Recent Developments for Introducing a Hexafluoroisopropanol Unit into the Vitamin D Side Chain

Publication date: Available online 14 July 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Fumihiro Kawagoe, Toru Sugiyama, Motonari Uesugi, Atsushi Kittaka
Among numerous studies on synthetic approaches to and the biological activities of vitamin D analogues, we herein focused on falecalcitriol, an analogue of calcitriol (1α,25-dihydroxyvitamin D3), in which a 26,26,26,27,27,27-hexafluoroisopropanol unit has been introduced into the side chain. Falecalcitriol was designed to escape from the metabolism of CYP24A1 and has been used as a drug to treat secondary hypoparathyroidism since 2001. Its metabolite, the 23-hydroxy form, retains biological activity and resistants to further metabolism. Recent developments in synthetic methodologies for introducing the hexafluoroisopropanol unit into the vitamin D CD-ring side chain were described herein.

Graphical abstract

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Properties of Purified CYP2R1 in a Reconstituted Membrane Environment and its 25-Hydroxylation of 20-Hydroxyvitamin D3

Publication date: Available online 14 July 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Chloe Y.S. Cheng, Tae-Kang Kim, Saowanee Jeayeng, Andrzej T. Slominski, Robert C. Tuckey
Recent studies indicate that CYP2R1 is the major 25-hydroxylase catalyzing the first step in vitamin D activation. Since the catalytic properties of CYP2R1 have been poorly studied to date and it is a membrane protein, we examined the purified enzyme in a membrane environment. CYP2R1 was expressed in E. coli and purified by nickel affinity- and hydrophobic interaction-chromatography and assayed in a reconstituted membrane system comprising phospholipid vesicles plus purified human NADPH-P450 oxidoreductase. CYP2R1 converted vitamin D3 in the vesicle membrane to 25-hydroxyvitamin D3 [25(OH)D3] with good adherence to Michaelis-Menten kinetics. The kinetic parameters for 25-hydroxylation of vitamin D3 by the two major vitamin D 25-hydroxylases, CYP2R1 and CYP27A1, were examined in vesicles under identical conditions. CYP2R1 displayed a slightly lower kcat than CYP27A1 but a much lower Km for vitamin D3, and thus an overall 17-fold higher catalytic efficiency (kcat/Km), consistent with CYP2R1 being the major vitamin D 25-hydroxylase. 20-Hydroxyvitamin D3 [20(OH)D3], the main product of vitamin D3 activation by an alternative pathway catalyzed by CYP11A1, was metabolized by CYP2R1 to 20,25-dihydroxyvitamin D3 [20,25(OH)2D3], with catalytic efficiency similar to that for the 25-hydroxylation of vitamin D3. 20,25(OH)2D3 retained full, or somewhat enhanced activity compared to the parent 20(OH)D3 for the inhibition of the proliferation of melanocytes and dermal fibroblasts, with a potency comparable to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The 20,25(OH)2D3 was also able to act as an inverse agonist on retinoic acid-related orphan receptor α, like its parent 20(OH)D3. Thus, the major findings of this study are that CYP2R1 can metabolize substrates in a membrane environment, the enzyme displays higher catalytic efficiency than CYP27A1 for the 25-hydroxylation of vitamin D, it efficiently hydroxylates 20(OH)D3 at C25 and this product retains the biological activity of the parent compound.



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Vitamin D levels in childhood and adolescence and cardiovascular risk factors in a cohort of healthy Australian children

Publication date: Available online 15 July 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Larry Ke, Rebecca S. Mason, Louise A. Baur, Chris T. Cowell, Xiaoying Liu, Sarah P. Garnett, Kaye E. Brock
As the prevalence of obesity appears to be increasing in Australia's youth the overall objective of this study was to examine serum 25-hydroxyvitamin D (25OHD) concentrations in a cohort of 8-year-olds (n=249) followed up at age 15 (n=162) and explore associations between 25OHD with cardiovascular disease (CVD) risk factors in these populations. This was done in two stages: the first, two cross-sectional analyses (at ages 8 and 15); and the second, a prospective analysis from age 8 to 15. At both ages data on 25OHD, blood lipids, and anthropometry were measured. Date of blood draw was used as a surrogate of sunlight exposure. Results were then analysed by multivariate linear analyses taking into account interaction and confounding. Mean 25OHD concentrations decreased from 94±25nmol/L to 63±16nmol/L between age 8 and 15 years (p<0.001). On cross-sectional analysis of 8year olds, no CVD risk factor was found to be significantly associated with 25OHD concentrations. On cross-sectional analysis of 15year olds lower 25OHD levels were significantly associated with higher body fat (adjusted β=−0.24, p=0.003). Prospectively, lower 25OHD levels in 8-year-old boys, but not girls, were significantly associated with higher blood total cholesterol (adjusted β=−0.28, p=0.040) and triglyceride levels (adjusted β=−0.33, p=0.030) at age 15. The limitation of these data is the relatively small sample sizes, however these results suggest that low 25OHD in childhood needs to be further investigated in larger cohort studies as there may be later cardiovascular consequences in adolescence.



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Butyrate-inserted Ni–Ti layered double hydroxide film for H2O2-mediated tumor and bacteria killing

Publication date: Available online 13 July 2017
Source:Materials Today
Author(s): Donghui Wang, Feng Peng, Jinhua Li, Yuqin Qiao, Qianwen Li, Xuanyong Liu
The selective tumor- and bacteria-killing property is promising for biomedical implants in directly contact with tumor tissue but still presents a considerable challenge. In this study, a butyrate-inserted Ni–Ti layered double hydroxide film (LDH/Butyrate) is prepared on the surface of nitinol alloy via a simple hydrothermal treatment. The prepared film can selectively inhibit tumor growth and metastasis and bacterial infection by taking advantage of the overproduced H2O2 in tumor and infection microenvironments: the pro-tumor and pro-infection molecule H2O2 can be consumed by LDH/Butyrate, and cytotoxic butyrate inserted in LDH/Butyrate is subsequently exchanged out. Such a novel endogenous stimuli-responsive platform is expected to prevent tumor overgrowth, metastasis and bacterial infection and will find a promising application in the design of localized drug-eluting systems.

Graphical abstract

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Ex vivo and in vivo evaluation of microemulsion based transdermal delivery of E. coli specific T4 bacteriophage: A rationale approach to treat bacterial infection

Publication date: 30 September 2017
Source:European Journal of Pharmaceutical Sciences, Volume 107
Author(s): Vaibhav Rastogi, Pragya Yadav, Anurag Verma, Jayanta K. Pandit
This study is focused on the development and evaluation of transdermal delivery of E. coli-specific T4 bacteriophages both ex-vivo and in-vivo using microemulsion as delivery carrier in eradicating the infection caused by E. coli. Microemulsions were prepared by mixing selected oil, surfactants and aqueous phase containing bacteriophages. The formulations were subjected to physicochemical characterization, ex-vivo and in-vivo permeation, stability studies, histological and immunofluorescence examination. The colloidal system exhibits a uniform size distribution, of finite size (150–320nm). Transmission electron microscopy revealed the encapsulation of bacteriophage in the aqueous globule. Ex-vivo permeation across skin was successfully achieved as 6×10⁶PFU/mL and 6.7×10⁶PFU/mL of T4 permeated from ME 6% and 10%, respectively. ME 6% was found to be thermodynamically stable and in-vivo permeation resulted in 5.49×10⁵PFU/mL of bacteriophages in the blood of the E. coli challenged rats, while 2.48×10⁵PFU/mL was detected in germ free rats, at the end of the study. Infected rats that were treated with bacteriophage were survived while significant mortality was observed in others. Histological and IL-6 immunofluorescence examination of the tissues revealed the efficacy/safety of the therapy. The microemulsion-based transdermal delivery of bacteriophage could be a promising approach to treat the infections caused by antibiotic-resistant bacteria.

Graphical abstract

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Impact of pneumococcal conjugate vaccine (PCV7 and PCV13) on pneumococcal invasive diseases in Italian children and insight into evolution of pneumococcal population structure

Publication date: Available online 14 July 2017
Source:Vaccine
Author(s): Romina Camilli, Fabio D'Ambrosio, Maria Del Grosso, Fernanda Pimentel de Araujo, Maria Grazia Caporali, Martina Del Manso, Giovanni Gherardi, Fortunato D'Ancona, Annalisa Pantosti
BackgroundThe use of PCV7 for children immunization was gradually implemented in the Italian regions starting from 2006 and was replaced by PCV13 in 2010–2011. In this study we aimed to assess the PCV impact on invasive pneumococcal diseases (IPD) incidence, serotype distribution and antibiotic resistance in Italian children under 5years old.MethodsAll IPD cases in children from 5 Italian regions (Emilia-Romagna, Lombardia, A. P. Bolzano, A. P. Trento, and Piemonte) reported through the nationwide surveillance system during 2008–2014 were included in this study. Pneumococcal isolates were subjected to serotyping, antibiotic susceptibility testing, and clonal analysis according to standard methods.ResultsDuring the study period overall IPD incidence decreased from 7.8 cases/100,000 inhabitants in 2008 to 3.0 cases/100,000 in 2014 (61% decrease, P<0.001). In particular, from 2008 to 2014, PCV7-type IPD decreased from 2.92 to 0.13 cases/100,000 inhabitants (95% decrease, P<0.001) while PCV13-non-PCV7 type IPD decreased from 3.2 to 0.89 cases/100,000 inhabitants (72% decrease, P=0.008).Conversely, non-vaccine serotype (NVS) IPD increased overtime, becoming more common than PCV13 serotype IPD in 2013–2014. Emergent NVS 24F and 12F were the most prevalent in 2014. Antibiotic resistance testing revealed an overall increasing trend in penicillin resistance, from 14% in 2008 to 23% in 2014. Erythromycin resistance showed a downward trend, from 38% in 2008 to 27% in 2014. While in 2008 PCV13 serotypes were the major responsible for antibiotic resistance, during the following years antimicrobial resistance due to NVS increased, mainly as a result of expansion of pre-existing clones.ConclusionsBoth PCVs led to a substantial decrease in vaccine-related IPD incidence in the children population. However NVS-related IPD increased, becoming the most prevalent in the last two-years period. Continuous surveillance is an essential tool to monitor evolution of pneumococcal population causing IPD in children.



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Calcium phosphate nanoparticle (CaPNP) for dose-sparing of inactivated whole virus pandemic influenza A (H1N1) 2009 vaccine in mice

Publication date: Available online 14 July 2017
Source:Vaccine
Author(s): Tülin Morçӧl, Brett L. Hurst, E. Bart Tarbet
The emergence of pandemic influenza strains, particularly the reemergence of the swine-derived influenza A (H1N1) in 2009, is reaffirmation that influenza viruses are very adaptable and influenza remains as a significant global public health treat. As recommended by the World Health Organization (WHO), the use of adjuvants is an attractive approach to improve vaccine efficacy and allow dose-sparing during an influenza emergency. In this study, we utilized CaPtivate Pharmaceutical's proprietary calcium phosphate nanoparticles (CaPNP) vaccine adjuvant and delivery platform to formulate an inactivated whole virus influenza A/CA/04/2009 (H1N1pdm) vaccine as a potential dose-sparing strategy. We evaluated the relative immunogenicity and the efficacy of the formulation in BALB/c mice following single intramuscularly administration of three different doses (0.3, 1, or 3µg based on HA content) of the vaccine in comparison to non-adjuvanted or alum-adjuvant vaccines. We showed that, addition of CaPNP in vaccine elicited significantly higher hemagglutination inhibition (HAI), virus neutralization (VN), and IgG antibody titers, at all dose levels, relative to the non-adjuvanted vaccine. In addition, the vaccine containing CaPNP provided equal protection with 1/3rd of the antigen dose as compared to the non-adjuvanted or alum-adjuvanted vaccines. Our data provided support to earlier studies indicating that CaPNP is an attractive vaccine adjuvant and delivery system and should play an important role in the development of safe and efficacious dose-sparing vaccines. Our findings also warrant further investigation to validate CaPNP's capacity as an alternative adjuvant to the ones currently licensed for influenza/pandemic influenza vaccination.



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Erratum to: Dye removal of AR27 with enhanced degradation and power generation in a microbial fuel cell using bioanode of treated clinoptilolite-modified graphite felt

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Shaping and Reshaping Transcriptome Plasticity during Evolution

Publication date: Available online 14 July 2017
Source:Trends in Biochemical Sciences
Author(s): Shobbir Hussain
Transcriptome plasticity, usually associated with alternative isoform generation, is recognised as a key mechanism driving proteomic diversity and biological complexity. Recent findings of Liscovitch-Brauer et al. and Ma et al. suggest that RNA base modifications are an additional central mode of transcriptome malleability that have the potential to determine evolutionary outcomes.



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Cell Polarity Regulates Biased Myosin Activity and Dynamics during Asymmetric Cell Division via Drosophila Rho Kinase and Protein Kinase N

Publication date: Available online 14 July 2017
Source:Developmental Cell
Author(s): Anna Tsankova, Tri Thanh Pham, David Salvador Garcia, Fabian Otte, Clemens Cabernard
Cell and tissue morphogenesis depends on the correct regulation of non-muscle Myosin II, but how this motor protein is spatiotemporally controlled is incompletely understood. Here, we show that in asymmetrically dividing Drosophila neural stem cells, cell intrinsic polarity cues provide spatial and temporal information to regulate biased Myosin activity. Using live cell imaging and a genetically encoded Myosin activity sensor, we found that Drosophila Rho kinase (Rok) enriches for activated Myosin on the neuroblast cortex prior to nuclear envelope breakdown (NEB). After NEB, the conserved polarity protein Partner of Inscuteable (Pins) sequentially enriches Rok and Protein Kinase N (Pkn) on the apical neuroblast cortex. Our data suggest that apical Rok first increases phospho-Myosin, followed by Pkn-mediated Myosin downregulation, possibly through Rok inhibition. We propose that polarity-induced spatiotemporal control of Rok and Pkn is important for unequal cortical expansion, ensuring correct cleavage furrow positioning and the establishment of physical asymmetry.

Graphical abstract

Teaser

Most cells divide symmetrically, but several cell types are known to generate unequal-sized siblings with different functions. Tsankova et al. report that the conserved polarity protein Pins controls the activity of the motor protein Myosin through two protein kinases, to ensure that Drosophila neural stem cells divide asymmetrically.


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Electronic, magnetic properties of transition metal doped Tl2S: First-principles study

Publication date: 15 December 2017
Source:Applied Surface Science, Volume 425
Author(s): Nahong Song, Yusheng Wang, Weiyang Yu, Liying Zhang, Yuye Yang, Yu Jia
In this paper, the structural, electric and magnetic properties of transition metal (TM) doped monolayer Tl2S are investigated by means of first-principles methods The results show that all the considered TM atoms are strongly bonded to the Tl vacancy site. The magnetic moment, the dilute magnetic semiconductor and metal characteristics are varied depending on the specific TM atoms. The TM doped Tl2S (TM-Tl2S) (from Sc to Ni) systems have fractional magnetic moments changing from 0.539μB to 4.479μB. However, Cu- and Zn-Tl2S systems exit the nonmagnetic ground states. The spin polarized metallic states are achieved by Sc, Ti, V, Mn and Fe doping, while spin polarized semiconducting states are realized by Cr, Co and Ni doping. The charge transfer, the total magnetic moment and the band gap obtained with PBE method are less than the values obtained by PBE+U, which suggests that the Hubbard U plays an important role in TM-Tl2S systems. In the case of two same types of TM atoms doped Tl2S systems, there exist AFM in Sc-, V-, Mn-Tl2S systems and FM only in Ti-Tl2S system. Interestingly, the Cr-, Fe-, Co-, Ni-Tl2S systems manifest paramagnetic. These findings may provide a new route for exploring two-dimensional diluted magnetic semiconductors experimentally and theoretically.



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Fertility And Pregnancy Issues In Brca-Mutated Breast Cancer Patients

Publication date: Available online 14 July 2017
Source:Cancer Treatment Reviews
Author(s): Matteo Lambertini, Oranite Goldrat, Angela Toss, Hatem A. Azim, Fedro A. Peccatori, Michail Ignatiadis, Lucia Del Mastro, Isabelle Demeestere
Fertility and pregnancy-related issues represent one of the main areas of concerns for young women with breast cancer. Carrying a germline deleterious BRCA mutation adds additional burden on this regard due to the specific issues that should be considered during the oncofertility counseling of this special patient group. Despite the availability of a growing amount of data in the general breast cancer population on the feasibility and safety of fertility preservation and pregnancy after diagnosis, numerous challenges remain for BRCA-mutated breast cancer patients in whom very limited studies have been performed so far. Therefore, studies aiming to address the specific issues of these patients, including the impact of the mutation on their fertility potential, the safety and efficacy of the different strategies for fertility preservation, and the feasibility of having a pregnancy after diagnosis, should be considered a research priority.The aim of the present manuscript is to perform an in depth overview on the role of BRCA mutations in breast cancer with a specific focus on their impact on reproductive potential, and to discuss the fertility and pregnancy issues faced by BRCA-mutated breast cancer patients. The final goal of this manuscript is to highlight current and upcoming knowledge in this field for trying to help physicians dealing with these patients during oncofertility counseling.



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Effect of Frequency and Focal Spacing on Transcranial Histotripsy Clot Liquefaction, Using Electronic Focal Steering

Publication date: Available online 14 July 2017
Source:Ultrasound in Medicine & Biology
Author(s): Tyler Gerhardson, Jonathan R. Sukovich, Aditya S. Pandey, Timothy L. Hall, Charles A. Cain, Zhen Xu
This in vitro study investigated the effects of ultrasound frequency and focal spacing on blood clot liquefaction via transcranial histotripsy. Histotripsy pulses were delivered using two 256-element hemispherical transducers of different frequency (250 and 500 kHz) with 30-cm aperture diameters. A 4-cm diameter spherical volume of in vitro blood clot was treated through 3 excised human skullcaps by electronically steering the focus with frequency proportional focal spacing: λ/2, 2 λ/3 and λ with 50 pulses per location. The pulse repetition frequency across the volume was 200 Hz, corresponding to a duty cycle of 0.08% (250 kHz) and 0.04% (500 kHz) for each focal location. Skull heating during treatment was monitored. Liquefied clot was drained via catheter and syringe in the range of 6–59 mL in 0.9–42.4 min. The fastest rate was 16.6 mL/min. The best parameter combination was λ spacing at 500 kHz, which produced large liquefaction through 3 skullcaps (23.1 ± 4.0, 37.1 ± 16.9 and 25.4 ± 16.9 mL) with the fast rates (3.2 ± 0.6, 5.1 ± 2.3 and 3.5 ± 0.4 mL/min). The temperature rise through the 3 skullcaps remained below 4°C.



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Freehand 3-D Ultrasound Imaging: A Systematic Review

Publication date: Available online 14 July 2017
Source:Ultrasound in Medicine & Biology
Author(s): Mohammad Hamed Mozaffari, Won-Sook Lee
Two-dimensional ultrasound (US) imaging has been successfully used in clinical applications as a low-cost, portable and non-invasive image modality for more than three decades. Recent advances in computer science and technology illustrate the promise of the 3-D US modality as a medical imaging technique that is comparable to other prevalent modalities and that overcomes certain drawbacks of 2-D US. This systematic review covers freehand 3-D US imaging between 1970 and 2017, highlighting the current trends in research fields, the research methods, the main limitations, the leading researchers, standard assessment criteria and clinical applications. Freehand 3-D US systems are more prevalent in the academic environment, whereas in clinical applications and industrial research, most studies have focused on 3-D US transducers and improvement of hardware performance. This topic is still an interesting active area for researchers, and there remain many unsolved problems to be addressed.



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Training Midwives to Perform Basic Obstetric Point-of-Care Ultrasound in Rural Areas Using a Tablet Platform and Mobile Phone Transmission Technology—A WFUMB COE Project

Publication date: Available online 14 July 2017
Source:Ultrasound in Medicine & Biology
Author(s): Sudhir Vinayak, Joyce Sande, Harvey Nisenbaum, Christian Pállson Nolsøe
Point-of-care ultrasound (POCUS) has become a topical subject and can be applied in a variety of ways with differing outcomes. The cost of all diagnostic procedures including obstetric ultrasound examinations is a major factor in the developing world and POCUS is only useful if it can be equated to good outcomes at a lower cost than a routine obstetric examination. The aim of this study was to assess a number of processes including accuracy of images and reports generated by midwives, performance of a tablet-sized ultrasound scanner, training of midwives to complete ultrasounds, teleradiology solution transmissions of images via internet, review of images by a radiologist, communication between midwife and radiologist, use of this technique to identify high-risk patients and improvement of the education and teleradiology model components. The midwives had no previous experience in ultrasound. They were stationed in rural locations where POCUS was available for the first time. After scanning the patients, an interim report was generated by the midwives and sent electronically together with all images to the main hospital for validation. Unique software was used to send lossless images by mobile phone using a modem. Transmission times were short and quality of images transmitted was excellent. All reports were validated by two experienced radiologists in our department and returned to the centers using the same transmission software. The transmission times, quality of scans, quality of reports and other parameters were recorded and monitored. Analysis showed excellent correlation between provisional and validated reports. Reporting accuracy of scans performed by the midwives was 99.63%. Overall flow turnaround time (from patient presentation to validated report) was initially 35 min but reduced to 25 min. The unique mobile phone transmission was faultless and there was no degradation of image quality. We found excellent correlation between final outcomes of the pregnancies and diagnoses on the basis of reports generated by the midwives. Only 1 discrepancy was found in the midwives' reports. Scan results versus actual outcomes revealed 2 discrepancies in the 20 patients identified as high risk. In conclusion, we found that it is valuable to train midwives in POCUS to use an ultrasound tablet device and transmit images and reports via the internet to radiologists for review of accuracy. This focus on the identification of high-risk patients can be valuable in a remote healthcare facility.



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Unmyelinated Peripheral Nerves Can Be Stimulated in Vitro Using Pulsed Ultrasound

Publication date: Available online 14 July 2017
Source:Ultrasound in Medicine & Biology
Author(s): Christopher J. Wright, Seyyed R. Haqshenas, John Rothwell, Nader Saffari
Appreciation for the medical and research potential of ultrasound neuromodulation is growing rapidly, with potential applications in non-invasive treatment of neurodegenerative disease and functional brain mapping spurring recent progress. However, little progress has been made in our understanding of the ultrasound–tissue interaction. The current study tackles this issue by measuring compound action potentials (CAPs) from an ex vivo crab walking leg nerve bundle and analysing the acoustic nature of successful stimuli using a passive cavitation detector (PCD). An unimpeded ultrasound path, new acoustic analysis techniques and simple biological targets are used to detect different modes of cavitation and narrow down the candidate biological effectors with high sensitivity. In the present case, the constituents of unmyelinated axonal tissue alone are found to be sufficient to generate de novo action potentials under ultrasound, the stimulation of which is significantly correlated to the presence of inertial cavitation and is never observed in its absence.



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Non-invasive Evaluation of Right Ventricular Function with Real-Time 3-D Echocardiography

Publication date: Available online 14 July 2017
Source:Ultrasound in Medicine & Biology
Author(s): Ran Chen, Meihua Zhu, Kacie Amacher, Xia Wu, David J. Sahn, Muhammad Ashraf
The aim of this study was to evaluate the accuracy and feasibility of real-time 3-D echocardiography (3-DE) in assessing right ventricular (RV) systolic function. A latex balloon was inserted into the right ventricle of 20 freshly harvested pig hearts which were then passively driven by a pulsatile pump apparatus. The RV global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS) and RV ejection fraction (RVEF), derived from 3-DE, as well as the RVEF obtained from 2-D echocardiography (2-DE) were quantified at different stroke volumes (30–70 mL) and compared with sonomicrometry data. In all comparisons, 3-D GLS, GCS, GAS, 2-D RVEF and 3-D RVEF exhibited strong correlations with sonomicrometry data (r = 0.89, 0.79, 0.74, 0.80, and 0.93, respectively; all p values < 0.001). Bland–Altman analyses revealed slight overestimations of echo-derived GLS, GCS, 2-DE RVEF and 3-DE RVEF compared with sonomicrometry values (bias = 1.55, 2.72, 3.59 and 2.21, respectively). Furthermore, there is better agreement among GLS, 3-D RVEF and the sonomicrometry values than between GCS and 2-D RVEF. Real-time 3-DE is more feasible and accurate for assessing RV function than 2-DE. GLS is a potential alternative parameter for quantifying RV systolic function.



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Congenital undifferentiated sarcoma associated to BCOR-CCNB3 gene fusion

Publication date: Available online 14 July 2017
Source:Pathology - Research and Practice
Author(s): Clara Alfaro-Cervello, Verónica Andrade-Gamarra, Gema Nieto, Lara Navarro, Susana Martín-Vañó, Juan Pablo García de la Torre, Maria Bengoa Caamaño, Mª Luisa García Mauriño, Rosa Noguera, Samuel Navarro
Small round cell sarcomas are aggressive bone and soft tissue tumors that predominantly affect children and young adults. A new group of sarcomas with a recurrent BCOR-CCNB3 gene fusion has been recently identified in previously unclassifiable small round cell sarcomas. BCOR-CCNB3 sarcomas share clinical and pathologic similarities with Ewing sarcoma, but show a stronger male predilection and less aggressiveness, as well as distinct gene expression profiling and pangenomic SNP array analyses.We report the unusual case of a congenital BCOR-CCNB3 retroperitoneal sarcoma in a female born at 34th gestational week, which was diagnosed in necropsy after 21h of life. Immunohistochemical analysis showed diffuse expression of CD99 and CCNB3. SNPa showed two focal segmentary deletions at 5q34 and 22q11.23, the latter harboring among others the SMARCB1/INI1 tumor suppressor gene. Immunohistochemistry confirmed loss of INI1 in tumor cells, which has not been previously reported in this type of undifferentiated sarcomas.



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PKC-δ attenuates the cancer stem cell among squamous cell carcinoma cells through down-regulating p63

Publication date: Available online 14 July 2017
Source:Pathology - Research and Practice
Author(s): Dongmei Zhang, Mingjing Fu, Lingyan Li, Huan Ye, Zhiqi Song, Yongjun Piao
Protein kinase C delta (PKC-δ) has been identified as a tumor suppressor. However, the effects of PKC-δ on the cancer stem cells in squamous cell carcinomas (SCC) have not been clarified. The purpose of this study was to detect the regulation of PKC-δ on cancer stem cell among SSC cells and the role of p63 during the regulation.Immunohistochemistry of human cutaneous SCC tissues was performed to detect the expression of PKC-δ. After the human SCC13 cells infected by recombinant adenoviruses, the cell proliferation were determined. The correlation of PKC-δ and p63 was detected by western blot. The colony forming activity and the number of cancer stem cells (CSCs) in SCC identified by double-staining with anti-integrin α6 and anti-CD71 antibodies were detected.The expression of PKC-δ was obviously decreased in SCC tissues compared with that in normal skin tissues. The higher protein level of p63 in SCC was attenuated by the transfection of PKC-δ. The higher proliferation capacity of SCC13 cells, the higher activity and expression of CSCs in SCC13 cells induced by p63 were significantly suppressed by the transfection of PKC-δ.In conclusion, PKC-δ played as a protective role in SCC partly by down-regulating p63, leading to the suppression of SCC cell proliferation, attenuation of the activity and expression of CSCs in SCC cells.



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Is toll-like receptor-2 really inhibiting FoxP3+ TLR2+ cells and enhancing the anti-tumour response in oral squamous cell carcinoma?

Publication date: Available online 14 July 2017
Source:Acta Histochemica
Author(s): Xi Zeng, Mao Li, Guang-dong Liao, Ming-Rong Xi




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Structural, rheological, antioxidant, and functional properties of β–glucan extracted from edible mushrooms Agaricus bisporus, Pleurotus ostreatus and Coprinus attrimentarius

Publication date: Available online 14 July 2017
Source:Bioactive Carbohydrates and Dietary Fibre
Author(s): Asma Ashraf Khan, Adil Gani, F.A. Masoodi, Umar Mushtaq, Azza Silotry Naik
β-glucan was extracted from three edible mushroom varieties namely Agaricus bisporus, Pleurotus ostreatus and Coprinus attrimentarius using hot water extraction method. The extracted β-glucan was studied to investigate its structural, rheological, antioxidant and functional properties. The ATR-FTIR was used to elicit the structural conformations of the three β-glucan and SEM was used to study the surface topography. The rheological properties showed that with the increase in the concentration of β-glucan, the elastic behavior increased. The antioxidant activities were determined using different assays like DPPH (2, 2-diphenyl-1-picryl-hydrazyl), reducing power, metal chelating ability and ABTS (2,2-Azino-bis, 3-ethylbenzothiazoline-6- sulfonic acid) and all these activities varied significantly (p≤0.05) among all the β-glucan, however the β-glucan from Coprinus attrimentarius showed the highest values for all antioxidant activities. As far as the functional properties were concerned, Coprinus β-glucan also showed the highest swelling power, fat binding, emulsifying properties, bile acid binding capacity and viscosity, however foaming properties were the highest in Pleurotus β-glucan.

Graphical abstract

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Extract critical factors affecting the length of hospital stay of pneumonia patient by data mining (case study: an Iranian hospital)

Publication date: Available online 13 July 2017
Source:Artificial Intelligence in Medicine
Author(s): Naghmeh Khajehali, Somayeh Alizadeh
MotivationPneumonia is a prevalent infection of lower respiratory tract caused by infected lungs. Length of stay (LOS) in hospital is one of the simplest and most important indicators in hospital activity that is used for different purposes. The aim of this study is to explore the important factors affecting the LOS of patients with pneumonia in hospitals.MethodsThe clinical data set for the study were collected from 387 patients in a specialized hospital in Iran between 2009 and 2015. Patients discharge summary includes their demographic details, reasons for admission, prescribed medications for the patient, the result of laboratory tests, and length of treatment.Results and conclusionsThe proposed model in the study demonstrates the way various scenarios of data processing impact on the scale efficiency model, which points to the significance of the pre-processing in data mining. In this article, some methods were utilized; it is noteworthy that Bayesian boosting method led to better results in identifying the factors affecting LOS (accuracy 95.17%). In addition, it was found that 58% of patients younger than 15 years old and 74% of the elderly within the age range of 74–88 were more vulnerable to pneumonia disease. Also, it was found that the Meropenem is a relatively more effective medicine compared to other antibiotics which are used to treat pneumonia in the majority of age groups. Regardless of the impact of various laboratory findings (including CRP, ESR, WBC, NA, K), the patients LOS decreased as a result of Meropenem.



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Detection principles of biological and chemical FET sensors

Publication date: 15 December 2017
Source:Biosensors and Bioelectronics, Volume 98
Author(s): Matti Kaisti
The seminal importance of detecting ions and molecules for point-of-care tests has driven the search for more sensitive, specific, and robust sensors. Electronic detection holds promise for future miniaturized in-situ applications and can be integrated into existing electronic manufacturing processes and technology. The resulting small devices will be inherently well suited for multiplexed and parallel detection. In this review, different field-effect transistor (FET) structures and detection principles are discussed, including label-free and indirect detection mechanisms. The fundamental detection principle governing every potentiometric sensor is introduced, and different state-of-the-art FET sensor structures are reviewed. This is followed by an analysis of electrolyte interfaces and their influence on sensor operation. Finally, the fundamentals of different detection mechanisms are reviewed and some detection schemes are discussed. In the conclusion, current commercial efforts are briefly considered.



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Effect of limb dominance and sex on neuromuscular activation patterns in athletes under 12 performing unanticipated side-cuts

Publication date: Available online 14 July 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Michael Del Bel, Alana Fairfax, Michelle Jones, Kendal Steele, Scott Landry
Non-contact ACL injuries are one of the most common injuries to the knee joint among adolescent/collegiate athletes, with sex and limb dominance being identified as risk factors. In children under 12 years of age (U12), these injuries occur less often and there is no sex-bias present. This study set out to explore if sex and/or limb dominance differences exist in neuromuscular activations in U12 athletes. Thirty-four U12 males and females had six bilateral muscles analyzed during unanticipated side-cuts. Principal component analysis was performed, capturing differences in overall magnitudes and timing of peak magnitudes. Two-way mixed-model ANOVAs determined significant limb effects with both sexes displaying i) greater magnitudes in the lateral gastrocnemius and both hamstrings in the dominant limb and ii) earlier timing of peak magnitudes in both gastrocnemii, both hamstrings and vastus medialis in the non-dominant limb, while no sex differences were identified. This study demonstrated that limb dominance, not sex, affects neuromuscular activation strategies in U12 athletes during unanticipated side-cuts. When developing injury prevention programs for younger athletes, an increased focus on balancing neuromuscular activations in both limbs could be beneficial in reducing the likelihood of ACL injuries in these athletes as they mature through puberty.



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Voluntary activation of the trapezius muscle in cases with neck/shoulder pain compared to healthy controls

Publication date: Available online 14 July 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Katrine Tholstrup Bech, Camilla Marie Larsen, Gisela Sjøgaard, Andreas Holtermann, Janet L. Taylor, Karen Søgaard
Subjects reporting neck/shoulder pain have been shown to generate less force during maximal voluntary isometric contractions (MVC) of the shoulder muscles compared to healthy controls. This has been suggested to be caused by a pain-related decrease in voluntary activation (VA) rather than lack of muscle mass. The aim of the present study was to investigate VA of the trapezius muscle during MVCs in subjects with and without neck/shoulder pain by use of the twitch interpolation technique.Ten cases suffering from pain and ten age and gender matched, healthy controls were included in the study. Upper trapezius muscle thickness was measured using ultrasonography and pain intensity was measured on a 100 mm visual analog scale (VAS). VA was calculated from five maximal muscle activation attempts. Superimposed stimuli were delivered to the accessory nerve at peak force and during a 2% MVC following the maximal contraction.Presented as mean±SD for cases and controls, respectively: VAS; 16.0±14.4mm and 2.1±4.1mm (P=0.004), MVC; 545±161N and 664±195N (P=0.016), upper trapezius muscle thickness; 10.9±1.9mm and 10.4±1.5mm (P=0.20), VA; 93.6±14.2% and 96.3±6.0% (P=0.29).In spite of significantly eight-fold higher pain intensity and ∼20% lower MVC for cases compared to controls, no difference was found in VA. Possible explanations for the reduction in MVC could be differences in co-activation of antagonists and synergists as well as muscle quality.



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Autophagy suppresses isoprenaline-induced M2 macrophage polarization via the ROS/ERK and mTOR signaling pathway

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Meihua Shan, Junfang Qin, Fengjiao Jin, Xiao Han, Haitao Guan, Xiaoge Li, Jiahui Zhang, Hongyao Zhang, Yue Wang
The objective of this study was to examine the effect of autophagy on stress-induced M2 macrophage polarization in the tumor microenvironment of breast cancer and to determine whether the underlying mechanism was related to the reactive oxygen species (ROS)/ERK and mTOR pathway. In vitro, we found that the basal autophagy level in mouse RAW 264.7 macrophages decreased with the incubation of tumor cell culture supernatant. Similarly, the polarization of RAW 264.7 to M2 macrophages was inhibited by the autophagy inducer rapamycin and increased by the autophagy inhibitor 3-MA or by siBeclin1. In addition, we found that not only was M2 molecule expression down-regulated but intracellular ROS generation was also blocked by autophagy induction. In vivo, we observed that mice that received an isoprenaline injection as a stress agent exhibited augmented implanted breast tumor growth, lung metastasis, intratumoral mRNA expression of M2 molecules and serum ROS generation. In contrast, the intratumoral expression of LC3-II and Beclin1 was decreased. In addition, we observed that isoprenaline induced the up-regulation of the intratumoral expression of phosphorylated mTOR, phosphorylated ERK1/2, phosphorylated Tyr705-STAT3 and HIF-1α, whereas rapamycin induced an opposite effect on the same molecules and could abolish the effects of isoprenaline. These results suggest that autophagy might suppress M2 macrophage polarization induced by isoprenaline via the ROS/ERK and mTOR signaling pathway. Our findings provide a theoretical basis for why high levels of stress hormones accelerate the progression of breast cancer, and autophagy may play a role in determining the outcomes of cancer therapy.

Graphical abstract

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Serotonin depletion increases seizure susceptibility and worsens neuropathological outcomes in kainate model of epilepsy

Publication date: Available online 14 July 2017
Source:Brain Research Bulletin
Author(s): Gisela H. Maia, Cátia S. Brazete, Joana I. Soares, Liliana L. Luz, Nikolai V. Lukoyanov
Serotonin is implicated in the regulation of seizures, but whether or not it can potentiate the effects of epileptogenic factors is not fully established. Using the kainic acid model of epilepsy in rats, we tested the effects of serotonin depletion on (1) susceptibility to acute seizures, (2) development of spontaneous recurrent seizures and (3) behavioral and neuroanatomical sequelae of kainic acid treatment. Serotonin was depleted by pretreating rats with p-chlorophenylalanine. In different groups, kainic acid was injected at 3 different doses: 6.5mg/kg, 9.0mg/kg or 12.5mg/kg. A single dose of 6.5mg/kg of kainic acid reliably induced status epilepticus in p-chlorophenylalanine-pretreated rats, but not in saline-pretreated rats. The neuroexcitatory effects of kainic acid in the p-chlorophenylalanine-pretreated rats, but not in saline-pretreated rats, were associated with the presence of tonic-clonic convulsions and high lethality. Compared to controls, a greater portion of serotonin-depleted rats showed spontaneous recurrent seizures after kainic acid injections. Loss of hippocampal neurons and spatial memory deficits associated with kainic acid treatment were exacerbated by prior depletion of serotonin. The present findings are of particular importance because they suggest that low serotonin activity may represent one of the major risk factors for epilepsy and, thus, offer potentially relevant targets for prevention of epileptogenesis.



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Prelimbic α1-adrenoceptors are involved in the regulation of depressive-like behaviors in the hemiparkinsonian rats

Publication date: Available online 14 July 2017
Source:Brain Research Bulletin
Author(s): Zhong Heng Wu, Qiao Jun Zhang, Cheng Xue Du, Yue Xi, Wen Juan Li, Fang Yuan Guo, Shu Qi Yu, Ya Xin Yang, Jian Liu
At present, it is not clear whether α1-adrenoceptors in the prelimbic cortex (PrL) are involved in Parkinson's disease-related depression. Here we examined effects of PrL α1-adrenoceptors on depressive-like behaviors in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. The lesion induced depressive-like responses as measured by the sucrose preference and forced swim tests compared to sham-operated rats. Intra-PrL injection of α1-adrenoceptor agonist phenylephrine induced or increased the expression of depressive-like behaviors in sham-operated and the lesioned rats. Further, intra-PrL injection of α1-adrenoceptor antagonist benoxathian produced antidepressant effects in two groups of rats. Intra-PrL injection of phenylephrine increased the mean firing rate of PrL pyramidal neurons in both sham-operated and the lesioned rats, while benoxathian decreased the mean firing rate of the neurons. Compared to sham-operated rats, the duration of phenylephrine and benoxathian action on the firing rate of the pyramidal neurons was shortened in the lesioned rats. Neurochemical results showed that intra-PrL injection of phenylephrine or benoxathian increased or decreased dopamine and noradrenaline and serotonin levels in the medial prefrontal cortex, ventral hippocampus and habenula in sham-operated and the lesioned rats, respectively. Altogether, these results suggest that activation and blockade of α1-adrenoceptors in the PrL change the firing activity of the pyramidal neurons, and then increase or decrease levels of three monoamines in the limbic and limbic-related brain regions, which are involved in the regulation of depressive-like behaviors. Additionally, the results also suggest that the dopaminergic lesion leads to hypofunctionality of α1-adrenoceptors on pyramidal neurons of the PrL.



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Vincristine, Ifosfamide, and Doxorubicin for Initial Treatment of Ewing Sarcoma in Adults

AbstractBackground.There are no clinical trials specifically addressing chemotherapy for adults with Ewing sarcoma (ES). Five‐year event‐free survival (EFS) of adults on pediatric studies of ES (44%–47%) is worse than that of children treated with the same therapy (69%). The object of this study was to review the results of therapy with vincristine, ifosfamide, and doxorubicin (VID) in the multidisciplinary treatment of adults with ES at our institution.Materials and Methods.Charts for adults treated for ES from 1995 to 2011 were retrospectively reviewed. Clinician‐reported radiographic tumor response, type of local therapy, pathologic response, and survival data were collected.Results.Seventy‐one patients were identified who received VID as initial therapy. The median age was 25 (range: 16–64). Forty‐two patients (59%) presented with a localized disease and 29 patients (41%) presented with a distant metastasis. Of all patients treated with VID, 83.6% showed a radiological response. Patients who presented with a localized disease had a 5‐year overall survival (OS) of 68% (median not reached), compared with 10.3% (median: 1.9 years) in those who presented with distant metastases. Five‐year EFS was 67%. The nine patients with a pelvic primary tumor had inferior 5‐year OS (42%) to the 33 with primary tumors at other sites (75%). The 5‐year OS of those who had greater than or equal to 95% necrosis after neoadjuvant VID (n = 20; 5‐year OS: 84%) was superior to those who had less than 95% necrosis (n = 13; 5‐year OS: 53%).Conclusion.In adults with primary ES, VID combined with an adjuvant strategy based on post‐treatment percent necrosis has favorable outcomes compared with historical adult controls.Implications for Practice.Ewing sarcoma (ES) is a rare tumor in adults, and there are no dedicated clinical trials in the adult population. Most therapy is modeled after the published pediatric studies, although the small numbers of adult patients included on those studies did significantly worse than the children. We modeled our treatment on other adult sarcomas and reviewed the charts of 71 adult patients with ES treated with vincristine, ifosfamide, and doxorubicin (VID). In adults with primary ES, VID combined with an adjuvant strategy based on post‐treatment percent necrosis has favorable outcomes compared with historical adult controls.

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Robert L. Comis: In Memoriam

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Geochemical characteristics of dissolved rare earth elements in acid mine drainage from abandoned high-As coal mining area, southwestern China

Abstract

Acid mine drainage (AMD) represents a major source of water pollution in the small watershed of Xingren coalfield in southwestern Guizhou Province. A detailed geochemical study was performed to investigate the origin, distribution, and migration of REEs by determining the concentrations of REEs and major solutes in AMD samples, concentrations of REEs in coal, bedrocks, and sediment samples, and modeling REEs aqueous species. The results highlighted that all water samples collected in the mining area are identified as low pH, high concentrations of Fe, Al, SO₄²⁻ and distinctive As and REEs. The spatial distributions of REEs showed a peak in where it is nearby the location of discharging of AMD, and then decrease significantly with distance away from the mining areas. Lots of labile REEs have an origin of coal and bedrocks, whereas the acid produced by the oxidation of pyrite is a prerequisite to cause the dissolution of coal and bedrocks, and then promoting REEs release in AMD. The North American Shale Composite (NASC)-normalized REE patterns of coal and bedrocks are enriched in light REEs (LREEs) and middle REEs (MREEs) relative to heavy REEs (HREEs). Contrary to these solid samples, AMD samples showed slightly enrichment of MREEs compared with LREEs and HREEs. This behavior implied that REEs probably fractionate during acid leaching, dissolution of bedrocks, and subsequent transport, so that the MREEs is primarily enriched in AMD samples. Calculation of REEs inorganic species for AMD demonstrated that sulfate complexes (Ln(SO₄)⁺and Ln(SO₄)₂⁻) predominate in these species, accounting for most of proportions for the total REEs species. The high concentrations of dissolved SO₄²⁻ and low pH play a decisive role in controlling the presence of REEs in AMD, as these conditions are necessary for formation of stable REEs-sulfate complexes in current study. The migration and transportation of REEs in AMD are more likely constrained by adsorption and co-precipitation of Fe-Al hydroxides/hydroxysulfate. In addition, the MREEs is preferentially captured by poorly crystalline Fe-Al hydroxides/hydroxysulfate, which favors that sediments also preserve NASC-normalized patterns with MREEs enrichment in the stream.

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Assessing the chemical behavior and spatial distribution of yttrium and rare earth elements (YREEs) in a coastal aquifer adjacent to the Urmia Hypersaline Lake, NW Iran

Abstract

This study aims to shed light on the seasonal behavior of yttrium and rare earth elements (YREEs) in the Urmia Aquifer (UA), in the immediate vicinity of Urmia Lake (UL) in Iran. Samples of groundwater, collected under dry and wet conditions in coastal wells of UA, suggest a large degree of variability in both YREE abundance and normalized patterns. Although weathering or water-rock interactions (between the surface/groundwater and rock samples) were predicted to be the most probable source in explaining YREEs in groundwater samples, results to the contrary indicate that the groundwater do not inherit aquifer rock-like YREE signatures in the study area; this might be due to the relative stability of YREEs during the process of water-rock interactions, which suggest that methods based on YREEs can be beneficial in discrimination of water sources. Furthermore, findings demonstrated no significant relationship between Ce/Ce* and salinity (0.08 and 0.05 in wet and dry seasons, respectively), and between Eu/Eu* and salinity (0.1 and −0.04 in wet and dry seasons, respectively). Dissimilarity of patterns of YREEs in rock and water samples reveals YREEs as no conservative tracers in determining the UL saltwater intrusion into coastal groundwater. Therefore, the groundwater YREE concentrations and fractionation patterns in UA warrant controlling by coastal aquifer need to be controlled by other chemical weathering, adsorption, desorption, and solution complexation reactions. Finally, comparison of REE concentration values in groundwater samples with corresponding indicative admissible drinking water concentrations (IAC) demonstrated their suitability for drinking purposes.

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Multi-class determination of pharmaceuticals in wastewaters by solid-phase extraction and liquid chromatography tandem mass spectrometry with matrix effect study

Abstract

In this work, a multi-class analytical method for determination of 22 frequently used pharmaceuticals was developed and validated. Analytes were from different classes for example macrolides, fluoroquinolones, tetracyclines, sulfonamides, anthelmintics, anesthetics, and others. Method was intended for analysis of aqueous samples so the sample preparation was done using solid-phase extraction (SPE). Different sorbents (C8, C18, polymeric, and ion exchange sorbents) combining different eluents (methanol, ethanol, acetonitrile, acetone, ethyl acetate) were investigated during development of sample preparation step. Samples were analyzed using HPLC-MS/MS, and therefore, chromatographic and mass spectrometer conditions were investigated. Optimal extraction efficiencies for most of the investigated analytes were obtained with Oasis HLB polymeric sorbents with acetonitrile as eluent. A study of matrix effect was carried out for wastewater treatment plant (WWTP) influent and effluent. The method was validated for linearity, detection limits and quantification limits, repeatability, and reproducibility. Method detection limits were in the range of 2.0–204.0 ng L⁻¹ for WWTP influent except for sulfaguanidine and dexamethasone. Also, method detection limits for WWTP effluent were from 1.0 to 115.4 ng L⁻¹. Method was successfully applied for analysis of real wastewater samples from municipal wastewater treatment plant. In the influent, pharmaceuticals from all investigated groups were present and the concentrations were from 50.0 to 4914.3 ng L⁻¹ for influent and 26.9 to 1699.2 ng L⁻¹ for effluent. It was also reported that some pharmaceuticals showed higher concentrations in the wastewater effluent than in the influent.

http://ift.tt/2tpB8nZ

Long term fine aerosols at the Cape Grim global baseline station: 1998 to 2016

Publication date: October 2017
Source:Atmospheric Environment, Volume 166
Author(s): Jagoda Crawford, David D. Cohen, Eduard Stelcer, Armand J. Atanacio
Fine aerosol measurements have been undertaken at the Cape Grim global baseline station since 1992. Ion beam analysis techniques were then used to determine the elemental composition of the samples from which source fingerprints can be determined. In this study six source fingerprints were identified to contribute to the measurements of PM2.5 at Cape Grim (from 1998 to 2016); fresh sea salt (57%), secondary sulfate and nitrates (14%), smoke (13%), aged sea salt (the product of NaCl reactions with SO2; 12%), soil dust (2.4%) and industrial metals (1.5%). Back trajectory analysis showed that local Tasmanian sources of soil dust contributed to the high soil dust measurements. High measurements of secondary aerosols were recorded when air masses were arriving from the Australian mainland, in the direction of the Victorian power stations.When air masses were arriving from the baseline sector, the maximum concentration of aged sea salt was 1.3 μg/m³, compared to overall maximum of 4.9 μg/m³. For secondary sulfates and nitrates the maximum concentrations were 2.5 and 7.5 μg/m³ from the baseline sector and overall, respectively. While measurements at Cape Grim can be affected from long range transport from mainland Australia and some local Tasmanian sources, the average concentrations of anthropogenic sources are still considerably lower than those measured at more populated areas. For example, at Lucas Heights (located south-west of the Sydney central business district, with little local sources) the average concentrations of secondary sulfates/nitrates and aged sea air were 1.4 and 1.0 μg/m³, respectively; compared to average concentrations of 0.8 and 0.6 μg/m³, at Cape Grim. The average concentrations of smoke were compatible at the two sites. The impact of primary aerosols from vehicle exhaust at Cape Grim was limited and no corresponding fingerprint was resolved.



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Modeling dry deposition of reactive nitrogen in China with RAMS-CMAQ

Publication date: October 2017
Source:Atmospheric Environment, Volume 166
Author(s): Xiao Han, Meigen Zhang, Andrei Skorokhod, Xingxia Kou
China has the world highest production of reactive nitrogen (Nr), and the Nr consumption increased sharply during the last decade. However, the potential environmental influence of dry nitrogen (N) deposition in China remains uncertain due to that the long-term measurement or remote sensing of various N species are difficult. This requires a better understanding of dry N deposition over China in its various forms and including magnitude and distribution features. Thus, the air quality modeling system RAMS-CMAQ was applied to simulate dry deposition of Nr over China from 2010 to 2014. The model results were then analyzed to investigate the long-term spatial and temporal distributions of major inorganic nitrogen (N) components (10 species) and selected organic N components (5 species). Comparisons between modeled and observed deposition rates and surface mass concentrations showed generally good agreement. Model results indicated a total dry N deposition budget of 9.31 Tg N yr⁻¹ in China, including 4.29 Tg N yr⁻¹ as NOy and 4.43 Tg N yr⁻¹ as NH3. NOy was the main component of dry N deposition in the Beijing-Tianjin-Hebei area (0.31  Tg N yr⁻¹), the Yangtze River Delta (0.29  Tg N yr⁻¹), and the Pearl River Delta (0.09  Tg N yr⁻¹), where the major megacity clusters of China are located. NH3 was the main component of dry N deposition in Shandong province (0.24  Tg N yr⁻¹), Northeast China (0.46  Tg N yr⁻¹), the Sichuan Basin (0.48  Tg N yr⁻¹), and central China (0.95  Tg N yr⁻¹), where the major agricultural regions are located. The highest values of the deposition flux for NH3 occurred in Shandong province (19.40  kg N ha⁻¹ yr⁻¹) and Beijing-Tianjin-Hebei (17.20  kg N ha⁻¹ yr⁻¹). The seasonal variation of total dry N deposition was obvious in the east part of China, and was higher in July and lower in January. The spatio-temporal variations and major sources of dry N deposition were strongly heterogeneous, implying that the comprehensive pollution control strategies should be implemented to reduce the risk associated with N deposition.



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Quantifying primary and secondary source contributions to ultrafine particles in the UK urban background

Publication date: October 2017
Source:Atmospheric Environment, Volume 166
Author(s): S.M.L. Hama, R.L. Cordell, P.S. Monks
Total particle number (TNC, ≥7 nm diameter), particulate matter (PM2.5), equivalent black carbon (eBC) and gaseous pollutants (NO, NO2, NOx, O3, CO) have been measured at an urban background site in Leicester over two years (2014 and 2015). A derived chemical climatology for the pollutants showed maximum concentrations for all pollutants during the cold period except O3 which peaked during spring. Quantification of primary and secondary sources of ultrafine particles (UFPs) was undertaken using eBC as a tracer for the primary particle number concentration in the Leicester urban area. At the urban background site, which is influenced by fresh vehicle exhaust emissions, TNC was segregated into two components, TNC = N1 + N2. The component N1 represents components directly emitted as particles and compounds which nucleate immediately after emission. The component N2 represents the particles formed during the dilution and cooling of vehicle exhaust emissions and by in situ new particle formation (NPF). The values of highest N1 (49%) were recorded during the morning rush hours (07:00–09:00 h), correlating with NOx, while the maximum contribution of N2 to TNC was found at midday (11:00–14:00 h), at around 62%, correlated with O3. Generally, the percentage of N2 (57%) was greater than the percentage of N1 (43%) for all days at the AURN site over the period of the study. For the first time the impact of wind speed and direction on N1 and N2 was explored. The overall data analysis shows that there are two major sources contributing to TNC in Leicester: primary sources (traffic emissions) and secondary sources, with the majority of particles being of secondary origin.

Graphical abstract

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Economic growth and environmental pollution in Myanmar: an analysis of environmental Kuznets curve

Abstract

This empirical study examines the short- and long-run relationship between GDP as an economic growth indicator and CO₂ emissions as an environmental pollution indicator in Myanmar by using annual time series data over the period of 1970–2014. It also carefully considered other proxies, such as trade openness, financial openness and urbanization, and structural breaks in the country. The fundamental objective of this study is to test the validity of environmental Kuznets curve (EKC) in the context of Myanmar. The dynamic estimates of the long- and short-term relationship among greenhouse gases (CO₂, CH₄, N₂O), GDP, trade intensity, financial openness, and urbanization growth are built through an autoregressive distributed lag (ARDL) model. The empirical findings indicate that there is positive short- and long-run relationship between CO₂ and GDP and thus, no evidence of EKC hypothesis is found for CO₂ in Myanmar. Nevertheless, the existence of the EKC is observed for CH₄ and N₂O. On the other hand, trade and financial openness have inverse relationship with CO₂ emissions. These results demonstrate that trade liberalization and financial openness will improve the environment quality in Myanmar in the long run.

http://ift.tt/2uoAOtJ

Erratum to: Long-Term Follow-Up after Phrenic Nerve Reconstruction for Diaphragmatic Paralysis: A Review of 180 Patients

J reconstr Microsurg
DOI: 10.1055/s-0037-1604271

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Full text

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Effects of salinity, C/S ratio, S/N ratio on the BESI process, and treatment of nanofiltration concentrate

Abstract

A laboratory-scale biodegradation and electron transfer based on the sulfur metabolism in the integrated (BESI^®) process was used to treat a saline petrochemical nanofiltration concentrate (NFC). The integrated process consisted of activated sludge sulfate reduction (SR), and sulfide oxidation (SO) reactors, and a biofilm nitrification reactor. During the process, the total removal efficiencies of chemical oxygen demand (COD), ammonia nitrogen, and total nitrogen (TN) were 76.2, 83.8, and 73.1%, respectively. In the SR reactor, most of the organic degradation occurred and approximately 70% COD were removed by the sulfate-reducing bacteria (SRB). In the SO reactor, both the autotrophic and heterotrophic denitrifications were observed to take place. In parallel, batch experiments were conducted to detect the effects of different C/S and S/N ratios on COD removal and denitrification efficiency. The batch experiments were also conducted to detect the effects of salinity on COD and sulfate reduction. The composition of pollutants in the wastewater was complex, and some existing organics were not degraded by the SRB. The non-SRB groups also played important roles in the reactor. Under salinity-induced stress, the metabolisms of the SRBs and non-SRB groups were both inhibited. However, 6 g/L NaCl did not have much effect on the final COD removal efficiency. In the batch experiments, the added sulfide served as the electron donor for autotrophic denitrification. The added organics provided substance for heterotrophic denitrification.

http://ift.tt/2tp83JD

Remediation of chromium-contaminated soil by electrokinetics and electrokinetics coupled with CaAl-LDH permeable reaction barrier

Abstract

The remediation of Cr(VI)-contaminated soil was investigated by electrokinetic (EK) and permeable-reactive-barrier assisted electrokinetic (EK-PRB). The medium of PRB was hydrocalumite (CaAl-LDH). The results showed that removal efficiency of hexavalent chromium (Cr(VI)) in EK-PRB and EK system was 96.49 and 85.50%, respectively. Simultaneously, the removal efficiency of total chromium (TCr) was 69.34 and 40.97% after 120-h treatment. The XRD, FTIR, and XPS analyses indicated that the reactive barrier media of CaAl-LDH successfully captured the chromium. Besides, the migration rate of chromium in EK-PRB was relatively faster than EK, since the media of PRB captured chromium in-time and reduced the influence of chromium accumulation on the migration of chromium. Moreover, the trivalent chromium (Cr(III)) was generated in EK/EK-PRB, and the chromium was stabilized in soil with the chemical speciations of oxidizable and residual fractions. Therefore, the treatment of EK-PRB and EK both increased the removal of chromium and decreased its environmental risks.

http://ift.tt/2tTcJuF

Color Pupillography in Dorsal Midbrain Syndrome.

Objective: The purpose of this study was to evaluate the pupil response to chromatic stimuli in patients with lesions in the dorsal midbrain and possibly gain new insights into the afferent pupillary pathways. Methods: Color pupillography was performed in 5 patients with dorsal midbrain syndrome (DMS), and their results were compared with those of 20 healthy control subjects. We used full-field red stimuli (605 nm) that primarily address the rod/cone system and blue stimuli (420 nm) that preferentially activate intrinsically photosensitive retinal ganglion cells (ipRGCs) directly, with a duration of 4 seconds and a stimulus intensity of 28 lx corneal illumination under mesopic conditions. One eye was stimulated, and the consensual pupil response was recorded and analyzed. Results: The pupillary light reflex in patients with DMS was reduced, differed in shape, and showed a prolonged latency time compared to normal subjects. The blue response was less affected than the red response: the mean maximal relative amplitude (M) was 15.8% (SD = 7.8) in patients with DMS compared with 43.0% (SD = 5.5) in normal subjects for red stimulation, and M = 40.8%, SD = 8.4 (DMS) with M = 58.3%, SD = 4.8 (normals) for blue stimulation. The reduction was 63% for red stimulation but only 30% for blue stimulation in patients with DMS. Moreover, there was a preserved postillumination pupil response to blue stimulation in DMS patients. Conclusions: In DMS, the melanopsin-mediated ipRGC pathway appeared relatively preserved. (C) 2017 by North American Neuro-Ophthalmology Society

http://ift.tt/2uoaIav

AIR-MRF: Accelerated iterative reconstruction for magnetic resonance fingerprinting

Publication date: Available online 14 July 2017
Source:Magnetic Resonance Imaging
Author(s): Christopher C. Cline, Xiao Chen, Boris Mailhe, Qiu Wang, Josef Pfeuffer, Mathias Nittka, Mark A. Griswold, Peter Speier, Mariappan S. Nadar
Existing approaches for reconstruction of multiparametric maps with magnetic resonance fingerprinting (MRF) are currently limited by their estimation accuracy and reconstruction time. We aimed to address these issues with a novel combination of iterative reconstruction, fingerprint compression, additional regularization, and accelerated dictionary search methods. The pipeline described here, accelerated iterative reconstruction for magnetic resonance fingerprinting (AIR-MRF), was evaluated with simulations as well as phantom and in vivo scans. We found that the AIR-MRF pipeline provided reduced parameter estimation errors compared to non-iterative and other iterative methods, particularly at shorter sequence lengths. Accelerated dictionary search methods incorporated into the iterative pipeline reduced the reconstruction time at little cost of quality.



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Assessing Residents’ Readiness for OR Autonomy: A Qualitative Descriptive Study of Expert Surgical Teachers’ Best Practices

Publication date: Available online 13 July 2017
Source:Journal of Surgical Education
Author(s): Xiaodong (Phoenix) Chen, Amy M. Sullivan, Adnan Alseidi, Gifty Kwakye, Douglas S. Smink
PurposeProviding resident autonomy in the operating room (OR) is one of the major challenges for surgical educators today. The purpose of this study was to explore what approaches expert surgical teachers use to assess residents' readiness for autonomy in the OR. We particularly focused on the assessments that experts make prior to conducting the surgical time-out.MethodsWe conducted semistructured in-depth interviews with expert surgical teachers from March 2016 to September 2016. Purposeful sampling and snowball sampling were applied to identify and recruit expert surgical teachers from general surgery residency programs across the United States to represent a range of clinical subspecialties. All interviews were audio-recorded, deidentified, and transcribed. We applied the Framework Method of content analysis, discussed and reached final consensus on the themes.ResultsWe interviewed 15 expert teachers from 9 institutions. The majority (13/15) were Program or Associate Program Directors; 47% (7/15) primarily performed complex surgical operations (e.g., endocrine surgery). Five themes regarding how expert surgical teachers determine residents' readiness for OR autonomy before the surgical time-out emerged. These included 3 domains of evidence elicited about the resident (resident characteristics, medical knowledge, and beyond the current OR case), 1 variable relating to attending characteristics, and 1 variable composed of contextual factors. Experts obtained one or more examples of evidence, and adjusted residents' initial autonomy using factors from the attending variable and the context variable.ConclusionsExpert surgical teachers' assessments of residents' readiness for OR autonomy included 5 key components. Better understanding these inputs can contribute to both faculty and resident development, enabling increased resident autonomy and preparation for independent practice.



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The Role of the Operating Room in Medical Student Education: Differing Perspectives of Learners and Educators

Publication date: Available online 13 July 2017
Source:Journal of Surgical Education
Author(s): Rebecca O'Neill, Michael Shapiro, Aziz Merchant
ObjectiveThe surgical clerkship is an integral part of third-year medical student education. The operating room (OR) is a heavily used setting, but it is unclear whether this setting is as effective as possible. To determine the role of the OR and potential improvements, it is necessary to analyze the perspectives of those involved, including surgeons, residents, and medical students.DesignAn electronic survey was distributed to the surgeons, surgical residents, and third-year medical students associated with Rutgers New Jersey Medical School. The questions were a combination of 5-point Likert scale questions and qualitative responses. The questions assessed the role of the OR, the information taught in the OR, the quality of the teaching and environment, and potential improvements.ResultsAttending surgeons and residents generally rated the OR more positively than medical students did. Medical students desired more hands-on participation and a greater focus on learning technical skills. In addition, most medical students rated the feedback and direct instruction in the OR as "poor." Furthermore, the attending surgeons and medical students disagreed about the main roles of the OR as well as the effectiveness of teaching in the OR. The medical students reported experiencing anxiety and intimidation in the OR and suggested several improvements, such as decreasing the length of the surgical clerkship.ConclusionsThere is significant disagreement between the surgeons and residents and the medical students regarding the roles and effectiveness of learning in the OR. This may help explain the reported medical student dissatisfaction and frustrations with the surgical clerkship.



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Enhancing Medical Curricula: The Role of a 1-Day Plastic Surgery Course as an Educational Adjunct for Medical Students

Publication date: Available online 13 July 2017
Source:Journal of Surgical Education
Author(s): Harry V.M. Spiers, Alexander Zargaran, Aasim Nisar Murtaza, Amal Thomas, Mohammed Adil A. Turki, Farida Ali
IntroductionPlastic surgery is underrepresented in medical school curricula. The St George׳s Surgical Society hosted a 1-day undergraduate course in plastic surgery. Our aim was to introduce students to plastic surgery and teach basic plastic surgical skills.MethodologyThe skills day consisted of lectures from consultants and a core trainee followed by registrar-taught workshops in suturing, tendon repair, and local flap design. Precourse and postcourse questionnaires assessed perceptions of plastic surgery, confidence in performing basic plastic surgical skills, and usefulness of course components.ResultsMany perceptions of plastic surgery saw statistically significant changes. The belief that plastic surgery covers a wide range of specialties increased by 36% (p = 0.01). A −32% change (p = 0.00) was seen in the perception of plastic surgery only being pursued as a career for financial gain. Delegates reported greater confidence in all components of basic plastic surgical skills. The most useful activity was reported as performing surgical skills on real tissue.ConclusionA 1-day course can significantly increase positive perceptions of plastic surgery, dispel preconceived false stereotypes, while improving student confidence in performing basic plastic surgery skills. It is important that university surgical societies provide opportunities for student education, to aid informed decisions about future careers.



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Editorial Overview: Antigen Processing and Presentation; many fingers in many pies

Publication date: Available online 14 July 2017
Source:Current Opinion in Immunology
Author(s): Peter Cresswell, Paul A Roche




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Ovarian aromatase loss-of-function mutant medaka undergo ovary degeneration and partial female-to-male sex reversal after puberty

Publication date: Available online 13 July 2017
Source:Molecular and Cellular Endocrinology
Author(s): Masatoshi Nakamoto, Yasushi Shibata, Kaoru Ohno, Takeshi Usami, Yasuhiro Kamei, Yoshihito Taniguchi, Takeshi Todo, Takashi Sakamoto, Graham Young, Penny Swanson, Kiyoshi Naruse, Yoshitaka Nagahama
Although estrogens have been generally considered to play a critical role in ovarian differentiation in non-mammalian vertebrates, the specific functions of estrogens during ovarian differentiation remain unclear. We isolated two mutants with premature stops in the ovarian aromatase (cyp19a1) gene from an N-ethyl-N-nitrosourea-based gene-driven mutagenesis library of the medaka, Oryzias latipes. In XX mutants, gonads first differentiated into normal ovaries containing many ovarian follicles that failed to accumulate yolk. Subsequently, ovarian tissues underwent extensive degeneration, followed by the appearance of testicular tissues on the dorsal side of ovaries. In the newly formed testicular tissue, strong expression of gsdf was detected in sox9a2-positive somatic cells surrounding germline stem cells suggesting that gsdf plays an important role in testicular differentiation during estrogen-depleted female-to-male sex reversal. We conclude that endogenous estrogens synthesized after fertilization are not essential for early ovarian differentiation but are critical for the maintenance of adult ovaries.



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MRTF-A mediated FN and ICAM-1 expression in AGEs-induced rat glomerular mesangial cells via activating STAT5

Publication date: Available online 13 July 2017
Source:Molecular and Cellular Endocrinology
Author(s): Qiuhong Chen, Junying Huang, Wenyan Gong, Zhiquan Chen, Jiani Huang, Peiqing Liu, Heqing Huang
Advanced glycation end products (AGEs), formed at an accelerated rate under diabetes, play a role in inflammation and fibrosis in mesangial areas in diabetic nephropathy (DN). However, the transcriptional modulator that mediates the cellular response to AGEs remains largely obscure. Our goal was to determine whether myocardin-related transcription factor (MRTF)-A, a key protein involved in the transcriptional regulation of smooth muscle cell phenotype, was responsible for the glomerular mesangial cells (GMCs) injury by AGEs, and, if so, how MRTF-A promoted mesangial dysfunction initiated by AGEs. In this study, MRTF-A was activated by AGEs in terms of protein expression and nuclear translocation in rat GMCs. MRTF-A overexpression synergistically enhanced the induction of FN and ICAM-1 by AGEs. In contract, depletion of MRTF-A abrogated the pathogenic program triggered by AGEs. Then, by interfering with MRTF-A, STAT1, STAT3 and STAT5 nuclear translocation were observed and we screened out STAT5, which was decreased obviously when MRTF-A depleted. Further investigation showed that MRTF-A interacted with STAT5 and promoted its nuclear accumulation and transcriptional activity. Therefore, our present findings suggested a role of MRTF-A in AGEs-induced GMCs injury, and further revealed that the underlying molecular mechanism was related to activating the nuclear factor STAT5.

Graphical abstract

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Clonal Evolution in Paired Endometrial Intraepithelial Neoplasia/Atypical Hyperplasia and Endometrioid Adenocarcinoma

Publication date: Available online 14 July 2017
Source:Human Pathology
Author(s): Mariano Russo, James Broach, Kathryn Sheldon, Kenneth R. Houser, Dajiang J. Liu, Joshua Kesterson, Rebecca Phaeton, Carrie Hossler, Nadine Hempel, Maria Baker, Jordan M. Newell, Richard Zaino, Joshua I. Warrick
Endometrial intraepithelial neoplasia (EIN) and atypical endometrial hyperplasia (AH) are histomorphologically-defined precursors to endometrioid adenocarcinoma, which are unified as EIN/AH by the World Health Organization. EIN/AH harbors a constellation of molecular alterations similar those found in endometrioid adenocarcinoma. However, the process of clonal evolution from EIN/AH to carcinoma is poorly characterized. To investigate, we performed next generation sequencing, copy number alteration (CNA) analysis, and immunohistochemistry for mismatch repair protein expression on EIN/AH and endometrioid adenocarcinoma samples from 6 hysterectomy cases with spatially distinct EIN/AH and carcinoma. In evaluating all samples, EIN/AH and carcinoma did not differ in mutational burden, CNA burden, or specific genes mutated (all p>0.1). All paired EIN/AH and carcinoma samples shared at least one identical somatic mutation, frequently in PI(3)K pathway members. Large CNAs (>10 genes in length) were identified in 83% of cases; paired EIN/AH and carcinoma samples shared at least one identical CNA in these cases. Mismatch repair protein expression matched in all paired EIN/AH and carcinoma samples. All paired EIN/AH and carcinoma samples had identical TCGA (The Cancer Genome Atlas) subtype, with three classified as "copy number low endometrioid" and three classified as "microsatellite instability hypermutated." While paired EIN/AH and carcinoma samples were clonal, private mutations (i.e. present in only one sample) were identified in EIN/AH and carcinoma in all cases, frequently in established cancer-driving genes. These findings indicate that EIN/AH gives rise to endometrioid adenocarcinoma by a complex process of subclone evolution, not a linear accumulation of molecular events.



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Emergency Medical Services Perspectives on Identifying and Reporting Victims of Elder Abuse, Neglect, and Self-Neglect

Publication date: Available online 13 July 2017
Source:The Journal of Emergency Medicine
Author(s): Tony Rosen, Cynthia Lien, Michael E. Stern, Elizabeth M. Bloemen, Regina Mysliwiec, Thomas J. McCarthy, Sunday Clark, Mary R. Mulcare, Daniel S. Ribaudo, Mark S. Lachs, Karl Pillemer, Neal E. Flomenbaum
BackgroundEmergency Medical Services (EMS) providers, who perform initial assessments of ill and injured patients, often in a patient's home, are uniquely positioned to identify potential victims of elder abuse, neglect, or self-neglect. Despite this, few organized programs exist to ensure that EMS concerns are communicated to or further investigated by other health care providers, social workers, or the authorities.ObjectiveTo explore attitudes and self-reported practices of EMS providers surrounding identification and reporting of elder mistreatment.MethodsFive semi-structured focus groups with 27 EMS providers.ResultsParticipants reported believing they frequently encountered and were able to identify potential elder mistreatment victims. Many reported infrequently discussing their concerns with other health care providers or social workers and not reporting them to the authorities due to barriers: 1) lack of EMS protocols or training specific to vulnerable elders; 2) challenges in communication with emergency department providers, including social workers, who are often unavailable or not receptive; 3) time limitations; and 4) lack of follow-up when EMS providers do report concerns. Many participants reported interest in adopting protocols to assist in elder protection. Additional strategies included photographically documenting the home environment, additional training, improved direct communication with social workers, a dedicated location on existing forms or new form to document concerns, a reporting hotline, a system to provide feedback to EMS, and community paramedicine.ConclusionsEMS providers frequently identify potential victims of elder abuse, neglect, and self-neglect, but significant barriers to reporting exist. Strategies to empower EMS providers and improve reporting were identified.



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The Editor's Choice

Publication date: August 2017
Source:Journal of Dermatological Science, Volume 87, Issue 2





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Epidermal iron metabolism for iron salvage

Publication date: August 2017
Source:Journal of Dermatological Science, Volume 87, Issue 2
Author(s): Masayuki Asano, Kenshi Yamasaki, Takashi Yamauchi, Tadashi Terui, Setsuya Aiba
BackgroundThe epidermis shows a reverse iron gradient from the basal layer to the stratum corneum and consequently, little epidermal intracellular iron is lost by desquamation.ObjectiveTo clarify the underlying mechanism of iron salvage.MethodsWe first used immunohistochemistry and mRNA quantification to demonstrate the distinctive expression pattern of iron metabolism molecules. The obtained results were confirmed using normal human epidermal keratinocytes (NHEKs) during in vitro differentiation. We next examined the effects of reducing ferroportin expression in vitro by ferroportin-specific siRNAs or hepcidin on the intracellular iron content of cultured NHEKs. Finally, we compared epidermal and systemic iron metabolism between Fpn^Epi-KO mice and control mice.ResultsThe results of both mRNA and protein expression analysis showed that most molecules participating in iron import and storage were expressed in the lower epidermis, while those involved in iron release from heme or iron transport were expressed in the upper epidermis. Consistent with their expression, keratinocyte differentiation reduced intracellular iron content. We next demonstrated that reducing ferroportin expression in vitro by ferroportin-specific siRNAs or hepcidin significantly increased the intracellular iron content. Finally, we showed that the iron content of the epidermis and squames was significantly greater in Fpn^Epi-KO mice than in control mice, and that Fpn^Epi-KO exhibited a more rapid decrease in blood hemoglobin concentration than control mice on a low iron diet.ConclusionThese studies demonstrated that the epidermis is equipped with a machinery by which intracellular iron in differentiated keratinocytes is excreted to the extracellular space before reaching the stratum corneum.



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The phosphodiesterase 4 inhibitor apremilast inhibits Th1 but promotes Th17 responses induced by 6-sulfo LacNAc (slan) dendritic cells

Publication date: August 2017
Source:Journal of Dermatological Science, Volume 87, Issue 2
Author(s): Stephanie Oehrl, Hridayesh Prakash, Annette Ebling, Nina Trenkler, Priscila Wölbing, Anja Kunze, Thomas Döbel, Marc Schmitz, Alexander Enk, Knut Schäkel
BackgroundThe phosphodiesterase 4 (PDE4) inhibitor apremilast increases cellular cAMP levels and has proven effective in the treatment of psoriasis and psoriasis arthritis. We recently described 6-sulfo LacNAc dendritic cells (slanDCs) as immature DCs in blood and as a subset of inflammatory dermal DCs in psoriasis with a pronounced capacity to produce proinflammatory cytokines and to program Th17/Th1 T cell responses.ObjectiveThe aim of this study was to investigate possible immune regulatory effects of the PDE4 inhibitor apremilast on slanDCs.MethodsIn vitro studies were performed analyzing the effects of apremilast on the proinflammatory function of slanDCs and their capacity to induce Th1/Th17-biased T cell responses.ResultsIncreasing cAMP levels in slanDCs by PDE4 inhibition strongly reduced production of IL-12 and TNF-α. In line with these findings, co-culture experiments with apremilast-pulsed slanDCs and allogeneic T cells either from psoriasis patients or healthy controls, revealed a significant reduction of IFN-γ production and expression of the transcription factor T-bet. In parallel, production of IL-23 and IL-1ß by slanDCs was increased and co-cultured T cells revealed a largely augmented IL-17 production and an upregulated RORyt expression.ConclusionsWe here demonstrate anti-inflammatory as well as Th17-promoting effects of apremilast when studying blood precursors of human inflammatory dermal dendritic cells. In the concert of the broad anti-inflammatory effects of apremilast on keratinocytes, fibroblasts and endothelial cells, the dual effect on slan⁺ inflammatory dermal DCs should be taken into account and may constrain therapeutic responses.



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Editorial board

Publication date: August 2017
Source:Journal of Dermatological Science, Volume 87, Issue 2





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Combined treatment with H1 and H4 receptor antagonists reduces inflammation in a mouse model of atopic dermatitis

Publication date: August 2017
Source:Journal of Dermatological Science, Volume 87, Issue 2
Author(s): Hanna Köchling, Katrin Schaper, Jenny Wilzopolski, Ralf Gutzmer, Thomas Werfel, Wolfgang Bäumer, Manfred Kietzmann, Kristine Rossbach
BackgroundHistamine 4 receptor (H4R) antagonists are considered as new therapeutics for the treatment of atopic dermatitis (AD) and first clinical trials have already shown promising results. Histamine 1 receptor (H1R) antagonists are traditionally used to treat AD although the evidence for the efficacy is weak. The combined blockade of both, H1R and H4R, might provide synergistic anti-inflammatory.ObjectiveThe study was performed to test the anti-inflammatory potential of a combined treatment with an H1R and an H4R antagonist in a mouse AD model.MethodsThe development of ovalbumin-induced AD-like skin lesions was analysed mice treated with the H1R inverse agonist mepyramine, the H4R antagonist JNJ-39758979 or a combination of both.ResultsMice treated with mepyramine plus JNJ-39758979 showed less severe skin lesions, with a diminished influx of inflammatory cells, a reduced epidermal thickening and a lower level of IL-33 in lesional skin. Scratching behaviour was ameliorated in mice treated with the combination. Moreover, total numbers of skin-draining lymph node cells and splenocytes were significantly reduced. Both substances given alone did not elicit this strong anti-inflammatory effect.ConclusionH1R and H4R antagonists provide synergistic anti-inflammatory effects in a mouse model of AD. The combined therapy with H1R and H4R antagonists might represent a new strategy for the treatment of AD.



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Immunological function of Langerhans cells in HIV infection

Publication date: August 2017
Source:Journal of Dermatological Science, Volume 87, Issue 2
Author(s): Takamitsu Matsuzawa, Youichi Ogawa, Kohji Moriishi, Shinji Shimada, Tatsuyoshi Kawamura
BackgroundLangerhans cells (LCs) are one of the initial target cells for HIV following sexual exposure and they are productively infected by HIV. HIV-infected LCs migrate to the draining lymph nodes (dLNs) and transmit the virus to CD4⁺ T cells, leading to the dissemination of HIV. In contrast with the role of LCs in initial HIV acquisition, little is known about the modulation of immune responses by HIV-infected LCs.ObjectiveWe aimed to elucidate the induction of HIV-specific CD8⁺ T cells and regulatory T cells (Tregs), both of which play important roles in regulating the progression of HIV infection.MethodsWe examined the inducibility of HLA-A*0201 restricted HIV-specific CD8⁺ T cells and Tregs by HIV-primed LCs or HIV-primed dendritic cells (DCs) as a control.ResultsThe number of HIV-specific CD8⁺ T cells induced by HIV-primed monocyte-derived LCs (mLCs) was significantly higher than that by HIV-primed monocyte-derived DCs (mDCs). Additionally, HIV-specific CD8⁺ T cells induced by HIV-primed mLCs produced more IFN-γ than HIV-nonspecific CD8⁺ T cells. HIV-primed human epidermal LCs also induced IFN-γ-producing HIV-specific CD8⁺ T cells. As for the induction of Tregs, HIV-primed mLCs and human epidermal LCs significantly impaired the induction of FoxP3^hiCD45RA⁻ effector Tregs than HIV-unprimed mLCs and human epidermal LCs.ConclusionsHIV-primed LCs trigger beneficial immune responses against HIV infection through the increased induction of HIV-specific CD8⁺ T cells and the decreased induction of effector Tregs in the initial phase of HIV infection, thereby contributing to the prolonged onset of AIDS.



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High-glucose environment induced intracellular O-GlcNAc glycosylation and reduced galectin-7 expression in keratinocytes: Implications on impaired diabetic wound healing

Publication date: August 2017
Source:Journal of Dermatological Science, Volume 87, Issue 2
Author(s): Shu-Mei Huang, Ching-Shuang Wu, Min-Hsi Chiu, Hui-Jun Yang, Gwo-Shing Chen, Cheng-Che E. Lan
BackgroundDiabetes is an important global health issue due to its increasing prevalence and association with various complications. Impaired wound healing is a serious complication associated with diabetes that frequently results in infection and amputation. Galectin-7 (Gal-7) has been reported to play an important role during skin wound healing. Previously, we had demonstrated that high glucose environment alters physiologic functions of keratinocytes and contributes to impaired wound healing in diabetic condition.ObjectiveIn this study, we hypothesized that Gal-7 expression of keratinocytes may be involved in delayed wound healing of diabetics.MethodsUsing cultured human keratinocytes and diabetic mice model, the Gal-7 expression was evaluated under high glucose environment.ResultsOur results demonstrated that high-glucose environment reduced Gal-7 expression, a molecule that plays an important role in keratinocyte migration. Additionally, we found that increased O-linked N-Acetyl-glucosamine (O-GlcNAc) is responsible for reduced Gal-7 expression in keratinocytes exposed to high glucose environment.ConclusionTaken together, restoring the levels of Gal-7 and O-GlcNAc glycosylation may present novel therapeutic approach to promote wound healing in diabetic patients.



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The caspase-1 inhibitor CARD18 is specifically expressed during late differentiation of keratinocytes and its expression is lost in lichen planus

Publication date: August 2017
Source:Journal of Dermatological Science, Volume 87, Issue 2
Author(s): Haihong Qin, Jiang Jin, Heinz Fischer, Michael Mildner, Maria Gschwandtner, Veronika Mlitz, Leopold Eckhart, Erwin Tschachler
BackgroundCARD18 contains a caspase recruitment domain (CARD) via which it binds to caspase-1 and thereby inhibits caspase-1-mediated activation of the pro-inflammatory cytokine interleukin (IL)-1β.ObjectivesTo determine the expression profile and the role of CARD18 during differentiation of keratinocytes and to compare the expression of CARD18 in normal skin and in inflammatory skin diseases.MethodsHuman keratinocytes were induced to differentiate in monolayer and in 3D skin equivalent cultures. In some experiments, CARD18-specific siRNAs were used to knock down expression of CARD18. CARD18 mRNA levels were determined by quantitative real-time PCR, and CARD18 protein was detected by Western blot and immunofluorescence analyses. In situ expression was analyzed in skin biopsies obtained from healthy donors and patients with psoriasis and lichen planus.ResultsCARD18 mRNA was expressed in the epidermis at more than 100-fold higher levels than in any other human tissue. Within the epidermis, CARD18 was specifically expressed in the granular layer. In vitro CARD18 was strongly upregulated at both mRNA and protein levels in keratinocytes undergoing terminal differentiation. In skin equivalent cultures the expression of CARD18 was efficiently suppressed by siRNAs without impairing stratum corneum formation. Epidermal expression of CARD18 was increased after ultraviolet (UV)B irradiation of skin explants. In skin biopsies of patients with psoriasis no consistent regulation of CARD18 expression was observed, however, in lesional epidermis of patients with lichen planus, CARD18 expression was either greatly diminished or entirely absent whereas in non-lesional areas expression was comparable to normal skin.ConclusionsOur results identify CARD18 as a differentiation-associated keratinocyte protein that is altered in abundance by UV stress. Its downregulation in lichen planus indicates a potential role in inflammatory reactions of the epidermis in this disease.



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Toll-like receptor 3 mediates UVB-induced MMP-13 and MMP-3 expressions in mice

Publication date: August 2017
Source:Journal of Dermatological Science, Volume 87, Issue 2
Author(s): Cheng Yao, Sangbum Han, Yu-Dan Tian, Chang-yup Shin, Chi-Hyun Park, Ye-Ji Kim, Dong Hun Lee, Jin Ho Chung




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A retrospective institutional study of the association of smoking with the severity of hidradenitis suppurativa

Publication date: August 2017
Source:Journal of Dermatological Science, Volume 87, Issue 2
Author(s): Clio Dessinioti, Chrisa Zisimou, Vassiliki Tzanetakou, George Ntritsos, George Kontochristopoulos, Christina Antoniou




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Ultraviolet B (UVB) induces development of early melanocytic progenitors via increased oxidative stress in vitro suggesting the use of antioxidants after regimentation in UVB phototherapy for vitiligo

Publication date: August 2017
Source:Journal of Dermatological Science, Volume 87, Issue 2
Author(s): Sebastian Yu, Hsin-Su Yu, Hsiao-Chi Lai, Ching-Shuang Wu, Hui-Ying Jheng, Cheng-Che Lan




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Serum levels and tissue expression of interleukin-31 in dermatitis herpetiformis and bullous pemphigoid

Publication date: August 2017
Source:Journal of Dermatological Science, Volume 87, Issue 2
Author(s): Diletta Bonciani, Lavinia Quintarelli, Elena Del Bianco, Beatrice Bianchi, Marzia Caproni




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Detection of mucous membrane pemphigoid autoantibodies by full-length BP180 enzyme-linked immunosorbent assay

Publication date: Available online 13 July 2017
Source:Journal of Dermatological Science
Author(s): Kentaro Izumi, Wataru Nishie, Yosuke Mai, Hideyuki Ujiie, Hiroaki Iwata, Ken Natsuga, Hiroshi Shimizu




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Regulatory T cell deficient scurfy mice exhibit a Th2/M2-like inflammatory response in the skin

Publication date: Available online 13 July 2017
Source:Journal of Dermatological Science
Author(s): Stefanie Haeberle, Verena Raker, Jessica Haub, Yong O. Kim, Shih-Yen Weng, Osman K. Yilmaz, Alexander Enk, Kerstin Steinbrink, Detlef Schuppan, Eva N. Hadaschik
BackgroundScurfy mice have a functional defect in regulatory T cells (Treg), which leads to lethal multi-organ inflammation. The missing Treg function results in uncontrolled autoimmune cellular and humoral inflammatory responses. We and others have previously shown that during the course of disease scurfy mice develop severe skin inflammation and autoantibodies including anti-nuclear autoantibodies (ANA).ObjectiveAutoimmune skin inflammation and ANA are hallmarks for the diagnosis of autoimmune connective tissue diseases; therefore we analyzed scurfy mice for typical signs of these diseases.MethodsIndirect immunofluorescence was used to specify the ANA pattern in scurfy mice. Skin fibrosis was assessed by cutaneous collagen accumulation (Goldeners trichrome staining), collagen crosslinking/disorganization (Sirus red polarimetry) and quantitative PCR for fibrosis-related transcripts. The cellular components of the inflammatory infiltrates in scurfy skin were analyzed by flow cytometry and intracellular cytokine staining.ResultsThe majority of scurfy mice developed ANA with a predominant AC-5 pattern typical for mixed connective tissue disease, especially scleroderma. Scurfy mice showed higher skin collagen content compared to WT controls with a significant tendency in upregulation of TIMP-1. CD3⁺CD4⁺ T cells in scurfy skin exhibited a strong Th2 deviation with a significant increase of IL-4, IL-5 and IL-13, and M2-polarized CD11b⁺MHCII⁺ macrophages compared to WT mice.ConclusionWe show that Scurfy mice show a predominant AC-5 ANA pattern typical for mixed connective tissue disease as in scleroderma. The autoimmune inflammation in scurfy skin mainly consists of CD4⁺ T cells with Th2 differentiation and alternatively-activated (M2) macrophages as it is found in scleroderma with advanced fibrosis.



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Performance of an integrated system combining microalgae and vertical flow constructed wetlands for urban wastewater treatment

Abstract

The present study investigated the performance of an integrated system, combining the sequential use of microalgae (MA) and vertical flow constructed wetland (VFCW) for the treatment of wastewaters produced at a university campus. Ecotoxicity and phytotoxicity assays were performed using respectively Daphnia magna and Lactuca sativa, whereas the genotoxicity of the wastewaters was assessed by using D. magna and Allium cepa. The results revealed that the major environmental impacts of the studied wastewaters are associated with the high eutrophication potential, due to high N-NH₃ (68.8 ± 25.7 mg L⁻¹), total P (7.71 ± 2.5 mg L⁻¹), and BOD₅ (526.4 ± 177 mg L⁻¹) values, pathogenic load, and genototoxicity (p < 0.0001). The results also showed that the integrated system (MA + VFCW) was not able to satisfactory reduce the total p values (only 4%). Nevertheless, the MA + VFCW system achieved very promising results for the nitrogen removal, with emphasis on N-NH₃ removal (100%) and the highest BOD₅ removal (57%). Neither the raw wastewaters nor the treated wastewaters were phytotoxic. The integrated system completely eliminated the ecotoxicity (100%) and genotoxicity (n.s.) of the raw wastewater and showed decontamination potential. Thus, the integrated system emerges as an innovative environmental technology and, with minor adjustments, might be efficiently used in large scale and eventually replace conventional wastewater treatment systems.

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ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells

Publication date: Available online 14 July 2017
Source:Cell Stem Cell
Author(s): Nicole I. Park, Paul Guilhamon, Kinjal Desai, Rochelle F. McAdam, Ellen Langille, Madlen O'Connor, Xiaoyang Lan, Heather Whetstone, Fiona J. Coutinho, Robert J. Vanner, Erick Ling, Panagiotis Prinos, Lilian Lee, Hayden Selvadurai, Gurnit Atwal, Michelle Kushida, Ian D. Clarke, Veronique Voisin, Michael D. Cusimano, Mark Bernstein, Sunit Das, Gary Bader, Cheryl H. Arrowsmith, Stephane Angers, Xi Huang, Mathieu Lupien, Peter B. Dirks
Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1^hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1^lo GSCs do not. Increasing ASCL1 levels in ASCL1^lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.

Graphical abstract

Teaser

Glioblastoma is characterized by a block in cellular differentiation. Park et al. identify a subset of glioblastoma stem cells (GSCs) that express high levels of the proneural transcription factor ASCL1 and differentiate in response to Notch inhibition, effectively abrogating their stemness properties and tumorigenic potential.


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Insulin Regulation of Proteostasis and Clinical Implications

Publication date: Available online 14 July 2017
Source:Cell Metabolism
Author(s): Haleigh A. James, Brian T. O'Neill, K. Sreekumaran Nair
Maintenance and modification of the cellular proteome are at the core of normal cellular physiology. Although insulin is well known for its control of glucose homeostasis, its critical role in maintaining proteome homeostasis (proteostasis) is less appreciated. Insulin signaling regulates protein synthesis and degradation as well as posttranslational modifications at the tissue level and coordinates proteostasis at the organism level. Here, we review regulation of proteostasis by insulin in postabsorptive, postprandial, and diabetic states. We present the effects of insulin on amino acid flux in skeletal muscle and splanchnic tissues, the regulation of protein quality control, and turnover of mitochondrial protein pools in humans. We also review the current evidence for the mechanistic control of proteostasis by insulin and insulin-like growth factor 1 receptors based on preclinical studies. Finally, we discuss irreversible posttranslational modifications of the proteome in diabetes and how future investigations will provide new insights into mechanisms of diabetic complications.

Teaser

James et al. provide a comprehensive review of insulin's crucial role in maintaining human proteostasis. They discuss current knowledge and gaps in the molecular mechanisms regulating protein turnover, modification, and quality control, and also highlight detrimental clinical effects of insulin deficiency and resistance on proteostasis, and its role in diabetic complications.


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