Publication date: February 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 176
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Τετάρτη 29 Νοεμβρίου 2017
Editorial board
Comparative Profiling of Adrenal Steroids in Maternal and Umbilical Cord Blood
Publication date: Available online 28 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Simon Travers, Laetitia Martinerie, Pascal Boileau, Qiong-Yao Xue, Marc Lombès, Eric Pussard
Fetal steroidome in late pregnancy receives multiple contributions from both maternal and fetal adrenals as well as from placenta. Depressed glucocorticoid levels have been reported in fetal blood at birth, yet studies on mineralocorticoid pathways are sparse. To investigate biosynthesis pathways at birth, adrenal steroids profiles were established in paired mothers and neonates. Forty-six paired healthy term newborns and their mothers from the Aldo cohort were assessed. Steroidomic profiles of mineralocorticoids, glucocorticoids and adrenal androgens were established from umbilical cord and maternal blood at birth using a highly sensitive and specific LC-MS/MS methodology. As compared to maternal blood, umbilical cord blood exhibited high levels of steroids precursors (progesterone and 11-deoxycorticosterone) contrasting with a collapse in corticosterone levels. Consecutively, 18-hydroxycorticosterone and aldosterone levels were also depressed in neonates. Similarly, umbilical cord blood levels of both 17-hydroxyprogesterone and 11-deoxycortisol were higher while cortisol levels sharply decreased. The product-to-substrate ratios evaluating the 11-hydroxylation step (corticosterone/11-deoxycorticosterone and cortisol/11-deoxycortisol) fell for both pathways. As expected, cortisone and 11-dehydrocorticosterone levels exceed those of cortisol and corticosterone in umbilical cord blood reflecting the strong placental 11-β-hydroxysteroid-dehydrogenase type 2 (11βHSD2) activity. Dehydroepiandrosterone-sulphate levels are higher in neonates, while both androstenedione and testosterone levels sharply fell. No significant difference in steroid levels could be observed according the gender except higher testosterone concentrations in umbilical cord of boys. Moreover, a strong and negative relationship between testosterone and progesterone levels was recorded in umbilical cord of boys. These adrenal steroidomic profiling demonstrate a deficit in mineralocorticoids (aldosterone, 18-hydroxycorticosterone and corticosterone) and glucocorticoids (cortisol) in term neonates, reflecting either a relative defect in 11-hydroxylase activity or more likely the strong placental 11-β-HSD2 activity. Collectively, these findings should be taken into account for a better understanding of regulatory interactions between placenta and fetal adrenal.
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Steroidogenic enzymes, their products and sex steroid receptors during testis development and spermatogenesis in the domestic cat (Felis catus)
Publication date: Available online 28 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Beate C. Braun, Minami W. Okuyama, Karin Müller, Martin Dehnhard, Katarina Jewgenow
In the present study we comprehensively characterize intratesticular sex steroid production, metabolism and receptors in the domestic cat to elucidate the role of testosterone, estradiol and progesterone in testis development, steroid synthesis and spermatogenesis. There is a great demand for new concepts of fertility control in domestic (feral) cats and wild felids. The acquired knowledge will help to understand the regulation of spermatogenesis in felids, and may reveal new target points for male contraception.Progesterone and androgens are produced throughout all stages of testicular development; their synthesizing enzymes are mainly expressed in Leydig cells, and to a much lesser extent also in tubular cells. Aromatase (CYP19A1), the estrogen synthesizing enzyme, is only present in the tubuli and is first detectable in spermatocytes and round spermatids at puberty. As shown by elevated expression of the enzymes steroid 5-α-reductase type 1 (SRD5A) and aldo-keto-reductase family 1 member C3 (AKR1C3), the capacity to metabolize particular steroids increases during testis development. Apparently, this refers to a decreasing intra-testicular testosterone concentration per mg tissue with increasing testis weight during postpuberty. The increasing potential of sulfation of E2 by estrogen sulfotransferase (SULT1E1) with ongoing development might be responsible for the low level of unconjugated intratesticular estradiol in all stages of development probably due to facilitated excretion of conjugated estrogens.For the first time, expression of the progesterone membrane receptor components 1 and 2 (PGRMC1, PGRMC2) was studied in mammalian testis tissue. Both of these and also the progesterone receptor (PGR) are expressed depending on the developmental stage and cell type, suggesting an important regulatory role of progesterone in the testis. Androgen receptor (AR) is present in almost all cell types except for some spermatogenic cells. The co-localization of aromatase with estrogen receptor alpha (ESR1) in spermatocytes and round spermatids of domestic cat testis indicates an auto-/paracrine function of estrogen in spermatogenesis. In summary, the testis of the domestic cat is an important source of sex steroids. All of them could act within the testis but additionally, at least androgens and estrogens are likely secreted by the testis, partly as conjugated steroids.
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DIABETES INDUCES MITOCHONDRIAL DYSFUNCTION AND ALTERS CHOLESTEROL HOMEOSTASIS AND NEUROSTEROIDOGENESIS IN THE RAT CEREBRAL CORTEX
Publication date: Available online 26 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Simone Romano, Nico Mitro, Silvia Giatti, Silvia Diviccaro, Marzia Pesaresi, Roberto Spezzano, Matteo Audano, Luis Miguel Garcia-Segura, Donatella Caruso, Roberto Cosimo Melcangi
The nervous system synthesizes and metabolizes steroids (i.e., neurosteroidogenesis). Recent observations indicate that neurosteroidogenesis is affected by different nervous pathologies. Among these, long-term type 1 diabetes, together with other functional and biochemical changes, has been shown to alter neuroactive steroid levels in the nervous system. Using an experimental model of type 1 diabetes (i.e., streptozotocin injection) we here show that the levels of these molecules are already decreased in the rat cerebral cortex after one month of the initiation of the pathology. Moreover, decreased levels of free cholesterol, together with alterations in the expression of molecules involved in cholesterol biosynthesis, bioavailability, trafficking and metabolism were detected in the rat cerebral cortex after one month of diabetes. Furthermore, mitochondrial functionality was also affected in the cerebral cortex and consequently may also contribute to the decrease in neuroactive steroid levels. Altogether, these results indicate that neurosteroidogenesis is an early target for the effect of type 1 diabetes in the cerebral cortex.
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Characterization of equine GST A3-3 as a steroid isomerase
Publication date: Available online 24 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Helena Lindström, Shawna M. Peer, Nancy H. Ing, Bengt Mannervik
Glutathione transferases (GSTs) comprise a superfamily of enzymes prominently involved in detoxication by making toxic electrophiles more polar and therefore more easily excretable. However some GSTs have developed alternative functions. Thus, a member of the Alpha class GSTs in pig and human tissues is involved in steroid hormone biosynthesis, catalyzing the obligatory double-bond isomerization of Δ5-androstene-3,17-dione to Δ4-androstene-3,17-dione and of Δ5-pregnene-3,20-dione to Δ4-pregnene-3,20-dione on the biosynthetic pathways to testosterone and progesterone. The human GST A3-3 is the most efficient steroid double-bond isomerase known so far in mammals. The current work extends discoveries of GST enzymes that act in the steroidogenic pathways in large mammals. The mRNA encoding the steroid isomerase GST A3-3 was cloned from testis of the horse (Equus ferus caballus). The concentrations of GSTA3 mRNA were highest in hormone-producing organs such as ovary, testis and adrenal gland. EcaGST A3-3 produced in E. coli has been characterized and shown to have highly efficient steroid double-bond isomerase activity, exceeding its activities with conventional GST substrates. The enzyme now ranks as one of the most efficient steroid isomerases known in mammals and approaches the activity of the bacterial ketosteroid isomerase, one of the most efficient enzymes of all categories known today. The high efficiency and the tissue distribution of EcaGST A3-3 support the view that the enzyme plays a physiologically significant role in the biosynthesis of steroid hormones.
Graphical abstract
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Highlights from the 20th Workshop on Vitamin D in Orlando, Mar. 28–31, 2017
Publication date: Available online 24 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Martin Hewison, James C. Fleet, Marie B. Demay, Sylvia Christakos, Roger Bouillon, JoEllen Welsh, John H. White
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EFFLUX TRANSPORT of ESTROGEN GLUCURONIDES by HUMAN MRP2, MRP3, MRP4 and BCRP
Publication date: Available online 22 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Erkka Järvinen, Feng Deng, Heidi Kidron, Moshe Finel
Estrone, estradiol and estriol are endogenous human estrogens that are rapidly conjugated with glucuronic acid in both intestinal and hepatic epithelial cells. The resulting glucuronides, estrone-3-glucuronide (E1-G), estradiol-3- and 17-glucuronides (E2-3G and E2-17G), as well as estriol-3- and 16-glucuronides (E3-3G and E3-16G) are found in human plasma and urine. Unlike E2-17G, the efflux transport of other estrogen glucuronides by human transporters has not yet been investigated comprehensively. We have studied the transport of E1-G, E2-3G, E3-3G, E3-16G and estrone-3-sulfate (E1-S), another important estrogen conjugate, using the vesicular transport assay with recombinant human MRP2, MRP3, MRP4, MDR1 and BCRP that were expressed in insect cells. The transport screening assays revealed that whereas E1-S was a good and specific substrate for BCRP, the less transporter-specific conjugates, E1-G and E2-3G, were still transported by BCRP at 10-fold higher rates than E1-S. BCRP also transported E3-16G at higher rates than the studied MRPs, while it transported E3-3G at lower rates than MRP3. MRP2 exhibited lower or equal transport rates of E1-G, E2-3G, E3-3G and E3-16G in comparison to MRP3 and BCRP in the screening assays, mainly due to its high Km values, between 180 and 790μM. MRP3 transported all the tested glucuronides at rather similar rates, at Km values below 20μM, but lower Vmax values than other transporters. In the case of E3-3G, MRP3 was the most active transporter in the screening assay. MRP4 transported only E3-16G at considerable rates, while none of the tested estrogen conjugates was transported by MDR1 at higher rates than control vesicles. These new results, in combination with previously reported in vivo human data, stimulate our understanding on the substrate specificity and role of efflux transporters in disposition of estrogen glucuronides in humans.
Graphical abstract
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Impact of vitamin D on pregnancy-related disorders and on offspring outcome
Publication date: Available online 21 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Karoline von Websky, Ahmed Abdallah Hasan, Christoph Reichetzeder, Oleg Tsuprykov, Berthold Hocher
Observational studies from all over the world continue to find high prevalence rates of vitamin D insufficiency and deficiency in many populations, including pregnant women. Beyond its classical function as a regulator of calcium and phosphate metabolism, vitamin D elicits numerous effects in the human body. Current evidence highlights a vital role of vitamin D in mammalian gestation. During pregnancy, adaptations in maternal vitamin D metabolism lead to a physiologic increase of vitamin D levels, mainly because of an increased renal production, although other potential sources like the placenta are being discussed. A sufficient supply of mother and child with calcium and vitamin D during pregnancy ensures a healthy bone development of the fetus, whereas lack of either of these nutrients can lead to the development of rickets in the child. Moreover, vitamin D insufficiency during pregnancy has consistently been associated with adverse maternal and neonatal pregnancy outcomes. In multitudinous studies, low maternal vitamin D status was associated with a higher risk for preeclampsia, gestational diabetes mellitus and other gestational diseases. Likewise, several negative consequences for the fetus have been reported, including fetal growth restriction, increased risk of preterm birth and a changed susceptibility for later-life diseases. However, study results are diverging and causality has not been proven so far. Meta-analyses on the relationship between maternal vitamin D status and pregnancy outcomes revealed a wide heterogeneity of studied populations and the applied methodology in vitamin D assessment. Until today, clinical guidelines for supplementation cannot be based on high-quality evidence and it is not clear if the required intake for pregnant women differs from non-pregnant women. Long-term safety data of vitamin D supplementation in pregnant women has not been established and overdosing of vitamin D might have unfavorable effects, especially in mothers and newborns with mutations of genes involved in vitamin D metabolism. Reliable data from large observational and interventional randomized control trials are urgently needed as a basis for any detailed and safe recommendations for supplementation in the general population and, most importantly, in pregnant women. This is of utmost importance, as ensuring a sufficient vitamin D-supply of mother and child implies a great potential for the prevention of birth complications and development of diseases.
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Transition from androgenic to neurosteroidal action of 5α-androstane-3α, 17β-diol through the type A γ-aminobutyric acid receptor in prostate cancer progression
Publication date: Available online 15 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Ding Xia, Doan V. Lai, Weijuan Wu, Zachary D. Webb, Qing Yang, Lichao Zhao, Zhongxin Yu, Jessica E. Thorpe, Bryan C. Disch, Michael A. Ihnat, Muralidharan Jayaraman, Danny N. Dhanasekaran, Kelly L. Stratton, Michael S. Cookson, Kar-Ming Fung, Hsueh-Kung Lin
Androgen ablation is the standard of care prescribed to patients with advanced or metastatic prostate cancer (PCa) to slow down disease progression. Unfortunately, a majority of PCa patients under androgen ablation progress to castration-resistant prostate cancer (CRPC). Several mechanisms including alternative intra-prostatic androgen production and androgen-independent androgen receptor (AR) activation have been proposed for CRPC progression. Aldo-keto reductase family 1 member C3 (AKR1C3), a multi-functional steroid metabolizing enzyme, is specifically expressed in the cytoplasm of PCa cells; and positive immunoreactivity of the type A γ-aminobutyric acid receptor (GABAAR), an ionotropic receptor and ligand-gated ion channel, is detected on the membrane of PCa cells. We studied a total of 72 radical prostatectomy cases by immunohistochemistry, and identified that 21 cases exhibited positive immunoreactivities for both AKR1C3 and GABAAR. In the dual positive cancer cases, AKR1C3 and GABAAR subunit α1 were either expressed in the same cells or in neighboring cells. Among several possible substrates, AKR1C3 reduces 5α-dihydrotesterone (DHT) to form 5α-androstane-3α, 17β-diol (3α-diol). 3α-diol is a neurosteroid that acts as a positive allosteric modulator of the GABAAR in the central nervous system (CNS). We examined the hypothesis that 3α-diol-regulated pathological effects in the prostate are GABAAR-dependent, but are independent of the AR. In GABAAR-positive, AR-negative human PCa PC-3 cells, 3α-diol significantly stimulated cell growth in culture and the in ovo chorioallantoic membrane (CAM) xenograft model. 3α-diol also up-regulated expression of the epidermal growth factor (EGF) family of growth factors and activation of EGF receptor (EGFR) and Src as measured by quantitative polymerase chain reaction and immunoblotting, respectively. Inclusion of GABAAR antagonists reversed 3α-diol-stimulated tumor cell growth, expression of EGF family members, and activation of EGFR and Src to the level observed in untreated cells. Results from the present study suggest that 3α-diol may act as an alternative intra-prostatic neurosteroid that activates AR-independent PCa progression. The involvement of AKR1C3-mediated steroid metabolisms in modulating GABAAR activation and promoting PCa progression requires continued studies.
Graphical abstract
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BranchAnalysis2D/3D automates morphometry analyses of branching structures
Source:Journal of Neuroscience Methods, Volume 294
Author(s): Aditya Srinivasan, Jesús Muñoz-Estrada, Justin R. Bourgeois, Julia W. Nalwalk, Kevin M. Pumiglia, Volney L. Sheen, Russell J. Ferland
BackgroundMorphometric analyses of biological features have become increasingly common in recent years with such analyses being subject to a large degree of observer bias, variability, and time consumption. While commercial software packages exist to perform these analyses, they are expensive, require extensive user training, and are usually dependent on the observer tracing the morphology.New methodTo address these issues, we have developed a broadly applicable, no-cost ImageJ plugin we call 'BranchAnalysis2D/3D', to perform morphometric analyses of structures with branching morphologies, such as neuronal dendritic spines, vascular morphology, and primary cilia.ResultsOur BranchAnalysis2D/3D algorithm allows for rapid quantification of the length and thickness of branching morphologies, independent of user tracing, in both 2D and 3D data sets.Comparison with existing methodsWe validated the performance of BranchAnalysis2D/3D against pre-existing software packages using trained human observers and images from brain and retina. We found that the BranchAnalysis2D/3D algorithm outputs results similar to available software (i.e., Metamorph, AngioTool, Neurolucida), while allowing faster analysis times and unbiased quantification.ConclusionsBranchAnalysis2D/3D allows inexperienced observers to output results like a trained observer but more efficiently, thereby increasing the consistency, speed, and reliability of morphometric analyses.
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Enhancement of the mechanical and thermal properties of injection-molded polylactide parts by the addition of acrylated epoxidized soybean oil
Publication date: 15 February 2018
Source:Materials & Design, Volume 140
Author(s): L. Quiles-Carrillo, S. Duart, N. Montanes, S. Torres-Giner, R. Balart
This work reports the effect of acrylated epoxidized soybean oil (AESO) addition on the mechanical, thermal, and thermomechanical properties of polylactide (PLA) parts obtained by injection molding. To this end, AESO, a chemically multi-functionalized vegetable oil, was incorporated into PLA during melt processing. The PLA parts with AESO contents in the 2.5–7.5wt% range showed a remarkable enhancement in both elongation at break and impact-absorbed energy while their tensile and flexural strength as well as thermomechanical properties were maintained or slightly improved. Additionally, the AESO-containing PLA parts presented higher thermal stability and lower crystallinity. The improvement achieved was ascribed to a dual effect of plasticization in combination with a chain-extension and/or cross-linking process of the PLA chains by the highly reactive acrylate and epoxy groups present in AESO. The use of AESO thus represents an environmentally friendly solution to obtain toughened PLA materials of high interest in, for instance, rigid packaging, automotive or building and construction applications.
Graphical abstract
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A novel multiscale silver paste for die bonding on bare copper by low-temperature pressure-free sintering in air
Publication date: 15 February 2018
Source:Materials & Design, Volume 140
Author(s): Jie Li, Xin Li, Lei Wang, Yun-Hui Mei, Guo-Quan Lu
Nanosilver sintering is expected to overcome the limitation of relatively high production cost and become widely available for the die bonding of power electronics. A potential application of nanosilver sintering is bare copper bonding, where replacing substrates with auxiliary silver or other plating that can damage bonding would be advantageous. Here, we introduce a novel multiscale silver paste containing both nanoparticles (20–100nm) and microparticles (1–5μm) for the bonding of high-power chips on a bare copper substrate by pressure-free sintering in air. The energy potential difference generated in the surface force field was critical in the formation of sintering necks between the nano and microparticles, which, together with other microparticles, formed the high-density sintered structure. Despite the development of a copper oxide film, the interfacial bonding was comparable to or higher than the sintering force due to the high surface energy of porous sintered structure and easy diffusion of nanoparticles occurred. A processing temperature of 265°C was considered optimal for bare copper joint (shear strength: 53MPa, transient thermal impedance: 0.132°C/W) considering the trade-off between achieving excellent mechanical and thermal properties while minimizing oxidation.
Graphical abstract
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Thermal properties of graphene/metal composites with aligned graphene
Publication date: 15 February 2018
Source:Materials & Design, Volume 140
Author(s): Ke Chu, Xiao-hu Wang, Yu-biao Li, Da-jian Huang, Zhong-rong Geng, Xi-long Zhao, Hong Liu, Hu Zhang
Graphene holds great potential in metal matrix composites for thermal management due to its excellent thermal properties. However, the graphene/metal composites possessing both high thermal conductivity (TC) and low coefficient of thermal expansion (CTE) have not yet been realized. Herein, we reported an efficient strategy to achieve a high alignment of graphene nanosheets (GNSs) in GNS/Cu composites through a vacuum filtration method followed by spark plasma sintering. Because of the highly aligned GNSs and laminated structure, the GNS/Cu composites exhibited notably anisotropic thermal properties. Intriguingly, the composites showed a reversed anisotropic behavior between TC and CTE as a function of GNS fraction, in which the in-plane TC was substantially higher than through-plane TC, whereas oppositely the through-plane CTE displayed a larger drop than in-plane CTE. Promisingly, the composite with 30vol% GNSs delivered a high in-plane TC of 458W/mK and a low through-plane CTE of 6.2ppm/K, corresponding to a 35% TC enhancement and a 64% CTE reduction compared to pure Cu, respectively. The present GNS/Cu composites with high in-plane TC and low through-plane CTE are promising candidates for specific thermal management applications that require an efficient in-plane heat dissipation but a good through-plane dimensional stability.
Graphical abstract
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Yawning—its anatomy, chemistry, role, and pathological considerations
Source:Progress in Neurobiology
Author(s): Heinz Krestel, Claudio L. Bassetti, Olivier Walusinski
Yawning is a clinical sign of the activity of various supra- and infratentorial brain regions including the putative brainstem motor pattern, hypothalamic paraventricular nucleus, probably the insula and limbic structures that are interconnected via a fiber network. This interaction can be seen in analogy to other cerebral functions arising from a network or zone such as language. Within this network, yawning fulfills its function in a stereotype, reflex-like manner; a phylogenetically old function, preserved across species barriers, with the purpose of arousal, communication, and maybe other functions including respiration. Abnormal yawning with ≥3 yawns/15min. without obvious cause arises from lesions of brain areas involved in the yawning zone, its trajectories causing a disconnection syndrome, or from alteration of network activity by physical or metabolic etiologies including medication.
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Implementing near real-time vaccine safety surveillance using the Clinical Practice Research Datalink (CPRD)
Source:Vaccine, Volume 35, Issue 49, Part B
Author(s): Andreia Leite, Sara L. Thomas, Nick J. Andrews
IntroductionNear real-time vaccine safety surveillance (NRTVSS) using electronic health records is increasingly used to rapidly detect vaccine safety signals. NRTVSS has not been fully implemented in the UK. We assessed the feasibility of implementing this surveillance using the UK Clinical Practice Research Datalink (CPRD).MethodsWe selected seasonal influenza vaccine/Guillain-Barré Syndrome (GBS) as an example of a rare outcome and measles-mumps-rubella (MMR) vaccine/febrile seizures as a positive control. For influenza/GBS we implemented a system for the 2013/2014 and 2014/2015 influenza seasons; for MMR/seizures the surveillance period was July 2014–June 2015. We used the continuous Poisson-based maximized sequential probability ratio test (PMaxSPRT), comparing observed-to-expected events, for both pairs. We calculated an age-sex-adjusted rate using 5years of historic data and used this rate to calculate the expected number of events in pre-specified post-vaccination risk-window (GBS: 0–42days, seizures: 6–21days). For MMR/seizures we also implemented the system using the Binominal-based maximized sequential probability ratio test (BMaxSPRT). For this, we compared seizures in the risk-window (6–21days) to a control window (0–5 and 22–32days). Delays in recording outcomes influence the data available, so we adjusted the expected number of events using a historical distribution of delays in recording GBS/febrile seizures. Analyses were run using data up to each CPRD monthly release. We also performed power calculations for detecting increases in relative risk (RR) from 1.5 to 10.ResultsFor influenza/GBS we implemented a system in both seasons with no signal. Power to detect a signal was >80% for RR≥4. For MMR/seizures we were able to identify a signal with PMaxSPRT but not with BMaxSPRT. Power≥80% for RR≥2.5 for both tests.ConclusionCPRD is a potential data source to implement NRTVSS to exclude large increases in the risk of rare outcomes after seasonal influenza and lower increases in risk for more frequent outcomes.
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Editorial Board/Aims and Scope
Source:Vaccine, Volume 35, Issue 49, Part B
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Attitudes about vaccines to prevent Ebola virus disease in Guinea at the end of a large Ebola epidemic: Results of a national household survey
Source:Vaccine, Volume 35, Issue 49, Part B
Author(s): Kathleen L. Irwin, Mohamed F. Jalloh, Jamaica Corker, Barry Alpha Mahmoud, Susan J. Robinson, Wenshu Li, Nyuma E. James, Musa Sellu, Mohammad B. Jalloh, Alpha Ahmadou Diallo, LaRee Tracy, Rana Hajjeh, Amanda VanSteelandt, Rebecca Bunnell, Lise Martel, Pratima L. Raghunathan, Barbara Marston
IntroductionIn 2014–2016, an Ebola epidemic devastated Guinea; more than 3800 cases and 2500 deaths were reported to the World Health Organization. In August 2015, as the epidemic waned and clinical trials of an experimental, Ebola vaccine continued in Guinea and neighboring Sierra Leone, we conducted a national household survey about Ebola-related knowledge, attitudes, and practices (KAP) and opinions about "hypothetical" Ebola vaccines.MethodsUsing cluster-randomized sampling, we selected participants aged 15+ years old in Guinea's 8 administrative regions, which had varied cumulative case counts. The questionnaire assessed socio-demographic characteristics, experiences during the epidemic, Ebola-related KAP, and Ebola vaccine attitudes. To assess the potential for Ebola vaccine introduction in Guinea, we examined the association between vaccine attitudes and participants' characteristics using categorical and multivariable analyses.ResultsOf 6699 persons invited to participate, 94% responded to at least 1 Ebola vaccine question. Most agreed that vaccines were needed to fight the epidemic (85.8%) and that their family would accept safe, effective Ebola vaccines if they became available in Guinea (84.2%). These measures of interest and acceptability were significantly more common among participants who were male, wealthier, more educated, and lived with young children who had received routine vaccines. Interest and acceptability were also significantly higher among participants who understood Ebola transmission modes, had witnessed Ebola response teams, knew Ebola-affected persons, believed Ebola was not always fatal, and would access Ebola treatment centers. In multivariable analyses of the majority of participants living with young children, interest and acceptability were significantly higher among those living with vaccinated children than among those living with unvaccinated children.DiscussionThe high acceptability of hypothetical vaccines indicates strong potential for introducing Ebola vaccines across Guinea. Strategies to build public confidence in use of Ebola vaccines should highlight any similarities with safe, effective vaccines routinely used in Guinea.
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Ethics, pregnancy, and ZIKV vaccine research & development
Publication date: 14 December 2017
Source:Vaccine, Volume 35, Issue 49, Part B
Author(s): The Ethics Working Group on ZIKV Research and PregnancyRuth R.FadenCarleigh B.KrubinerAnne D.LyerlyMargaret O.LittleAllisonAugustRichard H.BeigiAnna P.DurbinRuth A.KarronNancy E.KassFlorenciaLunaRicardoPalaciosAlexander RobertoPreciosoCarlaSaenzJeanne S.SheffieldBeatrizThoméCorresponding author.
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Randomized Split-face, Controlled Comparison of Treatment with 1565 nm Non-ablative Fractional Laser for Enlarged Facial Pores
Abstract
Enlarged pores are common cosmetic concerns1. Though non-ablative fractional lasers (NAFLs) have been used reducing enlarged facial pores, a prospective, split-face, controlled study with objective assessment is still in blank. 1,565 nm NAFL (M22 ™ ResurFX™, Lumenis® Ltd, Yokneam, Israel), proved effective on skin elasticity and stretch marks2, was further aimed to assess for its safety and efficacy on enlarged facial pores.
This article is protected by copyright. All rights reserved.
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Anti-tumour necrosis factor-α antibodies and B cell homeostasis in human inflammatory bowel diseases
Source:International Immunopharmacology, Volume 54
Author(s): Caterina Defendenti, Fabiola Atzeni, Sergio Malandrin, Sandro Ardizzone, Piero Luigi Almasio, Simone Saibeni, Cristina Bezzio, Simona Bollani, Raffaele Salerno, Paolo Declich, Zoe Sarno, Savino Bruno, Rossella Talotta, Piercarlo Sarzi-Puttini
BackgroundThe expression of CD70 on T cells is greatly enhanced by antigen-presenting cell (APC)-associated signals, such as tumour necrosis factor(TNF)-α, which is constitutionally high in patients with inflammatory bowel disease (IBD). Experimentally, the chronic activation of CD27 as a result of the constitutive expression of CD70 leads to the demise of B cells in bone marrow (BM) and the secondary lymphoid organs. The aim of this study was to assess the number and phenotype of circulating B cell in untreated IBD patients and their counterparts treated with biological anti-TNF drugs.MethodsThe study involved 13 untreated IBD patients, 36 IBD patients treated with biological drugs, and 10 healthy controls. The B cell phenotypes were assessed by means of flow cytometry using monoclonal antibodies specific for CD20, CD19, CD3, CD27 and CD43. In order to evaluate B cell development in bone marrow and peripheral B cell activation, we identified four B cell subsets: hematogones (HBs: CD20+19+3−27−43+), memory B cells (MBs: CD20+19+3−27+43−), pre-plasmablasts (PPBs: CD20+19+3−27+43+), and plasmablasts (PBs: CD20−19+3−27+43+).ResultsThe total number of B cells in the untreated patients was three times lower than that in the patients treated with biological drug (p<0.001), and half that in the healthy controls (p=0.03). The between-group differences (including the healthy donors) were statistically significant in the case of HBs and MBs, but not in the case of PPBs and PBs. Only one treated patient showed a transiently large increase in PPBs. There were statistically significant differences in all of the parameters between the untreated patients and those receiving biological therapy, and in some cases between the untreated patients and healthy controls, but never between the controls and the treated patients. Four non-responders to anti-TNF therapy had a smaller number of total circulating B cells than the untreated patients.ConclusionsAnti-TNF drugs disinhibit B cell production in IBD patients, but maintain the constant homeostasis of circulating B cells. The presence of individual variations may allow the activity of anti-TNF drugs to be monitored by studying B cell subgroups.
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Chemical characterization of PM 2.5 collected from a rural coastal island of the Bay of Bengal (Bhola, Bangladesh)
Abstract
This work focuses on the chemical characterization of fine aerosol particles (PM2.5) collected from a rural remote island of the Bay of Bengal (Bhola, Bangladesh) from April to August, 2013. PM2.5 particle-loaded filters were analyzed for organic carbon (OC), elemental carbon (EC), water-soluble ions, and selected saccharides (levoglucosan, mannosan, galactosan, arabitol, and mannitol). The average PM2.5 mass was 15.0 ± 6.9 μg m−3. Organic carbon and elemental carbon comprised roughly half of the analyzed components. Organic carbon was the predominant contributor to total carbon (TC) and accounting for about 28% of PM2.5 mass. Secondary organic carbon (SOC) was inferred to be ~ 26% of OC. The sum of ions comprised ~ 27% of PM2.5 mass. The contribution of sea salt aerosol was smaller than expected for a sea-near site (17%), and very high chloride depletion was observed (78%). NssSO42− was a dominant ionic component with an average concentration of 2.0 μg m−3 followed by Na+, NH4+, and nssCa2+. The average concentration of arabitol and mannitol was 0.11 and 0.14 μg m−3, respectively, while levoglucosan and its stereoisomers (mannosan and galactosan) were bellow detection limit. NH4+/SO42− equivalent ratio was 0.30 ± 0.13 indicating that secondary inorganic aerosol is not the main source of SO42−. Enrichment factor (EF) analysis showed that SO42− and NO3− were enriched in atmospheric particles compared to sea aerosol and soil indicating their anthropogenic origin. Higher OC/EC ratio (3.70 ± 0.88) was a good indicator of the secondary organic compounds formation. Other ratios (OC/EC, K+/EC, nssSO42−/EC) and correlation analysis suggested mixed sources for carbonaceous components. Arabitol and mannitol both showed strong correlation with EC having R 2 value 0.89 and 0.95, respectively. Air mass trajectories analysis showed that concentrations of soil and anthropogenic species were lower for air masses originating from the sea (May–August) and were higher when air came from land (April).
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Quantitative Measurements Versus Receiver Operating Characteristics and Visual Grading Regression in CT Images Reconstructed with Iterative Reconstruction
Source:Academic Radiology
Author(s): Kristin Jensen, Hilde Kjernlie Andersen, Örjan Smedby, Bjørn Helge Østerås, Anette Aarsnes, Anders Tingberg, Erik Fosse, Anne Catrine Martinsen
Rationale and ObjectivesThis study aimed to evaluate the correlation of quantitative measurements with visual grading regression (VGR) and receiver operating characteristics (ROC) analysis in computed tomography (CT) images reconstructed with iterative reconstruction.Materials and MethodsCT scans on a liver phantom were performed on CT scanners from GE, Philips, and Toshiba at three dose levels. Images were reconstructed with filtered back projection (FBP) and hybrid iterative techniques (ASiR, iDose, and AIDR 3D of different strengths). Images were visually assessed by five readers using a four- and five-grade ordinal scale for liver low contrast lesions and for 10 image quality criteria. The results were analyzed with ROC and VGR. Standard deviation, signal-to-noise ratios, and contrast-to-noise ratios were measured in the images.ResultsAll data were compared to FBP. The results of the quantitative measurements were improved for all algorithms. ROC analysis showed improved lesion detection with ASiR and AIDR and decreased lesion detection with iDose. VGR found improved noise properties for all algorithms, increased sharpness with iDose and AIDR, and decreased artifacts from the spine with AIDR, whereas iDose increased the artifacts from the spine. The contrast in the spine decreased with ASiR and iDose.ConclusionsImproved quantitative measurements in images reconstructed with iterative reconstruction compared to FBP are not equivalent to improved diagnostic image accuracy.
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Prognostic Factors for Survival After Transarterial Chemoembolization Combined with Sorafenib in the Treatment of BCLC Stage B and C Hepatocellular Carcinomas
Source:Academic Radiology
Author(s): Jia-yan Ni, Jian Kong, Hong-liang Sun, Yao-ting Chen, Jiang-hong Luo, Wei-dong Wang, Dong Chen, Xiong-ying Jiang, Lin-feng Xu
Rationale and ObjectiveThe objective of this study was to analyze prognostic factors for survival after transarterial chemoembolization (TACE) combined with sorafenib for hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stages B and C.Materials and MethodsClinical data of 198 patients with BCLC stage B and C HCCs who underwent TACE combined with sorafenib between June 2012 and January 2017 were retrospectively collected and analyzed. Survival curves were detected using log-rank test. Univariate analysis was performed using log-rank test with respect to 11 prognostic factors potentially affecting survival. All statistically significant prognostic factors identified by univariate analysis were entered into a Cox proportion hazards regression model to identify independent predictors of survival. P values were two-sided and P < 0.05 was considered statistically significant.ResultsBy the end of this study, the median follow-up duration was 43.6 months. The median overall survival (OS) of the patients was 21.0 months (95% confidence interval [CI]: 16.94–25.05), and the 1-, 2-, 3- and 5-year OS rates were 72%, 43%, 28%, and 4%, respectively. Tumor size (χ2 = 33.607, P < 0.0001), tumor number (χ2 = 4.084, P = 0.043), Child-Pugh class (χ2 = 33.187, P < 0.0001), BCLC stage (χ2 = 50.224, P < 0.0001), portal vein tumor thrombus (χ2 = 88.905, P < 0.0001), Eastern Cooperative Oncology Group (ECOG) performance status (χ2 = 98.007, P < 0.0001), extrahepatic spread (χ2 = 34.980, P < 0.0001), TACE times (χ2 = 8.350, P = 0.015), and sorafenib treatment strategy (χ2 = 81.593, P < 0.0001) were found to be significantly associated with OS by univariate analysis. Multivariate analysis showed that BCLC stage (95% CI: 1.133–3.982, P = 0.019), extrahepatic spread (95% CI: 1.136–2.774, P = 0.012), and sorafenib treatment duration (95% CI: 0.352–0.574, P = 0.000) were independent prognostic factors associated with OS. There were no serious treatment-related adverse events.ConclusionsThis study showed that extrahepatic spread was a risk factor, and sorafenib treatment and superior BCLC stage were protective factors. Therefore, the study indicated that TACE combined with sorafenib was an effective and safe treatment for patients with BCLC stage B HCC without extrahepatic spread.
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The Study of Clear Cell Renal Cell Carcinoma with MR Diffusion Kurtosis Tensor Imaging and Its Histopathologic Correlation
Source:Academic Radiology
Author(s): Guangyu Wu, Zizhou Zhao, Qiuying Yao, Wen Kong, Jianrong Xu, Jin Zhang, Guiqin Liu, Yongming Dai
Rationale and ObjectivesThe objective of this study was to compare the performance of diffusion kurtosis tensor imaging and diffusion-weighted imaging in the characterization of clear cell renal cell carcinoma (ccRCC) and their correlations with tumor histopathology.Materials and MethodsNinety-one patients diagnosed with ccRCC who underwent diffusion kurtosis tensor imaging were included in this study. Fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, mean kurtosis (MK), radial kurtosis (Krad), and axial kurtosis (Kax) data were produced. A nuclear grade of 1–4 (G1–4) was assigned for each case based on the Fuhrman grading system, whereas tumor histopathology was characterized by the nuclear-to-cytoplasm ratio, the cell nuclei count, and the cell volume fraction.ResultsAll of the metric values except for Kax and fractional anisotropy could be used to discriminate G1 vs G3, G1 vs G4, G2 vs G3, and G2 vs G4, whereas MK and Kax could be used to discriminate G3 vs G4 (P < 0.05). Moreover, the MK and Krad values exhibited better performance in differentiating G2 from G3 (P < 0.04 compared to the other metrics). The nuclear-to-cytoplasm ratio was positively correlated with the MK, Krad, and Kax values (P < 0.001) and negatively correlated with the mean diffusivity, radial diffusivity, and axial diffusivity values (P < 0.001), whereas the cell volume fraction and the cell nuclei count did not correlate with any metric examined.ConclusionThe kurtosis metrics were superior to the diffusion metrics in grading ccRCC.
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High-risk Plaque and Calcification Detected by Coronary CT Angiography to Predict Future Cardiovascular Events After Percutaneous Coronary Intervention
Source:Academic Radiology
Author(s): Nobuo Tomizawa, Kodai Yamamoto, Shinichi Inoh, Takeshi Nojo, Sunao Nakamura
Rationale and ObjectivesThe purpose of this study was to investigate whether high-risk plaque (HRP) and calcium assessed by coronary computed tomography (CT) could predict future cardiovascular events after second-generation drug-eluting stent (DES) placement.Materials and MethodsWe analyzed 317 patients from December 2012 to April 2015 who underwent coronary CT followed by DES placement. HRP was defined as a plaque with positive remodeling and low attenuation or a plaque with a napkin-ring sign. Coronary calcium was assessed by Agatston score (AS). Patients were divided into three groups: low risk, HRP negative and AS <400; intermediate risk, HRP positive and AS ≥400; high risk, HRP positive and AS ≥400. The primary end point was a composite of all-cause mortality, myocardial infarction, fatal arrhythmia, or repeated revascularization. Kaplan-Meier analysis was used to estimate the distribution of time to events.ResultsA total of 74 events (23%) occurred during a median follow-up of 25.8 months. Patients with primary end points had HRP more frequently (70% vs 51%, P = 0.003) and were more calcified (AS, 471 [interquartile range, 143–1614] vs 289 [interquartile range, 63–787]; P = 0.01) than patients without primary end points. The frequency of primary end point increased significantly in the intermediate- and high-risk patients (P = 0.0011). Multivariate analysis showed that the hazard ratio of the intermediate- and high-risk groups was 1.91 (95% confidence interval, 1.04–3.77; P = 0.037) and 2.66 (95% confidence interval, 1.27–5.73; P = 0.009), respectively.ConclusionPlaque and calcification analysis by coronary CT could predict future cardiovascular events after second-generation DES placement.
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Irinotecan and Oxaliplatin Might Provide Equal Benefit as Adjuvant Chemotherapy for Patients with Resectable Synchronous Colon Cancer and Liver-confined Metastases: A Nationwide Database Study
Background: Although irinotecan and oxaliplatin are both standard treatments for advanced colon cancer, it remains unknown whether either is effective for patients with resectable synchronous colon cancer and liver-confined metastasis (SCCLM) after curative surgery. Patients and Methods: A population-based cohort of patients diagnosed with de novo SCCLM between 2004 and 2009 was established by searching the database of the Taiwan Cancer Registry and the National Health Insurance Research Database of Taiwan. Patients who underwent curative surgery as their first therapy followed by chemotherapy doublets were classified into the irinotecan group or oxaliplatin group accordingly. Patients who received radiotherapy or did not receive chemotherapy doublets were excluded. Results: We included 6,533 patients with de novo stage IV colon cancer. Three hundred and nine of them received chemotherapy doublets after surgery; 77 patients received irinotecan and 232 patients received oxaliplatin as adjuvant chemotherapy. The patients in both groups exhibited similar overall survival (median: not reached vs. 40.8 months, p=0.151) and time to the next line of treatment (median: 16.5 vs. 14.3 months, p=0.349) in both univariate and multivariate analyses. Additionally, patients with resectable SCCLM had significantly shorter median overall survival than patients with stage III colon cancer who underwent curative surgery and subsequent adjuvant chemotherapy, but longer median overall survival than patients with de novo stage IV colon cancer who underwent surgery only at the primary site followed by standard systemic chemotherapy (p<0.001). Conclusion: Irinotecan and oxaliplatin exhibited similar efficacy in patients who underwent curative surgery for resectable SCCLM.
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Robotic-assisted Transperitoneal Infrarenal Para-aortic Lymphadenectomy for Gynecological Malignancies: Comparison with a Laparoscopic Approach
Background/Aim: We evaluated the clinical feasibility and surgical outcomes of robotic-assisted transperitoneal infrarenal para-aortic lymphadenectomy (TIPAL) in patients with gynecological malignancies. Patients and Methods: The perioperative outcomes in 90 patients with gynecological malignancies who underwent laparoscopic (n=43) or robotic-assisted (n=47) TIPAL were compared retrospectively. Results: The operative time for pelvic and total lymphadenectomy were significantly shorter in the robotic-assisted approach, whereas the time for infrarenal para-aortic lymphadenectomy did not differ statistically. In contrast, the number of infrarenal para-aortic lymph nodes was significantly higher in the robotic-assisted approach. We compared the time per retrieved lymph node in both approaches, and those for pelvic, infrarenal para-aortic, and total lymphadenectomy were significantly shorter in the robotic-assisted approach. Conclusion: In our study, the robotic-assisted TIPAL took less time to retrieve a lymph node than the laparoscopic approach. The robotic-assisted approach for TIPAL is feasible for the staging and treatment of patients with gynecological malignancies.
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Anastomotic Leakage Using Linear Stapling Device with Pre-attached Bioabsorbable Polyglycolic Acid Felt After Laparoscopic Anterior Resection
Aim: Many studies have evaluated the risk factors for anastomotic leakage after laparoscopic anterior resection. In this study in order to increase the tightness of anastomoses and prevent bleeding from their staple lines, a linear stapler with pre-attached bioabsorbable polyglycolic acid (PGA) felt was used for rectal transection, and the short-term surgical outcomes were evaluated. Patients and Methods: A prospective registry of 62 patients with rectosigmoidal or rectal carcinoma who initially underwent laparoscopic anterior resection using PGA felt for rectal transection was reviewed. Results: The overall frequency of anastomotic leakage was 1.6% (1/62), and none of the patients developed postoperative staple line bleeding or other adverse events related to the use of PGA felt. Conclusion: The frequency of anastomotic leakage was relatively low, and therefore the use of a linear stapler with pre-attached bioabsorbable PGA felt might reduce the risk of adverse events related to anastomosis, especially anastomotic leakage.
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Association Between PD-L1 Expression and Metabolic Activity on 18F-FDG PET/CT in Patients with Small-sized Lung Cancer
Aim: We evaluated the metabolic characteristics of small-sized lung cancer using 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) with regard to programmed cell death ligand 1 (PD-L1) expression. Materials and Methods: PD-L1 expression was evaluated by immunohistochemistry with the antibody clone SP142 in 263 patients with surgically resected primary small-sized lung cancer. Specimens with <5% tumor membrane staining were considered negative. We examined the association between the frequency of PD-L1 expression and the maximum standardized uptake value (SUVmax) in preoperative 18F-FDG PET/CT. Results: Among patients with non-small cell lung cancer (NSCLC), the SUVmax was significantly higher in those with PD-L1 expression than in those without (p<0.0001). However, there was no correlation between SUVmax and PD-L1 expression in patients with neuroendocrine tumors (p=0.9638). Multivariate analysis revealed that smoking and a high SUVmax were independent predictors of PD-L1 expression. Conclusion: PD-L1 expression was related to high glucose metabolism in small-sized NSCLC.
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A Glissonean Approach with Individual Isolation During Right Hemi-Hepatectomy After Portal Vein Embolization
Background/Aim: Although the Glissonean approach in hemi-hepatectomy is a very useful technique, right hemi-hepatectomy with Glissonean approach after portal vein embolization (PVE) is difficult because of the obstructing materials located at the right portal branch. The aim of this study was to evaluate the utility of the Glissonean approach with an individual isolation technique (GI technique) in right hemi-hepatectomies after PVE. Patients and Methods: We retrospectively analyzed 21 patients who underwent the GI technique between March 2007 and June 2012. Results: In one of the 21 patients, we could not perform the GI technique because of severe adhesions following previous operation; however, there were no troubles in the remaining 20 cases. In addition, none of the patients that were treated using this method developed massive ascites after right hemi-hepatectomy, despite 8 patients (40%) exhibiting severe fibrosis (F3 or F4). Conclusion: Even in right hemi-hepatectomy following PVE, our GI technique may be a useful procedures for patients.
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Mucinous Cystic Neoplasms Lined by Abundant Mucinous Epithelium Frequently Involve KRAS Mutations and Malignant Progression
Background: Pancreatic and hepatic mucinous cyst neoplasms (MCNs) have a malignant potential, but indolent MCNs are not uncommon. Materials and Methods: The pathological and genetic characteristics of resected MCNs (n=15) categorized by the amount of mucin of the lining epithelium were investigated. Results: MCNs were divided into two groups: (i) a rich (r)-MCN group (n=6), in which more than half of the epithelium was lined by abundant mucinous epithelium; and (ii) a poor (p)-MCN group (n=9), which consisted of the remaining cases. Three patients in the r-MCN group showed invasive carcinoma or high-grade dysplasia, whereas all patients in the p-MCN group showed low-grade dysplasia. Mutations of Kirsten rat sarcoma viral oncogene homolog (KRAS) were more frequent in the r-MCN group (83%) (p-MCN; 11%, p<0.05). Conclusion: Mucinous MCNs more frequently have KRAS mutations and higher risk of malignant progression.
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Outcome Evaluation of HER2 Breast Cancer Patients with Limited Brain Metastasis
Background/Aim: To appraise the outcome of limited brain metastasis (BMs) from HER2 breast cancer. Patients and Methods: The study cohort included sixty-six patients Treatments consisted of surgery followed by radiotherapy (RT), or radiosurgery (SRS/HSRS) or whole brain radiotherapy (WBRT). Results: Surgery followed by RT was performed in 25.8% of patients, SRS/HSRS alone in 48.5%, and WBRT alone in 25.7%. The median follow-up time was 23.4 months and 32.5 months for alive patients. Local recurrence occurred in 16 (24.2%) patients. The median, 1-, 2-, 3-year local control were (median not reached=nr), 87.5%, 71.2%, and 63.0%. The median 1-, 2-, 3-year overall survival were 30.7 months (95%CI: 18.9-42.6 months), 78.5%, 57.4%, 43.3%. Karnofsky Performance Scale (KPS), number of BMs, local treatment performed, the presence of extracranial (EC) metastases at the time of BMs diagnosis, and the administration of trastuzumab affected survival. Conclusion: HER2BC patients with good performance status, controlled EC disease and single BM had better outcome. In this long-term survivor patients, local BMs treatment can affect survival.
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Characterization of Prognostic Factors and the Efficacy of Adjuvant S-1 Chemotherapy in Patients with Post-surgery Extrahepatic Bile Duct Cancer
Background/Aim: There is no clear consensus on the type of adjuvant therapy that should be used for patients with extrahepatic bile duct cancer. Patients and Methods: Two hundred and seventy-one patients that had undergone surgical resection for extrahepatic bile duct cancer composed the study cohort. Demographics, treatments, and relationships between the potential prognostic factors and survival rates were analyzed. Results: The overall 3-year and 5-year survival rates for post-surgery extrahepatic bile duct cancer patients were 49.0% and 35.4%, respectively. Multivariate analysis revealed that regional lymph node metastasis was an independent negative prognostic factor. We observed a significant correlation between node-positive extrahepatic bile duct cancer and postoperative local recurrence, liver metastasis, peritoneal dissemination, and post-surgery lymph node metastasis. Adjuvant S-1 chemotherapy showed a favorable hazard ratio in patients with lymph node metastases or positive vascular invasion. Conclusion: We recommend the use of adjuvant S-1 therapy in patients with lymph node metastases or microvascular invasion.
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BRAF, NRAS and C-KIT Advanced Melanoma: Clinico-pathological Features, Targeted-Therapy Strategies and Survival
Background/Aim: The mutational status of stage III and IV melanomas should be recognized in order to allow for targeted therapies. The aim of our study was the characterization of BRAF, NRAS and C-KIT melanoma patients, in order to define their optimal management. Patients and Methods: Between 1991 and 2015, 63 mutated melanoma patients were treated and monitored during their diagnostic and therapeutic management at a single institution. Results: BRAF-mutated melanoma patients were the most common, representing 70% of the study population, while NRAS- and C-KIT-mutated melanoma represented 19% and 11% respectively. BRAF-mutated melanomas were mostly located at sites of intermittent sun exposure, and were associated with higher Breslow thickness and an increased number of mitosis. NRAS mutated melanoma were mainly observed in chronic sun-damaged areas and had a negative prognostic value, with shorter time to progression and a high incidence of central nervous system involvement. C-KIT mutated melanoma were located at acral and mucosal sites. Overall survival observed in the three groups of patients revealed wide differences. Conclusion: BRAF, NRAS and C-KIT melanomas constitute distinct clinico-pathological entities. BRAF-mutated melanoma benefit from both anti-BRAF and anti-MEK targeted therapies while triple-negative melanomas could benefit from novel anti-CTLA-4 and anti-PD-L1 immunotherapeutic approaches.
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FOLFOX as First-line Therapy for Gastric Cancer with Severe Peritoneal Metastasis
Background/Aim: Severe peritoneal metastasis (PM) from advanced gastric cancer (AGC) causes massive ascites and inadequate oral intake. Because patients with severe PM are often not included in clinical trials, little is known regarding the efficacy and safety of oxaliplatin with l-leucovorin and bolus/continuous infusion of 5-fluorouracil (FOLFOX) for them. Patients and Methods: We retrospectively studied AGC patients with massive ascites and/or inadequate oral intake due to severe PM treated with FOLFOX as the first-line treatment. Results: Only 39 (10%) of 378 AGC patients had severe PM; 10 received FOLFOX. The median progression-free and overall survivals were 7.5 and 13.2 months, respectively. Ascites decreased in seven of nine patients with ascites, and oral intake improved in four of seven patients with an inadequate oral intake. Common grade 3-4 adverse events included neutropenia and anemia. Conclusion: This study suggests that FOLFOX is effective and manageable for AGC patients with severe PM.
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Incidence and Risk Factors of Symptomatic Hiatal Hernia Following Resection for Gastric and Esophageal Cancer
Background/Aim: Symptomatic hiatal hernia (HH) following resection for gastric or esophageal cancer is a potentially life-threatening event that may lead to emergent surgery. However, the incidence and risk factors of this complication remain unclear. Patients and Methods: Data of patients who underwent resection for gastric or esophageal cancer between 2005 and 2012 were assessed and the incidence of symptomatic HH was evaluated. Factors associated with an increased risk for HH were investigated. Results: Resection of gastric or esophageal cancer was performed in 471 patients. The primary tumor was located in the stomach, cardia and esophagus in 36%, 24%, and 40% of patients, respectively. The incidence of symptomatic HH was 2.8% (n=13). All patients underwent surgical hernia repair, 8 patients (61.5%) required emergent procedure, and 3 patients (23%) underwent bowel resection. Morbidity and mortality after HH repair was 38% and 8%, respectively. Factors associated with increased risk for symptomatic HH included Body-Mass-Index (median BMI with HH 27 (23-35) vs. BMI without HH 25 (15-51), p=0.043), diabetes (HH rate: with diabetes, 6.3% vs. without diabetes, 2%, p=0.034), tumor location (HH rate: stomach, 1.2% vs. esophagus, 1.1% vs. cardia, 7.9%, p=0.001), and resection type (HH rate: total/subtotal gastrectomy, 0.7% vs. transthoracic esophagectomy, 2.7% vs. extended gastrectomy, 6.1%, p=0.038). Conclusion: HH is a major adverse event after resection for gastric or esophageal cancer especially among patients undergoing extended gastrectomy for cardia cancer requiring a high rate of repeat surgery. Therefore, intensive follow-up examinations for high-risk patients and early diagnosis of asymptomatic patients are essential for selecting patients for elective surgery to avoid unpredictable emergent events with high morbidity and mortality.
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A Prospective Study of Intensity-modified Radiation Therapy in Comparison with Conventional 3D-RT for BR Pancreatic Cancer Patients with Arterial Involvement
Background/Aim: Intensity-modulated radiation therapy (IMRT) is a form of radiation therapy that allows accurate irradiation with reduced damage to surrounding tissues. Here, we analyzed borderline-resectable pancreatic cancer (BRPC) with arterial abutment (BR-A) patients with IMRT as neoadjuvant therapy and performed comparisons with patients with conventional RT to clarify the advantages of IMRT as a neoadjuvant therapy. Patients and Methods: Thirty BR-A patients treated at our hospital between January 2012 and December 2015 were divided into two groups: 12 patients underwent conventional 3D-RT before resection (RT group); and 18 patients underwent IMRT before resection (IMRT group). We analyzed safety, tumor resection rate, histological classification of the tumor and overall survival. Results: The R0 rate was 84% for the IMRT group and 83% for the RT group. Local therapeutic effects as assessed by Evans classification showed a higher local control rate in the IMRT group (Grade: 1, 0%; 2a, 25%; 2b, 41.6%; 3, 17%; 4, 8%) than in the RT group (Grade: 1, 17%; 2a, 50%; 2b, 17%; 3, 17%; 4, 0%). The cumulative dose of S1 treatment as adjuvant therapy was much smaller in the RT group (18.3%) compared to that in the IMRT group (57.1%, p=0.047), and with better subsequent overall survival rate (MST 32 months vs. 13.8 months, p=0.0273). Conclusion: The IMRT group showed a better control rate than the RT group. The neoadjuvant IMRT has advantages of higher completion rate of adjuvant chemotherapy with better nutritional status and better subsequent overall survival rate (OS).
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Pancreatic Mucinous Cystic Neoplasm Communicating with Main Pancreatic Duct: An Unrecognized Presentation of Pancreatic Mucinous Neoplasm?
Mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs) are two well recognized entities of precursor cystic lesions of pancreatic duct adenocarcinoma. The characteristic features of MCNs are the lined mucinous epithelium with underlying ovarian-type stroma, but without communication with the ducts, while that for IPMNs are the communication with the ducts but without the underlying ovarian-type stroma. Here we report a case of MCN communicating with the main pancreatic duct in a 68-year-old woman. The initial radiographic diagnosis was pancreatic IPMN with main pancreatic involvement and this was also confirmed during gross examination. Histologically, the pancreatic cystic neoplasm was lined with mucinous epithelium with underlying ovarian-type of stroma. Immunohistochemical stains confirmed that the stroma cells were positive for ER, PR, alpha-inhibin and focally positive for CD10. The final pathologic diagnosis was pancreatic mucinous cystic neoplasm communicating with the main pancreatic duct. To the best of our knowledge, this is the second pathology confirmed case of MCN communicating with the main pancreatic duct. A careful gross examination and bivalvation of the main duct communicating with the cystic neoplasm helps render the correct diagnosis. If more cases are reported in the future, the MCN communicating with duct could become a new entity of pancreatic mucinous neoplasm.
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Predictive Factors and a Survival Score for Patients Irradiated for Metastatic Spinal Cord Compression from Carcinoma of the Salivary Glands
Aim: To our knowledge, this is the first study focusing on metastatic spinal cord compression (MSCC) from carcinoma of the salivary glands. Patients and Methods: Nine patients receiving radiation alone were evaluated for improvement of motor deficits, post-radiation gait function and survival. Results: Of nine characteristics (radiation program, age, sex, additional metastases to bone or to other organs, dynamic of motor deficits, pre-radiation gait function, number of vertebrae affected by MSCC, general condition), strong trends were found for associations between improved motor deficits and their dynamic (p=0.05), post-radiation gait function and pre-treatment ambulatory status (p=0.08) and between survival and additional metastases to other organs (p=0.07), dynamic of motor deficits (p=0.07) and general condition (p=0.07). In addition, a survival score was created. Patients with 2-3 points had a significantly better 6-month survival than those with 0-1 points (100% vs. 0%, p=0.027). Conclusion: Characteristics predicting outcomes identified in this study and the new survival score can guide physicians when making treatment decisions.
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Stereotactic Body Radiation Therapy in Primary and Metastatic Liver Disease
Background/Aim: The aim of this study was to investigate the treatment outcomes and toxicities in patients with liver disease treated by Stereotactic Body Radiation Therapy (SBRT). Patients and Methods: From 2007 to 2016, 43 patients with 58 lesions (6 primary and 37 metastatic liver tumors) were treated with SBRT. Results: Local Control was reached in 47 out of 58 (81%) treated lesions with 12 and 24-month rates of 81% and 74% respectively. The progression-free survival at 12 and 24 months was 42% and 36%, respectively. The disease specific survival at 12 and 24 months was 74% and 46% respectively. Median overall survival (OS) was 20 months and the rates of OS were 74% and 46% at 12 and 24 months respectively. Toxicity was very low consisting mainly of Grade 1 and 2. Conclusion: SBRT provides good local control for both primary and metastatic liver lesions, with minimal toxicity.
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One-pot synthesis of pH-responsive charge-switchable PEGylated nanoscale coordination polymers for improved cancer therapy
Publication date: February 2018
Source:Biomaterials, Volume 156
Author(s): Yu Yang, Ligeng Xu, Wenjun Zhu, Liangzhu Feng, Jingjing Liu, Qian Chen, Ziliang Dong, Jiayue Zhao, Zhuang Liu, Meiwan Chen
Nanoscale coordination polymers (NCPs) are promising nanomedicine platforms featured with biodegradability and versatile functionalities. However, multi-step post-synthesis surface modification is usually required to functionalize as-made NCPs before their biomedical applications. Moreover, efforts are still required to design therapeutic NCPs responsive to the unique tumor microenvironment to achieve more specific and effective therapy. Herein, we uncover a simple yet general strategy to synthesize a series of polyethylene glycol (PEG) modified NCPs via a one-step method by adding poly-histidine-PEG co-polymer into the mixture of metal ions and organic ligands during NCPs formation. With NCPs consisting Ca2+/dicarboxylic cisplatin (IV) prodrug as the example, we show that such Ca/Pt(IV)@pHis-PEG NCPs are highly sensitive to pH changes. With slightly negative charges and compact structure under pH 7.4 during blood circulation, those NCPs exhibit efficient passive accumulation in the tumor, in which the reduced pH (c.a. 6.5) would trigger charge conversion and size expansion to enhance their tumor retention and cell internationalization. After cellular uptake, NCPs within cell endo-/lysosomes with further reduced pH would then lead to decomposition of those NCPs and thus drug release. Chemotherapy with Ca/Pt(IV)@pHis-PEG NCPs in our animal tumor model demonstrates great efficacy under low drug doses, and is found to be particularly effective towards solid tumors with reduced pH.
Graphical abstract
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A mitochondrial-targeting near-infrared fluorescent probe for bioimaging and evaluating endogenous superoxide anion changes during ischemia/reperfusion injury
Source:Biomaterials, Volume 156
Author(s): Xiaoyue Han, Rui Wang, Xinyu Song, Fabiao Yu, Changjun Lv, Lingxin Chen
The outburst of superoxide anion (O2−) in mitochondrial during ischemia/reperfusion (I/R) process will cause a series of oxidative damage including polarity loss of mitochondrial membrane potential, overload of secondary cellular calcium, and cascade apoptosis. To monitor the O2− level fluctuations as well as to evaluate the relationship between O2− concentration and the degree of cell apoptosis during I/R process, we propose a ratiometric near-infrared mitochondrial targeting fluorescent probe Mito-Cy-Tfs for the detection of level changes of O2− in cells and in vivo. The probe Mito-Cy-Tfs is composed of three moieties: near-infrared heptamethine cyanine as fluorescence signal transducer, trifluoromethanesulfonamide as fluorescence modulator, and lipophilic triphenylphosphonium cation as mitochondrial guider. The probe can well locate in mitochondria and respond the concentration changes of endogenous O2− selectively and sensitively. The probe has been successfully utilized to image the endogenous O2− fluctuations in four kinds of cell I/R models (glucose deprivation/reperfusion, serum deprivation/reperfusion, oxygen deprivation/reperfusion and glucose-serum-oxygen deprivation/reperfusion). The probe also exhibits deep tissue penetration for real-time imaging of O2−concentration in liver of I/R mice model. We confirm that the adoption of ischemic preconditioning (IPC) and postconditioning (IPTC) can protect liver from I/R injury. The probe can be employed to accurately indicate and evaluate the mutual relationship between the levels of O2− and the degrees of organ damage during I/R, IPC and IPTC processes. The above applications make our new probe a potential candidate for the clinical surgery assessment.
http://ift.tt/2jtIXpQ
Mechanistic insights into the role of glycosaminoglycans in delivery of polymeric nucleic acid nanoparticles by molecular dynamics simulations
Publication date: February 2018
Source:Biomaterials, Volume 156
Author(s): Deniz Meneksedag-Erol, Tian Tang, Hasan Uludağ
Delivery of polynucleotide-based therapeutics into target cells involves interactions with glycosaminoglycan chains that are located on cell membrane milieu. Mechanisms governing glycosaminoglycan-mediated changes in the nanoparticulate structures of polymer-polynucleotide complexes are unknown, and cannot be fully elucidated without atomistic level details of molecular interactions. We selected a representative nanoparticulate system consisting of a short interfering RNA (siRNA)-polyethylenimine complex, and performed all-atom molecular dynamics simulations with the prototypical glycosaminoglycan heparin. We monitored the binding between the complex constituents and the heparin, and identified key features contributing to the response of the siRNA nanoparticles to heparin. We observed three main metastable states that the siRNA nanoparticles might visit in the presence of heparin, which can be translated into different functional outcomes. By correlating our data with the widely different and seemingly contradictory roles previously assigned to glycosaminoglycans, this study provides unique insights into the discrepancies in the experimental literature concerning the role of glycosaminoglycans in the polymeric nanoparticle delivery.
Graphical abstract
http://ift.tt/2hZnPau
When stem cells meet graphene: Opportunities and challenges in regenerative medicine
Source:Biomaterials, Volume 155
Author(s): Kenry, Wong Cheng Lee, Kian Ping Loh, Chwee Teck Lim
Recent advances in stem cell research and nanotechnology have significantly influenced the landscape of tissue engineering and regenerative medicine. Precise and reproducible control of the fate of stem cells and their lineage specification have, therefore, become more crucial than ever for the success of stem cell-based technologies. Extensive research has been geared towards developing materials that are capable of mimicking the physiological microenvironment of stem cells and at the same time, controlling their eventual fate. An interesting example of these materials is two-dimensional graphene and its related derivatives. A high specific surface area coupled with superior chemical stability, biocompatibility, and flexibility in functionalization render graphene-based nanomaterials one of the most exciting platforms for tissue engineering and regenerative medicine applications, especially for stem cell growth, proliferation, and differentiation. In this review, we discuss the love-hate relationship between stem cells and graphene-based nanomaterials in tissue engineering and regenerative medicine. We first discuss the role and importance of stem cells in tissue engineering and regenerative medicine. We then highlight the use of nanomaterials for stem cell control, the interaction between stem cells and graphene nanomaterials as well as their biocompatibility, biodistribution, and biodegradability considerations. We also offer our perspectives on the various challenges and opportunities facing the use of graphene and its derivatives for stem cell growth and differentiation.
http://ift.tt/2i0cWWe
Option grids in melanoma - an underused tool
It is not uncommon for patients faced with a new diagnosis of malignant melanoma to experience significant upset and confusion. During this distressing period, NICE guidance (NG14) recommends that patients with AJCC Stage IB-IIC disease should consider whether they wish to undergo sentinel lymph node biopsy (SLNB)1. The decision to undergo SLNB can be difficult and should ideally be reached following informed and considered discussion with patients guided as to the relative merits of SLNB by their plastic surgeon.
http://ift.tt/2jyDJt8
Effect of carpal tunnel release on median nerve epineurial flux
It is believed that increased pressure that develops in the carpal tunnel syndrome (CTS) leads to nerve compression and a gradual decrease in neurovascular blood flow. Animal experiments showed that early nerve release restores neurovascular flow; however, late decompression has no effect.1 This finding raises the questions of whether carpal tunnel release increases blood flow in the median nerve and whether nerve ischemia may be associated with carpal tunnel etiology. The objective of this study was to evaluate the immediate effects of tunnel release and determine its influence on median nerve flux.
http://ift.tt/2i4ySQ5
Patient-specific puzzle implant preformed with 3d-printed rapid prototype model for combined orbital floor and medial wall fracture
The management of combined orbital floor and medial wall fractures involving the inferomedial strut is challenging due to absence of stable cornerstone. In this article, we proposed surgical strategies using customized 3D puzzle implant preformed with Rapid Prototype (RP) skull model.
http://ift.tt/2jxQcNt
Uranium(VI) sorption complexes on silica in the presence of calcium and carbonate
Publication date: February 2018
Source:Journal of Environmental Radioactivity, Volume 182
Author(s): Alaaeldine Sh. Saleh, Jun-Yeop Lee, Yongheum Jo, Jong-Il Yun
Uranium sorption on minerals and related solids depends to a large degree on its aqueous speciation. The present work attempts to understand the U(VI) sorption behavior on silica under environmentally relevant conditions, i.e. at neutral to weakly alkaline pH and in the presence of dissolved calcium and carbonate. Under these conditions, Ca(UO2)(CO3)32− and Ca2(UO2)(CO3)3(aq) complexes emerge as the dominant aqueous U(VI) species. The U(VI) sorption affinity was measured as a function of contact time, solution pH, and humic acid. The U(VI) sorption decreased with increase of pH and was not affected by the addition of 50 mg/L humic acid. On the other hand, nitric acid was more effective than EDTA and carbonate at desorbing U(VI). Generally, the U(VI) sorbed on silica at neutral pH was less readily desorbed than that sorbed at higher pH values. Therefore, the U(VI) complex favorably sorbed on silica at the neutral pH is more strongly bound to the silica surface than that sorbed at higher pH values. Time-resolved laser fluorescence spectroscopy confirmed the results of the batch sorption experiments and revealed the presence of two surface U(VI) complexes with fluorescence lifetimes 251 ± 8 μs and 807 ± 24 μs.
Graphical abstract
http://ift.tt/2Ao6VNE
Postmortem MRI and histology demonstrate differential iron accumulation and cortical myelin organization in early- and late-onset Alzheimer's disease
Source:Neurobiology of Aging, Volume 62
Author(s): Marjolein Bulk, Walid M. Abdelmoula, Rob J.A. Nabuurs, Linda M. van der Graaf, Coen W.H. Mulders, Aat A. Mulder, Carolina R. Jost, Abraham J. Koster, Mark A. van Buchem, Remco Natté, Jouke Dijkstra, Louise van der Weerd
Previous MRI studies reported cortical iron accumulation in early-onset (EOAD) compared to late-onset (LOAD) Alzheimer disease patients. However, the pattern and origin of iron accumulation is poorly understood. This study investigated the histopathological correlates of MRI contrast in both EOAD and LOAD. T2*-weighted MRI was performed on postmortem frontal cortex of controls, EOAD, and LOAD. Images were ordinally scored using predefined criteria followed by histology. Nonlinear histology-MRI registration was used to calculate pixel-wise spatial correlations based on the signal intensity. EOAD and LOAD were distinguishable based on 7T MRI from controls and from each other. Histology-MRI correlation analysis of the pixel intensities showed that the MRI contrast is best explained by increased iron accumulation and changes in cortical myelin, whereas amyloid and tau showed less spatial correspondence with T2*-weighted MRI. Neuropathologically, subtypes of Alzheimer's disease showed different patterns of iron accumulation and cortical myelin changes independent of amyloid and tau that may be detected by high-field susceptibility-based MRI.
http://ift.tt/2BloDOA
Blistering and Skin Fragility Due to Imatinib Therapy: Loss of Laminin and Collagen IV as a Possible Cause of Cutaneous Basement Membrane Instability
Abstract: Imatinib mesylate (Glivec; Novartis AG, Basel, Switzerland) is a tyrosine kinase inhibitor which is used in the treatment of oncologic diseases like chronic myeloid leukemia and gastrointestinal stroma tumor (GIST). Among cutaneous side effects, bullous reactions are rare. The authors describe the case of a 66-year-old woman developing blistering and skin fragility on her hands, foot, lower legs, and back after intake of imatinib for treatment of GIST. Biopsy showed vacuolar alteration at the dermoepidermal junction (DEJ) associated with a few lymphocytes and a subepidermal blister. The upper papillary dermis below the vacuolar alteration and below the blister showed hyalinization and loss of elastic microfibrils. Direct immunofluorescence was negative for deposits of immunoglobulins. Immunofluorescence on cryosections revealed loss of laminin and collagen IV in vacuoles at the DEJ. Electron microscopy showed dissolution of lamina lucida and lamina densa of the basement membrane below as well as next to the vacuoles and blister. In conclusion, the authors present the first patient with GIST with blistering and skin fragility due to imatinib therapy. As a pathophysiological explanation the authors propose loss of laminin and collagen IV at the DEJ leading to basement membrane instability and blistering. This case also suggests additional features reminiscent of lichen sclerosus induced by imatinib, a drug which is actually known for its antifibrotic effects. Reprints: Sebastian Mühl, MD, Universitätshautklinik Münster, Dermatohistologisches Labor, Von-Esmarch-Strasse 58, D-48149 Münster, Germany (e-mail: Sebastian.Muehl@ukmuenster.de). The authors declare no conflicts of interest. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
http://ift.tt/2AoJdAQ
http://ift.tt/2AoJdAQ
Relationship Between Pityriasis Lichenoides and Mycosis Fungoides: A Clinicopathological, Immunohistochemical, and Molecular Study
Background: Several cases of pityriasis lichenoides (PL) have been reported to evolve into mycosis fungoides (MF). Objective: To elucidate clues to this progression. Methods: Fifty-eight patients with PL between 2000 and 2013 (follow-up: 3–16 years, average: 8.3). Results: A total of 3 (5.2%) of the 58 patients with PL developed MF after 3–11 years of prolonged clinical course. Papules and small plaques characterized PLs, and patches and larger plaques subsequent MFs. A total of 35 of 41 (85%) followed up non-MF associated patients with PL reported lasting complete remissions. Histopathologically, apoptotic keratinocytes disappeared mostly or completely in subsequent MFs. The presence of epidermotropism, folliculotropism, and epidermal lymphocytic nuclear atypia in PLs was not predictive of MF. CD8+ cells were the dominant intraepidermal lymphocytes in the 3 PLs but remained so in only 1 subsequent MF. CD7+ lymphocytes decreased substantially in 2 MFs, and lymphocytic nuclear atypia increased markedly in 1. T-cell receptor gene rearrangement studies demonstrated clonal populations in 1 of 2 studied PLs and in all 3 subsequent MFs. Conclusions: A few PLs may evolve into MF. Prolonged clinical course, appearance of patches and larger plaques, markedly increased lymphocytic nuclear atypia, marked diminution of apoptotic keratinocytes and CD7+ and CD8+ lymphocytes, and clonal T-cell receptor gene rearrangement may serve as clues. Reprints: Reuven Bergman, MD, Department of Dermatology, Rambam Health Care Campus and the Bruce Rappaport Faculty of Medicine, Technion, Haifa 3109601, Israel (e-mail: r_bergman@rambam.health.gov.il). The authors declare no conflicts of interest. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
http://ift.tt/2imzzaT
http://ift.tt/2imzzaT
Intradermal Proliferative Fasciitis Occurring With Chondrodermatitis Nodularis Helicis
Abstract: Nodular fasciitis is a benign myofibroblastic tumor. Its uncommon variant, proliferative fasciitis (PF), can present in an even less common intradermal form. We report a case of intradermal PF of the ear in a 45-year-old man who presented with recurrent episodes of pain and swelling of the lesion. Histologic examination showed a dermal, nodular proliferation of ganglion-like basophilic fibroblasts with prominent nuclei and nucleoli, admixed with foamy histiocytes and areas of spindle cells arranged in intersecting fascicles in a fibromyxoid background. Lesional cells stained positive for smooth muscle actin and were negative for AE1/AE3, p63, and Melan-A. CD68 highlighted intervening histiocytes. We postulate that the underlying chondrodermatitis nodularis helicis was a triggering etiology, consistent with the current speculation that intradermal PF results from trauma. Reprints: Sasha Getty, MS4, UC Irvine Dermatology, 118 Med Surg 1, Irvine, CA 92697-2400 (e-mail: sgetty@uci.edu@uci.edu). The authors declare no conflicts of interest. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
http://ift.tt/2AmsqhR
http://ift.tt/2AmsqhR
Young adult e-cigarette use outcome expectancies: Validity of a revised scale and a short scale
Source:Addictive Behaviors, Volume 78
Author(s): Pallav Pokhrel, Tony H. Lam, Ian Pagano, Crissy T. Kawamoto, Thaddeus A. Herzog
The revised youth e-cigarette outcome expectancies measure adds new items informed by recent qualitative research with young adult e-cigarette users, especially in the domain of positive "smoking" experience. Positive "smoking" experience represents beliefs that use of e-cigarettes provides outcomes associated with a better "smoking" alternative: for example, an alternative that is more socially approved, more suitable for indoor use, and that provides a safer means of enjoying nicotine. In addition, we tested a short, 8-item version of the measure which may be more easily incorporated into surveys. We tested the validity of the revised measure, both long and short versions, in terms of factor structure and associations of the expectancy factors with current e-cigarette use, e-cigarette use susceptibility, and e-cigarette use dependence. Participants were young adults (N=470; 65% women; mean age=20.9, SD=2.1). Results replicated the findings of the previous study as well as highlighted the importance of the added domain of positive "smoking" experience and the validity of the short scale. Furthermore, results showed that positive outcome expectancies are strongly associated with e-cigarette use dependence. The long and short versions of the revised youth e-cigarette outcome expectancies scale appear to be valid and useful for application not only among cigarette smokers and e-cigarette users but also among never smokers and never e-cigarette users.
http://ift.tt/2zQa7lS
RACK1 is an organ-specific prognostic predictor in OSCC
Publication date: January 2018
Source:Oral Oncology, Volume 76
Author(s): Sai Liu, JiaJia Liu, Jiongke Wang, Junxin Cheng, Xin Zeng, Ning Ji, Jing Li, Qianming Chen
ObjectivesThis study aims to verify that RACK1 is an organ-specific prognostic predictor in patients with oral squamous cell carcinoma (OSCC).Experimental designThe RACK1 expression level was assessed by immunohistochemistry (IHC) in a total of 342 OSCC patients from 3 independent cohorts. The multivariate hazard ratios for Overall Survival (OS) was determined by Cox proportional hazards regression model. OS was analyzed in 460 Head Neck Squamous Cell Carcinoma (HNSCC) patients from TCGA data set. The expression level of RACK1 was analyzed in 60 cases multiple organ tissue microarrays representing both normal and cancer tissues by IHC, and in TCGA database of mRNA abundance in cancers and paired normal tissues.ResultsThe median follow-up times of patients in the study was 74, 52, and 78 months. High expression of RACK1 was identified in tumors from 103 of 151 patients (68.2%), 51 of 83 patients (61.4%), and 59 of 108 patients (54.6%). Compared with low expression, high expression of RACK1 was strongly associated with worse OS, with HR of 0.5995 (95% CI, 0.3929 to 0.9147; P=0.0176), 0.4402 (95% CI, 0.2321 to 0.8348; P=0.0120), and 0.5010 (95% CI, 0.2886 to 0.8699; P=0.0141). This finding is consistent with TCGA HNSCC data (P=0.0276). Tissue microarrays analyses showed different protein expression level of RACK1 in multiple human carcinomas and this finding is consistent with the TCGA database analysis of RACK1 mRNA abundance.ConclusionOur findings demonstrated that RACK1 is a good independent organ-specific predictor of the risk of death in OSCC.
http://ift.tt/2Aoda4l
Complete Atrioventricular Heart Block From an Epilepsy Treatment
Source:Pediatric Neurology
Author(s): Kelly M. Brinkley, Mark D. Ayers, Deborah K. Sokol
http://ift.tt/2ioUavj
A meta-analysis of the association between vocalizations and expressive language in children with autism spectrum disorder
Source:Research in Developmental Disabilities, Volume 72
Author(s): Jena McDaniel, Kathryn D'Ambrose Slaboch, Paul Yoder
BackgroundTargeting the frequency or complexity of prelinguistic vocalizations might improve the language trajectory of children with autism spectrum disorder (ASD) who exhibit continued expressive language deficits.AimsThis meta-analysis evaluates the strength of the association between various measures of vocalizations and expressive language in young children with ASD and five putative moderators of that association to inform prelinguistic intervention development: consonant-centricity, communicativeness, concurrent versus longitudinal research design, risk for correlated measurement error, and publication status.Methods and proceduresWe systematically searched databases and other sources for correlations between vocalizations and expressive language in children with ASD less than 9 years old. Using robust variance estimation, we calculated the weighted mean effect size and conducted moderator analyses.Outcomes and resultsNine studies (19 reports), which included 362 participants and 109 unique effect sizes, met inclusion criteria. The weighted mean effect size between vocalizations and expressive language was significant (r=0.50, 95% CI [0.23, 0.76]). As predicted, concurrent correlations were significantly stronger than longitudinal correlations. Other moderator effects were not detected.Conclusions and implicationsYoung children with ASD demonstrate a strong association between vocalizations and expressive language skills. Future experimental studies should investigate causal relations to guide intervention development.
http://ift.tt/2i1prAw
Corticospinal excitability during motor imagery is reduced in young adults with developmental coordination disorder
Source:Research in Developmental Disabilities, Volume 72
Author(s): C. Hyde, I. Fuelscher, J. Williams, J.A.G. Lum, J. He, P. Barhoun, P.G. Enticott
While a compelling body of behavioral research suggests that individuals with developmental coordination disorder (DCD) experience difficulties engaging motor imagery (MI), very little is known about the neural correlates of this deficit. Since corticospinal excitability is a predictor of MI proficiency in healthy adults, we reasoned that decreased MI efficiency in DCD may be paralleled by atypical primary motor cortex (PMC) activity. Participants were 29 young adults aged 18- 36 years: 8 with DCD (DCD) and 21 controls. Six participants with DCD and 15 controls showed behavioral profiles consistent with the use of a MI strategy (MI users) while performing a novel adaptation of the classic hand laterality task (HLT). Single-pulse transcranial magnetic stimulation (TMS) was administered to the hand node of the left PMC (hPMC) at 50ms, 400ms or 650ms post stimulus presentation during the HLT. Motor-evoked potentials (MEPs) were recorded from the right first dorsal interosseous (FDI) via electromyography. As predicted, MI users with DCD were significantly less efficient than MI using controls, shown by poorer performance on the HLT. Importantly, unlike healthy controls, no evidence of enhanced hPMC activity during MI was detected in our DCD group. Our data are consistent with the view that inefficient MI in DCD may be subserved by decreased hPMC activity. These findings are an important step towards clarifying the neuro-cognitive correlates of poor MI ability and motor skill in individuals with DCD.
http://ift.tt/2jvUrt4
Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis
This analysis of data from an open-label, nonrandomized, multicohort study of patients from the VE-BASKET trial evaluates the efficacy and safety of vemurafenib in the treatment of adults with BRAF V600–mutant Erdheim-Chester disease or Langerhans cell histiocytosis.
http://ift.tt/2AIb9Aw
http://ift.tt/2AIb9Aw
Using first bout effect to study the mechanisms underlying eccentric exercise induced force loss
Publication date: Available online 29 November 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Orawan Prasartwuth, Roongtip Suteebut, Jitapa Chawawisuttikool, Utku Yavuz S, Kemal Turker S
IntroductionThe first bout of eccentric exercise is known to have a protective effect on the consequent bouts. This effect is still disputable as it is not known whether it protects muscle damage by reducing force production or by improving force recovery in the healing process. The underlying mechanisms of this protective effect have not been fully understood.ObjectivesTo determine the mechanisms of this protective effect, three different loads were used for the first eccentric bout. This was done to investigate whether the protective effect is related to the size of the load in the first bout. To determine the neural adaptations, voluntary activation was assessed and to determine the muscular adaptations, the resting twitch was measured.MethodThirty healthy participants were selectively allocated into three groups (low-, moderate- and high-load group) to match for maximal voluntary contraction (MVC) (n = 10 per group). Participants in each group performed only one of the three sets of ten eccentric (ECC) exercises of the elbow flexors (10%, 20% and 40% of MVC) as their first eccentric bout. The second bout of eccentric exercise was performed two weeks later and was identical for all the three groups, i.e., 40% ECC.ResultsThe results showed that for the first bout, MVC, voluntary activation and the resting twitch displayed significant (p < 0.0001) interaction (group x time). This was not the case however for the second bout as there was no significant (group x time) interaction in all outcome variables immediately after exercise. When the first and second bouts were compared, it was found that the high-load group had faster recovery in MVC at day 1 and 4 corresponding to voluntary activation and only at day 4 corresponding to the resting twitch.ConclusionsIn this study, it was found that high-load exercise aids fast recovery either via neural or muscular adaptations.
http://ift.tt/2zAn2Ep
Annual methane budgets of sheep grazing systems were regulated by grazing intensities in the temperate continental steppe: A two-year case study
Publication date: February 2018
Source:Atmospheric Environment, Volume 174
Author(s): Lei Ma, Mengying Zhong, Yuhao Zhu, Helong Yang, Douglas A. Johnson, Yuping Rong
Methane (CH4) emission from animal husbandry accounts for a large percentage of anthropogenic contributions to CH4 emissions. Fully understanding of grazing management effects on the CH4 budget is essential for mitigating CH4 emissions in the temperate grazing steppe systems. Annual CH4 budgets for the sheep grazed steppes at various grazing intensities, un–grazing (UG, 0 sheep ha−1year−1), defer grazing (DG, 1.0 sheep ha−1 year−1), moderate grazing (MG, 1.43 sheep ha−1year−1), and heavy grazing (HG, 2.43 sheep ha−1year−1) were assessed across 2012–2014 in the agro–pastoral region of northern China. Annual soil CH4 uptake averaged across 2012–2014 were 1.1 ± 0.1, 2.4 ± 0.2, 2.2 ± 0.2, and 1.3 ± 0.1 kg CH4–C ha−1 for UG, DG (only 2013–2014), MG and HG sites. Non–growing season CH4 uptake comprised 50.0 ± 4.3% of annual CH4 uptake in 2012–2013 and 37.7 ± 2.0% in 2013–2014. DG and MG significantly promoted annual soil CH4 uptake (P < 0.05), while there was no difference between HG and UG (P > 0.05). Bell–shaped relationship was presented between stocking rates and soil CH4 uptake (r2 = 0.59, P < 0.05). Annual soil CH4 uptake significant linearly and positively correlated with root biomass (r2 = 0.30, P < 0.05). Annual CH4 budgets for the grazed grasslands were −1.1 ± 0.1, 5.7 ± 0.6, 11.5 ± 1.5 and 15.5 ± 1.3 kg CH4–C ha−1 year−1 in UG, DG (only 2013–2014), MG and HG across 2012–2014. Soil CH4 uptake could offset 29.7 ± 5.6, 15.9 ± 4.3 and 6.8 ± 1.0% of total annual CH4 emissions from sheep, sheepfold and faeces in DG, MG, and HG. All grazed steppes are sources for atmospheric CH4 and the magnitude is regulated by grazing intensities. Sheep CH4 emissions for 1–g liveweight gain were 0.21, 0.32 and 0.37 g CH4–C in DG, MG and HG, respectively. DG is the recommended grazing management in this region to achieve greater herbage mass, higher sheep performance and lower CH4 emissions simultaneously.
Graphical abstract
http://ift.tt/2AkWWsl
Outdoor particulate air pollution and indoor renovation associated with childhood pneumonia in China
Publication date: February 2018
Source:Atmospheric Environment, Volume 174
Author(s): Wei Jiang, Chan Lu, Yufeng Miao, Yuguang Xiang, Lv Chen, Qihong Deng
BackgroundPneumonia is a common early-childhood respiratory infection that leads to long-term health impacts, but its risk factors remain unclear.ObjectiveTo examine the association between early life exposure to both outdoor and indoor air pollution and childhood pneumonia.MethodsWe conducted a retrospective cohort study of 2598 children aged 3–6 years in Changsha, China (2011-2012). Children's life-time prevalence of pneumonia and exposure to indoor air pollution related to home renovation were surveyed by a questionnaire answered by the parents. Children's exposure to outdoor air pollution, including nitrogen dioxide (NO2), sulfur dioxide (SO2), and particulate matter with an aerodynamic diameter ≤ 10 μm (PM10), was estimated using the measured concentrations at monitoring stations. Association between childhood pneumonia and exposure to indoor and outdoor air pollution during both prenatal and postnatal periods were examined by using logistic regression model in terms of odds ratio (OR) and 95% confidence interval (CI).ResultsLife-time prevalence of pneumonia in preschool children in Changsha is high, up to 38.6%.We found that childhood pneumonia was associated with postnatal exposure to outdoor particulate air pollutant PM10, adjusted OR (95% CI) = 1.26 (1.00–1.57) for per 6 μg/m3 increase in the concentration. Pneumonia was also associated with postnatal exposure to indoor renovation, adjusted OR (95% CI) = 1.30 (1.02–1.64) for new furniture and 1.30 (1.00–1.69) for redecoration. Combined exposure to outdoor high PM10 and indoor renovation significantly increased the pneumonia risk. Sensitivity analysis indicated that the association was heterogeneous in different subgroups, but stronger in male and younger children.ConclusionHigh prevalence of childhood pneumonia in China may be associated with postnatal exposure to ambient particulate air pollution and house renovation.
Graphical abstract
http://ift.tt/2AlyYx6
Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach
Publication date: 15 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 112
Author(s): Yumi Yamamoto, Pyry A. Välitalo, Yin Cheong Wong, Dymphy R. Huntjens, Johannes H. Proost, An Vermeulen, Walter Krauwinkel, Margot W. Beukers, Hannu Kokki, Merja Kokki, Meindert Danhof, Johan G.C. van Hasselt, Elizabeth C.M. de Lange
Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human, and to predict drug concentration-time profiles in multiple CNS compartments on available human data of four drugs (acetaminophen, oxycodone, morphine and phenytoin).Values of the system-specific parameters in the rat CNS PBPK model were replaced by corresponding human values. The contribution of active transporters for the four selected drugs was scaled based on differences in expression of the pertinent transporters in both species. Model predictions were evaluated with available pharmacokinetic (PK) data in human brain extracellular fluid and/or cerebrospinal fluid, obtained under physiologically healthy CNS conditions (acetaminophen, oxycodone, and morphine) and under pathophysiological CNS conditions where CNS physiology could be affected (acetaminophen, morphine and phenytoin).The human CNS PBPK model could successfully predict their concentration-time profiles in multiple human CNS compartments in physiological CNS conditions within a 1.6-fold error. Furthermore, the model allowed investigation of the potential underlying mechanisms that can explain differences in CNS PK associated with pathophysiological changes. This analysis supports the relevance of the developed model to allow more effective selection of CNS drug candidates since it enables the prediction of CNS target-site concentrations in humans, which are essential for drug development and patient treatment.
Graphical abstract
http://ift.tt/2il2lJh
Novel controlled ionic gelation strategy for chitosan nanoparticles preparation using TPP-β-CD inclusion complex
Publication date: 15 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 112
Author(s): Anjali Pant, Jeetendra Singh Negi
The aim of this study was to develop a novel controlled ionic gelation strategy for chitosan nanoparticle preparation to avoid particle aggregation tendency associated with conventional ionic gelation process. In this study inclusion complexation behaviour of sodium tripolyphosphate (TPP) with beta cyclodextrin (β-CD) has been investigated. The TPP-β-CD inclusion complex was characterized by FT-IR, XRD and DSC techniques. The complexation behaviour was also investigated by molecular docking study. The results showed that the TPP molecule formed inclusion complex with β-CD. Further, TPP-β-CD inclusion complex was used to prepare chitosan nanoparticles. The chitosan nanoparticles based on TPP-β-CD inclusion complex had smaller size of 104.2nm±0.608, good PDI value of 0.346±0.016 and acceptable zeta potential of +27.33mV±0.416. The surface characteristics of chitosan nanoparticles were also observed with transmission electron microscopy. Results indicates that TPP-β-CD inclusion complex can be used for the formation of chitosan nanoparticles with smaller and more uniform particle size in comparison to conventional TPP based chitosan nanoparticles.
Graphical abstract
http://ift.tt/2ikqKPb
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Summary Insulinomas are rare neuroendocrine tumours that classically present with fasting hypoglycaemia. This case report discusses an un...
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