bluuebunny/crossref_metadata_2025 huggingface dataset:
Salvianolic Acid A Protects Against Diabetic Nephropathy through Ameliorating Glomerular Endothelial Dysfunction via Inhibiting AGE-RAGE Signaling
Authors: Hou Biyu , Qiang Guifen , Zhao Yuerong , Yang Xiuying , Chen Xi , Yan Yu , Wang Xiaobo , Liu Chenge , Zhang Li , Du Guanhua
Published: December 2017

Background/Aims: Glomerular endothelium dysfunction leads to the progression of renal architectonic and functional abnormalities in early-stage diabetic nephropathy (DN). Advanced glycation end products (AGEs) and receptor for AGEs (RAGE) are proved to play important roles in diabetic nephropathy. This study investigated the role of Salvianolic acid A (SalA) on early-stage DN and its possible underlying mechanism. Methods: In vitro AGEs formation and breaking rate were measured to illustrate the effect of SalA on AGEs. Type 2 diabetic nephropathy rats were induced by high-fat diet and low-dose streptozocin (STZ). After eight-week treatment with SalA 1 mg/kg/day, 24h-urine protein, creatinine clearance was tested and renal structural injury was assessed by PAS and PASM staining. Primary glomerular endothelial cell permeability was evaluated after exposed to AGEs. AGEs-induced RhoA/ROCK and subsequently activated disarrange of cytoskeleton were assessed by western blot and immunofluorescence. Results: Biochemical assay and histological examination demonstrated that SalA markedly reduced endothelium loss and glomerular hyperfiltration, suppressed glomerular hypertrophy and mesangial matrix expansion, eventually reduced urinary albumin and ameliorated renal function. Further investigation suggested that SalA exerted its renoprotective effects through inhibiting AGE-RAGE signaling. It not only inhibited formation of AGEs and increased its breaking in vitro, but also reduced AGEs accumulation in vivo and downregulated RAGE expression. SalA restored glomerular endothelial permeability through suppressing AGEs-induced rearrangement of actin cytoskeleton via AGE-RAGE-RhoA/ ROCK pathway. Moreover, SalA attenuated oxidative stress induced by AGEs, subsequently alleviated inflammation and restored the disturbed autophagy in glomerular endothelial cell and diabetic rats via AGE-RAGE-Nox4 axis. Conclusion: Our study indicated that SalA restored glomerular endothelial function and alleviated renal structural deterioration through inhibiting AGE-RAGE, thus effectively ameliorated early-stage diabetic nephropathy. SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.
Down Regulation of the Munc18b-syntaxin-11 Complex and β1-tubulin Impairs Secretion and Spreading in Neonatal Platelets
Authors: Caparrós-Pérez Eva , Teruel-Montoya Raúl , Palma-Barquero Verónica , Torregrosa José , Blanco José , Delgado Juan , Lozano María , Vicente Vicente , Sola-Visner Martha , Rivera José , Martínez Constantino , Ferrer-Marín Francisca
Published: December 2017

Neonatal platelets are hyporeactive and show impaired agonist-induced secretion despite no obvious abnormalities in their granules. Here, we examined, for the first time, the ultrastructure of neonatal and adult platelets following agonist activation. Under resting conditions, neonatal and adult platelets appeared ultrastructurally identical. Following agonist stimulation, however, noticeable degranulation occurred in adult platelets, while granules in neonatal platelets remained clearly visible and apparently unable to centralize or fuse. To investigate the underlying mechanisms, we first examined the expression levels of the main SNARE proteins, which mediate the membrane fusion events required for exocytosis. Neonatal platelets showed significantly reduced levels of syntaxin-11 and its regulator, Munc18b. Since granule centralization depends on contraction of the microtubule ring, we also examined the expression of its main component, β1-tubulin. Noteworthy, we found decreased TUBB1 mRNA and protein levels in neonatal platelets, while TUBB2A and TUBB isoforms were overexpressed, partially compensating for that deficiency. Finally, supporting the functional consequences of defective exocytosis, adhesion kinetic assays, performed in plasma-free medium, demonstrated delayed adhesion and spreading of neonatal platelets. This is the first report showing marked reductions of syntaxin-11–Munc18b complex and β1-tubulin in neonatal platelets, indicating that these proteins, required for platelet degranulation, are developmentally regulated.
Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Dabigatran Etexilate Oral Liquid Formulation in Infants with Venous Thromboembolism
Authors: Halton Jacqueline , Picard Anne-Caroline , Harper Ruth , Huang Fenglei , Brueckmann Martina , Gropper Savion , Maas Hugo , Tartakovsky Igor , Nurmeev Ildar , Mitchell Lesley , Brandão Leonardo , Chalmers Elizabeth , Albisetti Manuela
Published: December 2017

Venous thromboembolism (VTE) is more frequent in infants than in older children. Treatment guidelines in children are adapted from adult VTE data, but do not currently include direct oral anticoagulant use. Dabigatran etexilate (DE) use in the paediatric population with VTE therefore requires verification. We investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship, safety and tolerability of DE oral liquid formulation (OLF) in infants with VTE (aged < 12 months) who had completed standard anticoagulant treatment in an open-label, phase IIa study. Patients received a single-dose of DE OLF (based on an age- and weight-adjusted nomogram) yielding an exposure comparable to 150 mg in adults. The PK end point was plasma concentration of total dabigatran; PD end points included activated partial thromboplastin time (aPTT), ecarin clotting time (ECT) and diluted thrombin time (dTT). Safety end points included incidence of all bleeding and other adverse events (AEs). Ten patients were screened; eight entered the study (age range, 41–169 days). The geometric mean (gMean) total dabigatran plasma concentrations 2 hours post-dose (around peak concentrations) were 120 ng/mL with a geometric coefficient of variation (gCV) of 62.1%. The gMean at 12 hours post-dosing was 60.4 ng/mL (gCV 30%). PK/PD relationship was linear for ECT and dTT (R
2 = 0.858 and 0.920, respectively), while total dabigatran concentration and aPTT showed a non-linear correlation. There were no deaths, treatment discontinuations or treatment-related AEs. In conclusion, DE was well tolerated without any treatment-related AEs in infants. The observed PK/PD relationships were comparable with the established profile in older patients with VTE.
Species diversity and community structure of fruit-feeding butterflies (Lepidoptera: Nymphalidae) in an eastern amazonian forest
Authors: Martins Lucas Pereira , Araujo Junior Elias da Costa , Martins Ananda Regina Pereira , Duarte Marcelo , Azevedo Gisele Garcia
Published: December 2017

Deforestation has negative impacts on diversity and community patterns of several taxa. In the eastern Amazon, where much deforestation is predicted for the coming years, forests patches may be essential to maintain the local biodiversity. Despite increasing concerns about the conservation of threatened areas, few studies have been performed to analyze the communities of diversified groups, such as insects, in the eastern Amazon. Here, we investigated species diversity and community structure of fruit-feeding butterflies, a well-known bioindicator group, in a threatened remnant of an eastern Amazonian forest located on Maranhão Island, northeastern Brazil. Fruit-feeding butterflies were sampled monthly for one year. Diversity and evenness indices, richness estimators, rarefaction curve, and rank-abundance plot were used to describe community structure in the study area. We captured 529 fruit-feeding butterflies in four subfamilies, 23 genera and 34 species. The three most abundant species, Hamadryas februa, Hamadryas feronia, and Hermeuptychia cf. atalanta are indicators of disturbed habitats and represented more than half of the collected individuals. Richness estimators revealed that between 87 and 94% of the fruit-feeding butterfly species were sampled, suggesting few additional records would be made for the area. Our results indicate that human-caused disturbances have altered local community patterns and provide baseline data for future research in threatened regions of the eastern Amazon.
Errata: Levantamento de Polychaeta (Annelida) na Baía do Almirantado, Ilha Rei George (Antártica)
Authors: Garraffoni André Rinaldo Senna , Moura Filipe Rodrigues , Vasconcelos Poliana Estevão , Araújo Fernanda Figueiredo de , Passos Flávio Dias
Published: December 2017

No artigo Levantamento de Polychaeta (Annelida) na Baía do Almirantado, Ilha Rei George (Antártica), com número de DOI: 10.1590/S0031-10492012001300001, publicado no periódico Papéis Avulsos de Zoologia, Volume 52(13):151‑165, 2012, na página 165:onde se lia:dos Santos, A.S.; Nogueira, J.M.M.; Fukuda, M.V. & Christoffersen, M.L. 2020. New terebellids (Polychaeta: Terebellidae) from northeastern Brazil. Zootaxa, 2389:1‑46.leia-se:dos Santos, A.S.; Nogueira, J.M.M.; Fukuda, M.V. & Christoffersen, M.L. 2010. New terebellids (Polychaeta: Terebellidae) from northeastern Brazil. Zootaxa, 2389:1‑46.
A presença da Galeria Collectio no mercado de arte brasileiro durante a década de 1970
Authors: Vallego Rachel
Published: December 2017

Este primeiro estudo pretende resgatar a história da galeria Collectio por meio de seu posicionamento na mídia, em anúncios publicitários, reportagens ou entrevistas publicadas na imprensa brasileira entre 1970 e 1973, o que nos permitirá um ponto de vista privilegiado do crescimento do mercado de arte brasileiro. A trajetória da galeria seria marcada por uma ação intensa e impacto profundo no crescimento visto naqueles anos, especialmente no que diz respeito aos leilões de arte moderna, em que esteve particularmente engajada. O artigo oferece uma avaliação do crescimento do mercado de arte na década de 1970, pontuando em paralelo o processo de consagração do modernismo brasileiro.
A historicidade do cinema
Authors: Rancière Jacques
Published: December 2017

Este artigo de Jacques Rancière, publicado originalmente em 1998 no livro De l’histoire au cinéma, organizado por Antoine de Baecque e Christian Delage, trata da historicidade do cinema, na medida em que esta historicidade está intimamente relacionada ao “regime estético da arte”, que é um regime de compreensão da arte, em sua distinção entre o sensível e o pensável. O cinema, analisado no interior do “regime estético”, relaciona-se com sua historicidade na medida em que está entrelaçado em três acepções da palavra “história”: o tipo de trama em que um filme consiste, a função de memorialização que ele cumpre e a maneira como atesta uma participação em um destino comum.
Jardins do ocidente e do oriente: ordenamento ou recriação da paisagem
Authors: Afonso Cintia Maria
Published: December 2017

Este trabalho analisa a estrutura formal de jardins ocidentais e orientais, buscando identificar similaridades, adaptações e variações ao longo do tempo. O intercâmbio cultural e de ideias entre os povos também diz respeito aos jardins, já que princípios de regularidade e simetria podem ser identificados em jardins do antigo Egito, Pérsia, Espanha, Índia, Itália e França. Já os antigos jardins chineses e japoneses seguem princípios baseados na compartimentação de espaços, assimetria e complementaridade de formas, retrabalhados nos jardins ingleses construídos a partir do século XVIII. A abordagem é direcionada à sequência ao longo do tempo mais do que à comparação de jardins de um mesmo período ou ao estudo de variações locais. Pretende-se que o conhecimento histórico possibilite a compreensão das transformações dos jardins, subsidiando atividades projetuais contemporâneas.
Bénédict Pictet
Authors: Wolfe Stephen
Published: December 2017

Recent research on Genevan theologian Benedict Pictet (1655–1724) concludes that he is a “transitional” theologian between the high Reformed orthodoxy of his uncle, Francis Turretin, and the “enlightened orthodoxy” of his cousin (and son of Francis) Jean-Alphonse Turretin. This essay shows that Pictet is remarkably consistent with Francis on the issues of the relationship of faith and reason and natural theology, and thereby calls into question Pictet’s place in the typical narrative of Reformed orthodoxy’s small steps towards rationalism.
Osthoff’s Law in Latin
Authors: Sayeed Ollie
Published: December 2017

The sound change known as Osthoff’s Law, shortening a long vowel before a resonant-consonant cluster, was first explicitly described to have applied in the prehistory of Greek by Osthoff (1884). Since then, the existence of a similar sound change in Latin has been controversial in the literature, with claimed examples such as *vēntus > ventus ‘wind’. At one end, Simkin (2004) argues that Osthoff’s Law never took place in Latin; at the other, Weiss (2009) claims at least three independent rounds of Osthoff’s Law in the history of the Italic branch. I summarize the synchronic facts about pre-cluster vowel length in classical Latin using a comprehensive survey of the Latin lexicon, with a historical explanation for the vowel length in every form containing a cluster. I argue that Osthoff’s Law happened in Latin (contra Simkin), but only once (contra Weiss), around the 2nd century BCE.
Molpa: A newly recorded genus (Orthoptera: Tettigoniidae: Phaneropterinae) from China
Authors: WU CHAO , YANG ZHEN , LIU CHUN-XIANG , ZONG CHENG
Published: December 2017

The genus Molpa Walker was previously considered to be disjunctly distributed in broad-leaf rain forests in India and Malaysia. Here we report one new species Molpa dulongensis sp. nov. from subtropic broad-leaf rain forests in southwestern Yunnan Province in China. This is a part of the Indo-Burma biodiversity hotspot area. So we can infer that Molpa is continuously distributed in broad-leaf rain forests found in Oriental Region. Redescription of the genus Molpa and description of the new species Molpa dulongensis sp. nov. are provided. The types are deposited in Insect Collection of Institute of Zoology, Chinese Academy of Sciences, Beijing, China (IZCAS).
Regional Climate Response Collaboratives: Multi-Institutional Support for Climate Resilience
Authors: Averyt Kristen , Derner Justin D. , Dilling Lisa , Guerrero Rafael , Joyce Linda , McNeeley Shannon , McNie Elizabeth , Morisette Jeffrey , Ojima Dennis , O’Malley Robin , Peck Dannele , Ray Andrea J. , Reeves Matt , Travis William
Published: December 2017

Federal investments by U.S. agencies to enhance climate resilience at regional scales grew over the past decade (2010s). To maximize efficiency and effectiveness in serving multiple sectors and scales, it has become critical to leverage existing agency-specific research, infrastructure, and capacity while avoiding redundancy. We discuss lessons learned from a multi-institutional “regional climate response collaborative” that comprises three different federally supported climate service entities in the Rocky Mountain west and northern plains region. These lessons include leveraging different strengths of each partner, creating deliberate mechanisms to increase cross-entity communication and joint ownership of projects, and placing a common priority on stakeholder-relevant research and outcomes. We share the conditions that fostered successful collaboration, which can be transferred elsewhere, and suggest mechanisms for overcoming potential barriers. Synergies are essential for producing actionable research that informs climate-related decisions for stakeholders and ultimately enhances climate resilience at regional scales.
Verification of Land–Atmosphere Coupling in Forecast Models, Reanalyses, and Land Surface Models Using Flux Site Observations
Authors: Dirmeyer Paul A. , Chen Liang , Wu Jiexia , Shin Chul-Su , Huang Bohua , Cash Benjamin A. , Bosilovich Michael G. , Mahanama Sarith , Koster Randal D. , Santanello Joseph A. , Ek Michael B. , Balsamo Gianpaolo , Dutra Emanuel , Lawrence David M.
Published: December 2017

This study compares four model systems in three configurations (LSM, LSM + GCM, and reanalysis) with global flux tower observations to validate states, surface fluxes, and coupling indices between land and atmosphere. Models clearly underrepresent the feedback of surface fluxes on boundary layer properties (the atmospheric leg of land–atmosphere coupling) and may overrepresent the connection between soil moisture and surface fluxes (the terrestrial leg). Models generally underrepresent spatial and temporal variability relative to observations, which is at least partially an artifact of the differences in spatial scale between model grid boxes and flux tower footprints. All models bias high in near-surface humidity and downward shortwave radiation, struggle to represent precipitation accurately, and show serious problems in reproducing surface albedos. These errors create challenges for models to partition surface energy properly, and errors are traceable through the surface energy and water cycles. The spatial distribution of the amplitude and phase of annual cycles (first harmonic) are generally well reproduced, but the biases in means tend to reflect in these amplitudes. Interannual variability is also a challenge for models to reproduce. Although the models validate better against Bowen-ratio-corrected surface flux observations, which allow for closure of surface energy balances at flux tower sites, it is not clear whether the corrected fluxes are more representative of actual fluxes. The analysis illuminates targets for coupled land–atmosphere model development, as well as the value of long-term globally distributed observational monitoring.
Fine Structure, Instabilities, and Turbulence in the Lower Atmosphere: High-Resolution In Situ Slant-Path Measurements with the DataHawk UAV and Comparisons with Numerical Modeling
Authors: Balsley Ben B. , Lawrence Dale A. , Fritts David C. , Wang Ling , Wan Kam , Werne Joe
Published: December 2017

A new platform for high-resolution in situ measurements in the lower troposphere is described and its capabilities are demonstrated. The platform is the small GPS-controlled DataHawk unmanned aerial system (UAS), and measurements were performed under stratified atmospheric conditions at Dugway Proving Ground, Utah, on 11 October 2012. The measurements included spiraling vertical profiles of temperature and horizontal wind vectors, from which the potential temperature θ, mechanical energy dissipation rate ε, Brunt–Väsälä frequency N, temperature structure parameter CT2, Thorpe and Ozmidov scales LT and LO, and Richardson number Ri were inferred. Profiles of these quantities from ~50 to 400 m reveal apparent gravity wave modulation at larger scales, persistent sheet-and-layer structures at scales of ~30–100 m, and several layers exhibiting significant correlations of large ε, CT2, LT, and small Ri. Smaller-scale flow features suggest local gravity waves and Kelvin–Helmholtz instabilities exhibiting strong correlations, yielding significant vertical displacements and inducing turbulence and mixing at smaller scales. Comparisons of these results with a direct numerical simulation (DNS) of similar multiscale dynamics indicate close agreement between measured and modeled layer character and evolution, small-scale dynamics, and turbulence intensities. In particular, a detailed examination of the potential biases in inferred quantities and/or misinterpretation of the underlying dynamics as a result of the specific DataHawk sampling trajectory is carried out using virtual sampling paths through the DNS and comparing these with the DataHawk measurements.
Estimation of Rain Rate from Airborne Doppler W-Band Radar in CalWater-2
Authors: Fairall C. W. , Matrosov Sergey Y. , Williams Christopher R. , Walsh E. J.
Published: December 2017

The NOAA W-band radar was deployed on a P-3 aircraft during a study of storm fronts off the U.S. West Coast in 2015 in the second CalWater (CalWater-2) field program. This paper presents an analysis of measured equivalent radar reflectivity factor Zem profiles to estimate the path-averaged precipitation rate and profiles of precipitation microphysics. Several approaches are explored using information derived from attenuation of Zem as a result of absorption and scattering by raindrops. The first approach uses the observed decrease of Zem with range below the aircraft to estimate column mean precipitation rates. A hybrid approach that combines Zem in light rain and attenuation in stronger rain performed best. The second approach estimates path-integrated attenuation (PIA) via the difference in measured and calculated normalized radar cross sections (NRCSm and NRCSc, respectively) retrieved from the ocean surface. The retrieved rain rates are compared to estimates from two other systems on the P-3: a Stepped Frequency Microwave Radiometer (SFMR) and a Wide-Swath Radar Altimeter (WSRA). The W-band radar gives reasonable values for rain rates in the range 0–10 mm h−1 with an uncertainty on the order of 1 mm h−1. Mean profiles of Zem, raindrop Doppler velocity, attenuation, and precipitation rate in bins of rain rate are also computed. A method for correcting measured profiles of Zem for attenuation to estimate profiles of nonattenuated profiles of Ze is examined. Good results are obtained by referencing the surface boundary condition to the NRCS values of PIA. Limitations of the methods are discussed.
A New Approach for Estimating the Observation Impact in Ensemble–Variational Data Assimilation
Authors: Buehner Mark , Du Ping , Bédard Joël
Published: December 2017

Two types of approaches are commonly used for estimating the impact of arbitrary subsets of observations on short-range forecast error. The first was developed for variational data assimilation systems and requires the adjoint of the forecast model. Comparable approaches were developed for use with the ensemble Kalman filter and rely on ensembles of forecasts. In this study, a new approach for computing observation impact is proposed for ensemble–variational data assimilation (EnVar). Like standard adjoint approaches, the adjoint of the data assimilation procedure is implemented through the iterative minimization of a modified cost function. However, like ensemble approaches, the adjoint of the forecast step is obtained by using an ensemble of forecasts. Numerical experiments were performed to compare the new approach with the standard adjoint approach in the context of operational deterministic NWP. Generally similar results are obtained with both approaches, especially when the new approach uses covariance localization that is horizontally advected between analysis and forecast times. However, large differences in estimated impacts are obtained for some surface observations. Vertical propagation of the observation impact is noticeably restricted with the new approach because of vertical covariance localization. The new approach is used to evaluate changes in observation impact as a result of the use of interchannel observation error correlations for radiance observations. The estimated observation impact in similarly configured global and regional prediction systems is also compared. Overall, the new approach should provide useful estimates of observation impact for data assimilation systems based on EnVar when an adjoint model is not available.
Change and Stability?
Authors: Ramstedt Mats
Published: December 2017

Over the past two decades, alcohol consumption in Sweden has grown by 20 per cent as a result of an increasing consumption of wine and strong beer. The rise is driven by a combination of factors such as the higher physical availability and lower real prices of alcohol, which suggests that alcohol has become much more affordable. In addition, the possibilities to bring back cheaper alcohol from other EU countries have been greatly extended during the Swedish EU membership. No definite patterns were found with respect to certain social and demographic changes during the study period. Despite the significant increase in consumption, indicators of alcohol-related harms did not show consistently increasing trends. It is not evident why the increasing availability should have such different effects on various population sub-groups, and there are obviously other relevant factors at play. Widespread political concern at the implications of the rising availability of alcohol has led Sweden to spend more per capita than any other European country on alcohol policy and prevention initiatives. It will be a continuous challenge for policy makers to find measures that limit the harms caused by alcohol in the Swedish society.
It Seemed like a Good Idea at the Time
Authors: Berends Lynda , Hunter Barbara
Published: December 2017

■ AIM

Identify whether centralised assessment and intake programs are useful for alcohol and drug systems.

■ DESIGN

Review of evaluation findings on centralised programs in Ontario, Canada, the USA and Victoria, Australia.

■ FINDINGS

Models implemented in Canada and the US operated at local level and variations were a product of settings and stakeholders. Some advances were made. The assessment and referral centres (A/Rs) in Canada accounted for around one fifth of all case loads. A greater proportion of treatment naïve people attended A/Rs and these agencies had a considerable network of services. However, A/Rs were not the hub of the system; many agencies developed their own intake structures and A/Rs took on treatment functions. In the US, only some locations with centralised intake units (CIUs) reported a greater uptake of referrals and high needs clients were more likely to attend. Centralisation resulted in improved assessments and increased levels of client satisfaction but not treatment matching. Some treatment agencies in Victoria developed centralised models for screening / assessment while referral destinations were generally in-house. In rural settings, there was cross-agency centralisation.

■ CONCLUSIONS

Centralised intake requires extensive implementation planning to counter pressures that impede the potential for systems change.
Administrative Challenges in the Finnish Alcohol and Drug Treatment System
Authors: Kuussaari Kristiina , Partanen Airi
Published: December 2017

This article examines the National Plan for Mental Health and Substance Use Work (the MIELI plan), published in Finland in 2009. We place the plan into a wider context of changes in Finnish social and health services and have also studied responses to the plan.

The data is provided by national documents, complemented by an online enquiry and some journal articles as feedback material.

The MIELI plan is implemented in conjunction with a municipal and service system reform in Finland. While the proposals of the plan clearly carry a potential for change in the treatment system, there are also great challenges. For instance, to what extent can this kind of plan influence reality? Can the proposals really change anything in the treatment system, or does the potential change emerge from elsewhere? Responses to the plan indicate that referral-free access to treatment, the principle of a single entry point and primary-level services in general were considered important proposals in the MIELI plan. At the other end of the scale, the implementation of the plan and its medical orientation were received less positively.
Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012
Authors: Hussain Maha , Daignault-Newton Stephanie , Twardowski Przemyslaw W. , Albany Costantine , Stein Mark N. , Kunju Lakshmi P. , Siddiqui Javed , Wu Yi-Mi , Robinson Dan , Lonigro Robert J. , Cao Xuhong , Tomlins Scott A. , Mehra Rohit , Cooney Kathleen A. , Montgomery Bruce , Antonarakis Emmanuel S. , Shevrin Daniel H. , Corn Paul G. , Whang Young E. , Smith David C. , Caram Megan V. , Knudsen Karen E. , Stadler Walter M. , Feng Felix Y. , Chinnaiyan Arul M.
Published: December 2017

Purpose

To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) and whether ETS fusions predict response.

Patients and Methods

Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response. Secondary objectives were: safety, measurable disease RR (mRR), progression-free survival (PFS), and molecular biomarker analysis. A total of 148 patients were randomly assigned to detect a 20% PSA RR improvement.

Results

A total of 148 patients with mCRPC were randomly assigned: arm A, n = 72; arm B, n = 76. There were no differences in PSA RR (63.9% v 72.4%; P = .27), mRR (45.0% v 52.2%; P = .51), or median PFS (10.1 v 11 months; P = .99). ETS fusions did not predict response. Exploratory analysis of tumor sequencing (80 patients) revealed: 41 patients (51%) were ETS positive, 20 (25%) had DNA-damage repair defect (DRD), 41 (51%) had AR amplification or copy gain, 34 (43%) had PTEN mutation, 33 (41%) had TP53 mutation, 39 (49%) had PIK3CA pathway activation, and 12 (15%) had WNT pathway alteration. Patients with DRD had significantly higher PSA RR (90% v 56.7%; P = .007) and mRR (87.5% v 38.6%; P = .001), PSA decline ≥ 90% (75% v 25%; P = .001), and longer median PFS (14.5 v 8.1 months; P = .025) versus those with wild-type tumors. Median PFS was longer in patients with normal PTEN (13.5 v 6.7 months; P = .02), TP53 (13.5 v 7.7 months; P = .01), and PIK3CA (13.8 v 8.3 months; P = .03) versus those with mutation or activation. In multivariable analysis adjusting for clinical covariates, DRD association with PFS remained significant.

Conclusion

Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with mCRPC outcomes.
Intravenous Iron for Treatment of Anemia in the 3 Perisurgical Phases: A Review and Analysis of the Current Literature
Authors: Peters Frank , Ellermann Ines , Steinbicker Andrea U.
Published: December 2017

Anemia is a common comorbidity throughout the entire hospital stay. Treatment options include intravenous (IV) iron, oral iron, erythropoietin, and red blood cell (RBC) transfusions. IV iron has gained in popularity with the implementation of patient blood management programs. A variety of studies have been performed to investigate the use of IV iron in preoperative, perioperative, and postoperative settings. An objective review on these studies has yet to be performed. The current narrative review provides an overview of trials investigating IV iron use in the preoperative, perioperative, and postoperative settings. We performed a literature research of English articles published between 1964 and March 2017 in Pubmed including Medline and The Cochrane Library. Only studies with a control group were included. The final review includes 20 randomized controlled trials (RCTs), 7 observational trials, and 5 retrospective studies. Measured outcomes included hemoglobin (Hb) levels, reticulocyte counts, and/or RBC concentrates. Meta-analyses of RCTs using IV iron administration before surgery led to an increase in Hb levels, a reduction of RBC use, and an improvement in patient outcome. Only a few studies investigated the use of IV iron in the perioperative setting. These studies recommended the use of perioperative IV iron in cases of severe anemia in orthopedic surgery but not in all types of surgery. Published RCTs in the postoperative setting have shown positive effects of IV iron on Hb levels, length of hospital stay, and transfusion requirements. Some studies demonstrated an increase of Hb of 0.5–1 g/dL over 4 weeks postoperatively, but the clinical relevance and effect of this increase on an improvement of patient’s long-term outcomes are uncertain. To summarize, the evidence to use IV iron is strongest in the preoperative setting, while it remains an individual treatment decision to administer IV iron perioperatively or postoperatively.
Prospective Observational Study of Intraoperative Anesthetic Events in District Hospitals in Namibia
Authors: Ottaway Andrew J. , Kabongo Leonard
Published: December 2017

BACKGROUND:

Access to safe surgery and anesthesia care is grossly inadequate in low- and middle-income countries, with a shortage of anesthesia providers contributing to this crisis. In Namibia, medical officers typically receive no >3 months of informal training in anesthesia. This study sought to determine the prevalence, currently unknown, of intraoperative adverse anesthetic events in this setting. Further, we assessed surgical volume, complications, and mortality outcomes at the district hospital level.

METHODS:

This was a prospective observational study over 7 months involving 4 district hospitals from geographically separate and diverse areas of Namibia. A standardized protocol was used to record adverse anesthetic events during surgery, surgical volume, and complications including mortality.

RESULTS:

A total of 737 surgical procedures were performed during the study period. There was a 10% prevalence of adverse anesthetic events intraoperatively. Of these, 70% were related to hypotension and 17% due to hypoxia and/or difficult/failed intubation. Ninety-eight percent of patients were classed as low risk (American Society of Anesthesiologists I or II). Seventy-two percent of the surgical workload was in obstetrics and gynecology, with over half being for urgent obstetrics. Perioperative mortality rate was 1.4/1000, with an overall surgical complication rate of 1.6% and a surgical infection rate of 0.8%.

CONCLUSIONS:

We found a 10% prevalence of adverse anesthetic events intraoperatively when anesthesia was administered by medical officers with no >3 months of informal training in this low-resource environment. The patients were considered low risk by the medical officers responsible for the anesthesia, yet these events had the potential to lead to patient harm.
Mu-Opioid Receptors in Ganglia, But Not in Muscle, Mediate Peripheral Analgesia in Rat Muscle Pain
Authors: Bagues Ana , Martín María Isabel , Higuera-Matas Alejandro , Esteban-Hernández Jesús , Ambrosio Emilio , Sánchez-Robles Eva María
Published: December 2017

BACKGROUND:

Previous studies have demonstrated the participation of peripheral μ-opioid receptors (MOR) in the antinociceptive effect of systemically administered morphine and loperamide in an orofacial muscle pain model, induced by hypertonic saline, but not in a spinally innervated one, in rats. In this study, we determine whether this peripheral antinociceptive effect is due to the activation of MOR localized in the muscle, ganglia, or both.

METHODS:

To determine the local antinociceptive effect of morphine and loperamide, 2 models of acute muscle pain (trigeminal and spinal) were used. Also, to study the MOR expression, protein quantification was performed in the trigeminal and spinal ganglia, and in the muscles.

RESULTS:

The behavioral results show that the intramuscular injection of morphine and loperamide did not exert an antinociceptive effect in either muscle (morphine: P = .63, loperamide: P = .9). On the other hand, MOR expression was found in the ganglia but not in the muscles. This expression was on average 44% higher (95% confidence interval, 33.3–53.9) in the trigeminal ganglia than in the spinal one.

CONCLUSIONS:

The peripheral antinociceptive effect of systemically administered opioids may be due to the activation of MOR in ganglia. The greater expression of MOR in trigeminal ganglia could explain the higher antinociceptive effect of opioids in orofacial muscle pain than in spinal muscle pain. Therefore, peripheral opioids could represent a promising approach for the treatment of orofacial pain.
Effect of age-dependent bone electron density on the calculated dose distribution from kilovoltage and megavoltage photon and electron radiotherapy in paediatric MRI-only treatment planning
Authors: Zeinali-Rafsanjani B , Faghihi R , Mosleh-Shirazi MA , Saeedi-Moghadam M , Jalli R , Sina S
Published: December 2017

Objective:

MRI-only treatment planning (TP) can be advantageous in paediatric radiotherapy. However, electron density extraction is necessary for dose calculation. Normally, after bone segmentation, a bulk density is assigned. However, the variation of bone bulk density in patients makes the creation of pseudo CTs challenging. This study aims to assess the effects of bone density variations in children on radiation attenuation and dose calculation for MRI-only TP.

Methods:

Bone contents of <15-year-old children were calculated, and substituted in the Oak Ridge National Laboratory paediatric phantoms. The percentage depth dose and beam profile of 150 kVp and 6 MV photon and 6 MeV electron beams were then calculated using Xcom, MCNPX (Monte Carlo N-particle version X) and ORLN phantoms.

Results:

Using 150 kVp X-rays, the difference in attenuation coefficient was almost 5% between an 11-year-old child and a newborn, and ~8% between an adult and a newborn. With megavoltage radiation, the differences were smaller but still important. For an 18 MV photon beam, the difference of radiation attenuation between an 11-year-old child and a newborn was 4% and ~7.4% between an adult and a newborn. For 6 MeV electrons, dose differences were observed up to the 2 cm depth. The percentage depth dose difference between 1 and 10-year-olds was 18.5%, and between 10 and 15-year-olds was 24%.

Conclusion:

The results suggest that for MRI-only TP of photon- or electron-beam radiotherapy, the bone densities of each age group should be defined separately for accurate dose calculation.

Advances in knowledge:

This study highlights the need for more age-specific determination of bone electron density for accurate dose calculations in paediatric MRI-only radiotherapy TP.
In vivo genome editing in animals using AAV-CRISPR system: applications to translational research of human disease
Authors: Lau Cia-Hin , Suh Yousin
Published: December 2017

Adeno-associated virus (AAV) has shown promising therapeutic efficacy with a good safety profile in a wide range of animal models and human clinical trials. With the advent of clustered regulatory interspaced short palindromic repeat (CRISPR)-based genome-editing technologies, AAV provides one of the most suitable viral vectors to package, deliver, and express CRISPR components for targeted gene editing. Recent discoveries of smaller Cas9 orthologues have enabled the packaging of Cas9 nuclease and its chimeric guide RNA into a single AAV delivery vehicle for robust in vivo genome editing. Here, we discuss how the combined use of small Cas9 orthologues, tissue-specific minimal promoters, AAV serotypes, and different routes of administration has advanced the development of efficient and precise in vivo genome editing and comprehensively review the various AAV-CRISPR systems that have been effectively used in animals. We then discuss the clinical implications and potential strategies to overcome off-target effects, immunogenicity, and toxicity associated with CRISPR components and AAV delivery vehicles. Finally, we discuss ongoing non-viral-based ex vivo gene therapy clinical trials to underscore the current challenges and future prospects of CRISPR/Cas9 delivery for human therapeutics.
Better understanding of childhood asthma, towards primary prevention – are we there yet? Consideration of pertinent literature
Authors: Gur Michal , Hakim Fahed , Bentur Lea
Published: December 2017

Asthma is a chronic disease, characterized by reversible airway obstruction, airway inflammation and hyper-reactivity. The prevalence of asthma has risen dramatically over the past decade, affecting around 300,000,000 people. The etiology is multifactorial, with genetic, epigenetic, developmental and environmental factors playing a role. A complex interaction between the intrauterine environment, the developing immune system, the infant's microbiome and infectious organisms may lead to the development of allergic sensitization and asthma. Thus, a large number of studies have investigated the risk factors for childhood asthma, with a meticulous search of modifiable factors that could aid in primary prevention.

We present a current literature review from 2014-2017, as well as older classic publications, on the pathogenesis and the potential modifiable factors for primary prevention of asthma. No ideal preventive measure has yet been found. Rather, creating favorable prenatal and postnatal environments, minimal exposure to hostile environmental factors, prevention of infections in early life, allergic desensitization and nutritional modifications could possibly reduce asthma inception. In the era of personalized medicine, identifying individual risk factors and tailoring specific preventive measures is warranted.
Pathophysiology and treatment of patients with beta-thalassemia – an update
Authors: Fibach Eitan , Rachmilewitz Eliezer A.
Published: December 2017

Thalassemia (thal) is an autosomal recessive, hereditary, chronic hemolytic anemia due to a partial or complete deficiency in the synthesis of α-globin chains (α-thal) or β-globin chains (β-thal) that compose the major adult hemoglobin (α2β2).It is caused by one or more mutations in the corresponding genes. The unpaired globin chains are unstable; they precipitate intracellularly, resulting in hemolysis, premature destruction of red blood cell [RBC] precursors in the bone marrow, and a short life-span of mature RBCs in the circulation. The state of anemia is treated by frequent RBC transfusions. This therapy results in the accumulation of iron (iron overload), a condition that is exacerbated by the breakdown products of hemoglobin (heme and iron) and the increased iron uptake for the chronic accelerated, but ineffective, RBC production. Iron catalyzes the generation of reactive oxygen species, which in excess are toxic, causing damage to vital organs such as the heart and liver and the endocrine system.

Herein, we review recent findings regarding the pathophysiology underlying the major symptoms of β-thal and potential therapeutic modalities for the amelioration of its complications, as well as new modalities that may provide a cure for the disease.
CHARACTERISTICS OF THE MICROBIOCENOSIS OF THE VAGINAL TRACT AND ITS ROLE IN INITIATING THE INFLAMMATORY PROCESS IN THE ENDOMETRIUM IN WOMEN WITH REPRODUCTIVE DISORDERS
Authors: Данусевич Ирина , Danusevich Irina , Иванова Елена , Ivanova Elena , Михалевич Исай , Mikhalevich Isai
Published: December 2017

Background. Microbiological disorders in the genital tract predispose to the development of chronic pelvic diseases and
subsequently worsen the prognosis for reproductive function, causing infertility, miscarriage.
Aims: study of the microbiocenosis of the vaginal tract and its role in initiating inflammatory process in endometrium
in women with reproductive disorders.
Materials and methods. The study included 50 patients with reproductive disorders with histological confirmation of
the diagnosis of chronic endometritis and 50 patients with reproductive disorders without chronic endometritis. Mi-
crobiological studies of the biotope of the vagina were carried out according to the guidelines. The counting of immune
cells was carried out in peripheral blood with flow cytofluorimeter. Methods of mathematical statistics implemented
in the application package Statistica 6.1 (StatSoft Inc., USA) were used in the study. Used criteria were Student’s t-test
and Fisher criterion with a significance level less than 5 % (p ≤ 0.05).
Results and conclusions. Conditionally pathogenic microflora in women with chronic endometritis in the cervical ca-
nal is represented by candidiasis, herpesviruses, ureaplasma and facultative-anaerobically positive microorganisms.
Candida, obligate-anaerobic gram-negative, and facultative anaerobic gram-positive microorganisms predominated
in the endometrium.
The secondary immunodeficiency state is characterized by suppressor activity of T-lymphocytes; the decrease in mi-
crobicide activity of blood, pronounced inhibition of the humoral link of the immune system. Violations of the balance
of the indigenous and conditionally pathogenic microflora accompanied by a secondary immunodeficiency may be the
initiator of chronic inflammation in the endometrium.
EFFICIENCY OF INVASIVE REVASCULARIZATION FOR ACUTE CORONARY SYNDROME WITH ST ELEVATION
Authors: Cодномова Лариса , Sodnomova Larisa , Булутова Наталья , Bulutova Natalya
Published: December 2017

The primary and main method of treating ACS with ST elevation is timely restoration of coronary vessel patency.
Material and methods. 273 medical records of patients admitted with provisional diagnosis of ACS with ST elevation
were studied. Statistical data were processed in Microsoft Excel and Statistica 10 (StatSoft Inc., USA).
Results. One third of patients with ACS with ST elevation were admitted at «the golden hour» since symptoms onset.
234 (86 %) patients underwent coronary angiography. Primary percutaneous intervention (PCI), coronary stenting were
performed for 117 patients, thrombolysis – for 23 and thrombolysis with subsequent PCI was carried out in 34 cases.
Assessment of RCI efficiency, invasive revascularization in terms of IM frequency and mortality showed the following:
the incidence of myocardial infarction in the group with PCI and without PCI was the same – 94 % against 98 % re-
spectively; however the mortality in patients with STEMI was lower in the group with performed invasive revascular-
ization – 4 % against 12 % (p = 0.04). Decrease is observed in both total mortality and mortality in the first 24 hours
for STEMI patients – 3 % in the PCI group, compared to 9 % in the other group (p = 0.04). The suvival rate for STEMI
patients was better for first time PCI – mortality 2.7 % against 12 % in the group without revascularization (p = 0.01).
PATHOMORPHOLOGICAL DIAGNOSTICS OF CHRONIC APPENDICITIS
Authors: Дремина Наталья , Dremina Nataliya , Шурыгина Ирина , Shurygina Irina , Панасюк Александр , Panasyuk Aleksandr , Каня Олег , Kanya Oleg , Шурыгин Михаил , Shurygin Mikhail
Published: December 2017

The review is devoted to the problem of diagnostics and differential diagnostics of chronic appendicitis. As it is commonly
known, the very existence of chronic appendicitis is still considered controversial. The article describes the current ideas
on chronic appendicitis (primary, secondary, residual and recurrent), presents the list of morphological manifestations
in the vermiform appendix at chronic inflammation, discovered at routine histological examination: dystrophic changes
in the form of atrophy of all layers of appendix with sclerosis or hypotrophy of various degree, up to appendiclausis
and disappearance of mucous membrane, and lipomatosis of submucosa. The authors discuss the complexity of diag-
nostics predetermined by lack of precise criteria of the disease; show the possibility of evaluation of the expression of
cytoadherence molecules for diagnostics of the disease, in particular of VCAM-1 and ICAM-1 for differential diagnostics
of chronic appendicitis. The role of suppressor of signal cytokine proteins SOCS3 in chronic inflammation is discussed.
The data demonstrate the increase of T-lymphocytes and neurons in chronic appendicitis as an increase of PGP 9.5
(panneuronal marker protein gene product 9.5) level. It has been shown, that immunohistochemical staining on p44
MAPK has an advantage in differential diagnostics of chronic appendicitis – specific staining of subserous and muscle
layer of the wall is observed only at the discussed pathology of the appendix.
In spite of multiple studies and acknowledgment of the fact that chronic form of appendicitis is a separate disease,
the diagnostics of this pathology still presents quite a problem especially when only routine methods of examination
are used. Thus, we found it necessary to introduce additional immunomorphologic methods into the clinical practice.