bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic enhancement of parasiticidal activity of amphotericin B using copaiba oil in nanoemulsified carrier for oral delivery: an approach for non‐toxic chemotherapy
Authors: Gupta Pramod K , Jaiswal Anil K , Asthana Shalini , Teja B Venkatesh , Shukla Prashant , Shukla Minakshi , Sagar Neeti , Dube Anuradha , Rath Srikanta K , Mishra Prabhat R 
Published: April 2015

Background and PurposeThe aim of this study was to devise a nanoemulsified carrier system (CopNEC) to improve the oral delivery of amphotericin B (AmB) by increasing its oral bioavailability and synergistically enhance its antileishmanial activity with copaiba oil (Cop).Experimental ApproachThe AmB encapsulated NEC (CopNEC‐AmB) comprised of Cop, d‐α‐tocopheryl polyethylene glycol 1000 succinate and phosphatidylcholine was prepared by high‐pressure homogenization method. Stability study of CopNEC‐AmB was carried out in simulated gastric fluid and simulated intestinal fluid. The CopNEC‐AmB and plain AmB were compared as regards their in vitro antileishmanial activity, pharmacokinetics, organ distribution and toxicity.Key ResultsThe optimal CopNEC‐AmB had a small globule size, low polydispersity index, high ζ potential and encapsulation efficiency. The high resolution transmission electron microscopy illustrated spherical particle geometry with homogeny in their sizes. The optimal CopNEC‐AmB was found to be stable in gastrointestinal fluids showing insignificant changes in globule size and encapsulation efficiency. The AUC0–48 value of CopNEC‐AmB in rats was significantly improved showing 7.2‐fold higher oral bioavailability than free drug. The in vitro antileishmanial activity of CopNEC‐AmB was significantly higher than that of the free drug as Cop synergistically enhanced the antileishmanial effect of AmB by causing drastic changes in the morphology of Leishmania parasite and rupturing its plasma membrane. The CopNEC‐AmB showed significantly less haemolytic toxicity and cytotoxicity and did not change the histopathology of kidney tissues as compared with AmB alone.Conclusions and ImplicationsThis prototype CopNEC formulation showed improved bioavailability and had a non‐toxic synergistic effect on the antileishmanial activity of AmB.
Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol‐sensitive TRPC cation channels
Authors: Maier T , Follmann M , Hessler G , Kleemann H‐W , Hachtel S , Fuchs B , Weissmann N , Linz W , Schmidt T , Löhn M , Schroeter K , Wang L , Rütten H , Strübing C 
Published: April 2015

Background and PurposeThe cation channel transient receptor potential canonical (TRPC) 6 has been associated with several pathologies including focal segmental glomerulosclerosis, pulmonary hypertension and ischaemia reperfusion‐induced lung oedema. We set out to discover novel inhibitors of TRPC6 channels and investigate the therapeutic potential of these agents.Experimental ApproachA library of potential TRPC channel inhibitors was designed and synthesized. Activity of the compounds was assessed by measuring intracellular Ca2+ levels. The lead compound SAR7334 was further characterized by whole‐cell patch‐clamp techniques. The effects of SAR7334 on acute hypoxic pulmonary vasoconstriction (HPV) and systemic BP were investigated.Key ResultsSAR7334 inhibited TRPC6, TRPC3 and TRPC7‐mediated Ca2+ influx into cells with IC50s of 9.5, 282 and 226 nM, whereas TRPC4 and TRPC5‐mediated Ca2+ entry was not affected. Patch‐clamp experiments confirmed that the compound blocked TRPC6 currents with an IC50 of 7.9 nM. Furthermore, SAR7334 suppressed TRPC6‐dependent acute HPV in isolated perfused lungs from mice. Pharmacokinetic studies of SAR7334 demonstrated that the compound was suitable for chronic oral administration. In an initial short‐term study, SAR7334 did not change mean arterial pressure in spontaneously hypertensive rats (SHR).Conclusions and ImplicationsOur results confirm the role of TRPC6 channels in hypoxic pulmonary vasoregulation and indicate that these channels are unlikely to play a major role in BP regulation in SHR. SAR7334 is a novel, highly potent and bioavailable inhibitor of TRPC6 channels that opens new opportunities for the investigation of TRPC channel function in vivo.
Still Searching for the Zipperump‐a‐Zoo: A Reflection After 40 Years
Authors: Sternberg Robert J. 
Published: April 2015

AbstractIn this article, I describe chronologically my attempts over a 40‐year career to understand the nature of human intelligence. I explain how later attempts built on earlier ones, with each attempt revealing the earlier one to be too limited and narrow in the questions it asked. In my early work, I envisioned intelligence in terms of components of information processing. Later, I viewed these components as contributing to three distinct but related aspects of intelligence: analytical, creative, and practical. I came to realize the importance of contextual factors in determining what constitutes adaptive behavior. Still later, I viewed wisdom as part of the mix. The search has been rewarding, except for the fact that I have not yet completed it and never will.
Designing a new model for cosmetic adverse reaction monitoring in China
Authors: Lu Changfei , Cheng Gang , Shen Lu , Tian Yuejie , Zhou Zhijun , Li Xinlin , Du Xiaoxi 
Published: April 2015

SummaryBackgroundThe monitoring of cosmetic adverse reactions (CARs) in China has progressed to a new stage of development because of government institutional reforms.ObjectiveTo discuss and formulate an appropriate model for CAR monitoring in China.MethodsThe formulation of a new CAR‐monitoring model under the administration of the Food and Drug Supervision Department is discussed on the basis of China's current national conditions and with reference to the previous CAR‐monitoring and drug‐monitoring models of the organization formerly known as the Ministry of Health of the People's Republic of China.ResultsThe preliminary design of the CAR‐monitoring model is considered to be a long‐term development goal of CAR monitoring. The monitoring model at this stage was developed on the basis of China's national conditions; specifically, the development of a two‐level (national and provincial agencies) monitoring system that relies on CAR‐monitoring sentinels, and reports that cover CARs with definite causal associations.ConclusionThis model is developed on both theoretical and practical foundations, and can function as a proper monitoring model at the initial stage of current CAR monitoring through an appropriate pilot programme, exploration, and improvement.
Surgery for rectal cancer after high‐dose radiotherapy for prostate cancer: is sphincter preservation relevant?
Authors: Buscail E. , Blondeau V. , Adam J.‐P. , Pontallier A. , Laurent C. , Rullier E. , Denost Q. 
Published: April 2015

AbstractAimThe feasibility and outcome of sphincter‐saving resection for rectal cancer were assessed in patients previously treated by high‐dose radiotherapy for prostate cancer.MethodBetween 2000 and 2012, 1066 patients underwent rectal excision for rectal cancer. Of these, 236 were treated by conventional radiotherapy (45 Gy) and sphincter‐saving resection (Group A) and 12 were treated by external‐beam radiotherapy (EBRT) for prostate cancer (70 Gy) and sphincter‐saving resection (Group B) of whom five had a metachronous and seven a synchronous cancer. The end‐points were surgical morbidity, pelvic sepsis, reoperation and definitive stoma.ResultsTumour characteristics were similar in both groups. Surgical morbidity (67% vs 25%, P = 0.004), anastomotic leakage (50% vs 10%, P = 0.001, and reoperation (50% vs 17%, P = 0.011) were significantly higher in Group B. Multivariate analyses showed that EBRT for prostate cancer was the only independent factor for anastomotic leakage (OR = 5.12; 95% CI 1.45–18.08; P = 0.011) and definitive stoma (OR = 10.56; 95% CI 3.02–39.92; P < 0.001).ConclusionHigh‐dose radiotherapy for prostate cancer increases morbidity from rectal surgery and the risk of a permanent stoma. This suggests that a delayed coloanal anastomosis or a Hartmann procedure should be proposed as an alternative to low anterior resection in this population.
Taking the Bitter with the Sweet: Sugarcane's Return as a Driver of Tropical Deforestation
Authors: Obidzinski Krystof , Kusters Koen , Gnych Sophia 
Published: April 2015

AbstractOver more than 400 years, large areas of tropical forest in Brazil, the Caribbean, the Philippines, Australia, and other parts of the world were cleared to make way for sugarcane plantations. There is a general consensus in the scientific community that since the 1950s, the frontier expansion of sugarcane has stabilized and direct pressure on tropical forests from sugarcane expansion has diminished. Here, we show, however, that sugarcane plantations are on the cusp of returning as a major driver of deforestation in Indonesia. The Indonesian government has developed preferential policies designed to boost sugar production in the name of national food security, and is seeking to convert more than 1 million hectares of tropical forest into sugarcane plantations. If fully developed, the plantation expansion program will undermine Indonesia's goal of reducing greenhouse gas emissions. The scale of the expansion program is such that it will radically alter the global environmental impact of sugarcane.
Use of IVIg to identify potential miRNA targets for allograft rejection and GvHD therapy
Authors: Padet Lauriane , Loubaki Lionel , Bazin Renée 
Published: April 2015

AbstractAllograft rejection (AR) and graft‐versus‐host disease (GvHD) are serious complications following transplantation. Micro‐RNAs (miRNAs) have recently been identified as key players in the regulation of these disorders. Because intravenous immunoglobulin (IVIg) has shown therapeutic potential for the prophylaxis and post‐transplant reduction of AR and GvHD, we hypothesized that the effect of IVIg could result from the modulation of specific miRNA expression. To identify such miRNA, we performed mixed lymphocyte reactions (MLRs) as an in vitro model of AR and GvHD, with or without IVIg. We herein show that IVIg strongly inhibits the MLRs. This inhibition is associated with a modulation in the expression of miRNAs implicated in the regulation of pro‐inflammatory cytokine (IL‐2, IL‐6, IFN‐γ) and costimulatory molecule (CD80) expression. We propose that these identified miRNAs could represent potential therapeutic targets for the prevention and therapy of AR and GvHD.
Faster‐acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart
Authors: Heise T. , Hövelmann U. , Brøndsted L. , Adrian C. L. , Nosek L. , Haahr H. 
Published: April 2015

AimsTo evaluate the pharmacokinetics and pharmacodynamics of faster‐acting insulin aspart and insulin aspart in a randomized, single‐centre, double‐blind study.MethodsFifty‐two patients with type 1 diabetes (mean age 40.3 years) received faster‐acting insulin aspart, insulin aspart, or another faster aspart formulation (not selected for further development), each as a single 0.2 U/kg subcutaneous dose, under glucose‐clamp conditions, in a three‐way crossover design (3–12 days washout between dosing).ResultsFaster‐acting insulin aspart had a faster onset of exposure compared with insulin aspart, shown by a 57% earlier onset of appearance [4.9 vs 11.2 min; ratio 0.43, 95% confidence interval (CI) 0.36; 0.51], a 35% earlier time to reach 50% maximum concentration (20.7 vs 31.6 min; ratio 0.65, 95% CI 0.59; 0.72) and a greater early exposure within 90 min after dosing. The greatest difference occurred during the first 15 min, when area under the serum insulin aspart curve was 4.5‐fold greater with faster‐acting insulin aspart than with insulin aspart. Both treatments had a similar time to maximum concentration, total exposure and maximum concentration. Faster‐acting insulin aspart had a significantly greater glucose‐lowering effect within 90 min after dosing [largest difference: area under the curve for the glucose infusion rate (AUCGIR), 0–30 min ratio 1.48, 95% CI 1.13; 2.02] and 17% earlier time to reach 50% maximum glucose infusion rate (38.3 vs 46.1 min; ratio 0.83, 95% CI 0.73; 0.94). The primary endpoint (AUCGIR, 0–2 h) was 10% greater for faster‐acting insulin aspart, but did not reach statistical significance (ratio 1.10, 95% CI 1.00; 1.22). Both treatments had similar total and maximum glucose‐lowering effects, indicating similar overall potency.ConclusionsFaster‐acting insulin aspart was found to have earlier onset and higher early exposure than insulin aspart, and a greater early glucose‐lowering effect, with similar potency.
The impact of governance and transparency on firm investment in Vietnam
Authors: Malesky Edmund , McCulloch Neil , Nhat Nguyen Duc 
Published: April 2015

AbstractA large literature asserts a causal relationship between the quality of economic governance and economic performance. However, attempts to establish such a link at an aggregate level have met with considerable methodological criticism. This paper seeks to overcome this limitation. We match a panel of Vietnamese enterprises from 2006 to 2010 with a unique panel dataset measuring sub‐national economic governance to estimate a relationship between local governance and private investment. We do not find a significant relationship between investment and most traditional forms of governance. However, there is one important exception – transparency, especially the public posting of planning documents, is strongly associated with higher investment across a range of different specifications. Our results have significant implications for policy, given the prevailing theory that changes in the quality of local economic governance will spur improved economic performance.
Outcomes of light‐chain amyloidosis patients treated with first‐line bortezomib: a collaborative retrospective multicenter assessment
Authors: Gatt Moshe E. , Hardan Izhar , Chubar Evgeni , Suriu Celia , Tadmor Tamar , Shevetz Olga , Patachenco Paulina , Dally Najib , Yeganeh Shay , Ballan‐Haj Mouna , Cohen Yael , Trestman Svetlana , Muchtar Eli , Magen Hila , Jakubinsky Julia , Avivi Irit ,   the Israeli MM study group
Published: April 2015

AbstractLight‐chain amyloidosis (AL) is associated with low survival rates, particularly in patients with cardiac involvement. We evaluated the outcome of 73 consecutive, non‐selected ‘real‐world’ AL patients, treated with first‐line bortezomib‐based induction, focusing on the benefit of concurrent administration of alkylating agents. Most patients had renal (77%), cardiac (66%), or multiorgan (74%) involvement. Sixty‐eight per cent (n = 50) received alkylating agent (mostly cyclophosphamide). Severe adverse events were seen in 45%, most evident in patients with cardiac involvement, with no increased toxicity in patients receiving an alkylator agent. Hematological response (HemR) was obtained in 77% of patients, including 33% very good partial responses and 19% complete responses. Age <70 yr, lack of cardiac and peripheral neurologic involvement, and co‐administration of an alkylating agent were associated with significantly improved HemR. NYHA cardiac failure staging was the only independent factor affecting overall survival. Administration of an alkylating agent and the achievement of both HemR and organ response were associated with a statistically significant improved survival in those surviving the first 6 months of induction. First‐line bortezomib‐based regimen resulted in favorable response and survival in newly diagnosed patients. Co‐administration of an alkylating agent improved outcome without increasing treatment‐related toxicity.
In vivo relative quantitative proteomics reveals HMGB1 as a downstream mediator of oestrogen‐stimulated keratinocyte migration
Authors: Shin Jung U , Noh Ji Yeon , Lee Ju Hee , Lee Won Jai , Yoo Jong Shin , Kim Jin Young , Kim Hyeran , Jung Inhee , Jin Shan , Lee Kwang Hoon 
Published: April 2015

AbstractIt is known that oestrogen influences skin wound healing by modulating the inflammatory response, cytokine expression and extracellular matrix deposition; accelerating re‐epithelialization; and stimulating angiogenesis. To identify novel proteins associated with effects of oestrogen on keratinocyte, stable isotope labelling by amino acids in cell culture (SILAC)‐based mass spectrometry was performed. Using SILAC, quantification of 1085 proteins was achieved. Among these proteins, 60 proteins were upregulated and 32 proteins were downregulated. Among significantly upregulated proteins, high‐mobility group protein B1 (HMGB1) has been further evaluated for its role in the effect of oestrogen on keratinocytes. HMGB1 expression was strongly induced in oestrogen‐treated keratinocytes in dose‐ and time‐dependent manner. Further, HMGB1 was able to significantly accelerate the rate of HaCaT cell migration. To determine whether HMGB1 is involved in E2‐induced HaCaT cell migration, cells were transfected with HMGB1 siRNA. Knockdown of HMGB1 blocked oestrogen‐induced keratinocyte migration. Collectively, these experiments demonstrate that HMGB1 is a novel downstream mediator of oestrogen‐stimulated keratinocyte migration.
Interaction of Mycobacterium leprae with the HaCaT human keratinocyte cell line: new frontiers in the cellular immunology of leprosy
Authors: Lyrio Eloah C.D. , Campos‐Souza Ivy C. , Corrêa Luiz C.D. , Lechuga Guilherme C. , Verícimo Maurício , Castro Helena C. , Bourguignon Saulo C. , Côrte‐Real Suzana , Ratcliffe Norman , Declercq Wim , Santos Dilvani O. 
Published: April 2015

AbstractLeprosy is a chronic granulomatous disease caused by Mycobacterium leprae affecting the skin and peripheral nerves. Despite M. leprae invasion of the skin and keratinocytes importance in innate immunity, the interaction of these cells in vitro during M. leprae infection is poorly understood. Conventional and fluorescence optical microscopy, transmission electronic microscopy, flow cytometry and ELISA were used to study the in vitro interaction of M. leprae with the HaCaT human keratinocyte cell line. Keratinocytes uptake of M. leprae is described, and modulation of the surface expression of CD80 and CD209, cathelicidin expression and TNF‐α and IL‐1β production of human keratinocytes are compared with dendritic cells and macrophages during M. leprae interaction. This study demonstrated that M. leprae interaction with human keratinocytes enhanced expression of cathelicidin and greatly increased TNF‐α production. The highest spontaneous expression of cathelicidin was by dendritic cells which are less susceptible to M. leprae infection. In contrast, keratinocytes displayed low spontaneous cathelicidin expression and were more susceptible to M. leprae infection than dendritic cells. The results show, for the first time, an active role for keratinocytes during infection by irradiated whole cells of M. leprae and the effect of vitamin D on this process. They also suggest that therapies which target cathelicidin modulation may provide novel approaches for treatment of leprosy.
Molecular features of the sortase enzyme family
Authors: Bradshaw William J. , Davies Abigail H. , Chambers Christopher J. , Roberts April K. , Shone Clifford C. , Acharya K. Ravi 
Published: April 2015

Bacteria possess complex and varying cell walls with many surface exposed proteins. Sortases are responsible for the covalent attachment of specific proteins to the peptidoglycan of the cell wall of Gram‐positive bacteria. Sortase A of Staphylococcus aureus, which is seen as the archetypal sortase, has been shown to be essential for pathogenesis and has therefore received much attention as a potential target for novel therapeutics. Being widely present in Gram‐positive bacteria, it is likely that other Gram‐positive pathogens also require sortases for their pathogenesis. Sortases have also been shown to be of significant use in a range of industrial applications. We review current knowledge of the sortase family in terms of their structures, functions and mechanisms and summarize work towards their use as antibacterial targets and microbiological tools.
Large carbon release legacy from bark beetle outbreaks across Western United States
Authors: Ghimire Bardan , Williams Christopher A. , Collatz G. James , Vanderhoof Melanie , Rogan John , Kulakowski Dominik , Masek Jeffrey G. 
Published: April 2015

AbstractWarmer conditions over the past two decades have contributed to rapid expansion of bark beetle outbreaks killing millions of trees over a large fraction of western United States (US) forests. These outbreaks reduce plant productivity by killing trees and transfer carbon from live to dead pools where carbon is slowly emitted to the atmosphere via heterotrophic respiration which subsequently feeds back to climate change. Recent studies have begun to examine the local impacts of bark beetle outbreaks in individual stands, but the full regional carbon consequences remain undocumented for the westernUS. In this study, we quantify the regional carbon impacts of the bark beetle outbreaks taking place in westernUSforests. The work relies on a combination of postdisturbance forest regrowth trajectories derived from forest inventory data and a process‐based carbon cycle model tracking decomposition, as well as aerial detection survey (ADS) data documenting the regional extent and severity of recent outbreaks. We find that biomass killed by bark beetle attacks across beetle‐affected areas in westernUSforests from 2000 to 2009 ranges from 5 to 15 Tg C yr−1and caused a reduction of net ecosystem productivity (NEP) of about 6.1–9.3 Tg C y−1by 2009. Uncertainties result largely from a lack of detailed surveys of the extent and severity of outbreaks, calling out a need for improved characterization across westernUSforests. The carbon flux legacy of 2000–2009 outbreaks will continue decades into the future (e.g., 2040–2060) as committed emissions from heterotrophic respiration of beetle‐killed biomass are balanced by forest regrowth and accumulation.
Brain metabolism in minimal hepatic encephalopathy assessed by 3.0‐Tesla magnetic resonance spectroscopy
Authors: Kooka Yohei , Sawara Kei , Endo Ryujin , Kato Akinobu , Suzuki Kazuyuki , Takikawa Yasuhiro 
Published: April 2015

AimTo examine whether the brain exhibits metabolic disorder prior to overt hepatic encephalopathy in patients with liver cirrhosis (LC), the intracerebral glutamine and myo‐inositol levels were determined using 3.0‐Tesla (T)1H (proton) magnetic resonance spectroscopy (MRS).MethodsWe tested 21 LC patients, including seven patients with minimal hepatic encephalopathy (MHE).ResultsNo significant differences were noted between the two patient groups in terms of the severity of LC, levels of blood ammonia or levels of blood or liver enzymes. In the MHE group, the levels of brain glutamine were significantly higher than those in the non‐MHE group, whereas the levels of brain myo‐inositol were significantly lower. This demonstrated that MHE patients were already exhibiting metabolic disorder in the brain, similar to those observed during overt hepatic encephalopathy.ConclusionA quantitative analysis of this phenomenon using MRS may contribute to an early and objective diagnosis of MHE.