Optimizing success and avoiding mishaps in the most difficult image guided breast biopsies

Publication date: Available online 24 August 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Sughra Raza, Sona A. Chikarmane, Eva C. Gombos, Dianne Georgian-Smith, Elisabeth P. Frost
Breast cancer is an increasing challenge in developed and limited resource areas of the world. Early detection of breast cancer offers the best chance for optimal care and best outcomes. A critical step in early detection is to obtain efficient and accurate tissue diagnoses. While image-guided core needle breast biopsies are usually straightforward for experienced breast imagers, there are some not uncommon scenarios which present particular challenges. In this review article we will discuss these difficult situations and offer our tried and true methods to ensure safe and successful biopsies, while using stereotactic, ultrasound, and MRI guidance.



http://ift.tt/2vkUQTL

The molecular mechanism and post-transcriptional regulation characteristic of Tetragenococcus halophilus acclimation to osmotic stress revealed by quantitative proteomics

Publication date: Available online 24 August 2017
Source:Journal of Proteomics
Author(s): Jieting Lin, Hebin Liang, Junwei Yan, Lixin Luo
Tetragenococcus halophilus is a moderate halophilic bacterium which was widely used in fermentation processes, growing in a broad range of salinity conditions, and can survive a saturated 26.47% w/w NaCl concentration. However, the mechanism of this outstanding ability to acclimate to extracellular osmotic stress still remains unknown. The current study firstly conducted a quantitative proteomic analysis to identify alterations of the cellular proteome under both hypo-osmotic and hyper-osmotic stress conditions. A total of 1405 proteins were identified and differentially accumulated proteins were analyzed, further functional annotations were performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The results revealed that both hypo- and hyper-osmotic stresses have prominent impacts on the synthesis of proteins involving in multiple cellular functions. Further analyses of the differentially accumulated proteins suggested that the adaptation strategies T. halophilus applies to deal with hypo- and hyper-osmotic stress conditions may be distinct. Comparison of the differentially accumulated proteins in both transcriptomic and proteomic study indicated the existence of post-transcriptional modification during salinity adaptation of T. halophilus. The current study generated a proteomic atlas of differentially accumulated proteins under both hypo- and hyper-osmotic stress conditions, provided an overview of the molecular mechanism of osmotic acclimation of T. halophilus.SignificanceThe current study aimed to reveal how the moderately halophilic Tetragenococcus halophilus adapt to extracellular salinity stress, which is the first proteomic study analyzing the differences in proteome of Tetragenococcus halophilus between hypo- and hyper-osmotic stress to our knowledge. By analyzing the differences in the accumulating levels of the proteome via isobaric labeling-based quantitative proteomic study, we identified proteins with significantly different accumulation levels which may play important roles in the adaptation process to extracellular salinity stress. Examining the cellular functions of these proteins according to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, a draft view of how the bacterium act to acclimate to osmotic stress has been drawn. Further analysis revealing the differences between the transcriptome and proteome suggested that some proteins may undergo post-transcriptional regulation during acclimation process, which still remains unstudied and needs further investigations. The results of the current study can help researchers to gain insights and further reveal the halophilic mechanism of halophiles.

Graphical abstract

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Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib

Publication date: Available online 24 August 2017
Source:Journal of Proteomics
Author(s): Simon Vyse, Frank McCarthy, Malgorzata Broncel, Angela Paul, Jocelyn P. Wong, Amandeep Bhamra, Paul H. Huang
Acquired drug resistance impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapies to overcome resistance represents an unmet need. Understanding the signalling that drives drug resistance will facilitate the development of new salvage therapies to treat patients with secondary TKI resistance. In this study, we utilise mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only 6% and 9.7% of the quantified phosphoproteome is altered upon the acquisition of pazopanib and dasatinib resistance respectively. Pazopanib resistant cells display elevated phosphorylation in cytoskeletal regulatory pathways while dasatinib resistant cells show an upregulation of the insulin receptor/IGF-1R signalling pathway. Drug response profiling rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance.SignificancePazopanib and dasatinib are tyrosine kinase inhibitors (TKIs) approved for the treatment of multiple cancer types. Patients who are treated with these drugs are prone to the development of drug resistance and consequently tumour relapse. Here we use quantitative phosphoproteomics to characterise the signalling pathways which are enriched in cells that have acquired resistance to these two drugs. Furthermore, targeted drug screens were used to identify salvage therapies capable of overcoming pazopanib and dasatinib resistance. This data advances our understanding of the mechanisms of TKI resistance and highlights candidate targets for cancer therapy.



http://ift.tt/2gaLLdw

The medical threat of mamba envenoming in sub-Saharan Africa revealed by genus-wide analysis of venom composition, toxicity and antivenomics profiling of available antivenoms

Publication date: Available online 24 August 2017
Source:Journal of Proteomics
Author(s): Stuart Ainsworth, Daniel Petras, Mikael Engmark, Roderich D. Süssmuth, Gareth Whiteley, Laura-Oana Albulescu, Taline D. Kazandjian, Simon C. Wagstaff, Paul Rowley, Wolfgang Wüster, Pieter C. Dorrestein, Ana Silvia Arias, José M. Gutiérrez, Robert A. Harrison, Nicholas R. Casewell, Juan J. Calvete
Mambas (genus Dendroaspis) are among the most feared of the medically important elapid snakes found in sub-Saharan Africa, but many facets of their biology, including the diversity of venom composition, remain relatively understudied. Here, we present a reconstruction of mamba phylogeny, alongside genus-wide venom gland transcriptomic and high-resolution top-down venomic analyses. Whereas the green mambas, D. viridis, D. angusticeps, D. j. jamesoni and D. j. kaimosae, express 3FTx-predominant venoms, black mamba (D. polylepis) venom is dominated by dendrotoxins I and K. The divergent terrestrial ecology of D. polylepis compared to the arboreal niche occupied by all other mambas makes it plausible that this major difference in venom composition is due to dietary variation. The pattern of intrageneric venom variability across Dendroaspis represented a valuable opportunity to investigate, in a genus-wide context, the variant toxicity of the venom, and the degree of paraspecific cross-reactivity between antivenoms and mamba venoms. To this end, the immunological profiles of the five mamba venoms were assessed against a panel of commercial antivenoms generated for the sub-Saharan Africa market. This study provides a genus-wide overview of which available antivenoms may be more efficacious in neutralising human envenomings caused by mambas, irrespective of the species responsible. The information gathered in this study lays the foundations for rationalising the notably different potency and pharmacological profiles of Dendroaspis venoms at locus resolution. This understanding will allow selection and design of toxin immunogens with a view to generating a safer and more efficacious pan-specific antivenom against any mamba envenomation.Biological significanceThe mambas (genus Dendroaspis) comprise five especially notorious medically important venomous snakes endemic to sub-Saharan Africa. Their highly potent venoms comprise a high diversity of pharmacologically active peptides, including extremely rapid-acting neurotoxins. Previous studies on mamba venoms have focused on the biochemical and pharmacological characterisation of their most relevant toxins to rationalize the common neurological and neuromuscular symptoms of envenomings caused by these species, but there has been little work on overall venom composition or comparisons between them. Only very recently an overview of the composition of the venom of two Dendroaspis species, D. angusticeps and D. polylepis, has been unveiled through venomics approaches. Here we present the first genus-wide transcriptomic-proteomic analysis of mamba venom composition. The transcriptomic analyses described in this paper have contributed 29 (D. polylepis), 23 (D. angusticeps), 40 (D. viridis), 25 (D. j. jamesoni) and 21 (D. j. kaimosae), novel full-length toxin sequences to the non-redundant Dendroaspis sequence database. The mamba genus-wide venomic analysis demonstrated that major D. polylepis venom components are Kunitz-fold family toxins. This feature is unique in relation to the relatively conserved three-finger toxin (3FTx)-dominated venom compositions of the green mambas. Venom variation was interpreted in the context of dietary variation due to the divergent terrestrial ecology of D. polylepis compared to the arboreal niche occupied by all other mambas. Additionally, the degree of cross-reactivity conservation of mamba venoms was assessed by antivenomics against a panel of commercial antivenoms generated for the sub-Saharan Africa market. This study provides a genus-wide overview to infer which available antivenoms may be capable of neutralising human envenomings caused by mambas, irrespective of the species responsible. The information gathered in this study lays the foundations for rationalising the pharmacological profiles of mamba venoms at locus resolution. This understanding will contribute to the generation of a safer and more efficacious pan-Dendroaspis therapeutic antivenom against any mamba envenomation.

Graphical abstract

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Structural identification of N-linked carbohydrates using the GUcal application: A tutorial

Publication date: Available online 24 August 2017
Source:Journal of Proteomics
Author(s): Gabor Jarvas, Marton Szigeti, Andras Guttman
In recent years, analytical glycomics gained a significant role due to the rapidly increasing number of glycoproteins introduced as biopharmaceuticals. One of the frequently used methods for the analysis of complex carbohydrates is capillary electrophoresis with laser induced fluorescent detection (CE-LIF). CE-LIF is a high resolution separation technique with excellent sensitivity capable of discriminating between closely related positional and linkage carbohydrate isomers. Individual glycan structures corresponding to the separated peaks in an electropherogram are identified according to their glucose unit (GU) values by mining the built in database. This tutorial introduces the practical use of the GUcal application, a recently developed glycoinformatics tool, which automatically calculates GU values for all sample components of interest in an electropherogram using either the bracketing standard approach or the recently published triple internal standard method. Furthermore, a worked example demonstrates the way glycan structural elucidation of human immunoglobulin G is processed with the help of this simple and rapid GU value calculation application.SignificanceBiopharmaceuticals have seen something of tremendous development in recent years, which governs the parallel blooming of analytical glycomics. One of the frequently used methods for the analysis of complex carbohydrates is capillary electrophoresis with laser induced fluorescent detection (CE-LIF). CE-LIF is a high resolution separation technique with excellent sensitivity capable of discriminating between closely related positional and linkage carbohydrate isomers. While CE instrumentation is well developed, the related bioinformatics tools are lagging behind. According to our best knowledge, this is the first tutorial paper on the recently disseminated GUcal application, which automatically calculates GU values for all sample components of interest in an electropherogram using either the bracketing standard approach or the new triple internal standard method. On the top the step-by-step instruction how to use the application, the paper includes a worked example demonstrates the way glycan structure elucidation of human immunoglobulin G is processed with the help of the simple and rapid GU value calculation of this new application. After very short training period, the software can be used readily for cutting-edge glycomics of exploratory research or high-throughput routine analysis.

Graphical abstract

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Rooted in the Community: Assessing the Reintegration Impacts of Agriculture on Rural Veterans

Publication date: Available online 24 August 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Karen Besterman-Dahan, Margeaux Chavez, Eni Njoh
ObjectiveTo assess the impact of a Veteran-oriented community agricultural initiative (CAI) on transitioning rural Veterans.DesignConvergent mixed-method program evaluation.SettingA Veteran-oriented farm-to-market CAI in rural Washington State.ParticipantsVeterans who were members of the CAI.Main Outcome MeasuresHealth, well-being, and reintegration were assessed by self-reported data from interview, demographic survey, validated health quality of life measure (Veterans RAND-12 -VR-12), validated reintegration measure (Military to Civilian Questionnaire -M2C-Q), and general satisfaction survey.ResultsVeteran participants were primarily Caucasian (88.4%, n=38) and male (74.4%, n=32) and most had a service-connected disability rating (58.2%, n=25). Qualitative and quantitative data revealed that the veterans participating in this CAI experienced health and reintegration benefits. Results on the M2C-Q, VR-12, and the satisfaction survey suggest that participating in this CAI contributed to improved mental, physical, and emotional health and vocational skills, community connectedness, and interpersonal communication. Qualitative interviews supported quantitative findings and revealed that participating in the CAI provided Veterans with a sense of satisfaction, belonging, and helped decrease the stigma surrounding their Veteran status.ConclusionsVeterans who participate in this CAI reported general improvements in physical and mental health, including improvements in sleep, nutrition, exercise, and decreases in anxiety, pain, depression and medication and substance use, all known factors which impact Veteran reintegration.



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Low-dose-rate prostate brachytherapy: 4–8 week postimplant prostate-specific antigen a novel predictor of biochemical failure-free survival

Publication date: Available online 24 August 2017
Source:Brachytherapy
Author(s): Cameron M. Callaghan, Lin Wang, Abhishek Alluri, Andrew Lauve, Cynthia Boyer, William Russell
PurposeThe purpose of this study was to determine the relationship between patient, disease, and treatment variables and biochemical failure-free survival (bFFS) following low-dose-rate prostate brachytherapy (LDR-BT).Methods and MaterialsData from 624 consecutive patients who received LDR-BT for localized prostate cancer between 2002 and 2012 at a single institution were collected for various patient, disease, and treatment characteristics including a 4–8 week postimplant PSA (4–8wkPSA). Subgroup analysis was stratified by risk category and treatment regimen. Analysis was performed using Kaplan–Meier survival curves, Cox proportional hazard ratios (HRs), and receiver-operator characteristic curves.ResultsA total of 624 consecutive patients were included with followup time of 4.0 ± 3.1 years. Predictors of bFFS included PSA nadir and 4–8wkPSA (HR = 2.48, p = 0.000 and HR = 1.24, p = 0.000, respectively) for total population. Diabetes mellitus (p = 0.026), chronic obstructive pulmonary disease (p = 0.000), alcohol use (p = 0.024), and age (p = 0.002) were predictors for specific subgroups. Receiver-operator characteristic curves 4–8wkPSA were found to be significant (p = 0.036).Conclusion4–8wkPSA is a novel predictor of bFFS for patients receiving LDR-BT across several risk categories and treatment regimens with potential clinical utility as a prognostic indicator. Certain comorbidities and exposure histories also demonstrated significant relationships with bFFS including chronic obstructive pulmonary disease, diabetes mellitus, age, alcohol history, proton pump inhibitor use, PSA nadir, and PSA density.



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Clinical implementation of a novel Double-Balloon single-entry breast brachytherapy applicator

Publication date: Available online 24 August 2017
Source:Brachytherapy
Author(s): Bethany M. Anderson, Charles R. Wallace, Anna-Maria A. De Costa, Rupak K. Das
PurposeThe purpose of the study was to describe the clinical utilization of a novel Double-Balloon applicator for accelerated partial breast irradiation (APBI).Methods and MaterialsThe Double-Balloon single-entry breast applicator contains a single central treatment catheter, as well as four peripheral catheters that can be differentially loaded to customize radiation dose coverage. An inner balloon is filled with up to 7–30 cm³ of saline to increase separation between the peripheral catheters, and an outer balloon is filled with up to 37–115 cm³ of saline to displace breast tissue from the peripheral catheters. Treatment planning objectives include coverage of the breast planning target volume to a minimum of V90 > 90%, limiting dose heterogeneity such that V200 < 10 cm³ and V150 < 50 cm³, and limiting maximum dose to skin (<100% of prescription dose) and ribs (<145% of prescription dose).ResultsHigh-dose-rate APBI was delivered to 11 women using this device (34 Gy in 10 twice daily fractions). The mean V90 was 98.2% (range 94.2–99.4%). The mean skin Dmax with the Double-Balloon applicator was 83.3% (range 75.6–99.5%). The mean breast V200 was 5.8 cm³ (range 2.3–10.2 cm³), and the mean breast V150 was 32.9 cm³ (range 25.0–41.7 cm³). Pretreatment quality assurance was performed using CT prior to each morning fraction and ultrasound prior to each afternoon fraction.ConclusionsThe Double-Balloon applicator can be easily introduced into a previously existing brachytherapy program. APBI plans created with this applicator achieve excellent planning target volume coverage, while limiting skin dose and maintaining breast V200 < 10 cm³.



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Performance, emission, and combustion characteristics of twin-cylinder common rail diesel engine fuelled with butanol-diesel blends

Abstract

Nitrogen oxides and smoke are the substantial emissions for the diesel engines. Fuels comprising high-level oxygen content can have low smoke emission due to better oxidation of soot. The objective of the paper is to assess the potential to employ oxygenated fuel, i.e., n-butanol and its blends with the neat diesel from 0 to 30% by volume. The experimental and computational fluid dynamic (CFD) simulation is carried out to estimate the performance, combustion, and exhaust emission characteristics of n-butanol-diesel blends for various injection timings (9°, 12°, 15°, and 18°) using modern twin-cylinder, four-stroke, common rail direct injection (CRDI) engine. Experimental results reveal the increase in brake thermal efficiency (BTE) by ~ 4.5, 6, and 8% for butanol-diesel blends of 10% (Bu10), 20% (Bu20), and 30% (Bu30), respectively, compared to neat diesel (Bu0). Maximum BTE for Bu0 is 38.4%, which is obtained at 12° BTDC; however, for Bu10, Bu20 and Bu30 are 40.19, 40.9, and 41.7%, which are obtained at 15° BTDC, respectively. Higher flame speed of n-butanol-diesel blends burn a large amount of fuel in the premixed phase, which improves the combustion as well as emission characteristics. CFD and experimental results are compared and validated for all fuel blends for in-cylinder pressure and nitrogen oxides (NO_x), and found to be in good agreement. Both experimental and simulation results witnessed in reduction of smoke opacity, NO_x, and carbon monoxide emissions with the increasing n-butanol percentage in diesel fuel.

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Mortality and its Causes in a German Cohort with Diabetes Mellitus Type 1 after 20 Years of Follow-Up: The JEVIN Trial

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0043-113452

Background The JEVIN trial started as a cross-sectional study in 1989/90 in Jena. After a follow-up of more than 20 years, the mortality incidence of JEVIN participants with type 1 diabetes was surveyed. Methods 103 (78.6%) of the 131 JEVIN patients participating at baseline could be examined. 38 persons (36.9%) had deceased. All JEVIN survey data and routine examinations documented in the electronic patient record EMIL® of surviving and deceased participants were used for analyses. We compared the data of the surviving with the deceased participants (follow-up time: 2,166 person-years). Results The incidence rate of death was 1.75/100 person-years. Median observation time for all patients was 23.1 years (range 0.61–26.6 years). Mean age at death was 58.5 years (34.2–78.4 years), and diabetes duration 35 years (3.5–68.5 years). Most frequent causes of death were: cardiovascular diseases (48.2%, n=13) and infections (25.9%, n=7). There were no differences in age (p=0.302), diabetes duration (p=0.371), BMI (p=0.535), blood pressure (p=0.622/0.820), gender (p=0.566), and smoking status (p=0.709) between surviving and deceased persons. The mean HbA1c of the last year before death or last visit was higher in the deceased than surviving persons (7.5% vs. 7.0%; p=0.010). 57.4% of the surviving and 87.0% of the deceased participants had nephropathy (p=0.012), 79.7% vs. 89.7% retinopathy (p=0.241) and 61.4% vs. 63.3% neuropathy (p=0.860), but only nephropathy was significantly associated with increased mortality risk (HR=4.208, CI:1.226-14.440; HR=2.360, CI:0.696-8.004; HR=0.944, CI:0.436-2.043). Conclusions In the JEVIN population with diabetes mellitus type 1 only, diabetic nephropathy was associated with higher mortality risk.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Creatine Fuels the Thermic Effect of Feeding

Publication date: Available online 24 August 2017
Source:Cell Metabolism
Author(s): Alan R. Saltiel
The current obesity epidemic has focused a great deal of attention on cellular pathways of energy expenditure. While a crucial part of this process is diet-induced thermogenesis, the underlying mechanisms have remained unexplained. In this issue of Cell Metabolism, Kazak et al. (2017) describe a new thermogenic pathway in adipocytes that responds to diet overload, involving creatine cycling. These data suggest that this pathway might limit weight gain during overnutrition.

Teaser

The current obesity epidemic has focused a great deal of attention on cellular pathways of energy expenditure. While a crucial part of this process is diet-induced thermogenesis, the underlying mechanisms have remained unexplained. In this issue of Cell Metabolism, Kazak et al. (2017) describe a new thermogenic pathway in adipocytes that responds to diet overload, involving creatine cycling. These data suggest that this pathway might limit weight gain during overnutrition.


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Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity

Publication date: Available online 24 August 2017
Source:Cell Metabolism
Author(s): Lawrence Kazak, Edward T. Chouchani, Gina Z. Lu, Mark P. Jedrychowski, Curtis J. Bare, Amir I. Mina, Manju Kumari, Song Zhang, Ivan Vuckovic, Dina Laznik-Bogoslavski, Petras Dzeja, Alexander S. Banks, Evan D. Rosen, Bruce M. Spiegelman
Diet-induced thermogenesis is an important homeostatic mechanism that limits weight gain in response to caloric excess and contributes to the relative stability of body weight in most individuals. We previously demonstrated that creatine enhances energy expenditure through stimulation of mitochondrial ATP turnover, but the physiological role and importance of creatine energetics in adipose tissue have not been explored. Here, we have inactivated the first and rate-limiting enzyme of creatine biosynthesis, glycine amidinotransferase (GATM), selectively in fat (Adipo-Gatm KO). Adipo-Gatm KO mice are prone to diet-induced obesity due to the suppression of elevated energy expenditure that occurs in response to high-calorie feeding. This is paralleled by a blunted capacity for β3-adrenergic activation of metabolic rate, which is rescued by dietary creatine supplementation. These results provide strong in vivo genetic support for a role of GATM and creatine metabolism in energy expenditure, diet-induced thermogenesis, and defense against diet-induced obesity.

Graphical abstract

Teaser

Kazak et al. investigate the physiological effects of creatine energetics through loss of function of the rate-limiting enzyme glycine amidinotransferase (GATM) in adipose tissue. Adipo-Gatm KO mice cannot counteract increased calories with energy expenditure and gain weight. Their lower metabolic rate can be rescued by dietary creatine supplementation.


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The FGF21-CCL11 Axis Mediates Beiging of White Adipose Tissues by Coupling Sympathetic Nervous System to Type 2 Immunity

Publication date: Available online 24 August 2017
Source:Cell Metabolism
Author(s): Zhe Huang, Ling Zhong, Jimmy Tsz Hang Lee, Jialiang Zhang, Donghai Wu, Leiluo Geng, Yu Wang, Chi-Ming Wong, Aimin Xu
Type 2 cytokines are important signals triggering biogenesis of thermogenic beige adipocytes in white adipose tissue (WAT) during cold acclimation. However, how cold activates type 2 immunity in WAT remains obscure. Here we show that cold-induced type 2 immune responses and beiging in subcutaneous WAT (scWAT) are abrogated in mice with adipose-selective ablation of FGF21 or its co-receptor β-Klotho, whereas such impairments are reversed by replenishment with chemokine CCL11. Mechanistically, FGF21 acts on adipocytes in an autocrine manner to promote the expression and secretion of CCL11 via activation of ERK1/2, which drives recruitment of eosinophils into scWAT, leading to increases in accumulation of M2 macrophages, and proliferation and commitment of adipocyte precursors into beige adipocytes. These FGF21-elicited type 2 immune responses and beiging are blocked by CCL11 neutralization. Thus, the adipose-derived FGF21-CCL11 axis triggers cold-induced beiging and thermogenesis by coupling sympathetic nervous system to activation of type 2 immunity in scWAT.

Graphical abstract

Teaser

Zhe Huang et al. show that cold activates type 2 immune responses and beiging in subcutaneous WAT through an FGF21-CCL11 axis which drives eosinophil recruitment, M2 macrophage accumulation and proliferation and commitment of beige adipocyte precursors. These findings explain how the immune system communicates with sympathetic nerves to control adaptive thermogenesis.


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The Lymphatic Vasculature: Its Role in Adipose Metabolism and Obesity

Publication date: Available online 24 August 2017
Source:Cell Metabolism
Author(s): Noelia Escobedo, Guillermo Oliver
Obesity is a key risk factor for metabolic and cardiovascular diseases, and although we understand the mechanisms regulating weight and energy balance, the causes of some forms of obesity remain enigmatic. Despite the well-established connections between lymphatics and lipids, and the fact that intestinal lacteals play key roles in dietary fat absorption, the function of the lymphatic vasculature in adipose metabolism has only recently been recognized. It is well established that angiogenesis is tightly associated with the outgrowth of adipose tissue, as expanding adipose tissue requires increased nutrient supply from blood vessels. Results supporting a crosstalk between lymphatic vessels and adipose tissue, and linking lymphatic function with metabolic diseases, obesity, and adipose tissue, also started to accumulate in the last years. Here we review our current knowledge of the mechanisms by which defective lymphatics contribute to obesity and fat accumulation in mouse models, as well as our understanding of the lymphatic-adipose tissue relationship.

Teaser

Obesity and cardiovascular diseases are leading causes of death and disability. In this Review, Oliver and Escobedo expose the relationships between lymphatics, metabolism, and obesity and discuss how this knowledge will provide us with better tools to diagnose and treat some of these pathological conditions.


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Pulmonary fluorosis: a review

Abstract

The increased industrialization and improvised human lifestyle lead to a surge in environmental pollution nowadays. Even the chemicals which are known as prophylactic agents were currently liable to be toxic. One among them is inorganic fluoride whose wider application in numerous processes makes it as an inevitable environmental contaminant and industrial pollutant. Although the systemic toxicity of fluoride has been extensively studied, still there is lacuna in the field of pulmonary fluoride toxicity. Hence, we have focused on the molecular mechanism of action of fluoride compounds on pulmonary system. A study of literatures that focused on the potential physiological and toxicological consequences of fluoride on pulmonary system was carried out. The goal of this review is to present an overview of the research carried out till date on the molecular aspects of fluoride exposure with emphasis on pulmonary system and their possible mechanisms.

http://ift.tt/2xh4UP6

Internship Match and Entry Level Exam Performance of Undergraduate versus Graduate Level Didactic Students

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): B. Leonberg




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Teaching Multiculturalism in an Undergraduate Dietetics Course

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): H. Thornton




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Table of Contents

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9





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Registered Dietitians Facilitate Diabetes Training and Care within a Patient Centered Medical Home Care Delivery Model

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): M. McClarney, M. Timmerman, G. Woscyna, C. Hanson




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Disclosure Page

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement





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What's New Online

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9





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Outstanding Dietetics Student Awards, 2017

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9





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Table of Contents

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement





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2017-2018 Officers List and Committee Members

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9





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Sports Dietetics: Impact Beyond Playing Fields

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9
Author(s): Donna S. Martin




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Acknowledgements

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement





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Increased Malnutrition Diagnosis and Reimbursement Indicates Success of Academy of Nutrition and Dietetics Nutrition Focused Physical Exam (NFPE) Hands-on Training Workshop

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): B. Mordarski, R. Hand, J. Wolff, A. Steiber




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Breastfeeding after Gestational Diabetes: GIS Analysis of Maternal-Infant Health Interventions

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): E. MacQuillan, A. Curtis




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Middle East Dietetics Needs Assessment: Identifying Opportunities for Future Collaborative Activities

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): E. Myers, R. Hakeem, N. Bdour, T. Kour, F. Atayata, S. Tashtoush, N. Cakir Bicer, S. Sakar, C. Erginbas, R. Kahill, M. Herrera, M. Boyd




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Back to Basics: All About MyPlate Food Groups

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9
Author(s): Sarah Chang, Kristin Koegel




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Prevalence of Food Insecurity among Hospitalized Patients

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): D. Sowa, C. Hartney, A. Asthana, S. Peterson




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Deepening the Commitment to Interprofessional Education and Practice: Updates from the Global Forum on Innovation in Health Professional Education and the Interprofessional Education Collaborative

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): K. Eliot, K. Kolasa




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Role of Nutrition Focused Physical Exam (NFPE) in the Identification of Malnutrition in Pediatric Patients

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): R. Pipkorn, C. Leon, J. Crouse, N. Fabus, M.B. Feuling, C. Karls, E. Polzin, A. Smith, M. Froh




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Carbohydrate Intake Estimates Do Not Differ by Nursing or Nutrition Discipline or by Two Methods of Evaluation in Acute Care Diabetic Patients at an Academic Medical Center

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): B. Atkinson, M. Perrigue, S. Singh, D. Cuddeback, S. Roesor-Loken, A. Lillie, L. Suhr, D. Corl, W. Brent




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State Dietetic Practice Group Gets Involved in State Regulation Revisions: Relevant, Vital and Never Dull

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): P. Fatzinger McShane, J. Geer, J. Rowley




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Design and Synthesis of Benzoacridines as Estrogenic and Anti-Estrogenic Agents

Publication date: Available online 24 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Kohei Torikai, Rintaro Koga, Xiaohui Liu, Kaoru Umehara, Tatsuya Kitano, Kenji Watanabe, Tohru Oishi, Hiroshi Noguchi, Yasuyuki Shimohigashi
Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERβ (IC50 < μM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).

Graphical abstract

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Pyrrolizines: design, synthesis, anticancer evaluation and investigation of the potential mechanism of action

Publication date: Available online 24 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ahmed M. Gouda, Ahmed H. Abdelazeem, Hany A. Omar, Ashraf N. Abdalla, Mohammed A.S. Abourehab, Hamed I. Ali
A novel set of pyrrolizine-5-carboxamides has been synthesized and evaluated for their anticancer potential against human breast MCF-7, lung carcinoma A549 and hepatoma Hep3B cancer cell lines. Compound 10c was the most active against MCF-7 with IC50 value of 4.72 µM, while compound 12b was the most active against A549 and Hep3B cell lines. Moreover, kinases/COXs inhibition and apoptosis induction were suggested as potential molecular mechanisms for the anticancer activity of the novel pyrrolizines based on their structural features. The new compounds significantly inhibited COX-1 and COX-2 with IC50 values in the ranges of 5.78-11.96 µM and 0.1-0.78 µM, respectively with high COX-2 selectivity over COX-1. Interestingly, the most potent compound in MTT assay, compound 12b, exhibited high inhibitory activity against COX-2 with selectivity index (COX-1/COX-2) > 100. Meanwhile, compound 12b displayed weak to moderate inhibition of six kinases with inhibition% (7-20%) compared to imatinib (inhibition% = 1-38%). The results of cell cycle analysis, annexin V PI/FITC apoptosis assay and caspase-3/7 assay revealed that compound 12b has the ability to induce apoptosis. The docking results of compound 12b into the active sites of COXs, ALK1 and Aurora A indicated that it fits nicely inside their active sites. Overall, the current study highlighted the significant anticancer activity of the newly synthesized pyrrolizines with a potential multi-targeted mechanism which could serve as a base for future studies and further structural optimization into potential anticancer agents.

Graphical abstract

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β-Arrestin biased dopamine D2 receptor partial agonists: synthesis and pharmacological evaluation

Publication date: Available online 24 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Barbara Männel, Harald Hübner, Dorothée Möller, Peter Gmeiner
β-Arrestin biased G protein-coupled receptor ligands represent important molecular probes and may increase favorable drug action and safety as novel therapeutics. Starting from recently discovered hydroxy-substituted heterocyclic piperazine scaffolds, we have developed a series of dopamine D2 receptor ligands with a pyrazolo[1,5-a]pyridine as secondary pharmacophore that is functionalized in position 3 by a formyl or hydroxyiminomethyl substituent. The ligands, especially the benzoxazinone 9d, were found to display substantial β-arrestin-2 recruitment, while being nearly devoid of activity in a GTPγS binding assay. Investigating a new series of truncated analogs lacking a secondary pharmacophore, considerable β-arrestin-2 recruitment in the absence of G protein activation was found, when a 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one was combined with an N-propyl-substituted 1,4-diazepane (15c). Although 15c displayed reduced potency compared to 9d, the dose-response curves indicate that a hydroxy-substituted heterocyclic primary pharmacophore is sufficient for the functionally selective activation of D2R.

Graphical abstract

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Microcystins: Synthesis and structure–activity relationship studies toward PP1 and PP2A

Publication date: Available online 24 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Miriam Fontanillo, Maja Köhn
Microcystins are highly toxic cyanotoxins responsible for plant, animal and human poisoning. Exposure to microcystins, mainly through drinkable water and contaminated food, is a current world health concern. Although it is quite challenging, the synthesis of these potent cyanotoxins, analogs and derivatives helps to detect them, to evaluate their toxicological properties, and to elucidate their binding mechanisms to their main targets Protein Phosphatase-1 (PP1) and -2A (PP2A). This review focuses on synthetic approaches to prepare microcystins and analogs and compiles structure–activity relationship (SAR) studies that describe the unique features of microcystins that make them so potent.

Graphical abstract

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Phenolic Glycolipid Facilitates Mycobacterial Escape from Microbicidal Tissue-Resident Macrophages

Publication date: Available online 24 August 2017
Source:Immunity
Author(s): C.J. Cambier, Seónadh M. O'Leary, Mary P. O'Sullivan, Joseph Keane, Lalita Ramakrishnan
Mycobacterium tuberculosis (Mtb) enters the host in aerosol droplets deposited in lung alveoli, where the bacteria first encounter lung-resident alveolar macrophages. We studied the earliest mycobacterium-macrophage interactions in the optically transparent zebrafish. First-responding resident macrophages phagocytosed and eradicated infecting mycobacteria, suggesting that to establish a successful infection, mycobacteria must escape out of the initially infected resident macrophage into growth-permissive monocytes. We defined a critical role for mycobacterial membrane phenolic glycolipid (PGL) in engineering this transition. PGL activated the STING cytosolic sensing pathway in resident macrophages, inducing the production of the chemokine CCL2, which in turn recruited circulating CCR2⁺ monocytes toward infection. Transient fusion of infected macrophages with CCR2⁺ monocytes enabled bacterial transfer and subsequent dissemination, and interrupting this transfer so as to prolong mycobacterial sojourn in resident macrophages promoted clearing of infection. Human alveolar macrophages produced CCL2 in a PGL-dependent fashion following infection, arguing for the potential of PGL-blocking interventions or PGL-targeting vaccine strategies in the prevention of tuberculosis.Video Abstract

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Teaser

Cambier et al. find that activation of the STING pathway in lung-resident microbicidal macrophages by the mycobacterial surface lipid PGL enables bacterial escape by inducing the recruitment of mycobacterium-permissive monocytes via the CCL2-CCR2 chemokine axis. Their findings reveal a relocation strategy that enables mycobacterial dissemination, and argue for the potential of interventions targeting PGL in the prevention of tuberculosis.


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Late Presentation of Popliteal Angiosarcoma After Previously Treated Popliteal Artery Aneurysm

Publication date: Available online 23 August 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): M. Cherchi, S. Camparini




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Arteriovenous Fistulae for Haemodialysis: A Systematic Review and Meta-analysis of Efficacy and Safety Outcomes

Publication date: Available online 23 August 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): L.C. Bylsma, S.M. Gage, H. Reichert, S.L.M. Dahl, J.H. Lawson
BackgroundArteriovenous fistulae are the currently recommended gold standard vascular access modality for haemodialysis because of their prolonged patency, improved durability, and low risk of infection for those that mature. However, notable disadvantages are observed in terms of protracted maturation time, associated high rates of catheter use, and substantial abandonment rates. The aim of this study was to quantitatively summarize the outcomes of fistula patency, infection, maturation, and abandonment published in the scientific literature.MethodsThis was a systematic review and meta-analyses of studies evaluating fistula outcomes. Literature searches were conducted in multiple databases to identify observational and interventional studies of mean fistula patency rates at 1 year, infection risk, maturation time, and abandonment. Digitisation software was used to simulate individual patient level data from Kaplan–Meier survival plots.ResultsOver 8000 studies were reviewed, and from these, 318 studies were included comprising 62,712 accesses. For fistulas the primary unassisted, primary assisted, and secondary patency rates at one year were 64%, 73% and 79% respectively, however not all fistulas reported as patent could be confirmed as being clinically useful for dialysis (i.e. functional patency). For fistulas that were reported as mature, mean time to maturation was 3.5 months, however only 26% of created fistulas were reported as mature at 6 months and 21% of fistulas were abandoned without use. Overall risk of infection in fistula patients was 4.1% and the overall rate per 100 access days was 0.018.ConclusionsReported fistula patency rates may overstate their potential clinical utility when time to maturation, maturation rate, abandonment and infection are considered. Protracted maturation times, abandonment and infection all have a significant impact on evaluating the clinical utility of fistula creation. A rigorous and consistent set of outcomes definitions for hemodialysis access are necessary to clarify factors contributing to fistula success and the clinical consequence of fistula failure.



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Mothers' loss of control over eating during pregnancy in relation to their infants' appetitive traits

Publication date: 1 January 2018
Source:Appetite, Volume 120
Author(s): Rachel P. Kolko, Rachel H. Salk, Gina M. Sweeny, Marsha D. Marcus, Michele D. Levine




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Renal collision tumor composed of oncocytoma and mucinous tubular and spindle cell carcinoma: case report of an unprecedented entity

Publication date: Available online 24 August 2017
Source:Human Pathology
Author(s): Komal Arora, Ross Miller, Seema Mullick, Steven Shen, Alberto G. Ayala, Jae Y. Ro
Primary renal collision tumors composed of two histologically distinct components are rare with only isolated case reports in the medical literature. Oncocytoma is a benign renal neoplasm, which is thought to originate from distal tubular epithelial cells. Mucinous tubular and spindle cell carcinoma (MTSCC) of kidney is a rare, relatively recently described renal neoplasm that was first included in the 2004 World Health Organization RCC classification as a distinct entity. Current studies suggest the tumor originates from the proximal nephron, although it is still controversial. The presence of concurrent oncocytoma with conventional (clear cell) RCC, chromophobe RCC and papillary RCC has been previously described. However, the association of oncocytoma with MTSCC has not yet been reported to our knowledge. Herein, we report the first case of a renal collision tumor composed of oncocytoma and MTSCC.



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Postablation neuroma of the myometrium – a report of 5 cases

Publication date: Available online 24 August 2017
Source:Human Pathology
Author(s): Stewart F. Cramer, Debra S. Heller
When hysterectomy is performed for chronic pelvic pain, routine pathology examination often provides no explanation. However, analysis of small uterine nerves using immunostains may help to address this deficiency. Small uterine nerves tend to be sparse or absent in wide areas of normal myometrium. Some studies of uterine nerves have suggested that endometriosis, adenomyosis, and fibroids are not inherently painful, with increased small nerves in the inner uterine wall associated with the history of pelvic pain. Although such areas may appear normal on Hematoxylin and Eosin (H&E), we have found a subtle inner wall lesion termed inner myometrial elastosis, best detected with trichrome or elastic stains, which may be a reaction to microscopic tears of inner myometrium. Such tears may induce increased inner wall innervation via the generation of Nerve Growth Factor in granulation tissue. In the course of studying uterine nerves with immunostains, we found 5 cases with florid nerve proliferation, after deep endometrial ablation for abnormal uterine bleeding led to increased pelvic pain. We suggest that immunostains for postablation neuromas should be done in hysterectomies when pelvic pain increases after endometrial ablation. This may offer gynecologists and their patients an objective finding with a rational, scientific explanation for the pelvic pain.



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Ring Chromosome in Myeloid Neoplasms is Associated with Complex Karyotype and Disease Progression

Publication date: Available online 24 August 2017
Source:Human Pathology
Author(s): Matthew W Rosenbaum, Olga Pozdnyakova, Julia T Geyer, Paola Dal Cin, Robert Hasserjian
Ring chromosome (RC) is a poorly understood genetic anomaly seen in myeloid neoplasms. This study aims to shed light on the clinical significance of this finding. We identified 96 cases of myeloid neoplasms with RC from 3 academic hospitals. Clinicopathologic features and overall- (OS) and leukemia-free survival were reviewed and compared to cases of myeloid neoplasms lacking RC. We identified 59 acute myeloid leukemias (AML-RC) and 37 myelodysplastic syndromes (MDS-RC) with RC identified on routine karyotyping. 75% of AML-RC and 97% of MDS-RC had complex (>3 independent cytogenetic abnormalities) karyotypes. The median OS of AML-RC with complex karyotype was significantly shorter than AML-RC patients with a non-complex (≤3 independent cytogenetic abnormalities) karyotype (P=.001), but similar to AML patients with complex karyotype lacking RC (p=n.s.). Compared to complex karyotype MDS lacking RC, MDS-RC patients had shorter leukemia-free survival (P=.016) and a trend for shorter overall survival (P=.10). RCs are associated with an inferior leukemia-free survival in MDS with complex karyotype. AML-RC with complex karyotype had similar outcomes to complex karyotype AML lacking RC, but shorter survival than AML-RC with a non-complex karyotype. RCs were sometimes lost after therapy or appeared during disease relapse, suggesting that they may be associated with genetic instability.



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Avoiding Surgical Skill Decay: A Systematic Review on the Spacing of Training Sessions

Publication date: Available online 24 August 2017
Source:Journal of Surgical Education
Author(s): Dario Cecilio-Fernandes, Fokie Cnossen, Debbie A.D.C. Jaarsma, René A. Tio
ObjectiveSpreading training sessions over time instead of training in just 1 session leads to an improvement of long-term retention for factual knowledge. However, it is not clear whether this would also apply to surgical skills. Thus, we performed a systematic review to find out whether spacing training sessions would also improve long-term retention of surgical skills.DesignWe searched the Medline, PsycINFO, Embase, Eric, and Web of Science online databases. We only included articles that were randomized trials with a sample of medical trainees acquiring surgical motor skills in which the spacing effect was reported. The quality and bias of the articles were assessed using the Cochrane Collaboration's risk of bias assessment tool.ResultsWith respect to the spacing effect, 1955 articles were retrieved. After removing duplicates and articles that did not meet the inclusion criteria, 11 articles remained. The overall quality of the experiments was "moderate." Trainees in the spaced condition scored higher in a retention test than students in the massed condition.ConclusionsOur systematic review showed evidence that spacing training sessions improves long-term surgical skills retention when compared to massed practice. However, the optimal gap between the re-study sessions is unclear.



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TEAM: A Low-Cost Alternative to ATLS for Providing Trauma Care Teaching in Haiti

Publication date: Available online 24 August 2017
Source:Journal of Surgical Education
Author(s): Anton Kurdin, Andrew Caines, Darrell Boone, Andrew Furey
ObjectiveTrauma resuscitation protocols have unified the care of trauma patients and significantly improved outcomes. However, the success of the Advanced Trauma Life Support course is difficult to reproduce in developing countries due to set-up costs, limitations of resources, and variations of practice. The objective of this study is to assess the Trauma Evaluation and Management (TEAM) course as a low-cost alternative for trauma resuscitation teaching in Low and Middle Income Countries (LMIC).DesignAs part of the Team Broken Earth initiative, TEAM course was provided to the health care professionals in Haiti. At its conclusion, participants were asked to complete a survey evaluating the course. Qualitative and quantitative data were analyzed to evaluate the perception of the course.SettingThe course was provided in Port-au-Prince, Haiti.ParticipantsA total of 80 health care professionals participated in the course. Response was obtained from 69 participants, which comprised of 32 physicians, 10 Emergency Medical Technicians (EMT), 22 nurses, and 5 medical trainees.ResultsThe course was well received by physicians, nurses, and EMT with an average score of 90.6%. Question analysis revealed a lower satisfaction of physicians for the course manual and teaching materials, and information related to decisions for transfer of patients. EMT consistently felt that the course was not tailored to their learning and practice needs. Written feedback demonstrated several areas of weaknesses including need for improvements in translations, hands-on practice, and educational materials.ConclusionsOverall, the TEAM course was well received. Analysis demonstrated a need for adjustments specific to LMIC including a focus on prehospital assessment, increased nursing responsibilities, and unavailability of specialist's referrals. Team Broken Earth intends to take these findings into consideration and continue to provide the TEAM course to other LMIC.



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Coronary Artery Calcium Imaging in the ROBINSCA Trial

Publication date: Available online 23 August 2017
Source:Academic Radiology
Author(s): Marleen Vonder, Carlijn M. van der Aalst, Rozemarijn Vliegenthart, Peter M.A. van Ooijen, Dirkjan Kuijpers, Jan Willem Gratama, Harry J. de Koning, Matthijs Oudkerk
Rationale and ObjectivesTo describe the rationale, design, and technical background of coronary artery calcium (CAC) imaging in the large-scale population-based cardiovascular disease screening trial (Risk Or Benefit IN Screening for CArdiovascular Diseases [ROBINSCA]).Materials and MethodsFirst, literature search was performed to review the logistics, setup, and settings of previously performed CAC imaging studies, and current clinical CAC imaging protocols of participating centers in the ROBINSCA trial were evaluated. A second literature search was performed to evaluate the impact of computed tomography parameter settings on CAC score.ResultsBased on literature reviews and experts opinion an imaging protocol accompanied by data management protocol was created for ROBINSCA. The imaging protocol should consist of a fixed tube voltage, individually tailored tube current setting, mid-diastolic electrocardiography-triggering, fixed field-of-view, fixed reconstruction kernel, fixed slice thickness, overlapping reconstruction and without iterative reconstruction. The analysis of scans is performed with one type and version of CAC scoring software, by two dedicated and experienced researchers. The data management protocol describes the organization of data handling between the coordinating center, participating centers, and core analysis center.ConclusionIn this paper we describe the rationale and technical considerations to be taken in developing CAC imaging protocol, and we present a detailed protocol that can be implemented for CAC screening purposes.



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T2 Star-weighted Angiography (SWAN) Allows to Concomitantly Assess the Prostate Contour While Detecting Fiducials Before MR-based Intensity-modulated Radiation Therapy in Prostate Carcinoma

Publication date: Available online 23 August 2017
Source:Academic Radiology
Author(s): Pierre-Antoine Dirajlal, Eva Jambon, Agnes Albat-Esquirou, Chloe Galmiche, Jean-Christophe Bernhard, Nicolas Grenier, Thibaud Haaser, François H. Cornelis
PurposeTo evaluate the performance of T2 star-weighted angiography (SWAN) to concomitantly assess the prostate contour while detecting fiducials before magnetic resonance (MR)-based intensity-modulated radiation therapy (IMRT) in prostate carcinoma.Materials and MethodsForty patients (mean age: 73.1 ± 7.5 years; average Gleason score: 7 ± 1; average prostate-specific antigen: 14.7 ± 11.6 ng/mL) underwent MR and computed tomography imaging before fiducial-based IMRT. MR protocol included SWAN, T2-weighted (T2w) and diffusion-weighted imaging in a first group (n = 20) and SWAN, T2w and T2-star weighted imaging in a second group (n = 20). In group 1, the depiction of fiducials, image sharpness and visibility of prostate boundaries were independently evaluated by 2 readers on SWAN, T2w or diffusion-weighted images. In group 2, a similar evaluation was performed by 2 other readers on SWAN and T2-star images only. Depiction of fiducials was compared to computed tomography findings.ResultsThe median scores of visibility of prostate boundaries, image sharpness and depiction of fiducials by SWAN were above average to excellent for all readers. In group 1, readers correctly located 56 of 57 (98.2%) and 47 of 57 (82.5%) fiducials, respectively; and 50 of 51 (98%), and 48 of 51 (88.2%) fiducials in group 2, respectively.ConclusionBy allowing adequate visualization of the prostate boundaries and high depiction of fiducial markers concomitantly, SWAN might be used for treatment planning of IMRT. The use of this sequence might simplify the registration process and limit any errors associated with image fusion.



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Lepidic Predominant Pulmonary Lesions (LPL)

Publication date: Available online 24 August 2017
Source:Academic Radiology
Author(s): Jeffrey B. Alpert, Henry Rusinek, Jane P. Ko, Bari Dane, Harvey I. Pass, Bernard K. Crawford, Amy Rapkiewicz, David P. Naidich
Rationale and ObjectivesThis study aimed to differentiate pathologically defined lepidic predominant lesions (LPL) from more invasive adenocarcinomas (INV) using three-dimensional (3D) volumetric density and first-order texture histogram analysis of surgically excised stage 1 lung adenocarcinomas.Materials and MethodsThis retrospective study was institutional review board approved and Health Insurance Portability and Accountability Act compliant. Sixty-four cases of pathologically proven stage 1 lung adenocarcinoma surgically resected between September 2006 and October 2015, including LPL (n = 43) and INV (n = 21), were evaluated using high-resolution computed tomography. Quantitative measurements included nodule volume, percent solid volume (% solid), and first-order texture histogram analysis including skewness, kurtosis, entropy, and mean nodule attenuation within each histogram quartile. Binomial logistic regression models were used to identify the best set of parameters distinguishing LPL from INV.ResultsUnivariate analysis of 3D volumetric density and histogram features was statistically significant between LPL and INV groups (P < .05). Accuracy of a binomial logistic model to discriminate LPL from INV based on size and % solid was 85.9%. With optimized probability cutoff, the model achieves 81% sensitivity, 76.7% specificity, and area under the receiver operating characteristic curve of 0.897 (95% confidence interval, 0.821–0.973). An additional model based on size and mean nodule attenuation of the third quartile (Hu_Q3) of the histogram achieved similar accuracy of 81.3% and area under the receiver operating characteristic curve of 0.877 (95% confidence interval, 0.790–0.964).ConclusionsBoth 3D volumetric density and first-order texture analysis of stage 1 lung adenocarcinoma allow differentiation of LPL from more invasive adenocarcinoma with overall accuracy of 85.9%–81.3%, based on multivariate analyses of either size and % solid or size and Hu_Q3, respectively.



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Promoting Collaborations Between Radiologists and Scientists

Publication date: Available online 24 August 2017
Source:Academic Radiology
Author(s): John-Paul J. Yu, Bradley M. Spieler, Tiffany L. Chan, Elizabeth M. Johnson, Vikas Gulani, Kim L. Sandler, Ponnada A. Narayana, Winnie A. Mar, James M. Brian, Chin K. Ng
Radiology as a discipline thrives on the dynamic interplay between technological and clinical advances. Progress in almost all facets of the imaging sciences is highly dependent on complex tools sourced from physics, engineering, biology, and the clinical sciences to obtain, process, and view imaging studies. The application of these tools, however, requires broad and deep medical knowledge about disease pathophysiology and its relationship with medical imaging. This relationship between clinical medicine and imaging technology, nurtured and fostered over the past 75 years, has cultivated extraordinarily rich collaborative opportunities between basic scientists, engineers, and physicians. In this review, we attempt to provide a framework to identify both currently successful collaborative ventures and future opportunities for scientific partnership. This invited review is a product of a special working group within the Association of University Radiologists-Radiology Research Alliance.



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The Sixth Stage

Publication date: Available online 24 August 2017
Source:Academic Radiology
Author(s): Mohsin Mukhtar, Richard B. Gunderman




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Thoracic Quantitative Computed Tomography (QCT) Can Sensitively Monitor Bone Mineral Metabolism

Publication date: Available online 23 August 2017
Source:Academic Radiology
Author(s): Song Shou Mao, Dong Li, Younus Saleem Syed, Yanlin Gao, Yanting Luo, Ferdinand Flores, Janis Child, MacKenzie Cervantes, Kamyar Kalantar-Zadeh, Matthew J. Budoff
Rationale and ObjectiveSensitive detection of bone mineral density (BMD) change is a key issue to monitor and evaluate the individual bone health status, as well as bone metabolism and bone mineral status. The ability to use thoracic quantitative computed tomography (QCT) to detect the annual change of BMD remains unclear. We aimed to investigate the sensitivity in detecting age-related bone mineral loss using the thoracic QCT from the electrocardiographically gated heart scans in comparison to whole-body dual-energy X-ray absorptiometry (DXA) and standard lumbar QCT.Materials and MethodsA total of 121 asymptomatic patients' imaging data, including DXA whole body scan, cardiac CT scan, and abdomen scans were analyzed. The BMD of the thoracolumbar spine, upper, and lower extremities were measured using QCT and DXA, respectively. The age-related annual rate of bone density loss was computed and compared to the thoracic and lumbar QCT, as well DXA measures.ResultsThe age-related annual rate of bone loss with QCT was −0.70 mg/mL³ (−0.75%/y) in women, −0.83 mg/mL³ (−0.86%/y) in men in the thoracic and the lumbar trabecular QCT, respectively. Compared to the QCT, DXA demonstrates a lower annual rate of bone loss in the area of BMD measurement (P < .05 in all, excluding legs of women) in −0.45, −0.42, −0.67, and −0.46 in women, in −0.32, −0.02, −0.12, and −0.08 in men for thoracic, lumbar, leg, and arm, respectively.ConclusionWe conclude that the thoracic and the lumbar QCT provide a similar and more sensitive method for detecting bone mineral loss when compared to DXA.



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The Cerebellum is a Common Site of Affection in Leigh Syndrome

Publication date: Available online 24 August 2017
Source:Pediatric Neurology
Author(s): Josef Finsterer, Sinda Zarrouk-Mahjoub




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Severe Neutropenia and Anemia in a Child with Epilepsy and Copper Deficiency on a Ketogenic Diet

Publication date: Available online 24 August 2017
Source:Pediatric Neurology
Author(s): Houman Rashidian, YM Christiana Liu, Michael T Geraghty, Jeff Kobayashi, Elizabeth J. Donner, Robert J. Klaassen




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Alice in Wonderland Syndrome: a Historical and Medical Review

Publication date: Available online 24 August 2017
Source:Pediatric Neurology
Author(s): Osman Farooq, Edward J. Fine
Alice in Wonderland syndrome is a disorienting neurological condition that affects human perception to the senses of vision, hearing, touch, sensation and the phenomenon of time. Individuals affected with Alice in Wonderland syndrome can experience alterations in their perception to the size of objects or their own body parts, known as metamorphopsias. It is known to occur in conditions including migraine, epilepsy, as well as certain intoxicants and infectious diseases. The name refers to Lewis Carrol's well-known children's book Alice's Adventures in Wonderland, in which the title character experiences alterations of sensation in which she felt that her body had grown too tall or too small, or parts of her body were changing shape, size or relationship to the rest of her body. The syndrome was described in 1952 by Caro Lippman, and given its name in 1955 by John Todd. The metamorphopsias characteristic of this condition are also sometimes referred to as Lilliputian hallucinations, as a reference to the fictional island of Lilliput in the novel Gulliver's Travels, written by Jonathan Swift in 1726. As such, many literary and medical publications have roots in the description of this syndrome. The purpose of this review is to summarize the literary and historical significance of Alice in Wonderland syndrome as well as to provide the reader with a medical overview of the condition.



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Acylpeptide Hydrolase is a Component of the Cellular Response to DNA Damage

Publication date: Available online 24 August 2017
Source:DNA Repair
Author(s): Zhihong Zeng, Stuart L. Rulten, Claire Breslin, Anastasia Zlatanou, Victoria Coulthard, Keith W. Caldecott
Acylpeptide hydrolase (APEH) deacetylates N-alpha-acetylated peptides and selectively degrades oxidised proteins, but the biochemical pathways that are regulated by this protease are unknown. Here, we identify APEH as a component of the cellular response to DNA damage. Although APEH is primarily localised in the cytoplasm, we show that a sub-fraction of this enzyme is sequestered at sites of nuclear damage following UVA irradiation or following oxidative stress. We show that localization of APEH at sites of nuclear damage is mediated by direct interaction with XRCC1, a scaffold protein that accelerates the repair of DNA single-strand breaks. We show that APEH interacts with the amino-terminal domain of XRCC1, and that APEH facilitates both single-strand break repair and cell survival following exposure to H2O2 in human cells. These data identify APEH as a novel proteolytic component of the DNA damage response.



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Proximity effects in chromosome aberration induction by low-LET ionizing radiation

Publication date: Available online 24 August 2017
Source:DNA Repair
Author(s): John James Tello Cajiao, Mario Pietro Carante, Mario Antonio Bernal Rodriguez, Francesca Ballarini
Although chromosome aberrations are known to derive from distance-dependent mis-rejoining of chromosome fragments, evaluating whether a certain model describes such "proximity effects" better than another one is complicated by the fact that different approaches have often been tested under different conditions. Herein, a biophysical model ("BIANCA", i.e. BIophysical ANalysis of Cell death and chromosome Aberrations) was upgraded, implementing explicit chromosome-arm domains and two new models for the dependence of the rejoining probability on the fragment initial distance, r. Such probability was described either by an exponential function like exp(-r/r0), or by a Gaussian function like exp(-r²/2σ²), where r0 and σ were adjustable parameters. The second, and last, parameter was the yield of "Cluster Lesions" (CL), where "Cluster Lesion" defines a critical DNA damage producing two independent chromosome fragments. The model was applied to low-LET-irradiated lymphocytes (doses: 1–4Gy) and fibroblasts (1-6.1Gy). Good agreement with experimental yields of dicentrics and centric rings, and thus their ratio ("F-ratio"), was found by both the exponential model (with r0=0.8μm for lymphocytes and 0.7μm for fibroblasts) and the Gaussian model (with σ=1.1μm for lymphocytes and 1.3μm for fibroblasts). While the former also allowed reproducing dose-responses for excess acentric fragments, the latter substantially underestimated the experimental curves. Both models provided G-ratios (ratio of acentric to centric rings) higher than those expected from randomness, although the values calculated by the Gaussian model were lower than those calculated by the exponential one. For lymphocytes the calculated G-ratios were in good agreement with the experimental ones, whereas for fibroblasts both models substantially underestimated the experimental results, which deserves further investigation. This work suggested that, although both models performed better than a step model (which previously allowed reproducing the F-ratio but underestimated the G-ratio), an exponential function describes proximity effects better than a Gaussian one.



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Anatomical and functional properties of the foot and leg representation in areas 3b, 1 and 2 of primary somatosensory cortex in humans: A 7T fMRI study

Publication date: 1 October 2017
Source:NeuroImage, Volume 159
Author(s): Michel Akselrod, Roberto Martuzzi, Andrea Serino, Wietske van der Zwaag, Roger Gassert, Olaf Blanke
Primary somatosensory cortex (S1) processes somatosensory information and is composed of multiple subregions. In particular, tactile information from the skin is encoded in three subregions, namely Brodmann areas (BAs) 3b, 1 and 2, with each area representing a complete map of the contralateral body. Although, much is known about the somatotopic organization of the hand in human S1, less research has been carried out regarding the somatotopic maps of the foot and leg in S1. Moreover, a latero-medial S1 organization along the superior part of the postcentral gyrus has been reported when moving from hip to toes, yet to date there is no study investigating leg/foot maps within the different subregions of S1. Using ultra-high field MRI (7T), we mapped six cortical representations of the lower limb (hip to toes) at the single subject level and performed this analysis separately for BAs 3b, 1 and 2. Analyzing the BOLD responses associated with tactile stimulations of the mapped foot and leg regions on each side, we quantified the extent and the strength of activation to determine somatotopic organization. In addition, we investigated whether each mapped representation also responded to the stimulation of other body parts (i.e. response selectivity) and conducted dissimilarity analysis relating these anatomical and functional properties of S1 to the physical structure of the lower limbs. Our data reveal somatotopy for the leg, but not for the foot in all investigated BAs, with large inter-subject variability. We found only minor differences between the properties of the three investigated BAs, suggesting that S1 maps for the lower limbs differ from those described for the hand. We also describe greater extent/strength of S1 activation for the big toe representation (compared to the other mapped representations) within all BAs, suggesting a possible homology between the first digit of upper and lower extremity in humans, and report different patterns of selectivity in the foot representations (i.e. lower selectivity) compared to the other leg representations (i.e. greater selectivity). These data provide a detailed description of human S1 subregions for the foot and leg, highlight the importance of high-resolution mapping studies and of single subject analysis, and indicate potential differences between the lower and the upper limb.



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Gαq/p63RhoGEF interaction in RhoA/Rho kinase signaling: investigation in Gitelman’s syndrome and implications with hypertension

Abstract

Purpose

Gitelman's syndrome (GS) presents normo-hypotension and absence of cardiovascular–renal remodeling despite high angiotensin II (Ang II), activation of renin–angiotensin–aldosterone system and is a human model of endogenous antagonism of Ang II signaling, opposite to hypertension. GS's clinical presentation leads to questions regarding what features might be responsible. One area of investigation involves Ang II signaling. In hypertensive patients, RhoA/Rho kinase (RhoA/ROCK) pathway activation by Ang II is involved in hypertension development/maintenance and induction of long-term consequences (cardiovascular–renal remodeling), while GS has reduced p63RhoGEF gene and protein levels and ROCK activity. Ang II signaling is mediated by Gαq, which interacts with p63RhoGEF via the α6–αN linker connecting p63RhoGEF's DH and PH domains acting as a conformational switch to activate RhoA/ROCK signaling.

Methods

We have investigated in GS patients, the presence of mutations in either p63RhoGEF's α6–αN linker domain and in Gαq's Ala253, Trp263, and Tyr356 residues, crucial for p63RhoGEF–Gαq interplay.

Results

No mutations have been found in specific aminoacids of p63RhoGEF α6–αN linker and Gαq, key for p63RhoGEF/Gαq interplay.

Conclusions

Gitelman's syndrome normo/hypotension and lack of cardiovascular–renal remodeling are not due to mutations of p63RhoGEF α6–αN linker and Gαq interactions. This opens the way for investigations on different coding and no-coding regions (p63RhoGEF and Gαq promoters) and on altered transcriptional/post-transcriptional regulation. Clarification of how these biochemical/molecular mechanisms work/interact would provide insights into mechanisms involved in the GS's Ang II signaling fine tuning, in human physiology/pathophysiology in general and could also identify significant targets for intervention in the treatments of hypertension.

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Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations

Publication date: Available online 24 August 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): William B. Grant, Barbara J. Boucher, Harjit P. Bhattoa, Henry Lahore
Many health benefits are attributed to vitamin D, with those findings supported mostly by observational outcome studies of relationships to serum 25-hydroxyvitamin D [25(OH)D]. However, many randomized controlled trials (RCTs) aiming to confirm those findings have failed, perhaps because serum 25(OH)D is an index of UVB exposure and non-vitamin D mechanisms or because disease reduces serum 25(OH)D content. But the most likely reason for that failure is inappropriate design, conduct, analysis, and interpretation of RCTs. Most RCTs used principles designed to test pharmaceutical drugs; that design incorporates the assumptions that the RCT is the sole source of the agent and that dose-response relationships are linear. However, neither assumption is true for vitamin D, since neither vitamin D dose-responses or health outcome-serum 25(OH)D concentration relationships are linear—larger changes being induced with low rather than high baseline 25(OH)D values. Here, we propose a hybrid observational approach to vitamin D RCT design, based primarily on serum 25(OH)D concentration, requiring an understanding of serum 25(OH)D concentration-health outcome relationships, measuring baseline 25(OH)D values, recruiting non-replete subjects, measuring serum 25(OH)D during the trial for adjustment of supplemental doses for achievement of pretrial selection of target 25(OH)D values, where possible, and analyzing health outcomes in relation to those data rather than solely to vitamin D dosages.



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Renate Brosch. What We ‘See’ when We Read: Visualization and Vividness in Reading Fictional Narratives

Publication date: Available online 24 August 2017
Source:Cortex
Author(s): Renate Brosch
Visualization is defined as the production of mental images in the process of reading (Esrock 2005: 633). This article is concerned with varieties of visualization during an absorbing reading of a fictional narrative, the mental images that range from an indistinct and largely automatic default visualization to the much more vivid images that occur at significant stages in the narrative.Neuroscientific studies of vision have collected a large and impressively varied body of experimental evidence for two major processing streams - the dorsal and the ventral -specialized for vision-for-action and visionfor-perception respectively. Further experiments distinguish different dispositional specializations: visualizers with a high spatial visualizing ability demonstrating a more efficient use of resources in the dorsal pathway, and those with a high object visualization and more efficient use of the ventral pathway (Kozhevnikov et al. 2010: 29). We can assume that both types of mental processing will be prompted in fictional narratives with differences in prominence depending on their authors' inclinations and the design and purpose of the narrative text. According to Amedeo D'Angiulli and colleagues (2013: 7), who conducted elaborate tests of vividness in mental imagery using written descriptive passages as stimulus, dynamic imagery was significantly less vivid than static imagery. These results confirm traditional literary criticism based on introspection which argues that detailed description of static objects elicits an especially lively imagination. However, narratives can provoke even stronger visualizations by rendering subjective moments of seeing in which a fictional character is emotionally involved. In encouraging readers to shift now and then from the default mode of motion-oriented visualizing to a more affective and more conscious object visualization, literary fictions exercise their power to evoke imaginings that one would not generate by oneself. This may indicate that literary narratives can prove a training ground for expanding one's visualizing capacities.



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Understanding active sampling strategies: empirical approaches and implications for attention and decision research

Publication date: Available online 24 August 2017
Source:Cortex
Author(s): Jacqueline Gottlieb
In natural behavior we actively gather information using attention and active sensing behaviors (such as shifts of gaze) to sample relevant cues. However, while attention and decision making are naturally coordinated, in the laboratory they have been dissociated. Attention is studied independently of the actions it serves. Conversely, decision theories make the simplifying assumption that the relevant information is given to the decision maker, and do not attempt to describe how she may learn and implement active sampling policies. In this paper I review recent studies that address questions of attentional learning, cue validity and information seeking in humans and non-human primates. These studies suggest that learning a sampling policy involves large scale interactions between networks of attention and valuation, and that these policies are motivated by reward maximization, uncertainty reduction and the intrinsic utility of cognitive states. I discuss the importance of using such paradigms for formalizing the role of attention and devising more realistic theories of decision making that capture a broader range of empirical observations.



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Editorial Board

Publication date: September 2017
Source:Journal of Autoimmunity, Volume 83





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Redirecting T cells with Chimeric Antigen Receptor (CAR) for the treatment of childhood acute lymphoblastic leukemia

Publication date: Available online 24 August 2017
Source:Journal of Autoimmunity
Author(s): Andrea Biondi, Chiara F. Magnani, Sarah Tettamanti, Giuseppe Gaipa, Ettore Biagi
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Nowadays the survival rate is around 85%. Nevertheless, an urgent clinical need is still represented by primary refractory and relapsed patients who do not significantly benefit from standard approaches, including chemo-radiotherapy and hematopoietic stem cell transplantation (HSCT). For this reason, immunotherapy has so far represented a challenging novel treatment opportunity, including, as the most validated therapeutic options, cancer vaccines, donor-lymphocyte infusions and tumor-specific immune effector cells. More recently, unexpected positive clinical results in ALL have been achieved by application of gene-engineered chimeric antigen expressing (CAR) T cells. Several CAR designs across different trials have generated similar response rates, with Complete Response (CR) of 60–90% at 1 month and an Event-Free Survival (EFS) of 70% at 6 months. Relevant challenges anyway remain to be addressed, such as amelioration of technical, cost and feasibility aspects of cell and gene manipulation and the necessity to face the occurrence of relapse mechanisms. This review describes the state of the art of ALL immunotherapies, the novelties in terms of gene manipulation approaches and the problems emerged from early clinical studies. We describe and discuss the process of clinical translation, including the design of a cell manufacturing protocol, vector production and regulatory issues. Multiple antigen targeting and combination of CAR T cells with molecular targeted drugs have also been evaluated as latest strategies to prevail over immune-evasion.



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Uncomplicated

Publication date: Available online 23 August 2017
Source:The Journal of Emergency Medicine
Author(s): Meghan G. Liroff




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Safety Threats During the Care of Infants with Hypoglycemic Seizures in the Emergency Department: A Multicenter, Simulation-Based Prospective Cohort Study

Publication date: Available online 24 August 2017
Source:The Journal of Emergency Medicine
Author(s): Barbara M. Walsh, Sandeep Gangadharan, Travis Whitfill, Marcie Gawel, David Kessler, Robert A. Dudas, Jessica Katznelson, Megan Lavoie, Khoon-Yen Tay, Melinda Hamilton, Linda L. Brown, Vinay Nadkarni, Marc Auerbach
BackgroundErrors in the timely diagnosis and treatment of infants with hypoglycemic seizures can lead to significant patient harm. It is challenging to precisely measure medical errors that occur during high-stakes/low-frequency events. Simulation can be used to assess risk and identify errors.ObjectiveWe hypothesized that general emergency departments (GEDs) would have higher rates of deviations from best practices (errors) compared to pediatric emergency departments (PEDs) when managing an infant with hypoglycemic seizures.MethodsThis multicenter simulation-based prospective cohort study was conducted in GEDs and PEDs. In situ simulation was used to measure deviations from best practices during management of an infant with hypoglycemic seizures by inter-professional teams. Seven variables were measured: five nonpharmacologic (i.e., delays in airway assessment, checking dextrose, starting infusion, verbalizing disposition) and two pharmacologic (incorrect dextrose dose and incorrect dextrose concentration). The primary aim was to describe and compare the frequency and types of errors between GEDs and PEDs.ResultsFifty-eight teams from 30 hospitals (22 GEDs, 8 PEDs) were enrolled. Pharmacologic errors occurred more often in GEDs compared to PEDs (p = 0.043), while nonpharmacologic errors were uncommon in both groups. Errors more frequent in GEDs related to incorrect dextrose concentration (60% vs. 88%; p = 0.025), incorrect dose (20% vs. 56%; p = 0.033), and failure to start maintenance dextrose (33% vs. 65%; p = 0.040).ConclusionsDuring the simulated care of an infant with hypoglycemic seizures, errors were more frequent in GEDs compared to PEDs. Decreasing annual pediatric patient volume was the best predictor of errors on regression analysis.



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Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson's disease

Publication date: Available online 24 August 2017
Source:Brain Stimulation
Author(s): Ariana Q. Farrand, Kristi L. Helke, Rebecca A. Gregory, Monika Gooz, Vanessa K. Hinson, Heather A. Boger
BackgroundParkinson's disease (PD) is a progressive, neurodegenerative disorder with no disease-modifying therapies, and symptomatic treatments are often limited by debilitating side effects. In PD, locus coeruleus (LC) noradrenergic neurons degenerate prior to substantia nigra (SN) dopaminergic neurons. Vagus nerve stimulation (VNS) beneficially alters LC neurons, and decreases pro-inflammatory markers, allowing functional improvement of LC and its targets, making it a potential PD therapeutic.ObjectiveTo assess therapeutic potential of VNS in a PD model.MethodsTo mimic the progression of degeneration associated with PD, rats received a systemic injection of the noradrenergic neurotoxin DSP-4, followed one week later by bilateral intrastriatal injection of the dopaminergic neurotoxin 6-hydroxydopamine. At this time, a subset of rats also had vagus cuffs implanted. After eleven days, rats received a precise VNS regimen twice a day for ten days, and locomotion was measured during the afternoon session daily. Immediately following final stimulation, rats were euthanized, and left dorsal striatum, bilateral SN and LC were sectioned for immunohistochemical detection of monoaminergic neurons (tyrosine hydroxylase, TH), α-synuclein, astrocytes (GFAP) and microglia (Iba-1).ResultsVNS significantly increased locomotion of lesioned rats. It also resulted in increased expression of TH in striatum, SN, and LC; decreased expression of α-synuclein in SN; and decreased expression of glial markers in the SN and LC of lesioned rats. Additionally, after VNS, TH was higher in the LC and Iba-1 lower in the SN of saline-treated rats.ConclusionsThese data suggest that VNS has potential as a novel PD therapeutic.



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