Stepwise intervention including 1-on-1 counseling is highly effective in increasing influenza vaccination among health care workers

Publication date: Available online 4 January 2017
Source:American Journal of Infection Control
Author(s): Younghee Jung, Mihye Kwon, Jeongmi Song
BackgroundThe influenza vaccination rate among health care workers (HCWs) remains suboptimal. We attempted to increase vaccine uptake in HCWs by nonmandatory measures, including 1-on-1 counseling.MethodsIn 2015 we used a stepwise approach including (1) text messaging on the last day of the vaccination period, (2) extending the vaccination period by 3 days, (3) education for the low uptake group, and (4) 1-on-1 counseling for unvaccinated HCWs after the 3 interventions.ResultsThere were 1,433 HCWs included. By the end of the initial 3 days, the uptake rate was 80.0% (1,146/1,433). During an extension for a further 3 days, 33 additional HCWs received the vaccine. One month after starting the vaccination, 90.1% (1,291/1,433) of the HCWs were vaccinated, but this included only 76.1% (210/276) of the doctors (lowest among HCWs). After 3 educational presentations targeted at the unvaccinated doctors, no additional individuals were vaccinated in the following 2 weeks. After 1-on-1 counseling for unvaccinated HCWs, the overall vaccination rate increased to 94.7% (1,357/1,433) in 2015, higher than in the previous year (82.5%, P < .001). Of the unvaccinated doctors, 63.2% (43/68) were vaccinated, therefore achieving 92.4% (255/276) compliance, higher than the 56.5% in the previous year (152/269, P < .001).ConclusionsStepwise intervention including 1-on-1 counseling is effective in increasing influenza vaccination rates among HCWs.



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Despite awareness of recommendations, why do health care workers not immunize pregnant women?

Publication date: Available online 4 January 2017
Source:American Journal of Infection Control
Author(s): Anat Gesser-Edelsburg, Yaffa Shir-Raz, Samah Hayek, Sharon Aassaraf, Lior Lowenstein
Studies indicate uncertainty surrounding vaccination safety and efficacy for pregnant women, causing a central problem for health authorities. In this study, approximately 26% of participants do not recommend the tetanus, diphtheria, and acellular pertussis and influenza vaccines to their patients, although being aware of the health ministry recommendations. We found significant statistical discrepancies between the knowledge about the recommendations and their actual implementation, revealing the concerns of health care workers regarding vaccine safety.



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Transmission of Salmonella enteritidis after endoscopic retrograde cholangiopancreatography because of inadequate endoscope decontamination

Publication date: Available online 4 January 2017
Source:American Journal of Infection Control
Author(s): Paul Robertson, Andrew Smith, Margaret Anderson, Jackie Stewart, Kate Hamilton, Sandra McNamee, Evonne T. Curran
We report a historic nosocomial outbreak of Salmonella enteritidis affecting 4 inpatients who underwent endoscopic retrograde cholangiopancreatography. The cause was attributed to inadequate decontamination of an on-loan endoscope used over a weekend. This report highlights the risks of using on-loan endoscopes, particularly regarding their commissioning and adherence to disinfection protocols. In an era of increasing antibiotic resistance, transmission of Enterobacteriaceae by endoscopes remains a significant concern.



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Risk of sharps injuries among home care aides: Results of the Safe Home Care survey

Publication date: Available online 4 January 2017
Source:American Journal of Infection Control
Author(s): Natalie M. Brouillette, Margaret M. Quinn, David Kriebel, Pia K. Markkanen, Catherine J. Galligan, Susan R. Sama, Rebecca J. Gore, Angela K. Laramie, Letitia Davis
ObjectivesHome care (HC) aides constitute an essential, rapidly growing workforce. Technology advances are enabling complex medical care at home, including procedures requiring the percutaneous use of sharp medical devices, also known as sharps. Objectives were to quantify risks of sharps injuries (SI) in a large HC aide population, compare risks between major occupational groups, and evaluate SI risk factors.MethodsA questionnaire survey was administered to aides hired by HC agencies and directly by clients. One thousand one hundred seventy-eight aides completed questions about SI and potential risk factors occurring in the 12 months before the survey. SI rates were calculated and Poisson regression models identified risk factors.ResultsAides had a 2% annual risk of experiencing at least 1 SI (95% confidence interval [CI], 1.1-2.6). Client-hired aides, men, and immigrants had a higher risk than their counterparts. Risk factors among all HC aides included helping a client use a sharp device (rate ratio [RR], 5.62; 95% CI, 2.75-11.50), observing used sharps lying around the home (RR, 2.68; 95% CI, 1.27-5.67), and caring for physically aggressive clients (RR, 2.82; 95% CI, 1.36-5.85).ConclusionsHC aides experience serious risks of SI. Preventive interventions are needed, including safety training for clients and their families, as well as aides.



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No bacterial growth found in spiked intravenous fluids over an 8-hour period

Publication date: Available online 4 January 2017
Source:American Journal of Infection Control
Author(s): Richard E. Haas, Edwin Beitz, Amy Reed, Howard Burtnett, Jason Lowe, Arthur E. Crist, Kevin A. Stierer, Allan M. Birenberg
Protocol changes prompted by the Joint Commission mandating intravenous (IV) fluid bags to be used within 1 hour of spiking because of possible bacterial contamination have sparked clinical and economic concerns. This study investigated the degree of bacterial growth in which samples were obtained from spiked IV fluid bags at the time of spiking and 1, 2, 4, and 8 hours after spiking. No bacterial growth occurred in any of the 80 bags of Lactated Ringer's (LR) IV solutions sampled. This study demonstrated that LR IV bags do not support any bacterial growth for up to 8 hours after spiking.



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Evaluation of paeonol-loaded transethosomes as transdermal delivery carriers

Publication date: 1 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 99
Author(s): Z.X. Chen, B. Li, T. Liu, X. Wang, Y. Zhu, L. Wang, X.H. Wang, X. Niu, Y. Xiao, Q. Sun
Paeonol shows effective anti-allergic, anti-inflammatory and analgesic activities. However, because of its poor solubility in water and high volatility at room temperature, the application of this drug is restricted in the clinic. The objective of this research was to develop a biocompatible paeonol formulation with improved stability, skin delivery and pharmacokinetic efficiency. In this paper, paeonol-loaded vesicles were prepared using an ethanol injection method. Nano-vesicles were characterized for their physical properties and encapsulation efficiency (EE). Drug permeation behavior in vitro and deposition quantity in porcine ear skin were measured with a Valia-Chien (V-C) diffusion device. Additionally, a validated and sensitive high performance liquid chromatography (HPLC) method was developed to analyze paeonol concentrations in rat plasma after transdermal administration. The results showed that the particle-size order of the nano-vesicles was the following: transethosomes (122.5±7.5nm)<transfersomes (256.5±8.9nm). Compared to the paeonol transfersomes, the transethosomes had a higher EE (85.5±5.2%), and they showed a spherical morphology with a smooth surface when viewed under a transmission electron microscope (TEM). In an in vitro permeation study, the paeonol transethosomes showed an enhanced transdermal flux of 95.7±8.8μg/cm²/h and a higher deposition quantity in porcine ear skin compared to the transfersomes. A one-compartment first-order absorption model could be used to describe the pharmacokinetics of paeonol in rats after transdermal administration. The AUC of the paeonol transethosomes was approximately 1.57- and 3.52-fold higher than those of the transfersomes and a saturated solution of paeonol in 35% ethanol, respectively. The results demonstrated that the paeonol transethosomes had a narrow size distribution, high encapsulation efficiency, and long residence in the plasma. This formulation remarkably enhanced the bioavailability of paeonol.

Graphical abstract

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A new approach to mineralization of flaxseed (Linum usitatissimum L.) for trace element analysis by flame atomic absorption spectrometry

Publication date: 1 June 2017
Source:Food Chemistry, Volume 224
Author(s): João P.S. Oliveira, Francisco L.F. Silva, Raimundo J.G. Monte, Wladiana O. Matos, Gisele S. Lopes
A new approach to the analysis of Cu, Fe, Mn and Zn in flaxseed was developed based on infrared-assisted acid digestion. Quantitation by flame atomic absorption spectrometry yields results in agreement with those arising from aggressive total decomposition using conventional microwave-assisted (MW) digestions. A full factorial design in two levels was applied to evaluate the impact of significant variables for all elements to determine optimal experimental conditions. A desirability function revealed these to be: 2.0g sample mass, 8mL of HNO3 and 8min of heating time in the IR system. Precision better than 10% (RSD) was obtained, superior to that of a combined IR-MW approach. Sample preparation based on IR-assisted digestion provides a rapid and inexpensive alternative to other conventional techniques for the analysis of complex samples and is able to accommodate relatively large masses of sample, alleviating potential homogeneity issues as well as enhancing detection power.



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Nanostructured biosensor for detecting glucose in tear by applying fluorescence resonance energy transfer quenching mechanism

Publication date: 15 May 2017
Source:Biosensors and Bioelectronics, Volume 91
Author(s): Longyi Chen, Wai Hei Tse, Yi Chen, Matthew W. McDonald, James Melling, Jin Zhang
In this paper, a nanostructured biosensor is developed to detect glucose in tear by using fluorescence resonance energy transfer (FRET) quenching mechanism. The designed FRET pair, including the donor, CdSe/ZnS quantum dots (QDs), and the acceptor, dextran-binding malachite green (MG-dextran), was conjugated to concanavalin A (Con A), an enzyme with specific affinity to glucose. In the presence of glucose, the quenched emission of QDs through the FRET mechanism is restored by displacing the dextran from Con A. To have a dual-modulation sensor for convenient and accurate detection, the nanostructured FRET sensors were assembled onto a patterned ZnO nanorod array deposited on the synthetic silicone hydrogel. Consequently, the concentration of glucose detected by the patterned sensor can be converted to fluorescence spectra with high signal-to-noise ratio and calibrated image pixel value. The photoluminescence intensity of the patterned FRET sensor increases linearly with increasing concentration of glucose from 0.03mmol/L to 3mmol/L, which covers the range of tear glucose levels for both diabetics and healthy subjects. Meanwhile, the calibrated values of pixel intensities of the fluorescence images captured by a handhold fluorescence microscope increases with increasing glucose. Four male Sprague-Dawley rats with different blood glucose concentrations were utilized to demonstrate the quick response of the patterned FRET sensor to 2µL of tear samples.



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Dry ashing and microwave-induced plasma optical emission spectrometry as a fast and cost-effective strategy for trace element analysis

Publication date: May 2017
Source:Microchemical Journal, Volume 132
Author(s): Charles B. Williams, Thomas G. Wittmann, Tina McSweeney, Paul Elliott, Bradley T. Jones, George L. Donati




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Facile synthesis and spectroscopic characterization of fluorinated graphene with tunable C/F ratio via Zn reduction

Publication date: 1 April 2017
Source:Applied Surface Science, Volume 400
Author(s): Xianqing Liang, Ming Lao, Deyou Pan, Shuiying Liang, Dan Huang, Wenzheng Zhou, Jin Guo
A facile approach has been developed to synthesize fluorinated graphene (FG) nanosheets with tunable C/F ratio through liquid-phase exfoliation of fluorinated graphite (FGi) in N-methyl-2-pyrrolidone (NMP) and subsequent reduction with Zn powder. The evolution of surface composition and electronic structure of FG is investigated by X-ray photoelectron spectroscopy (XPS), X-ray absorption near-edge structure (XANES) spectroscopy and Raman spectroscopy. It is shown that the C/F atomic ratio of FG can be easily varied by Zn reduction with different reaction time and addition of diluted HCl solution. Both XPS and XANES results indicate the effective removal of covalent CF bonds and progressive restoration of sp²-hybridized structure upon the treatment of FG with Zn. Raman measurements further reveal that Zn reduction can effectively restore the π-electron conjugated electronic structure and reduce the optical gap of FG. This study provides a simple and effective route to tailor the surface composition and electronic structure of FG for potential applications.

Graphical abstract

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Tacrolimus-Eluting Suture Inhibits Neointimal Hyperplasia: An Experimental In Vivo Study in Rats

Publication date: Available online 4 January 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): K. Ak, E. Ak, O. Dericioglu, T. Canak, J. Akbuga, N. Ozkan, S. Cetinel, S. Isbir, S. Arsan, A. Cobanoglu
Objective/BackgroundNeointimal hyperplasia (NIH) remains one of the leading causes of graft failure after vascular anastomoses. Cytotoxic drugs, such as rapamycin and tacrolimus, have been shown to inhibit the development of NIH. In this study, the aim was to test the impact of a sustained releasing tacrolimus–chitosan-eluting suture on the development of NIH in a rat model.MethodsAfter tacrolimus–chitosan coating of a 7/0 polyvinylidene difluoride (PVDF) Trofilen^® suture, the tacrolimus concentration on the coated suture and in vitro release trials were performed spectrophotometrically. Twelve Wistar rats were included. After midline laparotomy, a 7–8 mm longitudinal aortotomy in the infrarenal aorta was made and then closed by a bare 7/0 PVDF (group C, n = 6) and a 7/0 tacrolimus–chitosan coated PVDF suture (0.65 μg/cm tacrolimus [0.9 wt%] + 1.82 μg/cm chitosan [2.28 wt%]) (group T, n = 6). After 1 month, rats were sacrificed and aortotomy sites were examined histologically by ratio of intimal area (including neointima) and immunohistochemically by α-smooth muscle actin (ASMA) and proliferating cell nuclear antigen (PCNA) immunostaining. The PCNA positive cells were indexed to total cell number and expressed as percentage.ResultsIn vitro tacrolimus release tests for a 7/0 tacrolimus–chitosan coated PVDF suture were confirmed for 1 month without an initial burst release. Endothelialisation over the aortotomy line occurred in both groups. The area of neointima was significantly reduced in group T compared with group C (ratio 0.22 ± 0.12 vs. 0.42 ± 0.11; p = .017) 1 month post-operatively. Likewise, the percentage of PCNA immunostaining significantly decreased in group C compared with group T (3.83 ± 2.85% vs. 11.17 ± 7.78%; p = .026). The cells constituting NIH were positive for ASMA immunostaining.ConclusionsTacrolimus–chitosan-eluting suture is shown to be an effective way to reduce NIH without interfering with normal endothelialisation.



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Commentary on “Macroscopic and Histological Analysis of Vessel Wall Reaction after Mechanochemical Endovenous Ablation Using the Clarivein OC Device in an Animal Model”

Publication date: Available online 4 January 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): M.E. Vuylsteke




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Clinimetric Evaluation of the Vascular Quality of Life Questionnaire in Patients with Lower Limb Ischaemia

Publication date: Available online 4 January 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): A.P. Conijn, T.B.K. Santema, S. Bipat, M.J.W. Koelemay, R.J. de Haan
ObjectivesAlthough commonly used to measure health related quality of life in patients with lower limb ischaemia, the measurement properties of the VascuQol and its assumed underlying health dimensions have not been studied in depth. The objective of this study was therefore to evaluate aspects of reliability and validity of the Dutch version of the VascuQol in patients with intermittent claudication (IC) and critical limb ischaemia (CLI).MethodsTwo datasets containing 195 patients with IC and 150 patients with CLI were used. Face validity of the VascuQol was examined in interviews with patients and a survey among health professionals. Homogeneity and structural validity of the VascuQol were assessed using Cronbach's α coefficients and explanatory factor analysis. Furthermore, convergent validity and known group validity were assessed.ResultsDuring the face validity interviews, three items were indicated as less relevant. Homogeneity analysis showed that the α coefficient of the VascuQol was .93, while the symptoms and social domains had α coefficients below the threshold of .70. The original five domains of the VascuQol could not be reproduced. Instead, factor analysis yielded a three factor solution. Moderate correlations were found for the activities, social and emotional VascuQol domains and matching health domains of other patient reported outcome measures (PROMs). Lower convergent correlations were observed for the pain domain and the sumscore of the VascuQol. The VascuQol was able to distinguish between patients' level of HRQL in relation to their disease severity (IC versus CLI patients).ConclusionsThere is room for improvement of the VascuQol questionnaire. Further clinimetric studies should be performed to strengthen clinically relevant findings based on this instrument.



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Energy dissipation dataset for reversible logic gates in quantum dot-cellular automata

Publication date: February 2017
Source:Data in Brief, Volume 10
Author(s): Ali Newaz Bahar, Mohammad Maksudur Rahman, Nur Mohammad Nahid, Md. Kamrul Hassan
This paper presents an energy dissipation dataset of different reversible logic gates in quantum-dot cellular automata. The proposed circuits have been designed and verified using QCADesigner simulator. Besides, the energy dissipation has been calculated under three different tunneling energy level at temperature T=2K. For estimating the energy dissipation of proposed gates; QCAPro tool has been employed.



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Direct acting oral anticoagulant: Bench to bedside

Publication date: Available online 3 January 2017
Source:Medical Journal Armed Forces India
Author(s): D.S. Chadha, P. Bharadwaj
Vitamin K antagonists are an effective group of oral anticoagulants. However because of genetic variability in their metabolism and multiple food and drug interactions, these drugs have narrow therapeutic window with unpredictable anticoagulant effects requiring constant monitoring. Several newer direct acting oral anticoagulants have been approved for prevention of stroke in patients with nonvalvular atrial fibrillation and treatment or prevention of venous thromboembolism. The direct acting oral anticoagulants include the direct thrombin inhibitor (dabigatran) and the factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). These have a better safety and efficacy profile compared to Vitamin K antagonists. Some of the limitations of these drugs include increased risk of gastrointestinal bleeding (except apixaban), increased risk for thrombotic complication upon sudden cessation of therapy and inability to monitor the anticoagulation efficacy. Recent availability of the antidote to these drugs has further strengthened their safety profile. In the current review we will discuss these agents with focus on their potential clinical uses and limitations.



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Ectopic pregnancy – Review of 80 cases

Publication date: Available online 3 January 2017
Source:Medical Journal Armed Forces India
Author(s): S.K. Kathpalia, D. Arora, Namrita Sandhu, Pooja Sinha
BackgroundEctopic pregnancy or extrauterine pregnancy will invariably result in abortion or rupture. Though there are risk factors for ectopic pregnancy, but at times the condition can occur without any apparent predisposing factor. Cases admitted with provisional diagnosis of ectopic pregnancy were included in this prospective study.MethodsEighty suspected cases of ectopic pregnancy were incorporated in the study. The management was done based on standard practice. All the cases underwent urine pregnancy test, routine blood investigations including blood group, and transvaginal ultrasound. Serial βhCG was measured in cases where the diagnosis was not clear initially.ResultsIncidence of ectopic was 2.46 per 100 deliveries; there was no apparent risk factor in 28.7% and many cases had more than one risk factor. 'Triad' of ectopic was present in only 21 cases. Sixteen cases were asymptomatic and two were admitted as emergency. Ultrasound findings were inconsistent and wide ranging. In 37 doubtful cases, βhCG was measured serially.There was one case of suspected interstitial pregnancy confirmed on laparoscopy. Twenty-seven cases were managed medically, and 9 were managed expectantly. Forty-six cases were managed surgically either by laparoscopy or by laparotomy. Salpingectomy was performed in 37 cases, and salpingostomy in 7 cases either laparoscopically or by laparotomy.ConclusionEctopic pregnancy can be managed by laparotomy, operative laparoscopy, and medically and occasionally by observation alone. Management must be customized to the clinical condition and needs of future fertility of the patient.



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Glued intraocular lens with descemet stripping endothelial keratoplasty in aphakic bullous keratopathy

Publication date: Available online 3 January 2017
Source:Medical Journal Armed Forces India
Author(s): Anita Mani, P.S. Moulick, Alok Sati, Sandeep Gupta




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Translabyrinthine approach to internal auditory meatus: A retrospective study

Publication date: Available online 4 January 2017
Source:Medical Journal Armed Forces India
Author(s): Sunil Goyal, Kiran Natarajan, Amarnath Devarasetty, T. Sarankumar, Neha Chauhan, Mohan Kameswaran
BackgroundEar and the lateral skull base surgery is challenging and yet fascinating for a Neuro-otologist. A thorough knowledge of the complex anatomy is indispensable for the surgeon in order to provide the best possible care.MethodsThe aim of the study was to highlight the present day indications for translabyrinthine approach to IAM from a Neuro-otologist perspective.ResultsThere were a total of 7 patients who underwent Translabyrinthine approach at our centre. In the present study we have reported cases of Vestibular Schwannoma, Facial nerve schwannoma, Cholesteatoma involving the IAM, Meniere's disease with refractory vertigo which were managed via translabyrinthine approach. We also encountered, probably the first reported case, tuberculoma of the IAM which was clinical suspected to be vestibular schwannoma.ConclusionThe article presents different clinical situations where this approach can be suitably utilized and has been dealt with via a retrospective study encountered at our centre.



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Radioiodine – the success story of Nuclear Medicine

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Reply to letter of Adams and Kwee: Critical considerations on the predictive value of end-of-treatment FDG/PET in lymphoma

http://ift.tt/2hQZjGn

Distinguishing synchronous from metachronous manifestation of distant metastases: a prognostic feature in differentiated thyroid carcinoma

Abstract

Aim

Distant metastasis has a negative impact on survival in differentiated thyroid carcinoma (DTC). The timing of this manifestation, however, is of unknown prognostic relevance. The aim of this retrospective study was to investigate the potential significance of discriminating synchronous versus metachronous distant metastases (SDM vs. MDM) for the outcome of patients with DTC.

Methods

We retrospectively analyzed a consecutive cohort of n = 89 patients with distant metastases of DTC (43 with follicular, 46 with papillary DTC histology; mean age 52.6 ± 17.7 years) undergoing radioiodine treatment at our institution. All patients were treated with the same protocol consisting of ablative radioiodine therapy (RIT, 3.7 GBq) and one post-ablation treatment after 3 months (3.7–11.1 GBq). Further cycles of RIT were administered for recurrent, progressive or newly developed metastatic disease. We distinguished 2 types of distant metastases according to the time of manifestation: SDM (within ≤12 months after DTC diagnosis) and MDM (occurring >12 months after diagnosis). Tumor-related survival was analyzed using the Kaplan–Meier method. Uni- and multivariate analyses including the Cox proportional hazards model were performed with a significance level of p < 0.05.

Results

The mean follow-up period was 13.8 ± 1.2 years. SDM were present in 49 (55.1 %), MDM in 40 (44.9 %) patients. MDM were associated with shorter tumor-related survival (p = 0.002). 5-year and 10-year survival rates were 68.5 % and 34.8 % for MDM, and 84.3 % and 66.9 % for SDM, respectively. Within both age subgroups of <45 and ≥45 years, SDM were also linked with longer survival. No effect on tumor-related survival was found for the co-variables sex, lymph node metastases and histologic type.

Conclusion

Distinguishing synchronous from metachronous manifestation of distant metastases may add an important prognostic feature to risk stratification in DTC, as proven metachronous appearance is associated with impaired survival.

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68 Ga-PSMA PET/CT with MRI fusion: spinal cord metastasis from prostate cancer

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Volume-based predictive biomarkers of sequential FDG-PET/CT for sunitinib in cancer of unknown primary: identification of the best benefited patients

Abstract

Purpose

To test the performance of sequential ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in predicting survival after sunitinib therapies in patients with cancer of unknown primary (CUP).

Methods

CUP patients were enrolled for sequential PET/CT scanning for sunitinib and a control group. Univariate and multivariate analysis were applied to test the efficacy of sunitinib therapy in CUP patients. Next, sequential analyses involving PET/CT parameters were performed to identify and validate sensitive PET/CT biomarkers for sunitinib therapy. Finally, time-dependent receiver operating characteristic (TDROC) analyses were performed to compare the predictive accuracy.

Results

Multivariate analysis proved that sunitinib group had significantly improved survival (p < 0.01) as compared to control group. After cycle 2 of therapy, multivariate analysis identified volume-based PET/CT parameters as sensitive biomarkers for sunitinib (p < 0.01). TDROC curves demonstrated whole-body total lesion glycolysis reduction (Δ WTLG) and follow-up WTLG to have good accuracy for efficacy prediction. This evidence was validated after cycle 4 of therapy with the same method.

Conclusion

Sunitinib therapy proved effective in treatment of CUP. PET/CT volume-based parameters may help predict outcome of sunitinib therapy, in which Δ WTLG and follow-up WTLG seem to be sensitive biomarkers for sunitinib efficacy. Patients with greater reduction and lower WTLG at follow-up seem to have better survival outcome.

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Brain perfusion SPECT for brain death assessment

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Clinical values of left ventricular mechanical dyssynchrony assessment by gated myocardial perfusion SPECT in patients with acute myocardial infarction and multivessel disease

Abstract

Purpose

The aim of this study was to evaluate the prognostic value of additional evaluation of left ventricular mechanical dyssynchrony (LVMD) by gated myocardial perfusion single-photon emission computed tomography (GMPS) in patients with acute myocardial infarction (MI) and multivessel disease.

Methods

One hundred and nine acute MI patients with >50 % stenosis in at least one non-culprit artery who underwent GMPS within 2 weeks were enrolled. All patients underwent successful revascularization of the culprit arteries. Those with previous MI, atrial fibrillation, or frequent ventricular premature complexes, cardiac devices, significant patient motion, or procedure-related events were excluded. Phase standard deviation (PSD) and phase histogram bandwidth (PBW) were measured for assessment of LVMD. Patients were followed up for a median of 26 months after index MI, for composite major adverse cardiac events (MACE), which consisted with all-cause death, unplanned hospitalization due to heart failure and severe ventricular arrhythmias (sustained ventricular tachycardia or ventricular fibrillation). Independent predictors of MACE were evaluated.

Results

MACE occurred in 22 patients (20 %). Stress PSD (53.3 ± 17.3° vs. 35.3 ± 18.9°; p <0.001), stress PBW (147.6 ± 54.6° vs. 96.8 ± 59.2°; p = 0.001) and resting PBW (126.8 ± 37.5° vs. 96.6 ± 48.9°; p = 0.001) were significantly higher in patients with MACE compared to those without. Multivariate analysis revealed that stress PSD ≥45.5° and stress PBW ≥126.0° were predictive of MACE, as well as suboptimal non-culprit artery revascularization (SNR) and renin-angiotensin system (RAS) blockade medication. Higher stress PSD and stress PBW were associated with poorer prognosis both in patients with and without SNR, and those with RAS blockade medication, but not in those without RAS blockade medication.

Conclusions

LVMD measured by GMPS showed added prognostic value in acute MI with multivessel disease. GMPS could serve as a comprehensive evaluation imaging tool in patients with acute MI and multivessel disease.

http://ift.tt/2iAF1or

Critical considerations on the predictive value of end-of-treatment FDG-PET in lymphoma

http://ift.tt/2hQUywh

The delicate balance between present and future

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Do we need FDG-PET/CT to assess atherosclerosis?

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123 I-mIBG scintigraphy in neuroblastoma: development of a SIOPEN semi-quantitative reporting ,method by an international panel

Abstract

Purpose

A robust method is required to standardise objective reporting of diagnostic ¹²³I-mIBG images in neuroblastoma. Prerequisites for an appropriate system are low inter- and intra-observer error and reproducibility across a broad disease spectrum. We present a new reporting method, developed and tested for SIOPEN by an international expert panel.

Method

Patterns of abnormal skeletal ¹²³I-mIBG uptake were defined and assigned numerical scores [0–6] based on disease extent within 12 body segments. Uptake intensity was excluded from the analysis. Data sets from 82 patients were scored independently by six experienced specialists as unblinded pairs (pre- and post-induction chemotherapy) and in random order as a blinded study. Response was defined as ≥50 % reduction in post induction score compared with baseline.

Results

In total, 1968 image sets were reviewed individually. Response rates of 88 % and 82 % were recorded for patients with baseline skeletal scores ≤23 and 24-48 respectively, compared with 44 % response in patients with skeletal scores >48 (p = 0.02). Reducing the number of segments or extension scale had a small but statistically negative impact upon the number of responses detected. Intraclass correlation coefficients [ICCs] calculated for the unblinded and blinded study were 0.95 at diagnosis and 0.98 and 0.99 post-induction chemotherapy, respectively.

Conclusions

The SIOPEN mIBG score method is reproducible across the full spectrum of disease in high risk neuroblastoma. Numerical assessment of skeletal disease extent avoids subjective evaluation of uptake intensity. This robust approach provides a reliable means with which to examine the role of 123I mIBG scintigraphy as a prognostic indicator in neuroblastoma.

http://ift.tt/2hQY8GB

Recurrent bladder carcinoma: clinical and prognostic role of 18 F-FDG PET/CT

Abstract

Aim

A small number of studies evaluated the detection rate of lesions from bladder carcinoma (BC) of 18 F-FDG PET/CT in the restaging process. However, the prognostic role of FDG PET/CT still remains unclear. The aim of the present study was to evaluate the accuracy, the effect upon treatment decision, and the prognostic value of FDG PET/CT in patients with suspected recurrent BC.

Materials and Methods

Forty-one patients affected by BC underwent FDG PET/CT for restaging purpose. The diagnostic accuracy of visually interpreted FDG PET/CT was assessed compared to histology (n = 8), other diagnostic imaging modalities (contrast-enhanced CT in 38/41 patients and MRI in 15/41) and clinical follow-up (n = 41). Semiquantitative PET values (SUVmax, SUVmean, SUL, MTV, TLG) were calculated using a graph-based method. Progression-free survival (PFS) and overall survival (OS) were assessed by using Kaplan-Meier curves. The risk of progression (hazard ratio, HR) was computed by Cox regression analysis by considering all the available variables.

Results

PET was considered positive in 21 of 41 patients. Of these, recurrent BC was confirmed in 20 (95 %). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FDG PET/CT were 87 %, 94 %, 95 %, 85 %, 90 %. AUC was 0.9 (95 %IC 0.8-1). Bayesian positive and negative likelihood ratios were 14.5 and 0.13, respectively. FDG PET/CT findings modified the therapeutic approach in 16 patients (modified therapy in 10 PET-positive patients, watch-and-wait in six PET-negative patients). PFS was significantly longer in patients with negative scan vs. those with pathological findings (85 % vs. 24 %, p < 0.05; HR = 12.4; p = 0.001). Moreover, an unremarkable study was associated with a longer OS (88 % vs. 47 % after 2 years and 87 % vs. 25 % after 3 years, respectively, p < 0.05). Standardized uptake value (SUV)max > 6 and total lesion glycolysis (TLG) > 8.5 were recognized as the most accurate thresholds to predict PFS (2-year PFS 62 % for SUVmax < 6 vs. 15 % for SUVmax > 6, p = 0.018; 2-year PFS 66 % for TLG < 8.5 vs. 18 % for TLG > 8.5, p = 0.09).

Conclusion

A very good diagnostic performance for FDG PET/CT was confirmed in patients with suspected recurrent BC. FDG PET/CT allowed for a change in treatment decision in about 40 % of cases and showed an important prognostic value in assessing PFS and OS.

http://ift.tt/2iAF17V

The role of FDG PET/CT in patients treated with neoadjuvant chemotherapy for localized bone sarcomas

Abstract

Purpose

The histological response to neoadjuvant chemotherapy is an important prognostic factor in patients with osteosarcoma (OS) and Ewing sarcoma (EWS). The aim of this study was to assess baseline primary tumour FDG uptake on PET/CT, and serum values of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), to establish whether these factors are correlated with tumour necrosis and prognosis.

Methods

Patients treated between 2009 and 2014 for localized EWS and OS, who underwent FDG PET/CT as part of their staging work-up, were included. The relationships between primary tumour SUVmax at baseline (SUV1), SUVmax after induction chemotherapy (SUV2), metabolic response calculated as [(SUV1 − SUV2)/SUV1)] × 100, LDH and ALP and tumour response/survival were analysed. A good response (GR) was defined as tumour necrosis >90 % in patients with OS, and grade II-III Picci necrosis (persitence of microscopic foci only or no viable tumor) in patients with Ewing sarcoma.

Results

The study included 77 patients, 45 with EWS and 32 with OS. A good histological response was achieved in 53 % of EWS patients, and 41 % of OS patients. The 3-year event-free survival (EFS) was 57 % in EWS patients and 48 % OS patients. The median SUV1 was 5.6 (range 0 – 17) in EWS patients and 7.9 (range 0 – 24) in OS patients (p = 0.006). In EWS patients the GR rate was 30 % in those with a high SUV1 (≥6) and 72 % in those with a lower SUV1 (p = 0.0004), and in OS patients the GR rate was 29 % in those with SUV1 ≥6 and 64 % in those with a lower SUV1 (p = 0.05). In the univariate analysis the 3-year EFS was significantly better in patients with a low ALP level (59 %) than in those with a high ALP level (22 %, p = 0.02) and in patients with a low LDH level (62 %) than in those with a high LDH level (37 %, p = 0.004). In EWS patients the 3-year EFS was 37 % in those with a high SUV1 and 75 % in those with a low SUV1 (p = 0.004), and in OS patients the 3-year EFS was 32 % in those with a high SUV1 and 66 % in those with a low SUV1 (p = 0.1). Histology, age and gender were not associated with survival. In the multivariate analysis, SUV1 was the only independent pretreatment prognostic factor to retain statistical significance (p = 0.017). SUV2 was assessed in 25 EWS patients: the median SUV2 was 1.9 (range 1 – 8). The GR rate was 20 % in patients with a high SUV2, and 67 % in those with a low SUV2 (p = 0.02). A good metabolic response (SUV reduction of ≥55 %) was associated with a 3-year EFS of 80 % and a poor metabolic response with a 3-year EFS of 20 % (p = 0.05). In the OS patients the median SUV2 was 2.7 (range 0 – 4.5). Neither SUV2 nor the metabolic response was associated with outcome in OS patients.

Conclusion

FDG PET/CT is a useful and noninvasive tool for identifying patients who are more likely to be resistant to chemotherapy. If this finding is confirmed in a larger series, SUV1, SUV2 and metabolic response could be proposed as factors for stratifying EWS patients to identify those with high-grade localized bone EWS who would benefit from risk-adapted induction chemotherapy.

http://ift.tt/2hQWZis

Acknowledging gray areas: 2015 vs. 2009 American Thyroid Association differentiated thyroid cancer guidelines on ablating putatively low-intermediate-risk patients

Abstract

Purpose

Typically formulated by investigators from "world centres of excellence," differentiated thyroid carcinoma (DTC) management guidelines may have more limited applicability in settings of less expert care and fewer resources. Arguably the world's leading DTC guidelines are those of the American Thyroid Association, revised in 2009 ("ATA 2009") and 2015 ("ATA 2015"). To further explore the issue of "real-world applicability" of DTC guidelines, we retrospectively compared indications for ablation using ATA 2015 versus ATA 2009 in a two-centre cohort of ablated T1–2, M0 DTC patients (N = 336). Based on TNM status and histology, these patients were low–intermediate risk, but many ultimately had other characteristics suggesting elevated or uncertain risk.

Methods

Working by consensus, two experienced nuclear medicine physicians considered patient and treatment characteristics to classify each case as having "no indication," a "possible indication," or a "clear indication" for ablation according to ATA 2009 or ATA 2015. The physicians also identified reasons for classification changes between ATA 2015 versus ATA 2009. Classification was unblinded, but the physicians had cared for only 138/336 patients, and the charts encompassed September 2010–October 2013, several years before the classification was performed.

Results

One hundred of 336 patients (29.8 %) changed classification regarding indication for ablation using ATA 2015 versus ATA 2009. Most reclassified patients (70/100) moved from "no indication" or "clear indication" to "possible indication." Reflecting this phenomenon, "possible indication" became the largest category according to the ATA 2015 classification (141/336, 42.0 %, versus 96/336, 28.6 %, according to ATA 2009). Many reclassifications were attributable to multiple clinicopathological characteristics, most commonly, stimulated thyroglobulin or anti-thyroglobulin antibody levels, multifocality, bilateral involvement, or capsular/nodal invasion.

Conclusions

Regarding indications for ablation, ATA 2015 appears to better "acknowledge grey areas," i.e., patients with ambiguous or unavailable data requiring individualised, nuanced decision-making, than does ATA 2009.

http://ift.tt/2iAD1MQ

Lymphocyte function following radium-223 therapy in patients with metastasized, castration-resistant prostate cancer

Abstract

Purpose

Therapy with the alpha-emitter radium-223 chloride (²²³Ra) is an innovative therapeutic option in patients with metastasized, castration-resistant prostate cancer. However, radiotherapy can lead to hematopoietic toxicity. The aim of this study was to determine if ²²³Ra therapy induces an impairment of cellular antimicrobial immune responses.

Methods

In 11 patients receiving ²²³Ra treatment, lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) were determined, using lymphocyte transformation testing and ELISpot, respectively. Lymphocyte function after stimulation with mitogens and microbial antigens was assessed prior to therapy and at day 1, 7 and 28 after therapy.

Results

Lymphocyte proliferation and the production of interferon-γ and interleukin-10 towards mitogens and antigens remained unchanged after therapy. Consistent with these in vitro data, we did not observe infectious complications after treatment.

Conclusions

The results argue against an impairment of lymphocyte function after ²²³Ra therapy. Thus, immune responses against pathogens should remain unaffected.

http://ift.tt/2hQSl3Y

Predictive medicine: towards a multi-parametric imaging for a personal risk stratification

http://ift.tt/2iALUGt

Adjuvant post-operative I-131 therapy in differentiated thyroid carcinoma: are the 2015 ATA guidelines an exact science or a dark art?

http://ift.tt/2hQYKvZ

Editorial European Journal of Nuclear Medicine and Molecular Imaging

http://ift.tt/2iAIVOf

Preclinical in vivo and in vitro comparison of the translocator protein PET ligands [ 18 F]PBR102 and [ 18 F]PBR111

Abstract

Purpose

To determine the metabolic profiles of the translocator protein ligands PBR102 and PBR111 in rat and human microsomes and compare their in vivo binding and metabolite uptake in the brain of non-human primates (Papio hamadryas) using PET-CT.

Methods

In vitro metabolic profiles of PBR102 and PBR111 in rat and human liver microsomes were assessed by liquid chromatography–tandem mass spectrometry. [¹⁸F]PBR102 and [¹⁸F]PBR111 were prepared by nucleophilic substitution of their corresponding p-toluenesulfonyl precursors with [¹⁸F]fluoride. List mode PET-CT brain imaging with arterial blood sampling was performed in non-human primates. Blood plasma measurements and metabolite analysis, using solid-phase extraction, provided the metabolite profile and metabolite-corrected input functions for kinetic model fitting. Blocking and displacement PET-CT scans, using PK11195, were performed.

Results

Microsomal analyses identified the O-de-alkylated, hydroxylated and N-de-ethyl derivatives of PBR102 and PBR111 as the main metabolites. The O-de-alkylated compounds were the major metabolites in both species; human liver microsomes were less active than those from rat. Metabolic profiles in vivo in non-human primates and previously published rat experiments were consistent with the microsomal results. PET-CT studies showed that K₁ was similar for baseline and blocking studies for both radiotracers; V_T was reduced during the blocking study, suggesting low non-specific binding and lack of appreciable metabolite uptake in the brain.

Conclusions

[¹⁸F]PBR102 and [¹⁸F]PBR111 have distinct metabolic profiles in rat and non-human primates. Radiometabolites contributed to non-specific binding and confounded in vivo brain analysis of [¹⁸F]PBR102 in rodents; the impact in primates was less pronounced. Both [¹⁸F]PBR102 and [¹⁸F]PBR111 are suitable for PET imaging of TSPO in vivo. In vitro metabolite studies can be used to predict in vivo radioligand metabolism and can assist in the design and development of better radioligands.

http://ift.tt/2hQOVyf

Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype

Publication date: March 2017
Source:Neurobiology of Aging, Volume 51
Author(s): Shorena Janelidze, Joakim Hertze, Katarina Nägga, Karin Nilsson, Christer Nilsson, Malin Wennström, Danielle van Westen, Kaj Blennow, Henrik Zetterberg, Oskar Hansson
Blood-brain barrier (BBB) dysfunction might be an important component of many neurodegenerative disorders. In this study, we investigated its role in dementia using large clinical cohorts. The cerebrospinal fluid (CSF)/plasma albumin ratio (Qalb), an indicator of BBB (and blood-CSF barrier) permeability, was measured in a total of 1015 individuals. The ratio was increased in patients with Alzheimer's disease, dementia with Lewy bodies or Parkinson's disease dementia, subcortical vascular dementia, and frontotemporal dementia compared with controls. However, this measure was not changed during preclinical or prodromal Alzheimer's disease and was not associated with amyloid positron emission tomography or APOE genotype. The Qalb was increased in diabetes mellitus and correlated positively with CSF biomarkers of angiogenesis and endothelial dysfunction (vascular endothelial growth factor, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1). In healthy elderly, high body mass index and waist-hip ratio predicted increased Qalb 20 years later. In summary, BBB permeability is increased in major dementia disorders but does not relate to amyloid pathology or APOE genotype. Instead, BBB impairment may be associated with diabetes and brain microvascular damage.



http://ift.tt/2j4ZxL3

Oligomeric amyloid-β peptide disrupts olfactory information output by impairment of local inhibitory circuits in rat olfactory bulb

Publication date: March 2017
Source:Neurobiology of Aging, Volume 51
Author(s): Bin Hu, Chi Geng, Xiao-Yu Hou
Although early olfactory dysfunction has been found in patients with Alzheimer's disease, the underlying mechanisms remain unclear. In this study, we investigated whether and how oligomeric amyloid-β peptide (Aβ) affects the responses of mitral cells (MCs). We found that oligomeric Aβ1–42 increased spontaneous and evoked firing rates but decreased the ratio of evoked to spontaneous firings in MCs. Aβ1–42 oligomers showed no impact on the hyperactivity exerted by pharmacological blockage of GABAA receptors, suggesting an involvement of GABAergic inhibitory transmission in Aβ1 to 42–induced over-excitability. It was further determined that Aβ1–42 oligomers inhibited the frequency of spontaneous inhibitory postsynaptic currents and miniature inhibitory postsynaptic currents, as well as the amplitude of miniature inhibitory postsynaptic currents in MCs. Both recurrent and lateral inhibition of MCs, which are critical for odor discrimination, were also disrupted by Aβ1–42 oligomers. The above data indicate that Aβ impairs local inhibitory circuits and thereby leads to perturbations of olfactory information output in the olfactory bulb. This study reveals a cellular and synaptic basis of olfactory deficits associated with Alzheimer's disease.



http://ift.tt/2iICs4c

A review of AirQ Models and their applications for forecasting the air pollution health outcomes

Abstract

Even though clean air is considered as a basic requirement for the maintenance of human health, air pollution continues to pose a significant health threat in developed and developing countries alike. Monitoring and modeling of classic and emerging pollutants is vital to our knowledge of health outcomes in exposed subjects and to our ability to predict them. The ability to anticipate and manage changes in atmospheric pollutant concentrations relies on an accurate representation of the chemical state of the atmosphere. The task of providing the best possible analysis of air pollution thus requires efficient computational tools enabling efficient integration of observational data into models. A number of air quality models have been developed and play an important role in air quality management. Even though a large number of air quality models have been discussed or applied, their heterogeneity makes it difficult to select one approach above the others. This paper provides a brief review on air quality models with respect to several aspects such as prediction of health effects.

http://ift.tt/2iPOlCs

Spinal neuropeptide expression and neuropathic behavior in the acute and chronic phases after spinal cord injury: effects of progesterone administration

Publication date: Available online 3 January 2017
Source:Peptides
Author(s): María F. Coronel, Marcelo J. Villar, Pablo R. Brumovsky, Susana L. González
Patients with spinal cord injury (SCI) develop chronic pain that severely compromises their quality of life. We have previously reported that progesterone (PG), a neuroprotective steroid, could offer a promising therapeutic strategy for neuropathic pain. In the present study, we explored temporal changes in the expression of the neuropeptides galanin and tyrosine (NPY) and their receptors (GalR1 and GalR2; Y1R and Y2R, respectively) in the injured spinal cord and evaluated the impact of PG administration on both neuropeptide systems and neuropathic behavior. Male rats were subjected to spinal cord hemisection at T13 level, received daily subcutaneous injections of PG or vehicle, and were evaluated for signs of mechanical and thermal allodynia. Real time PCR was used to determine relative mRNA levels of neuropeptides and receptors, both in the acute (1day) and chronic (28 days) phases after injury. A significant increase in Y1R and Y2R expression, as well as a significant downregulation in GalR2 mRNA levels, was observed 1day after SCI. Interestingly, PG early treatment prevented Y1R upregulation and resulted in lower NPY, Y2R and GalR1 mRNA levels. In the chronic phase, injured rats showed well-established mechanical and cold allodynia and significant increases in galanin, NPY, GalR1 and Y1R mRNAs, while maintaining reduced GalR2 expression. Animals receiving PG treatment showed basal expression levels of galanin, NPY, GalR1 and Y1R, and reduced Y2R mRNA levels. Also, and in line with previously published observations, PG-treated animals did not develop mechanical allodynia and showed reduced sensitivity to cold stimulation. Altogether, we show that SCI leads to considerable changes in the spinal expression of galanin, NPY and their associated receptors, and that early and sustained PG administration prevents them. Moreover, our data suggest the participation of galaninergic and NPYergic systems in the plastic changes associated with SCI-induced neuropathic pain, and further supports the therapeutic potential of PG- or neuropeptide-based therapies to prevent and/or treat chronic pain after central injuries.



http://ift.tt/2j9BAX1

Dopamine D1-like receptor in lateral habenula nucleus affects contextual fear memory and long-term potentiation in hippocampal CA1 in rats

Publication date: 15 March 2017
Source:Behavioural Brain Research, Volume 321
Author(s): Jiangping Chan, Xin Guan, Yiling Ni, Lilu Luo, Liqiang Yang, Pengyue Zhang, Jichuan Zhang, Yanmei Chen
The Lateral Habenula (LHb) plays an important role in emotion and cognition. Recent experiments suggest that LHb has functional interaction with the hippocampus and plays an important role in spatial learning. LHb is reciprocally connected with midbrain monoaminergic brain areas such as the ventral tegmental area (VTA). However, the role of dopamine type 1 receptor (D1R) in LHb in learning and memory is not clear yet. In the present study, D1R agonist or antagonist were administered bilaterally into the LHb in rats. We found that both D1R agonist and antagonist impaired the acquisition of contextual fear memory in rats. D1R agonist or antagonist also impaired long term potentiation (LTP) in hippocampal CA3-CA1 synapses in freely moving rats and attenuated learning induced phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) at Ser831 and Ser845 in hippocampus. Taken together, our results suggested that dysfunction of D1R in LHb affected the function of hippocampus.



http://ift.tt/2j4JNaW

Settlement ecology in Bronze Age Messenia

Publication date: March 2017
Source:Journal of Anthropological Archaeology, Volume 45
Author(s): Christopher S. Jazwa, Kyle A. Jazwa
In this paper, we model patterns of expansion and contraction of settlement in Bronze Age Messenia (ca. 3100–1050 BCE) using the ideal free distribution (IFD). We rank potential settlement locations on the landscape using environmental and cultural variables, including watershed size, which is a proxy for fresh water availability, net primary productivity, and the distance to the location of the Palace of Nestor at Pylos, a central site of political importance throughout most of the Bronze Age. The settlement chronology for the region is derived from an existing database of survey data and conforms to the predictions of the IFD. The highest-ranked habitats were settled first and the population expanded to lower-ranked habitats as population density increased. The data also conforms to the IFD prediction that important political centers should follow the same pattern, expanding from higher- to lower-ranked habitats. This model helps to provide an understanding of the effects of the unique environmental and cultural landscape of the region on settlement prior to the rise of the major Mycenaean centers in mainland Greece. The application of the IFD to a sociopolitically complex case demonstrates its broad potential for understanding historical trajectories in settlement patterns throughout the world.



http://ift.tt/2hQGCSS

Ink spot lentigo

Publication date: Available online 3 January 2017
Source:Annales de Dermatologie et de Vénéréologie
Author(s): M. Berger, L. Thomas, S. Dalle




http://ift.tt/2j9BXRb

Syndrome des cheveux incoiffables : association de malfaiteurs

Publication date: Available online 3 January 2017
Source:Annales de Dermatologie et de Vénéréologie
Author(s): O. Dereure




http://ift.tt/2iaNOKQ

Traitement du mélanome métastatique. Gestion de risque

Publication date: Available online 4 January 2017
Source:Annales de Dermatologie et de Vénéréologie
Author(s): C. Lebbe, C. Robert




http://ift.tt/2j9BVcc

c-FLIP Expression in Foxp3-Expressing Cells Is Essential for Survival of Regulatory T Cells and Prevention of Autoimmunity

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Carlos Plaza-Sirvent, Marc Schuster, Yvonne Neumann, Ulrike Heise, Marina C. Pils, Klaus Schulze-Osthoff, Ingo Schmitz
Regulatory T (Treg) cells are critical for the shutdown of immune responses and have emerged as valuable targets of immunotherapies. Treg cells can rapidly proliferate; however, the homeostatic processes that limit excessive Treg cell numbers are poorly understood. Here, we show that, compared to conventional T cells, Treg cells have a high apoptosis rate ex vivo correlating with low c-FLIP expression. Treg-specific deletion of c-FLIP in mice resulted in fatal autoimmune disease of a scurfy-like phenotype characterized by absent peripheral Treg cells, activation of effector cells, multi-organ immune cell infiltration, and premature death. Surprisingly, blocking CD95L did not rescue Treg survival in vivo, suggesting additional survival functions of c-FLIP in Treg cells in addition to its classical role in the inhibition of death receptor signaling. Thus, our data reveal a central role for c-FLIP in Treg cell homeostasis and prevention of autoimmunity.

Graphical abstract

Teaser

The mechanisms regulating homeostasis of regulatory T (Treg) cells are incompletely understood. Plaza-Sirvent et al. demonstrate that expression of the caspase-8-inhibitor c-FLIP is essential for Treg survival and prevention of autoimmunity because mice lacking c-FLIP in this cell type die early on due to fatal autoimmune disease.


http://ift.tt/2iAkQXJ

Biphasic Dependence of Glioma Survival and Cell Migration on CD44 Expression Level

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Rebecca L. Klank, Stacy A. Decker Grunke, Benjamin L. Bangasser, Colleen L. Forster, Matthew A. Price, Thomas J. Odde, Karen S. SantaCruz, Steven S. Rosenfeld, Peter Canoll, Eva A. Turley, James B. McCarthy, John R. Ohlfest, David J. Odde
While several studies link the cell-surface marker CD44 to cancer progression, conflicting results show both positive and negative correlations with increased CD44 levels. Here, we demonstrate that the survival outcomes of genetically induced glioma-bearing mice and of high-grade human glioma patients are biphasically correlated with CD44 level, with the poorest outcomes occurring at intermediate levels. Furthermore, the high-CD44-expressing mesenchymal subtype exhibited a positive trend of survival with increased CD44 level. Mouse cell migration rates in ex vivo brain slice cultures were also biphasically associated with CD44 level, with maximal migration corresponding to minimal survival. Cell simulations suggest that cell-substrate adhesiveness is sufficient to explain this biphasic migration. More generally, these results highlight the potential importance of non-monotonic relationships between survival and biomarkers associated with cancer progression.

Graphical abstract

Teaser

Klank et al. describe a biphasic relationship between CD44 expression levels and survival/cell migration rates in glioma. Intermediate CD44 levels in glioblastoma are linked to high tumor cell migration rates and poor survival, while both low and high CD44 levels were a positive prognostic indicator. These results illustrate the potential importance of non-monotonic relationships between survival and biomarkers associated with cancer progression.


http://ift.tt/2iAobWQ

Conformational Freedom of the LRP6 Ectodomain Is Regulated by N-glycosylation and the Binding of the Wnt Antagonist Dkk1

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Kyoko Matoba, Emiko Mihara, Keiko Tamura-Kawakami, Naoyuki Miyazaki, Shintaro Maeda, Hidenori Hirai, Samuel Thompson, Kenji Iwasaki, Junichi Takagi
LDL-receptor-related protein 6 (LRP6) is a single-pass membrane glycoprotein with a large modular ectodomain and forms a higher order signaling platform upon binding Wnt ligands on the cell surface. Although multiple crystal structures are available for fragments of the LRP6 ectodomain, we lack a consensus view on the overall molecular architecture of the full-length LRP6 and its dynamic aspects. Here, we used negative-stain electron microscopy to probe conformational states of the entire ectodomain of LRP6 in solution and found that the four-module ectodomain undergoes a large bending motion hinged at the junction between the second and the third modules. Importantly, the extent of inter-domain motion is modulated by evolutionarily conserved N-glycan chains proximal to the joint. We also found that the LRP6 ectodomain becomes highly compact upon complexation with the Wnt antagonist Dkk1, suggesting a potential role for the ectodomain conformational change in the regulation of receptor oligomerization and signaling.

Graphical abstract

Teaser

Matoba et al. imaged the LRP6 ectodomain fragment using negative-stain EM single-particle analysis and found that it undergoes flexible motion regulated by N-glycans near the hinge region.


http://ift.tt/2iAuk5s

Telomere Recognition and Assembly Mechanism of Mammalian Shelterin

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Fabian Erdel, Katja Kratz, Smaranda Willcox, Jack D. Griffith, Eric C. Greene, Titia de Lange
Shelterin is a six-subunit protein complex that plays crucial roles in telomere length regulation, protection, and maintenance. Although several shelterin subunits have been studied in vitro, the biochemical properties of the fully assembled shelterin complex are not well defined. Here, we characterize shelterin using ensemble biochemical methods, electron microscopy, and single-molecule imaging to determine how shelterin recognizes and assembles onto telomeric repeats. We show that shelterin complexes can exist in solution and primarily locate telomeric DNA through a three-dimensional diffusive search. Shelterin can diffuse along non-telomeric DNA but is impeded by nucleosomes, arguing against extensive one-dimensional diffusion as a viable assembly mechanism. Our work supports a model in which individual shelterin complexes rapidly bind to telomeric repeats as independent functional units, which do not alter the DNA-binding mode of neighboring complexes but, rather, occupy telomeric DNA in a "beads on a string" configuration.

Graphical abstract

Teaser

The shelterin complex safeguards mammalian telomeres. Erdel et al. purify the full shelterin complex and visualize how individual complexes interact with DNA. They find that preassembled shelterin complexes can exist in solution and can rapidly find telomeric repeats by three-dimensional diffusion to ensure efficient and persistent telomere protection.


http://ift.tt/2iArNbr

TRIM28 Controls a Gene Regulatory Network Based on Endogenous Retroviruses in Human Neural Progenitor Cells

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Per Ludvik Brattås, Marie E. Jönsson, Liana Fasching, Jenny Nelander Wahlestedt, Mansoureh Shahsavani, Ronny Falk, Anna Falk, Patric Jern, Malin Parmar, Johan Jakobsson
Endogenous retroviruses (ERVs), which make up 8% of the human genome, have been proposed to participate in the control of gene regulatory networks. In this study, we find a region- and developmental stage-specific expression pattern of ERVs in the developing human brain, which is linked to a transcriptional network based on ERVs. We demonstrate that almost 10,000, primarily primate-specific, ERVs act as docking platforms for the co-repressor protein TRIM28 in human neural progenitor cells, which results in the establishment of local heterochromatin. Thereby, TRIM28 represses ERVs and consequently regulates the expression of neighboring genes. These results uncover a gene regulatory network based on ERVs that participates in control of gene expression of protein-coding transcripts important for brain development.

Graphical abstract

Teaser

Brattås et al. report that endogenous retroviruses are bound by TRIM28 in human neural progenitor cells. This results in the establishment of local heterochromatin that affects nearby gene expression, suggesting a role for endogenous retroviruses in the control of transcriptional networks in the developing human brain.


http://ift.tt/2iArY6v

Cochlear Cell Modeling Using Disease-Specific iPSCs Unveils a Degenerative Phenotype and Suggests Treatments for Congenital Progressive Hearing Loss

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Makoto Hosoya, Masato Fujioka, Takefumi Sone, Satoshi Okamoto, Wado Akamatsu, Hideki Ukai, Hiroki R. Ueda, Kaoru Ogawa, Tatsuo Matsunaga, Hideyuki Okano
Hearing impairments are the most common symptom of congenital defects, and they generally remain intractable to treatment. Pendred syndrome, the most frequent syndromic form of hereditary hearing loss, is associated with mutations in the anion exchanger pendrin. Loss of pendrin function as an anion exchanger is thought to be causative, but rodent models do not exhibit progressive deafness. Here, we report a degenerative phenotype exhibiting mutant pendrin aggregates and increased susceptibility to cellular stresses in cochlear epithelial cells induced from patient-derived induced pluripotent stem cells (iPSCs). These degenerative phenotypes were rescued by site-specific gene corrections. Moreover, low-dose rapamycin and metformin reduced aggregation and cell death. Our results provide an unexpected, comprehensive understanding of deafness due to "degenerative cochlear disease" and may contribute to rational therapeutic development. This iPSC-based disease model provides an approach to the study of pathogenesis and therapeutic development for hereditary hearing loss.

Graphical abstract

Teaser

Hosoya et al. establish an in vitro cochlear cell model derived from Pendred syndrome (PDS)-specific hiPSCs and reveal a degenerative phenotype characterized by intracellular aggregations and increased susceptibilities to cellular stresses. The PDS iPSC model provides an approach for a rational treatment strategy for progressive hearing loss.


http://ift.tt/2iAnqwQ

NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Maria B. Olsen, Gunn A. Hildrestrand, Katja Scheffler, Leif Erik Vinge, Katrine Alfsnes, Vuk Palibrk, Junbai Wang, Christine G. Neurauter, Luisa Luna, Jostein Johansen, Jonas D.S. Øgaard, Ingrid K. Ohm, Geir Slupphaug, Anna Kuśnierczyk, Arnt E. Fiane, Sverre-Henning Brorson, Lili Zhang, Lars Gullestad, William E. Louch, Per Ole Iversen, Ingunn Østlie, Arne Klungland, Geir Christensen, Ivar Sjaastad, Pål Sætrom, Arne Yndestad, Pål Aukrust, Magnar Bjørås, Alexandra V. Finsen
Myocardial infarction (MI) triggers a reparative response involving fibroblast proliferation and differentiation driving extracellular matrix modulation necessary to form a stabilizing scar. Recently, it was shown that a genetic variant of the base excision repair enzyme NEIL3 was associated with increased risk of MI in humans. Here, we report elevated myocardial NEIL3 expression in heart failure patients and marked myocardial upregulation of Neil3 after MI in mice, especially in a fibroblast-enriched cell fraction. Neil3^−/− mice show increased mortality after MI caused by myocardial rupture. Genome-wide analysis of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) reveals changes in the cardiac epigenome, including in genes related to the post-MI transcriptional response. Differentially methylated genes are enriched in pathways related to proliferation and myofibroblast differentiation. Accordingly, Neil3^−/− ruptured hearts show increased proliferation of fibroblasts and myofibroblasts. We propose that NEIL3-dependent modulation of DNA methylation regulates cardiac fibroblast proliferation and thereby affects extracellular matrix modulation after MI.

Graphical abstract

Teaser

Olsen et al. show that the DNA repair enzyme, NEIL3, has impact on survival after myocardial infarction in mice. They find that NEIL3 regulates cardiac fibroblast proliferation and thereby affects extracellular matrix modulation. They propose that NEIL3 operates by regulating DNA methylation of genes important for fibroblast proliferation and differentiation.


http://ift.tt/2iArMUV

Amplification of Adipogenic Commitment by VSTM2A

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Blandine Secco, Étienne Camiré, Marc-Antoine Brière, Alexandre Caron, Armande Billong, Yves Gélinas, Anne-Marie Lemay, Kevin M. Tharp, Peter L. Lee, Stéphane Gobeil, Jean V. Guimond, Natacha Patey, David A. Guertin, Andreas Stahl, Élie Haddad, David Marsolais, Yohan Bossé, Kivanc Birsoy, Mathieu Laplante
Despite progress in our comprehension of the mechanisms regulating adipose tissue development, the nature of the factors that functionally characterize adipose precursors is still elusive. Defining the early steps regulating adipocyte development is needed for the generation of tools to control adipose tissue size and function. Here, we report the discovery of V-set and transmembrane domain containing 2A (VSTM2A) as a protein expressed and secreted by committed preadipocytes. VSTM2A expression is elevated in the early phases of adipogenesis in vitro and adipose tissue development in vivo. We show that VSTM2A-producing cells associate with the vasculature and express the common surface markers of adipocyte progenitors. Overexpression of VSTM2A induces adipogenesis, whereas its depletion impairs this process. VSTM2A controls preadipocyte determination at least in part by modulating BMP signaling and PPARγ2 activation. We propose a model in which VSTM2A is produced to preserve and amplify the adipogenic capability of adipose precursors.

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Secco et al. identify VSTM2A as a factor expressed and secreted by adipose precursors. They show that VSTM2A amplifies adipogenic commitment by promoting BMP4 signaling and PPARγ2 activation. These results indicate that VSTM2A functionally controls early events in adipocyte development.


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Modeling Dynamics and Function of Bone Marrow Cells in Mouse Liver Regeneration

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Elisa Pedone, Vlad-Aris Olteanu, Lucia Marucci, Maria Isabel Muñoz-Martin, Sameh A. Youssef, Alain de Bruin, Maria Pia Cosma
In rodents and humans, the liver can efficiently restore its mass after hepatectomy. This is largely attributed to the proliferation and cell cycle re-entry of hepatocytes. On the other hand, bone marrow cells (BMCs) migrate into the liver after resection. Here, we find that a block of BMC recruitment into the liver severely impairs its regeneration after the surgery. Mobilized hematopoietic stem and progenitor cells (HSPCs) in the resected liver can fuse with hepatocytes, and the hybrids proliferate earlier than the hepatocytes. Genetic ablation of the hybrids severely impairs hepatocyte proliferation and liver mass regeneration. Mathematical modeling reveals a key role of bone marrow (BM)-derived hybrids to drive proliferation in the regeneration process, and predicts regeneration efficiency in experimentally non-testable conditions. In conclusion, BM-derived hybrids are essential to trigger efficient liver regeneration after hepatectomy.

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Hepatocyte replication is considered the main mechanism of liver regeneration after hepatectomy in mammals. Pedone et al. report that bone marrow cells can migrate into the liver upon resection and fuse with the hepatocytes. The derived hybrids are essential for efficient liver regeneration, which is also predicted by mathematical modeling.


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Networks of Cultured iPSC-Derived Neurons Reveal the Human Synaptic Activity-Regulated Adaptive Gene Program

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Priit Pruunsild, C. Peter Bengtson, Hilmar Bading
Long-term adaptive responses in the brain, such as learning and memory, require synaptic activity-regulated gene expression, which has been thoroughly investigated in rodents. Using human iPSC-derived neuronal networks, we show that the human and the mouse synaptic activity-induced transcriptional programs share many genes and both require Ca²⁺-regulated synapse-to-nucleus signaling. Species-specific differences include the noncoding RNA genes BRE-AS1 and LINC00473 and the protein-coding gene ZNF331, which are absent in the mouse genome, as well as several human genes whose orthologs are either not induced by activity or are induced with different kinetics in mice. These results indicate that lineage-specific gain of genes and DNA regulatory elements affects the synaptic activity-regulated gene program, providing a mechanism driving the evolution of human cognitive abilities.

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Using comparative analysis of synaptic activity-responsive gene expression programs in human and mouse neuronal networks, Pruunsild et al. uncover differences that are due to lineage-specific acquisition of genes and DNA regulatory elements. Such genetic alterations and the resulting changes in activity-driven transcription may be relevant for the evolution of human cognitive abilities.


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Brain State Dependence of Hippocampal Subthreshold Activity in Awake Mice

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Brad K. Hulse, Evgueniy V. Lubenov, Athanassios G. Siapas
Monitoring the membrane potential of individual neurons has uncovered how single-cell properties contribute to network processing across different brain states in neocortex. In contrast, the subthreshold modulation of hippocampal neurons by brain state has not been systematically characterized. To address this, we combined whole-cell recordings from dentate granule cells and CA1 pyramidal neurons with multisite extracellular recordings and behavioral measurements in awake mice. We show that the average membrane potential, amplitude of subthreshold fluctuations, and distance to spike threshold are all modulated by brain state. Furthermore, even within individual states, rapid variations in arousal are reflected in membrane potential fluctuations. These factors produce depolarizing ramps in the membrane potential of hippocampal neurons that precede ripples and mirror transitions to a network regime conducive for ripple generation. These results suggest that there are coordinated shifts in the subthreshold dynamics of individual neurons that underlie the transitions between distinct modes of hippocampal processing.

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Hulse et al. show that the average membrane potential and the amplitude of subthreshold fluctuations of hippocampal neurons systematically change with brain state and arousal. This results in membrane potential ramps that precede ripples and mirror transitions to a network regime conducive for ripple generation.


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Medial and Lateral Entorhinal Cortex Differentially Excite Deep versus Superficial CA1 Pyramidal Neurons

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Arjun V. Masurkar, Kalyan V. Srinivas, David H. Brann, Richard Warren, Daniel C. Lowes, Steven A. Siegelbaum
Although hippocampal CA1 pyramidal neurons (PNs) were thought to comprise a uniform population, recent evidence supports two distinct sublayers along the radial axis, with deep neurons more likely to form place cells than superficial neurons. CA1 PNs also differ along the transverse axis with regard to direct inputs from entorhinal cortex (EC), with medial EC (MEC) providing spatial information to PNs toward CA2 (proximal CA1) and lateral EC (LEC) providing non-spatial information to PNs toward subiculum (distal CA1). We demonstrate that the two inputs differentially activate the radial sublayers and that this difference reverses along the transverse axis, with MEC preferentially targeting deep PNs in proximal CA1 and LEC preferentially exciting superficial PNs in distal CA1. This differential excitation reflects differences in dendritic spine numbers. Our results reveal a heterogeneity in EC-CA1 connectivity that may help explain differential roles of CA1 PNs in spatial and non-spatial learning and memory.

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Masurkar et al. reveal a patterned connectivity from spatial- and non-spatial areas of entorhinal cortex to specific subpopulations of CA1 pyramidal neurons, uncovering a potential mechanism by which functionally distinct processing channels arise during learning and memory guided behaviors.


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Synucleins Have Multiple Effects on Presynaptic Architecture

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Karina J. Vargas, Nikolas Schrod, Taylor Davis, Ruben Fernandez-Busnadiego, Yumiko V. Taguchi, Ulrike Laugks, Vladan Lucic, Sreeganga S. Chandra
Synucleins (α, β, γ-synuclein) are a family of abundant presynaptic proteins. α-Synuclein is causally linked to the pathogenesis of Parkinson's disease (PD). In an effort to define their physiological and pathological function or functions, we investigated the effects of deleting synucleins and overexpressing α-synuclein PD mutations, in mice, on synapse architecture using electron microscopy (EM) and cryoelectron tomography (cryo-ET). We show that synucleins are regulators of presynapse size and synaptic vesicle (SV) pool organization. Using cryo-ET, we observed that deletion of synucleins increases SV tethering to the active zone but decreases the inter-linking of SVs by short connectors. These ultrastructural changes were correlated with discrete protein phosphorylation changes in αβγ-synuclein−/− neurons. We also determined that α-synuclein PD mutants (PARK1/hA30P and PARK4/hα-syn) primarily affected presynaptic cytomatrix proximal to the active zone, congruent with previous findings that these PD mutations decrease neurotransmission. Collectively, our results suggest that synucleins are important orchestrators of presynaptic terminal topography.

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Synucleins (α, β, γ-synuclein) are abundant presynaptic proteins, with α-synuclein linked to the pathogenesis of Parkinson's disease. Vargas et al. investigate the effects of deleting synucleins and overexpressing mutated α-synuclein on synapse architecture using electron microscopy. They find that synucleins regulate presynaptic terminal size and synaptic vesicle distribution.


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Sema-1a Reverse Signaling Promotes Midline Crossing in Response to Secreted Semaphorins

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Melissa Hernandez-Fleming, Ethan W. Rohrbach, Greg J. Bashaw
Commissural axons must cross the midline to form functional midline circuits. In the invertebrate nerve cord and vertebrate spinal cord, midline crossing is mediated in part by Netrin-dependent chemoattraction. Loss of crossing, however, is incomplete in mutants for Netrin or its receptor Frazzled/DCC, suggesting the existence of additional pathways. We identified the transmembrane Semaphorin, Sema-1a, as an important regulator of midline crossing in the Drosophila CNS. We show that in response to the secreted Semaphorins Sema-2a and Sema-2b, Sema-1a functions as a receptor to promote crossing independently of Netrin. In contrast to other examples of reverse signaling where Sema1a triggers repulsion through activation of Rho in response to Plexin binding, in commissural neurons Sema-1a acts independently of Plexins to inhibit Rho to promote attraction to the midline. These findings suggest that Sema-1a reverse signaling can elicit distinct axonal responses depending on differential engagement of distinct ligands and signaling effectors.

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In bilaterally symmetric animals, assembling precise neural circuits at the midline is critical for the coordination of the two sides of the body. Hernandez-Fleming et al. now uncover an important role for Sema-1a reverse signaling in controlling midline axon crossing.


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Hox2 Genes Are Required for Tonotopic Map Precision and Sound Discrimination in the Mouse Auditory Brainstem

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Kajari Karmakar, Yuichi Narita, Jonathan Fadok, Sebastien Ducret, Alberto Loche, Taro Kitazawa, Christel Genoud, Thomas Di Meglio, Raphael Thierry, Joao Bacelo, Andreas Lüthi, Filippo M. Rijli
Tonotopy is a hallmark of auditory pathways and provides the basis for sound discrimination. Little is known about the involvement of transcription factors in brainstem cochlear neurons orchestrating the tonotopic precision of pre-synaptic input. We found that in the absence of Hoxa2 and Hoxb2 function in Atoh1-derived glutamatergic bushy cells of the anterior ventral cochlear nucleus, broad input topography and sound transmission were largely preserved. However, fine-scale synaptic refinement and sharpening of isofrequency bands of cochlear neuron activation upon pure tone stimulation were impaired in Hox2 mutants, resulting in defective sound-frequency discrimination in behavioral tests. These results establish a role for Hox factors in tonotopic refinement of connectivity and in ensuring the precision of sound transmission in the mammalian auditory circuit.

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Karmakar et al. find that the Hoxa2 and Hoxb2 transcription factors are required in mouse brainstem cochlear neurons for the tonotopic maturation of synaptic targeting from their peripheral auditory afferents and for the precision of sound discrimination in adult mice.


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Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Han Gao, Matt C. Danzi, Claire S. Choi, Mehran Taherian, Camilla Dalby-Hansen, Ditte G. Ellman, Pernille M. Madsen, John L. Bixby, Vance P. Lemmon, Kate L. Lambertsen, Roberta Brambilla
In multiple sclerosis (MS), soluble tumor necrosis factor (TNF) is detrimental via activation of TNF receptor 1 (TNFR1), whereas transmembrane TNF is beneficial primarily by activating TNF receptor 2 (TNFR2). Here, we investigate the role of TNFR2 in microglia and monocytes/macrophages in experimental autoimmune encephalomyelitis (EAE), a model of MS, by cell-specific gene targeting. We show that TNFR2 ablation in microglia leads to early onset of EAE with increased leukocyte infiltration, T cell activation, and demyelination in the central nervous system (CNS). Conversely, TNFR2 ablation in monocytes/macrophages results in EAE suppression with impaired peripheral T cell activation and reduced CNS T cell infiltration and demyelination. Our work uncovers a dichotomy of function for TNFR2 in myeloid cells, with microglial TNFR2 providing protective signals to contain disease and monocyte/macrophagic TNFR2 driving immune activation and EAE initiation. This must be taken into account when targeting TNFR2 for therapeutic purposes in neuroinflammatory diseases.

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Gao et al. uncover a dichotomy of functions for microglial versus monocyte/macrophagic TNFR2 in EAE pathophysiology. They demonstrate that TNFR2 in microglia is protective and provides signals to contain neuroinflammation, whereas TNFR2 in monocytes/macrophages is detrimental and drives immune activation and EAE initiation.


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EBI2 Expression and Function: Robust in Memory Lymphocytes and Increased by Natalizumab in Multiple Sclerosis

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Aurélie S. Clottu, Amandine Mathias, Andreas W. Sailer, Myriam Schluep, Jörg D. Seebach, Renaud Du Pasquier, Caroline Pot
The interaction between oxysterols and the G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2) fine-tunes immune cell migration, a mechanism efficiently targeted by several disease-modifying treatments developed to treat multiple sclerosis (MS), such as natalizumab. We previously showed that memory CD4⁺ T lymphocytes migrate specifically in response to 7α,25-dihydroxycholesterol (7α,25-OHC) via EBI2 in the MS murine model experimental autoimmune encephalomyelitis. However, the EBI2 expression profile in human lymphocytes in both healthy and MS donors is unknown. Here, we characterize EBI2 biology in human lymphocytes. We observed that EBI2 is functionally expressed on memory CD4⁺ T cells and is enhanced under natalizumab treatment. These data suggest a significant role for EBI2 in human CD4⁺ T cell migration, notably in patients with MS. Better knowledge of EBI2 involvement in autoimmunity may therefore lead to an improved understanding of the physiopathology of MS.

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Clottu et al. investigated the expression and function of the oxysterol receptor EBI2 in human primary lymphocytes. They show that EBI2 regulates human lymphocyte migration in vitro and that its expression and migratory response are increased in memory CD4⁺ T cells from multiple sclerosis patients treated with natalizumab.


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Interplay between Obesity-Induced Inflammation and cGMP Signaling in White Adipose Tissue

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Abhishek Sanyal, Jennifer Naumann, Linda Sarah Hoffmann, Agnieszka Chabowska-Kita, Anna Ehrlund, Andreas Schlitzer, Peter Arner, Matthias Blüher, Alexander Pfeifer
Current worldwide figures suggest that obesity is pandemic. Understanding the underlying molecular mechanisms would help develop viable anti-obesity therapies. Here, we assess the influence of obesity-induced inflammation on white adipocyte cyclic guanosine monophosphate (cGMP) signaling, which is beneficial for adipocyte differentiation and thermogenesis. We find that murine gonadal and not inguinal fat is prone to obesity-induced inflammation. Correspondingly, the cGMP cascade is dysregulated in gonadal but not in inguinal fat of obese mice. Analysis of two independent human cohorts reveals a defective cGMP pathway only in visceral fat of obese subjects. Congruently, cGMP signaling is dysregulated in tumor necrosis factor α (TNF-α)-treated primary white adipocytes. TNF-α-mediated suppression of sGCβ1 is mediated via NF-κB, whereas PKG is repressed by JNK signaling. Additionally, TNF-α-activated JNK signaling suppresses PPARγ and aP2. Taken together, the intensity of obesity-induced inflammation dictates the amplitude of cGMP signaling dysregulation in white adipocytes through distinct pathways.

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Sanyal et al. report that the dysregulation of cGMP signaling in adipose tissue of obese mice is proportional to the degree of metaflammation through distinct pathways. Since targeting cGMP signaling ameliorates obesity and associated co-morbidities, knowledge gained from this study suggests avenues for therapy.


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Proteomic Analysis of Pemphigus Autoantibodies Indicates a Larger, More Diverse, and More Dynamic Repertoire than Determined by B Cell Genetics

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Jing Chen, Qi Zheng, Christoph M. Hammers, Christoph T. Ellebrecht, Eric M. Mukherjee, Hsin-Yao Tang, Chenyan Lin, Huijie Yuan, Meng Pan, Jana Langenhan, Lars Komorowski, Don L. Siegel, Aimee S. Payne, John R. Stanley
In autoantibody-mediated diseases such as pemphigus, serum antibodies lead to disease. Genetic analysis of B cells has allowed characterization of antibody repertoires in such diseases but would be complemented by proteomic analysis of serum autoantibodies. Here, we show using proteomic analysis that the serum autoantibody repertoire in pemphigus is much more polyclonal than that found by genetic studies of B cells. In addition, many B cells encode pemphigus autoantibodies that are not secreted into the serum. Heavy chain variable gene usage of serum autoantibodies is not shared among patients, implying targeting of the coded proteins will not be a useful therapeutic strategy. Analysis of autoantibodies in individual patients over several years indicates that many antibody clones persist but the proportion of each changes. These studies indicate a dynamic and diverse autoantibody response not revealed by genetic studies and explain why similar overall autoantibody titers may give variable disease activity.

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Chen et al. use proteomic analysis of serum human autoantibodies to follow the autoimmune response in the autoantibody-mediated disease pemphigus. They find that direct genetic analysis of autoimmune B cells is not representative of the actual circulating autoantibody repertoire, which is more diverse than previously thought.


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Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Pornpimol Charoentong, Francesca Finotello, Mihaela Angelova, Clemens Mayer, Mirjana Efremova, Dietmar Rieder, Hubert Hackl, Zlatko Trajanoski
The Cancer Genome Atlas revealed the genomic landscapes of human cancers. In parallel, immunotherapy is transforming the treatment of advanced cancers. Unfortunately, the majority of patients do not respond to immunotherapy, making the identification of predictive markers and the mechanisms of resistance an area of intense research. To increase our understanding of tumor-immune cell interactions, we characterized the intratumoral immune landscapes and the cancer antigenomes from 20 solid cancers and created The Cancer Immunome Atlas (https://tcia.at/). Cellular characterization of the immune infiltrates showed that tumor genotypes determine immunophenotypes and tumor escape mechanisms. Using machine learning, we identified determinants of tumor immunogenicity and developed a scoring scheme for the quantification termed immunophenoscore. The immunophenoscore was a superior predictor of response to anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) and anti-programmed cell death protein 1 (anti-PD-1) antibodies in two independent validation cohorts. Our findings and this resource may help inform cancer immunotherapy and facilitate the development of precision immuno-oncology.

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Analyses of publicly available cancer genomics data with respect to immunologically relevant parameters can provide important insights but are challenging. Charoentong et al. analyzed data for 20 solid cancers and developed TCIA, a web-accessible resource that allows researchers to mine the data for immunological insights.


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Effect of Immediate Administration of Antibiotics in Patients With Sepsis in Tertiary Care: A Systematic Review and Meta-analysis

Publication date: Available online 3 January 2017
Source:Clinical Therapeutics
Author(s): Amy N.B. Johnston, Joon Park, Suhail A. Doi, Vicki Sharman, Justin Clark, Jemma Robinson, Julia Crilly
PurposeThe goal of this review was to synthesize existing evidence regarding outcomes (mortality) for patients who present to the emergency department, are administered antibiotics immediately (within 1 hour) or later (>1 hour), and are diagnosed with sepsis.MethodsA search of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL, using the MeSH descriptors "sepsis," "systemic inflammatory response syndrome," "mortality," "emergency," and "antibiotics," was performed to identify studies reporting time to antibiotic administration and mortality outcome in patients with sepsis. The included studies (published in English between 1990 and 2016) listed patient mortality based on time to antibiotic administration. Studies were evaluated for methodologic quality, and data were extracted by using a data extraction form tailored to this study. From an initial pool of 582 potentially relevant studies, 11 studies met our inclusion criteria, 10 of which had quantitative data for meta-analysis. Three different models (a random effects model, a bias-adjusted quality-effects [synthetic bias] model, and an inverse variance heterogeneity model) were used to perform the meta-analysis.FindingsThe pooled results suggest a significant 33% reduction in mortality odds for immediate (within 1 hour) compared with later (>1 hour) antibiotic administration (OR, 0.67 [95% CI, 0.59–0.75]) in patients with sepsis.ImplicationsImmediate antibiotic administration (<1 hour) seemed to reduce patient mortality. There was some minor negative asymmetry suggesting that the evidence may be biased toward the direction of effect. Nevertheless, this study provides strong evidence for early, comprehensive, sepsis management in the emergency department.



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Indirect Treatment Comparisons of Ibrutinib Versus Physician’s Choice and Idelalisib Plus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia

Publication date: Available online 3 January 2017
Source:Clinical Therapeutics
Author(s): Sonja Sorensen, Mark Wildgust, Nishan Sengupta, Cristina Trambitas, Joris Diels, Suzy van Sanden, Yingxin Xu, Emily Dorman
PurposeTreatment options for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) are limited. Until recently, few effective treatment options existed, and even with the advent of new agents, studies evaluating comparative efficacy are scarce. In the Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE) Phase III study, ibrutinib, an oral, once-a-day, first-in-class covalent Bruton tyrosine kinase inhibitor, improved progression-free survival (PFS) and overall survival (OS) compared with ofatumumab (PFS hazard ratio [HR] = 0.106 and OS HR = 0.369 [adjusted for crossover] at a median of 16 months' follow-up). We sought to establish the relative efficacy of ibrutinib versus other treatment options for patients with R/R CLL using indirect comparison methods.MethodsA systematic literature review was conducted to identify clinical trials sharing a common treatment arm with the RESONATE Phase III trial such that a network meta-analysis or indirect treatment comparisons (ITCs) could be conducted. Two trials were identified, each using the same comparator (ofatumumab) as the RESONATE study. Two pairwise ITCs were conducted using the Bucher method to establish the relative treatment efficacy of ibrutinib versus (1) idelalisib plus ofatumumab in the first study and (2) physician's choice, defined as a mix of therapies commonly used in R/R CLL, in the second study. Odds ratios for these ITCs were calculated for overall response rate (ORR) and HRs for PFS and OS.FindingsA strong and consistent trend of superiority for ibrutinib was observed via these ITC models with idelalisib plus ofatumumab and physician's choice for ORR, PFS, and OS. Ibrutinib revealed prolonged PFS and OS versus comparators (PFS HR = 0.06; 95% CI, 0.04–0.11; and OS HR = 0.25; 95% CI, 0.12–0.54), physician's choice (PFS HR = 0.41; 95% CI, 0.25–0.66; and OS HR = 0.50; 95% CI, 0.23–1.08), and idelalisib plus ofatumumab. These findings were robust and continued to favor ibrutinib when adjusting (where appropriate) for underlying differences in patient population between the trials. Some trial differences were not accounted for in the models and thus some limitations remain; however, consistency of results supports the overall findings.ImplicationsIn a randomized Phase III study, ibrutinib significantly improved ORR, PFS, and OS in patients with R/R CLL versus ofatumumab. In ITC models that used ofatumumab as the common comparator, ibrutinib appears to have higher ORR and longer PFS and OS versus both idelalisib plus ofatumumab and physician's choice. In the absence of head-to-head studies and taking into consideration inherent limitations of ITCs, these models provide useful estimates of comparative efficacy.



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Frontal Fibrosing Alopecia: A research letter

Frontal fibrosing alopecia (FFA) is a primary cicatricial alopecia first described by Kossard in 1994. It is considered a clinical variant of lichen planopilaris (LPP). In the last two decades, there have been an explosion of cases worldwide. While predominately seen in Caucasian, post-menopausal women, it has been reported in various ethnicities including African-Americans, Hispanics, Asians, and Indians as well as in pre-menopausal women and men.^1-5 Characterized by progressive, scarring frontotemporal hair loss with perifollicular erythema, follicular keratinization, and reduced follicular orifices, the most common finding is bandlike recession of the scalp hairline.^1-5 Accompanying features include eyebrow thinning, eyelash loss, body hair loss, facial papules, lonely hairs, and occipital alopecia.^1-5 While typically asymptomatic, pruritus and trichodynia can occur. Eyebrow thinning often presents prior to scalp hairline regression and has been seen with milder hairline regression compared to individuals who do not experience eyebrow thinning first.^2-4 Other dermatoses seen in patients with FFA include lichen planus on regions other than the scalp and lichen planus pigmentosus in non-Cacuasians.

This article is protected by copyright. All rights reserved.

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Sequentially-crosslinked bioactive hydrogels as nano-patterned substrates with customizable stiffness and degradation for corneal tissue engineering applications

Publication date: March 2017
Source:Biomaterials, Volume 120
Author(s): Muhammad Rizwan, Gary S.L. Peh, Heng-Pei Ang, Nyein Chan Lwin, Khadijah Adnan, Jodhbir S. Mehta, Wui Siew Tan, Evelyn K.F. Yim
Naturally-bioactive hydrogels like gelatin provide favorable properties for tissue-engineering but lack sufficient mechanical strength for use as implantable tissue engineering substrates. Complex fabrication or multi-component additives can improve material strength, but often compromises other properties. Studies have shown gelatin methacrylate (GelMA) as a bioactive hydrogel with diverse tissue growth applications. We hypothesize that, with suitable material modifications, GelMA could be employed for growth and implantation of tissue-engineered human corneal endothelial cell (HCEC) monolayer. Tissue-engineered HCEC monolayer could potentially be used to treat corneal blindness due to corneal endothelium dysfunction. Here, we exploited a sequential hybrid (physical followed by UV) crosslinking to create an improved material, named as GelMA+, with over 8-fold increase in mechanical strength as compared to regular GelMA. The presence of physical associations increased the subsequent UV-crosslinking efficiency resulting in robust materials able to withstand standard endothelium insertion surgical device loading. Favorable biodegradation kinetics were also measured in vitro and in vivo. We achieved hydrogels patterning with nano-scale resolution by use of oxygen impermeable stamps that overcome the limitations of PDMS based molding processes. Primary HCEC monolayers grown on GelMA+ carrier patterned with pillars of optimal dimension demonstrated improved zona-occludin-1 expression, higher cell density and cell size homogeneity, which are indications of functionally-superior transplantable monolayers. The hybrid crosslinking and fabrication approach offers potential utility for development of implantable tissue-engineered cell-carrier constructs with enhanced bio-functional properties.



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Nanoparticles for radiooncology: Mission, vision, challenges

Publication date: March 2017
Source:Biomaterials, Volume 120
Author(s): Leoni A. Kunz-Schughart, Anna Dubrovska, Claudia Peitzsch, Alexander Ewe, Achim Aigner, Samuel Schellenburg, Michael H. Muders, Silke Hampel, Giuseppe Cirillo, Francesca Iemma, Rainer Tietze, Christoph Alexiou, Holger Stephan, Kristof Zarschler, Orazio Vittorio, Maria Kavallaris, Wolfgang J. Parak, Lutz Mädler, Suman Pokhrel
Cancer is one of the leading non-communicable diseases with highest mortality rates worldwide. About half of all cancer patients receive radiation treatment in the course of their disease. However, treatment outcome and curative potential of radiotherapy is often impeded by genetically and/or environmentally driven mechanisms of tumor radioresistance and normal tissue radiotoxicity. While nanomedicine-based tools for imaging, dosimetry and treatment are potential keys to the improvement of therapeutic efficacy and reducing side effects, radiotherapy is an established technique to eradicate the tumor cells. In order to progress the introduction of nanoparticles in radiooncology, due to the highly interdisciplinary nature, expertise in chemistry, radiobiology and translational research is needed. In this report recent insights and promising policies to design nanotechnology-based therapeutics for tumor radiosensitization will be discussed. An attempt is made to cover the entire field from preclinical development to clinical studies. Hence, this report illustrates (1) the radio- and tumor-biological rationales for combining nanostructures with radiotherapy, (2) tumor-site targeting strategies and mechanisms of cellular uptake, (3) biological response hypotheses for new nanomaterials of interest, and (4) challenges to translate the research findings into clinical trials.



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