Publication date: Available online 5 March 2018
Source:Trends in Cognitive Sciences
Author(s): Linda B. Smith, Swapnaa Jayaraman, Elizabeth Clerkin, Chen Yu
New efforts are using head cameras and eye-trackers worn by infants to capture everyday visual environments from the point of view of the infant learner. From this vantage point, the training sets for statistical learning develop as the sensorimotor abilities of the infant develop, yielding a series of ordered datasets for visual learning that differ in content and structure between timepoints but are highly selective at each timepoint. These changing environments may constitute a developmentally ordered curriculum that optimizes learning across many domains. Future advances in computational models will be necessary to connect the developmentally changing content and statistics of infant experience to the internal machinery that does the learning.
http://ift.tt/2I5iiLD
Τρίτη 6 Μαρτίου 2018
The Developing Infant Creates a Curriculum for Statistical Learning
Effect of dental monomers and initiators on Streptococcus mutans oral biofilms
Publication date: Available online 6 March 2018
Source:Dental Materials
Author(s): Nancy J. Lin, Courtney Keeler, Alison M. Kraigsley, Jing Ye, Sheng Lin-Gibson
ObjectiveResin-based composites are known to elute leachables that include unincorporated starting materials. The objective of this work was to determine the effect of common dental monomers and initiators on Streptococcus mutans biofilm metabolic activity and biomass.MethodsS. mutans biofilms were inoculated in the presence of bisphenol A glycerolate dimethacrylate (BisGMA), triethylene glycol dimethacrylate (TEGDMA), camphorquinone (CQ), and ethyl 4-(dimethylamino)benzoate (4E) at 0.01μg/mL up to 500μg/mL, depending on the aqueous solubility of each chemical. Biofilms were evaluated at 4h and 24h for pH (n=3–8), biomass via crystal violet (n=12), metabolic activity via tetrazolium salt (n=12), and membrane permeability for selected concentrations via confocal microscopy (n=6). Parametric and non-parametric statistics were applied.Results500μg/mL TEGDMA reduced 24h metabolic activity but not biomass, similar to prior results with leachables from undercured BisGMA-TEGDMA polymers. 50μg/mL BisGMA reduced biofilm biomass and activity, slightly delayed the pH drop, and decreased the number of cells with intact membranes. 100μg/mL CQ delayed the pH drop and metabolic activity at 4h but then significantly increased the 24h metabolic activity. 4E had no effect up to 10μg/mL.SignificanceMonomers and initiators that leach from resin composites affect oral bacterial biofilm growth in opposite ways. Leachables, which can be released for extended periods of time, have the potential to alter oral biofilm biomass and activity and should be considered in developing and evaluating new dental materials.
Graphical abstract
http://ift.tt/2G4ASmw
Validation of 3D skin imaging for objective repeatable quantification of severity of atrophic acne scarring
Abstract
Background
One major sequelae of acne is atrophic scarring, yet objective tools to assess scars are lacking. Neither depth nor volume of atrophic scars is readily evaluable clinically and standard 2D photography is significantly affected by lighting and shadows. The aim of our study was to define and evaluate parameters of 3D imaging that can be used to assess severity of atrophic acne scarring.
Methods
Single center study of 31 patients with acne scarring. A target area of 3 × 3 cm was defined on the face. The global severity of atrophic acne scarring in the target area was evaluated by 5 dermatologists and scars were counted and categorized by size (scars < 2 mm, 2-4 mm, and > 4 mm in diameter). Three dimensional images of the target area were acquired with the LifeViz Micro® system and analysis was performed using MountainsMaps® software. An algorithm was developed to quantify the scar volume loss: shape removal step, with an order 5 polynomial, and to calculate the Valley void volume 80% (Vvv 80%) defined in the ISO-25178 standard for 3D surface texture.
Results
Correlation coefficient of the Vvv parameter to mean global severity at the target area rating was 0.77. The volume of scars evaluated with the Vvv parameter was mainly impacted by scars > 2 mm. The evaluations demonstrated good repeatability (with an intra-class correlation coefficient ICC = 0.98).
Conclusions
We demonstrate convergent validation to clinical assessment and repeatability of 3D skin imaging in atrophic acne scarring. Image analysis is straightforward and can be integrated into an automated workflow.
http://ift.tt/2oPGedT
Changes in filaggrin degradation products and corneocyte surface texture by season
Summary
Background
During the winter in northern countries, the risk of dermatitis is increased due to low temperature and humidity. Dermatitis is particularly common on weather-exposed skin such as the cheeks and hands. Recently, increased numbers of unidentified nanosized protrusions on the corneocyte surface were associated with dermatitis and deficiency of natural moisturizing factor (NMF).
Objectives
To investigate the effect of season on NMF levels and corneocyte surface texture in cheek and hand skin of healthy adults.
Methods
Eighty healthy volunteers (40 male and 40 female) were recruited: 40 aged 18–40 years and 40 aged ≥ 70 years. Cheek and dorsal hand skin was tape stripped in the winter and summer. Analysis for NMF and corneocyte surface texture was done (Dermal Texture Index, DTI). Potential confounders were registered and adjusted for.
Results
In cheek skin, NMF levels were reduced and DTI elevated during the winter compared with the summer. Older participants had higher NMF levels than younger participants. In the summer, DTI level was dependent on self-reported ultraviolet exposure. In hand skin, NMF levels were higher during the winter than in the summer, and female participants had higher NMF levels than male participants.
Conclusions
Seasonal effects on NMF and DTI on the cheeks and hands were found, suggesting an influence of climatic factors at the biochemical and ultrastructural levels. Significant variations were also observed regarding age and sex, making it difficult to draw firm conclusions. Our study adds new pieces to the puzzle of seasonal differences in xerosis and dermatitis.
http://ift.tt/2Ftn8nt
The impact of in-scanner head motion on structural connectivity derived from diffusion MRI
Source:NeuroImage, Volume 173
Author(s): Graham L. Baum, David R. Roalf, Philip A. Cook, Rastko Ciric, Adon F.G. Rosen, Cedric Xia, Mark A. Elliott, Kosha Ruparel, Ragini Verma, Birkan Tunç, Ruben C. Gur, Raquel E. Gur, Danielle S. Bassett, Theodore D. Satterthwaite
Multiple studies have shown that data quality is a critical confound in the construction of brain networks derived from functional MRI. This problem is particularly relevant for studies of human brain development where important variables (such as participant age) are correlated with data quality. Nevertheless, the impact of head motion on estimates of structural connectivity derived from diffusion tractography methods remains poorly characterized. Here, we evaluated the impact of in-scanner head motion on structural connectivity using a sample of 949 participants (ages 8-23 years old) who passed a rigorous quality assessment protocol for diffusion magnetic resonance imaging (dMRI) acquired as part of the Philadelphia Neurodevelopmental Cohort. Structural brain networks were constructed for each participant using both deterministic and probabilistic tractography. We hypothesized that subtle variation in head motion would systematically bias estimates of structural connectivity and confound developmental inference, as observed in previous studies of functional connectivity. Even following quality assurance and retrospective correction for head motion, eddy currents, and field distortions, in-scanner head motion significantly impacted the strength of structural connectivity in a consistency- and length-dependent manner. Specifically, increased head motion was associated with reduced estimates of structural connectivity for network edges with high inter-subject consistency, which included both short- and long-range connections. In contrast, motion inflated estimates of structural connectivity for low-consistency network edges that were primarily shorter-range. Finally, we demonstrate that age-related differences in head motion can both inflate and obscure developmental inferences on structural connectivity. Taken together, these data delineate the systematic impact of head motion on structural connectivity, and provide a critical context for identifying motion-related confounds in studies of structural brain network development.
http://ift.tt/2HcsNeB
Severe acute respiratory distress syndrome in a liver transplant patient
Publication date: Available online 6 March 2018
Source:Medical Mycology Case Reports
Author(s): Nicholas M. Moore., Laurie A. Proia
This case report presents a 46-year old man with a failed liver transplant who presented with malaise and dyspnea. Imaging studies revealed diffuse reticulonodular infiltrates and innumerable miliary nodules and a left upper lobe consolidative mass. Examination of bronchoalveolar lavage fluid demonstrated yeast cells with broad-based budding. He was diagnosed with pulmonary blastomycosis and started therapy with liposomal amphotericin. In spite of therapy, he clinically worsened, developing acute respiratory distress syndrome (ARDS) and eventually expired.
http://ift.tt/2FjxIdj
Invasive pulmonary mucormycosis and aspergillosis in a patient with decompensated hepatic cirrhosis
Publication date: Available online 6 March 2018
Source:Medical Mycology Case Reports
Author(s): Jon G. Persichino, Argun D. Can, Tam T. Van, Michele N. Matthews, Scott G. Filler
Invasive pulmonary mucormycosis and aspergillosis are rare, life-threatening fungal infections. Most documented cases have been reported in non-cirrhotic patients with diabetes mellitus, neutropenia, or treatment with corticosteroids. The prevalence of each infection is low among patients with hepatic cirrhosis. We report the first likely case of combined invasive pulmonary mucormycosis and aspergillosis in a male with decompensated hepatic cirrhosis. This report also highlights the first non-diabetic case of invasive pulmonary mucormycosis with decompensated hepatic cirrhosis.
http://ift.tt/2FjdmVs
Subcutaneous abscesses caused by Trichophyton rubrum in the unilateral groin of an immunocompromised patient: A case report
Publication date: Available online 6 March 2018
Source:Medical Mycology Case Reports
Author(s): Utako Okata-Karigane, Yasuki Hata, Emiko Watanabe-Okada, Shunichi Miyakawa, Michi Ota, Yutaka Uzawa, Shigekazu Iguchi, Atsushi Yoshida, Ken Kikuchi
A 60-year-old Japanese man presented with multiple subcutaneous nodules in his left groin. Histologically, the nodules consisted of suppurative granulomas and abscesses not involving the hair follicles. Trichophyton rubrum TWCC57922 was detected by fungal culture and polymerase chain reaction (PCR) sequencing of the rDNA genes. We diagnosed these nodules as deeper dermal dermatophytosis, a rare form of invasive dermatophytosis. He was treated with terbinafine. We compared these findings with previous reports of deep dermal dermatophytosis.
http://ift.tt/2FoIYFn
Two Cases of Fungal Keratitis Caused by Metarhizium anisopliae
Publication date: Available online 6 March 2018
Source:Medical Mycology Case Reports
Author(s): Abigail L. Goodman, Shawn R. Lockhart, Colleen B. Lysen, Lars F. Westblade, Carey-Ann D. Burnham, Eileen M. Burd
We present two cases of keratitis due to Metarhizium anisopliae in geographically separated areas of the United States. The isolates were microscopically similar but morphologically different and were identified by ribosomal DNA sequencing. Both isolates had low minimum inhibitory concentration (MIC) values to caspofungin and micafungin, but high MIC values to amphotericin B. The morphologic and antifungal susceptibility differences between the two isolates indicate possible polyphylogeny of the group.
http://ift.tt/2Fkn4qH
Constructional Apraxia
Source:Cortex
Author(s): Roberto Cubelli, Sergio Della Sala
http://ift.tt/2G1AqW4
Editorial Board
Source:Artificial Intelligence in Medicine, Volume 86
http://ift.tt/2D5A1id
Underdiagnosed and undertreated psoriasis: Nuances of treating psoriasis affecting the scalp, face, intertriginous areas, genitals, hands, feet, and nails
Abstract
Psoriasis of the scalp, face, intertriginous areas, genitals, hands, feet, and nails is often underdiagnosed, and disease management can be challenging. Despite the small surface area commonly affected by psoriasis in these locations, patients have disproportionate levels of physical impairment and emotional distress. Limitations in current disease severity indices do not fully capture the impact of disease on a patient's quality of life, and, combined with limitations in current therapies, many patients do not receive proper or adequate care. In this review, we discuss the clinical manifestations of psoriasis in these less commonly diagnosed areas and its impact on patient quality of life. We also examine clinical studies evaluating the effectiveness of therapies on psoriasis in these regions. This article highlights the need to individualize treatment strategies for psoriasis based on the area of the body that is affected and the emerging role of biologic therapy in this regard.
http://ift.tt/2I8Hcty
Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib.
http://ift.tt/2FkSk4T
Harnessing the Power of Proteomics to Assess Drug Safety and Guide Clinical Trials.
http://ift.tt/2FYVFYo
International External Validation Study of the 2014 European Society of Cardiology Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy (EVIDENCE-HCM).
http://ift.tt/2FmpxwW
Predicting the Future in Hypertrophic Cardiomyopathy.
http://ift.tt/2G0DUYF
Persistent Long-Term Structural, Functional, and Metabolic Changes After Stress-Induced (Takotsubo) Cardiomyopathy.
http://ift.tt/2G0DUI9
Genetic and Functional Profiling of CD16-Dependent Natural Killer Activation Identifies Patients at Higher Risk of Cardiac Allograft Vasculopathy.
http://ift.tt/2D6hq5A
Glucose-Lowering Therapies and Heart Failure in Type 2 Diabetes Mellitus: Mechanistic Links, Clinical Data, and Future Directions.
http://ift.tt/2FYAYMh
Return-to-Play for Athletes With Genetic Heart Diseases.
http://ift.tt/2G014yz
Letter by Jin-shan and Xue-bin Regarding Article, "Coronary Plaque Characterization in Psoriasis Reveals High-Risk Features That Improve After Treatment in a Prospective Observational Study".
http://ift.tt/2FmTUDx
Letter by Hjuler et al Regarding Article, "Coronary Plaque Characterization in Psoriasis Reveals High-Risk Features That Improve After Treatment in a Prospective Observational Study".
http://ift.tt/2G1OX4a
Response by Lerman et al to Letters Regarding Article, "Coronary Plaque Characterization in Psoriasis Reveals High-Risk Features That Improve After Treatment in a Prospective Observational Study".
http://ift.tt/2D3dTox
Letter by Spartalis et al Regarding Article, "Cardiomyocyte Regeneration: A Consensus Statement".
http://ift.tt/2G1OSNU
Safety and Efficacy of Autologous Tissue-derived Mesenchymal Stem Cells for Radiation-Induced Xerostomia: A Randomized, Placebo-Controlled Phase I/II Trial (MESRIX)
Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Christian Grønhøj, David H. Jensen, Peter Vester-Glowinski, Siri Beier Jensen, Allan Bardow, Roberto S. Oliveri, Lea Munthe Fog, Lena Specht, Carsten Thomsen, Sune Darkner, Michael Jensen, Vera Müller, Katalin Kiss, Tina Agander, Elo Andersen, Anne Fischer-Nielsen, Christian von Buchwald
BackgroundSalivary gland hypofunction and xerostomia are major complications to head and neck radiotherapy. This trial assessed the safety and efficacy of adipose tissue-derived mesenchymal stem cell (ASC) therapy for radiation-induced xerostomia.Patient and MethodsThis randomized, placebo-controlled phase I/II trial included 30 patients, randomized in a 1:1 ratio to receive ultrasound-guided transplantation of ASCs or placebo to the submandibular glands. Patients had previously received radiotherapy for a T1-2, N0-2A, human papillomavirus-positive, oropharyngeal squamous cell carcinoma. The primary outcome was the change in unstimulated whole salivary flow rate, measured before and after the intervention. All assessments were performed one month prior (baseline) and one and four months following ASC or placebo administration.ResultsNo adverse events were detected. Unstimulated whole salivary flow rates significantly increased in the ASC-arm at one (33%; p=0.048) and four months (50%; p=0.003), but not in the placebo-arm (p=0.6 and p=0.8), compared to baseline. The ASC-arm symptom scores significantly decreased on the xerostomia and VAS questionnaires, in the domains of thirst (-22%, p=0.035) and difficulties in eating solid foods (-2%, p=0.008) after four months compared to baseline. The ASC-arm showed significantly improved salivary gland functions of inorganic element secretion and absorption, at baseline and four months, compared to the placebo-arm. Core-needle biopsies showed increases in serous gland tissue and decreases in adipose and connective tissues in the ASC-arm compared to the placebo-arm (p=0.04 and p=0.02, respectively). MRIs showed no significant differences between groups in gland size or intensity (p < 0.05).ConclusionsASC therapy for radiation-induced hypofunction and xerostomia was safe and significantly improved salivary gland functions and patient-reported outcomes. These results should encourage further exploratory and confirmatory trials.
http://ift.tt/2G1vHUi
The Biology of SBRT: LQ or Something New?
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): J Martin Brown
http://ift.tt/2D6e6Hy
A method for automatic selection of parameters in NTCP modelling
Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Damianos Christophides, Ane L. Appelt, Arief Gusnanto, John Lilley, David Sebag-Montefiore
PurposeIn this study we present a fully automatic method to generate multiparameter normal tissue complication probability (NTCP) models and compare its results with a published model of the same patient cohort.Methods and MaterialsData were analysed from 345 rectal cancer patients treated with external radiotherapy to predict the risk of patients developing grade 1 or ≥2 cystitis. In total 23 clinical factors were included in the analysis as candidate predictors of cystitis.Principal component analysis (PCA) was used to decompose the bladder dose volume histogram (DVHs) into 8 principal components (PCs), explaining more than 95% of the variance. The dataset of clinical factors and PCs was divided into training (70%) and test (30%) datasets, with the training dataset used by the algorithm to compute an NTCP model. The first step of the algorithm was to obtain a bootstrap sample, followed by multicollinearity reduction using the variance inflation factor (VIF) and genetic algorithm optimisation to determine an ordinal logistic regression model that minimises the Bayesian information criterion (BIC). The process was repeated 100 times and the model with the minimum BIC was recorded on each iteration. The most frequent model was selected as the final 'automatically generated model' (AGM). The published model and AGM were fitted on the training datasets and the risk of cystitis was calculated.ResultsThe two models had no significant differences in predictive performance both for the training and test datasets (p-value>0.05), and found similar clinical and dosimetric factors as predictors. Both models exhibited good explanatory performance on the training dataset (p-values>0.44) which was reduced on the test datasets (p-values<0.05).ConclusionsThe predictive value of the AGM is equivalent to the expert-derived published model. It demonstrates potential in saving time, tackling problems with a large number of parameters and standardising variable selection in NTCP modelling.
http://ift.tt/2G1ex98
The Resident Individual Development Plan as a Guide for Radiation Oncology Mentorship
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Huaising C. Ko, Randall J. Kimple
http://ift.tt/2FkQ3qn
Total Mesorectal Excision versus Local Excision Following Preoperative Chemoradiotherapy in Rectal Cancer with Lymph Node Metastasis: A Propensity Score-Matched Analysis
Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Young Seob Shin, Jin-hong Park, Sang Min Yoon, Jin Cheon Kim, Chang Sik Yu, Seok-Byung Lim, In Ja Park, Tae Won Kim, Yong Sang Hong, Kyu-pyo Kim, Eun Kyung Choi, Seung Do Ahn, Sang-Wook Lee, Jong Hoon Kim
BackgroundLocal excision (LE) in good responders to preoperative chemoradiotherapy (PCRT), which is considered as a good alternative to total mesorectal excision (TME) in early-stage rectal cancer, is not commonly recommended for node-positive (cN+) cases. This study aimed to determine whether LE outcomes were comparable to TME outcomes in cN+ rectal cancer patients who were good responders.Materials and MethodsThis retrospective study included clinical T2-3 and cN+ low rectal cancer patient who received PCRT followed by TME or LE. Clinical stage T1 or T4 tumors, upper-to-middle rectal tumors (>7 cm from anal verge), and synchronous distant metastases were excluded. Lymph nodes ≥5 mm in size were defined as tumor-positive, and patients with metastatic lymph nodes >20 mm in size were excluded. Preoperative chemoradiotherapy comprised radiation (50–50.4 Gy/25–28 fractions over 5 weeks) with two cycles of 5-fluorouracil or oral capecitabine. Propensity scores were computed from tumor and patient variables and used for one-to-one matched analysis. Local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were compared between the two matched groups.ResultsBetween January 2007 and December 2013, 563 and 55 patients underwent TME and LE, respectively. Median follow-up period was 54 months. In propensity score-matched analysis, 48 patients were included in each group. No statistical differences were observed in 3-year LRFS (97.9% vs. 97.9%, p = 0.994), 3-year DFS (91.5% vs. 91.4%, p = 0.968), or 3-year OS (93.7% vs. 97.9%, p = 0.809) between TME and LE groups.ConclusionsIn clinical N+ rectal cancer patients, oncological outcomes of PCRT followed by LE were comparable to those of TME; this finding might be applicable only to those patients with good response in the primary tumor and small lymph node metastases.
http://ift.tt/2G1hCpX
Contemporary statewide practice pattern assessment of the palliative treatment of bone metastasis
Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Daniel E. Spratt, Brandon Mancini, James A. Hayman, Thomas Boike, Lori Pierce, Jean M. Moran, Michael M. Dominello, Mark Fireman, Kent Griffith, Shruti Jolly
PurposePalliative radiotherapy for bone metastases is often viewed as a single entity, despite national guidelines providing input principally only for painful uncomplicated bone metastases. Data surrounding the treatment of bone metastases is often gleaned from questionnaires of what providers would theoretically do in practice or population-based data lacking critical granular information. Herein, we investigate the real-world treatment of bone metastases with radiotherapy.Methods and MaterialsTwenty diverse institutions across the state of XXXXX had data extracted on their 10 most recent cases of radiotherapy delivered for the treatment of bone metastases at their institution between January and February of 2017. Uni- and multivariable binary logistic regression was used to assess use of single fraction (8 Gy x 1) radiotherapy.ResultsA total of 196 cases were eligible for inclusion. Twenty-eight different fractionation schedules were identified. The most common schedule was 3 Gy x 10 fractions (n=100, 51.0%), 4 Gy x 5 fractions (n=32, 16.3%), and 8 Gy x 1 (n=15, 7.7%). Significant predictors for use of single fraction radiotherapy were presence of oligometastatic disease (p=0.008), prior overlapping radiotherapy (p=0.050), and academic practice type (p=0.039). Twenty-nine cases (14.8%) received >10 fractions (median 15, range 11-20 fractions). Intensity modulated radiotherapy was used in 14 cases (7.1%), stereotactic body radiotherapy in 11 cases (5.6%), and image guidance with cone beam CT in 11 cases (5.6%). Amongst simple painful bone metastases (no prior surgery, cord compression, fracture, soft tissue extension, or overlapping prior radiotherapy; n=70), only 12.9% were treated with 8 Gy x 1.ConclusionsBone metastases represent a heterogeneous disease, and the radiotherapeutic treatment of bone metastases is similarly diverse. Future work is needed to understand barrier to single fraction use, and clinical trials are necessary to establish appropriate guidelines for the breadth of this complex disease.
http://ift.tt/2D4XrEx
Scholarly Impact of Student Participation in Radiation Oncology Research
Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): M. Paracha, K.N. Kim, M.M. Qureshi, A. Shah, A. Agarwal, T. Sachs, S. Sarfaty, A.E. Hirsch
IntroductionLiterature evaluating student authorship has used the H-index (Hi), a measure of scholarly impact. However, student authorship over time is less well defined. In this study, we evaluated the rate of non-doctoral student authors publishing in an academic journal over time. Additionally, we analyzed the effects student authors have on the scholarly impact of corresponding authors (CA) by comparing their respective Hi.MethodsWe created a database of authors that published articles in the International Journal of Radiation Oncology Biology Physics (IJROBP) in 2006, 2010, and 2014 that included CA, degree and student author designations. CAs' Hi were obtained from Scopus (scopus.com). Student authorship rates were compared between the sampled years. The data was divided into two groups, CA publishing with student authors (SA) and those without (nSA). CAs' median and mean Hi with standard deviation (sd) and a 95% confidence interval (CI) were compared between SA and nSA.ResultsA total of 1,728 published articles were identified with 1,477 unique CA. Percentage of published articles with student authors increased from 44.4% in 2006, 52.9% in 2010 to 55.9% in 2014, p=0.0003. In overall analysis, mean Hi was higher for SA as compared to nSA (24.3 vs. 22.9), although this did not achieve statistical significance (p=0.094). Mean Hi (sd) in 2006, 2010 and 2014 were 27.9 (16.6), 23.6 (16.7) and 18.5 (14.6), respectively. Mean Hi was significantly higher for SA compared to nSA in years 2006 (29.5 vs. 26.6, p=0.048) and 2010 (24.9 vs. 21.9, p=0.038) but not in 2014 (18.5 vs. 18.4, p=0.963).ConclusionStudent authorship rates in IJROBP are increasing. The data suggest that student participation in research may benefit both corresponding and student authors. Creating and expanding research programs to integrate research into medical education may enhance students' experience and encourage interest in radiation oncology.
Teaser
Student authorship rates over time are ill defined. This is an analysis of the effects of student authorship on scholarly impact in radiation oncology by comparing the H-indices of corresponding authors in IJROBP that published with and without student authors in 2006-2014. Students are not a detriment to scholarly productivity; student authorship rates increased and corresponding authors publishing with student authors had higher H-indices compared to those that did not publish with student authors.http://ift.tt/2FZXwfC
Applying Lean-Six-Sigma Methodology in radiotherapy: Lessons learned by the breast daily repositioning case
Source:Radiotherapy and Oncology
Author(s): Pietro Mancosu, Giorgia Nicolini, Giulia Goretti, Fiorenza De Rose, Davide Franceschini, Chiara Ferrari, Giacomo Reggiori, Stefano Tomatis, Marta Scorsetti
Background & purposeLean Six Sigma Methodology (LSSM) was introduced in industry to provide near-perfect services to large processes, by reducing improbable occurrence. LSSM has been applied to redesign the 2D-2D breast repositioning process (Lean) by the retrospective analysis of the database (Six Sigma).Materials & methodsBreast patients with daily 2D-2D matching before RT were considered. The five DMAIC (define, measure, analyze, improve, and control) LSSM steps were applied. The process was retrospectively measured over 30 months (7/2014–12/2016) by querying the RT Record&Verify database. Two Lean instruments (Poka-Yoke and Visual Management) were considered for advancing the process. The new procedure was checked over 6 months (1–6/2017).Results14,931 consecutive shifts from 1342 patients were analyzed. Only 0.8% of patients presented median shifts >1 cm. The major observed discrepancy was the monthly percentage of fractions with almost zero shifts (AZS = 13.2% ± 6.1%). Ishikawa fishbone diagram helped in defining the main discrepancy con-causes. Procedure harmonization involving a multidisciplinary team to increase confidence in matching procedure was defined. AZS was reduced to 4.8% ± 0.6%. Furthermore, distribution symmetry improvement (Skewness moved from 1.4 to 1.1) and outlier reduction, verified by Kurtosis diminution, demonstrated a better "normalization" of the procedure after the LSSM application.ConclusionsLSSM was implemented in a RT department, allowing to redesign the breast repositioning matching procedure.
http://ift.tt/2tpDJU6
DAHANCA 10 – Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group
Source:Radiotherapy and Oncology
Author(s): Jens Overgaard, Camilla Molich Hoff, Hanne Sand Hansen, Lena Specht, Marie Overgaard, Pernille Lassen, Elo Andersen, Jørgen Johansen, Lisbeth Juhler Andersen, Jan Folkvard Evensen, Jan Alsner, Cai Grau
PurposeTo evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of the head and neck (HNSCC).Patients and methodsPatients eligible for primary radiotherapy and who had Hb values below 14.0 g/dl were randomized to receive accelerated fractionated radiotherapy with or without darbepoetin alfa. Patients also received the hypoxic radiosensitizer nimorazole. Darbepoetin alfa was given weekly during radiotherapy or until the Hb value exceeded 15.5 g/dl.ResultsFollowing a planned interim analysis which showed inferiority of the experimental treatment the trial was stopped after inclusion of 522 patients (of a planned intake of 600). Of these, 513 were eligible for analysis (254 patients treated with darbepoetin alfa and 259 patients in the control group). Overall, the patients were distributed according to the stratification parameters (gender, T and N staging, tumor site). Treatment with darbepoetin alfa increased the Hb level to the planned value in 81% of the patients. The compliance was good without excess serious adverse events.The results showed a poorer outcome with a 5-year cumulative loco-regional failure rate of 47% vs. 34%, Hazard Ratio (HR): 1.53 [1.16–2.02], for the darbepoetin alfa vs. control arm, respectively. This was also seen for the endpoints of event-free survival (HR: 1.36 [1.09–1.69]), disease-specific death (HR: 1.43 [1.08–1.90]), and overall survival (HR: 1.30 [1.02–1.64]). There was no enhanced risk of cardio-vascular events observed in the experimental arm or any significant differences in acute or late radiation related morbidity. All univariate analyses were confirmed in a multivariate setting.ConclusionCorrection of the Hb level with darbepoetin alfa during radiotherapy of patients with HNSCC resulted in a significantly poorer tumor control and survival.
http://ift.tt/2oOkgYF
An atlas to aid delineation of para-aortic lymph node region in cervical cancer: Design and validation of contouring guidelines
Source:Radiotherapy and Oncology
Author(s): Lorna G. Keenan, Kathy Rock, Aini Azmi, Osama Salib, Charles Gillham, Orla McArdle
IntroductionPrevious studies have investigated the anatomical distribution of para-aortic lymph nodes (PAN) in patients with cervical cancer. However, an atlas for accurate clinical target volume (CTV) delineation has yet to be defined. The purpose of this study was to design and verify a computerized tomography (CT) atlas to provide guidance for contouring the PAN CTV in patients with cervical cancer.Materials and methodsThis prospective study included 21 cervical cancer patients (design cohort) with 39 pathological PAN identified on (18)F-FDG PET-CT. PAN [left lateral para-aortic (LLPA), aorto-caval (AC), right para-caval (RPC) nodes] were delineated on CT simulation scans. Measurements were taken from the volumetric centre of the nodes to the edge of aorta and inferior vena-cava (IVC). Initially the aorta and IVC were expanded by the mean distance to the lymph node centre to create a CTV. Expansion margins were then increased asymmetrically until the CTV resulted in a clinically acceptable number of PAN included. The CTV was validated on a further 10 patients (validation cohort) with 29 PAN. A detailed contouring guide and accompanying visual atlas for elective PAN CTV delineation was created based on the validated margins.ResultsFor the design cohort (n = 21 patients, 39 PAN), the mean distance from the centre of the node to the aorta was 8 mm (range 4–17) for both LLPA (range 4–17) and AC (range 4–15) regions. Mean distance from the IVC to the centre of the nodes was 5 mm (range 4–6) in the RPC region and 6 mm (range 3–15) in the AC region. No PAN was superior to the T12-L1 interspace or the left renal vein or inferior to the L5-S1 interspace. For validation cohort (n = 10 patients, 29 PAN), mean distance from centre of the node to the aorta was 9 mm (range 5–15) in the LLPA region, 7 mm (range 6.5–14) in the AC region. Mean distance from the ICV to the centre of the nodes was 3 mm (range 2.5–4) in the RPC region and 5 mm (range 3–10) in the AC region. A CTV expansion from the aorta of 10 mm circumferentially and 15 mm laterally, and from the IVC of 8 mm anteromedially and 6 mm posterolaterally resulted in coverage of 97% (38/39) of PAN in the design cohort. On prospective validation, the described CTV included 97% (28/29) of PAN in the validation cohort.ConclusionWe propose the following PAN CTV; expansion from aorta of 10 mm circumferentially except 15 mm laterally, expansion from the IVC of 8 mm anteromedial and 6 mm posterolaterally. The suggested CTV includes 97% (28/29) PAN in a validated patient cohort. A detailed guide and accompanying visual atlas is provided to aid delineation of the PAN CTV in patients with cervical cancer.
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A First‐in‐Human Phase 1 Study of OPB‐111077, a Small‐Molecule STAT3 and Oxidative Phosphorylation Inhibitor, in Patients with Advanced Cancers
AbstractLessons Learned. OPB‐111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation that exhibited promising anticancer activity in preclinical models.In this first‐in‐human phase I study of OPB‐111077 in unselected advanced cancers, treatment‐emergent adverse events, most frequently nausea, fatigue, and vomiting, were generally mild to moderate in intensity and could be medically managed.Overall, only modest clinical activity was observed after OPB‐111077 given as monotherapy. Notable antitumor activity was seen in a subject with diffuse large B‐cell lymphoma.Background.OPB‐111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation with promising anticancer activity in preclinical models.Methods.Open‐label, phase I trial of OPB‐111077 in advanced cancers with no available therapy of documented benefit. Initial dose escalation in unselected subjects was followed by dose expansion. Patients received oral OPB‐111077 daily in 28‐day cycles until loss of clinical benefit.Results.Eighteen subjects enrolled in dose escalation, and 127 in dose expansion. Dose‐limiting toxicities were observed at 300 mg and 400 mg QD; maximum tolerated dose was defined as 250 mg QD. Frequently reported treatment‐emergent adverse events (TEAEs) included nausea, fatigue, and vomiting. TEAEs were generally mild to moderate and could be medically managed. OPB‐111077 reached micromolar drug concentrations, had an elimination half‐life of approximately 1 day, and reached steady‐state by day 8. A durable partial response was observed in one subject with diffuse large B‐cell lymphoma. Seven subjects with diverse tumor types had stable disease or minor responses for at least eight treatment cycles (224 days).Conclusion.OPB‐111077 is generally well tolerated, and its pharmacokinetic profile is sufficient for further clinical development. Notable clinical activity was observed in a subject with diffuse large B‐cell lymphoma. Overall, modest efficacy was observed against unselected tumors.
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The Development of Wrap-Up Processes in Text Reading: A Study of Children's Eye Movements.
http://ift.tt/2Fj4bV0
A Memory Advantage for Past-Oriented Over Future-Oriented Performance Feedback.
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The peptide toxin δ-hexatoxin-MrIX inhibits fast inactivation of NaVs in mouse cerebellar granule cells
Publication date: Available online 6 March 2018
Source:Peptides
Author(s): Dongfang Tang, Zhen Xiao, Yan Xu, Jiao Zeng, Dezheng Peng, Songping Liang, Cheng Tang, Zhonghua Liu
Spider venom is rich in peptide toxins that could be used to explore the structure and function of voltage-gated sodium channels (NaVs). This study has characterized a 44-amino acid peptide toxin, δ-hexatoxin-MrIX (δ-HXTX-MrIX), from the venom of the spider Macrothele raveni. δ-hexatoxin-MrIX potently inhibited the fast inactivation of NaVs in mouse cerebellar granule cells (CGCs) with an EC50 of 35.3 ± 5.9 nM. The toxin shifted both the steady-state activation and the steady-state inactivation curves of CGC NaVs to the hyperpolarized direction. δ-hexatoxin-MrIX also acted on NaV1.3 and NaV1.4 channels heterologously expressed in HEK293T cells, as well a s on NaVs in acutely isolated cockroach DUM neurons. However, the NaV1.5, NaV1.7 and NaV1.8 channels were resistant to δ-hexatoxin-MrIX. The toxin inhibited the fast inactivation of NaV1.3 and NaV1.4 with high affinity (EC50 values of 82.0 ± 3.0 nM and 24.0 ± 4.7 nM, respectively), but the saturating dose of toxin showed distinct efficacy on these two types of channels. δ-hexatoxin-MrIX is a peptide toxin acting on CGC NaVs and could be used as a pharmacological tool to explore the role of NaVs in granule cell maturation during cerebellum development.
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Editorial Board
Publication date: 15 March 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 6
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Biophysical and biological evaluation of optimized stapled peptide inhibitors of the linear ubiquitin chain assembly complex (LUBAC)
Publication date: 15 March 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 6
Author(s): Francisco Aguilar-Alonso, Amanda L. Whiting, Ye Joon Kim, Federico Bernal
Linear ubiquitylation, in which ubiquitin units are covalently linked through N- and C-terminal amino acids, is a unique cellular signaling mechanism. This process is controlled by a single E3 ubiquitin ligase, the linear ubiquitin chain assembly complex (LUBAC), which is composed of three proteins – HOIL-1L, HOIP and SHARPIN. LUBAC is involved in the activation of the canonical NF-κB pathway and has been linked to NF-κB dependent malignancies. In this work, we present HOIP-based stapled alpha-helical peptides designed to inhibit LUBAC through the disruption of the HOIL-1L-HOIP interaction and loss of the functional complex. We find our HOIP peptides to be active LUBAC ubiquitylation inhibitors in vitro, though through interaction with HOIP rather than HOIL. Active peptides were shown to have inhibitory effects on cell viability, reduced NF-κB activity and decreased production of NF-κB related gene products. This work further demonstrates the potential of LUBAC as a therapeutic target and of the use of stapled peptides as inhibitors of protein-protein interactions.
Graphical abstract
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Evaluation of sequence variability in HIV-1 gp41 C-peptide helix-grafted proteins
Publication date: 15 March 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 6
Author(s): Rachel L. Tennyson, Susanne N. Walker, Terumasa Ikeda, Reuben S. Harris, Brian R. McNaughton
Many therapeutically-relevant protein-protein interactions (PPIs) have been reported that feature a helix and helix-binding cleft at the interface. Given this, different approaches to disrupting such PPIs have been developed. While short peptides (<15 amino acids) typically do not fold into a stable helix, researchers have reported chemical approaches to constraining helix structure. However, these approaches rely on laborious, and often expensive, chemical synthesis and purification. Our premise is that protein-based solutions that stabilize a therapeutically-relevant helix offer a number of advantages. In contrast to chemically constrained helical peptides, or minimal/miniature proteins, which must be synthesized (at great expense and labor), a protein can be expressed in a cellular system (like all current protein therapeutics). If selected properly, the protein scaffold can stabilize the therapeutically-relevant helix. We recently reported a protein engineering strategy, which we call "helix-grafted display", and applied it to the challenge of suppressing HIV entry. We have reported helix-grafted display proteins that inhibit formation of an intramolecular PPI involving HIV gp41 C-peptide helix, and HIV gp41 N-peptide trimer, which contain C-peptide helix-binding clefts. Here, we used yeast display to screen a library of grafted C-peptide helices for N-peptide trimer recognition. Using 'hits' from yeast display library screening, we evaluated the effect helix mutations have on structure, expression, stability, function (target recognition), and suppression of HIV entry.
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Publication date: 15 March 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 6
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Graphical abstract TOC
Publication date: 15 March 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 6
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Graphical abstract TOC
Publication date: 15 March 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 6
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High Expression of Integrin αvβ3 Enables Uptake of Targeted Fluorescent Probes into Ovarian Cancer Cells and Tumors
Publication date: Available online 6 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Scott K. Shaw, Cynthia L. Schreiber, Felicia M. Roland, Paul M. Battles, Seamus P. Brennan, Simon J. Padanilam, Bradley D. Smith
The cell line OVCAR-4 was recently ranked as one of the most representative cell lines for high grade serous ovarian cancer (HGSOC). However, little work has been done to assess the susceptibility of OVCAR-4 cells and tumors to the more common types of molecular targeting. Proteome profiles suggest OVCAR-4 express high levels of integrin αvβ3 receptors. Using flow cytometry with fluorescent antibodies we determined that OVCAR-4 cells have high number of integrin αvβ3 receptors ([9.8 ± 2.5] x 104 /cell) compared to the well-characterized cell line U87-MG ([5.2 ± 1.4] x 104 /cell). However, OVCAR-4 cells also have roughly three times the surface area of U87-MG cells, so the average αvβ3 receptor density is actually lower (11 ± 3 versus 18 ± 6 receptors/µm2). A series of new fluorescent molecular probes was prepared with structures comprised of a deep-red squaraine fluorophore (∼680 nm emission) covalently attached to zero, one, or two cyclic pentapeptide cRGD sequences for integrin targeting. Microscopy studies showed that uptake of the divalent probe into cultured OVCAR-4 cells was 2.2 ± 0.4 higher than the monovalent probe, which in turn was 2.2 ± 0.4 higher than the untargeted probe. This probe targeting trend was also seen in OVCAR-4 mouse tumor models. The results suggest that clinically relevant OVCAR-4 cells can be targeted using molecular probes based on αvβ3 integrin receptor antagonists such as the cRGD peptide. Furthermore, deep-red fluorescent cRGD-squaraine probes have potential as targeted stains of cancerous tissue associated with HGSOC in surgery and pathology settings.
Graphical abstract
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Structure-activity relationships in a new class of non-substrate-like covalent inhibitors of the bacterial glycosyltransferase LgtC
Publication date: Available online 6 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Yong Xu, Jon Cuccui, Carmen Denman, Tripty Maharjan, Brendan W. Wren, Gerd K. Wagner
Lipooligosaccharide (LOS) structures in the outer core of Gram-negative mucosal pathogens such as Neisseria meningitidis and Haemophilus influenzae contain characteristic glycoepitopes that contribute significantly to bacterial virulence. An important example is the digalactoside epitope generated by the retaining α-1,4-galactosyltransferase LgtC. These digalactosides camouflage the pathogen from the host immune system and increase its serum resistance. Small molecular inhibitors of LgtC are therefore sought after as chemical tools to study bacterial virulence, and as potential candidates for anti-virulence drug discovery. We have recently discovered a new class of non-substrate-like inhibitors of LgtC. The new inhibitors act via a covalent mode of action, targeting a non-catalytic cysteine residue in the LgtC active site. Here, we describe, for the first time, structure-activity relationships for this new class of glycosyltransferase inhibitors. We have carried out a detailed analysis of the inhibition kinetics to establish the relative contribution of the non-covalent binding and the covalent inactivation steps for overall inhibitory activity. Selected inhibitors were also evaluated against a serum-resistant strain of Haemophilus influenzae, but did not enhance the killing effect of human serum.
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High Mobility Group A (HMGA) proteins: Molecular instigators of breast cancer onset and progression
Publication date: Available online 6 March 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Riccardo Sgarra, Silvia Pegoraro, Gloria Ros, Carlotta Penzo, Eusebio Chiefari, Daniela Foti, Antonio Brunetti, Guidalberto Manfioletti
Cancer heterogeneity is one of the factors that constitute an obstacle towards an efficient targeting of this multifaceted disease. Molecular information can help in classifying cancer subtypes and in providing clinicians with novel targeted therapeutic opportunities. In this regard, classification of breast cancer into intrinsic subtypes based on molecular profiling represents a valuable prototype.The High Mobility Group A (HMGA) chromatin architectural factors (HMGA1a, HMGA1b, and HMGA2) have a relevant and causal role in breast cancer onset and development, by influencing virtually all cancer hallmarks. The regulation of HMGA expression is under the control of major pathways involved in cell proliferation and survival, as well as in other cancer-related processes, thereby suggesting, for the HMGA members, a high degree of homology and overlapping activities. Despite of this evidence, HMGA proteins display also specific functions.In this review, we provide an overview of (i) the pathways involved in HMGA transcriptional and post-transcriptional regulation, (ii) the utilization of HMGA as molecular markers, and (iii) the biological role of HMGA in the context of breast cancer. We focus on the potential significance of HMGA in governing the onset and development of this tumour, as well as on the potential of these factors as novel specific targets for preventing and treating strategies. The emerging picture is a highly interconnected triad of proteins that could mutually influence each other, either in a competitive or cooperative manner, and that, in our opinion, should be considered as a unified and integrated protein system.
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P2X receptor-ion channels in the inflammatory response in adipose tissue and pancreas—potential triggers in onset of type 2 diabetes?
Source:Current Opinion in Immunology, Volume 52
Author(s): Ivana Novak, Anna Solini
Type 2 diabetes is reaching an alarming prevalence worldwide. Its complex pathogenesis certainly includes a pivotal role of low-grade inflammation, which could be triggered by excessive purinergic signaling. In this complex scenario, extracellular ATP impairs the function of two key players: β-cell and adipose tissue. In the former, P2Y and possibly some P2X receptors-ion channels regulate insulin secretion, but it is still debated whether excessive ATP can via P2X receptors impair β-cell function directly or whether cell damage is due to an excessive systemic release of cytokines. In human adipocytes, the P2X7 receptor promotes the release of inflammatory cytokines, at least in part via inflammasome activation, likely contributing to systemic insulin resistance. This receptor-inflammasome system is also strongly activated in macrophages infiltrating both pancreas and adipose tissue, mediating a deleterious cross-talk that perpetuates the damage.
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Development of a Device-Assisted Nerve-Regeneration Procedure in Disruptive Lesions of the Brachial Plexus
J reconstr Microsurg
DOI: 10.1055/s-0038-1627472
Background We describe the development of a new surgical procedure to be used in the treatment of disruptive brachial plexus (BP) lesions. It is centered on an artificial device designed to assist nerve regeneration by providing a confined and protected environment. Nerve fibers can repair inside the device, while the adverse massive scar-tissue formation is limited to the outside of the device. Methods Steps in the development of the procedure were (1) definition of the rationale, (2) design of the device, (3) choice of an in vivo translational model, (4)refinement of the surgical procedure, and (5) performance of an in vivo pilot study as a proof of concept. An interdisciplinary team from several laboratories was involved in this work over a period of 6 years. Results Results showed the absence of significant scar tissue in the regenerate and the presence of myelinated fibers aligned proximodistally between the stumps. This surgical approach can be seen not only as a definitive treatment but also as an early examination and stabilization before some different surgery will be later performed. It may also be used as additional protection for traditional surgery like end-to-end coaptation. Conclusions We conclude that the availability of a suitable device-assisted early treatment, even if not to be considered definitive, could help in addressing the BP lesions at an earlier stage and this may improve the final outcome. Our evidence justifies further experimentation on this approach.
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Donor-Site Outcomes for the Osteocutaneous Radial Forearm Free Flap
J reconstr Microsurg
DOI: 10.1055/s-0038-1635087
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
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Initial Management of Traumatic Digit Amputations: A Retrospective Study of Functional Outcomes
J reconstr Microsurg
DOI: 10.1055/s-0038-1626692
Background Traumatic amputation of one or more digits can have a serious detrimental effect on social and economic standings which can be mitigated by successful replantation. Little has been recorded on preoperative management before replantation and how this affects the outcomes of the replanted digit. Methods A retrospective cohort study was conducted and data collected over an 18-month period. Three protocols for preoperative management were examined: minimal (basic wound management), complete Buncke (anticoagulation, dry dressing on amputate placed on indirect ice and absence of a digital block), and incomplete (any two or three criteria from complete Buncke in addition to the minimal) protocols. Data was collected on survival rate, secondary operations, and complication rate. Function was defined by sensation, range of movement, and strength. Results Seventy four of 177 digits were replanted with an overall survival rate of 86.5%. The rates for minimal, incomplete, and complete protocols were 95%, 87%, and 91%, respectively, and not significantly different. The complication rate was significantly different between the complete (20%) and minimal (60%) protocols (p = 0.0484). Differences in sensation and grip strength were statistically significant between protocols (p = 0.0465 and p = 0.0430, respectively). Anticoagulation, no digital block and dry gauze all showed reduced complication rates in comparison to their counterparts. Conclusions The Buncke protocol, which includes anticoagulation, no digital block, and dry gauze, was found to significantly reduce the complication rate which suggests that it prevents compromise of tissue integrity. Significant differences were found between protocols for sensation and grip strength. A higher-powered study is needed to investigate the effects of preoperative management on complication rates and functional outcomes.
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An Easy Method to Make a Microscale
J reconstr Microsurg
DOI: 10.1055/s-0038-1635089
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Immunohistochemical Detection of Motor Endplates in the Long-Term Denervated Muscle
J reconstr Microsurg
DOI: 10.1055/s-0038-1627463
Background We have demonstrated that the native motor zone (NMZ) within a muscle is an ideal target for performing nerve-muscle-endplate band grafting (NMEG) to restore motor function of a denervated muscle. This study was designed to determine spatiotemporal alterations of the myofibers, motor endplates (MEPs), and axons in the NMZ of long-term denervated muscles for exploring if NMEG-NMZ technique would have the potential for delayed reinnervation. Methods Sternomastoid (SM) muscles of adult female Sprague-Dawley rats (n = 21) were experimentally denervated and denervation-induced changes in muscle weight, myofiber size, MEPs, and intramuscular nerve axons were evaluated histomorphometrically and immunohistochemically at the end of 3, 6, and 9 months after denervation. The values obtained from the ipsilateral normal side served as control. Results The denervated SM muscles exhibited a progressive reduction in muscle weight (38%, 31%, and 19% of the control) and fiber diameter (52%, 40%, and 28% of the control) for 3-, 6-, and 9-month denervation, respectively. The denervated MEPs were still detectable even 9 months after denervation. The mean number of the denervated MEPs was 79%, 65%, and 43% of the control in the 3-, 6-, and 9-month denervated SM, respectively. Degenerated axons in the denervated muscles became fragmented. Conclusions Persistence of MEPs in the long-term denervated SM suggests that some surgeries targeting the MEPs such as NMEG-NMZ technique should be effective for delayed reinnervation. However, more work is needed to develop strategies for preservation of muscle mass and MEPs after denervation.
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Impact of Obesity on Outcomes in Breast Reconstruction: A Systematic Review and Meta-Analysis
J reconstr Microsurg
DOI: 10.1055/s-0038-1627449
Background Increased rates of both breast cancer and obesity have resulted in more obese women seeking breast reconstruction. Studies demonstrate that these women are at increased risk for perioperative complications. A systematic review was conducted to assess the outcomes in obese women who underwent breast reconstruction following mastectomy. Methods Cochrane, PUBMED, and EMBASE electronic databases were screened and data were extracted from included studies. The clinical outcomes assessed were surgical complications, medical complications, length of postoperative hospital stay, reoperation rate, and patient satisfaction. Results Out of 33 studies met the inclusion criteria for the review and 29 provided enough data to be included in the meta-analysis (71,368 patients, 20,061 of whom were obese). Obese women (body mass index > 30 kg/m2) were 2.29 times more likely to experience surgical complications (95% confidence interval (CI) 2.19–2.39; p < 0.00001), 2.89 times more likely to have medical complications (95% CI 2.50–3.35; p < 0.00001), and had a 1.91 times higher risk of reoperation (95% CI 1.75–2.07; p < 0.00001). The most common complication, wound dehiscence, was 2.51 times more likely in obese women (95% CI 1.80–3.52; p < 0.00001). Sensitivity analysis confirmed that obese women were more likely to experience surgical complications (risk ratio 2.36, 95% CI 2.22–2.52; p < 0.00001). Conclusions This study provides evidence that obesity increases the risk of complications in both implant-based and autologous reconstruction. Additional prospective and observational studies are needed to determine if the weight reduction prior to reconstruction reduces the perioperative risks associated with obesity.
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Erratum to: A 35-Year Evolution of Free Flap-Based Breast Reconstruction at a Large Urban Academic Center
J reconstr Microsurg
DOI: 10.1055/s-0038-1632385
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Short-interval intracortical inhibition: Comparison between conventional and threshold-tracking techniques
Source:Brain Stimulation
Author(s): Gintaute Samusyte, Hugh Bostock, John Rothwell, Martin Koltzenburg
BackgroundShort-interval intracortical inhibition (SICI) is conventionally measured as the relative amplitude reduction of motor evoked potentials (MEPs) by subthreshold conditioning stimuli. In threshold-tracking SICI (T-SICI), stimulus intensity is instead adjusted repeatedly to maintain a constant MEP and inhibition is measured as the relative threshold increase. T-SICI is emerging as a useful diagnostic test, but its relationship to conventional amplitude SICI (A-SICI) is unclear.ObjectiveTo compare T-SICI and its reliability with conventional A-SICI measurements.MethodsIn twelve healthy volunteers (6 men, median age 30 years), conventional and T-SICI were recorded at conditioning stimuli (CS) of 50–80% resting motor threshold (RMT) and interstimulus interval of 2.5 ms. Measurements were repeated on the same day and at least a week later by a single operator.ResultsAcross the CS range, mean group T-SICI showed a strong linear relationship to the mean group values measured by conventional technique (y = 29.7–0.3x, R2 = 0.99), but there was considerable interindividual variability. At CS 60–80% RMT, T-SICI had excellent intraday (intraclass correlation coefficient, ICC, 0.81–0.92) and adequate-to-excellent interday (ICC 0.61–0.88) reproducibility. Conventional SICI took longer to complete (median of 5.8 vs 3.8 min, p < 0.001) and tended to have poorer reproducibility (ICC 0.17–0.42 intraday, 0.37–0.51 interday). With T-SICI, smaller sample sizes were calculated for equally powered interventional studies.ConclusionThe close relationship between conventional and T-SICI suggests that both techniques reflect similar cortical inhibitory mechanisms. Threshold-tracking measurements of SICI may be able to improve reproducibility, to shorten acquisition time and to reduce sample sizes for interventional studies compared with the conventional technique.
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Creation of knock out and knock in mice by CRISPR/Cas9 to validate candidate genes for human male infertility, interest, difficulties and feasibility
Source:Molecular and Cellular Endocrinology
Author(s): Zine-Eddine Kherraf, Beatrice Conne, Amir Amiri-Yekta, Marie Christou Kent, Charles Coutton, Jessica Escoffier, Serge Nef, Christophe Arnoult, Pierre F. Ray
High throughput sequencing (HTS) and CRISPR/Cas9 are two recent technologies that are currently revolutionizing biological and clinical research. Both techniques are complementary as HTS permits to identify new genetic variants and genes involved in various pathologies and CRISPR/Cas9 permits to create animals or cell models to validate the effect of the identified variants, to characterize the pathogeny of the identified variants and the function of the genes of interest and ultimately to provide ways of correcting the molecular defects.We analyzed a cohort of 78 infertile men presenting with multiple morphological anomalies of the sperm flagella (MMAF), a severe form of male infertility. Using whole exome sequencing (WES), homozygous mutations in autosomal candidate genes were identified in 63% of the tested subjects. We decided to produce by CRISPR/cas9 four knock-out (KO) and one knock-in (KI) mouse lines to confirm these results and to increase our understanding of the physiopathology associated with these genetic variations. Overall 31% of the live pups obtained presented a mutational event in one of the targeted regions. All identified events were insertions or deletions localized near the PAM sequence. Surprisingly we observed a high rate of germline mosaicism as 30% of the F1 displayed a different mutation than the parental event characterized on somatic tissue (tail), indicating that CRISPR/Cas9 mutational events kept happening several cell divisions after the injection.Overall, we created mouse models for 5 distinct loci and in each case homozygous animals could be obtained in approximately 6 months. These results demonstrate that the combined use of WES and CRISPR/Cas9 is an efficient and timely strategy to identify and validate in a mutations responsible for infertility phenotypes in human.
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Glucocorticoid receptor gene expression in a CLP-induced ARDS-like rat model treated with dexamethasone and metyrapone
Source:Molecular and Cellular Endocrinology
Author(s): Roseli Soncini, Joseana Vieira, Ana Carolina Ramos Lopes, Silvia Graciela Ruginsk, Erika K. Incerpi, Angel Roberto Barchuk
Glucocorticoids (GCs) are used for acute respiratory distress syndrome (ARDS) to improve or prevent lung injury. The mechanisms underlying the effects of GCs involve inadequate GC-receptor (GR)-mediated downregulation of pro-inflammatory factors despite elevated levels of cortisol. Within this context, knowledge of the transcriptional pattern of the GR gene in response to variations in physiological parameters may shed light on this issue. We addressed this problem by measuring plasmatic corticosterone (CCT) levels and assessing GR expression at transcript and protein levels in rats with caecal ligation and puncture (CLP)-induced ARDS-like syndrome treated with dexamethasone and metyrapone. Seventy male rats were randomized into three main groups: Naïve (any treatment), Sham (caecum-exposed) and CLP. CLP animals were divided into three groups according to pretreatments performed before surgery: CLP sal (0.9% NaCl ip), CLP metyrapone (50 mg.kg-1 ip) and CLP dexamethasone (0.5 mg.kg-1 ip). Our results showed that CLP sal promotes elevation in CCT levels, which are significantly reduced with metyrapone to levels comparable to untreated animals when dexamethasone is used. In this hormonal milieu, the GR gene transcript levels of both variants, GRα and GRβ, are produced in comparable levels and in response to caecum-exposing surgery. Nonetheless, the expression of the GRα variant demonstrated positive sensitivity to variations in CCT levels and was downregulated in animals treated with dexamethasone. Moreover, nuclear translocation of GR protein decreased with high levels of plasma CCT and higher GR translocation was found in animals with moderate CCT levels; in either case, the process seemed to be positively associated with the CLP procedure.
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Directory: AAO Officers and Organizations
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
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Editorial Board
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
http://ift.tt/2to6ela
Automatic 3-dimensional cephalometric landmarking based on active shape models in related projections
Publication date: March 2018
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
Author(s): Jesús Montúfar, Marcelo Romero, Rogelio J. Scougall-Vilchis
IntroductionThis article presents a novel technique for automatic cephalometric landmark localization on 3-dimensional (3D) cone-beam computed tomography (CBCT) volumes by using an active shape model to search for landmarks in related projections.MethodsTwenty-four random CBCT scans from a public data set were imported and processed into Matlab (MathWorks, Natick, Mass). Orthogonal coronal and sagittal projections (digitally reconstructed radiographs) were created, and 2 trained active shape models were used to locate cephalometric landmarks on each. Finally, by relating projections, 18 tridimensional landmarks were located on CBCT volume representations.ResultsFrom our 3D gold standard, a 3.64-mm mean error in localization of cephalometric landmarks was achieved with this method, with the highest localization errors in the porion and sella regions because of the low volume definition.ConclusionsThe proposed algorithm for automatic 3D landmarking on CBCT volumes seems to be useful for 3D cephalometric analysis. This study shows that a fast 2-dimensional landmark search can be useful for 3D localization, which could save computational time compared with a full-volume analysis. Also, this research confirms that by using CBCT for cephalometry, there are no distortion projections, and full structure information of a virtual patient is manageable in a personal computer.
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Author's response
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
Author(s): Priti Subhash Mulimani
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Table of Contents
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
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Fixed-functional appliance treatment and growth hormone therapy
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
Author(s): S.P. Singh, Raj Kumar Verma, Sombir Singh, Nameksh Bhupali, Sanjeev Verma
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Way to evidence-based decision aids in orthodontics
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
Author(s): Alexander Spassov, Dragan Pavlovic
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Authors' response
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
Author(s): Kate Parker, Susan J. Cunningham, Aviva A. Petrie, Fiona S. Ryan
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Unacceptable acceptance
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
Author(s): Peter M. Greco
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Did someone push Lucy out of the tree?
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
Author(s): Herman S. Duterloo
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A short discussion on the evidence and ethics of orthodontic research
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
Author(s): Nikolaos Pandis
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Lingual mandibular osteonecrosis after dental impressions for orthodontic study models
Publication date: March 2018
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
Author(s): Carmen Cerruto, Alessandro Ugolini, Mauro Cozzani
A 43-year-old man sought orthodontic treatment to close anterior diastemas. During the impression procedure for routine documentation, the orthodontic assistant exerted excessive pressure on the metallic tray; 2 days later, the patient reported the detachment of a small piece of mucosa overlying the mylohyoid crest and was referred to a maxillofacial surgeon with a diagnosis of lingual mandibular osteonecrosis. The etiology of bony osteonecrosis is discussed, together with the anatomic variations that can be present in the basal bone and that must be carefully checked before an impression is taken.
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Effect of supplemental vibration on orthodontic treatment with aligners: A randomized trial
Publication date: March 2018
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
Author(s): Mina Katchooi, Bobby Cohanim, Sandra Tai, Burcu Bayirli, Charles Spiekerman, Greg Huang
IntroductionSupplemental vibration has been reported to accelerate orthodontic tooth movement and reduce discomfort. Our purpose was to investigate the effects of AcceleDent on Invisalign treatment. This randomized clinical trial was carried out in 2 orthodontic private practices with a 1:1 allocation ratio.MethodsAdult patients who were beginning their orthodontic treatment were randomly allocated to either an active (A) or a sham (B) AcceleDent Aura device (OrthoAccel Technologies, Inc. Houston, TX). All patients were placed on a 1-week aligner change regimen, and fit was evaluated every 3 weeks. The outcomes were the ability to complete the initial set of aligners and the incisor irregularity measurements for those who completed their regimen of aligners. In addition, aligner compliance, pain levels, and oral health-related quality of life data were gathered from questionnaires. The subjects, investigators, and assessors were all blinded to the treatment arms.ResultsTwenty-seven subjects were randomized into 2 groups (A and B), 1 subject discontinued treatment, and 13 subjects were analyzed in each group. The Fisher exact test showed no significant difference in completion rates between the 2 groups (group A, 77%; group B, 85%; P = 1). Independent-sample t tests showed no significant difference between the final irregularity index or change in irregularity index between the 2 groups. Compliance was similar in both groups. The Wilcoxon rank sum test showed minimal differences in pain levels. Quality of life responses were similar in both groups. No serious harm was observed.ConclusionsWe found no evidence that the AcceleDent Aura device impacts the ability to complete a series of aligners with a 1-week change regimen or the final alignment achieved in adult patients. It also had no significant effect on the reduction of orthodontic pain or oral health-related quality of life parameters when used with Invisalign.
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Expectations: Contractual, entrepreneurial, or professional
Publication date: March 2018
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
Author(s): Laurance Jerrold
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Gastric emptying rate before and after orthodontic treatment examined with the [13C] breath test: A pilot study
Publication date: March 2018
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 153, Issue 3
Author(s): Jumpei Suzuki, Kazuo Shimazaki, Sarina Koike, Takashi Ono
IntroductionOrthodontic patients with malocclusion have significantly lower masticatory and gastrointestinal digestive function than persons with normal occlusion. Although several studies have suggested that masticatory function is improved after orthodontic treatment, the relationship between such improvement and change in gastrointestinal symptoms has not been quantitatively evaluated. In this study, we aimed to investigate the change in masticatory function and the gastric emptying rate in patients with malocclusion, before and after orthodontic treatment.MethodsSeven women with malocclusion, before (pretreatment group) and after orthodontic treatment (posttreatment group), and 7 healthy dentate female volunteers (control group) underwent a 13C-acetate breath test (13CO2) with a liquid meal and the color changeable gum test, along with completing the frequency scale for symptoms of gastroesophageal reflux and a questionnaire on food intake. Between-group differences were evaluated.ResultsThe pretreatment group had significantly longer maximum 13CO2 exhalation time and lower masticatory function, quantified using a higher red-color value on the gum test and the questionnaire on food intake, than did the posttreatment and control groups. No significant differences were identified between the posttreatment and the control groups.ConclusionsWe provide evidence of improvement of masticatory function after orthodontic treatment, which was associated with a faster rate of gastric emptying.
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Editorial Board
Source:Biological Psychology, Volume 133
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Adipose Dendritic Cells Come Out of Hiding
Publication date: 6 March 2018
Source:Cell Metabolism, Volume 27, Issue 3
Author(s): Nelson M. LaMarche, Lydia Lynch
In this issue of Cell Metabolism, Macdougall et al. (2018) identify two subsets of conventional dendritic cells in visceral adipose tissue and demonstrate that these subsets engage distinct adipocyte-associated signaling pathways to drive their tolerogenic phenotypes in the lean state.
Teaser
In this issue of Cell Metabolism, Macdougall et al. identify two subsets of conventional dendritic cells in visceral adipose tissue and demonstrate that these subsets engage distinct adipocyte-associated signaling pathways to drive their tolerogenic phenotypes in the lean state.http://ift.tt/2FZsy7m
High Cholesterol at the Heart of Phagolysosomal Damage
Publication date: 6 March 2018
Source:Cell Metabolism, Volume 27, Issue 3
Author(s): Andrew P. Lieberman, Joel A. Swanson
Phagolysosome membrane rupture can trigger a maladaptive immune response that promotes tissue damage. In Science, Cantuti-Castelvetri et al. (2018) report that cholesterol-rich myelin debris overwhelms reverse cholesterol transport in aged phagocytes, leading to cholesterol crystal formation, damaged phagolysosomes, and limited tissue repair.
Teaser
Phagolysosome membrane rupture can trigger a maladaptive immune response that promotes tissue damage. In Science, Cantuti-Castelvetri et al. report that cholesterol-rich myelin debris overwhelms reverse cholesterol transport in aged phagocytes, leading to cholesterol crystal formation, damaged phagolysosomes, and limited tissue repair.http://ift.tt/2FkBmDG
The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications
Publication date: 6 March 2018
Source:Cell Metabolism, Volume 27, Issue 3
Author(s): Chris Carrico, Jesse G. Meyer, Wenjuan He, Brad W. Gibson, Eric Verdin
Post-translational modification of lysine residues via reversible acylation occurs on proteins from diverse pathways, functions, and organisms. While nuclear protein acylation reflects the competing activities of enzymatic acyltransferases and deacylases, mitochondrial acylation appears to be driven mostly via a non-enzymatic mechanism. Three protein deacylases, SIRT3, SIRT4, and SIRT5, reside in the mitochondria and remove these modifications from targeted proteins in an NAD+-dependent manner. Recent proteomic surveys of mitochondrial protein acylation have identified the sites of protein acetylation, succinylation, glutarylation, and malonylation and their regulation by SIRT3 and SIRT5. Here, we review recent advances in this rapidly moving field, their biological significance, and their implications for mitochondrial function, metabolic regulation, and disease pathogenesis.
Teaser
Carrico et al. review recent advances in mapping and understanding acylation modifications to mitochondrial proteins, such as acetylation and succinylation, and their regulation by the sirtuins SIRT3–5. Best practices for proteome-wide mass spectrometry are discussed, followed by case studies of how acylation modulates protein function and health.http://ift.tt/2FkBjYw
Food for Training—Western Diet and Inflammatory Memory
Publication date: 6 March 2018
Source:Cell Metabolism, Volume 27, Issue 3
Author(s): Parimal Samir, R. K. Subbarao Malireddi, Thirumala-Devi Kanneganti
In recent years, trained immunity has emerged as an attractive concept to explain cross-protection against pathogens mediated by the innate immune system. Using a diet-based sterile inflammation model, Christ et al. (2018) have shown in a recent issue of Cell that trained immunity may also play a critical role in responding to diet and endogenous sterile triggers.
Teaser
In recent years, trained immunity has emerged as an attractive concept to explain cross-protection against pathogens mediated by the innate immune system. Using a diet-based sterile inflammation model, Christ et al. (2018) have shown in a recent issue of Cell that trained immunity may also play a critical role in responding to diet and endogenous sterile triggers.http://ift.tt/2G4pPtD
Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence
Publication date: 6 March 2018
Source:Cell Metabolism, Volume 27, Issue 3
Author(s): Luis Rajman, Karolina Chwalek, David A. Sinclair
Nicotinamide adenine dinucleotide (NAD), the cell's hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD+-sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body's resilience, not just to one disease, but to many, thereby extending healthy human lifespan.
Teaser
Nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of cellular processes that control the body's response to stress. Rajman et al. discuss NAD boosters, small molecules that raise NAD+ levels, which are now considered to be highly promising for the treatment of multiple diseases and the potential extension of human lifespan.http://ift.tt/2D55gKb
Paracrine Interactions within the Pancreatic Islet Determine the Glycemic Set Point
Publication date: 6 March 2018
Source:Cell Metabolism, Volume 27, Issue 3
Author(s): Rayner Rodriguez-Diaz, R. Damaris Molano, Jonathan R. Weitz, Midhat H. Abdulreda, Dora M. Berman, Barbara Leibiger, Ingo B. Leibiger, Norma S. Kenyon, Camillo Ricordi, Antonello Pileggi, Alejandro Caicedo, Per-Olof Berggren
Every animal species has a signature blood glucose level or glycemic set point. These set points are different, and the normal glycemic levels (normoglycemia) of one species would be life threatening for other species. Mouse normoglycemia can be considered diabetic for humans. The biological determinants of the glycemic set point remain unclear. Here we show that the pancreatic islet imposes its glycemic set point on the organism, making it the bona fide glucostat in the body. Moreover, and in contrast to rodent islets, glucagon input from the alpha cell to the insulin-secreting beta cell is necessary to fine-tune the distinctive human set point. These findings affect transplantation and regenerative approaches to treat diabetes because restoring normoglycemia may require more than replacing only the beta cells. Furthermore, therapeutic strategies using glucagon receptor antagonists as hypoglycemic agents need to be reassessed, as they may reset the overall glucostat in the organism.
Graphical abstract
Teaser
It is not known if there is a leading organ that maintains blood glucose levels within the narrow physiological range. Rodriguez-Diaz and colleagues show that the pancreatic islet serves as the systemic glucostat and that paracrine glucagon input from alpha cells is essential for setting the glycemic set point. Therapeutic strategies using glucagon receptor antagonists to lower glycemia should thus be reassessed.http://ift.tt/2FZelar
Lactobacillus gasseri in the Upper Small Intestine Impacts an ACSL3-Dependent Fatty Acid-Sensing Pathway Regulating Whole-Body Glucose Homeostasis
Publication date: 6 March 2018
Source:Cell Metabolism, Volume 27, Issue 3
Author(s): Paige V. Bauer, Frank A. Duca, T.M. Zaved Waise, Helen J. Dranse, Brittany A. Rasmussen, Akshita Puri, Mozhgan Rasti, Catherine A. O'Brien, Tony K.T. Lam
Long-chain acyl-CoA synthetase (ACSL)-dependent upper small intestinal lipid metabolism activates pre-absorptive pathways to regulate metabolic homeostasis, but whether changes in the upper small intestinal microbiota alter specific fatty acid-dependent pathways to impact glucose homeostasis remains unknown. We here first find that upper small intestinal infusion of Intralipid, oleic acid, or linoleic acid pre-absorptively increases glucose tolerance and lowers glucose production in rodents. High-fat feeding impairs pre-absorptive fatty acid sensing and reduces upper small intestinal Lactobacillus gasseri levels and ACSL3 expression. Transplantation of healthy upper small intestinal microbiota to high-fat-fed rodents restores L. gasseri levels and fatty acid sensing via increased ACSL3 expression, while L. gasseri probiotic administration to non-transplanted high-fat-fed rodents is sufficient to restore upper small intestinal ACSL3 expression and fatty acid sensing. In summary, we unveil a glucoregulatory role of upper small intestinal L. gasseri that impacts an ACSL3-dependent glucoregulatory fatty acid-sensing pathway.
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Teaser
Bauer et al. report that a glucoregulatory pre-absorptive ACSL3-dependent fatty acid-sensing pathway in the upper small intestine is compromised by a high-fat diet. Fatty acid sensing and glucose homeostasis are restored by probiotic Lactobacillus gasseri administration or by transplantation of microbiota from chow-fed animals.http://ift.tt/2FkBgMk
Visceral Adipose Tissue Immune Homeostasis Is Regulated by the Crosstalk between Adipocytes and Dendritic Cell Subsets
Publication date: 6 March 2018
Source:Cell Metabolism, Volume 27, Issue 3
Author(s): Claire E. Macdougall, Elizabeth G. Wood, Jakob Loschko, Valeria Scagliotti, Féaron C. Cassidy, Mark E. Robinson, Niklas Feldhahn, Leandro Castellano, Mathieu-Benoit Voisin, Federica Marelli-Berg, Carles Gaston-Massuet, Marika Charalambous, M. Paula Longhi
Visceral adipose tissue (VAT) has multiple roles in orchestrating whole-body energy homeostasis. In addition, VAT is now considered an immune site harboring an array of innate and adaptive immune cells with a direct role in immune surveillance and host defense. We report that conventional dendritic cells (cDCs) in VAT acquire a tolerogenic phenotype through upregulation of pathways involved in adipocyte differentiation. While activation of the Wnt/β-catenin pathway in cDC1 DCs induces IL-10 production, upregulation of the PPARγ pathway in cDC2 DCs directly suppresses their activation. Combined, they promote an anti-inflammatory milieu in vivo delaying the onset of obesity-induced chronic inflammation and insulin resistance. Under long-term over-nutrition, changes in adipocyte biology curtail β-catenin and PPARγ activation, contributing to VAT inflammation.
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Teaser
Macdougall et al. report key mechanisms that control the immune function of conventional dendritic cells in visceral adipose tissue. The upregulation of adipocyte-related pathways in conventional dendritic cells promotes an anti-inflammatory phenotype in visceral adipose tissue under homeostatic conditions and delays the onset of obesity-induced inflammation and insulin resistance.http://ift.tt/2FZtWqE
Actomyosin-Mediated Tension Orchestrates Uncoupled Respiration in Adipose Tissues
Publication date: 6 March 2018
Source:Cell Metabolism, Volume 27, Issue 3
Author(s): Kevin M. Tharp, Michael S. Kang, Greg A. Timblin, Jon Dempersmier, Garret E. Dempsey, Peter-James H. Zushin, Jaime Benavides, Catherine Choi, Catherine X. Li, Amit K. Jha, Shingo Kajimura, Kevin E. Healy, Hei Sook Sul, Kaoru Saijo, Sanjay Kumar, Andreas Stahl
The activation of brown/beige adipose tissue (BAT) metabolism and the induction of uncoupling protein 1 (UCP1) expression are essential for BAT-based strategies to improve metabolic homeostasis. Here, we demonstrate that BAT utilizes actomyosin machinery to generate tensional responses following adrenergic stimulation, similar to muscle tissues. The activation of actomyosin mechanics is critical for the acute induction of oxidative metabolism and uncoupled respiration in UCP1+ adipocytes. Moreover, we show that actomyosin-mediated elasticity regulates the thermogenic capacity of adipocytes via the mechanosensitive transcriptional co-activators YAP and TAZ, which are indispensable for normal BAT function. These biomechanical signaling mechanisms may inform future strategies to promote the expansion and activation of brown/beige adipocytes.
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Teaser
Tharp et al. show that brown adipocytes engage tensional actomyosin machinery, similar to muscle tissues, following adrenergic stimulation to mediate the thermogenic program and normal BAT function. These effects are mechanistically mediated through the YAP/TAZ pathway and, on a broad level, highlight the importance of cellular mechanics for cell metabolism.http://ift.tt/2D5YaoG
Proteome Imbalance of Mitochondrial Electron Transport Chain in Brown Adipocytes Leads to Metabolic Benefits
Publication date: 6 March 2018
Source:Cell Metabolism, Volume 27, Issue 3
Author(s): Ruchi Masand, Esther Paulo, Dongmei Wu, Yangmeng Wang, Danielle L. Swaney, David Jimenez-Morales, Nevan J. Krogan, Biao Wang
Brown adipose tissue (BAT) thermogenesis is critical for thermoregulation and contributes to total energy expenditure. However, whether BAT has non-thermogenic functions is largely unknown. Here, we describe that BAT-specific liver kinase b1 knockout (Lkb1BKO) mice exhibited impaired BAT mitochondrial respiration and thermogenesis but reduced adiposity and liver triglyceride accumulation under high-fat-diet feeding at room temperature. Importantly, these metabolic benefits were also present in Lkb1BKO mice at thermoneutrality, where BAT thermogenesis was not required. Mechanistically, decreased mRNA levels of mtDNA-encoded electron transport chain (ETC) subunits and ETC proteome imbalance led to defective BAT mitochondrial respiration in Lkb1BKO mice. Furthermore, reducing mtDNA gene expression directly in BAT by removing mitochondrial transcription factor A (Tfam) in BAT also showed ETC proteome imbalance and the trade-off between BAT thermogenesis and systemic metabolism at room temperature and thermoneutrality. Collectively, our data demonstrate that ETC proteome imbalance in BAT regulates systemic metabolism independently of thermogenesis.
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Teaser
Masand and Paulo et al. demonstrate that Lkb1 and Tfam regulate mtDNA-encoded ETC gene expression, and their deficiencies in BAT lead to ETC proteome imbalance, a mismatch between proportional ETC complexes. This ETC proteome imbalance locally in BAT can cause systemic adaptive responses, which ultimately result in metabolic fitness.http://ift.tt/2FZhsiP
The Pericyte of the Pancreatic Islet Regulates Capillary Diameter and Local Blood Flow
Publication date: 6 March 2018
Source:Cell Metabolism, Volume 27, Issue 3
Author(s): Joana Almaça, Jonathan Weitz, Rayner Rodriguez-Diaz, Elizabeth Pereira, Alejandro Caicedo
Efficient insulin secretion requires a well-functioning pancreatic islet microvasculature. The dense network of islet capillaries includes the islet pericyte, a cell that has barely been studied. Here we show that islet pericytes help control local blood flow by adjusting islet capillary diameter. Islet pericytes cover 40% of the microvasculature, are contractile, and are innervated by sympathetic axons. Sympathetic adrenergic input increases pericyte activity and reduces capillary diameter and local blood flow. By contrast, activating beta cells by increasing glucose concentration inhibits pericytes, dilates islet capillaries, and increases local blood flow. These effects on pericytes are mediated by endogenous adenosine, which is likely derived from ATP co-released with insulin. Pericyte coverage of islet capillaries drops drastically in type 2 diabetes, suggesting that, under diabetic conditions, islets lose this mechanism to control their own blood supply. This may lead to inadequate insulin release into the circulation, further deteriorating glycemic control.
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Teaser
Almaça et al. study pericyte cells, which wrap around capillary endothelial cells, in the islets of the pancreas and show that islet pericytes help control local blood flow by adjusting islet capillary diameter. They further show that this mechanism in lost in diabetes, which may lead to inadequate insulin supply.http://ift.tt/2Fk8N9y
Yeast Mitoribosome Large Subunit Assembly Proceeds by Hierarchical Incorporation of Protein Clusters and Modules on the Inner Membrane
Publication date: 6 March 2018
Source:Cell Metabolism, Volume 27, Issue 3
Author(s): Rui Zeng, Erin Smith, Antoni Barrientos
Mitoribosomes are specialized for the synthesis of hydrophobic membrane proteins encoded by mtDNA, all essential for oxidative phosphorylation. Despite their linkage to human mitochondrial diseases and the recent cryoelectron microscopy reconstruction of yeast and mammalian mitoribosomes, how they are assembled remains obscure. Here, we dissected the yeast mitoribosome large subunit (mtLSU) assembly process by systematic genomic deletion of 44 mtLSU proteins (MRPs). Analysis of the strain collection unveiled 37 proteins essential for functional mtLSU assembly, three of which are critical for mtLSU 21S rRNA stability. Hierarchical cluster analysis of mtLSU subassemblies accumulated in mutant strains revealed co-operative assembly of protein sets forming structural clusters and preassembled modules. It also indicated crucial roles for mitochondrion-specific membrane-binding MRPs in anchoring newly transcribed 21S rRNA to the inner membrane, where assembly proceeds. Our results define the yeast mtLSU assembly landscape in vivo and provide a foundation for studies of mitoribosome assembly across evolution.
Graphical abstract
Teaser
Despite the biomedical relevance of the mitochondrial protein synthesis machinery, how mitoribosome biogenesis occurs remains largely unknown. By systematic deletion of 44 mitoribosome proteins in yeast, Zeng et al. describe a mitoribosome subunit assembly pathway, which occurs in contact with the mitochondrial inner membrane and involves hierarchical incorporation of protein clusters and modules.http://ift.tt/2G0tGb3
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Summary Insulinomas are rare neuroendocrine tumours that classically present with fasting hypoglycaemia. This case report discusses an un...
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