Role preferences of patients with alcohol use disorders

Publication date: September 2018
Source:Addictive Behaviors, Volume 84
Author(s): Anke Friedrichs, Anna Silkens, Jens Reimer, Ludwig Kraus, Norbert Scherbaum, Daniela Piontek, Jeanette Röhrig, Jochen Hempleman, Martin Härter, Angela Buchholz
AimsShared decision making (SDM) is increasingly demanded in medical decision making. SDM acknowledges patients' role preferences in decision making processes. There has been limited research on SDM and role preferences in substance use disorders; results are promising. Aim of this study was to investigate role preferences of patients with alcohol use disorders (AUD), and to identify predictors of these preferences.MethodCross-sectional data collected from June 2013 to May 2014 in four detoxification wards in Germany during a randomised controlled trial (RCT, Registration Code 01GY1114) was analysed.Of the 250 patients with AUD who were included in the RCT, data from 242 patients [65% male; mean age = 45.2 years (sd = 10.3)] were analysed. Participants' role preferences were assessed with the Control Preference Scale. Potential correlates were drawn from instruments used in the RCT; multinomial logistic regression was used.Results90% (n = 217) of the AUD patients preferred an active or shared role in decision-making, 10% (n = 25) preferred a passive role. Patients' desire for help was associated with their role preference (OR = 3.087, p = .05). The model's goodness of fit was Nagelkerke's R² = 0.153 [χ² (24) = 25.206, p = .395].ConclusionsPatients' preference for an active role in decision-making underscores the importance of involving patients in their treatment planning. Patients' desire for help seems to be an important determinant of paternalistic decision making. However, further research is needed to determine whether patients' role preferences are related to their behavior during their treatment referral and recovery.



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Posttraumatic stress disorder and tobacco use: A systematic review and meta-analysis

Publication date: September 2018
Source:Addictive Behaviors, Volume 84
Author(s): Irene Pericot-Valverde, Rebecca J. Elliott, Mollie E. Miller, Jennifer W. Tidey, Diann E. Gaalema
Posttraumatic stress disorder (PTSD) and tobacco use are prevalent conditions that co-occur at striking rates in the US. Previous reviews examined prevalence and factors associated with cigarette smoking among individuals with PTSD but have not been summarized since 2007. Moreover, none explored rates and factors associated with the use of other tobacco products. This study aimed to systematically review the most recent literature examining the comorbidity of PTSD and tobacco use to provide prevalence rates, as well as summarize the literature exploring other factors associated with tobacco use among individuals with PTSD. Studies were identified using a systematic search of keywords related to tobacco use and PTSD within the following databases: PubMed, PsycINFO, Web of Knowledge, CINAHL, PsycARTICLES, and Cochrane Clinical Trials Library. The studies included in this review (N = 66) showed that the prevalence of current use of tobacco products in individuals with PTSD was 24.0% and the rate of PTSD among users of tobacco products was 20.2%. Additionally, results demonstrated that individuals with PTSD present with high levels of nicotine dependence and heavy use of tobacco products, as well as underscore the importance of negative emotional states as a contributing factor to tobacco use among individuals with PTSD. It is imperative that future studies continue monitoring tobacco use among individuals with PTSD while also assessing factors identified as having a prominent role in tobacco use among individuals with PTSD. These findings also demonstrate the need for more innovative approaches to reduce the pervasive tobacco use among individuals with PTSD.



https://ift.tt/2G440IJ

Predicting risky health behaviors 35 years later: Are parents or teacher's reports of childhood behavior problems a better judge of outcomes?

Publication date: September 2018
Source:Addictive Behaviors, Volume 84
Author(s): Jaimee Stuart
ObjectivesThis study sought to understand (1) whether parents and teachers reports of childhood behavioral problems could predict smoking and alcohol consumption 35 years later, and (2) whether propensity for smoking and alcohol consumption differed on the basis of informant agreement in their classification of behavioral syndromes.MethodsParticipants included those from the Aberdeen Children of the 1950s study (ACONF) with full childhood information as well as self-reports in adulthood (n = 1342). Latent Class Analysis was conducted to identify patterns of childhood problem behaviors as rated by teachers and parents. Regression models were then conducted predicting adulthood smoking and alcohol consumption. Informant agreement categories were constructed and differences across categories in both smoking and alcohol consumption were tested.ResultsThree subtypes of childhood behavior problems were identified by both teachers and parents: "Normative," "Externalizing," and "Internalizing,". Parents also identified a distinct fourth group "Mixed". Teacher's classification of the child as externalizing significantly predicted greater likelihood of being a current smoker, and parents' classification as internalizing predicted lower likelihood of being an ex-smoker. Parents' ratings as externalizing and mixed also predicted lower levels of alcohol consumption, which was opposite to the predicted effect. Additionally, informant agreement of externalizing indicated a greater propensity of smoking in adulthood, but did not indicate differences in alcohol consumption.ConclusionsThis study suggests that it is important to consider additive information from multiple informants when examining the life-course effects of childhood behavioral problems on risky health behaviors in adulthood.



https://ift.tt/2jMYiSV

Catalytic co-aromatization of methane and heptane as an alkane model compound over Zn-Ga/ZSM-5: A mechanistic study

Publication date: 15 November 2018
Source:Applied Catalysis B: Environmental, Volume 236
Author(s): Qingyin Li, Peng He, Jack Jarvis, Amit Bhattacharya, Xiaohui Mao, Aiguo Wang, Guy M. Bernard, Vladimir K. Michaelis, Hongbo Zeng, Lijia Liu, Hua Song
The joint conversion of methane and heptane, a model compound of paraffin-rich raffinate oil, over a Zn-Ga modified zeolite catalyst has been investigated at various reaction times. In comparison with the performance from a N2 environment, the introduction of methane highly promotes the formation of light aromatic compounds with a single phenyl ring, and increased carbon number and substitution index of chemical constituents formed are indicative of methane incorporation into the liquid product. In addition, with prolonged time, the interaction between catalyst and methane molecules is enhanced. Through cleavage of methane molecules, the formed moieties likely participate in the aromatization reaction, which results in the growth of larger aromatic components through further condensation. According to the NMR spectra, witnessing methane engagement into the phenyl carbon and alkyl carbon sites of the formed liquid aromatics along with increasing reaction time is evidenced ¹³C-methane incorporation into aromatics. The excellent catalytic performance of Zn-Ga/ZSM-5 might be ascribed to the greatly dispersed metal species on the catalyst surface as well as a certain amount of medium and weak acid sites. With regards to the spent catalyst, the presence of methane could inhibit the aggregation of loaded active metals and coke formation during the co-aromatization process. The elucidation on the co-conversion of methane and high alkane provides great potential for the utilization of natural gas resources and intermediates formed from petrochemical industries.

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The Samarco mine tailing disaster: A possible time-bomb for heavy metals contamination?

Publication date: 1 October 2018
Source:Science of The Total Environment, Volumes 637–638
Author(s): Hermano M. Queiroz, Gabriel N. Nóbrega, Tiago O. Ferreira, Leandro S. Almeida, Thais B. Romero, Sandra T. Santaella, Angelo F. Bernardino, Xosé L. Otero
In November 2015, the largest socio-environmental disaster in the history of Brazil occurred when approximately 50 million m³ of mine tailings were released into the Doce River (SE Brazil), during the greatest failure of a tailings dam worldwide. The mine tailings passed through the Doce River basin, reaching the ecologically important estuary 17 days later. On the arrival of the mine wastes to the coastal area, contamination levels in the estuarine soils were measured to determine the baseline level of contamination and to enable an environmental risk assessment. Soil and tailings samples were collected and analyzed to determine the redox potential (Eh), pH, grain size and mineralogical composition, total metal contents (Fe, Mn, Cr, Zn, Ni, Cu, Pb and Co) and organic matter content. The metals were fractionated to elucidate the mechanisms governing the trace metal dynamics. The mine tailings are mostly composed of Fe (mean values for Fe: 45,200 ± 2850; Mn: 433 ± 110; Cr: 63.9 ± 15.1; Zn: 62.4 ± 28.4; Ni: 24.7 ± 10.4; Cu: 21.3 ± 4.6; Pb: 20.2 ± 4.6 and Co: 10.7 ± 4.8 mg kg⁻¹), consisting of Fe-oxyhydroxides (goethite, hematite); kaolinite and quartz. The metal contents of the estuarine soils, especially the surface layers, indicate trace metal enrichment caused by the tailings. However, the metal contents were below threshold levels reported in Brazilian environmental legislation. Despite the fact that only a small fraction (<2%) of the metals identified are readily bioavailable (i.e. soluble and exchangeable fraction), trace metals associated with Fe oxyhydroxides contributed between 69.8 and 87.6% of the total contents. Control of the trace metal dynamics by Fe oxyhydroxides can be ephemeral, especially in wetland soils in which the redox conditions oscillate widely. Indeed, the physicochemical conditions (Eh < 100 mV and circumneutral pH) of estuarine soils favor Fe reduction microbial pathways, which will probably increase the trace metal bioavailability and contamination risk.

Graphical abstract

https://ift.tt/2rAfEXD

Hazard potential of widespread but hidden historic offshore heavy metal (Pb, Zn) contamination (Gulf of Cadiz, Spain)

Publication date: 1 October 2018
Source:Science of The Total Environment, Volumes 637–638
Author(s): Till J.J. Hanebuth, Mary Lee King, Isabel Mendes, Susana Lebreiro, Francisco J. Lobo, Ferdinand K. Oberle, Laura Antón, Paulo Alves Ferreira, Maria Isabel Reguera
Natural and human-induced seabed sediment disturbances affect wide areas of the global coastal ocean. These recurrent to chronic disturbances mobilize significant amounts of material, including substances that have the potential to significantly harm the environment once re-released. This very challenging issue is difficult to deal with if sub-surface contaminant concentrations are unknown. Based on the analysis of 11 new, up to 5-m long sediment cores taken offshore in the Gulf of Cadiz, the contamination history (using the trace elements lead and zinc) is well documented over major parts of the gulf. Ore mining and metal processing industries on the southwestern Iberian Peninsula started five thousand years ago and experienced a first peak during the Roman Period, which can be detected over the entire gulf. The Industrial Era added a massive, shelf-wide heavy metal excursion of unprecedented dimension. This metal contamination to the coastal ocean decreased in the 1990s and appears to be today limited to larger areas off the Tinto/Odiel and Guadiana River mouths. The unforeseen, significant finding of this study is that the gulf-wide, peak heavy metal concentration, stemming from the Industrial Era, is widely overlain by a modern sediment veneer just thick enough to cover the contaminant horizon, but thin enough to have this layer within the reach of natural or human-induced sediment mobilization events.

Graphical abstract

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Mechanochemical synthesis of novel heterostructured Bi2S3/Zn-Al layered double hydroxide nano-particles as efficient visible light reactive Z-scheme photocatalysts

Publication date: 15 September 2018
Source:Applied Surface Science, Volume 452
Author(s): Zhao Li, Qiwu Zhang, Xinzhong Liu, Min Chen, Lei Wu, Ziqiang Ai
Herein, we demonstrated, for the first time, the synthesis of novel Z-scheme heterostructures of Bi2S3/Zn–Al LDH nanoparticles via a mechanochemical route, and the high efficiency as visible-light-driven photocatalysts for the degradation of organic pollutant of methylene blue dye (MB). The samples were characterized comprehensively by a set of analytical methods: XRD, XPS, FTIR, UV/VIS/NIR spectroscopy, SEM-EDS, BET measurement, EIS analysis, PL measurement, ESR, Hall Effect measurement and quantitative evaluation of photocatalytic degradation of MB under visible light irradiation. Compared with the pure Bi2S3, greatly enhanced photocatalytic activity from the Bi2S3/LDH nanoparticles was observed and a possible mechanism ascribed to the formation of Z-scheme was discussed based on the well matching results from the characterizations by different methods. No obvious decrease in the activity was observed with the reused examination. The easy preparation of the efficient LDH-based Z-scheme photocatalytic systems through mechanochemical method may contribute much in environmental remediation.

Graphical abstract

https://ift.tt/2rAoHrn

Chemical characterization of PM 2.5 from a southern coastal city of China: applications of modeling and chemical tracers in demonstration of regional transport

Abstract

An intensive sampling campaign of airborne fine particles (PM_2.5) was conducted at Sanya, a coastal city in Southern China, from January to February 2012. Chemical analyses and mass reconstruction were used identify potential pollution sources and investigate atmospheric reaction mechanisms. A thermodynamic model indicated that low ammonia and high relative humidity caused the aerosols be acidic and that drove heterogeneous reactions which led to the formation of secondary inorganic aerosol. Relationships among neutralization ratios, free acidity, and air-mass trajectories suggest that the atmosphere at Sanya was impacted by both local and regional emissions. Three major transport pathways were identified, and flow from the northeast (from South China) typically brought the most polluted air to Sanya. A case study confirmed strong impact from South China (e.g., Pearl River Delta region) (contributed 76.8% to EC, and then this result can be extended to primary pollutants) when the northeast winds were dominant. The Weather Research Forecasting Black carbon model and trace organic markers were used to apportion local pollution versus regional contributions. Results of the study offer new insights into the atmospheric conditions and air pollution at this coastal city.

https://ift.tt/2I5p6fH

Mitochondrial Translation Efficiency Controls Cytoplasmic Protein Homeostasis

Publication date: Available online 10 May 2018
Source:Cell Metabolism
Author(s): Tamara Suhm, Jayasankar Mohanakrishnan Kaimal, Hannah Dawitz, Carlotta Peselj, Anna E. Masser, Sarah Hanzén, Matevž Ambrožič, Agata Smialowska, Markus L. Björck, Peter Brzezinski, Thomas Nyström, Sabrina Büttner, Claes Andréasson, Martin Ott
Cellular proteostasis is maintained via the coordinated synthesis, maintenance, and breakdown of proteins in the cytosol and organelles. While biogenesis of the mitochondrial membrane complexes that execute oxidative phosphorylation depends on cytoplasmic translation, it is unknown how translation within mitochondria impacts cytoplasmic proteostasis and nuclear gene expression. Here we have analyzed the effects of mutations in the highly conserved accuracy center of the yeast mitoribosome. Decreased accuracy of mitochondrial translation shortened chronological lifespan, impaired management of cytosolic protein aggregates, and elicited a general transcriptional stress response. In striking contrast, increased accuracy extended lifespan, improved cytosolic aggregate clearance, and suppressed a normally stress-induced, Msn2/4-dependent interorganellar proteostasis transcription program (IPTP) that regulates genes important for mitochondrial proteostasis. Collectively, the data demonstrate that cytosolic protein homeostasis and nuclear stress signaling are controlled by mitochondrial translation efficiency in an inter-connected organelle quality control network that determines cellular lifespan.

Graphical abstract

Teaser

Suhm et al. show that mitochondrial protein translation impacts cytoplasmic proteostasis and nuclear gene expression. By analyzing mutations in the highly conserved mitochondrial ribosome, they show that mitochondrial translation accuracy is linked to cytoplasmic proteostasis, ROS, and a novel interorganellar proteostasis transcription program (IPTP), impacting chronological lifespan.


https://ift.tt/2ruZVJl

The Polycomb-Dependent Epigenome Controls β Cell Dysfunction, Dedifferentiation, and Diabetes

Publication date: Available online 10 May 2018
Source:Cell Metabolism
Author(s): Tess Tsai-Hsiu Lu, Steffen Heyne, Erez Dror, Eduard Casas, Laura Leonhardt, Thorina Boenke, Chih-Hsiang Yang, Sagar, Laura Arrigoni, Kevin Dalgaard, Raffaele Teperino, Lennart Enders, Madhan Selvaraj, Marius Ruf, Sunil J. Raja, Huafeng Xie, Ulrike Boenisch, Stuart H. Orkin, Francis C. Lynn, Brad G. Hoffman, Dominic Grün, Tanya Vavouri, Adelheid M. Lempradl, J. Andrew Pospisilik
To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combine deep epigenome mapping with single-cell transcriptomics to mine for evidence of chromatin dysregulation in type 2 diabetes. We find two chromatin-state signatures that track β cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-silenced domains and loss of expression at an epigenomically unique class of lineage-defining genes. β cell-specific Polycomb (Eed/PRC2) loss of function in mice triggers diabetes-mimicking transcriptional signatures and highly penetrant, hyperglycemia-independent dedifferentiation, indicating that PRC2 dysregulation contributes to disease. The work provides novel resources for exploring β cell transcriptional regulation and identifies PRC2 as necessary for long-term maintenance of β cell identity. Importantly, the data suggest a two-hit (chromatin and hyperglycemia) model for loss of β cell identity in diabetes.

Graphical abstract

Teaser

Lu et al. provide evidence of chromatin dysregulation in type 2 diabetes in mice and humans. Loss of Polycomb silencing in mouse pancreas triggers hyperglycemia-independent dedifferentiation of β cells and diabetes, suggesting a two-hit (chromatin and hyperglycemia) model for loss of β cell identity in diabetes.


https://ift.tt/2wuwP1z

Arginase 2 Suppresses Renal Carcinoma Progression via Biosynthetic Cofactor Pyridoxal Phosphate Depletion and Increased Polyamine Toxicity

Publication date: Available online 10 May 2018
Source:Cell Metabolism
Author(s): Joshua D. Ochocki, Sanika Khare, Markus Hess, Daniel Ackerman, Bo Qiu, Jennie I. Daisak, Andrew J. Worth, Nan Lin, Pearl Lee, Hong Xie, Bo Li, Bradley Wubbenhorst, Tobi G. Maguire, Katherine L. Nathanson, James C. Alwine, Ian A. Blair, Itzhak Nissim, Brian Keith, M. Celeste Simon
Kidney cancer, one of the ten most prevalent malignancies in the world, has exhibited increased incidence over the last decade. The most common subtype is "clear cell" renal cell carcinoma (ccRCC), which features consistent metabolic abnormalities, such as highly elevated glycogen and lipid deposition. By integrating metabolomics, genomic, and transcriptomic data, we determined that enzymes in multiple metabolic pathways are universally depleted in human ccRCC tumors, which are otherwise genetically heterogeneous. Notably, the expression of key urea cycle enzymes, including arginase 2 (ARG2) and argininosuccinate synthase 1 (ASS1), is strongly repressed in ccRCC. Reduced ARG2 activity promotes ccRCC tumor growth through at least two distinct mechanisms: conserving the critical biosynthetic cofactor pyridoxal phosphate and avoiding toxic polyamine accumulation. Pharmacological approaches to restore urea cycle enzyme expression would greatly expand treatment strategies for ccRCC patients, where current therapies only benefit a subset of those afflicted with renal cancer.

Graphical abstract

Teaser

Ochocki et al. show that clear cell renal cell carcinoma (ccRCC) tumors have altered ammonia metabolism with multiple urea cycle enzymes being significantly underexpressed. Loss of the urea cycle enzyme arginase2 (ARG2) promotes ccRCC tumor progression by conserving essential biosynthetic cofactor pools and preventing toxic polyamine build up.


https://ift.tt/2ryBvyn

Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes

Publication date: Available online 10 May 2018
Source:Cell Metabolism
Author(s): Elizabeth F. Sutton, Robbie Beyl, Kate S. Early, William T. Cefalu, Eric Ravussin, Courtney M. Peterson
Intermittent fasting (IF) improves cardiometabolic health; however, it is unknown whether these effects are due solely to weight loss. We conducted the first supervised controlled feeding trial to test whether IF has benefits independent of weight loss by feeding participants enough food to maintain their weight. Our proof-of-concept study also constitutes the first trial of early time-restricted feeding (eTRF), a form of IF that involves eating early in the day to be in alignment with circadian rhythms in metabolism. Men with prediabetes were randomized to eTRF (6-hr feeding period, with dinner before 3 p.m.) or a control schedule (12-hr feeding period) for 5 weeks and later crossed over to the other schedule. eTRF improved insulin sensitivity, β cell responsiveness, blood pressure, oxidative stress, and appetite. We demonstrate for the first time in humans that eTRF improves some aspects of cardiometabolic health and that IF's effects are not solely due to weight loss.

Graphical abstract

Teaser

Sutton et al. conduct the first supervised controlled feeding trial to test whether intermittent fasting has benefits in humans in the absence of weight loss. Prediabetic men following a form of intermittent fasting called early time-restricted feeding improved their insulin sensitivity, blood pressure, and oxidative stress levels without losing weight.


https://ift.tt/2wucrxJ

Assessment of reactive nitrogen mitigation potential of different nitrogen treatments under direct-seeded rice and wheat cropping system

Abstract

The reactive nitrogen (Nr) pollution is a serious environmental problem. A wise application of nitrogen fertilizer is important for mitigating Nr loss. Field experiments were undertaken during the direct-seeded rice and winter-wheat growing seasons from 2014 to 2015 in Nanjing, one of the typical rice-wheat rotation regions in China, to evaluate the potential of different nitrogen fertilizers for mitigating Nr (N₂O, NH₃ emissions, and NO₃⁻ leaching) losses. Seven different fertilizer treatments were included in this study: a no fertilizer treatment (NF), conventional fertilizer (CF), urea-ammonium mixed nitrogen fertilizer (UA), stabilized urea (UHD; urea + hydroquinone + dicyandiamide), sulfur-coated urea (SCU), urea formaldehyde (UF) and organic fertilizer (OF). In comparison with the CF, all the fertilizer treatments except for UA decreased NH₃ volatilization by 14.5–36.0% (p < 0.05), while none of the N fertilizers had an obvious mitigation effect on N₂O emissions and NO₃⁻ leaching during the rice and wheat seasons. Further analyses showed that the UHD, UF and OF treatments reduced the yield-scaled Nr loss (NLI) by 32.6–42.5% for the rice season and by 15.5–34.5% for the wheat season as compared to the CF; other treatments relative to CF had no obvious effect with regard to lowering the NLI. UHD, UF and OF could be adopted as an effective mitigation alternative to reduce Nr loss and maintain crop yield in future rice/wheat production.

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https://ift.tt/2G5HWh4

Low-temperature co-purification of NO x and Hg 0 from simulated flue gas by Ce x Zr y Mn z O 2 /r-Al 2 O 3 : the performance and its mechanism

Abstract

In this study, series of Ce_x Zr_y Mn_z O₂/r-Al₂O₃ catalysts were prepared by impregnation method and explored to co-purification of NO_x and Hg⁰ at low temperature. The physical and chemical properties of the catalysts were investigated by XRD, BET, FTIR, NH₃-TPD, H₂-TPR, and XPS. The experimental results showed that 10% Ce_0.2Zr_0.3Mn_0.5O₂/r-Al₂O₃ yielded higher conversion on co-purification of NO_x and Hg⁰ than the other prepared catalysts at low temperature, especially at 200–300 °C. 91% and 97% convert rate of NO_x and Hg⁰ were obtained, respectively, when 10% Ce_0.2Zr_0.3Mn_0.5O₂/r-Al₂O₃ catalyst was used at 250 °C. Moreover, the presence of H₂O slightly decreased the removal of NO_x and Hg⁰ owing to the competitive adsorption of H₂O and Hg⁰. When SO₂ was added, the removal of Hg⁰ first increased slightly and then presented a decrease due to the generation of SO₃ and (NH₄)₂SO₄. The results of NH₃-TPD indicated that the strong acid of 10% Ce_0.2Zr_0.3Mn_0.5O₂/r-Al₂O₃ improved its high-temperature activity. XPS and H₂-TPR results showed there were high-valence Mn and Ce species in 10% Ce_0.2Zr_0.3Mn_0.5O₂/r-Al₂O₃, which could effectively promote the removal of NO_x and Hg⁰. Therefore, the mechanisms of Hg⁰ and NO_x removal were proposed as Hg (ad) + [O] → HgO (ad), and 2NH₃/NH₄⁺ (ad) + NO₂ (ad) + NO (g) → 2 N₂ + 3H₂O/2H⁺, respectively.

Graphical abstract

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https://ift.tt/2jLK050

A Combinatorial Lipid Code Shapes the Electrostatic Landscape of Plant Endomembranes

Publication date: Available online 10 May 2018
Source:Developmental Cell
Author(s): Matthieu Pierre Platre, Lise C. Noack, Mehdi Doumane, Vincent Bayle, Mathilde Laetitia Audrey Simon, Lilly Maneta-Peyret, Laetitia Fouillen, Thomas Stanislas, Laia Armengot, Přemysl Pejchar, Marie-Cécile Caillaud, Martin Potocký, Alenka Čopič, Patrick Moreau, Yvon Jaillais
Membrane surface charge is critical for the transient, yet specific recruitment of proteins with polybasic regions to certain organelles. In eukaryotes, the plasma membrane (PM) is the most electronegative compartment of the cell, which specifies its identity. As such, membrane electrostatics is a central parameter in signaling, intracellular trafficking, and polarity. Here, we explore which are the lipids that control membrane electrostatics using plants as a model. We show that phosphatidylinositol-4-phosphate (PI4P), phosphatidic acidic (PA), and phosphatidylserine (PS) are separately required to generate the electrostatic signature of the plant PM. In addition, we reveal the existence of an electrostatic territory that is organized as a gradient along the endocytic pathway and is controlled by PS/PI4P combination. Altogether, we propose that combinatorial lipid composition of the cytosolic leaflet of organelles not only defines the electrostatic territory but also distinguishes different functional compartments within this territory by specifying their varying surface charges.

Teaser

Platre et al. show that plant plasma membrane-derived compartments each have a distinct electrostatic signature, set up by a combinatorial code of anionic phospholipids. This "electrostatic code" may represent a fundamental patterning principle of the endomembrane system and be a key determinant in protein targeting.


https://ift.tt/2KTMZVd

Ingestion of Food Particles Regulates the Mechanosensing Misshapen-Yorkie Pathway in Drosophila Intestinal Growth

Publication date: Available online 10 May 2018
Source:Developmental Cell
Author(s): Qi Li, Niraj K. Nirala, Yingchao Nie, Hsi-Ju Chen, Gary Ostroff, Junhao Mao, Qi Wang, Lan Xu, Y. Tony Ip
The intestinal epithelium has a high cell turnover rate and is an excellent system to study stem cell-mediated adaptive growth. In the Drosophila midgut, the Ste20 kinase Misshapen, which is distally related to Hippo, has a niche function to restrict intestinal stem cell activity. We show here that, under low growth conditions, Misshapen is localized near the cytoplasmic membrane, is phosphorylated at the threonine 194 by the upstream kinase Tao, and is more active toward Warts, which in turn inhibits Yorkie. Ingestion of yeast particles causes a midgut distention and a reduction of Misshapen membrane association and activity. Moreover, Misshapen phosphorylation is regulated by the stiffness of cell culture substrate, changing of actin cytoskeleton, and ingestion of inert particles. These results together suggest that dynamic membrane association and Tao phosphorylation of Misshapen are steps that link the mechanosensing of intestinal stretching after food particle ingestion to control adaptive growth.

Teaser

Yeast is a natural food source for fruit flies, and accumulation of yeast particles in their midgut causes expansion of the gut tube. Li et al. show that such expansion triggers a mechanosensing mechanism leading to the relief of inhibition of Yorkie-mediated tissue growth by the upstream kinase Misshapen.


https://ift.tt/2rAmN9D

PCYT1A Regulates Phosphatidylcholine Homeostasis from the Inner Nuclear Membrane in Response to Membrane Stored Curvature Elastic Stress

Publication date: Available online 10 May 2018
Source:Developmental Cell
Author(s): Afreen Haider, Yu-Chen Wei, Koini Lim, Antonio D. Barbosa, Che-Hsiung Liu, Ursula Weber, Marek Mlodzik, Kadri Oras, Simon Collier, M. Mahmood Hussain, Liang Dong, Satish Patel, Anna Alvarez-Guaita, Vladimir Saudek, Benjamin J. Jenkins, Albert Koulman, Marcus K. Dymond, Roger C. Hardie, Symeon Siniossoglou, David B. Savage
Cell and organelle membranes consist of a complex mixture of phospholipids (PLs) that determine their size, shape, and function. Phosphatidylcholine (PC) is the most abundant phospholipid in eukaryotic membranes, yet how cells sense and regulate its levels in vivo remains unclear. Here we show that PCYT1A, the rate-limiting enzyme of PC synthesis, is intranuclear and re-locates to the nuclear membrane in response to the need for membrane PL synthesis in yeast, fly, and mammalian cells. By aligning imaging with lipidomic analysis and data-driven modeling, we demonstrate that yeast PCYT1A membrane association correlates with membrane stored curvature elastic stress estimates. Furthermore, this process occurs inside the nucleus, although nuclear localization signal mutants can compensate for the loss of endogenous PCYT1A in yeast and in fly photoreceptors. These data suggest an ancient mechanism by which nucleoplasmic PCYT1A senses surface PL packing defects on the inner nuclear membrane to control PC homeostasis.

Graphical abstract

Teaser

Phosphatidylcholine (PC) is the major constituent of cellular membranes. Haider et al. show that PCYT1A, the rate-limiting enzyme of PC synthesis, translocates onto the inner nuclear membrane in response to increased PC need in yeast, fly, and mammalian cells. This PCYT1A re-localization is governed by membrane stored curvature elastic stress.


https://ift.tt/2KSez5p

Intracellular Calcium Mobilization Is Required for Sonic Hedgehog Signaling

Publication date: Available online 10 May 2018
Source:Developmental Cell
Author(s): Dana Klatt Shaw, Derrick Gunther, Michael J. Jurynec, Alexis A. Chagovetz, Erin Ritchie, David Jonah Grunwald
Graded Shh signaling across fields of precursor cells coordinates patterns of gene expression, differentiation, and morphogenetic behavior as precursors form complex structures, such as the nervous system, the limbs, and craniofacial skeleton. Here we discover that intracellular calcium mobilization, a process tightly controlled and readily modulated, regulates the level of Shh-dependent gene expression in responding cells and affects the development of all Shh-dependent cell types in the zebrafish embryo. Reduced expression or modified activity of ryanodine receptor (RyR) intracellular calcium release channels shifted the allocation of Shh-dependent cell fates in the somitic muscle and neural tube. Mosaic analysis revealed that RyR-mediated calcium mobilization is required specifically in Shh ligand-receiving cells. This work reveals that RyR channels participate in intercellular signal transduction events. As modulation of RyR activity modifies tissue patterning, we hypothesize that alterations in intracellular calcium mobilization contribute to both birth defects and evolutionary modifications of morphology.

Teaser

Traditionally, the ryanodine receptor has been associated with mediating the release of calcium from intracellular stores to trigger muscle contraction. Klatt Shaw et al. demonstrate levels of ryanodine receptor activity tune a cell's response to Hedgehog signaling, affecting Hedgehog-dependent gene expression and tissue patterning.


https://ift.tt/2rB2Qzp

Analyzing the uncertainty of diffusive gel-based passive samplers as tools for evaluating the averaged contamination of surface water by organic pollutants

Abstract

Agarose gel-based passive samplers are nowadays one of the most effective sampling devices able to provide a quantitative evaluation of water contamination level for a broad range of organic contaminants. These devices show significant improvements in comparison to the previous passive samplers dedicated to hydrophilic compounds because they tend to reduce the effect of hydrodynamic flow conditions on the uptake rate of compounds and thus subsequently to improve their accuracy. However, albeit their effects minimized, hydrodynamic water flow and temperature are reported as variables likely to change the uptake rate of compounds that may lead to some inaccuracy if they are not adequately taken into account. This work aims to investigate the magnitude of effects of such uncorrected variables on the bias of the deduced water contamination level. The analysis of the error structure shows that the uncertainty on the diffusivity of contaminants in agarose gel and its dependency on temperature are the most inferring factors. At 8 °C, these factors are, respectively, responsible of 34 and 33% of the squared uncertainty on the final deduced contamination level. The overall uncertainty for a single exposed passive sampler is in the order of 39% and drops to 23% if threesamplers are co-exposed (at 8 °C). Despite this uncertainty, we present results for a set of pesticides and personal care products throughout a field monitoring conducted over a 4-month period, which show the potential of passive samplers to allow assessing the temporal trend of water contamination.

https://ift.tt/2KVtawK

Accelerated carbonation of wood combustion ash for CO 2 removal from gaseous streams and storage in solid form

Abstract

In this work, ash generated by the combustion of wood in a central heating plant was used to remove and permanently store by accelerated carbonation CO₂ contained in a gas mixture simulating biogas. The process was studied as an alternative treatment to the ones currently available on the market for biogas upgrading. The process was investigated at laboratory scale by setting up a facility for directly contacting the wood ash and the synthetic biogas in a fixed bed reactor. The process was able to completely remove CO₂ during its initial phase. After about 30 h, CO₂ started to appear again in the outlet stream and its concentration rapidly increased. The specific CO₂ uptake achieved in solid carbonate form was of about 200 g/kg of dry wood ash. This value is an order of magnitude higher than the ones found for waste incineration bottom ash carrying out similar experiments. The difference was ascribed to the physicochemical properties of the ash, characterized by a fine particle size (d₅₀ < 0.2 mm) and high content of reactive phases with CO₂ (e.g., Ca hydroxides). The leaching behavior of the wood ash was examined before and after the accelerated carbonation process showing that the release of several elements was lower after the treatment; Ba leaching in particular decreased by over two orders of magnitude. However, the release of the critical elements for the management of this type of residues (especially Cr and sulfates) appeared not to be significantly affected, while V leaching increased.

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Dynamic filtration and static adsorption of lead ions in aqueous solution by use of blended polysulfone membranes with nano size MCM-41 particles coated by polyaniline

Abstract

MCM-41 mesopore was prepared by hydrothermal method and used for synthesis of polyaniline/MCM-41 nanocomposite via in situ polymerization. The nanocomposite was blended with polysulfone to prepare mixed matrix membrane in different content of nanocomposite by phase inversion method. Structural and surface properties of the samples were characterized by SEM, XRD, FTIR, AFM, TGA, BET, and zeta potential measurements. Effect of the nanocomposite content on the hydrophilicity, porosity, and permeability of the membrane was determined. Membrane performance was evaluated for removal of lead ions in dynamic filtration and static adsorption. The membranes were found as effective adsorptive filters for removal of lead ions via interactions between active sites of nanocomposite in membrane structure and lead ions during filtration. Results of batch experiments proved adsorptive mechanism of membranes for removal of lead ions with the maximum adsorption capacity of 19.6 mg/g.

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Clonal neutrophil infiltrates in concurrent Sweet's syndrome and acute myeloid leukemia: a case report and literature review

Publication date: Available online 10 May 2018
Source:Cancer Genetics
Author(s): Wenbin Mo, Xiaoxue Wang, Yue Wang, Yan Li, Rui Zhang
Sweet's syndrome (SS), also known as acute febrile neutrophilic dermatosis is often associated with a hematological malignancy, especially acute myeloid leukemia (AML) and myeloid dysplasia syndrome. Histopathologically, SS is characterized by diffuse infiltrates in the upper dermis, predominantly consisting of mature neutrophils. The origin of neutrophils invading the skin remains unknown. Herein, we report a patient with concurrent acute monoblastic leukemia and SS who initially presented with discrete erythematous papules and nodules on the neck. Single nucleotide polymorphism (SNP) array and next generation sequencing (NGS) revealed a concordant fms-related tyrosine kinase-3 (FLT-3) gene mutation in the bone marrow and skin lesion, indicating that the neutrophilic infiltrates were clonally related to the underlying myeloid neoplasm. This is the first case report of concurrent SS and AML, in which SNP array and NGS analysis were applied to confirm the clonality of the neutrophilic infiltrates.



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Non-Invasive Early Detection of Malignant Pulmonary Nodules by FISH-Based Sputum Test

Publication date: Available online 10 May 2018
Source:Cancer Genetics
Author(s): Dekel Shlomi, Nir Peled, Yehuda A. Schwarz, Guy W. Soo Hoo, Raj K. Batra, Gershon Fink, Tal Kaplan, Scott Mollan, William R. Burfeind Jr.
BackgroundEarly detection decreases lung cancer mortality. The Target-FISH Lung Cancer Detection (LCD) Test is a non-invasive test designed to detect chromosomal changes (deletion or amplification) via Fluorescence in situ Hybridization (FISH) in sputum specimens from persons suspected of having lung cancer. We evaluated the performance of the LCD test in patients with highly suspicious pulmonary nodules who were scheduled for a biopsy procedure.MethodsInduced sputum was collected from patients who were scheduled for biopsy of a solitary pulmonary nodule (0.8-3 cm) in one of 6 tertiary medical centers in the US and Israel. The lung cancer detection (LCD) Test combined sputum cytology and Target-FISH analysis on the same target cells and the results were compared to the pathology. Participants with non-surgical negative biopsy results were followed for 2 years to determine their final diagnosis.ResultsOf the 173 participants who were evaluated, 112 were available for analysis. Overall, the LCD test had a sensitivity of 85.5% (95% CI, 76.1-92.3), specificity of 69% (95% CI, 49.2-84.7) and an accuracy of 81.3% (95% CI, 72.8-88). The positive and negative predictive values (PPV, NPV) were 88.8% and 62.5% respectively. The LCD test was positive in 9 of 11 lung cancer patients who had an initial negative biopsy.ConclusionsIn a cohort of patients with highly suspicious lung nodules, the LCD test is a non-invasive option with good sensitivity and a high positive predictive value. A positive LCD test reinforces the need to aggressively pursue a definitive diagnosis of suspicious nodules.



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Challenges in Next Generation Sequencing Analysis of Somatic Mutations in Transplant Patients

Publication date: Available online 10 May 2018
Source:Cancer Genetics
Author(s): Hui Chen, Rajyalakshmi Luthra, Keyur P Patel, Mark Routbort, Asif Rashid, Sinchita Roy-Chowdhuri, Alexander Lazar, Russell Broaddus, Jawad Manekia, Rajesh R Singh, Anna Yemelyanova
Analysis of somatic mutations in solid tumors and hematologic malignancies using targeted next generation sequencing (NGS)-based assays has become part of routine oncology practice as well as clinical trials. The use of paired tumor-normal DNA samples increases confidence of somatic calls. NGS assays that utilize unique patient identifiers (SNP IDs) allow further comparison of samples within a run or paired tumor/normal samples. The sources of germline DNA include peripheral blood (PB) and formalin-fixed paraffin-embedded tissue (FFPE). However, the source of normal can be problematic, especially in transplant setting. Herein, we report two cases of NGS-based molecular testing in a patient with mycosis fungoides treated with stem cell transplant [SCT] (Pt1) and a patient with lung adenocarcinoma who previously had acute leukemia cured by SCT. These cases highlight the importance of selecting an appropriate normal sample for excluding germline polymorphisms during somatic mutation testing. Initial analyses that included concurrent PB sample failed to filter known germline polymorphisms. Repeat analyses using pre-transplant PB/bone marrow allowed for the successful subtraction of germline variants. Somatic mutations in PTEN and ERBB4 (Pt1) and CDKN2A, KRAS, KDR, and TP53 (Pt2) were reported with confidence. Selection of an appropriate source of germline DNA for NGS-based somatic mutation testing for patients with SCT transplant can be challenging. Particular attention to the clinical history is crucial for accurate interpretation and reporting.



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Exposure–response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer

Abstract

Purpose

Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final pooled phase II OS and safety data to assess alectinib dose selection.

Methods

A semi-parametric Cox proportional hazards model analyzed relationships between individual median observed steady-state trough concentrations (C_trough,ss) for combined exposure of alectinib and its major metabolite (M4), baseline covariates (demographics and disease characteristics) and OS. Univariate logistic regression analysis analyzed relationships between C_trough,ss and incidence of adverse events (AEs: serious and Grade ≥ 3).

Results

Overall, 92% of patients (n = 207/225) had C_trough,ss data and were included in the analysis. No statistically significant relationship was found between C_trough,ss and OS following alectinib treatment. The only baseline covariates that statistically influenced OS were baseline tumor size and prior crizotinib treatment duration. Larger baseline tumor size and shorter prior crizotinib treatment were both associated with shorter OS. Logistic regression confirmed no significant relationship between C_trough,ss and AEs.

Conclusion

Alectinib 600 mg BID provides systemic exposures at plateau of response for OS while maintaining a well-tolerated safety profile. This analysis confirms alectinib 600 mg BID as the recommended global dose for patients with crizotinib-resistant ALK-positive NSCLC.

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Extracting cancer mortality statistics from death certificates: A hybrid machine learning and rule-based approach for common and rare cancers

Publication date: Available online 10 May 2018
Source:Artificial Intelligence in Medicine
Author(s): Bevan Koopman, Guido Zuccon, Anthony Nguyen, Anton Bergheim, Narelle Grayson
ObjectiveDeath certificates are an invaluable source of cancer mortality statistics. However, this value can only be realised if accurate, quantitative data can be extracted from certificates—an aim hampered by both the volume and variable quality of certificates written in natural language. This paper proposes an automatic classification system for identifying all cancer related causes of death from death certificates.MethodsDetailed features, including terms, n-grams and SNOMED CT concepts were extracted from a collection of 447,336 death certificates. The features were used as input to two different classification sub-systems: a machine learning sub-system using Support Vector Machines (SVMs) and a rule-based sub-system. A fusion sub-system then combines the results from SVMs and rules into a single final classification. A held-out test set was used to evaluate the effectiveness of the classifiers according to precision, recall and F-measure.ResultsThe system was highly effective at determining the type of cancers for both common cancers (F-measure of 0.85) and rare cancers (F-measure of 0.7). In general, rules performed superior to SVMs; however, the fusion method that combined the two was the most effective.ConclusionThe system proposed in this study provides automatic identification and characterisation of cancers from large collections of free-text death certificates. This allows organisations such as Cancer Registries to monitor and report on cancer mortality in a timely and accurate manner. In addition, the methods and findings are generally applicable beyond cancer classification and to other sources of medical text besides death certificates.



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Resección hepática radioguiada con 18F-DOPA en un paciente con carcinoma medular de tiroides metastásico

Publication date: Available online 10 May 2018
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): J. López-Gómez, S. Medina-Ornelas, M.A. Salazar-Álvarez, M. Álvarez-Bojórquez, N. Zaragoza-Cruz, J. Melchor-Ruan, A. Álvarez-Cano
IntroducciónEl carcinoma medular representa el 1-2% de todas las neoplasias tiroideas malignas. El 13-20% de los pacientes presenta metástasis a distancia, afectando al hígado en el 45% de los casos.Presentación de un casoUna mujer de 50 años de edad, diagnosticada de carcinoma medular de tiroides, fue sometida a tiroidectomía total y disección cervical modificada en 1999. Se trataron con resección quirúrgica 2 recidivas ganglionares en el cuello; durante el periodo de vigilancia, la paciente desarrolló niveles elevados de calcitonina, identificándose la localización de la recidiva en el hígado mediante PET/TC con ¹⁸F-DOPA. La actividad metabólica no se asoció a lesión visible en TC, RM y ecografía. La cirugía radioguiada con ¹⁸F-DOPA permitió la resección anatómica de los segmentos IVb y V.DiscusiónEn pacientes con carcinoma medular y elevación de calcitonina durante el periodo de vigilancia, la PET/TC con ¹⁸F-DOPA es una opción para evaluar la localización de la recidiva. La resección radioguiada fue posible en esta paciente, cuya recidiva hepática no resultó visible con ningún otro método de imagen.ConclusiónLa resección hepática radioguiada con ¹⁸F-DOPA en el carcinoma medular de tiroides metastásico es factible cuando la localización de la recidiva no puede identificarse anatómicamente mediante otros estudios de imagen.IntroductionMedullary carcinoma accounts for 1–2% of all thyroid malignancies. 13–20% of patients present with distant metastasis, with 45% of the cases affecting the liver.Clinical caseA 50-year-old woman, diagnosed with medullary thyroid carcinoma, was treated with total thyroidectomy and a modified neck dissection in 1999. Two lymph node recurrences in the neck were treated with surgical resection; during surveillance, she developed elevated calcitonin levels, the recurrence site was identified with ¹⁸F-DOPA PET/CT in the liver. Metabolic activity was not associated with a visible lesion in CT, MRI nor ultrasound. Radioguided surgery with ¹⁸F-DOPA allowed an anatomic resection of segments IVb and V.DiscussionIn patients with medullary carcinoma and elevated calcitonin during surveillance, ¹⁸F-DOPA PET/CT is an option to evaluate the site of recurrence. Radioguided resection was feasible in this patient, whose hepatic recurrence was not visible with any other imaging method.ConclusionRadioguided hepatic resection with ¹⁸F-DOPA in metastatic medullary thyroid carcinoma is feasible when the recurrence site is not anatomically identified by any other imaging studies.



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Diferente captación de 123I-MIBG en los 2 lóbulos hepáticos principales: un misterio persistente sin resolver

Publication date: Available online 10 May 2018
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): M. Bonacina, D. Albano, N. Steimberg, G. Bosio, L. Camoni, F. Bertagna, R. Giubbini, G. Mazzoleni
ObjetivoDespués de la inyección del radiofármaco se observa con frecuencia una concentración incrementada de ¹²³I-MIBG en el lóbulo hepático izquierdo en comparación con el derecho, pero la razón de este hallazgo sigue siendo desconocida. Nuestro objetivo fue analizar retrospectivamente el patrón de absorción de ¹²³I-MIBG entre los 2 lóbulos hepáticos y correlacionar nuestros resultados con algunas características epidemiológicas/clínicas.Material y métodosSe seleccionaron 94 gammagrafías ¹²³I-MIBG de 71 pacientes. Las regiones de interés se dibujaron en los lóbulos derecho e izquierdo utilizando secciones tomográficas transversales y se calcularon relaciones de actividad de izquierda a derecha (relación I/D) a las 6 y 24horas de la administración del radiofármaco.ResultadosVeintisiete exámenes fueron positivos para lesiones hipermetabólicas, mientras que los 67 restantes fueron negativos. En todos los casos las relaciones medias de I/D temprana y tardía fueron superiores a 1; la relación I/D temprana media fue de 1,37 y la relación I/D tardía de 1,52. La relación I/D tardía fue significativamente mayor que la precoz. No hubo diferencias en la relación I/D con respecto a la edad, sexo, enfermedad primaria y resultado de la gammagrafía.ConclusionesLa absorción de ¹²³I-MIBG fue mayor en el lóbulo hepático izquierdo en comparación con el derecho, y esta relación no se correlacionó con ninguna característica epidemiológica o clínica. La razón de este metabolismo todavía no se ha explicado, y algunas hipótesis biomoleculares podrían ser probadas en modelos 3D dinámicos in vitro.PurposeAfter radiopharmaceutical injection, a heightened ¹²³I-MIBG concentration is frequently observed in the left hepatic lobe compared to the right one, but the reason of this finding remains unknown. Our aim was to retrospectively analyze the different ¹²³I-MIBG uptake pattern between the two hepatic lobes and correlate our results with some epidemiological/clinical features.Material and methodsNinety-four ¹²³I-MIBG scintigraphies from 71 patients were selected. Regions of interest were drawn in the right and left lobes using transverse tomographic sections and left to right activity ratios (L/R ratio) were calculated at 6 and 24h after radiotracer administration.ResultsTwenty-seven examinations were positive for hypermetabolic lesions while the remaining 67 were negative. In all cases mean early and delayed L/R ratios were greater than 1.00; average early L/R ratio was 1.37 and delayed L/R ratio 1.52. The delayed L/R ratio was significantly higher than the early one. There was no difference in the L/R ratios with regard to age, gender, primary disease and result of scintigraphy.Conclusions¹²³I-MIBG uptake was higher in left hepatic lobe compared to right and this ratio did not correlate with any epidemiological or clinical feature. The reason of this metabolic is not yet explained and some biomolecular hypotheses could be tested in 3D dynamic in vitro models.



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JMJD3 inhibition protects against isoproterenol-induced cardiac hypertrophy by suppressing β-MHC expression

Publication date: Available online 10 May 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zhen Guo, Jing Lu, Jingyan Li, Panxia Wang, Zhenzhen Li, Yao Zhong, Kaiteng Guo, Junjian Wang, Jiantao Ye, Peiqing Liu
Jumonji domain-containing protein D3 (JMJD3), a histone 3 lysine 27 (H3K27) demethylase, has been extensively studied for their participation in development, cellular physiology and a variety of diseases. However, its potential roles in cardiovascular system remain unknown. In this study, we found that JMJD3 played a pivotal role in the process of cardiac hypertrophy. JMJD3 expression was elevated by isoproterenol (ISO) stimuli both in vitro and in vivo. Overexpression of wild-type JMJD3, but not the demethylase-defective mutant, promoted cardiomyocyte hypertrophy, as implied by increased cardiomyocyte surface area and the expression of hypertrophy marker genes. In contrary, JMJD3 silencing or its inhibitor GSK-J4 suppressed ISO-induced cardiac hypertrophy. Mechanistically, JMJD3 was recruited to demethylate H3K27me3 at the promoter of β-MHC to promote its expression and cardiac hypertrophy. Thus, our results reveal that JMJD3 may be a key epigenetic regulator of β-MHC expression in cardiomyocytes and a potential therapeutic target for cardiac hypertrophy.

Graphical abstract

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Chronic hyperinsulinemia promotes meta-inflammation and extracellular matrix deposition in adipose tissue: Implications of nitric oxide

Publication date: Available online 10 May 2018
Source:Molecular and Cellular Endocrinology
Author(s): Durgesh Kumar, Kripa Shankar, Saraswati Patel, Abhishek Gupta, Salil Varshney, Sanchita Gupta, Sujith Rajan, Ankita Srivastava, Achchhe Lal Vishwakarma, Anil N. Gaikwad
Various imperative studies support the notion that hyperinsulinemia (HI) itself serves as the common link between adipose tissue inflammation (ATI) and metabolic syndrome. However, the contribution of HI mediated ATI and its metabolic consequences are yet to be explored. We induced chronic HI per se in mice by administration of exogenous insulin for 8 weeks through mini-osmotic pumps. For the reduction of circulating insulin in response to excess calorie intake, we have partially ablated β-cells by using streptozotocin (STZ) in the diet-induced obesity (DIO) and genetic mice models (db/db). Flow cytometry analysis was performed for the quantification of immune cells in stromal vascular fraction (SVF) isolated from epididymal white adipose tissue (eWAT). Our studies demonstrated that chronic HI augmented ATI in terms of elevated pro-inflammatory cells (M1 macrophages and NK-cells) and suppressed anti-inflammatory cells (M2 macrophages, eosinophils and regulatory T-cells). These results were correlated with altered obesity-associated metabolic phenotype. Partial reduction of circulating insulin level attenuated excess calorie-induced ATI and improved insulin sensitivity. Mechanistically, an imbalance in M1 and M2 macrophage proportions in eWAT promoted iNOS (inducible nitric oxide synthase): arginase-1 imbalance that resulted into extracellular matrix (ECM) deposition and insulin resistance (IR) development. However, iNOS^−/- mice were protected from HI-induced M1:M2 macrophage imbalance, ECM deposition and IR in adipose tissue. Overall, we conclude that chronic HI per se contributed in ATI and iNOS corroborated ECM deposition.

Graphical abstract

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Cancer stem cells: regulation programs, immunological properties and immunotherapy

Publication date: Available online 9 May 2018
Source:Seminars in Cancer Biology
Author(s): Dingxiao Zhang, Dean G. Tang, Kiera Rycaj
It is becoming increasingly clear that virtually all types of human cancers harbor a small population of stem-like cancer cells (i.e., cancer stem cells, CSCs). These CSCs preexist in primary tumors, can self-renew and are more tolerant of standard treatments, such as antimitotic and molecularly targeted agents, most of which preferentially eliminate differentiated and proliferating cancer cells. CSCs are therefore postulated as the root of therapy resistance, relapse and metastasis. Aside from surgery, radiation, and chemotherapy, immunotherapy is now established as the fourth pillar in the therapeutic armamentarium for patients with cancer, especially late-stage and advanced cancers. A better understanding of CSC immunological properties should lead to development of novel immunologic approaches targeting CSCs, which, in turn, may help prevent tumor recurrence and eliminate residual diseases. Here, with a focus on CSCs in solid tumors, we review CSC regulation programs and recent transcriptomics-based immunological profiling data specific to CSCs. By highlighting CSC antigens that could potentially be immunogenic, we further discuss how CSCs can be targeted immunologically.



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World Thyroid Day Recognized Globally on May 25th

World Thyroid Day Recognized Globally
American Thyroid Association^® collaborates with International Thyroid Societies
May 25, 2018

On May 25^th the American Thyroid Association^® (ATA) (www.thyroid.org), in cooperation with the European Thyroid Association (www.eurothyroid.com), will be making an extraordinary effort to promote its year-round goals —focus attention on that small butterfly-shaped gland at the base of the neck that causes approximately 20 million Americans to experience thyroid disease.   In addition to the millions who have some form of thyroid disease, it is estimated that more than 12 percent of the U.S. population will develop a thyroid condition during their lifetime.

The important goal of the ATA^® and our sister thyroid organizations is to get the word out about Thyroid! Perhaps the most stunning statistics are that up to 60 percent of those with thyroid disease are unaware of their condition and that women are five to eight times more likely than men to have thyroid problems.  Almost everyone knows someone affected by thyroid disease or thyroid cancer and the ATA is proud to promote international awareness on World Thyroid Day so that symptoms, diagnosis, and treatment of conditions are available around the globe.  If you or someone you know are experiencing thyroid symptoms, make an appointment to see a thyroid specialist – you can find one in your area (in the US and internationally) by using the ATA Physician Referral Tool and you can read up on the thyroid educational materials in the ATA Thyroid Information Library.

The ATA^® is the leading organization devoted to thyroid biology and to the prevention and treatment of thyroid disease through excellence in research, clinical care, education, and public health.  Our mission assures that we communicate the importance of the thyroid gland, which produces hormones that influence every cell, tissue, and organ in the body. Thyroid hormones regulate the body's metabolism—the rate at which the body produces energy from nutrients and oxygen—and affects critical body functions, such as energy level and heart rate. Through its mission, the ATA^® supports the clinicians and researchers who are at the frontlines of thyroid treatments and research. We also work with the public, patients, and their families to educate and increase awareness of thyroid diseases.

ATA^® member of 30 years, Dr. Gregory Brent – Chair, Department of Medicine from the University of California-Los Angeles says that, "The ATA has been my professional home since my fellowship and it has been a privilege to serve with my many valued colleagues and with such a committed and talented staff. I am most grateful to my mentors, who have encouraged and guided me. The professional and personal growths I have experienced from my involvement with the ATA are immeasurable."

The ATA Patient Thyroid Information library is just a few clicks away on the ATA^® website – http://www.thyroid.org/thyroid-information/ and we encourage you to check back regularly for updates and new materials.  We are also pleased to offer many of our brochures in Spanish – http://www.thyroid.org/informacion-sobre-la-tiroides/ and provide a translator on the website for most languages.  The ATA website provides easy-to-access, patient-friendly information on topics such as:

Hypothyroidism: One of the most common thyroid conditions that occurs when the thyroid gland does not produce enough thyroid hormone. Symptoms include fatigue, depression, forgetfulness, irregular menses and weight gain. Treatment of hypothyroidism is usually with a synthetic form of thyroid hormone called "levothyroxine." Hashimoto's Thyroiditis is an autoimmune disease affecting the thyroid is the most common cause of hypothyroidism in the US, affecting mostly women. Diagnosis is usually confirmed by symptoms suggesting thyroid underactivity, positive anti-thyroid antibodies, and small goiter (thyroid enlargement) on physical examination. Patients with an elevated blood level of TSH and/or goiter are treated with thyroxine (T4).

On the opposite side of the spectrum is Hyperthyroidism and this occurs when the thyroid gland produces too much thyroid hormone. Symptoms include irritability, nervousness, muscle weakness, unexplained weight loss, sleep disturbances, vision problems and eye irritation. One type of hyperthyroidism, Graves' disease, is an autoimmune disorder that is partly genetic.
In addition to these common thyroid conditions, we also know that Thyroid Cancer is the most rapidly increasing form of cancer in the United States. The American Cancer Society estimates 53,990 new cases of thyroid cancer will be diagnosed in 2018 resulting in over 2,000 deaths. When thyroid cancer is identified and treated early, the majority of patients can be completely cured.

Mary Catherine Petermann whose father was diagnosed with Anaplastic Thyroid Cancer in 2006 describes how the ATA impacted her search for help, "The ATA was a valuable resource for our family when my dad was diagnosed with Anaplastic Thyroid Cancer. When you are faced with a detrimental diagnosis where even a few days can make the difference in life or death, understanding your options quickly is critical. The ATA website offers a one-stop shop for patients and caregivers to find specialists, current clinical trials, general thyroid cancer information, and links to other patient support groups and information"  Mary Catherine's father was treated by ATA member physicians at Mayo Clinic and has clean scans as of October 2016.

For thyroid cancer, Endocrinologists can sometimes employ minimally invasive procedures to distinguish thyroid cancer from benign thyroid nodules, which are common in the population. The ATA produces management guidelines for thyroid diseases and thyroid cancer, which, are open to the public and can accessed on the ATA website here: https://www.thyroid.org/professionals/ata-professional-guidelines/
We invite and encourage you to take a moment on the 25^th of May, World Thyroid Day, to help ATA^® continue to serve patients, families, and the physicians to treat them by making a donation on the ATA^® World Thyroid Day Donation Page:   https://www.crowdrise.com/world-thyroid-day

Your donation will help ATA continue the important work of education, research, and awareness on this most important disease.  No donation is too small and if you would like to make a recurring donation throughout the year, please visit this page: https://www.givedirect.org/donate/?cid=723 and select frequency that is good for you.

Your interest and support help make a positive impact on the lives of so many who struggle with thyroid conditions and thyroid cancer every day and we thank you for joining us and helping carry-out the ATA^® mission!
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The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis and treatment of thyroid disorders and thyroid cancer. ATA is an international individual membership organization for over 1,700 clinicians and researchers from 43 countries around the world, representing a broad diversity of medical disciplines. It also serves the public, patients and their family through education and awareness efforts

Celebrating its 95^th anniversary, ATA delivers its mission through several key endeavors: the publication of highly regarded monthly journals, THYROID, Clinical Thyroidology, VideoEndocrinology and Clinical Thyroidology for the Public; annual scientific meetings; biennial clinical and research symposia; research grant programs for young investigators, support of online professional, public and patient educational programs; and the development of guidelines for clinical management of thyroid disease.

More information about ATA is found at www.thyroid.org.

The post <i>World Thyroid Day </i>Recognized Globally on May 25th appeared first on American Thyroid Association.

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Le diagnostic de FPI : un long fleuve tranquille ?

Publication date: Available online 5 May 2018
Source:Revue des Maladies Respiratoires
Author(s): J.-M. Naccache, H. Nunes




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La chimiothérapie inhalée – partie 2 : clinique et applications potentielles

Publication date: Available online 3 May 2018
Source:Revue des Maladies Respiratoires
Author(s): R. Rosière, J. Hureaux, V. Levet, K. Amighi, N. Wauthoz
Les tumeurs pulmonaires présentent une incidence importante et sont la cause d'un grand nombre de décès avec un taux de survie globale à 5 ans qui reste très faible malgré les progrès réalisés en thérapeutique avec l'avènement des thérapies ciblées et de l'immunothérapie. Dans ce contexte, la chimiothérapie inhalée est une voie de recherche potentielle pour proposer une intensification thérapeutique locorégionale. Cette revue se base sur l'analyse des études cliniques utilisant la chimiothérapie inhalée. Elle traite des avantages de cette approche en termes d'apport pharmacocinétique et d'index thérapeutique, des limitations rencontrées telles que les possibles contre-indications et les effets indésirables locaux ainsi que des problématiques identifiées liées à des aspects techniques lors de l'administration (dispositif d'inhalation et infrastructures pour limiter la propagation de l'aérosol et l'exposition au personnel médical). Ensuite, la revue présente brièvement les développements potentiels en vue de répondre à ses problématiques. Pour finir, la dernière partie traite des applications potentielles en discutant de la distribution de l'agent anticancéreux inhalé dans les voies respiratoires affectées par des tumeurs pulmonaires et enfin des indications potentielles dans l'arsenal thérapeutique actuel.Lung tumours have a high incidence and cause many deaths worldwide. Despite progresses in treatment with targeted therapies and immunotherapies, the global 5-year survival rate remains low. In this context, inhaled chemotherapy could provide a means to intensify current therapeutic modalities. This review is based on clinical studies of inhaled chemotherapy against lung tumours. The advantages of this approach in terms of pharmacokinetic ratio and therapeutic index are presented as well as the limitations including contraindications and pulmonary side effects. Moreover, the challenges linked to technical aspects around administration are identified (inhalation device and facilities to limit aerosol propagation and exposure of healthcare professionals). The current developments proposed to overcome these challenges are described briefly. Also discussed are the potential applications for the distribution of the inhaled anticancer drug into tumour-bearing respiratory tracts and finally the potential indications for current therapeutic modalities.



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La chimiothérapie inhalée – partie 1 : concept et challenges technologiques actuels

Publication date: Available online 3 May 2018
Source:Revue des Maladies Respiratoires
Author(s): R. Rosière, J. Hureaux, V. Levet, K. Amighi, N. Wauthoz
Les chimiothérapies occupent toujours une place importante dans la prise en charge de patients présentant un ou des tumeurs pulmonaires, primaires et métastases, et ce malgré de graves effets secondaires décrits. Afin de réduire ces derniers et aussi intensifier l'activité des agents thérapeutiques, différentes stratégies ont été décrites. Parmi celles-ci, l'utilisation des nanomédecines et de la voie d'administration pulmonaire des chimiothérapies. Cette dernière approche ne peut cependant être réalisée de manière efficace et sans danger sans une adaptation des techniques d'inhalation actuellement disponibles, c'est-à-dire des dispositifs d'inhalation et des formulations médicamenteuses. Cette revue présente différents développements précliniques qui tendent actuellement à apporter des solutions aux principales limitations observées avec l'inhalation de chimiothérapie dans le traitement des tumeurs pulmonaires. Ces solutions portent notamment sur l'utilisation d'inhalateurs à poudre sèche et de stratégies de formulation adéquates telles que (i) les formes à libération contrôlée et à rétention pulmonaire prolongée et (ii) les nanomédecines.Despite severe adverse effects, chemotherapy is still widely used in the treatment of lung tumors, including primary lung tumors and metastases. In order to reduce the risk of harm and to intensify treatment responses, several strategies have been described recently. These include the use of nanomedicine-based chemotherapies and pulmonary drug delivery. However, to treat lung tumors, inhalation cannot be effective and safe without an adaptation of current inhalation techniques, i.e. inhalation devices and drug formulations. This can be very challenging. This review presents recent preclinical developments that could address the limitations observed with aerosolized chemotherapy. The solutions involve the use of dry powder inhalers and advanced drug formulations, such as controlled and sustained release formulations and nanomedicine-based formulations.



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Les chambres d’exposition environnementale (CEE) : un nouvel outil dans la recherche académique et industrielle

Publication date: Available online 3 May 2018
Source:Revue des Maladies Respiratoires
Author(s): N. Khayath, C. Radu, I. Choual, S. Jilani, L. Vecellio, N. Domis, F. De Blay
Face à l'augmentation de l'asthme, de la rhinite et de la conjonctivite allergiques, il existe un besoin réel de progresser dans la compréhension des mécanismes physiopathologiques et d'accélérer la recherche clinique. Toutefois, les études cliniques traditionnelles en milieu naturel sont longues et présentent de nombreux biais, notamment en raison de la variabilité de l'exposition allergénique. De plus, les tests de provocation allergénique, particulièrement dans l'asthme, sont d'excellents outils pour déterminer l'efficacité d'une molécule. Les chambres d'exposition environnementale (CEE) permettent de réaliser des tests de provocation avec une exposition allergénique contrôlée à grande échelle, sensibles, spécifiques et reproductibles. Elles permettent également un recueil précis des symptômes allergiques, ce qui en fait des outils très intéressants tant pour la recherche clinique que fondamentale. Ces trente dernières années, elles ont été surtout utilisées dans le développement des thérapies anti-allergiques, en particulier dans la rhinite allergique. Le but du développement de la CEE de Strasbourg (ALYATEC^®) est double : obtenir une standardisation et un contrôle de l'exposition allergénique et non allergénique supérieure aux autres chambres mais aussi pouvoir offrir un banc d'essai pour l'asthme et les anti-asthmatiques en toute sécurité.Airborne allergic diseases (allergic asthma, rhinitis and conjunctivitis) have reached epidemic proportions and are a great burden for both society and individuals. Therefore we need to better understand the physiopathological mechanisms and to increase clinical research in these diseases. However, traditional outpatient studies are difficult and have number of limitations, in particular the variability of allergen exposure. Yet allergen provocation tests, especially bronchial challenges in asthma, are excellent tools to measure the efficiency of anti-allergic therapies. Environmental exposure chambers (EEC) allow the performance of controlled allergen provocation tests on a large scale with remarkable sensitivity, specificity and reproducibility. Moreover, they allow a precise collection of allergic symptoms, making them interesting tools for patho-physiological and clinical studies. During the last thirty years, they have assisted the study of anti-allergic therapies and provided data on their pharmacodynamic characteristics, particularly in allergic rhinitis. However, there are still no EEC tests centered on asthma. The EEC of Strasbourg (ALYATEC^®) was developed to fulfill two objectives: to allow standardized allergenic and non-allergenic exposures with better control of the parameters than in other EEC and to offer a place to study asthma and anti-asthmatic therapies safely.



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Numéro 4/2018. Réponses

Publication date: Available online 27 April 2018
Source:Revue des Maladies Respiratoires





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Cœur droit et altitude

Publication date: Available online 7 May 2018
Source:Revue des Maladies Respiratoires
Author(s): R. Naeije
IntroductionLa pression partielle inspiratoire en oxygène diminue avec l'altitude. L'hypoxie provoque une vasoconstriction pulmonaire, qui peut être cause d'hypertension pulmonaire et donc de défaillance cardiaque droite.État des connaissancesLa vasoconstriction pulmonaire hypoxique varie considérablement. L'exposition à l'altitude s'accompagne d'une augmentation de la pression artérielle pulmonaire en proportion de la vasoconstriction initiale. Des échocardiographies réalisées en altitude montrent que la pression artérielle pulmonaire moyenne s'y établit généralement à 20mmHg, soit la limite supérieure de la normale normoxique. La postcharge du ventricule droit n'est alors que modérément augmentée, avec quelques perturbations fonctionnelles démontrées par imagerie, mais préservation d'une adaptation aux contraintes de l'effort physique. Dans moins de 1 % des cas, il y a hypertension pulmonaire hypoxique franche avec ou sans défaillance cardiaque droite.PerspectivesL'impact pronostique de l'hypertension pulmonaire et des altérations associées de la fonction cardiaque en altitude n'est pas défini. Le traitement de l'hypertension pulmonaire hypoxique repose empiriquement sur une évacuation à une altitude inférieure, sur l'administration d'oxygène et sur la prise de vasodilatateurs pulmonaires. Ces stratégies thérapeutiques ne sont pas rigoureusement validées.ConclusionsUne défaillance cardiaque droite peut survenir lors d'une exposition à l'altitude. Cette complication rare devrait faire l'objet d'études épidémiologiques et interventionnelles prospectives.IntroductionAltitude is associated with a decrease in partial pressure of oxygen. Hypoxia induces pulmonary vasoconstriction with subsequent fixed increase in pulmonary artery pressure, and eventual right heart failure.Current knowledgeHigh altitude exposure is associated with an increase in pulmonary artery pressure that is proportional to initial vasoconstriction. Echocardiographic evaluations on a large number of subjects show that the altitude-induced increase in pulmonary pressure is generally modest and does not exceed the 25mmHg that are diagnostic of pulmonary hypertension. This does not greatly increase right ventricular afterload, so that imaging of the right ventricle only shows some alterations of indices of systolic or diastolic function, but preserved contractile reserve during exercise. In less than 1% of cases, hypoxic vasoconstriction is strong and may be a cause of severe pulmonary hypertension and right heart failure.PerspectivesThe prognostic relevance of altitude-induced pulmonary hypertension and associated cardiac function alterations is not known. Treatment of hypoxic pulmonary hypertension relies on evacuation to a lower altitude, oxygen and pulmonary vasodilators. These treatment strategies have not been rigorously evaluated.ConclusionsAltitude may be a cause of right heart failure. This uncommon complication of altitude exposure requires further epidemiological and therapeutic studies.



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Numéro 4/2018. Questions

Publication date: Available online 26 April 2018
Source:Revue des Maladies Respiratoires





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Editorial board

Publication date: March 2018
Source:Revue des Maladies Respiratoires, Volume 35, Issue 3





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L’interprétation des EFR peut-elle encore faire l’impasse sur une définition statistique de la normalité ?

Publication date: March 2018
Source:Revue des Maladies Respiratoires, Volume 35, Issue 3
Author(s): J.-F. Dessanges, D. Baud, A. Charloux, L. Plantier




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Limite inférieure de la normale ou ratio fixe pour le diagnostic de BPCO : est-ce si important ?

Publication date: March 2018
Source:Revue des Maladies Respiratoires, Volume 35, Issue 3
Author(s): P.-R. Burgel




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Preparation breeds success: Brain activity predicts remembering

Publication date: Available online 9 May 2018
Source:Cortex
Author(s): Jane E. Herron, Lisa H. Evans
Successful retrieval of episodic information is thought to involve the adoption of memory states that ensure that stimulus events are treated as episodic memory cues (retrieval mode) and which can bias retrieval towards specific memory contents (retrieval orientation). The neural correlates of these memory states have been identified in many neuroimaging studies, yet critically there is no direct evidence that they facilitate retrieval success. We cued participants before each test item to prepare to complete an episodic (retrieve the encoding task performed on the item at study) or a non-episodic task. Our design allowed us to separate event-related potentials (ERPs) elicited by the preparatory episodic cue according to the accuracy of the subsequent memory judgment. We predicted that a correlate of retrieval orientation should be larger in magnitude preceding correct source judgments than that preceding source errors. This hypothesis was confirmed. Preparatory ERPs at bilateral frontal sites were significantly more positive-going when preceding correct source judgements than when preceding source errors or correct responses in a non-episodic baseline task. Furthermore this effect was not evident prior to recognised items associated with incorrect source judgements. This pattern of results indicates a direct contribution of retrieval orientation to the recovery of task-relevant information and highlights the value of separating preparatory neural activity at retrieval according to subsequent memory accuracy. Moreover, at a more general level this work demonstrates the important role of pre-stimulus processing in ecphory, which has remained largely neglected to date.



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Episodic memory for natural and transformed food

Publication date: Available online 10 May 2018
Source:Cortex
Author(s): Marilena Aiello, Miriam Vignando, Francesco Foroni, Giulio Pergola, Paola Rossi, Maria Caterina Silveri, Raffaella I. Rumiati
It has been proposed that the conceptual knowledge of food and its putative subdivision into natural (i.e., fruit/vegetables) and transformed (i.e., food that underwent thermic or non-thermic processing) may follow the living/non-living distinction. In the present study, we investigated whether the advantage for living things compared to non-living things observed in episodic memory (the so-called animacy effect) extends to natural foods and transformed foods respectively. We pursued this issue in two experiments. In Experiment 1, we measured episodic memory for natural and transformed foods in young participants. In Experiment 2, we enrolled dementia-free centenarians, patients with Alzheimer's disease (DAT), Progressive primary aphasia (PPA), and healthy controls whose episodic memory was also tested for living/non-living things. Results showed that young participants had better recognition memory for transformed foods compared to natural foods. This difference disappeared in centenarians and patients. However, centenarians and PPA exhibited enhanced levels of false alarms with natural food, and DAT patients with both natural and transformed food. As far as the living/non-living distinction is concerned, the episodic memory for the living category appears more resilient to the decline compared to the non-living category in patients, particularly those with PPA. In conclusion, our study shows that transformed food is better remembered than natural food, suggesting that it is more salient and possibly relevant from an evolutionary perspective. The natural/transformed distinction appears susceptible to erosion only in the presence of a high degree of episodic memory impairment. These results offer novel insight on episodic memory of food, and also extend the current knowledge on the animacy effect in episodic memory.



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An empirical, 21st century evaluation of phrenology

Publication date: Available online 9 May 2018
Source:Cortex
Author(s): O. Parker Jones, F. Alfaro-Almagro, S. Jbabdi
Phrenology was a nineteenth century endeavour to link personality traits with scalp morphology, which has been both influential and fiercely criticised, not least because of the assumption that scalp morphology can be informative of underlying brain function. Here we test the idea empirically rather than dismissing it out of hand. Whereas nineteenth century phrenologists had access to coarse measurement tools (digital technology referring then to fingers), we were able to re-examine phrenology using 21^st century methods and thousands of subjects drawn from the largest neuroimaging study to date. High-quality structural MRI was used to quantify local scalp curvature. The resulting curvature statistics were compared against lifestyle measures acquired from the same cohort of subjects, being careful to match a subset of lifestyle measures to phrenological ideas of brain organisation, in an effort to evoke the character of Victorian times. The results represent the most rigorous evaluation of phrenological claims to date.



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Variations within a subtype: Developmental surface dyslexias in English

Publication date: Available online 10 May 2018
Source:Cortex
Author(s): Saskia Kohnen, Lyndsey Nickels, Leonie Geigis, Max Coltheart, Genevieve McArthur, Anne Castles
Surface dyslexia is characterised by poor reading of irregular words while nonword reading can be completely normal. Previous work has identified several theoretical possibilities for the underlying locus of impairment in surface dyslexia. In this study, we systematically investigated whether children with surface dyslexia showed different patterns of reading performance that could be traced back to different underlying levels of impairment. To do this, we tested 12 English readers, replicating previous work in Hebrew (Gvion & Friedmann, 2013; 2016; Friedmann & Lukov, 2008; Friedmann & Gvion, 2016). In our sample, we found that poor irregular word reading was associated with deficits at the level of the orthographic input lexicon and with impaired access to meaning and spoken word forms after processing written words in the orthographic input lexicon. There were also children whose surface dyslexia seemed to be caused by impairments of the phonological output lexicon. We suggest that further evidence is required to unequivocally support a fourth pattern where the link between orthography and meaning is intact while the link between orthography and spoken word forms is not functioning. All patterns found were consistent with dual route theory while possible patterns of results, which would be inconsistent with dual route theory, were not detected.



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Executive Dysfunction Contributes to Verbal Encoding and Retrieval Deficits in Posterior Cortical Atrophy

Publication date: Available online 10 May 2018
Source:Cortex
Author(s): Deepti Putcha, Scott M. McGinnis, Michael Brickhouse, Bonnie Wong, Janet C. Sherman, Bradford C. Dickerson
Posterior Cortical Atrophy (PCA) is a neurodegenerative syndrome that typically presents with predominant visual and spatial impairments. The early diagnostic criteria specify a relative sparing of functioning in other cognitive domains, including executive functions, language, and episodic memory, yet little is known of the cognitive profile of PCA as the disease progresses. Studies of healthy adults and other posterior cortical lesion patients implicate posterior parietal and temporal regions in executive functions of working memory and verbal fluency, both of which may impact episodic memory. Relatively little has been reported about these cognitive functions in PCA, and to our knowledge there has not yet been a study of the impact of such deficits on memory function in PCA. We sought to examine PCA patients' performance on tests of executive function and the associations to verbal episodic memory encoding, storage, and delayed recall. Nineteen individuals with PCA underwent neuropsychological and neuroimaging evaluations as part of a comprehensive clinical assessment. We developed a novel consensus rating method—the Neuropsychological Assessment Rating (NAR) scale—to grade the severity of test performance impairments in selected cognitive domains and subdomains. Hypothesis-driven analyses demonstrated relative deficits in working memory and lexical-semantic retrieval. Preliminary analyses suggested associations between both deficits and atrophy in the left-hemisphere inferior parietal lobule. These executive deficits were also associated with impairments in verbal encoding and delayed recall, but not with recognition discriminability. We conclude that deficits in verbal executive functions impact verbal episodic memory in PCA. Our findings also support theories emphasizing the role of the posterior parietal cortex in supporting executive and lexical-semantic contributions to verbal episodic memory.



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Preclinical characterization and clinical evaluation of tacrolimus eye drops

Publication date: 30 July 2018
Source:European Journal of Pharmaceutical Sciences, Volume 120
Author(s): Andrea Luaces-Rodríguez, Rosario Touriño-Peralba, Iria Alonso-Rodríguez, Xurxo García-Otero, Miguel González-Barcia, María Teresa Rodríguez-Ares, Laura Martínez-Pérez, Pablo Aguiar, Noemí Gómez-Lado, Jesús Silva-Rodríguez, Michel Herranz, Álvaro Ruibal-Morell, María Jesús Lamas, Francisco J. Otero-Espinar, Anxo Fernández-Ferreiro
Severe allergic ocular diseases as atopic keratoconjunctivitis can induce corneal damage due to inflammatory substances released from giant papillae. Tacrolimus eye drops are one of the current therapeutic alternatives for its treatment. This work is aimed at developing and characterizing a 0.03% tacrolimus ophthalmic formulation, which was introduced in three types of vehicles (BBS, PVA and Hyaluronic Acid). For this, we have performed in vitro (stability studies) and in vivo assays (corneal permanence time measured directly by Positron Emission Tomography) of three potential formulations. Next, the best formulation was selected, and its toxicological profile and clinical effectiveness have been evaluated. The biopermanence studies (direct measurements and PET/CT) showed that the formulations with PVA and Hyaluronic Acid present more retention time on the ocular surface of rats than PBS. From the stability study, we have determined that tacrolimus with PVA in cold storage is the best option. Tacrolimus with PVA has shown lower cytotoxicity than cyclosporine at early times. On the other hand, the pilot study performed has shown significant improvements in patients, with no noticeable adverse reactions. Based on stability, biopermanence, safety and clinical effectiveness studies, we concluded that tacrolimus-PVA eye drops are a suitable candidate for its clinical application in inflammatory ophthalmology diseases.

Graphical abstract

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Salt formation improved the properties of a candidate drug during early formulation development

Publication date: 30 July 2018
Source:European Journal of Pharmaceutical Sciences, Volume 120
Author(s): Kalle Sigfridsson, Matti Ahlqvist, Martin Lindsjö, Stefan Paulsson
The purpose of this study was to investigate if AZD5329, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development as an oral immediate release (IR) solid dosage form as a final product. The neutral form of AZD5329 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Crystalline material of a maleic acid salt and a fumaric acid salt of AZD5329 were obtained. X-ray powder diffractiometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the two salts. The fumarate salt of AZD5329 is anhydrous, the crystallization is reproducible and the hygroscopicity is acceptable. Early polymorphism assessment work using slurry technique did not reveal any better crystal modification or crystallinity for the fumarate salt. For the maleate salt, the form isolated originally was found to be a solvate, but an anhydrous form was found in later experiments; by suspension in water or acetone, by drying of the solvate to 100–120 °C or by subjecting the solvate form to conditions of 40 °C/75%RH for 3 months. The dissolution behavior and the chemical stability (in aqueous solutions, formulations and solid-state) of both salts were also studied and found to be satisfactory. The compound displays sensitivity to low pH, and the salt of the maleic acid, which is the stronger acid, shows more degradation during stability studies, in line with this observation. The presented data indicate that the substance fulfils basic requirements for further development of an IR dosage form, based on the characterization on crystalline salts of AZD5329.

Graphical abstract

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Constraints on somatosensory map development: mutants lead the way

Publication date: December 2018
Source:Current Opinion in Neurobiology, Volume 53
Author(s): Patricia Gaspar, Nicolas Renier
In the rodent somatosensory system, the disproportionally large whisker representation and their specialization into barrel-shaped units in the different sensory relays has offered experimentalists with an ideal tool to identify mechanisms involved in brain map formation. These combine three intertwined constraints: Firstly, fasciculation of the incoming axons; secondly, early neural activity; finally, molecular patterning. Sophisticated genetic manipulations in mice have now allowed dissecting these mechanisms with greater accuracy. Here we discuss some recent papers that provided novel insights into how these different mapping rules and constraints interact to shape the barrel map.



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Tau-mediated synaptic and neuronal dysfunction in neurodegenerative disease

Publication date: August 2018
Source:Current Opinion in Neurobiology, Volume 51
Author(s): Tara E Tracy, Li Gan
The accumulation of pathological tau in the brain is associated with neuronal deterioration and cognitive impairments in tauopathies including Alzheimer's disease. Tau, while primarily localized in the axons of healthy neurons, accumulates in the soma and dendrites of neurons under pathogenic conditions. Tau is found in both presynaptic and postsynaptic compartments of neurons in Alzheimer's disease. New research supports that soluble forms of tau trigger pathophysiology in the brain by altering properties of synaptic and neuronal function at the early stages of disease progression, before neurons die. Here we review the current understanding of how tau-mediated synaptic and neuronal dysfunction contributes to cognitive decline. Delineating the mechanisms by which pathogenic tau alters synapses, dendrites and axons will help lay the foundation for new strategies that can restore neuronal function in tauopathy.



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