

Results

The implant length affected ITV more than PTV and ISQ, and significantly affected pBICA, BICA, and 3D BIC%. A longer implant increased pBICA and BICA but decreased 3D BIC%. The Spearman coefficients were high (>0.78) for the correlations between the three 3D BIC parameters and the three indexes of the initial implant stability.

Conclusions

pBICA, BICA, and 3D BIC% are useful when deciding on treatment plans related to various implant lengths, since these 3D BIC parameters are predictive of the initial implant stability.

http://ift.tt/2z7rTwp

Table of Contents

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Editorial Board

http://ift.tt/2AZ93Z7

Prevalence of type I sensitization to alpha-gal in forest service employees and hunters: Is the blood type an overlooked risk factor in epidemiological studies of the α-Gal syndrome?

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Table of Contents

http://ift.tt/2iAJBCe

Editorial Board

http://ift.tt/2AZ93Z7

Prevalence of type I sensitization to alpha-gal in forest service employees and hunters: Is the blood type an overlooked risk factor in epidemiological studies of the α-Gal syndrome?

http://ift.tt/2iCqw2x

ABBV-085, an Antibody Drug Conjugate, in Subjects With Advanced Solid Tumors

Conditions:   Advanced Solid Tumors;   Undifferentiated Pleomorphic Sarcoma;   Squamous Cell Carcinoma of the Head and Neck;   Carcinoma of the Breast
Intervention:   Drug: ABBV-085
Sponsor:   AbbVie
Recruiting

http://ift.tt/2zVpMPu

ABBV-085, an Antibody Drug Conjugate, in Subjects With Advanced Solid Tumors

Conditions:   Advanced Solid Tumors;   Undifferentiated Pleomorphic Sarcoma;   Squamous Cell Carcinoma of the Head and Neck;   Carcinoma of the Breast
Intervention:   Drug: ABBV-085
Sponsor:   AbbVie
Recruiting

http://ift.tt/2zVpMPu

Psoas Muscle Area as a Prognostic Factor for Survival in Patients with an Asymptomatic Infrarenal Abdominal Aortic Aneurysm: A Retrospective Cohort Study

Publication date: Available online 20 November 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Reza Indrakusuma, Jendé L. Zijlmans, Hamid Jalalzadeh, R. Nils Planken, Ron Balm, Mark J.W. Koelemay
ObjectivesLoss of muscle mass has been associated with poor survival in several surgical patient populations, including those with an abdominal aortic aneurysm (AAA). We wanted to replicate these findings and assesse the association between psoas muscle area (PMA) and survival in patients with an asymptomatic AAA.MethodsPatients with an asymptomatic infrarenal AAA who underwent computed tomography (CT) scanning between January 1, 2007, and December 31, 2013, were included in this single-centre retrospective cohort study. PMA was measured with thresholding on an axial image at the centre level of the third lumbar vertebra. The lowest tertile of PMA in all patients was used as a cutoff value for a low PMA. Then, in separate analyses for conservatively and surgically managed patients, survival was estimated with the Kaplan–Meier method. Differences in survival between patients with and without a low PMA were tested with the log-rank test.ResultsOf 228 patients, 104 were managed conservatively and 124 underwent AAA repair. Seventy-seven patients (62%) had an endovascular repair. In these 228 patients, the median PMA was 16.83 cm², while the cutoff value for low PMA was 14.56 cm². Patients who were managed conservatively were more often classified as having low PMA (45/104, 43%, vs. 31/124, 25%; p = .004) and were significantly older (mean 73.44 ± 9.05 years vs. 69.03 ± 7.46 years; p < .001). Low PMA was not associated with survival, either in patients managed conservatively, or in those who underwent AAA repair (p = .512 and p = .311, respectively).ConclusionsThe association between low PMA and poor survival could not be replicated; in this study, low PMA was not associated with survival in patients with an asymptomatic AAA. Further research is recommended before PMA can be used for pre-operative risk stratification.



http://ift.tt/2hQlMJG

Generation of complement molecular complex C5b-9 (C5b-9) in response to poly-traumatic hemorrhagic shock and evaluation of C5 cleavage inhibitors in non-human primates

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): R. Madelaine Paredes, Sarah Reyna, Philip Vernon, Douglas K. Tadaki, Jurandir J. Dallelucca, Forest Sheppard
Severe trauma initiates a systemic inflammatory cascade and that involves early activation of complement and cleavage of C5 into C5a (anaphylatoxin) and C5b (C5b-9 membrane attack complex). We examined activation of C5 in non-human primate (NHP) models of hemorrhagic shock.Blood plasma concentrations of C5b-9 were significantly increased in NHPs in response to hemorrhage alone and were further increased with the addition of tissue trauma. The onset of increased C5 cleavage was accelerated in NHPs that experienced decompensated poly-traumatic hemorrhagic shock. Next, to identify an effective inhibitor of NHP C5 cleavage in vitro, as a first step in the development of a potential therapy, three inhibitors of human C5 cleavage and hemolysis were tested in vitro. NHP C5 cleavage and complement-mediated hemolysis were successfully inhibited by pre-treatment of serum samples with a small, inhibitory peptide RA101348. Commercially-available C5 inhibitory antibodies were found to exhibit species-specific efficacy in vitro. Quidel's A217 antibody demonstrated dose-dependent inhibition of C5 cleavage and hemolysis in NHP samples, whereas LGM-Eculizumab only inhibited complement-mediated hemolysis in human samples.This study shows that complement activation in NHPs following experimental poly-traumatic hemorrhagic shock is consistent with clinical reports, and that cleavage of C5 and complement-mediated hemolysis can be effectively inhibited in vitro using a small peptide inhibitor. Taken together, these findings offer a clinically-relevant vehicle and a potential strategy for treatment of hemorrhagic shock with poly-traumatic injury.



http://ift.tt/2hQUiUj

Limax extract ameliorates cigarette smoke-induced chronic obstructive pulmonary disease in mice

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Xue Liang, Jian Wang, Ruijuan Guan, Li Zhao, Defu Li, Zhen Long, Qian Yang, Jingyi Xu, Ziyi Wang, Jinkui Xie, Wenju Lu
Chronic obstructive pulmonary disease (COPD) is a chronic, progressive and lethal lung disease with few treatments. Limax, a mollusk with lung, has been widely used to control phlegm and cough in China, yet whether Limax has a positive effect on COPD is unknown. This study investigated the effects of water-soluble extract from Limax on COPD development and the underlying mechanisms. The results showed that Limax extract improved lung function, relieved emphysema and suppressed the inflammation in the lungs of CS-challenged mice, as evidenced by diminished release of IL-6, KC, TNF-α, IFN-γ, Muc5AC, IL-17 and diminished mRNA expression of Muc5B. Moreover, Limax extract also inhibited phosphorylation of P38 and ERK and increased the expression of PPARγ. More interestingly, Limax extract (0.1μg/ml) inhibited CSE-induced release of IL-6 in vitro, which was substantially abrogated by heat treatment, and filtrate obtained from the deproteinized Limax extract with the 100KD ultrafiltration membrane, inhibited the secretion of IL-6. Taken together, these results suggest that, Limax extract prevents COPD development via inhibition of inflammation and mucus production, thus has a potential preventive and therapeutic application in COPD.



http://ift.tt/2jKz62R

Lipopolysaccharide (LPS)-mediated priming of toll-like receptor 4 enhances oxidant-induced prostaglandin E2 biosynthesis in primary murine macrophages

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Yan Zhang, Orisa J. Igwe
Agonists and pseudo-agonists for toll-like receptor 4 (TLR4) are common in our environment. Thus, human exposure to these agents may result in "priming or sensitization" of TLR4. A body of evidence suggests that LPS-mediated sensitization of TLR4 can increase the magnitude of responses to exogenous agents in multiple tissues. We have previously shown that reactive oxygen and nitrogen species (RONS) stimulate TLR4. There is no evidence that LPS-primed TLR4 can influence the magnitude of responses to oxidants from either endogenous or exogenous sources. In the present study, we directly tested the hypothesis that LPS-primed TLR4 will sensitize primary murine peritoneal macrophages (pM) to oxidant-mediated prostaglandin E2 (PGE2) production. We used potassium peroxychromate (PPC) and potassium peroxynitrite (PPN) as direct in vitro sources of exogenous RONS. Our results showed that a direct treatment with PPC or PPN alone as sources of exogenous oxidants had a limited effect on PGE2 biosynthesis. In contrast, pM sensitized by prior incubation with LPS-EK, a TLR4-specific agonist, followed by oxidant stimulation exhibited increased transcriptional and translational expression of cyclooxygenase-2 (COX-2) with enhanced PGE2 biosynthesis/production only in pM derived from TLR4-WT mice but not in TLR4-KO mice. Thus, we have shown a critical role for LPS-primed TLR4 in oxidant-induced inflammatory phenotypes that have the potential to initiate, propagate and maintain many human diseases.



http://ift.tt/2hPO8DU

Broncho-Vaxom in pediatric recurrent respiratory tract infections: A systematic review and meta-analysis

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Ju Yin, Baoping Xu, Xiantao Zeng, Kunling Shen
ObjectivesAssess the efficacy and safety of Broncho-Vaxom in pediatric recurrent respiratory tract infections (RRTIs).MethodsPublished randomized controlled trials (RCTs) of Broncho-Vaxom for pediatric RRTI were searched using PubMed, Embase, Cochrane Library, CBM, CNKI, WanFang Data, and VIP databases up to January 2017. Risk of bias was evaluated in accordance to the guidelines of the Cochrane collaboration and the level of evidence was graded according to the GRADE.Results53 RCTs involving 4851 pediatric patients were included in this meta-analysis. It showed that Broncho-Vaxom was positively correlated with a reduction in the frequency of respiratory infection [MD=−2.33, 95% CI (−2.75, −1.90), P<0.00001] compared to the control group. The Broncho-Vaxom group was more effective than control groups in relation to the duration of antibiotics course, infections, fever, cough, and wheezing, increasing serum immunoglobulin levels (IgG, IgA or IgM), and T-lymphocytes subtype (CD3+, CD4+, or CD8+). However, Broncho-Vaxom had higher adverse event rates [RR=1.39, 95% CI (1.02, 1.88), P=0.04]; these were not serious and did not influence the treatment course.ConclusionBroncho-Vaxom shows a good efficacy for pediatric RRTIs on the basis of routine therapy (e.g. anti-infection and antiviral therapy). However, the level of evidence was low and more international multicenter clinical trials are needed to explore the efficacy and safety of Broncho-Vaxom.



http://ift.tt/2jKdvqZ

Clinicopathologic Predictive Factors of Cervical Lymph Node Metastasis in Differentiated Thyroid Cancer

Publication date: Available online 20 November 2017
Source:Acta Otorrinolaringológica Española
Author(s): Ronghao Sun, Hua Zhang, Kun Liu, Jinchuan Fan, Guojun Li, Xicheng Song, Chao Li
BackgroundCervical lymph node metastasis (LNM) has been proven to be a predictor for locoregional recurrence in differentiated thyroid carcinoma (DTC). Clinicopathological features could be effective predictive factors for central and lateral LNM of DTC, and provide references to surgeons for cervical neck dissection.MethodsRetrospective analysis of clinicopathological data was performed on 420 patients who underwent initial surgery from 2010 to 2015.ResultsThe incidence of central and lateral LNM was calculated. Of 420 patients, 247 (58.8%) exhibited central LNM, and 185 (44.1%) exhibited lateral LNM. There were 29 (6.9%) cases confirmed to have skip metastasis. Univariate and multivariate analysis revealed that tumour location, tumour size, multifocality, capsular invasion, affected lobes, and age were independent predictors of central LNM. Tumour location, capsular invasion, affected lobes, and tumour size were independent predictors of lateral LNM.ConclusionsOur findings suggest that tumour location, affected lobes, capsular invasion, age, tumour size and multifocality may be taken as predictive factors for cervical LNM of DTC. Meticulous perioperative evaluation of cervical LNM and prophylactic cervical lymph node dissection that aims to remove the occult lymph nodes may be an option for DTC with risk factors.



http://ift.tt/2jHAMtW

Specific Organ Targeted Vestibular Physiotherapy: The Pivot in the Contemporary Management of Vertigo and Imbalance

Abstract

Introduction

Advancements in our understanding of vestibular physiology and how it is changes in different diseases have established that of the three therapeutic approaches to treat disorders of the vestibular system viz. pharmacotherapy, surgery and physical therapy, it is the later i.e., physical therapy which is the most efficacious modality in the management of balance disorders. The futility of vestibular sedatives in the correction of vestibular disorders and in the restoration of balance and the very limited role of surgery has now been recognised. Advancements in vestibulometry now enable us to localise any lesion in the vestibular system with utmost precision and also determine the exact cause of the balance disorder. The site of lesion and the specific organ that is defective can now be very precisely identified. Treatment modalities especially that for physical therapy hence have to be organ specific, and if possible, also disease specific.

Aims and Objectives

The study aims at evaluating the efficacy of physiotherapy in the management of balance disorders and also assesses the efficacy of organ targeted physical therapy, a new concept in restoring balance after vestibulometry has identified the offending organ.

Materials and Methods

The study was conducted in the specialised physical therapy unit for balance and gait disorder patients which is a part of Vertigo and Deafness Clinic in Kolkata, India. Special instruments for physical therapy devised by the first author were used for stimulation of specific sense organs in the vestibular labyrinth that were found to be defective in vestibulometry. Specially made Virtual reality programs were used in patients suffering from psychogenic balance disorders. The pre and post therapy status was evaluated by different standard scales to assess balance and dizziness.

Results

Very promising results were obtained. Organ targeted physiotherapy where defective sense organs were specifically stimulated showed remarkable improvement in different measures. Virtual reality exercises too showed very promising results in patients of psychogenic vertigo.

http://ift.tt/2mMCqLY

Specific Organ Targeted Vestibular Physiotherapy: The Pivot in the Contemporary Management of Vertigo and Imbalance

Abstract

Introduction

Advancements in our understanding of vestibular physiology and how it is changes in different diseases have established that of the three therapeutic approaches to treat disorders of the vestibular system viz. pharmacotherapy, surgery and physical therapy, it is the later i.e., physical therapy which is the most efficacious modality in the management of balance disorders. The futility of vestibular sedatives in the correction of vestibular disorders and in the restoration of balance and the very limited role of surgery has now been recognised. Advancements in vestibulometry now enable us to localise any lesion in the vestibular system with utmost precision and also determine the exact cause of the balance disorder. The site of lesion and the specific organ that is defective can now be very precisely identified. Treatment modalities especially that for physical therapy hence have to be organ specific, and if possible, also disease specific.

Aims and Objectives

The study aims at evaluating the efficacy of physiotherapy in the management of balance disorders and also assesses the efficacy of organ targeted physical therapy, a new concept in restoring balance after vestibulometry has identified the offending organ.

Materials and Methods

The study was conducted in the specialised physical therapy unit for balance and gait disorder patients which is a part of Vertigo and Deafness Clinic in Kolkata, India. Special instruments for physical therapy devised by the first author were used for stimulation of specific sense organs in the vestibular labyrinth that were found to be defective in vestibulometry. Specially made Virtual reality programs were used in patients suffering from psychogenic balance disorders. The pre and post therapy status was evaluated by different standard scales to assess balance and dizziness.

Results

Very promising results were obtained. Organ targeted physiotherapy where defective sense organs were specifically stimulated showed remarkable improvement in different measures. Virtual reality exercises too showed very promising results in patients of psychogenic vertigo.

http://ift.tt/2mMCqLY

Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve [RESEARCH ARTICLE]

Gaëlle Odelin, Emilie Faure, Fanny Coulpier, Maria Di Bonito, Fanny Bajolle, Michele Studer, Jean-Francois Avierinos, Patrick Charnay, Piotr Topilko, and Stephane Zaffran

Although cardiac neural crest cells are required at early stages of arterial valve development, their contribution during valvular leaflet maturation remains poorly understood. Here we show in mouse that neural crest cells from pre-otic and post-otic regions make distinct contributions to the arterial valve leaflets. Genetic fate-mapping analysis of neural crest Krox20-expressing cells reveals a large contribution to the borders and the interleaflet triangles of the arterial valves. Loss of Krox20 function results in hyperplastic aortic valve and partially penetrant bicuspid aortic valve formation. Similar defects are observed in neural crest Krox20 deficiency embryos. Genetic lineage tracing in Krox20^–/– mutant mice shows that endothelial-derived cells are normal whereas neural crest-derived cells are abnormally increased in number and misplaced in the valve leaflets. In contrast, genetic ablation of Krox20-expressing cells using is not sufficient to cause an aortic valve defect, suggesting that adjacent cells can compensate this depletion. Our findings unravel a critical role of Krox20 in arterial valve development and reveal that excess of neural crest cells may be associated to bicuspid aortic valve.

http://ift.tt/2AjrAD1

PDGFR{alpha} / PDGFR{beta} signaling balance modulates progenitor cell differentiation into white and beige adipocytes [RESEARCH ARTICLE]

Zhanguo Gao, Alexes C. Daquinag, Fei Su, Brad Snyder, and Mikhail G. Kolonin

Relative abundance of thermogenic beige adipocytes and lipid-storing white adipocytes in adipose tissue underlie its metabolic activity. The roles of adipocyte progenitor cells, which express PDGFRα or PDGFRβ, in adipose tissue function have remained unclear. Here, by defining the developmental timing of PDGFRα and PDGFRβ expression in mouse subcutaneous and visceral adipose depots, we uncover depot-specificity of preadipocyte delineation. We demonstrate that PDGFRα expression precedes PDGFRβ expression in all subcutaneous but only in a fraction of visceral adipose stromal cells. We show that high fat diet feeding or thermoneutrality in early postnatal development can induce PDGFRβ+ lineage recruitment to generate white adipocytes. In contrast, the contribution of PDGFRβ+ lineage to beige adipocytes is minimal. We provide evidence that human adipose tissue also contains distinct progenitor populations differentiating into beige or white adipocytes depending on PDGFRβ expression. Based on PDGFRα or PDGFRβ deletion and ectopic expression experiments, we conclude that the PDGFRα / PDGFRβ signaling balance determines progenitor commitment to beige or white adipogenesis, respectively. Our study suggests that adipocyte lineage specification and metabolism can be modulated through PDGFR signaling.

http://ift.tt/2zUcpQ7

HNF1B controls epithelial organization and cell polarity during ureteric bud branching and collecting duct morphogenesis [RESEARCH ARTICLE]

Audrey Desgrange, Claire Heliot, Ilya Skovorodkin, Saad U. Akram, Janne Heikkilä, Veli-Pekka Ronkainen, Ilkka Miinalainen, Seppo J. Vainio, and Silvia Cereghini

Kidney development depends critically on proper ureteric bud branching giving rise to the entire collecting duct system. The transcription factor HNF1B is required for the early steps of ureteric bud branching. Yet, the molecular and cellular events regulated by HNF1B are poorly understood. We report that specific removal of Hnf1b from the ureteric bud leads to defective cell-cell contacts and apico-basal polarity during the early branching events. High resolution ex vivo imaging combined with a membranous fluorescent reporter strategy show decreased mutant cell-rearrangements during mitosis-associated cell dispersal and severe epithelial disorganisation. Molecular analysis reveals downregulation of Gdnf-Ret pathway components and suggests that HNF1B acts both upstream and downstream of Ret-signaling by directly regulating Gfrα1 and Etv5.

Subsequently, Hnf1b-deletion leads to massively mispatterned ureteric tree network, defective collecting duct differentiation and disrupted tissue architecture leading to cystogenesis. Consistently, mRNA-seq analysis shows that the most impacted genes encode intrinsic cell-membrane components with transporter activity. Our study uncovers a fundamental and recurrring role of HNF1B in epithelial organization during early ureteric bud branching and further patterning and differentiation of the collecting duct system.

http://ift.tt/2AiWQlG

Drosophila embryonic type II neuroblasts: origin, temporal patterning, and contribution to the adult central complex [RESEARCH ARTICLE]

Kathleen T. Walsh and Chris Q. Doe

Drosophila neuroblasts are an excellent model for investigating how neuronal diversity is generated. Most brain neuroblasts generate a series of ganglion mother cells (GMCs) that each make two neurons (type I lineage), but sixteen brain neuroblasts generate a series of intermediate neural progenitors (INPs) that each produce 4-6 GMCs and 8-12 neurons (type II lineage). Thus, type II lineages are similar to primate cortical lineages, and may serve as models for understanding cortical expansion. Yet the origin of type II neuroblasts remains mysterious: do they form in the embryo or larva? If they form in the embryo, do their progeny populate the adult central complex, as do the larval type II neuroblast progeny? Here we present molecular and clonal data showing that all type II neuroblasts form in the embryo, produce INPs, and express known temporal transcription factors. Embryonic type II neuroblasts and INPs undergo quiescence, and produce embryonic-born progeny that contribute to the adult central complex. Our results provide a foundation for investigating the development of the central complex, and tools for characterizing early-born neurons in central complex function.

http://ift.tt/2zUckfh

FOX and ETS family transcription factors regulate the pigment cell lineage in planarians [RESEARCH ARTICLE]

Xinwen He, Nicole Lindsay-Mosher, Yan Li, Alyssa M. Molinaro, Jason Pellettieri, and Bret J. Pearson

Many pigment cells acquire unique structural properties and gene expression profiles during animal development. The underlying differentiation pathways have been well characterized in cells formed during embryogenesis, such as the neural crest-derived melanocyte. However, much less is known about the developmental origins of pigment cells produced in adult organisms during tissue homeostasis and repair. Here we report a lineage analysis of ommochrome- and porphyrin-producing cells in the brown, freshwater planarian Schmidtea mediterranea. Using an RNA-sequencing approach, we identified two classes of markers expressed in sequential fashion when new pigment cells are generated during regeneration or in response to pigment cell ablation. We also report roles for FOXF-1 and ETS-1 transcription factors, as well as an FGF Receptor-like molecule, in the specification and maintenance of this cell type. Together, our results provide the first insight into mechanisms of adult pigment cell development in the strikingly colorful Platyhelminthes phylum.

http://ift.tt/2AiU1ks

The Xenopus primordial germ cell transcriptome identifies sox7: a novel role in early PGC development [RESEARCH ARTICLE]

Amanda M. Butler, Dawn A. Owens, Lingyu Wang, and Mary Lou King

Xenopus primordial germ cells (PGCs) are determined by the presence of maternally derived germ plasm. Germ plasm components both protect PGCs from somatic differentiation and begin a unique gene expression program. Segregation of the germline from the endodermal lineage occurs during gastrulation, and PGCs subsequently initiate zygotic transcription. However, the gene-network(s) that operate to both preserve and promote germline differentiation are poorly understood. Here, we utilized RNA-sequencing analysis to comprehensively interrogate PGC and neighboring endoderm cell mRNAs after lineage segregation. We identified 1,865 transcripts enriched in PGCs compared to endoderm cells. We next compared the PGC-enriched transcripts to previously identified maternal, vegetally-enriched transcripts, and found that >50% of maternal transcripts were enriched in PGCs, including sox7. PGC-directed sox7 knockdown and over-expression studies revealed an early requirement for sox7 in germ plasm localization, zygotic transcription, and PGC number. We identified oct60 as the most highly expressed and enriched OCT3/4 homologue in PGCs. We compared the Xenopus PGC transcriptome with human PGC transcripts and showed that 80% of genes are conserved, underscoring the usefulness of Xenopus for human based studies.

http://ift.tt/2zTtFVJ

Differential spatial distribution of miR165/6 determines variability in plant root anatomy [RESEARCH ARTICLE]

G. Di Ruocco, G. Bertolotti, E. Pacifici, L. Polverari, M. Tsiantis, S. Sabatini, P. Costantino, and R. Dello Ioio

A clear example of interspecific variation is the number of root cortical layers in plants. The genetic mechanisms underlying this variability are poorly understood, partly due to the lack of a convenient model. Here, we demonstrate that Cardamine hirsuta, unlike Arabidopsis thaliana, has two cortical layers that are patterned during late embryogenesis. We show that a miR165/6-dependent distribution of the HOMEODOMAIN LEUCINE ZIPPER III (HD-ZIPIII) transcription factor PHABULOSA (PHB) controls this pattern. Our findings reveal that interspecies variation in miRNA distribution can determine differences in anatomy in plants.

http://ift.tt/2AiWHyE

Shep regulates Drosophila neuronal remodeling by controlling transcription of its chromatin targets [RESEARCH ARTICLE]

Dahong Chen, Ryan K. Dale, and Elissa P. Lei

Neuronal remodeling is critical to form the mature nervous system and can lead to neuropsychiatric diseases when disrupted. Global gene expression changes in neurons during remodeling as well as the factors that regulate these changes remain poorly defined. To elucidate this process, we performed RNA-seq on isolated Drosophila larval and pupal neurons and found up-regulated synaptic signaling and down-regulated gene expression regulators as a result of normal neuronal metamorphosis. We further tested the role of alan shepard (shep), which encodes an evolutionarily conserved RNA-binding protein required for proper neuronal remodeling. Depletion of shep in neurons prevents the execution of metamorphic gene expression patterns, and shep-regulated genes correspond to Shep chromatin and/or RNA-binding targets. Reduced expression of a Shep-inhibited target gene we identified, brat, is sufficient to rescue neuronal remodeling defects of shep knockdown flies. Our results reveal direct regulation of transcriptional programs by Shep to regulate neuronal remodeling during metamorphosis.

http://ift.tt/2zS8ovD

Cohesin facilitates zygotic genome activation in zebrafish [RESEARCH ARTICLE]

Michael Meier, Jenny Grant, Amy Dowdle, Amarni Thomas, Jennifer Gerton, Philippe Collas, Justin M. O'Sullivan, and Julia A. Horsfield

At zygotic genome activation (ZGA), changes in chromatin structure are associated with new transcription immediately following the maternal-to-zygotic transition (MZT). The nuclear architectural proteins, cohesin and CCCTC-binding factor (CTCF), contribute to chromatin structure and gene regulation. We show here that normal cohesin function is important for ZGA in zebrafish. Depletion of cohesin subunit Rad21 delays ZGA without affecting cell cycle progression. In contrast, CTCF depletion has little effect on ZGA whereas complete abrogation is lethal. Genome wide analysis of Rad21 binding reveals a change in distribution from pericentromeric satellite DNA, and few locations including the miR-430 locus (whose products are responsible for maternal transcript degradation), to genes, as embryos progress through the MZT. After MZT, a subset of Rad21 binding overlaps pioneer factor Pou5f3, which activates early expressed genes. Rad21 depletion disrupts the formation of nucleoli and RNA polymerase II foci, suggestive of global defects in chromosome architecture. We propose that Rad21/cohesin redistribution to active areas of the genome is key to the establishment of chromosome organization and the embryonic developmental program.

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Three-dimensional printing modeling: application in maxillofacial and hand fractures and resident training

Abstract

Background

Imaging techniques in reconstructive surgery are of great assistance not only in diagnosis but also in preoperative planning; however, they are often limited to interpreting three-dimensional structures on flat surfaces. Three-dimensional (3D) printing has made it possible to overcome these limitations by allowing the creation of customized 3D anatomical models. We set out to create 3D printed models to demonstrate its application in maxillofacial and hand fractures and resident training.

Methods

Ten patients with hand and craniofacial fractures of different types were studied. Computed tomography was performed; the image files were processed digitally, and 3D models were subsequently printed. The quality and accuracy of the obtained models were rigorously evaluated, and the models were then used by plastic surgery teachers and residents in the preoperative planning.

Results

The comparative measurements confirmed that the models are at real scale with a 1:1 ratio; the pre-cast osteosynthesis plates were perfectly matched to the patient's anatomy intraoperatively, and the lengths of the pre-selected screws were accurate. The anesthetic surgical time was reduced by 20%. Teachers and residents were satisfied with the use of models for clinical discussions of patients and for preoperative planning and the advantages of manipulating physical models were highlighted.

Conclusions

We have created low-cost, good quality, reliable, and accurate 3D printed models for the preoperative planning of reconstructive surgeries of maxillofacial and hand fractures, reducing the operative times and providing a new academic teaching tool in the training of residents of plastic surgery.

Level of Evidence: Level IV, therapeutic study.

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The association between interpersonal problems and treatment outcome in patients with eating disorders

Abstract

Background

Interpersonal problems are thought to play an essential role in the development and maintenance of eating disorders. The aim of the current study was to investigate whether a specific interpersonal profile could be identified in a group of patients diagnosed with Bulimia Nervosa, Binge Eating Disorder, or Eating Disorders Not Otherwise Specified, and to explore if specific types of interpersonal problems were systematically related to treatment outcome in this group of patients.

Methods

The participants were 159 patients who received systemic/narrative outpatient group psychotherapy. Interpersonal problems were measured at baseline, and eating disorder symptoms were measured pre- and post treatment. Data were analysed with the Structural Summary Method, a particular method for the analysis of the Inventory of Interpersonal Problems, and hierarchical regression analysis was conducted.

Results

The patients demonstrated a generally Non-assertive and Friendly-submissive interpersonal style. No significant association between the overall level of interpersonal problems and treatment outcome was identified. However, the results showed a correlation between being cold and hostile and poor treatment outcome, while being domineering showed a trend approaching significance in predicting better treatment outcome.

Conclusion

The results indicate that patients with eating disorders show a specific interpersonal profile, and suggest that particular types of interpersonal problems are associated with treatment outcome.

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cGMP is involved in Zn tolerance through the modulation of auxin redistribution in root tips

Publication date: March 2018
Source:Environmental and Experimental Botany, Volume 147
Author(s): Ping Zhang, Liangliang Sun, Jun Qin, Jinpeng Wan, Ruling Wang, Shuang Li, Jin Xu
Excess zinc (Zn) inhibits primary root (PR) growth but induces lateral root (LR) formation. Both auxin and cGMP play a role in controlling root growth in plants. However, whether and how their interaction is involved in Zn-regulated root development remain unclear. Here, we reported that excess Zn leads to auxin accumulation in root tips, as indicated by DR5:GUS expression. Further study showed that excess Zn represses PIN4:GFP abundance in root tips and that PR elongation and LR formation in the pin4 mutant is insensitive to excess Zn. Excess Zn also elevates cyclic guanosine monophosphate (cGMP) production in seedlings. Supplementation with the exogenous cGMP donor 8-bromoguanosine 3′,5′-cyclic guanosine monophosphate (8-Br-cGMP) increased PR elongation and LR formation in Zn-treated seedlings, whereas the guanylate cyclase (GC) inhibitor LY83583 decreased these processes. Additional physiological and genetic analyses indicated that PIN4 is involved in cGMP-modulated root development in Zn-treated seedlings. Taken together, these results indicate that Zn-regulated cGMP production plays an important role in modulating root development by maintaining PIN4 abundance in excess Zn-treated roots and subsequent adaptation to Zn toxicity.



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Structural studies of a green-emitting terbium doped calcium zinc phosphate phosphor

Publication date: 5 March 2018
Source:Journal of Molecular Structure, Volume 1155
Author(s): B. Ramesh, G.R. Dillip, B. Rambabu, S.W. Joo, B. Deva Prasad Raju
In this study, a new green emitting CaZn2(PO4)2:Tb³⁺ phosphors were synthesized through solid-state reaction route. The phosphors were characterized structurally by X-ray diffraction, Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). All the synthesized phosphors were crystallized in triclinic crystal structure with P1¯ space group. The phosphate groups in the phosphors were confirmed by FTIR analysis. The surface elements O 1s, P 2p, Ca 2p, Zn 2p and Tb 3d were studied by high-resolution XPS spectra. Upon excitation at 378 nm, the dominant green emission of CaZn2(PO4)2:Tb³⁺ phosphors at 542 nm were noticed in the emission spectra. For various emission wavelengths (at 435 and 489 nm) and constant excitation wavelength (at 378 nm), the decay curves have shown two different decay dynamics of phosphors. The lighting properties such as Commission International de l'Eclairage (x = 0.319, y = 0.398) and color temperature (5995 K) were calculated.

Graphical abstract

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Zinc and lead accumulation characteristics and in vivo distribution of Zn2+ in the hyperaccumulator Noccaea caerulescens elucidated with fluorescent probes and laser confocal microscopy

Publication date: March 2018
Source:Environmental and Experimental Botany, Volume 147
Author(s): Ngoc Dinh, Antony van der Ent, David R. Mulligan, Anh V. Nguyen
Tolerance and accumulation of multiple trace elements simultaneously in hyperaccumulator species enable these plants to grow on sites contaminated with these elements. In this study, accumulation and tolerance to zinc (Zn) and lead (Pb) by the hyperaccumulator Noccaea caerulescens (Brassicaceae) was investigated using different Zn²⁺ and Pb²⁺ treatments in hydroponic culture. The results confirmed that N. caerulescens has a high capacity for Zn²⁺ accumulation while having high levels of Pb²⁺ tolerance. The younger plants were more tolerant to Zn²⁺ and Pb²⁺ than the older plants. The accumulation of Zn²⁺ in shoots or roots was not significantly affected by treatment regime or plant age. Pb accumulated mainly in the roots (0.16–0.23wt% dry mass), confirming substantial tolerance to Pb. The concentration of phosphorus (P) in older plant shoots decreased ∼25% in the plants treated with Zn²⁺, but enhanced ∼26% in the plants treated with Zn²⁺+Pb²⁺. The high ratio of Zn to P in both fresh and dry leaves is suggestive of the formation of insoluble Zn-salts. The Zn²⁺ distribution in living cells was examined using three selective fluorescent probes (Zinpyr-1, Newport Green DCF and Phen Green SK). The fluorescent probes showed that Zn²⁺ was mainly located in the apoplastic space of the leaf epidermal cells. Selective fluorescent probes in combination with laser confocal microscopy proved a useful tool for elucidating cellular and tissue-level distribution of Zn²⁺ in living plant cells at high resolution. However, the expected vacuolar sequestration of Zn²⁺ was not observed, which may be explained by insufficient penetration of the fluorophores.



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Chronic exposure to low-level cadmium induced zinc-copper dysregulation

Publication date: March 2018
Source:Journal of Trace Elements in Medicine and Biology, Volume 46
Author(s): Soisungwan Satarug, Muneko Nishijo, Pailin Ujjin, Michael R. Moore
Background and objectivesExposure to cadmium (Cd) has been associated with aberrant zinc and copper homeostasis. This study investigated if Cd exposure impairs renal reabsorption of metals.MethodsRenal tubular reabsorption of metals were calculated from urine to serum metal ratios and analyzed for an independent association with Cd exposure levels, using data from 100 men and 100 women, aged 16–60 years.ResultsThe smoking prevalence was 30% in men and 0% in women. The male and female means (SD) for urine Cd were 0.54 (0.43) and 0.62 (0.43) μg/g creatinine. The mean (SD) for fractional zinc reabsorption was 77.2 (23) % in men and 87.7 (13.3) % in women, while the copper reabsorption was 100% in both men and women. Lower zinc reabsorption levels were associated with higher Cd exposure (P<0.001), higher serum copper to zinc ratios (P=0.007) and higher tubular impairment levels (P=0.024). Reduced zinc reabsorption was particularly severe in smokers as those with high Cd exposure had 44.9% and 37.2% (P<0.001) lower zinc reabsorption than those with low and moderate exposures. The mean zinc reabsorption in male non-smokers with high Cd exposure was 25.8% (P<0.001) and 18.2% (P=0.003) lower than those with low and moderate exposures, while the corresponding figure for female non-smokers was 17% (P<0.001), and 12.8% (P=0.013), respectively.ConclusionsThis is the first report demonstrating Cd-dose dependent reduction in renal zinc reabsorption and high serum copper to zinc ratios.



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Perception of Curability Among Advanced Cancer Patients: An International Collaborative Study

AbstractBackground.There are limited data on illness understanding and perception of cure among advanced cancer patients around the world. The aim of the study was to determine the frequency and factors associated with inaccurate perception of curability among advanced cancer patients receiving palliative care across the globe.Materials and Methods.Secondary analysis of a study to understand the core concepts in end‐of‐life care among advanced cancer patients receiving palliative care from 11 countries across the world. Advanced cancer patients were surveyed using a Patient Illness Understanding survey and Control Preference Scale. Descriptive statistics and multicovariate logistic regression analysis were performed.Results.Fifty‐five percent (763/1,390) of patients receiving palliative care inaccurately reported that their cancer is curable. The median age was 58, 55% were female, 59% were married or had a partner, 48% were Catholic, and 35% were college educated. Sixty‐eight percent perceived that the goal of therapy was "to get rid of their cancer," and 47% perceived themselves as "seriously ill." Multicovariate logistic regression analysis shows that accurate perception of curability was associated with female gender (odds ratio [OR] 0.73, p = .027), higher education (OR 0.37, p < .0001), unemployment status (OR 0.69, p = .02), and being from France (OR 0.26, p < .0001) and South Africa (OR 0.52, p = .034); inaccurate perception of curability was associated with better Karnofsky performance status (OR 1.02 per point, p = .0005), and being from Philippines (OR 15.49, p < .0001), Jordan (OR 8.43, p < .0001), Brazil (OR 2.17, p = .0037), and India (OR 2.47, p = .039).Conclusion.Inaccurate perception of curability in advanced cancer patients is 55% and significantly differs by gender, education, performance status, employment status, and country of origin. Further studies are needed to develop strategies to reduce this misperception of curability in advanced cancer patients.Implications for Practice.The findings of this study indicate that inaccurate perception of curability among advanced cancer patients is 55%. Inaccurate perception of curability significantly differs by gender, education, performance status, employment status, and country of origin. There is great need to facilitate improved patient–physician communication so as to improve health care outcomes and patient satisfaction.

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Revisiting Expectations in an Era of Precision Oncology

AbstractAs we enter an era of precision medicine and targeted therapies in the treatment of metastatic cancer, we face new challenges for patients and providers alike as we establish clear guidelines, regulations, and strategies for implementation. At the crux of this challenge is the fact that patients with advanced cancer may have disproportionate expectations of personal benefit when participating in clinical trials designed to generate generalizable knowledge. Patient and physician goals of treatment may not align, and reconciliation of their disparate perceptions must be addressed. However, it is particularly challenging to manage a patient's expectations when the goal of precision medicine—personalized response—exacerbates our inability to predict outcomes for any individual patient. The precision medicine informed consent process must therefore directly address this issue. We are challenged to honestly, clearly, and compassionately engage a patient population in an informed consent process that is responsive to their vulnerability, as well as ever‐evolving indications and evidence. This era requires a continual reassessment of expectations and goals from both sides of the bed.

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Trailblazing Precision Oncology for Rare Tumor Subtypes

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Enhancing Next‐Generation Sequencing‐Guided Cancer Care Through Cognitive Computing

AbstractBackground.Using next‐generation sequencing (NGS) to guide cancer therapy has created challenges in analyzing and reporting large volumes of genomic data to patients and caregivers. Specifically, providing current, accurate information on newly approved therapies and open clinical trials requires considerable manual curation performed mainly by human "molecular tumor boards" (MTBs). The purpose of this study was to determine the utility of cognitive computing as performed by Watson for Genomics (WfG) compared with a human MTB.Materials and Methods.One thousand eighteen patient cases that previously underwent targeted exon sequencing at the University of North Carolina (UNC) and subsequent analysis by the UNCseq informatics pipeline and the UNC MTB between November 7, 2011, and May 12, 2015, were analyzed with WfG, a cognitive computing technology for genomic analysis.Results.Using a WfG‐curated actionable gene list, we identified additional genomic events of potential significance (not discovered by traditional MTB curation) in 323 (32%) patients. The majority of these additional genomic events were considered actionable based upon their ability to qualify patients for biomarker‐selected clinical trials. Indeed, the opening of a relevant clinical trial within 1 month prior to WfG analysis provided the rationale for identification of a new actionable event in nearly a quarter of the 323 patients. This automated analysis took <3 minutes per case.Conclusion.These results demonstrate that the interpretation and actionability of somatic NGS results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing could potentially improve patient care by providing a rapid, comprehensive approach for data analysis and consideration of up‐to‐date availability of clinical trials.Implications for Practice.The results of this study demonstrate that the interpretation and actionability of somatic next‐generation sequencing results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing can significantly improve patient care by providing a fast, cost‐effective, and comprehensive approach for data analysis in the delivery of precision medicine. Patients and physicians who are considering enrollment in clinical trials may benefit from the support of such tools applied to genomic data.

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Ovarian and Uterine Functions in Female Survivors of Childhood Cancers

AbstractAdult survivors of childhood cancers are more prone to developing poor reproductive and obstetrical outcomes than their siblings and the general population as a result of previous exposure to chemotherapy and radiation during childhood. Chemotherapy drugs exert cytotoxic effects systemically and therefore can damage the ovaries, leading to infertility, premature ovarian failure, and, to a lesser extent, spontaneous abortions. They have very limited or no deleterious effects on the uterus that can be recognized clinically. By contrast, radiation is detrimental to both the ovaries and the uterus, thereby causing a greater magnitude of adverse effects on the female reproductive function. These include infertility, premature ovarian failure, miscarriage, fetal growth restrictions, perinatal deaths, preterm births, delivery of small‐for‐gestational‐age infants, preeclampsia, and abnormal placentation. Regrettably, the majority of these adverse outcomes arise from radiation‐induced uterine injury and are reported at higher incidence in the adult survivors of childhood cancers who were exposed to uterine radiation during childhood in the form of pelvic, spinal, or total‐body irradiation. Recent findings of long‐term follow‐up studies evaluating reproductive performance of female survivors provided some reassurance to female cancer survivors by documenting that pregnancy and live birth rates were not significantly compromised in survivors, including those who had been treated with alkylating agents and had not received pelvic, cranial, and total‐body irradiation. We aimed in this narrative review article to provide an update on the impact of chemotherapy and radiation on the ovarian and uterine function in female survivors of childhood cancer.Implications for Practice.Adult survivors of childhood cancers are more prone to developing a number of poor reproductive and obstetrical outcomes than their siblings and the general population as a result of previous exposure to chemotherapy and radiation during childhood. The impact of radiation therapy on the female genital system is greater than chemotherapy regimens because radiation is detrimental to both the uterus and the ovaries, whereas toxic effects of chemotherapy drugs are confined to the ovaries. Therefore, radiation‐induced uterine damage accounts for most poor obstetrical outcomes in the survivors. These include infertility, miscarriages, stillbirths, fetal growth restrictions, preeclampsia, and preterm deliveries.

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Anti‐Hu‐Associated Autoimmune Limbic Encephalitis in a Patient with PD‐1 Inhibitor‐Responsive Myxoid Chondrosarcoma

AbstractAutoimmune encephalitis is an uncommon complication of immune checkpoint inhibitor therapy. This article reports a case of fatal anti‐Hu‐associated autoimmune limbic encephalitis presenting within 8 weeks following anti‐PD1 therapy in a patient with myxoid chondrosarcoma and pre‐existing anti‐Hu antibodies. Although tumor reduction occurred in response to PD‐1 inhibitor therapy, the patient had a rapidly progressive decline in neurologic function despite initial stabilization with immunosuppression. Considering the increasing use of immune checkpoint inhibitors for the treatment of various malignancies, an increase in the occurrence of neurologic adverse events is likely, requiring prompt intervention and enhanced pharmacovigilance in malignancies associated with onconeuronal antibodies.

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Therapeutic Anticoagulation in Patients with Primary Brain Tumors or Secondary Brain Metastasis

AbstractPatients with primary or metastatic brain tumors are at increased risk of developing venous thromboses. However, the potential benefit of therapeutic anticoagulation in these patients must be weighed against the deadly complication of intracranial hemorrhage. In this review, we summarize available evidence and recent studies of intracranial bleeding risks in primary and metastatic tumors and the impact of therapeutic anticoagulation. We find that for the majority of primary and treated metastatic brain tumors, the risk of spontaneous bleeding is acceptable and not further increased by careful therapeutic anticoagulation with low molecular weight heparin or direct oral anticoagulants, although thrombocytopenia (platelet count less than 50,000/μL) and other coagulopathies are relative contraindications. Patients with brain metastasis from melanoma, renal cell carcinoma, choriocarcinoma, thyroid carcinoma, and hepatocellular carcinoma have a higher tendency to bleed spontaneously than noted in patients with other malignancies, and thus warrant routine brain imaging and alternative strategies such as inferior vena cava filter placement in the acute setting of venous thromboembolism before consideration of therapeutic anticoagulation.Implications for Practice.Malignant gliomas are associated with increased risks of both venous thromboses and intracranial hemorrhage, but the additional bleeding risk associated with therapeutic anticoagulation appears acceptable, especially after treatment of primary tumors. Most patients with treated brain metastasis have a low risk of intracranial hemorrhage associated with therapeutic anticoagulation, and low molecular weight heparin is currently the preferred agent of choice. Patients with untreated brain metastasis from melanoma, renal cell carcinoma, thyroid cancer, choriocarcinoma, and hepatocellular carcinoma have a higher propensity for spontaneous intracranial bleeding, and systemic anticoagulation may be contraindicated in the acute setting of venous thromboembolism.

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Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Necuparanib Combined with Nab‐Paclitaxel and Gemcitabine in Patients with Metastatic Pancreatic Cancer: Phase I Results

AbstractLessons Learned. Despite the compelling preclinical rationale of evaluating the genetically engineered heparin derivative, necuparanib, combined with standard therapy in metastatic pancreas adenocarcinoma, the results were ultimately disappointing.Safety was documented, although dose escalation was limited by the number of subcutaneous injections, the potential for skin toxicity (cellulitis), and low‐level anticoagulant effect. Nonetheless, the hypothesis of targeting prothrombotic pathways in pancreas adenocarcinoma remains compelling.Background.Necuparanib is derived from unfractionated heparin and engineered for reduced anticoagulant activity while preserving known heparin‐associated antitumor properties. This trial assessed the safety, pharmacokinetics (PK), pharmacodynamics, and initial efficacy of necuparanib combined with gemcitabine ± nab‐paclitaxel in patients with metastatic pancreatic cancer.Methods.Patients received escalating daily subcutaneous doses of necuparanib plus 1,000 mg/m2 gemcitabine (days 1, 8, 15, and every 28 days). The protocol was amended to include 125 mg/m2 nab‐paclitaxel after two cohorts (following release of the phase III MPACT data). The necuparanib starting dose was 0.5 mg/kg, with escalation via a modified 3 + 3 design until the maximum tolerated dose (MTD) was determined.Results.Thirty‐nine patients were enrolled into seven cohorts (necuparanib 0.5, 1 mg/kg + gemcitabine; necuparanib 1, 2, 4, 6, and 5 mg/kg + nab‐paclitaxel + gemcitabine). The most common adverse events were anemia (56%), fatigue (51%), neutropenia (51%), leukopenia (41%), and thrombocytopenia (41%). No deaths and two serious adverse events were potentially related to necuparanib. Measurable levels of necuparanib were seen starting at the 2 mg/kg dose. Of 24 patients who received at least one dose of necuparanib + nab‐paclitaxel + gemcitabine, 9 (38%) achieved a partial response and 6 (25%) achieved stable disease (63% disease control rate). Given a cellulitis event and mild activated partial thromboplastin time increases at 6 mg/kg, the 5 mg/kg dose was considered the MTD and selected for further assessment in phase II.Conclusion.Acceptable safety and encouraging signals of activity in patients with metastatic pancreatic cancer receiving necuparanib, nab‐paclitaxel, and gemcitabine were demonstrated.

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Phase II Trial Using a Combination of Oxaliplatin, Capecitabine, and Celecoxib with Concurrent Radiation for Newly Diagnosed Resectable Rectal Cancer

AbstractLessons Learned. Colorectal cancers exhibit a high level of cyclooxygenase‐2 (COX‐2) expression with strong preclinical rationale for improved clinical outcomes with COX‐2 inhibition. Celecoxib is a COX‐2 inhibitor and we have shown that it can be safely combined with capecitabine and oxaliplatin as part of neoadjuvant treatment with radiation therapy (RT) in rectal cancer.There was a significant improvement in skin toxicity with this combination as compared with historical data. Considering the field has moved on to single‐agent capecitabine, we believe future trials with capecitabine and celecoxib hold potential.Background.Improved survival is seen among patients with rectal cancer who achieve pathologic complete response (pCR) after neoadjuvant therapy. Cyclooxygenase‐2 (COX‐2) expression is increased in gastrointestinal malignancies and it may serve as a target to enhance pathologic response. A trial combining chemoradiation and COX‐2 inhibition was conducted to evaluate the pCR rate, surgical outcomes, survival, and treatment toxicity.Methods.Patients with resectable (T3‐4, N1‐2) rectal cancer within 12 cm of the anal verge were included in this phase II clinical trial. The neoadjuvant treatment consisted of capecitabine 850 mg/m2 b.i.d. Monday through Friday for 5 weeks, weekly oxaliplatin 50 mg/m2 intravenous (IV), celecoxib 200 mg b.i.d. daily, along with concurrent 45 gray radiation therapy in 25 fractions.Results.Thirty‐two patients were included in the final analysis. The primary endpoint was pCR: 31% (95% confidence interval [CI]: 16%–50%). Secondary endpoints were surgical downstaging (SD): 75% (95% CI: 57%–89%) and sphincter‐sparing surgery (SSS): 56% (95% CI: 38%–74%). Common grade >3 toxicities were diarrhea and abnormal liver function tests (9% each). Grade 0 and 1 toxicities included radiation dermatitis (59% and 34%, respectively) and proctitis (63% and 28%, respectively). At 3 years, disease‐free survival and overall survival (OS) were 84% (95% CI: 65%–93%) and 94% (95% CI: 77%–98%), respectively.Conclusion.Chemoradiation with celecoxib in rectal cancer was well tolerated and demonstrated high rates of pCR, SD, and SSS. Improvement in skin toxicity (34% grade 1 and no grade 3/4) as compared with historical results (43%–78% grade 3/4) seems to be a significant improvement with addition of celecoxib to neoadjuvant chemotherapy.

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Adverse Event Reporting in Clinical Trials: Time to Include Duration as Well as Severity

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Phase I Pharmacokinetic Study of Nivolumab in Korean Patients with Advanced Solid Tumors

AbstractLessons Learned. This pharmacokinetic study of nivolumab showed that there is little ethnic difference in the handling of nivolumab.Nivolumab was well tolerated in Korean patients.Background.This phase I study of nivolumab, an anti‐programmed cell death‐1 (anti‐PD‐1) monoclonal antibody, investigated the pharmacokinetics and safety of nivolumab in Korean patients with advanced solid tumors. Findings were compared with results from Japan and the U.S.Materials and Methods.In this two‐part study, patients received a single dose of nivolumab (1, 3, and 10 mg/kg; ONO‐4538‐13) and were followed up for 3 weeks. Those who met the required criteria proceeded to the second part (ONO‐4538‐14), and received the same dose as in part one every 2 weeks.Results.Six patients per dose level were enrolled (n = 18). The mean elimination half‐life of nivolumab among the groups ranged from 15.0 to 19.1 days. The maximum serum concentration and area under serum concentration–time curve increased almost dose‐proportionally at doses from 1 to 10 mg/kg. Adverse drug reactions (ADRs; mostly grade ≤2) were reported in seven patients (38.9%). ADRs grade ≥3 occurred in one patient (5.6%; pneumonitis). Three patients (16.7%) developed ADRs related to thyroid dysfunction.Conclusion.The pharmacokinetic parameters of nivolumab were similar among patients from Korea, Japan, and the U.S. The safety profile was consistent with findings from previous studies.

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Specific Organ Targeted Vestibular Physiotherapy: The Pivot in the Contemporary Management of Vertigo and Imbalance

Abstract

Introduction

Advancements in our understanding of vestibular physiology and how it is changes in different diseases have established that of the three therapeutic approaches to treat disorders of the vestibular system viz. pharmacotherapy, surgery and physical therapy, it is the later i.e., physical therapy which is the most efficacious modality in the management of balance disorders. The futility of vestibular sedatives in the correction of vestibular disorders and in the restoration of balance and the very limited role of surgery has now been recognised. Advancements in vestibulometry now enable us to localise any lesion in the vestibular system with utmost precision and also determine the exact cause of the balance disorder. The site of lesion and the specific organ that is defective can now be very precisely identified. Treatment modalities especially that for physical therapy hence have to be organ specific, and if possible, also disease specific.

Aims and Objectives

The study aims at evaluating the efficacy of physiotherapy in the management of balance disorders and also assesses the efficacy of organ targeted physical therapy, a new concept in restoring balance after vestibulometry has identified the offending organ.

Materials and Methods

The study was conducted in the specialised physical therapy unit for balance and gait disorder patients which is a part of Vertigo and Deafness Clinic in Kolkata, India. Special instruments for physical therapy devised by the first author were used for stimulation of specific sense organs in the vestibular labyrinth that were found to be defective in vestibulometry. Specially made Virtual reality programs were used in patients suffering from psychogenic balance disorders. The pre and post therapy status was evaluated by different standard scales to assess balance and dizziness.

Results

Very promising results were obtained. Organ targeted physiotherapy where defective sense organs were specifically stimulated showed remarkable improvement in different measures. Virtual reality exercises too showed very promising results in patients of psychogenic vertigo.

http://ift.tt/2mMCqLY

Specific Organ Targeted Vestibular Physiotherapy: The Pivot in the Contemporary Management of Vertigo and Imbalance

Abstract

Introduction

Advancements in our understanding of vestibular physiology and how it is changes in different diseases have established that of the three therapeutic approaches to treat disorders of the vestibular system viz. pharmacotherapy, surgery and physical therapy, it is the later i.e., physical therapy which is the most efficacious modality in the management of balance disorders. The futility of vestibular sedatives in the correction of vestibular disorders and in the restoration of balance and the very limited role of surgery has now been recognised. Advancements in vestibulometry now enable us to localise any lesion in the vestibular system with utmost precision and also determine the exact cause of the balance disorder. The site of lesion and the specific organ that is defective can now be very precisely identified. Treatment modalities especially that for physical therapy hence have to be organ specific, and if possible, also disease specific.

Aims and Objectives

The study aims at evaluating the efficacy of physiotherapy in the management of balance disorders and also assesses the efficacy of organ targeted physical therapy, a new concept in restoring balance after vestibulometry has identified the offending organ.

Materials and Methods

The study was conducted in the specialised physical therapy unit for balance and gait disorder patients which is a part of Vertigo and Deafness Clinic in Kolkata, India. Special instruments for physical therapy devised by the first author were used for stimulation of specific sense organs in the vestibular labyrinth that were found to be defective in vestibulometry. Specially made Virtual reality programs were used in patients suffering from psychogenic balance disorders. The pre and post therapy status was evaluated by different standard scales to assess balance and dizziness.

Results

Very promising results were obtained. Organ targeted physiotherapy where defective sense organs were specifically stimulated showed remarkable improvement in different measures. Virtual reality exercises too showed very promising results in patients of psychogenic vertigo.

http://ift.tt/2mMCqLY

Polysialylated Neural Cell Adhesion Molecule Supports Regeneration of Neurons in the Nucleus Ambiguus After Unilateral Recurrent Laryngeal Nerve Avulsion in Adult Rats

A correlation appears to exist between the expression of the polysialic acid neural cell adhesion molecule (PSA-NCAM) and repair in central nervous system (CNS) diseases. However, the expression of PSA-NCAM in the CNS after peripheral nerve injury remains unclear. This study aimed to evaluate the expression of PSA-NCAM in the ipsilateral nucleus ambiguus (NA) after unilateral recurrent laryngeal nerve (RLN) avulsion.

http://ift.tt/2jbMx7V

Voltammetric Sensing of Biomolecules at Carbon Based Electrode Interfaces: A Review

Publication date: Available online 17 November 2017
Source:TrAC Trends in Analytical Chemistry
Author(s): Dhanjai, Ankita Sinha, Xianbo Lu, Lingxia Wu, Dongqin Tan, Yun Li, Jiping Chen, Rajeev Jain
Biomolecules are integral constituents of living beings which regulate numerous biochemical functions of the body. Analysis of various small molecules (metabolites, neurotransmitters, amino acids, vitamins) and macromolecules (nucleic acids, proteins) is of prime importance in modern time due to increasing disbalance in natural metabolism of human body. Irregularities and alteration in concentration of biomolecules lead to different kinds of genetic, metabolic and cancerous diseases which have created a great requirement of highly sensitive, accurate and stable detection systems for their quick and specific screening. In this review, redox interactions of biomolecules at carbon based electrode interfaces have been discussed using voltammetry. It is divided into subsections, starting with an introduction into the field and a description of its current state. This is followed by a large section describing carbon nanomaterials (CNs) based volammetric sensors for different small biomolecules and macromolecules. The next section of the review gives conclusion, challenges and future perspective in sensing biomolecules at CNs based electrodes. Advanced approaches for fabrication of portable integrated electrochemical devices for various point of care diagnostic applications have also been included at the end.

Graphical abstract

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Fungus-derived photoluminescent carbon nanodots for ultrasensitive detection of Hg2+ ions and photoinduced bactericidal activity

Publication date: Available online 20 November 2017
Source:Sensors and Actuators B: Chemical
Author(s): Sada Venkateswarlu, Buddolla Viswanath, Ankireddy Seshadri Reddy, Minyoung Yoon
Herein, we present a sustainable solvent-free synthetic procedure to produce carbon nanodots from common edible mushrooms (Pleurotus spp.). The resulting mushroom carbon nanodots (MCDs) exhibit stable blue fluorescence with high quantum yield (25%). The MCDs are highly dispersible in water because of the enormous number of oxygen- and nitrogen-containing functional groups on the surface. The MCDs can be used as an effective fluorescent probe for label-free detection of Hg²⁺ ions (detection limit: 4.13nM). To improve the sensitivity, dihydrolipoicacid acid was attached to the surface of MCDs, resulting in ultra-sensitivity in Hg²⁺ ion sensing, with a detection limit as low as 17.4 pM. In addition, the MCDs can be used for the labeling of bacteria and as a photoinduced bactericidal agent. Light irradiation of E. coli treated with MCDs showed excellent bactericidal activity relative to the control. These sustainable and affordable carbon materials are potentially compatible for monitoring toxic metals and as a potent visible-light-responsive bactericidal probe.

Graphical abstract

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Enhanced recovery in patients having free tissue transfer for head and neck cancer: does it make a difference?

Programmes for Enhanced Recovery after Surgery (ERAS) accelerate recovery, reduce morbidity, and shorten hospital stay in a wide range of surgical specialties. We established a standardised multimodal ERAS pathway for patients who were being treated by free tissue transfer for head and neck cancer to evaluate its benefit. Our primary outcome was duration of hospital stay, and secondary outcomes included complications, number of days to first mobilisation, and readmission rates. We compared 100 consecutive patients who followed the ERAS programme with a control group of 40 consecutive patients who had free tissue transfer before the ERAS programme was introduced.

http://ift.tt/2jc9pEp

Are patients satisfied with the head and neck skin cancer service? An evaluation of outpatient services with a review of published reports

Scientific publications place much emphasis on postoperative outcomes such as recurrence, but little attention to patients' satisfaction. The purpose of this evaluation was to find out patients' reported outcomes after their initial consultation, treatment, and follow-up appointments for non-melanoma skin cancer of the head and neck. We used an adapted version of the European Organisation for Research and Treatment of Cancer (EORTC) validated questionnaire for patients' satisfaction to collect data prospectively from consenting patients between September and December 2015.

http://ift.tt/2zYwuCl

Cardiac Toxicity of Immune Checkpoint Inhibitors: Cardio-Oncology Meets Immunology.

Author: Varricchi, Gilda MD, PhD; Galdiero, Maria Rosaria MD, PhD; Tocchetti, Carlo G. MD, PhD

Page: 1989-1992

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Prognostic Value of Coronary Artery Calcium in the PROMISE Study (Prospective Multicenter Imaging Study for Evaluation of Chest Pain).

Author: Budoff, Matthew J. MD; Mayrhofer, Thomas PhD; Ferencik, Maros MD, PhD; Bittner, Daniel MD; Lee, Kerry L. PhD; Lu, Michael T. MD, MPH; Coles, Adrian PhD; Jang, James MD; Krishnam, Mayil MD, MBA; Douglas, Pamela S. MD; Hoffmann, Udo MD, MPH; On behalf of the PROMISE Investigators

Page: 1993-2005

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Computed Tomography or Functional Stress Testing for the Prediction of Risk: Can I Have My Cake and Eat It?.

Author: Newby, David E. DM, PhD

Page: 2006-2008

http://ift.tt/2iBm9EQ

Modeling Major Adverse Outcomes of Pediatric and Adult Patients With Congenital Heart Disease Undergoing Cardiac Catheterization: Observations From the NCDR IMPACT Registry (National Cardiovascular Data Registry Improving Pediatric and Adult Congenital Treatment).

Author: Jayaram, Natalie MD, MSB; Spertus, John A. MD, MPH; Kennedy, Kevin F. MS; Vincent, Robert MD; Martin, Gerard R. MD; Curtis, Jeptha P. MD; Nykanen, David MD; Moore, Phillip M. MD, MBA; Bergersen, Lisa MD, MPH

Page: 2009-2019

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Risk Adjustment Tools in Congenital Heart Disease: A Consumer's View.

Author: Lock, James E. MD

Page: 2020-2021

http://ift.tt/2iBJmGZ

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

Author: Hadinnapola, Charaka MA, MB, BChir; Bleda, Marta PhD; Haimel, Matthias BSc; Screaton, Nicholas BM, BCh, FRCR, FRCP; Swift, Andrew FRCP, PhD; Dorfmuller, Peter MD, PhD; Preston, Stephen D. FRCPath; Southwood, Mark PhD; Hernandez-Sanchez, Jules PhD; Martin, Jennifer BSc; Treacy, Carmen BSc; Yates, Katherine BSc; Bogaard, Harm MD, PhD; Church, Colin FRCP, PhD; Coghlan, Gerry MD, FRCP; Condliffe, Robin MD; Corris, Paul A. MBBS, FRCP; Gibbs, Simon MD, FRCP; Girerd, Barbara PhD; Holden, Simon FRCP, PhD; Humbert, Marc MD, PhD; Kiely, David G. MD; Lawrie, Allan PhD; Machado, Rajiv PhD; MacKenzie Ross, Robert MB, BChir; Moledina, Shahin MBChB; Montani, David MD, PhD; Newnham, Michael MBBS; Peacock, Andrew MD; Pepke-Zaba, Joanna PhD, FRCP; Rayner-Matthews, Paula BSc; Shamardina, Olga PhD; Soubrier, Florent MD, PhD; Southgate, Laura PhD; Suntharalingam, Jay MD, FRCP; Toshner, Mark MD; Trembath, Richard FRCP, FMedSci; Noordegraaf, Anton Vonk MD; Wilkins, Martin R. MD, FRCP, FMedSci; Wort, Stephen J. PhD, FRCP; Wharton, John PhD; NIHR BioResource-Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH; Graf, Stefan PhD *,,,; Morrell, Nicholas W. MD, FRCP, FMedSci *,,; Aitman, Timothy; Bennett, David; Caulfield, Mark; Chinnery, Patrick; Gale, Daniel; Koziell, Ania; Kuijpers, Taco W; Laffan, Michael A; Maher, Eamonn; Markus, Hugh S; Ouwehand, Willem H; Perry, David; Raymond, F Lucy; Roberts, Irene; Smith, Kenneth; Thrasher, Adrian; Watkins, Hugh; Williamson, Catherine; Woods, Geoffrey; Ashford, Sofie; Bradley, John R; Fletcher, Debra; Hammerton, Tracey; James, Roger; Kingston, Nathalie; Ouwehand, Willem H; Penkett, Christopher J; Raymond, F Lucy; Stirrups, Kathleen; Veltman, Marijke; Young, Tim; Ashford, Sofie; Brown, Matthew; Clements-Brod, Naomi; Davis, John; Dewhurst, Eleanor; Erwood, Marie; Frary, Amy; Linger, Rachel; Papadia, Sofia; Rehnstrom, Karola; Stark, Hannah; Allsup, David; Austin, Steve; Bakchoul, Tamam; Bariana, Tadbir K; Bolton-Maggs, Paula; Chalmers, Elizabeth; Collins, Peter; Erber, Wendy N; Everington, Tamara; Favier, Remi; Freson, Kathleen; Furie, Bruce; Gattens, Michael; Gomez, Keith; Greene, Daniel; Greinacher, Andreas; Hart, Daniel; Heemskerk, Johan WM; Henskens, Yvonne; Kazmi, Rashid; Keeling, David; Kelly, Anne M; Laffan, Michael A; Lambert, Michele P; Lentaigne, Claire; Liesner, Ri; Mangles, Sarah; Mathias, Mary; Millar, Carolyn M; Mumford, Andrew; Nurden, Paquita; Ouwehand, Willem H; Papadia, Sofia; Payne, Jeanette; Pasi, John; Perry, David J; Peerlinck, Kathelijne; Richards, Michael; Rondina, Matthew; Roughley, Catherine; Schulman, Sol; Schulze, Harald; Scully, Marie; Sivapalaratnam, Suthesh; Tait, R Campbell; Talks, Kate; Thachil, Jecko; Turro, Ernest; Toh, Cheng-Hock; Van Geet, Chris; De Vries, Minka; Warner, Timothy Q; Westbury, Sarah; Furnell, Abigail; Mapeta, Rutendo; Simeoni, Ilenia; Staines, Simon; Stephens, Jonathan; Stirrups, Kathleen; Whitehorn, Deborah; Watt, Christopher; Attwood, Antony; Daugherty, Louise; Deevi, Sri VV; Halmagyi, Csaba; Hu, Fengyuan; James, Roger; Matser, Vera; Meacham, Stuart; Megy, Karyn; Penkett, Christopher J; Stirrups, Kathleen; Titterton, Catherine; Tuna, Salih; Yu, Ping; von Ziegenweldt, Julie; Astle, William; Carss, Keren; Greene, Daniel; Lango-Allen, Hana; Turro, Ernest; Astle, William; Greene, Daniel; Richardson, Sylvia; Turro, Ernest; Calleja, Paul; Rankin, Stuart; Turek, Wojciech; Bryson, Christine; Anderson, Julie; Fletcher, Debra; McJannet, Coleen; Stock, Sophie; Young, Tim; Wassmer, Evangeline; Sohal, Aman; Santra, Saikat; Vogt, Julie; Chitre, Manali; Krishnakumar, Deepa; Ambegaonkar, Gautum; Maw, Anna; Armstrong, Ruth; Park, Soo-Mi; Mehta, Sarju; Paterson, Joan; Carmichael, Jenny; Allen, Louise; Hensiek, Anke; Firth, Helen; Stein, Penelope; Deegan, Patrick; Doffinger, Rainer; Parker, Alasdair; Bitner-Glindzicz, Maria; Scott, Richard; Hurst, Jane; Rosser, Elisabeth; Lees, Melissa; Clement, Emma; Henderson, Robert; Thompson, Dorothy; Gardham, Alice; Gissen, Paul; Josifova, Dragana; Thomas, Ellen; Patch, Chris; Deshpande, Charu; Flinter, Frances; Holder, Muriel; Canham, Natalie; Wakeling, Emma; Holder, Susan; Ghali, Neeti; Brady, Angie; Clowes, Virginia; MacLaren, Robert; Webster, Andrew; Moore, Anthony; Arno, Gavin; Michaelides, Michel; Rankin, Julia; Kurian, Manju; Murphy, Elaine; Carss, Keren; Sanchis-Juan, Alba; Erwood, Marie; Dewhurst, Eleanor; Grozeva, Detelina; Raymond, F Lucy; Reid, Evan; Woods, Geoff; Tischkowitz, Marc; Sandford, Richard; Ali, Sonia; Creaser-Myers, Amanda; Cookson, Victoria; DaCosta, Rosa; Dormand, Natalie; Ghataorhe, Pavandeep K; Greenhalgh, Alan; Huis in't Veld, Anna; Kennedy, Fiona; Mackenzie Ross, Rob; Masati, Larahmie; Meehan, Sharon; Othman, Shokri; Pollock, Val; Polwarth, Gary; Rhodes, Christopher J; Rue-Albrecht, Kevin; Schotte, Gwen; Shipley, Debbie; Tan, Yvonne; Wanjiku, Ivy; Wort, John; Smith, Kenneth; Kuijpers, Taco; Thrasher, Adrian; Thaventhiran, James; Brown, Matthew; Lango Allen, Hana; Simeoni, Ilenia; Staples, Emily; Samarghitean, Crina; Alachkar, Hana; Antrobus, Richard; Arumugakani, Gururaj; Bacchelli, Chiara; Baxendale, Helen; Bethune, Claire; Bibi, Shahnaz; Booth, Claire; Browning, Michael; Burns, Siobhan; Chandra, Anita; Cooper, Nichola; Davies, Sophie; Devlin, Lisa; Doffinger, Rainer; Drewe, Elizabeth; Edgar, David; Egner, William; Ghurye, Rohit; Gilmour, Kimberley; Goddard, Sarah; Gordins, Pavel; Grigoriadou, Sofia; Hackett, Scott; Hague, Rosie; Hayman, Grant; Herwadkar, Archana; Huissoon, Aarnoud; Jolles, Stephen; Kelleher, Peter; Kumararatne, Dinakantha; Lear, Sara; Longhurst, Hilary; Lorenzo, Lorena; Maimaris, Jesmeen; Manson, Ania; McDermott, Elizabeth; Murng, Sai; Nejentsev, Sergey; Noorani, Sadia; Oksenhendler, Eric; Ponsford, Mark; Qasim, Waseem; Quinti, Isabella; Richter, Alex; Sargur, Ravishankar; Savic, Sinisa; Seneviratne, Suranjith; Sewell, Carrock; Stauss, Hans; Thomas, Moira; Welch, Steve; Willcocks, Lisa; Yeatman, Nigel; Yong, Patrick

Page: 2022-2033

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Pulmonary Veno-Occlusive Disease: Welcome to the PAHty (Bostonian for Party).

Author: Miller, Dave P. MS; Farber, Harrison W. MD

Page: 2034-2036

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Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction.

Author: Cho, Jae Hyung MD; Zhang, Rui MD; Kilfoil, Peter J. PhD; Gallet, Romain MD; de Couto, Geoffrey PhD; Bresee, Catherine MS; Goldhaber, Joshua I. MD; Marban, Eduardo MD, PhD; Cingolani, Eugenio MD

Page: 2037-2050

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SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy.

Author: Tang, Xiaoqiang PhD *,; Chen, Xiao-Feng BSc *,; Wang, Nan-Yu BSc; Wang, Xiao-Man MD; Liang, Shu-Ting PhD; Zheng, Wei PhD; Lu, Yun-Biao PhD; Zhao, Xiang BSc; Hao, De-Long MSc; Zhang, Zhu-Qin PhD; Zou, Ming-Hui MD, PhD; Liu, De-Pei PhD; Chen, Hou-Zao PhD

Page: 2051-2067

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Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy.

Author: Calkins, Hugh MD; Corrado, Domenico MD, PhD; Marcus, Frank MD

Page: 2068-2082

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Gene Editing Could Help Pave the Way for Pig-to-Human Transplantations.

Author: Hampton, Tracy PhD

Page: 2083-2084

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Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor-Related Cardiotoxicity.

Author: Escudier, Marion MD; Cautela, Jennifer MD; Malissen, Nausicaa MD; Ancedy, Yann MD; Orabona, Morgane MD; Pinto, Johan MD; Monestier, Sandrine MD; Grob, Jean-Jacques MD, PhD; Scemama, Ugo MD; Jacquier, Alexis MD, PhD; Lalevee, Nathalie PhD; Barraud, Jeremie MD; Peyrol, Michael MD; Laine, Marc MD; Bonello, Laurent MD, PhD; Paganelli, Franck MD, PhD; Cohen, Ariel MD, PhD; Barlesi, Fabrice MD, PhD; Ederhy, Stephane MD; Thuny, Franck MD, PhD

Page: 2085-2087

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Letter by Violi et al Regarding Article, "Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure".

Author: Violi, Francesco MD; Letizia, Claudio MD; Carnevale, Roberto PhD

Page: 2088-2089

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Response by Sag et al to Letter Regarding Article, "Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure".

Author: Sag, Can Martin MD; Schnelle, Moritz MD, PhD; Shah, Ajay M. MD, FMedSci

Page: 2090-2091

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Letter by Li et al Regarding Article, "Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling".

Author: Li, Yangxin PhD; Liu, Bin MD, PhD; Liang, Chun MD, PhD

Page: 2092-2093

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Response by Du et al to Letter Regarding Article, "Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling".

Author: Du, Jie PhD; Ma, Xin-liang MD, PhD; Li, Yulin PhD; Chen, Boya

Page: 2094-2095

http://ift.tt/2AZM3sG

Cardiovascular Health in African Americans: A Scientific Statement From the American Heart Association.

Author: Carnethon, Mercedes R. PhD, FAHA, Chair; Pu, Jia PhD; Howard, George DrPH, FAHA; Albert, Michelle A. MD, MPH, FAHA; Anderson, Cheryl A.M. PhD, FAHA; Bertoni, Alain G. MD, MPH, FAHA; Mujahid, Mahasin S. PhD; Palaniappan, Latha MD, MS, FAHA; Taylor, Herman A. Jr MD, FAHA; Willis, Monte MD, PhD, FAHA; Yancy, Clyde W. MD, FAHA; On behalf of the American Heart Association Council on Epidemiology and Prevention; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Functional Genomics and Translational Biology; and Stroke Council

Page: e393-e423

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Cortactin: Cell Functions of A Multifaceted Actin-Binding Protein

Publication date: Available online 20 November 2017
Source:Trends in Cell Biology
Author(s): Michael Schnoor, Theresia E. Stradal, Klemens Rottner
Cortactin fulfills many functions in various cell types. These functions have been considered to derive from its ability to activate the Actin-related protein 2/3 (Arp2/3) complex, and are regulated by post-translational modifications, including phosphorylation and acetylation. New evidence suggests that cortactin regulates cell migration by controlling the deposition of extracellular matrix proteins rather than lamellipodial Arp2/3 activation, and that cortactin also functions in GTPase signaling, vesicular trafficking, and actomyosin contractility. These recent new findings and concepts are relevant for physiological and pathological cell functions, but have not yet been put into mechanistic context. Here, we reconsider current thinking on cortactin functions in different cell types during health and disease, and discuss potential directions of future research in cortactin biology.



http://ift.tt/2z7em8k

Comorbidities in a community sample of narcolepsy

To assess comorbidities in a community-based cohort of narcolepsy.

http://ift.tt/2jFlKoi

Association between Nighttime Sleep Duration, Midday Naps and Glycemic Levels in Japanese Patients with Type 2 Diabetes

To clarify the relationship between nighttime sleep duration, midday naps and glycemic control in Japanese patients diagnosed with type 2 diabetes (n=355) or impaired glucose tolerance (n=43).

http://ift.tt/2hQG3yK

Laryngeal candidiasis: our experience from sixty biopsy specimens

Persistent throat symptoms, such as dysphonia, globus and throat pain, are highly prevalent and are a significant cause of morbidity¹. In a number of cases a clear cause of these symptoms is not identified and many patients are treated empirically with lifestyle advice and/or anti-reflux medication².

This article is protected by copyright. All rights reserved.

http://ift.tt/2AYh68u

Laryngeal candidiasis: our experience from sixty biopsy specimens

Persistent throat symptoms, such as dysphonia, globus and throat pain, are highly prevalent and are a significant cause of morbidity¹. In a number of cases a clear cause of these symptoms is not identified and many patients are treated empirically with lifestyle advice and/or anti-reflux medication².

This article is protected by copyright. All rights reserved.

http://ift.tt/2AYh68u

Identifying and assessing human activity impacts on groundwater quality through hydrogeochemical anomalies and NO 3 − , NH 4 + , and COD contamination: a case study of the Liujiang River Basin, Hebei Province, P.R. China

Abstract

In the face of rapid economic development and increasing human activity, the deterioration of groundwater quality has seriously affected the safety of the groundwater supply in eastern China. Identifying and assessing the impact of human activities is key to finding solutions to this problem. This study is an effort to scientifically and systematically identify and assess the influence of human activities on groundwater based on irregularities in hydrochemical properties and water contamination, which are considered to directly result from anthropogenic activity. The combination of the hydrochemical anomaly identification (HAI) and the contaminant identification (CI) was proposed to identify the influence of human activities on groundwater quality. And the degree of abnormality was quantified by the background threshold value. The principal component analysis (PCA) and land use map were used to verify the reliability of the identification result. The final result show that the strong influence areas mainly distributed in the south of the basin and the affected indicators contained the major elements and NO₃⁻, NH₄⁺, COD. Impacts from anthropogenic activities can be divided into two types: mine drainage that disrupts natural water–rock interaction processes, agricultural cultivation, and sewage emissions that contribute to nitrate pollution.

http://ift.tt/2zTN5tC

Isolation of lead-resistant Arthrobactor strain GQ-9 and its biosorption mechanism

Abstract

In this study, lead-resistant bacterium Arthrobacter sp. GQ-9 with a resistant capability to cadmium, zinc, and copper was isolated from a heavy metal polluted soil. Microcalorimetry analysis was applied to assess the strain's microbial activity under Pb(II) stress and suggested that GQ-9's microbial activities under Pb(II) stress were stronger than a non-resistant strain. Biosorption batch experiments revealed that the optimal condition for adsorption of Pb(II) by GQ-9 was pH 5.5, a biomass dosage of 1.2 g L⁻¹, and an initial Pb(II) concentration of 100 mg L⁻¹ with a maximum biosorption capacity of 17.56 mg g⁻¹.Adsorption-desorption experiments and Fourier transform infrared spectroscopy (FTIR) analysis were applied to elucidate the biosorption mechanisms. Adsorption-desorption analysis showed that GQ-9 cells could sequester 56.60% of the adsorbed Pb(II) ions on the cell wall. FTIR analysis suggested that hydroxyl, carboxyl, amino, nitrile, and sulfhydryl groups and amide I, amide II bands on the GQ-9 cell wall participated in the complexation of Pb(II) ions. The present study illustrates that the lead-resistant bacteria GQ-9 has the potential for further development of an effective and ecofriendly adsorbent for heavy metal bioremediation.

http://ift.tt/2AgCERb

Fetal Exposure to Maternal Pregnancy Complications and Respiratory Health in Childhood

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


http://ift.tt/2AY7Fpl

Fetal Exposure to Maternal Pregnancy Complications and Respiratory Health in Childhood

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


http://ift.tt/2AY7Fpl

Innate Immune Activation by cGMP-AMP Nanoparticles Leads to Potent and Long-Acting Antiretroviral Response against HIV-1 [INFECTIOUS DISEASE AND HOST RESPONSE]

HIV-1 evades immune detection by the cGAS-STING cytosolic DNA-sensing pathway during acute infection. STING is a critical mediator of type I IFN production, and STING agonists such as cGMP-AMP (cGAMP) and other cyclic dinucleotides elicit potent immune and antitumor response. In this article, we show that administration of cGAMP, delivered by an ultra–pH-sensitive nanoparticle (NP; PC7A), in human PBMCs induces potent and long-acting antiretroviral response against several laboratory-adapted and clinical HIV-1 isolates. cGAMP-PC7A NP requires endocytosis for intracellular delivery and immune signaling activation. cGAMP-PC7A NP-induced protection is mediated through type I IFN signaling and requires monocytes in PBMCs. cGAMP-PC7A NPs also inhibit HIV-1 replication in HIV⁺ patient PBMCs after ex vivo reactivation. Because pattern recognition receptor agonists continue to show more clinical benefits than the traditional IFN therapy, our data present important evidence for potentially developing cGAMP or other STING agonists as a new class of immune-stimulating long-acting antiretroviral agents.

http://ift.tt/2hIt0vC

Critical Functions of IRF4 in B and T Lymphocytes [PILLARS OF IMMUNOLOGY]

http://ift.tt/2hEGNDd

In This Issue [IN THIS ISSUE]

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The Structural Basis for Complement Inhibition by Gigastasin, a Protease Inhibitor from the Giant Amazon Leech [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Complement is crucial to the immune response, but dysregulation of the system causes inflammatory disease. Complement is activated by three pathways: classical, lectin, and alternative. The classical and lectin pathways are initiated by the C1r/C1s (classical) and MASP-1/MASP-2 (lectin) proteases. Given the role of complement in disease, there is a requirement for inhibitors to control the initiating proteases. In this article, we show that a novel inhibitor, gigastasin, from the giant Amazon leech, potently inhibits C1s and MASP-2, whereas it is also a good inhibitor of MASP-1. Gigastasin is a poor inhibitor of C1r. The inhibitor blocks the active sites of C1s and MASP-2, as well as the anion-binding exosites of the enzymes via sulfotyrosine residues. Complement deposition assays revealed that gigastasin is an effective inhibitor of complement activation in vivo, especially for activation via the lectin pathway. These data suggest that the cumulative effects of inhibiting both MASP-2 and MASP-1 have a greater effect on the lectin pathway than the more potent inhibition of only C1s of the classical pathway.

http://ift.tt/2hFrNF8

Galectin-1: A Jack-of-All-Trades in the Resolution of Acute and Chronic Inflammation [BRIEF REVIEWS]

Regulatory signals provide negative input to immunological networks promoting resolution of acute and chronic inflammation. Galectin-1 (Gal-1), a member of a family of evolutionarily conserved glycan-binding proteins, displays broad anti-inflammatory and proresolving activities by targeting multiple immune cell types. Within the innate immune compartment, Gal-1 acts as a resolution-associated molecular pattern by counteracting the synthesis of proinflammatory cytokines, inhibiting neutrophil trafficking, targeting eosinophil migration and survival, and suppressing mast cell degranulation. Likewise, this lectin controls T cell and B cell compartments by modulating receptor clustering and signaling, thus serving as a negative-regulatory checkpoint that reprograms cellular activation, differentiation, and survival. In this review, we discuss the central role of Gal-1 in regulatory programs operating during acute inflammation, autoimmune diseases, allergic inflammation, pregnancy, cancer, and infection. Therapeutic strategies aimed at targeting Gal-1–glycan interactions will contribute to overcome cancer immunosuppression and reinforce antimicrobial immunity, whereas stimulation of Gal-1–driven immunoregulatory circuits will help to mitigate exuberant inflammation.

http://ift.tt/2hH1QW0

Complement Regulatory Protein Factor H Is a Soluble Prion Receptor That Potentiates Peripheral Prion Pathogenesis [INFECTIOUS DISEASE AND HOST RESPONSE]

Several complement proteins exacerbate prion disease, including C3, C1q, and CD21/35. These proteins of the complement cascade likely increase uptake, trafficking, and retention of prions in the lymphoreticular system, hallmark sites of early prion propagation. Complement regulatory protein factor H (fH) binds modified host proteins and lipids to prevent C3b deposition and, thus, autoimmune cell lysis. Previous reports show that fH binds various conformations of the cellular prion protein, leading us to question the role of fH in prion disease. In this article, we report that transgenic mice lacking Cfh alleles exhibit delayed peripheral prion accumulation, replication, and pathogenesis and onset of terminal disease in a gene-dose manner. We also report a biophysical interaction between purified fH and prion rods enriched from prion-diseased brain. fH also influences prion deposition in brains of infected mice. We conclude from these data and previous findings that the interplay between complement and prions likely involves a complex balance of prion sequestration and destruction via local tissue macrophages, prion trafficking by B and dendritic cells within the lymphoreticular system, intranodal prion replication by B and follicular dendritic cells, and potential prion strain selection by CD21/35 and fH. These findings reveal a novel role for complement-regulatory proteins in prion disease.

http://ift.tt/2hG6CD1

Cutting Edge: Anti-TIM-3 Treatment Exacerbates Pulmonary Inflammation and Fibrosis in Mice [CUTTING EDGE]

Promising results of immune checkpoint inhibitors have indicated the use of immunotherapy against malignant tumors. However, they cause serious side effects, including autoimmune diseases and pneumonitis. T cell Ig and mucin domain (TIM)-3 is a new candidate immune checkpoint molecule; however, the potential toxicity associated with anti–TIM-3 treatment is unknown. In this study, we investigated the pathological contribution of anti–TIM-3 mAb in a bleomycin-induced lung inflammation and fibrosis model. Anti–TIM-3–treated mice showed more severe inflammation and peribronchiolar fibrosis compared with control IgG-treated mice. Anti–TIM-3 mAb was associated with increased numbers of myofibroblasts, collagen deposition, and TGF-β1 production in lungs. TIM-3 expression was only detected on alveolar macrophages that protect against fibrosis by apoptotic cell clearance. Treatment with anti–TIM-3 mAb inhibited the phagocytic ability of alveolar macrophages in vivo, resulting in the defective clearance of apoptotic cells in lungs. In summary, anti–TIM-3 mAb treatment might cause pneumonitis and it should be used with caution in clinical settings.

http://ift.tt/2zVbe2q

Palmitate Conditions Macrophages for Enhanced Responses toward Inflammatory Stimuli via JNK Activation [INNATE IMMUNITY AND INFLAMMATION]

Obesity is associated with low-grade inflammation and elevated levels of circulating saturated fatty acids, which trigger inflammatory responses by engaging pattern recognition receptors in macrophages. Because tissue homeostasis is maintained through an adequate balance of pro- and anti-inflammatory macrophages, we assessed the transcriptional and functional profile of M-CSF–dependent monocyte-derived human macrophages exposed to concentrations of saturated fatty acids found in obese individuals. We report that palmitate (C16:0, 200 μM) significantly modulates the macrophage gene signature, lowers the expression of transcription factors that positively regulate IL-10 expression (MAFB, AhR), and promotes a proinflammatory state whose acquisition requires JNK activation. Unlike LPS, palmitate exposure does not activate STAT1, and its transcriptional effects can be distinguished from those triggered by LPS, as both agents oppositely regulate the expression of CCL19 and TRIB3. Besides, palmitate conditions macrophages for exacerbated proinflammatory responses (lower IL-10 and CCL2, higher TNF-α, IL-6, and IL-1β) toward pathogenic stimuli, a process also mediated by JNK activation. All of these effects of palmitate are fatty acid specific because oleate (C18:1, 200 μM) does not modify the macrophage transcriptional and functional profiles. Therefore, pathologic palmitate concentrations promote the acquisition of a specific polarization state in human macrophages and condition macrophages for enhanced responses toward inflammatory stimuli, with both effects being dependent on JNK activation. Our results provide further insight into the macrophage contribution to obesity-associated inflammation.

http://ift.tt/2hG6zXR

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN [AUTOIMMUNITY]

Type I IFN and nucleic acid–sensing TLRs are both strongly implicated in the pathogenesis of lupus, with most patients expressing IFN-induced genes in peripheral blood cells and with TLRs promoting type I IFNs and autoreactive B cells. About a third of systemic lupus erythematosus patients, however, lack the IFN signature, suggesting the possibility of type I IFN–independent mechanisms. In this study, we examined the role of type I IFN and TLR trafficking and signaling in xenobiotic systemic mercury-induced autoimmunity (HgIA). Strikingly, autoantibody production in HgIA was not dependent on the type I IFN receptor even in NZB mice that require type I IFN signaling for spontaneous disease, but was dependent on the endosomal TLR transporter UNC93B1 and the endosomal proton transporter, solute carrier family 15, member 4. HgIA also required the adaptor protein-3 complex, which transports TLRs from the early endosome to the late endolysosomal compartments. Examination of TLR signaling pathways implicated the canonical NF-B pathway and the proinflammatory cytokine IL-6 in autoantibody production, but not IFN regulatory factor 7. These findings identify HgIA as a novel type I IFN–independent model of systemic autoimmunity and implicate TLR-mediated NF-B proinflammatory signaling from the late endocytic pathway compartments in autoantibody generation.

http://ift.tt/2hG6J1p