bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics, safety, and tolerability of ceftolozane/tazobactam in healthy Japanese, Chinese, and white subjects
Authors: Aiudi Anthony , Miller Benjamin , Krishna Gopal , Adedoyin Adedayo , Xiao Alan 
Published: August 2016

AbstractCeftolozane/tazobactam, a novel antibacterial with potent activity against Gram‐negative pathogens, was developed for treatment of complicated urinary tract infections, including pyelonephritis, and intra‐abdominal infections. A phase 1 pharmacokinetic (PK) study of ceftolozane/tazobactam in healthy Japanese, Chinese, and white volunteers was conducted to assess the potential effect of ethnicity on PK. The PK of ceftolozane, tazobactam, and tazobactam metabolite M1 was compared after single 1.5‐ and 3‐g intravenous doses of ceftolozane/tazobactam. Ten Japanese, nine Chinese, and ten white subjects were enrolled, and 27 completed all doses of study medication. Dose‐normalized PK parameters for ceftolozane and tazobactam were similar among Japanese, Chinese, and white subjects (at 1.5‐g and 3‐g doses, ceftolozane area under the plasma concentration–time curve from zero to infinity [AUC0–∞] = 166.3, 165.9, and 185.5 h μg/mL, respectively, and 157.7, 158.5, and 181.2 h μg/mL, respectively; tazobactam AUC0–∞ = 48.5, 43.2, and 50.1 h μg/mL, respectively, and 47.3, 43.7, and 50.0 h μg/mL, respectively. The 90% CIs of their ratio estimates were within the range 0.80 to 1.25 with the exception of AUC0–∞ for ceftolozane after the 3‐g dose (0.79). The cumulative amount of ceftolozane and tazobactam excreted in urine was similar among ethnic groups. For all groups, treatment‐emergent adverse events (AEs) were mild; no deaths or serious AEs were reported. The PK of ceftolozane/tazobactam was approximately dose proportional (i.e. doubling the dose approximately doubles the exposure) and similar among the groups. No dosage adjustment is needed for ceftolozane/tazobactam in Japanese and Chinese patients.
Micropapillary colorectal carcinoma: clinical, pathological and molecular properties, including evidence of epithelial–mesenchymal transition
Authors: Gonzalez Raul S , Huh Won Jae , Cates Justin M M , Washington Kay , Beauchamp R Daniel , Coffey Robert J , Shi Chanjuan 
Published: August 2016

AimsColorectal carcinoma (CRC) with micropapillary (MP) features has only been described recently and is still being characterized.Methods and resultsWe reviewed the clinicopathological and molecular features of 42 CRC with MP features. Twenty‐nine cases were also evaluated for immunohistochemical evidence of epithelial–mesenchymal transition (EMT). The extent of MP features within our cohort ranged from 5% (13 cases) to 100% (one case). Twenty‐seven cases featured prominent cribriforming with dirty necrosis in the non‐MP component; nine displayed mucinous features. Twenty‐four of 29 cases (83%) demonstrated evidence of EMT. Thirty‐six cases (86%) showed advanced T‐category (pT3 or pT4), 31 (74%) had lymph node metastases and 23 (55%) had distant metastases. Median overall follow‐up was 36 months. Seventeen patients (40%) died of disease, with median survival of 23 months. Mutations were seen in 17 of 31 tested cases (55%), including 11 KRAS mutations and four BRAF V600E mutations. Microsatellite instability testing was performed on 21 cases; all were microsatellite‐stable. Compared to a cohort of 972 conventional CRC, MP CRC was more likely to present as stage IV disease (P < 0.001), but patients with MP CRC showed no significant differences in overall survival after adjusting for stage.ConclusionsMicropapillary features in CRC portend a high likelihood of advanced local disease and distant metastases. MP CRC is often associated with a cribriform pattern elsewhere in the tumour and cystic nodal metastases with prominent necrosis. They also show frequent mutations in KRAS and BRAF. Immunohistochemical evidence of EMT is common in MP CRC.
Granulopoiesis and granules of human neutrophils
Authors: Cowland Jack B. , Borregaard Niels 
Published: August 2016

SummaryGranules are essential for the ability of neutrophils to fulfill their role in innate immunity. Granule membranes contain proteins that react to environmental cues directing neutrophils to sites of infection and initiate generation of bactericidal oxygen species. Granules are densely packed with proteins that contribute to microbial killing when liberated to the phagosome or extracellularly. Granules are, however, highly heterogeneous and are traditionally subdivided into azurophil granules, specific granules, and gelatinase granules in addition to secretory vesicles. This review will address issues pertinent to formation of granules, which is a process intimately connected to maturation of neutrophils from their precursors in the bone marrow. We further discuss possible mechanisms by which decisions are made regarding sorting of proteins to constitutive secretion or storage in granules and how degranulation of granule subsets is regulated.
Transendothelial migration: unifying principles from the endothelial perspective
Authors: Muller William A. 
Published: August 2016

SummaryTransendothelial migration (TEM) of polymorphonuclear leukocytes (PMN) involves a carefully orchestrated dialog of adhesion and signaling events between leukocyte and endothelial cell. This article focuses on the contribution of endothelial cells to transmigration. The initiation of TEM itself generally requires interaction of PECAM on the leukocyte with PECAM at the endothelial cell border. This is responsible for the transient elevation of cytosolic‐free calcium ions in endothelium that is required for TEM and for recruitment of membrane from the lateral border recycling compartment (LBRC). TEM requires LBRC to move to the site at which TEM will take place and for VE‐cadherin to move away. Targeting of the LBRC to this site likely precedes movement of VE‐cadherin and may play a role in clearing VE‐cadherin from the site of TEM. The process of TEM can be dissected into steps mediated by distinct pairs of PMN/endothelial interacting molecules. CD99 regulates a step at or close to the end of TEM. CD99 signals through soluble adenylyl cyclase to activate PKA to trigger ongoing targeted recycling of the LBRC. Paracellular transmigration predominates (≥90% of events) in the cremaster muscle circulation, but transcellular migration may be more important at sites such as the blood‐brain barrier. Both processes involve many of the same molecules and recruitment of the LBRC.
Priming of the neutrophil respiratory burst: role in host defense and inflammation
Authors: El‐Benna Jamel , Hurtado‐Nedelec Margarita , Marzaioli Viviana  , Marie Jean‐Claude , Gougerot‐Pocidalo Marie‐Anne , Dang Pham My‐Chan 
Published: August 2016

SummaryNeutrophils are the major circulating white blood cells in humans. They play an essential role in host defense against pathogens. In healthy individuals, circulating neutrophils are in a dormant state with very low efficiency of capture and arrest on the quiescent endothelium. Upon infection and subsequent release of pro‐inflammatory mediators, the vascular endothelium signals to circulating neutrophils to roll, adhere, and cross the endothelial barrier. Neutrophils migrate toward the infection site along a gradient of chemo‐attractants, then recognize and engulf the pathogen. To kill this pathogen entrapped inside the vacuole, neutrophils produce and release high quantities of antibacterial peptides, proteases, and reactive oxygen species (ROS). The robust ROS production is also called ‘the respiratory burst’, and the NADPH oxidase or NOX2 is the enzyme responsible for the production of superoxide anion, leading to other ROS. In vitro, several soluble and particulate agonists induce neutrophil ROS production. This process can be enhanced by prior neutrophil treatment with ‘priming’ agents, which alone do not induce a respiratory burst. In this review, we will describe the priming process and discuss the beneficial role of controlled neutrophil priming in host defense and the detrimental effect of excessive neutrophil priming in inflammatory diseases.
Human neutrophils in the saga of cellular heterogeneity: insights and open questions
Authors: Scapini Patrizia , Marini Olivia , Tecchio Cristina , Cassatella Marco A. 
Published: August 2016

SummaryRecent findings have uncovered novel fascinating aspects of the biology of neutrophils, which ultimately attribute to these cells a broader role in inflammation and immunity. One aspect that is currently under intensive investigation is the notion of neutrophil ‘heterogeneity’. Studies examining neutrophils in a variety of acute and chronic inflammatory conditions report, in fact, the recovery of CD66b+ cells displaying neutrophil‐like morphology at different degrees of maturation/activation, able to exert either immunosuppressive or proinflammatory properties. These heterogeneous populations of mature and immature neutrophils are indicated with a variety of names, including ‘low density neutrophils (LDNs)’, ‘low density granulocytes (LDGs)’, ‘granulocytic‐myeloid derived suppressor cells (G‐MDSCs)’, and immunosuppressive neutrophils. However, due to the lack of discrete markers that can unequivocally allow their specific identification and isolation, the precise phenotype and function of all these presumably novel, neutrophil‐like, populations have not been correctly defined yet. Aim of this article is to summarize current knowledge on the mature and immature neutrophil populations described to date, featuring immunosuppressive or proinflammatory properties, often defined as ‘subsets’, as well as to critically discuss unresolved issues in the field.
International study on nurses’ views and experiences of compassion
Authors: Papadopoulos I. , Zorba A. , Koulouglioti C. , Ali S. , Aagard M. , Akman O. , Alpers L.‐M. , Apostolara P. , Biles J. , Martín‐García Á. , González‐Gil T. , Kouta C. , Krepinska R. , Kumar B.N. , Lesińska‐Sawicka M. , Lopez L. , Malliarou M. , Nagórska M. , Nissim S. , Nortvedt L. , Oter‐Quintana C. , Ozturk C. , Pangilinan S.B. , Papp K. , Eldar Regev O. , Rubiano F.O. , Tolentino Diaz M.Y. , Tóthová V. , Vasiliou M. 
Published: August 2016

BackgroundCompassion is considered the cornerstone of nursing practice. However, the recent failures in delivering high‐quality compassionate nursing care in the UK's National Health Service have brought the topic of compassion to the attention of the public, service providers, policy makers and academics.AimThe aim of this study was to explore the nurses’ views and experiences of a number of compassion‐related issues in nursing and describe similarities and differences at an international level as well as from the different nursing roles of the participating nurses.MethodsAn exploratory, cross‐sectional descriptive study, using the International Online Compassion Questionnaire. A total of 1323 nurses from 15 countries completed the questionnaire.ResultsThe majority of participants (59.5%) defined compassion as “Deep awareness of the suffering of others and wish to alleviate it” but definitions of compassion varied by country. Of participants, 69.6% thought compassion was very important in nursing and more than half (59.6%) of them argued that compassion could be taught. However, only 26.8% reported that the correct amount and level of teaching is provided. The majority of the participants (82.6%) stated that their patients prefer knowledgeable nurses with good interpersonal skills. Only 4.3% noted that they are receiving compassion from their managers. A significant relationship was found between nurses’ experiences of compassion and their views about teaching of compassion.ConclusionOur study is unique in identifying the views and experiences of nurses from 15 different countries worldwide. The findings reveal that compassion is neither addressed adequately in nursing education nor supported in the practice environment by managers.LimitationsSelf‐report bias was inherent to our survey study design. Furthermore, the individual cultural differences and similarities in the findings are difficult to extrapolate owing to the fact that our analysis was at country level, as well as at the level of the participating nurses.Implications for nursing policyUnderstanding the influence of culture on nurses’ views about compassion is critical in the current multicultural healthcare environment and merits further research. This will potentially drive changes in nursing education (ensuring that compassion is taught to nurses) and in the way healthcare leaders and managers foster a compassionate culture within their organizations (e.g. by leading by example and compassionate to their staff).
Strategies of burrowing in soft muddy sediments by diverse polychaetes
Authors: Dorgan Kelly M. , D'Amelio Catherine , Lindsay Sara M. 
Published: August 2016

AbstractMuddy sediments are elastic solids through which morphologically diverse animals extend burrows by fracture. Muddy sediments inhabited by burrowing infauna vary considerably in mechanical properties, however, and at high enough porosities, muds can be fluidized. In this study, we examined burrowing behaviors and mechanisms of burrow extension for three morphologically diverse polychaete species inhabiting soft muddy sediments. Worms burrowed in gelatin, a transparent analog for muddy sediments, and in natural sediments in a novel viewing box enabling visualization of behaviors and sediment responses. Individuals of Scalibregma inflatum and Sternaspis scutata can extend burrows by fracture, but both also extended burrows by plastic deformation and by combinations of fracture and plastic deformation. Mechanical responses of sediments corresponded to different burrowing behaviors in Scalibregma; direct peristalsis was used to extend burrows by fracture or a combination of plastic deformation and fracture, whereas a retrograde expansive peristaltic wave extended burrows by plastic deformation. Burrowing speeds differed between behaviors and sediment mechanical responses, with slower burrowing associated with plastic deformation. Sternaspis exhibited less variability in behavior and burrowing speed but did extend burrows by different mechanisms consistent with observations of Scalibregma. Individuals of Ophelina acuminata did not extend burrows by fracture; rather individuals plastically deformed sediments similarly to individuals of the related Armandia brevis. Our results extend the range of natural sediments in which burrowing by fracture has been observed, but the dependence of burrow extension mechanism on species, burrowing behavior, and burrowing speed highlights the need for better understanding of mechanical responses of sediments to burrowers.
miRNAs Regulate hERG
Authors: LIAN JIANGFANG , GUO JIAN , HUANG XIAOYAN , YANG XI , HUANG GUOCHANG , MAO HAIYAN , SUN HUAN HUAN , BA YANNA , ZHOU JIANQING 
Published: August 2016

miRNAs Regulate hERGBackgroundThe human ether‐a‐go‐go‐related gene (hERG) is the major molecular component of the rapidly activating delayed rectifier K+ current (Ikr). Impairment of hERG function is believed to be a mechanism causing long‐QT syndromes (LQTS). Growing evidences have shown that microRNAs (miRNAs) are involved in functional modulation of the hERG pathway. The purpose of this study was to screen and validate miRNAs that regulate the hERG pathway. The miRNAs identified in this study will provide new tools to assess the mechanism of LQTS.MethodsSix miRNAs were selected by algorithm predictions based on potential interaction with hERG. The effects of each miRNA on hERG were assessed by use of the Dual‐Luciferase Reporter assay system, qRT‐PCR, Western blotting, and confocal fluorescence microscopy. Furthermore, whole‐cell patch clamp technique was used to validate the effect of miR‐103a‐1 on the electrophysiological characteristic of the Ikr of the hERG protein channel.ResultsmiR‐134, miR‐103a‐1, miR‐143, and miR‐3619 significantly downregulated luciferase activity (P < 0.05) in a reporter test system. These 4 miRNAs significantly suppressed expression of hERG mRNA and protein in U2OS cells (P < 0.05).Corresponding AMOs rescued expression of hERG mRNA and protein. Confocal microscopy showed that all 4 miRNAs reduced the expression of both immature and mature hERG protein. miR‐103a‐1 decreased the maximum current and tail current amplitudes of hERG channel.ConclusionsExpression and functions of hERG are regulated by specific miRNAs.
Prohibitin involvement in the generation of mitochondrial superoxide at complex I in human sperm
Authors: Chai Ran‐Ran , Chen Guo‐Wu , Shi Hui‐Juan , O Wai‐Sum , Martin‐DeLeon Patricia A. , Chen Hong 
Published: August 2016

AbstractProhibitin (PHB), a major mitochondrial membrane protein, has been shown earlier in our laboratoryto regulate sperm motility via an alteration in mitochondrial membrane potential (MMP) in infertile men with poor sperm quality. To test if PHB expression is associated with sperm mitochondrial superoxide (mROS) levels, here we examined sperm mROS levels, high MMP and lipid peroxidation in infertile men with poor sperm motility (asthenospermia, A) and/or low sperm concentrations (oligoasthenospermia, OA). The diaphorase‐type activity of sperm mitochondrial complex I (MCI) and PHB expression were also determined. We demonstrate that mROS and lipid peroxidation levels are significantly higher in sperm from A and OA subjects than in normospermic subjects, whereas high MMP and PHB expression are significantly lower. A positive correlation between mROS and lipid peroxidation and a negative correlation of mROS with PHB expression, high MMP, and sperm motility were found in these subjects. The finding of similar diaphorase‐type activity levels of sperm MCI in the three groups studied suggests that the catalytic subunits of MCI in the matrix arm may produce mROS on its own. There may be a dysfunction of electron transport at MCI associated with decreased expression of PHB in sperm with poor quality. We conclude that mROS level is increased and associated with decreased PHB expression, and it may regulate sperm motility via increases in low MMP and lipid peroxidation. This is the first report on the involvement of PHB in human sperm motility loss associated with increased generation of mROS at MCI.
Insulin degludec/insulin aspart vs biphasic insulin aspart 30 twice daily in Japanese patients with type 2 diabetes: A randomized controlled trial
Authors: Onishi Yukiko , Yamada Kenichi , Zacho Jeppe , Ekelund Jan , Iwamoto Yasuhiko 
Published: August 2016

AbstractAims/IntroductionInsulin degludec/insulin aspart (IDegAsp) is a soluble combination of insulin degludec (70%) and insulin aspart (30%). The present exploratory trial investigated the safety of switching unit‐to‐unit from twice‐daily basal or pre‐mix insulin to twice‐daily IDegAsp in Japanese patients with type 2 diabetes.Materials and MethodsIn this 6‐week, open‐label, parallel‐group, controlled trial, 66 participants were randomized (1:1) to receive either IDegAsp or biphasic insulin aspart 30 (BIAsp 30) twice daily at the same total daily dose as pre‐trial insulin. During the trial, insulin doses were adjusted according to a pre‐specified algorithm to achieve pre‐breakfast and pre‐dinner plasma glucose of 4.4–7.2 mmol/L.ResultsNo severe hypoglycemic episodes occurred. There were no statistically significant differences in rates of confirmed hypoglycemia (rate ratio IDegAsp/BIAsp 30: 0.63, 95% confidence interval: 0.31–1.30) and confirmed nocturnal hypoglycemia (rate ratio: 0.49, 95% confidence interval: 0.10–2.38) for IDegAsp vs BIAsp 30. The hypoglycemia rate for IDegAsp was constant over the 6 weeks of treatment. IDegAsp and BIAsp 30 were both safe and well tolerated. Reduction in fasting plasma glucose was statistically significantly greater for IDegAsp than for BIAsp 30 (estimated treatment difference, IDegAsp‐BIAsp 30: −1.6 mmol/L, 95% confidence interval: −2.4 to −0.8). The apparent decrease in mean postprandial plasma glucose increment (IDegAsp: 4.2–3.8 mmol/L; BIAsp 30: 4.5–2.8 mmol/L) was not statistically significantly different between treatments (estimated treatment difference: 1.0 mmol/L, 95% confidence interval: −0.1 to 2.2).ConclusionsSwitching unit‐to‐unit from basal or pre‐mix insulin to IDegAsp seems not to be associated with any concerns related to hypoglycemia or general safety in Japanese patients with type 2 diabetes.
Convergent evolutionary reduction of atrial septation in lungless salamanders
Authors: Lewis Zachary R. , Hanken James 
Published: August 2016

AbstractNearly two thirds of the approximately 700 species of living salamanders are lungless. These species respire entirely through the skin and buccopharyngeal mucosa. Lung loss dramatically impacts the configuration of the circulatory system but the effects of evolutionary lung loss on cardiac morphology have long been controversial. For example, there is presumably little need for an atrial septum in lungless salamanders due to the absence of pulmonary veins and the presence of a single source of mixed blood flowing into the heart, but whether lungless salamanders possess an atrial septum and whether the sinoatrial aperture is located in the left or right atrium are unresolved; authors have stated opposing claims since the late 1800s. Here, we use micro‐computed tomography (μ‐CT) imaging, gross dissection and histological reconstruction to compare cardiac morphology among lungless plethodontid salamanders (Plethodontidae), salamanders with lungs, and the convergently lungless species Onychodactylus japonicus (Hynobiidae). Plethodontid salamanders have partial atrial septa and incomplete separation of the atrium into left and right halves. Partial septation is also seen in O. japonicus. Hence, lungless salamanders from two lineages convergently evolved similar morphology of the atrial septum. The partial septum in lungless salamanders can make it appear that the sinoatrial aperture is in the left atrium, but this interpretation is incorrect. Outgroup comparisons demonstrate that the aperture is located in a posterodorsal extension of the right atrium into the left side of the heart. Independent evolutionary losses of the atrial septum may have a similar developmental basis. In mammals, the lungs induce formation of the atrial septum by secreting morphogens to neighboring mesenchyme. We hypothesize that the lungs induce atrial septum development in amphibians in a similar fashion to mammals, and that atrial septum reduction in lungless salamanders is a direct result of lunglessness.
Repeated use of mifepristone and levonorgestrel and their effect on the ovarian function in mice
Authors: Chen Yuanyuan , Shi Xiaobo 
Published: August 2016

AbstractAimTo investigate the effects of repeated mifepristone and levonorgestrel use on estrous cycle and expression of ovarian follicle‐stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) in mice.MethodsOvarian FSHR and LHR mRNA expression was measured using real‐time quantitative reverse transcription–polymerase chain reaction, while the protein levels were measured using immunohistochemistry.ResultsRepeated use of mifepristone and levonorgestrel significantly lengthened the estrous cycle and decreased FSHR and LHR mRNA and protein expression in the ovaries of mice at 4, 24, and 48 days after discontinuing drug use. Repeated use of mifepristone and levonorgestrel had significant main effects on estrous cycle length and the mRNA expression and protein level of ovarian FSHR and LHR. Repeated mifepristone and levonorgestrel use and withdrawal time had a significant interaction with mouse estrous cycle (F = 16.65, P < 0.05), ovarian LHR and FSHR mRNA expression (F = 563.072, P < 0.05), and protein level (F = 6.536, P < 0.05).ConclusionRepeated use of mifepristone and levonorgestrel can lead to sustained damage to ovarian function through inhibition of ovarian FSHR and LHR expression in mice.