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Δευτέρα 8 Μαΐου 2017

Materials Nanoarchitecturing via Cation-Mediated Protein Assembly: Making Limpet Teeth without Mineral

Teeth are designed to deliver high forces while withstanding the generated stresses. Aside from isolated mineral-free exception (e.g., marine polychaetes and squids), minerals are thought to be indispensable for tooth-hardening and durability. Here, the unmineralized teeth of the giant keyhole limpet (Megathura crenulata) are shown to attain a stiffness, which is twofold higher than any known organic biogenic structures. In these teeth, protein and chitin fibers establish a stiff compact outer shell enclosing a less compact core. The stiffness and its gradients emerge from a concerted interaction across multiple length-scales: packing of hydrophobic proteins and folding into secondary structures mediated by Ca2+ and Mg2+ together with a strong spatial control in the local fiber orientation. These results integrating nanoindentation, acoustic microscopy, and finite-element modeling for probing the tooth's mechanical properties, spatially resolved small- and wide-angle X-ray scattering for probing the material ordering on the micrometer scale, and energy-dispersive X-ray scattering combined with confocal Raman microscopy to study structural features on the molecular scale, reveal a nanocomposite structure hierarchically assembled to form a versatile damage-tolerant protein-based tooth, with a stiffness similar to mineralized mammalian bone, but without any mineral.

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The teeth of the giant keyhole limpet (Megathura crenulata) are unmineralized but exhibit a stiffness, which is twofold higher than any known organic biogenic structures. This study reveals the structure–function relationship of a unique biological material.



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A Synaptic Transistor based on Quasi-2D Molybdenum Oxide

Biological synapses store and process information simultaneously by tuning the connection between two neighboring neurons. Such functionality inspires the task of hardware implementation of neuromorphic computing systems. Ionic/electronic hybrid three-terminal memristive devices, in which the channel conductance can be modulated according to the history of applied voltage and current, provide a more promising way of emulating synapses by a substantial reduction in complexity and energy consumption. 2D van der Waals materials with single or few layers of crystal unit cells have been a widespread innovation in three-terminal electronic devices. However, less attention has been paid to 2D transition-metal oxides, which have good stability and technique compatibility. Here, nanoscale three-terminal memristive transistors based on quasi-2D α-phase molybdenum oxide (α-MoO3) to emulate biological synapses are presented. The essential synaptic behaviors, such as excitatory postsynaptic current, depression and potentiation of synaptic weight, and paired-pulse facilitation, as well as the transition of short-term plasticity to long-term potentiation, are demonstrated in the three-terminal devices. These results provide an insight into the potential application of 2D transition-metal oxides for synaptic devices with high scaling ability, low energy consumption, and high processing efficiency.

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A quasi-2D transition-metal oxide, α-phase molybdenum oxide (α-MoO3), is used to fabricate nanoscale three-terminal memristive transistors. The essential biological synaptic behaviors, such as excitatory postsynaptic current, depression and potentiation of synaptic weight, paired-pulse facilitation, and the transition of short-term plasticity to long-term potentiation, are demonstrated in the three-terminal devices.



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Ink-Free Reversible Optical Writing in Monolayers by Polymerization of a Trifunctional Monomer: Toward Rewritable “Molecular Paper”

A Langmuir–Blodgett film consisting of a dense array of trifunctional monomers bearing three 1,8-diazaanthracene units is polymerized at an air/water interface or after transfer on solid substrates. The transfer does not affect the excimer fluorescence of the film, indicating that the monomers' packing with their diazaanthracene units stacked face-to-face is retained—a prerequisite for successful polymerization. The monomer film can be polymerized in confined areas on solid substrates by UV irradiation with a confocal microscope laser. The underlying chemistry of the polymerization, a [4+4]-cycloaddition of the diazaanthracene units, leads to disappearance of the fluorescence in the irradiated regions which enables writing into the monolayer on a µm scale—thus the term "molecular paper." The reaction can be reversed by heating which leads to a recovery of the fluorescence and to erasing of the writing. Alternative pathways for this phenomenon are discussed and control experiments are conducted to rule them out.

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"Molecular paper"—a nanometer thin, fluorescent film which can be depositedon various substrates and written onto by irradiation with a confocal microscope laser. Irradiation leads to disappearance of the fluorescence in the targeted area, allowing writing on a micrometer scale. This process is reversible by heating which recovers the film's fluorescence and "erases" the writing.



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Clickable Microgel Scaffolds as Platforms for 3D Cell Encapsulation

While microporous scaffolds are increasingly used for regenerative medicine and tissue repair applications, the most common techniques to fabricate these scaffolds use templating or top-down fabrication approaches. Cytocompatible bottom-up assembly methods afford the opportunity to assemble microporous systems in the presence of cells and create complex polymer-cell composite systems in situ. Here, microgel building blocks with clickable surface groups are synthesized for the bottom-up fabrication of porous cell-laden scaffolds. The facile nature of assembly allows for human mesenchymal stem cells to be incorporated throughout the porous scaffold. Particles are designed with mean diameters of ≈10 and 100 µm, and assembled to create varied microenvironments. The resulting pore sizes and their distribution significantly alter cell morphology and cytoskeletal formation. This microgel-based system provides numerous tunable properties that can be used to control multiple aspects of cellular growth and development, as well as providing the ability to recapitulate various biological interfaces.

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Microgel "building blocks" are designed and assembled in the presence of cells to create polymer-cell composites. These materials have highly tunable mechanical and chemical properties, allowing for a highly versatile cell culture platform.



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Highly Efficient Virus Rejection with Self-Organized Membranes Based on a Crosslinked Bicontinuous Cubic Liquid Crystal

To remove viruses from water, the use of self-assembling liquid crystals is presented as a novel method for the synthesis of membranes with a regular pore size (below 1 nm) and controlled pore structures. Nanostructured bicontinuous cubic liquid-crystalline (LC) thin films are photopolymerized onto a polysulfone support layer. It is found that these membranes reject the virus, Qβ bacteriophage (≈20 nm diameter) by >99.9999%. Prepressurization of the membrane appears to enhance their virus rejection properties. This is the first example of nanostructured LC membranes that are used for virus rejection, for which they show great potential.

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Virus rejection by a liquid crystal membrane is realized for the first time using a self-assembling mesogen stabilized by crosslinking in an ordered bicontinuous cubic phase. This structure allows for the level of control over pore size distribution necessary for efficient rejection of small particles including viruses while allowing for permeation of water. Applying pressurization to the membrane prior to testing results in improved virus removal efficiency and water flux.



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I strongly recommend that all practicing physicians consider such a list, and review it occasionally. I wish for the judgement to know what is best for my patients and to weigh the merits of interventions; surgically, medically, and radiotherapeutically. I wish that I can master the complexities of the practice of medicine and be worthwhile as a physician. I wish for the honesty and integrity to objectively assess my competencies and fallibilities. I wish for the intellectual drive to maintain currency of knowledge. I wish for the wisdom to assess and maintain appropriate costs for medical care. I wish for the integrity to avoid marketing my skills and accomplishments unrealistically and erroneously. I wish for the compassion that allows me to separate my personal problems from the needs of the patients that I serve. I wish for the courage to challenge the wisdom of those that create policies and regulations that fail to consider the full dimension and scope of medical care. Please p
























Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

Childhood Bullying Linked to Health Risks in Adulthood

Childhood bullying may lead to long-lasting health consequences, impacting psychosocial risk factors for cardiovascular health well into adulthood, according to a study published in Psychological Science, a journal of the Association for Psychological Science. The unique study tracked a diverse group of over 300 American men from first grade through their early thirties and the findings indicate that being a victim of bullying and being a bully were both linked to negative outcomes in adulthood.

The study, led by psychology researcher Karen A. Matthews of the University of Pittsburgh, showed that men who were bullies during childhood were more likely to smoke cigarettes and use marijuana, to experience stressful circumstances, and to be aggressive and hostile at follow-up more than 20 years later. Men who were bullied as children, on the other hand, tended to have more financial difficulties, felt more unfairly treated by others, and were less optimistic about their future two decades later.

These outcomes are especially critical, the researchers note, because they put the men at higher risk for poor health, including serious cardiovascular issues, later in life.

"The long term effects of bullying involvement are important to establish," says Matthews. "Most research on bullying is based on addressing mental health outcomes, but we wished to examine the potential impact of involvement in bullying on physical health and psychosocial risk factors for poor physical health."

Previous research has linked psychosocial risk factors like stress, anger, and hostility to increased risk of health problems such as heart attacks, stroke, and high blood pressure. Because bullying leads to stressful interpersonal interactions for both the perpetrators and targets, Matthews and colleagues hypothesized that both bullies and bullying victims might be at higher risk of negative health outcomes related to stress.

The research team recruited participants from the Pittsburgh Youth Study, a longitudinal study of 500 boys enrolled in Pittsburgh public schools in 1987 and 1988, when the boys were in the first grade. More than half of the boys in the original study were Black and nearly 60% of the boys' families received public financial assistance such as food stamps.

Along with regular assessments on psychosocial, behavioral, and biological risk factors for poor health, researchers collected data from children, parents, and teachers on bullying behavior when the participants were 10 to 12 years old.

Matthews and colleagues successfully recruited over 300 of the original study participants to complete questionnaires on psychosocial health factors such as stress levels, health history, diet and exercise, and socioeconomic status. Around 260 of the men came into the lab for blood draws, cardiovascular and inflammation assessments, and height and weight measurements.

Unexpectedly, neither bullying nor being bullied in childhood was related to inflammation or metabolic syndrome in adulthood. However, both childhood bullies and bullying victims had increased psychosocial risk factors for poor physical health.

The boys who engaged in more bullying in childhood tended to be more aggressive and were more likely to smoke in adulthood, risk factors for cardiovascular disease and other life-threatening diseases.

The boys with higher scores for being bullied tended to have lower incomes, more financial difficulties, and more stressful life experiences. They also perceived more unfair treatment relative to their peers. These outcomes are also related to risk for cardiovascular disease.

"The childhood bullies were still aggressive as adults and victims of bullies were still feeling like they were treated unfairly as adults," Matthews explained. "Both groups had a lot of stress in their adult lives – so the impact of childhood bullying lasts a long time!"

The effects of bullying were fairly similar for both Black and White men, as well as those participants who came from low socioeconomic status families.

Matthews and colleagues anticipate that both bullies and their victims may be at greater risk for poor physical health, including cardiovascular-disease events, over the long term. But they caution that many participants in the original study could not participate in this follow-up study because they were either deceased or incarcerated, which may have affected the results in unknown ways.

The findings suggest that identifying children who are at risk for involvement in bullying and intervening early on may yield long-term psychosocial and even physical health benefits that last into adulthood.

Co-authors on the research include J. Richard Jennings and Laisze Lee of the University of Pittsburgh and Dustin A. Pardini of Arizona State University.

This research was supported by National Heart, Lung, and Blood Institute Grant R01-HL111802. Data collection for the Pittsburgh Youth Study was funded by National Institute on Drug Abuse Grant DA411018, National Institute of Mental Health Grants MH48890 and MH50778, the Pew Charitable Trusts, and Office of Juvenile Justice and Delinquency Prevention Grant 96-MU-FX-0012.



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Utilization of health care services by migrants in Europe and The ethics of reporting all the results of clinical trials



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Warming Alters Prey Density and Biological Control in Conventional and Organic Agricultural Systems

<span class="paragraphSection"><div class="boxTitle"></div>Studies have shown that organically farmed fields promote natural predator populations and often have lower pest populations than conventional fields, due to a combination of increased predation pressure and greater plant resistance to pest damage. It is unknown how pest populations and predator efficacy may respond in these farming systems as global temperatures increase. To test these questions, we placed enclosures in eight alfalfa fields farmed using conventional (<span style="font-style:italic;">n</span> = 4) or organic (<span style="font-style:italic;">n</span> = 4) practices for 25 years. We stocked enclosures with pea aphids and 0, 2, or 4 predaceous ladybeetles. Half of the enclosures per field were then either left at ambient temperature or plastic-wrapped to warm them by 2 °C. Aphid abundances were similar in conventional and organic fields under ambient conditions, but were significantly more abundant in conventional than in organic fields when enclosures were warmed. Predator efficacy was reduced under low predator abundance (<span style="font-style:italic;">Hippodamia convergens </span>= 2) in conventional fields under warming conditions; predation strength in organic fields was unaffected by warming. Alfalfa biomass increased with increased predators in all farming and temperature treatments. Our study suggests that biological control may be more easily maintained in organic than in conventional systems as global temperature increases.</span>

http://ift.tt/2qLUQx2

Erratum

<span class="paragraphSection"><span style="font-style:italic;">Integrative and Comparative Biology</span> 56(6); doi:10.1093/icb/icw023.</span>

http://ift.tt/2ppCywQ

Erratum

<span class="paragraphSection"><span style="font-style:italic;">Integrative and Comparative Biology</span> 56(6); doi:10.1093/icb/icw043.</span>

http://ift.tt/2qM1pzQ

Erratum

<span class="paragraphSection"><span style="font-style:italic;">Integrative and Comparative Biology</span> 56(6); doi:10.1093/icb/icw083.</span>

http://ift.tt/2ppCVYl

Erratum

<span class="paragraphSection"><span style="font-style:italic;">Integrative and Comparative Biology</span><span style="font-style:italic;">,</span> 54(6):1084–98; doi:10.1093/icb/icu033</span>

http://ift.tt/2qLMXHT

Stem cell therapy for ischemic heart diseases

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Introduction</div>Ischemic heart diseases, especially the myocardial infarction, is a major hazard problem to human health. Despite substantial advances in control of risk factors and therapies with drugs and interventions including bypass surgery and stent placement, the ischemic heart diseases usually result in heart failure (HF), which could aggravate social burden and increase the mortality rate. The current therapeutic methods to treat HF stay at delaying the disease progression without repair and regeneration of the damaged myocardium. While heart transplantation is the only effective therapy for end-stage patients, limited supply of donor heart makes it impossible to meet the substantial demand from patients with HF. Stem cell-based transplantation is one of the most promising treatment for the damaged myocardial tissue.<div class="boxTitle">Sources of data</div>Key recent published literatures and ClinicalTrials.gov.<div class="boxTitle">Areas of agreement</div>Stem cell-based therapy is a promising strategy for the damaged myocardial tissue. Different kinds of stem cells have their advantages for treatment of Ischemic heart diseases.<div class="boxTitle">Areas of controversy</div>The efficacy and potency of cell therapies vary significantly from trial to trial; some clinical trials did not show benefit. Diverged effects of cell therapy could be affected by cell types, sources, delivery methods, dose and their mechanisms by which delivered cells exert their effects.<div class="boxTitle">Growing points</div>Understanding the origin of the regenerated cardiomyocytes, exploring the therapeutic effects of stem cell-derived exosomes and using the cell reprogram technology to improve the efficacy of cell therapy for cardiovascular diseases.<div class="boxTitle">Areas timely for developing research</div>Recently, stem cell-derived exosomes emerge as a critical player in paracrine mechanism of stem cell-based therapy. It is promising to exploit exosomes-based cell-free therapy for ischemic heart diseases in the future.</span>

http://ift.tt/2qLVp9W

Utilization of health care services by migrants in Europe—a systematic literature review

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Introduction</div>Our study reviewed the empirical evidence on the utilization of health care services by migrants in Europe, and on differences in health service utilization between migrants and non-migrants across European countries.<div class="boxTitle">Sources of data</div>A systematic literature review was performed, searching the databases Medline, Cinahl and Embase and covering the period from January 2009 to April 2016. The final number of articles included was 39.<div class="boxTitle">Areas of agreement</div>Utilization of accident and emergency services and hospitalizations were higher among migrants compared with non-migrants in most countries for which evidence was available. In contrast, screening and outpatient visits for specialized care were generally used less often by migrants.<div class="boxTitle">Areas of controversy</div>Utilization of general practitioner services among migrants compared with non-migrants presents a diverging picture.<div class="boxTitle">Growing points</div>Compared with previous systematic reviews, the results indicate a clearer picture of the differences in health service utilization between migrants and non-migrants in Europe.<div class="boxTitle">Areas timely for developing research</div>A comprehensive comparison across European countries is impossible because the number of studies is still limited. Further research should also help to identify barriers regarding the utilization of health care services by migrants.</span>

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Measuring maternal mortality: a systematic review of methods used to obtain estimates of the maternal mortality ratio (MMR) in low- and middle-income countries

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>The new global target for maternal mortality ratio (MMR) is a ratio below 70 maternal deaths per 100 000 live births by 2030. We undertook a systematic review of methods used to measure MMR in low- and middle-income countries.<div class="boxTitle">Sources of data</div>Systematic review of the literature; 59 studies included.<div class="boxTitle">Areas of agreement</div>Civil registration (5 studies), census (5) and surveys (16), Reproductive Age Mortality Studies (RAMOS) (4) and the sisterhood methods (11) have been used to measure MMR in a variety of settings.<div class="boxTitle">Areas of controversy</div>Middle-income countries have used civil registration data for estimating MMR but it has been a challenge to obtain reliable data from low-income countries with many only using health facility data (18 studies).<div class="boxTitle">Growing points and areas for further research</div>Based on the strengths and feasibility of application, RAMOS may provide reliable and contemporaneous estimates of MMR while civil registration systems are being introduced. It will be important to build capacity for this and ensure implementation research to understand what works where and how.</span>

http://ift.tt/2qLLKk3

The ethics of reporting all the results of clinical trials

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Introduction or background</div>The terms 'publication bias' and 'reporting bias' describe aspects of a phenomenon by which data from trials are not publicized, and so remain inaccessible. This may generate a false impression about the world; but those facts may have important implications for clinical decisions. Thus, the bias may leave patients worse off than they might be.<div class="boxTitle">Sources of data</div>Published journal articles.<div class="boxTitle">Areas of agreement</div>There is general agreement that the phenomenon happens, and that to the extent that it happens, it is undesirable for moral rather than simply epistemic reasons.<div class="boxTitle">Growing points</div>There is a growing demand across the board for data to be better publicized.<div class="boxTitle">Areas timely for developing research</div>There is room for further work on how protocols requiring that data be publicized might be enforced; should it be statutory, or non-statutory? Who should decide what should be made public? There is also room for work on what it is necessary to share, and on whether and how IP law should be reformed.</span>

http://ift.tt/2ppRDhM

Public health in England in 2016—the health of the public and the public health system: a review

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>This article describes the current state of the health of the public in England and the state of the public health professional service and systems.<div class="boxTitle">Sources of data</div>Data sources are wide ranging including the Global Burden of Disease, the Commonwealth Fund and Public Health England reports.<div class="boxTitle">Areas of agreement</div>There is a high burden of preventable disease and unacceptable inequalities in England. There is considerable expectation that there are gains to be made in preventing ill health and disability and so relieving demand on healthcare.<div class="boxTitle">Areas of controversy</div>Despite agreement on the need for prevention, the Government has cut public health budgets by a cumulative 10% to 2020.Public health professionals broadly supportive of remaining in the EU face an uphill battle to retain health, workplace and environmental protections following the 'Leave' vote.<div class="boxTitle">Growing points and areas timely for developing research</div>There is revitalized interest in air pollution. Extreme weather events are testing response and organizational skills of public health professionals and indicating the need for greater advocacy around climate change, biodiversity and protection of ecological systems. Planetary health and ecological public health are ideas whose time has certainly come.</span>

http://ift.tt/2qM1oMi

Implementing electronic records in NHS secondary care organizations in England: policy and progress since 1998

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>A number of different policies have aimed to introduce electronic records into National Health Service (NHS) secondary care organizations in England over recent years. There has been little formal attempt to explore the overall impact of these policies (as opposed to evaluations of individual initiatives) and how they have developed and progressed over time.<div class="boxTitle">Sources of data</div>National NHS IT policy documents and evaluations of national NHS IT policy between 1998 and 2015.<div class="boxTitle">Areas of agreement</div>There has been limited progress in implementing integrated electronic records in secondary organizations since 1998.<div class="boxTitle">Areas of controversy</div>The management and execution of NHS IT policy has been poor, with over ambitious aims contributing to the limited success.<div class="boxTitle">Growing points</div>Detailed guidance on how to implement electronic records in secondary care organizations is required. The ambitions of current policy should be revisited.<div class="boxTitle">Areas timely for developing further research</div>Research exploring the costs and benefits of different approaches to introducing electronic records is needed.</span>

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The effect of economic development on population health: a review of the empirical evidence

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Economic growth is considered an important determinant of population health.<div class="boxTitle">Sources of data</div>Relevant studies investigating the effect of economic growth on health outcomes were identified from Google Scholar and PubMed searches in economics and medical journals.<div class="boxTitle">Areas of agreement</div>Additional resources generated through economic growth are potentially useful for improving population health.<div class="boxTitle">Areas of controversy</div>The empirical evidence on the aggregate effect of economic growth on population health is rather mixed and inconclusive.<div class="boxTitle">Growing points</div>The causal pathways from economic growth to population health are crucial and failure or success in completing the pathways explains differences in empirical findings.<div class="boxTitle">Areas timely for developing research</div>Future research should investigate how additional resources can more effectively reach those in need and how additional resources can be used more efficiently. It is particularly relevant to understand why preventive health care in developing countries is very price elastic whereas curative health care is very health inelastic and how this understanding can inform public health policy.</span>

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Ocular oncology: advances in retinoblastoma, uveal melanoma and conjunctival melanoma

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Retinoblastoma, uveal and conjunctival melanomas are important malignancies within the remit of ocular oncology. Outlined are the diagnostic features and management principles, as well as advancements in the field and current challenges.<div class="boxTitle">Sources of data</div>Original papers, reviews and guidelines.<div class="boxTitle">Areas of agreement</div>Most eyes with retinoblastoma (International Intraocular Retinoblastoma Classification (IIRC) Group A–D) are salvaged, whereas advanced cases (Group E) remain a challenge. Despite a high rate of local tumour control in uveal melanoma, metastatic spread commonly occurs. Conjunctival melanoma is treated by complete resection, but high rates of local recurrence occur, with the possibility of systemic relapse and death.<div class="boxTitle">Areas of controversy</div>Use of the IIRC in retinoblastoma, and systemic screening in melanomas.<div class="boxTitle">Growing points</div>Utilization of novel treatment modalities in retinoblastoma and an increasing understanding of the genetic basis of melanomas.<div class="boxTitle">Areas timely for developing research</div>Improvements in chemotherapy delivery in retinoblastoma and prognostic tests in melanomas.</span>

http://ift.tt/2qUJnHX

Functional assessment of thoracic aortic aneurysms – the future of risk prediction?

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Introduction</div>Treatment guidelines for the thoracic aorta concentrate on size, yet acute aortic dissection or rupture can occur when aortic size is below intervention criteria. Functional imaging and computational techniques are a means of assessing haemodynamic parameters involved in aortic pathology.<div class="boxTitle">Sources of data</div>Original articles, reviews, international guidelines.<div class="boxTitle">Areas of agreement</div>Computational fluid dynamics and 4D flow MRI allow non-invasive assessment of blood flow parameters and aortic wall biomechanics.<div class="boxTitle">Areas of controversy</div>Aortic valve morphology (particularly bicuspid aortic valve) is associated with aneurysm of the ascending aorta, although the exact mechanism of aneurysm formation is not yet established.<div class="boxTitle">Growing points</div>Haemodynamic assessment of the thoracic aorta has highlighted parameters which are linked with both clinical outcome and protein changes in the aortic wall. Wall shear stress, flow displacement and helicity are elevated in patients with bicuspid aortic valve, particularly at locations of aneurysm formation.<div class="boxTitle">Areas timely for developing research</div>With further validation, functional assessment of the aorta may help identify patients at risk of aortic complications, and introduce new haemodynamic indices into management guidelines.</span>

http://ift.tt/2ppDFg2

The cancer risk related to meat and meat products

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Introduction</div>Meat has been classified by International Agency for Research on Cancer (IARC) as carcinogenic to humans. The evidence and the implications for health are reviewed.<div class="boxTitle">Sources of data</div>Evidence was obtained from published reports and systematic reviews published before and since the IARC decision.<div class="boxTitle">Areas of agreement</div>Epidemiology indicates that processed meat products are associated with increased risk of colorectal cancer. Evidence for red meat and for other cancers remains tentative.<div class="boxTitle">Areas of controversy</div>Several mechanisms for mutagenic effects of meat consumption have been identified but it is not clear which cause cancer in humans. The extent to which complete abstention from meat protects against cancer is also uncertain.<div class="boxTitle">Growing points</div>Prospective studies on meat consumption in western populations will continue to illuminate the details of carcinogenesis, and effective strategies for reducing risk.<div class="boxTitle">Areas timely for developing research</div>Further studies on the precise mechanisms of carcinogenesis in human populations would assist both food manufacturers and the general public to minimize risk.</span>

http://ift.tt/2qLBrw1

Cancer burden with ageing population in urban regions in China: projection on cancer registry data from World Health Organization

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>China is facing the challenges of an expanding ageing population and the impact of rapid urbanization, cancer rates are subsequently increasing. This study focuses on the changes of the ageing population and projects the incidence of common ageing-related cancers in the urban regions in China up to 2030.<div class="boxTitle">Sources of data</div>Cancer incidence data and population statistics in China were extracted from the International Agency for Research on Cancer.<div class="boxTitle">Areas of agreement</div>Due to improving longevity in China, continuous and remarkable increasing trends for the lung, colorectal and prostate cancers are expected.<div class="boxTitle">Growing points</div>The rate of expanding ageing population was taken into account when predicting the trend of cancer incidence; the estimations of ageing-related cancers were more factual and significant than using the conventional approach of age standardization.<div class="boxTitle">Areas timely for developing research</div>The incidence rates of lung, colorectal and prostate cancers will continue to rise in the future decades due to the rise of ageing population. Lifestyle modification such as cutting tobacco smoking rates and promoting healthier diets as well as cancer screening programs should be a health system priority in order to decrease the growing burden of cancer-related mortality and morbidity.</span>

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Editorial_Board



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Abstract from the Chinese Journal of Hypertension

<span class="paragraphSection">Relationship Between Red Blood Cell Distribution Width and the Risk Levels of Framingham Cardiovascular Score in Patients With Essential Hypertension</span>

http://ift.tt/2pWnWZk

Abstract from the Chinese Journal of Hypertension

<span class="paragraphSection">Effects of Ghrelin on Atherosclerotic Plaque Formation and Inflammatory Factor Expression in Apolipoprotein E Knockout Mice</span>

http://ift.tt/2ptVbkc

TCDD influences reservoir of antibiotic resistance genes in murine gut microbiome

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Dysbiosis of the gut microbiome via antibiotics, changes in diet, and infection can select for bacterial groups that more frequently harbor antimicrobial resistance genes (ARGs) and mobile genetic elements (MGEs). However, the impact of environmental toxicants on the reservoir of ARGs in the gut microbiome has received less attention. 2,3,7,8-tetrachlorodibenzo-<span style="font-style:italic;">p</span>-dioxin (TCDD) is a potent aryl hydrocarbon receptor (AhR) agonist with multiple toxic health effects including immune dysfunction. The selective pressure of TCDD on the abundance of ARG and MGE harboring gut populations was examined using C57BL/6 mice exposed to 0–30 μg/kg TCDD for 28 and 92 days with the latter having a 30-day recovery period. DNA extracted from temporally collected fecal pellets was characterized using a qPCR array with 384 assays targeting ARGs and MGEs. Fourteen genes, typically observed in <span style="font-style:italic;">Enterobacteriaceae</span>, increased significantly within eight days of initial dosing, persisted throughout the treatment period, and remained induced 30 days post dosing. A qPCR primer set targeting <span style="font-style:italic;">Enterobacteriaceae</span> also showed 10- to 100-fold higher abundance in TCDD treated groups, which was further verified using metagenomics. Results show a bloom of ARG harboring bacterial groups in the gut due to a xenobiotic compound that is not a metal, biocide, or antimicrobial.</span>

http://ift.tt/2pWz08T

The Janus face of iron on anoxic worlds: Iron oxides are both protective and destructive to life on the Early Earth and present-day Mars

<span class="paragraphSection"><div class="boxTitle">Abstract</div>The surface of the early Earth was probably subjected to a higher flux of ultraviolet (UV) radiation than today. UV radiation is known to severely damage DNA and other key molecules of life. Using a liquid culture and a rock analogue system we investigated the interplay of protective and deleterious effects of iron oxides under UV radiation on the viability of the model organism, <span style="font-style:italic;">Bacillus subtilis</span>. In the presence of hydrogen peroxide there exists a fine balance between iron oxide's protective effects against this radiation and its deleterious effects caused by Photo-Fenton reactions. The maximum damage was caused by a concentration of hematite of ∼1 mg/mL. Concentrations above this confer increasing protection by physical blockage of the UV radiation, concentrations below this cause less effective UV radiation blockage, but also a correspondingly less effective Photo-Fenton reaction, providing an overall advantage. These results show that on anoxic worlds, surface habitability under a high UV flux leaves life precariously poised between the beneficial and deleterious effects of iron oxides. These results have relevance to the Archean Earth, but also the habitability of the Martian surface, where high levels of UV radiation in combination with iron oxides and hydrogen peroxide can be found.</span>

http://ift.tt/2ptyiNK

Survival and electrotransformation of Pseudomonas syringae strains under simulated cloud-like conditions

<span class="paragraphSection"><div class="boxTitle">Abstract</div>To diversify their genetic material, and thereby allow adaptation to environmental disturbances and colonization of new ecological niches, bacteria use various evolutionary processes, including the acquisition of new genetic material by horizontal transfer mechanisms such as conjugation, transduction and transformation. Electrotransformation mediated by lightning-related electrical phenomena may constitute an additional gene transfer mechanism occurring in nature. The presence in clouds of bacteria such as <span style="font-style:italic;">Pseudomonas syringae</span> capable of forming ice nuclei that lead to precipitation and that are likely to be involved in triggering lightning<span style="font-style:italic;">,</span> led us to postulate that natural electrotransformation in clouds may contribute to the adaptive potential of these bacteria. Here we quantify the survival rate of ten <span style="font-style:italic;">P. syringae</span> strains in liquid and icy media under such electrical pulses and their capacity to acquire exogenous DNA. In comparison to two other bacteria (<span style="font-style:italic;">Pseudomonas sp.</span> N3 and <span style="font-style:italic;">Escherichia coli</span> TOP10), <span style="font-style:italic;">P. syringae</span> CC0094 appears to be best adapted for survival and for genetic electrotransformation under these conditions, which suggests that this bacterium would be able to survive and to get a boost in its adaptive potential whilst being transported in clouds and falling back to Earth with precipitation from storms.</span>

http://ift.tt/2pWfOIl

Characterization of the role of copCD in copper uptake and the “copper-switch” in Methylosinus trichosporium OB3b

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Methanotrophs, or methane-oxidizing bacteria exhibit a unique 'copper-switch' where expression of two forms of methane monooxygenase is controlled by the availability of copper. In the absence of copper, a cytoplasmic or soluble methane monooxygenase (sMMO) is expressed. In the presence of copper a membrane-bound or particulate methane monooxygenase (pMMO) is expressed. These two forms of MMO have very different properties, and elucidation of the basis of the copper-switch is of significant interest as methanotrophs are becoming increasingly popular for the valorization of methane. Recently it was suggested via characterization of a mutant of <span style="font-style:italic;">Methylosinus trichosporium</span> OB3b that expresses sMMO in the presence of copper (smmoC mutant) that the copper-switch may be based on <span style="font-style:italic;">copCD.</span> These genes encode for a periplasmic copper-binding protein and an inner membrane protein, respectively, and are used by other bacteria for copper uptake. Specific knockouts of <span style="font-style:italic;">copCD</span> in <span style="font-style:italic;">M. trichosporium</span> OB3b wildtype, however, show these genes are not part of the copper-switch in methanotrophs, nor do they appear to be critical for copper uptake. Rather, it appears that the constitutive expression of sMMO in the smmoC mutant of <span style="font-style:italic;">M. trichosporium</span> OB3b may be due to multiple lesions as smmoC was generated via random chemical mutagenesis.</span>

http://ift.tt/2peSVB8

Antifungal mechanism of [Ru III (NH 3 ) 4 catechol] + complex on fluconazole-resistant Candida tropicalis

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Candidiasis, a major opportunistic mycosis caused by <span style="font-style:italic;">Candida</span> sp., may comprise life-threatening systemic infections. The incidence of non-<span style="font-style:italic;">albicans</span> species is rising, particularly in South America and they are frequently drug resistant, causing unresponsive cases. Thus, novel antimycotic agents are required. Here we tested the antifungal activity of [Ru<sup>III</sup>(NH<sub>3</sub>)<sub>4</sub>catechol]<sup>+</sup> complex (RuCat), approaching possible action mechanisms on fluconazole-resistant <span style="font-style:italic;">Candida tropicalis</span>. RuCat significantly (<span style="font-style:italic;">P</span> < 0.05) inhibited the growth and viability of <span style="font-style:italic;">C. tropicalis</span> dose-dependently (IC<sub>50</sub> 20.3 μM). Cytotoxicity of RuCat upon murine splenocytes was lower (Selectivity Index = 16). Scanning electron microscopy analysis showed pseudohyphae formation, yeast aggregation and surface damage. RuCat-treated samples investigated by transmission electron microscopy showed melanin granule trafficking to cell surfaces and extracellular milieu. Surface-adherent membrane fragments and extracellular debris were also observed. RuCat treatment produced intense H<sub>2</sub>DCFDA labeling, indicating reactive oxygen species (ROS) production which caused increased lipoperoxidation. ROS are involved in the fungicidal effect as <span style="font-style:italic;">N</span>-acetyl-L-cysteine completely restored cell viability. Calcofluor White chitin staining suggests that 70 or 140 μM RuCat treatment for 2 h affected cell-wall structure. PI labeling indicated necrotic cell death. The present data indicate that RuCat triggers ROS production, lipoperoxidation and cell surface damage, culminating in selective necrotic death of drug-resistant <span style="font-style:italic;">C. tropicalis.</span></span>

http://ift.tt/2ptwTqs

Toward solar biodiesel production from CO 2 using engineered cyanobacteria

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Metabolic engineering of cyanobacteria has received attention as a sustainable strategy to convert carbon dioxide to various biochemicals including fatty acid-derived biodiesel. Recently, <span style="font-style:italic;">Synechococcus elongatus</span> PCC 7942, a model cyanobacterium, has been engineered to convert CO<sub>2</sub> to fatty acid ethyl esters (FAEEs) as biodiesel. Modular pathway has been constructed for FAEE production. Several metabolic engineering strategies were discussed to improve the production levels of FAEEs, including host engineering by improving CO<sub>2</sub> fixation rate and photosynthetic efficiency. In addition, protein engineering of key enzyme in <span style="font-style:italic;">S. elongatus</span> PCC 7942 was implemented to address issues on FAEE secretions toward sustainable FAEE production from CO<sub>2</sub>. Finally, advanced metabolic engineering will promote developing biosolar cell factories to convert CO<sub>2</sub> to feasible amount of FAEEs toward solar biodiesel.</span>

http://ift.tt/2pWl5Q3

Soil microbiome transfer method affects microbiome composition, including dominant microorganisms, in a novel environment

<span class="paragraphSection"><div class="boxTitle">Abstract</div>We show that choice of soil microbiome transfer method, <span style="font-style:italic;">i.e.</span> direct soil transfers and a common soil wash procedure, dramatically influences the microbiome that develops in a new environment, using high-throughput amplicon sequencing of 16S rRNA genes and the fungal ITS region. After three weeks of incubation in commercial potting mix, microbiomes were most similar to the source soil when a greater volume of initial soil was transferred (5% v/v transfer), and least similar when using a soil wash. Abundant operational taxonomic units (OTUs) were substantially affected by transfer method, suggesting that compounds transferred from the source soil, shifts in biotic interactions, or both, play an important role in their success.</span>

http://ift.tt/2ptGPAf

What Supervisors and Universities Can do to Enhance Doctoral Student Experience (and how they can help themselves)

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Over the past two decades, there has been a flurry of government papers and policy reports worldwide calling for increased number and diversity of doctoral researchers and a broadening of the curriculum to meet the developing needs of respective national 'knowledge-driven' economies. This has been followed by position papers and best practice examples of employability skills development in boundary-crossing doctoral programmes, especially in response to these initiatives. However, there is a disassociation between this ample literature expounding the new doctorate with its broader remit, inclusivity and production of 'industry-ready' graduates, and the comparatively sparse literature on the doctoral candidates' experiences of their programmes and career readiness. Within this review, we briefly outline international government initiatives and examples of the responses by Life Science and Biomedical doctoral programmes to address these various challenges. Further, we explore the recent literature on the lived experience of doctoral researchers by examining their perception of the recent changes to the research context to make recommendations for universities and supervisors on how to better support an ever more diverse doctoral population for a wide range of career opportunities. Examples of how doctoral researchers themselves can make the best of currently available opportunities are also provided.</span>

http://ift.tt/2pfcaL5

Toward establishing minimum requirements for extracellular electron transfer in Geobacter sulfurreducens

<span class="paragraphSection"><div class="boxTitle">Abstract</div>The highly redundant pathways for extracellular electron transfer in <span style="font-style:italic;">Geobacter sulfurreducens</span> must be simplified for this microorganism to serve as an effective chassis for applications such as the development of sensors and biocomputing. Five homologs of the periplasmic <span style="font-style:italic;">c</span>-type cytochromes, PpcA-E, offer the possibility of multiple routes of electron transfer across the periplasm. The presence of a large number of outer membrane <span style="font-style:italic;">c</span>-type cytochromes allows <span style="font-style:italic;">G. sulfurreducens</span> to adapt to disruption of an electron transfer pathway in the outer membrane. A strain in which genes for all five periplasmic cytochromes, PpcA-E, were deleted did not reduce Fe(III). Introducing <span style="font-style:italic;">ppcA</span> under the control of an IPTG-inducible system in the quintuple deletion strain yielded a strain that reduced Fe(III) only in the presence of IPTG. A strain lacking known major outer membrane cytochromes, OmcB, OmcE, OmcS, and OmcT, and putative functional homologs of OmcB, did not reduce Fe(III). Introduction of <span style="font-style:italic;">omcB</span> in this septuple deletion strain restored the ability to reduce Fe(III). These results demonstrate that it is possible to trim redundancy from the extracellular electron transfer pathways in <span style="font-style:italic;">G. sulfurreducens</span> in order to construct strains with defined extracellular electron transfer routes.</span>

http://ift.tt/2ptGRbl

Effect of halotolerant rhizobacteria isolated from halophytes on the growth of sugar beet ( Beta vulgaris L.) under salt stress

<span class="paragraphSection"><div class="boxTitle">ABSTRACT</div>Utilization of rhizobacteria that have associated with plant roots in harsh environments could be a feasible strategy to deal with limits to agricultural production caused by soil salinity. Halophytes occur naturally in high-salt environments, and their roots may be associated with promising microbial candidates for promoting growth and salt tolerance in crops. This study aimed to isolate efficient halotolerant plant-growth-promoting rhizobacterial strains from halophytes and evaluate their activity and effects on sugar beet (<span style="font-style:italic;">Beta vulgaris</span> L.) growth under salinity stress. A total of 23 isolates were initially screened for their ability to secrete 1-aminocyclopropane-1-carboxylate deaminase (ACD) as well as other plant-growth-promoting characteristics and subsequently identified by sequencing the 16S rRNA gene. Three isolates, identified as <span style="font-style:italic;">Micrococcus yunnanensis</span>, <span style="font-style:italic;">Planococcus rifietoensis</span> and <span style="font-style:italic;">Variovorax paradoxus</span>, enhanced salt stress tolerance remarkably in sugar beet, resulting in greater seed germination and plant biomass, higher photosynthetic capacity and lower stress-induced ethylene production at different NaCl concentrations (50–125 mM). These results demonstrate that salinity-adapted, ACD-producing bacteria isolated from halophytes could promote sugar beet growth under saline stress conditions.</span>

http://ift.tt/2ptBF7s

Genetics and evolution of Yersinia pseudotuberculosis O-specific polysaccharides: a novel pattern of O-antigen diversity

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<span class="paragraphSection"><div class="boxTitle">Abstract</div>O-antigen polysaccharide is a major immunogenic feature of the lipopolysaccharide of Gram-negative bacteria, and most species produce a large variety of forms that differ substantially from one another. There are 18 known O-antigen forms in the <span style="font-style:italic;">Yersinia pseudotuberculosis</span> complex, which are typical in being composed of multiple copies of a short oligosaccharide called an O unit. The O-antigen gene clusters are located between the <span style="font-style:italic;">hemH</span> and <span style="font-style:italic;">gsk</span> genes, and are atypical as 15 of them are closely related, each having one of five downstream gene modules for alternative main-chain synthesis, and one of seven upstream modules for alternative side-branch sugar synthesis. As a result, many of the genes are in more than one gene cluster. The gene order in each module is such that, in general, the earlier a gene product functions in O-unit synthesis, the closer the gene is to the 5<sup>΄</sup> end for side-branch modules or the 3<sup>΄</sup> end for main-chain modules. We propose a model whereby natural selection could generate the observed pattern in gene order, a pattern that has also been observed in other species.</span>

http://ift.tt/2pW4RGI

Microbial ecology of fermentative hydrogen producing bioprocesses: useful insights for driving the ecosystem function

<span class="paragraphSection"><div class="boxTitle">Abstract</div>One of the most important biotechnological challenges is to develop environment friendly technologies to produce new sources of energy. Microbial production of biohydrogen through dark fermentation, by conversion of residual biomass, is an attractive solution for short-term development of bioH<sub>2</sub> producing processes. Efficient biohydrogen production relies on complex mixed communities working in tight interaction. Species composition and functional traits are of crucial importance to maintain the ecosystem service. The analysis of microbial community revealed a wide phylogenetic diversity that contributes in different—and still mostly unclear—ways to hydrogen production. Bridging this gap of knowledge between microbial ecology features and ecosystem functionality is essential to optimize the bioprocess and develop strategies toward a maximization of the efficiency and stability of substrate conversion. The aim of this review is to provide a comprehensive overview of the most up-to-date biodata available and discuss the main microbial community features of biohydrogen engineered ecosystems, with a special emphasis on the crucial role of interactions and the relationships between species composition and ecosystem service. The elucidation of intricate relationships between community structure and ecosystem function would make possible to drive ecosystems toward an improved functionality on the basis of microbial ecology principles.</span>

http://ift.tt/2pW4PyA

Intestinal microbiome landscaping: insight in community assemblage and implications for microbial modulation strategies

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<span class="paragraphSection"><div class="boxTitle">Abstract</div>High individuality, large complexity and limited understanding of the mechanisms underlying human intestinal microbiome function remain the major challenges for designing beneficial modulation strategies. Exemplified by the analysis of intestinal bacteria in a thousand Western adults, we discuss key concepts of the human intestinal microbiome landscape, i.e<span style="font-style:italic;">.</span> the compositional and functional 'core', the presence of community types and the existence of alternative stable states. Genomic investigation of core taxa revealed functional redundancy, which is expected to stabilize the ecosystem, as well as taxa with specialized functions that have the potential to shape the microbiome landscape. The contrast between <span style="font-style:italic;">Prevotella-</span> and <span style="font-style:italic;">Bacteroides-</span>dominated systems has been well described. However, less known is the effect of not so abundant bacteria, for example, <span style="font-style:italic;">Dialister</span> spp. that have been proposed to exhibit distinct bistable dynamics. Studies employing time-series analysis have highlighted the dynamical variation in the microbiome landscape with and without the effect of defined perturbations, such as the use of antibiotics or dietary changes. We incorporate ecosystem-level observations of the human intestinal microbiota and its keystone species to suggest avenues for designing microbiome modulation strategies to improve host health.</span>

http://ift.tt/2pWbhWl

Forest microbiome: diversity, complexity and dynamics

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Globally, forests represent highly productive ecosystems that act as carbon sinks where soil organic matter is formed from residuals after biomass decomposition as well as from rhizodeposited carbon. Forests exhibit a high level of spatial heterogeneity and the importance of trees, the dominant primary producers, for their structure and functioning. Fungi, bacteria and archaea inhabit various forest habitats: foliage, the wood of living trees, the bark surface, ground vegetation, roots and the rhizosphere, litter, soil, deadwood, rock surfaces, invertebrates, wetlands or the atmosphere, each of which has its own specific features, such as nutrient availability or temporal dynamicy and specific drivers that affect microbial abundance, the level of dominance of bacteria or fungi as well as the composition of their communities. However, several microorganisms, and in particular fungi, inhabit or even connect multiple habitats, and most ecosystem processes affect multiple habitats. Forests are dynamic on a broad temporal scale with processes ranging from short-term events over seasonal ecosystem dynamics to long-term stand development after disturbances such as fires or insect outbreaks. The understanding of these processes can be only achieved by the exploration of the complex 'ecosystem microbiome' and its functioning using focused, integrative microbiological and ecological research performed across multiple habitats.</span>

http://ift.tt/2pW5RuE

Non-canonical transcription initiation: the expanding universe of transcription initiating substrates

<span class="paragraphSection"><div class="boxTitle">Abstract</div>RNA polymerase (RNAP) is the central enzyme of transcription of the genetic information from DNA into RNA. RNAP recognizes four main substrates: ATP, CTP, GTP and UTP. Experimental evidence from the past several years suggests that, besides these four NTPs, other molecules can be used to initiate transcription: (i) ribooligonucleotides (nanoRNAs) and (ii) coenzymes such as NAD<sup>+</sup>, NADH, dephospho-CoA and FAD. The presence of these molecules at the 5΄ ends of RNAs affects the properties of the RNA. Here, we discuss the expanding portfolio of molecules that can initiate transcription, their mechanism of incorporation, effects on RNA and cellular processes, and we present an outlook toward other possible initiation substrates.</span>

http://ift.tt/2ptRjzD

Staphylococcus aureus , phagocyte NADPH oxidase and chronic granulomatous disease

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Dysfunction of phagocytes is a relevant risk factor for staphylococcal infection. The most common hereditary phagocyte dysfunction is chronic granulomatous disease (CGD), characterized by impaired generation of reactive oxygen species (ROS) due to loss of function mutations within the phagocyte NADPH oxidase NOX2. Phagocytes ROS generation is fundamental to eliminate pathogens and to regulate the inflammatory response to infection. CGD is characterized by recurrent and severe bacterial and fungal infections, with <span style="font-style:italic;">Staphylococcus aureus</span> as the most frequent pathogen, and skin and lung abscesses as the most common clinical entities. <span style="font-style:italic;">Staphylococcus aureus</span> infection may occur in virtually any human host, presumably because of the many virulence factors of the bacterium. However, in the presence of functional NOX2, staphylococcal infections remain rare and are mainly linked to breaches of the skin barrier. In contrast, in patients with CGD, <span style="font-style:italic;">S. aureus</span> readily survives and frequently causes clinically apparent disease. Astonishingly, little is known why <span style="font-style:italic;">S. aureus</span>, which possesses a wide range of antioxidant enzymes (e.g. catalase, SOD), is particularly sensitive to control through NOX2. In this review, we will evaluate the discovery of CGD and our present knowledge of the role of NOX2 in <span style="font-style:italic;">S. aureus</span> infection.</span>

http://ift.tt/2pWuwz5

Eribulin rapidly reduces the aggressiveness of second primary breast cancer: a case report

Future Oncology May 2017, Vol. 13, No. 11s, Pages 51-54.


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Long-term treatment with eribulin in heavily pretreated women with metastatic breast cancer: a case series

Future Oncology May 2017, Vol. 13, No. 11s, Pages 25-33.


http://ift.tt/2pW8896

Coenzyme Q10 in breast cancer care

Future Oncology May 2017, Vol. 13, No. 11, Pages 1035-1041.


http://ift.tt/2ptSVsU

Retinal Hemorrhage in a High-Altitude Aid Post Volunteer Doctor: A Case Report

High Altitude Medicine & Biology , Vol. 0, No. 0.


http://ift.tt/2ppcnq0

Eribulin across multiple lines of chemotherapy: a retrospective study on quality of life and efficacy in metastatic breast cancer patients

Future Oncology May 2017, Vol. 13, No. 11s, Pages 11-23.


http://ift.tt/2ptJY35

Eribulin as an effective monotherapy in a chemo-pretreated woman with metastatic breast cancer: a case report

Future Oncology May 2017, Vol. 13, No. 11s, Pages 45-50.


http://ift.tt/2pWsRtl

Eribulin long-term response and rechallenge: report of two clinical cases

Future Oncology May 2017, Vol. 13, No. 11s, Pages 35-43.


http://ift.tt/2ptDYav

Eribulin efficacy based on type of metastatic site: a real-life study in heavily pretreated metastatic breast cancer

Future Oncology May 2017, Vol. 13, No. 11s, Pages 5-10.


http://ift.tt/2ptPLpj

Eribulin in the treatment of breast cancer: an important weapon in the treatment algorithm

Future Oncology May 2017, Vol. 13, No. 11s, Pages 1-3.


http://ift.tt/2ptaQ3i

The role of pathology in the management of patients with endometrial carcinoma

Future Oncology May 2017, Vol. 13, No. 11, Pages 1003-1020.


http://ift.tt/2pW7vfq

Adjuvant chemotherapy and follow-up for recurrences in localized testicular cancer

Future Oncology May 2017, Vol. 13, No. 11, Pages 947-950.


http://ift.tt/2ptRmLL

Immune checkpoint inhibitors in lung cancer: an update

Future Oncology May 2017, Vol. 13, No. 11, Pages 955-959.


http://ift.tt/2pWd6CC

Resectable pancreatic adenocarcinomas: will neoadjuvant FOLFIRINOX replace upfront surgery in the standard of care?

Future Oncology May 2017, Vol. 13, No. 11, Pages 951-953.


http://ift.tt/2pWeOUL

Pharmacogenetics of drug–drug interaction and drug–drug–gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6

Pharmacogenomics Ahead of Print.


http://ift.tt/2pYF4y1

Should a routine genotyping of CYP2D6 and CYP2C19 genetic polymorphisms be recommended to predict venlafaxine efficacy in depressed patients treated in psychiatric settings?

Pharmacogenomics Ahead of Print.


http://ift.tt/2q0IDl9

Corrigendum

Pharmacogenomics Ahead of Print.


http://ift.tt/2pYC1pM

Combination of Neuroprotective and Regenerative Agents for AGE-Induced Retinal Degeneration: In Vitro Study

To determine the most effective combination of neuroprotective and regenerative agents for cultured retinal neurons from advanced glycation end products- (AGEs-) induced degeneration, retinal explants of 7 adult Sprague-Dawley rats were three-dimensionally cultured in collagen gel and incubated in serum-free media and in 7 media; namely, AGEs, AGEs + 100 μM citicoline, AGEs + 10 ng/mL NT-4, AGEs + 100 μM TUDCA, AGEs + 100 μM citicoline + TUDCA (doublet), and AGEs + 100 μM citicoline + TUDCA + 10 ng/mL NT-4 (triplet) were examined. The number of regenerating neurites was counted after 7 days of culture, followed by performing TUNEL and DAPI staining. The ratio of TUNEL-positive cells to the number of DAPI-stained nuclei was calculated. Immunohistochemical examinations for the active form of caspase-9 and JNK were performed. All of the neuroprotectants increased the number of neurites and decreased the number of TUNEL-positive cells. However, the number of neurites was significantly higher, and the number of TUNEL-positive cells and caspase-9- and JNK-immunopositive cells was fewer in the retinas incubated with the combined three agents. Combination solutions containing citicoline, TUDCA, and NT-4 should be considered for neuroprotective and regenerative therapy for AGE-related retinal degeneration.

http://ift.tt/2qUiJiu

Ceftolozane-tazobactam activity against Pseudomonas aeruginosa clinical isolates from US hospitals: Report from an antimicrobial surveillance program (PACTS, 2012-2015) [PublishAheadOfPrint]

The activity of ceftolozane-tazobactam was compared to the activity of 7 antimicrobials against 3,851 Pseudomonas aeruginosa isolates collected from 32 US hospitals in the Program to Assess Ceftolozane-Tazobactam Susceptibility from 2012-2015. Ceftolozane-tazobactam and comparator susceptibilities were determined using the CLSI broth microdilution method at a central monitoring laboratory. For ceftolozane-tazobactam, 97.0% of the isolates were susceptible. Susceptibilities of the other antibacterials tested were: amikacin, 96.9%; cefepime, 85.9%; ceftazidime, 85.1%; colistin, 99.2%; levofloxacin, 76.6%; meropenem, 81.8%; and piperacillin-tazobactam, 80.4%.

Of the 699 (18.1%) meropenem nonsusceptible P. aeruginosa, 87.6% were susceptible to ceftolozane-tazobactam.

Six hundred and seven isolates (15.8%) were classified as multidrug-resistant (MDR), and 363 (9.4%) were classified as extensively drug resistant. Only 1 isolate was considered pan-drug resistant, which was resistant to all tested agents, including colistin. Of the 607 MDR isolates, 84.9% were ceftolozane-tazobactam susceptible and 76.9% of XDR isolates were ceftolozane-tazobactam susceptible. In vitro activity against drug resistant P. aeruginosa indicates ceftolozane-tazobactam may be an important agent in treating serious bacterial infections.



http://ift.tt/2pW3nMN

In Vitro activity of a novel glucan synthase inhibitor, SCY-078, against clinical isolates of Candida auris [PublishAheadOfPrint]

Candida auris, an emerging fungal pathogen that is associated with high mortality, has been identified in many countries across the world....



http://ift.tt/2ptxmJc

Development of high-grade daptomycin resistance in Corynebacterium striatum while on therapy [PublishAheadOfPrint]

We report of a 62-year-old male with ischemic cardiomyopathy complicated by cardiogenic shock who underwent placement of a left-ventricular assist device (HeartMate II LVAD) in July 2013 as destination therapy....



http://ift.tt/2pW1QpU

The synergistic efficacy of Aedes aegypti antimicrobial peptide cecropin A2 and tetracycline against Pseudomonas aeruginosa [PublishAheadOfPrint]

The increasing prevalence of antibiotic resistance has created an urgent need for alternative drugs with new mechanisms of action. Antimicrobial peptides (AMPs) are promising candidates that could address the spread of multidrug-resistant bacteria, either alone or in combination with conventional antibiotics. We studied the antimicrobial efficacy and bactericidal mechanism of cecropin A2, a 36-residue α-helical cationic peptide derived from Aedes aegypti cecropin A, focusing on the common pathogen Pseudomonas aeruginosa. The peptide showed little hemolytic activity and toxicity towards mammalian cells and the minimum inhibitory concentration (MIC) against most clinical P. aeruginosa isolates was 32–64 μg/ml, and its MICs versus other Gram-negative bacteria was 2–32 μg/ml. Importantly, cecropin A2 demonstrated synergistic activity against P. aeruginosa when combined with tetracycline, reducing the MICs of both agents by eight-fold. The combination was also effective in vivo in the P. aeruginosa/Galleria mellonella model (P < 0.001). We found that cecropin A2 bound to P. aeruginosa lipopolysaccharides, permeabilized the membrane and interacted with the bacterial genomic DNA, thus facilitating the translocation of tetracycline into the cytoplasm. In summary, the combination of cecropin A2 and tetracycline demonstrated synergistic antibacterial activity against P. aeruginosa in vitro and in vivo, offering an alternative approach for the treatment of P. aeruginosa infections.



http://ift.tt/2ptCxJ2

Pharmacokinetics of Efavirenz in 2-3 years old children: a high dose of 25 mg/kg per day [PublishAheadOfPrint]

Background: The MONOD ANRS 12206 trial was designated to assess simplification of a successful LPV-based antiretroviral treatment in young HIV-infected children using efavirenz (25 mg/kg/day) to preserve the protease inhibitors class before the age of 3. In this sub-study, EFV concentrations were measured to check the consistency of a 25 mg/kg EFV dose and to compare it with the 2016 FDA recommended dose.

Methods: Fifty-two children underwent blood sampling for pharmacokinetic study at 6-month and 12-month after switching to EFV. We applied a Bayesian approach to derive EFV pharmacokinetic parameters using the NONMEM nonlinear mixed-effect modeling program. The proportion of mid interval concentrations (C12h) in the EFV therapeutic pharmacokinetic thresholds (1-4 mg/L) was assessed according to different dose regimens (25 mg/kg in the MONOD study versus the 2016 FDA recommended dose).

Results: With both 25 mg/kg/day or 2016 FDA recommended EFV dose, simulations show that the majority of C12h were within the therapeutic ranges (62.6% vs 62.8%). However, there were more children underexposed with the 2016 FDA recommended dose: 11.6% vs. 1.2%. Conversely, there were more concentrations above the threshold of toxicity with a 25 mg/kg dose (36.2% vs. 25.6%) with C12h up to 15 mg/L. Only one child/52 was switched back to LPV because of persistent sleeping disorders, but was within therapeutic ranges.

Conclusions: A high EFV dose of 25 mg/kg per day in children under 3 years old achieved satisfactory therapeutic effective levels. However, the 2016 FDA recommended EFV dose appeared to provide more acceptable therapeutic safe profiles.



http://ift.tt/2pVZp6E

Outcomes with ceftazidime/avibactam in patients with carbapenem-resistant Enterobacteriaceae (CRE) infections: a multi-center study [PublishAheadOfPrint]

Ceftazidime-avibactam is a novel cephalosporin-beta-lactamase inhibitor combination that is active against many carbapenem-resistant Enterobacteriaceae (CRE). We describe a retrospective chart review whereby 60 patients received ceftazidime-avibactam for a CRE infection. In hospital mortality was 32%, 53% of patients had microbiological cure, and 65% had clinical success. In this severely ill population with CRE infections, ceftazidime-avibactam was an appropriate option.



http://ift.tt/2ptCxsw

The Etest performed directly on blood culture bottles is a reliable tool for detection of fluconazole-resistant Candida albicans isolates [PublishAheadOfPrint]

We assessed the ability of the Etest performed directly on positive blood cultures (ETDIR) to detect fluconazole susceptibility in 6 fluconazole-resistant and 12 fluconazole-susceptible Candida albicans isolates according to CLSI M27-A3 and EUCAST Def 7.2. Categorical agreement between ETDIR and broth microdilution was 100% when the trays were incubated at 25°C and trailing effect was ruled out. ETDIR is a reliable procedure when screening for the presence of fluconazole resistance in C. albicans.



http://ift.tt/2pVQqCo

In vitro activity of linezolid against clinically important gram-positive cocci in the United States: A 5-year summary of in vitro activity and resistance mechanisms from the LEADER Surveillance Program (2011--2015) [PublishAheadOfPrint]

This study describes linezolid susceptibility testing results for 6,741 gram-positive pathogens from 60 U.S. sites collected during 2015 for the LEADER Program. In addition, the study summarizes linezolid in vitro activity, resistance mechanisms, and molecular typing obtained for 2011 to 2015. During 2015, linezolid showed potent activity when tested against Staphylococcus aureus, inhibiting >99.9% of 3,031 isolates at ≤2 mg/liter. Similarly, linezolid showed coverage against 99.2% of coagulase-negative staphylococci, 99.7% of enterococci, and for 100.0% of Streptococcus pneumoniae, virdans group, and β-hemolytic streptococci tested. The overall linezolid resistance rate remained a modest <1% from 2011 to 2015. Staphylococci, specially Staphylococcus epidermidis, showed a range of linezolid resistance mechanisms. Increased annual trends for the presence of cfr among Staphylococcus aureus isolates were not observed, but 64.3% (9/14) of the isolates with decreased susceptibility (MIC, ≥4 mg/L) to linezolid carried this transferrable gene (2011—2015). The cfr gene was detected in 21.9% (7/32) of linezolid-resistant staphylococci other than S. aureus from 2011 to 2015. The optrA gene was noted in half (2/4) of linezolid-nonsusceptible Enterococcus faecalis from 2011 to 2015, while linezolid-nonsusceptible Enterococcus faecium showed alterations predominantly (16/16) in the 23S rRNA (G2576T). This report confirms a long record for the linezolid activity against gram-positive isolates in the United States since regulatory approval in 2000 and reposts the oxazolidinones evolving resistance mechanisms.



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Genetic and functional characterization of blaCTX-M-199, a novel tazobactam and sulbactam resistance-encoding gene located in a conjugative mcr-1-bearing IncI2 plasmid [PublishAheadOfPrint]

The study reported the genetic and functional characterization of a novel CTX-M-199 β-lactamase, which was encoded by a blaCTX-M-64 variant gene found in a conjugative mcr-1-bearing IncI2 plasmid and exhibited resistance to β-lactamase inhibitors, tazobactam and sulbactam.



http://ift.tt/2ptkId8

Towards Elimination of Pin-tract Infections: Novel Antibacterial Coating on Orthopaedic Wires [PublishAheadOfPrint]

Novel approaches to prevention of microbial infections after insertion of orthopedic external fixators are in great demand because of extremely high incidence rate of such infections, which can reach up to 100% for longer implant residence times. Monolaurin is an antimicrobial agent with known safety record, broadly used in food and cosmetic industries; however, its use in antimicrobial coatings of medical devices has not been studied in much detail. Here, we report the use of monolaurin as an antibacterial coating on external fixators for the first time. The monolaurin-coated Kirschner wires (K-wires) showed excellent antibacterial properties against three different bacterial strains – methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis. A ca. 6.0-log reduction of both planktonic and adherent bacteria was achieved, when using monolaurin-coated K-wires. At the same time, monolaurin-coated K-wires did not show any observable cytotoxicity with mouse osteoblast cell cultures. Overall, monolaurin-coated K-wires could be promising as potent antimicrobial materials for orthopaedic surgery.



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Comparative Analysis of Extended Spectrum Beta- Lactamase CTX-M-65-Producing Salmonella Infantis Isolates from Humans, Food Animals, and Retail Chickens in the United States [PublishAheadOfPrint]

We sequenced the genomes of ten Salmonella enterica serovar Infantis containing blaCTX-M-65 isolated from chicken, cattle, and human sources collected between 2012 and 2015 in the United States through routine NARMS surveillance and product sampling programs. We also completely assembled the plasmids from four of the isolates. All isolates had a D87Y mutation in the gyrA gene and harbored between 7 and 10 resistance genes (aph (4)-Ia, aac (3)-IVa, aph(3' )-Ic, blaCTX-M-65, fosA3, floR, dfrA14, sul1, tetA, aadA1) located in two distinct sites of a megaplasmid (~316-323kb) similar to that described in a blaCTX-M-65-positive S. Infantis isolated from a patient in Italy. High-quality single nucleotide polymorphism (hqSNP) analysis revealed that all U.S. isolates were closely related, separated by only 1 to 38 pairwise high quality SNPs, indicating a high likelihood that strains from humans, chicken, and cattle recently evolved from a common ancestor. The U.S. isolates were genetically similar to the blaCTX-M-65-positive S. Infantis isolate from Italy, with a separation of 34 to 47 SNPs. This is the first report of the blaCTX-M-65 gene and the pESI-like megaplasmid from S. Infantis in the United States, and illustrates the importance of applying a global One Health, human and animal perspective to combat antimicrobial resistance.



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New aspects of the interplay between penicillin binding proteins, murM and the two component system CiaRH of penicillin-resistant Streptococcus pneumoniae serotype 19A isolates from Hungary [PublishAheadOfPrint]

The Streptococcus pneumoniae clone Hungary19A-6 can expresses unusually high levels of β-lactam resistance which is in part due to mutations in the MurM gene encoding a transferase involved in the synthesis of branched peptidoglycan. Moreover it contains the allele ciaH232 encoding the histidine kinase CiaH (M Müller, P Marx, R Hakenbeck, and R Brückner, Microbiology 157:3104-12, 2011, doi: 10.1099/mic.0.053157-0). High-level penicillin resistance primarily requires the presence of low-affinity (mosaic) PBP genes as, for example, in strain Hu17, a closely related member of the Hungary19A-6 lineage. Interestingly, strain Hu15, is β-lactam sensitive due to the absence of mosaic PBPs. This unique situation prompted us to investigate the development of cefotaxime resistance in transformation experiments with genes known to play a role in this phenotype: pbp2x, pbp1a, murM and ciaH, and the penicillin sensitive recipient strains R6 and Hu15. Characterization of phenotypes, peptidoglycan composition and CiaR-mediated gene expression revealed several novel aspects of penicillin resistance. The murMHu17 gene which is highly similar to murM of Streptococcus mitis induced morphological changes which were partly reversed by ciaH232. MurMHu17 conferred cefotaxime resistance only in the presence of pbp2xHu17. The ciaH232 allele contributed to a remarkable increase in cefotaxime resistance in combination with pbp2xHu17 and pbp1aHu17, accompanied with higher expression levels of CiaR regulated genes, documenting that ciaH232 responds to PBP1aHu17 mediated changes in cell wall synthesis. Most importantly, the proportion of branched over linear muropeptides increased in cells containing mosaic PBPs suggesting an altered enzymatic activity of these proteins.



http://ift.tt/2pVUqTo

Gepotidacin (GSK2140944) In Vitro Activity against Gram-positive and Gram-negative Bacteria (MBC/MIC, Kill Kinetics, Checkerboard, PAE/SME tests) [PublishAheadOfPrint]

Gepotidacin is a first in class, novel triazaacenaphthylene antibiotic that inhibits bacterial DNA replication and has in vitro activity against susceptible and drug-resistant pathogens. Reference in vitro methods were used to investigate the minimum inhibitory (MIC) and minimum bactericidal concentration (MBC) activity of gepotidacin and comparator agents against Staphylococcus aureus Streptococcus pneumoniae and Escherichia coli. Gepotidacin in vitro activity was also evaluated using time-kill kinetics, broth microdilution checkerboard methods for synergy testing, and for postantibiotic and subinhibitory effects. MIC90 values for gepotidacin when tested against 50 S. aureus (including MRSA) and 50 S. pneumoniae (including penicillin-nonsusceptible) isolates were 0.5 μg/mL and for E. coli (n=25) was 4 μg/mL. Gepotidacin was bactericidal when tested against S. aureus, S. pneumoniae, and E. coli with minimum bactericidal concentration/MIC ratios of ≤4 against 98, 98, and 88% of isolates tested, respectively. Time-kill curves indicated that the bactericidal activity for gepotidacin was observed at 4 or 10x MIC concentrations at 24 hours for all isolates. For S. aureus, regrowth was observed in the presence of gepotidacin and the resulting gepotidacin MICs were 2- to 128-fold higher than baseline gepotidacin MICs. Checkerboard analysis of gepotidacin combined with other antimicrobials demonstrated no occurrences of antagonism with agents from multiple antimicrobial classes. The most common interaction when testing gepotidacin was indifference (fractional inhibitory concentration index >0.5-<2; 82.7% for gram-positive isolates and 82.6% for gram-negative isolates). The postantibiotic effect (PAE) for gepotidacin was short when tested against S. aureus (≤0.6 hours against MRSA and MSSA) and the PAE- sub-MIC effect (SME) was extended in length (>8 hours; 3 isolates at 1/2x MIC). The PAE for levofloxacin was modest (0.0-2.4 hours), and the PAE-SME observed varied from 1.2 to >9 hours at 1/2x MIC. These in vitro data indicate that gepotidacin is a bactericidal agent that exhibits a modest PAE and an extended PAE-SME when tested against gram-positive and -negative bacteria and merits further study for potential use in treating infections caused by these pathogens.



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The Tetrazole VT-1161 Is a Potent Inhibitor of Trichophyton rubrum through its Inhibition of T. rubrum CYP51 [PublishAheadOfPrint]

Prior to characterization of antifungal inhibitors that target this enzyme, Trichophyton rubrum CYP51 was expressed in Escherichia coli, purified and characterized. T. rubrum CYP51 bound lanosterol, obtusifoliol and eburicol with similar affinities (Kd values 22.7, 20.3 and 20.9 μM), but displayed substrate specificity insofar as only eburicol was demethylated in CYP51 reconstitution assays (turnover number 1.55 min-1, Km value 2 μM). The investigational agent VT-1161 bound tightly to T. rubrum CYP51 (Kd = 242 nM) with similar affinity as clotrimazole, fluconazole, ketoconazole and voriconazole (Kd values 179, 173, 312, and 304 nM, respectively), and with lower affinity than itraconazole (Kd = 53 nM). IC50 determinations using 0.5 μM CYP51 showed VT-1161 was a tight-binding inhibitor of T. rubrum CYP51 activity yielding an IC50 value of 0.14 μM compared to 0.26, 0.4 and 0.6 μM for itraconazole, fluconazole and ketoconazole, respectively. When tested against 34 clinical isolates, VT-1161 was a potent inhibitor of T. rubrum growth with MIC50, MIC90, and geometric mean MIC values of ≤0.03, 0.06, and 0.033 μg ml-1, respectively. With its selectivity versus human CYP51 and drug metabolizing CYPs having already been established, VT-1161 should prove safe and effective in combating T. rubrum infections in patients.



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Efficacy of Ceftaroline in a Rat Model of Endocarditis Against Methicillin-Susceptible Staphylococcus aureus Exhibiting the Cefazolin High Inoculum Effect [PublishAheadOfPrint]

Certain Staphylococcus aureus strains exhibit an inoculum effect (InE) with cefazolin (CFZ), which has been associated with therapeutic failures in high inoculum infections. We assessed the in vitro activity of ceftaroline (CPT), CFZ and nafcillin (NAF) against 17 type A β-lactamase (βla)-producing, methicillin-susceptible S. aureus (MSSA) strains, including the previously reported TX0117 that exhibits the CFZ InE and its β-lactamase (βla)-cured derivative, TX0117c. Additionally, we determined the pharmacokinetics of CPT in rats after single intramuscular doses of 20 and 40 mg/kg and evaluated the activity of CPT (40 mg/kg, Q 8 h), CFZ and NAF against TX0117 and TX0117c in a rat model of infective endocarditis. No InE was observed for CPT or NAF whereas a marked InE was detected for CFZ (MIC 8 - ≥ 128 μg/ml). CPT and NAF treatment against TX0117 resulted in mean bacterial counts of 2.3 and 2.1 log10 CFU/gm in vegetations, respectively, compared to a mean of 5.9 log10 CFU/gm in the CFZ treated group (CPT and NAF vs CFZ, P = 0.001; CPT vs NAF, P = 0.9830). Both CFZ and CPT were efficacious against βla-cured derivative TX0117c compared to T=0 (P= <0.0001 and 0.0015, respectively). Our data reiterate the in vivo consequences of the CFZ InE and show that CPT is not affected by this phenomenon. CPT might be a consideration for high-inoculum infections caused by MSSA exhibiting the CFZ InE.



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In Vitro Resistance Selection in Shigella flexneri by Azithromycin, Ceftriaxone, Ciprofloxacin, Levofloxacin, and Moxifloxacin [PublishAheadOfPrint]

Shigella flexneri continues to be a major cause of diarrhea-associated illness, and increasing resistance to first-line antimicrobials complicates the treatment of infections caused by this pathogen. We investigated the pharmacodynamics of current antimicrobial treatments for shigellosis to determine the likelihood of resistance promotion with continued global antimicrobial use. The mutant prevention concentration (MPC) and mutant selection window (MSW) were determined for azithromycin, ceftriaxone, ciprofloxacin, levofloxacin, and moxifloxacin against a wild-type strain of S. flexneri (ATCC 12022) and an isogenic gyrA mutant (m-12022). Time-kill assays were performed to determine antimicrobial killing. Concentrations of approved doses of ciprofloxacin, levofloxacin, and moxifloxacin are predicted to surpass the MPC for a majority of the dosage interval against ATCC 12022. However, against m-12022, concentrations of all fluoroquinolones are predicted to fall below the MPC and remain in the MSW for a majority of the dosage interval. Concentrations of ceftriaxone fall within the MSW for the majority of the dosage interval for both strains. All agents other than azithromycin displayed bactericidal activity in time-kill assays. Results of pharmacodynamic analyses suggest that all tested fluoroquinolones achieve a favorable AUC/MPC for ATCC 12022 and will restrict selective enrichment of mutants, but that mutant selection in m-12022 is likely if ciprofloxacin is used. Based on pharmacodynamic analyses, azithromycin and ceftriaxone are predicted to promote mutant selection in both strains. Confirmation of these findings and examination of novel treatment regimens using in vivo studies is warranted.



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Candida parapsilosis sensu lato in pediatric patients. Identification of cryptic species and antifungal susceptibility testing [PublishAheadOfPrint]

A total of 59 C. parapsilosis sensu stricto and 1 C. orthopsilosis recovered from catheters and blood cultures of pediatric patients of the Northeastern region of Argentina were studied. Susceptibility to azoles, amphotericin B, and echinocandins were tested by broth microdilution method. According to CLSI clinical breakpoints, more than 91% of the strains were azole-susceptible while 15% showed high amphotericin B MICs.



http://ift.tt/2ptCCMV

Influence of Experimental Cryptococcal Meningitis in Wistar Rats on Voriconazole Brain Penetration Assessed by Microdialysis [PublishAheadOfPrint]

To advance in the treatment of cryptococcal meningites is crucial to know the drug's free fraction that reaches the biophase. In the present study we applied the microdialysis (μD) as a tool to determine the free levels reached by voriconazole (VRC) in the brain of healthy and Cryptococcus neoformans infected rats. The infection was induced by the i.v. administration of 1⋅105 CFU of yeast. The dose administered was 5 mg/kg i.v. of VRC. Plasma and microdialysate samples were analyzed by LC-MS/MS and LC-UV methods. The free brain/free plasma ratio (fT) and popPK analysis were performed to evaluate the impact of infection on PK parameters of the drug. The brain penetration ratio showed an increase on brain exposure in infected animals (fThealthy = 0.85 vs fTinfected = 1.86). The structural PK model with two compartments and MM eliminating describes the VRC concentration-time profile in plasma and tissue simultaneously. The covariate infection was included in V2 and VM. Comparing the values observed in the tissue of infected and healthy animals, the levels reached in infected tissues were higher than the values described for MIC of VRC against Cryptococccus neoformans (0.03 -0.5 ug.mL-1) indicating its great potential to treat meningitis associated to C. neoformans.



http://ift.tt/2pVYNxU

Ivermectin induced Steven–Johnsons syndrome: case report

Stevens–Johnson syndrome is one of the manifestations of mucocutaneous adverse drug reactions. Although antimicrobials are responsible for greater than 50% of these adverse drug reactions, there is no document...

http://ift.tt/2pY9xw2

Fatal monomorphic ventricular tachycardia in a semi-urban setting in Cameroon: a case report

Ventricular tachycardia is a life threatening cardiac arrhythmia. It needs management with defibrillation, without which, immediate death may occur.

http://ift.tt/2q0aiCX

Estimation of single-year-of-age counts of live births, fetal losses, abortions, and pregnant women for counties of Texas

We provide a methodology for estimating counts of single-year-of-age live-births, fetal-losses, abortions, and pregnant women from aggregated age-group counts. As a case study, we estimate counts for the 254 c...

http://ift.tt/2pYzQSR

Characterizing neoantigens for personalized cancer immunotherapy

Aude-Hélène Capietto | Suchit Jhunjhunwala | Lélia Delamarre

http://ift.tt/2pYtBP7

Epstein-Barr virus-induced VEGF and GM-CSF drive nasopharyngeal carcinoma metastasis via recruitment and activation of macrophages

Chronic inflammation induced by persistent microbial infection plays an essential role in tumor progression. Although it is well documented that Epstein-Barr virus (EBV) infection is closely associated with nasopharyngeal carcinoma (NPC), how EBV-induced inflammation promotes NPC progression remains largely unknown. Here we report that tumor infiltration of tumor associated macrophages (TAM) and expression of CCL18, the cytokine preferentially secreted by TAM, closely correlate with serum EBV infection titers and tumor progression in two cohorts of NPC patients. In vitro, compared to EBV- NPC cell lines, EBV+ NPC cell lines exhibited superior capacity to attract monocytes and skew them to differentiate to a TAM-like phenotype. Cytokine profiling analysis revealed that NPC cells with active EBV replications recruited monocytes by VEGF and induced TAM by GM-CSF in an NFκB-dependent manner. Reciprocally, TAM induced epithelial-mesenchymal transition (EMT) and further NFκB activation of tumor cells by CCL18. In humanized mice, NPC cells with active EBV replications exhibited increased metastasis, and neutralization of CCL18, GM-CSF and VEGF significantly reduced metastasis. Collectively, our work defines a feed-forward loop between tumor cells and macrophages in NPC which shows how metastatic potential can evolve concurrently with virus-induced chronic inflammation.

http://ift.tt/2qjF4cM

Sarcoma eradication by doxorubicin and targeted TNF relies upon CD8+ T cell recognition of a retroviral antigen

Antibody-cytokine complexes may offer new tools to treat cancer. Here we show how TNF-linked antibodies, which recognize tumor-selective splice isoforms of fibronectin (F8-TNF), can be exploited to eradicate sarcomas in immunocompetent mice. We treated mice bearing WEHI-164 fibrosarcoma with a combination of F8-TNF and doxorubicin, curing the majority of treated animals (29/37). Notably, cured mice were resistant to re-challenge not only by WEHI-164 cells but also heterologous C51 or CT26 colorectal tumor cells in a CD8+ T cell-dependent process. Mechanistic analyses revealed that each tumor cell line presented AH1, a common endogenous retroviral peptide. Numbers of AH1-specific CD8+ T cells exhibiting cytotoxic capacity were increased by F8-TNF plus doxorubicin treatment, arguing that cognate CD8+ T cells contributed to tumor eradication. Sequence analysis of T cell receptors of CD8+ T cells revealed the presence of H-2Ld/AH1-specific T cells and an expansion of sequence diversity in treated mice. Overall, our findings provide evidence that retroviral genes contribute to tumoral immune surveillance in a process that can be generally boosted by F8-TNF and doxorubicin treatment.

http://ift.tt/2qUHfR8

TWIST1-WDR5-Hottip regulates Hoxa9 chromatin to facilitate prostate cancer metastasis

TWIST1 is a transcription factor critical for development which can promote prostate cancer metastasis. During embryonic development, TWIST1 and HOXA9 are co-expressed in mouse prostate and then silenced post-natally. Here we report that TWIST1 and HOXA9 co-expression are re-activated in mouse and human primary prostate tumors and are further enriched in human metastases, correlating with survival. TWIST1 formed a complex with WDR5 and the lncRNA Hottip/HOTTIP, members of the MLL/COMPASS-like H3K4 methylases, which regulate chromatin in the Hox/HOX cluster during development. TWIST1 overexpression led to co-enrichment of TWIST1 and WDR5 as well increased H3K4me3 chromatin at the Hoxa9/HOXA9 promoter which was dependent on WDR5. Expression of WDR5 and Hottip/HOTTIP was also required for TWIST1-induced upregulation of HOXA9 and aggressive cellular phenotypes such as invasion and migration. Pharmacological inhibition of HOXA9 prevented TWIST1-induced aggressive prostate cancer cellular phenotypes in vitro and metastasis in vivo. This study demonstrates a novel mechanism by which TWIST1 regulates chromatin and gene expression by cooperating with the COMPASS-like complex to increase H3K4 trimethylation at target gene promoters. Our findings highlight a TWIST1-HOXA9 embryonic prostate developmental program that is reactivated during prostate cancer metastasis and is therapeutically targetable.

http://ift.tt/2qjOhlD