The adaptor protein ARA55 and the nuclear kinase HIPK1 assist c-Myb in recruiting p300 to chromatin

Publication date: Available online 8 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Mads Bengtsen, Linda Sørensen, Linn Aabel, Marit Ledsaak, Vilborg Matre, Odd Stokke Gabrielsen
LIM-domain proteins, containing multiple cysteine-rich zinc finger-like motifs, have been shown to play diverse roles in several cellular processes. A common theme is that they mediate important protein-protein interactions that are key to their function. Androgen receptor-associated protein 55 (ARA55) belongs to this family of bridging proteins containing four C-terminal LIM domains. It has a dual role with functions both at focal adhesions and in the nucleus, apparently shuttling between the two compartments. In the present work, we have expanded our understanding of its nuclear functions by showing that it interacts with three nuclear regulators not previously linked to ARA55. We first identified ARA55 as a novel interaction partner of the nuclear kinase HIPK1 and found that ARA55, like HIPK1, also interacts with the transcription factor c-Myb. In search of a function for these associations, we observed that the coactivator p300 not only binds to c-Myb, but to ARA55 as well. When combined, c-Myb, p300, HIPK1 and ARA55 caused strong synergistic activation of a chromatinized reporter gene. In parallel, all partners, including p300, were efficiently recruited to chromatin at the c-Myb-bound promoter. Consistent with this cooperation, we found that c-Myb and ARA55 share a common set of target genes in an osteosarcoma cellular context. We propose that ARA55 and HIPK1 assist c-Myb in recruiting the coactivator and acetyltransferase p300 to chromatin.



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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

Brazilian Journal of Otorhinolaryngology

Print version ISSN 1808-8694

On-line version ISSN 1808-8686

Braz. j. otorhinolaryngol. vol.83 no.2 São Paulo 

http://dx.doi.org/10.1016/j.bjorl.2017.01.001 

EDITORIAL

Ethics in the twenty first century otolaryngology☆

Charles W. Cummings1 

1Johns Hopkins University, Baltimore, USA. E-mail: ccumming@jhmi.edu

In the United States, the climate of the practice of Medicine is in transition and under siege by policy revisionists and governmental/political opportunists. Regulatory and legislative hubris has enshrouded the medical arena through formulaic dictums and onerous regulations oft times constructed by individuals who have no clinical experience or knowledge. The art of Medicine is being dismantled by emphasis on outcomes based solely on statistical evidence, with no concern for the human variables. Objective analysis is not inherently bad provided the personal and social factors are properly emphasized in the analysis. Freedom to make clinical decisions MUST be preserved for optimal care.

This phenomenon exerts undue pressure on the clinician leading to professional frustration and anemia of job satisfaction. Also, the environment which enables the best of care is further challenged and compromised.

Never the less, we, as physicians, must continue to acknowledge our calling and respond to the gifts of our profession. It seems appropriate to review the commitments that we have made to ourselves and our patients. Over the years, I have created a wish list concerning the way I want to conduct myself to satisfy my professional goals. What follows are those wishes. 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 preserve the art of Medicine. We must steward our wonderful calling.

☆Please cite this article as: Cummings CW. Ethics in the twenty first century otolaryngology. Braz J Otorhinolaryngol. 2017;83:119.2

Conflicts of interest

The author declares no conflicts of interest.

© 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda.

 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

 

Sede da Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico Facial

Av. Indianópolia, 1287

04063-002 São Paulo/SP Brasil

Tel.: (0xx11) 5053-7500

Fax: (0xx11) 5053-7512

revista@aborlccf.org.br

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

6948891480

alsfakia@gmail.com

Magnetic Torque in Single Crystal Ni–Mn–Ga

Abstract

Magnetic shape memory alloys deform in an external magnetic field in two distinct ways: by axial straining—known as magnetic-field-induced strain—and by bending when exposed to torque. Here, we examine the magnetic torque that a magnetic field exerts on a long Ni–Mn–Ga rod. A single crystal specimen of Ni–Mn–Ga was constrained with respect to bending and subjected to an external magnetic field. The torque required to rotate the specimen in the field was measured as a function of the orientation of the sample with the external magnetic field, strain, and the magnitude of the external magnetic field. The torque was analyzed based on the changes in the free energy with the angle between the field and the sample. The contributions of magnetocrystalline anisotropy and shape anisotropy to the Zeeman energy determine the net torque. The torque is large when magneotcrystalline and shape anisotropies act synergistically and small when these anisotropies act antagonistically.

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Modeling the Cyclic Behavior of Shape Memory Alloys

Abstract

The phenomenon of functional fatigue occurs during cyclic loading of pseudoelastic shape memory alloys. We model this effect by considering an irreversible martensitic volume fraction in addition to the reversible amounts of austenite and martensite based on variational principles. The inclusion of irreversible martensitic volume fractions coincides with experimental observations and enables the model to be easily calibrated without any fitting functions. In our previous studies, we modeled the polycrystalline material structure by static discretization of a relatively large number of randomly chosen grain orientations, which required much numerical effort. In contrast, we now apply a dynamic representation of the orientation distribution function to the modeling of functional fatigue which has proven to be beneficial regarding the numerical performance. To this end, we take into account an averaged grain orientation parameterized by three Euler angles that serve as additional internal variables. This results in an extremely reduced numerical effort. The model derivation is given along with the numerical implementation and computer experiments on the cyclic behavior of shape memory alloys.

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Table of Contents

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Editorial Board

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Beginning at the End: Liturgy and the Care of the Dying

<span class="paragraphSection"><div class="boxTitle">Abstract</div>This issue of <span style="font-style:italic;">Christian Bioethics</span> brings together essays that offer theological responses to the final question of <span style="font-style:italic;">The Anticipatory Corpse</span>: “Might it not be that only theology can save medicine?” (<a href="#CIT0002" class="reflinks">Bishop 2011</a>, 313). In this essay, I begin to spell out what I had in mind when I asked that final question. For Christians, the right way to comport oneself to others—the right orientation—grows out of Divine Liturgy. This is theology in the most practical of senses. Liturgy is a set of practices, of rituals, that bring people into right relationship with one another. Liturgy tells us that its participants cannot give an account of their own existence, and it tells us that other human animals are not resources to be controlled, or bodies to be overpowered by technology or by their own wills. Thus, with Evagrius Ponticus, we can say that the theologian is the one who prays. It is primarily those faithful people who, by virtue of their faithfulness, understand how they are to comport themselves to others, because they are oriented to the Divine. It is through these Holy people that theology might save medicine.</span>

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Death and Christianity

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Jeffrey P. Bishop’s The Anticipatory Corpse has challenged the very foundations of medicine by claiming that the dead body is epistemically normative in contemporary medicine. Founding medicine upon the corpse results in a number of uncanny practices commonplace in medicine today. The normative corpse affects everything from ICU care, the care of permanent vegetative state patients, the push for legalized physician-assisted suicide, and brain death procedures to spiritual techniques employed to control the patient’s dying process. Contemporary medicine cannot save itself from creating nihilistic practices for the care of the dying since contemporary medicine is founded upon nihilism. Bishop concludes by asking: “Might it be that only theology can save medicine?” This issue of Christian Bioethics brings together several voices attempting to answer this question. The essays here provide diverse perspectives on how theology might provide a remedy to a philosophically-poisoned medicine. They include reflections on Augustine and Nietzsche, the Psalms and Heidegger, Maximus the Confessor and Watson the Supercomputer. The issue closes with Bishop weaving together wisdom from all four essays in the process of offering his own answer.</span>

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Desecularizing Death

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Dying has shifted over the past several hundred years from a religious to a secular process. This is due, in part, to pivotal moments in the West that affect how we experience death. Fourteenth-century Europe’s paradigm for Christian dying was challenged by the Industrial Revolution, the American Civil War, and the rise of a highly technical biomedicine. This paper argues that it might be possible to “desecularize” death through a renewed emphasis on Christian practices of caring for the dying and through the integration of physicians into conversations with their fellow congregants about the preparation for death.</span>

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Medicine, Machines, and Mourning: The Formation of Physicians and Praying the Psalms

<span class="paragraphSection"><div class="boxTitle">Abstract</div>This paper follows two main arguments. First, using the works of Jeffrey Bishop and Gerald McKenny, is the argument that medicine forms physicians to think of both patients and themselves as machines. Informed by medicine’s epistemological norm, the dead body, life is reduced to a series of mechanisms that resist the stasis of death aided by the efficient control of medicine. The physician is supposedly a neutral and objective scientific machine that harnesses the efficient power of medicine to exert force on the moving matter of the body in an attempt to control or at the very least resist death. The second argument counters the first by arguing for the Christian practice of praying the Psalms. The Psalms resist medicine’s attempted control of death by calling on the God who saves. The language of the Psalms allows medical providers to view themselves and their patients as contingent human beings.</span>

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The Meaning of Death and the Goal of Medicine: An Augustinian and Barthian Reassessment

<span class="paragraphSection"><div class="boxTitle">Abstract</div>This article explores medicine’s goals as they relate to the meaning of death and finitude through the lens of Jeffrey Bishop and Daniel Callahan. It concludes that arguments posed by these authors regarding death and medicine cohere with many rich Christian theological claims about the nature of life and death. Turning to St. Augustine and Karl Barth, one sees that the meaning of death and finitude ties to our theological anthropology as vulnerable creatures in relation to God. Understanding a transcendent meaning to death and life informs the limits to medicine’s institutional goals and practices.</span>

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Asclepius against the Crucified: Medical Nihilism and Incarnational Life in Death

<span class="paragraphSection"><div class="boxTitle">Abstract</div>In <span style="font-style:italic;">The Anticipatory Corpse</span>, Jeffrey Bishop argues that “death is medicine’s transcendental.” In this paper, I further explore this claim to show that modern medicine is nihilistic through (1) Heidegger’s critique of medical technology as Nietzschean ontotheology and (2) Heidegger’s ontology of Death and the Nothing. As a response to this double nihilism of medicine, I suggest that Maximus the Confessor’s metaphysics of the Incarnation reveals that creation from nothing gives way to fullness of life and that life is revealed in the death of Christ.</span>

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No Smoke Without Fire: Harm Reduction, E-Cigarettes and the Smoking Endgame

<span class="paragraphSection">Much public health research seeks to identify harm and then use that knowledge as the basis for preventive action through advice, policy and practice. Where harms cannot be removed, the focus may change to reducing them. What are the ethical issues that arise in harm reduction? The UK’s Royal College of Physicians’ (<a href="#phx003-B10" class="reflinks">RCP, 2016</a>) recent publication on electronic cigarettes (e-cigarettes) provides an excellent prompt to discussing this issue.</span>

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Commentary to ‘Social Health Disparities in Clinical Care: A New Approach to Medical Fairness’ by Puschel, Furlan and Dekkers

<span class="paragraphSection">The commentary brings up two topics. The first concerns whether and how a patient’s socioeconomic status (SES) should count in clinical care. We provide a brief summary of Puschel and colleagues’ view and discuss it in relation to other accounts. We share their conclusion; considering SES in clinical care can be justified from a fairness perspective. Yet, we question the claim that this is a new perspective, and argue that the reason for the claim of novelty is an insufficient use of references. This leads to the second topic, which is a discussion of citation practices in philosophical/ethics papers. We describe common deviations from academic standards, and suggest how unfortunate practices can be reduced.</span>

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Research Ethics Governance in Times of Ebola

<span class="paragraphSection">The Médecins Sans Frontières (MSF) ethics review board (ERB) has been solicited in an unprecedented way to provide advice and review research protocols in an ‘emergency’ mode during the recent Ebola epidemic. Twenty-seven Ebola-related study protocols were reviewed between March 2014 and August 2015, ranging from epidemiological research, to behavioural research, infectivity studies and clinical trials with investigational products at (very) early development stages. This article examines the MSF ERB’s experience addressing issues related to both the process of review and substantive ethical issues in this context. These topics include lack of policies regarding blood sample collection and use, and engaging communities regarding their storage and future use; exclusion of pregnant women from clinical and vaccine trials; and the difficulty of implementing timely and high-quality qualitative/anthropological research to consider potential upfront harms. Having noticed different standards across ethics committees (ECs), we propose that when multiple ethics reviews of clinical and vaccine trials are carried out during a public health emergency they should be accompanied by transparent communication between the ECs involved. The MSF ERB experience should trigger a broader discussion on the ‘optimal’ ethics review in an emergency outbreak and what enduring structural changes are needed to improve the ethics review process.</span>

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Power of Attorney for Research: The Need for a Clear Legal Mechanism

<span class="paragraphSection">A recent article in this journal described practical and conceptual difficulties faced by public health researchers studying scabies outbreaks in British residential care facilities (<a href="#phw035-B8" class="reflinks">Head <span style="font-style:italic;">et al.</span>, 2015</a>). Their study population was elderly, decisionally incapacitated residents, many of whom lacked a legally appropriate decision-maker for healthcare decisions. The researchers reported difficulties securing Research Ethics Committee approval. As practicing healthcare ethicists working in a large Canadian research hospital, we are familiar with this challenge and welcomed the authors’ invitation to join the discussion of the ‘outstanding ambiguities and further questions’ (<a href="#phw035-B8" class="reflinks">Head <span style="font-style:italic;">et al.</span>, 2015</a>: 5) that their experience uncovered. We propose a Power of Attorney for Research as one substantive solution to help address the problems they identified. Although we acknowledge the familiar shortcomings associated with Advance Directives in the clinical context, we believe that Powers of Attorney for Research Participation, accompanied by Advance Research Directives, may increase the likelihood of gaining deeper understandings of potential participant’s values and priorities and how they might apply to foreseeable research opportunities.</span>

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Omnipresent Health Checks May Result in Over-responsibilization

<span class="paragraphSection">Health checks identify (risk factors for) disease in individuals without a medical indication. More and more checks are offered by more providers on more risk factors and diseases, so we may speak of an omnipresence of health checks. Current ethical evaluation of health checks considers checks on an individual basis only. However, omnipresent checks have effects over and above the effects of individual health checks. They might give the impression that health is entirely manageable by individual actions and strengthen the norm of individual responsibility for health to the point where people hold themselves and others responsible for health outcomes they cannot reasonably be held accountable for. This process of so-called ‘over-responsibilization’ may result in increased feelings of guilt over health, decreased health solidarity and unfairly distributed health outcomes. Moreover, effects on privacy and peace of mind may be observed. Taking into account all possible harms and benefits of health checks in their ethical evaluation requires evaluation of health checks on an individual basis as well as on the level of all checks. Therefore, we urge the amendment of existing ethical evaluation to include the effects of an omnipresence of health checks. We make a first attempt at the formulation of amended criteria.</span>

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Contested Guideline Development in Australia’s Cervical Screening Program: Values Drive Different Views of the Purpose and Implementation of Organized Screening

<span class="paragraphSection">This article draws on an empirical investigation of how Australia’s cervical screening program came to be the way it is. The study was carried out using grounded theory methodology and primarily uses interviews with experts involved in establishing, updating or administering the program. We found strong differences in experts’ normative evaluations of the program and beliefs about optimal ways of achieving the same basic outcome: a reduction in morbidity and mortality caused by invasive cervical cancer. Our analysis demonstrates how variations in values and preferences associated with key concepts underpinning public health such as benefit, harm and burden led to different perspectives on the purpose of an organized cervical screening program. These variations were largely driven by different bases of professional experience. Differently conceived purposes in turn led to conflict over how the program should be operationalized. Following Frith’s model of empirical bioethics, the results of the study both draw on and inform the existing public health and screening ethics literature.</span>

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Is Anticipated Consent an Acceptable Model for a Unique Cohort of Research Participants? Commentary on Case Study of Scabies in Nursing Homes

<span class="paragraphSection">Scabies is a global problem and is of such concern that in 2013 it was added to the World Health Organization list of neglected tropical diseases.1¹ Due to its highly contagious nature, it is easily spread where humans are in close living environments, and is therefore of particular concern in nursing homes where it may affect both residents and staff. Hence, prompt diagnosis and appropriate treatment of cases are important to control the spread; however, this is hindered by current difficulties in rapid diagnosis. Conducting research with vulnerable populations involves careful attention to the interest of the individual. It is indisputable that all potential research subjects must have provided consent to participate in research, and it is less clear how to proceed when potential research subjects lack the capacity to provide consent.</span>

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Ending SNAP-Subsidized Purchases of Sugar-Sweetened Beverages: The Need for a Pilot Project

<span class="paragraphSection">Recent efforts by legislative officials and public health advocates to reform the US food stamp program, or Supplemental Nutrition Assistance Program (SNAP), have focused on restricting the types of foods eligible for purchase with SNAP benefits, specifically sugar-sweetened beverages (SSBs). We argue that it is, in principle, permissible for the US government to enact a SNAP-specific SSB ban prohibiting the purchase of SSBs with SNAP benefits. While the government has a duty to ensure that citizens meet their nutritional needs, since SSBs provide negligible nutrition, it has no obligation to subsidize them. Additionally, there is good reason to think that a SNAP-specific SSB ban would enable the government to better fulfill two other duties—improving citizens’ health and providing public services like Medicaid and Medicare in a more cost-effective manner. Still, because the costs and benefits of such a ban remain uncertain, we argue that the government should conduct well-designed pilot projects to help determine the effects of an SSB ban.</span>

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The Moral Life of Professionals in Newborn Screening in the Netherlands: A Qualitative Study

<span class="paragraphSection">Newborn screening (NBS) involves a complex logistical process, which depends on the close cooperation of many professionals, such as midwives, laboratory technicians, general practitioners and pediatricians. These professionals may encounter moral problems in the process, which have not been systematically studied before. This study fills this gap. We conducted interviews with 36 professionals involved in NBS in the Netherlands and made an inventory of the moral problems they encounter, as well as of the ways in which they tend to respond to them. The moral problems professionals encounter stem from interpersonal conflicts (when a professional’s values conflict with those of a colleague or the NBS protocol) and intrapersonal conflicts (when one professional fulfills different roles with conflicting moral commitments, or when a person’s professional role and personal moral intuitions clash). Given the complexity of the work of NBS professionals, the study suggests that the moral problems that occur on the work floor cannot easily be solved by means of offering better or more stringent policy guidelines. Rather, it should be appreciated that professionals contribute significantly to shaping the morality of NBS with the help of their daily choices, and they should be supported in carrying out this task—for example with the help of a moral training or regular multidisciplinary moral deliberation, facilitated by an ethicist.</span>

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Social Health Disparities in Clinical Care: A New Approach to Medical Fairness

<span class="paragraphSection">Social health disparities are increasing in most countries around the world. During the past two decades, a large amount of evidence has emerged about the health consequences of social inequalities. Despite such evidence, the concept of medical fairness, as traditionally defined by the World Medical Association, has remained unchallenged and even reinforced by some scholars who emphasize that doctors should remain neutral to the socioeconomic status of their patients when providing clinical care. The inconsistency between public health and clinical care perspectives raises tension between a narrow interpretation of the ethics of justice, which stresses the importance of equality and impartiality, and the ethics of care, which highlights the importance of particularity and individuality in clinical practice. This article analyzes the concept of medical fairness using the emerging evidence that demonstrates the impact of social health disparities on clinical care. It proposes a new approach of medical fairness based on equity rather than on equality and provides a consistent ethical framework based on Paul Ricoeur’s three levels of medical judgments. This integrative framework provides a better balance between public health and clinical care in medical practice.</span>

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Table of Contents

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Shifting the Focus While Conserving Commitments in Research Ethics

<span class="paragraphSection"><div class="boxTitle">Abstract</div>The papers in this volume are largely about research ethics and cover questions of consent, reproduction, pediatric research, ethical codes, and clinical relationships. Half the papers have this common aspect: they are conservative—in the sense of supporting the standard, prevailing, or popular view—but they shift the focus—supporting the standard views in terms of moral factors generally neglected by the literature. The volume provides a diverse set of papers for the reader: variously addressing abstract and concrete problems from within different philosophical traditions.</span>

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The Ethical Principles of the Portuguese Psychologists: A Universal Dimension

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Ethical principles are fundamental for the exercise of any profession. Portuguese psychologists have waited for 30 years for professional validation. This paper will define the Portuguese psychologists’ ethical principles, with a universal view as a starting point and then an adaptation to the cultural and professional reality in Portugal. The level of acceptability of these principles will be ascertained in a later paper.</span>

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Why is Coerced Consent Worse Than No Consent and Deceived Consent?

<span class="paragraphSection"><div class="boxTitle">Abstract</div>The Standard View in research ethics maintains that, under certain conditions, investigators may deceive subjects and may enroll subjects without their consent. In contrast, it is always impermissible to coerce subjects to enroll, even when the same conditions are satisfied. This view raises a question that, as far as we are aware, has received no attention in the literature. Why is it always impermissible to undermine the validity of subjects’ consent through coercion, but it can be permissible to undermine the validity of subjects’ consent through deception, and it can be permissible to enroll subjects without any consent at all? The present analysis suggests that the answer traces to the conditions on the appropriate treatment of subjects. This conclusion suggests that some requirements for human subjects research, and for valid consent more generally, trace not to the protection of subjects per se but to the proper behavior of agents.</span>

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What Does the Patient Say? Levinas and Medical Ethics

<span class="paragraphSection"><div class="boxTitle">Abstract</div>The patient–physician relationship is of primary importance for medical ethics, but it also teaches broader lessons about ethics generally. This is particularly true for the philosopher Emmanuel Levinas whose ethics is grounded in the other who “faces” the subject and whose suffering provokes responsibility. Given the pragmatic, situational character of Levinasian ethics, the “face of the other” may be elucidated by an analogy with the “face of the patient.” To do so, I draw on examples from Martin Winckler’s fictional physician narratives. In addition, I explore how the standpoint of the physician conceals a related but often unacknowledged dimension of care: the obligation to nurse. For both nurse and physician, one question encapsulates Levinas’ medical ethics: “What does the patient say?” Using this as my guiding question, I examine the context within which physician, nurse, and patient meet in order to highlight their shared vulnerability and the care relationship that binds them together.</span>

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Defining the Boundaries of a Right to Adequate Protection: A New Lens on Pediatric Research Ethics

<span class="paragraphSection"><div class="boxTitle">Abstract</div>We argue that the current ethical and regulatory framework for permissible risk levels in pediatric research can be helpfully understood in terms of children’s moral right to adequate protection from harm. Our analysis provides a rationale for what we propose as the highest level of permissible risk in pediatric research without the prospect of direct benefit: what we call “relatively minor” risk. We clarify the justification behind the usual standards of “minimal risk” and “a minor increase over minimal risk” and explain why it is permissible to impose any risks at all on child participants who do not stand to benefit directly from enrollment in research. Finally, we illuminate some aspects of the concept of “best interests.”</span>

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Defining Research Risk in Standard of Care Trials: Lessons from SUPPORT

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Recent controversy surrounding the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) and the Office for Human Resource Protection’s (OHRP) judgment that its informed consent procedures were inadequate has unmasked considerable confusion about OHRP’s definition of research risks. The controversy concerns application of that definition to trials comparing multiple treatments within the existing standard of care. Some have argued that it is impossible for such trials to pose research risks on the grounds that all risks associated with a standard-of-care treatment should instead be considered risks of treatment. However, analysis of OHRP’s definition demonstrates that some risks in such trials can be research risks.</span>

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Harms to “Others” and the Selection Against Disability View

<span class="paragraphSection"><div class="boxTitle">Abstract</div>In recent years, the question of whether prospective parents might have a moral obligation to select against disability in their offspring has piqued the attention of many prominent philosophers and bioethicists, and a large literature has emerged surrounding this question. Rather than looking to the most common arguments given in support of a positive response to the abovementioned question, such as those focusing on the harms disability may impose on the child created, duties and role-specific obligations, and impersonal ‘harms’, a less commonly made set of arguments is focused upon which looks to the harms that a decision not to select against disability may impose on others. Three different possible arguments supporting a limited duty of disability avoidance are thus identified and subsequently explored: harms to parents themselves, harms to existing family members, and harms to other existing members of society.</span>

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Fusobacterium nucleatum subspecies animalis influences pro-inflammatory cytokine expression and monocyte activation in human colorectal tumors

Chronic infection and associated inflammation have long been suspected to promote human<br />carcinogenesis. Recently, certain gut bacteria, including some in the Fusobacterium genus, have been implicated in playing a role in human colorectal cancer (CRC) development. However, the Fusobacterium species and subspecies involved and their oncogenic mechanisms remain to be determined. We sought to identify the specific Fusobacterium spp. and ssp. in clinical CRC specimens by targeted sequencing of Fusobacterium 16S ribosomal RNA gene. Five<br />Fusobacterium spp. were identified in clinical CRC specimens. Additional analyses confirmed<br />that Fusobacterium nucleatum ssp. animalis was the most prevalent F. nucleatum subspecies in human CRCs. We also assessed inflammatory cytokines in CRC specimens using immunoassays and found that expression of the cytokines interleukin-17A and tumor necrosis factor-alpha was markedly increased but interleukin-21 decreased in the colorectal tumors. Furthermore, the chemokine (C-C motif) ligand 20 was differentially expressed in colorectal tumors at all stages.<br /><br />In in vitro co-culture assays, F. nucleatum ssp. animalis induced CCL20 protein expression in<br />CRC cells and monocytes. It also stimulated the monocyte/macrophage activation and migration.<br /><br />Our observations suggested that infection with F. nucleatum ssp. animalis in colorectal tissue<br />could induce inflammatory response and promote CRC development. Further studies are<br />warranted to determine if F. nucleatum ssp. animalis could be a novel target for CRC prevention and treatment.

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Concurrent activation of β2-adrenergic receptor and blockage of GPR55 disrupts pro-oncogenic signaling in glioma cells

Publication date: Available online 8 May 2017
Source:Cellular Signalling
Author(s): Artur Wnorowski, Justyna Such, Rajib K. Paul, Robert P. Wersto, Fred E. Indig, Krzysztof Jozwiak, Michel Bernier, Irving W. Wainer
Activation of β2-adrenergic receptor (β2AR) and deorphanized GPR55 has been shown to modulate cancer growth in diverse tumor types in vitro and in xenograft models in vivo. (R,R′)-4′-methoxy-1-naphthylfenoterol [(R,R′)-MNF] is a bivalent compound that agonizes β2AR but inhibits GPR55-mediated pro-oncogenic responses. Here, we investigated the molecular mechanisms underlying the anti-tumorigenic effects of concurrent β2AR activation and GPR55 blockade in C6 glioma cells using (R,R′)-MNF as a marker ligand. Our data show that (R,R′)-MNF elicited G1-phase cell cycle arrest and apoptosis, reduced serum-inducible cell motility, promoted the phosphorylation of PKA target proteins, and inhibited constitutive activation of ERK and AKT in the low nanomolar range, whereas high nanomolar levels of (R,R′)-MNF were required to block GPR55-mediated cell motility. siRNA knockdown and pharmacological inhibition of β2AR activity were accompanied by significant upregulation of AKT and ERK phosphorylation, and selective alteration in (R,R′)-MNF responsiveness. The effects of agonist stimulation of GPR55 on various readouts, including cell motility assays, were suppressed by (R,R′)-MNF. Lastly, a significant increase in phosphorylation-mediated inactivation of β-catenin occurred with (R,R′)-MNF, and we provided new evidence of (R,R′)-MNF-mediated inhibition of oncogenic β-catenin signaling in a C6 xenograft tumor model. Thus, simultaneous activation of β2AR and blockade of GPR55 may represent a novel therapeutic approach to combat the progression of glioblastoma cancer.

Graphical abstract

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The HLA-DR mediated signalling increases the migration and invasion of melanoma cells, the expression and lipid raft recruitment of adhesion receptors, PD-L1 and signal transduction proteins

Publication date: Available online 8 May 2017
Source:Cellular Signalling
Author(s): Francesca Costantini, Giovanna Barbieri
The constitutive expression of Major Histocompatibility Complex (MHC) class II molecules is restricted to professional Antigen-Presenting Cells (APCs), nevertheless almost 50% of melanomas express constitutively the MHC class II molecules. Therefore, in two MHC class II constitutive expressing melanoma cell lines we studied the signalling mediated by the HLA-DR molecules in the aim to understand the consequence of class II mediated signalling on metastatic dissemination of melanoma. In particular, we reported that the HLA-DR mediated signalling play a new role in melanoma progression, increasing the migration and invasion of melanoma cells. Furthermore, we showed that the HLA-DR mediated signalling increases the expression and the lipid raft localisation of class II molecules, PD-L1 receptor, Integrin and CAM adhesion receptors, FAK, AKT and STAT3 signalling proteins. We also showed that the HLA-DR mediated signalling increases the activation of FAK, AKT, ERK, PKC and STAT3 signalling proteins and the expression of ILK, PAX, BRAF, ERK and PKC. Indeed, the results showed suggest that the HLA-DR mediated signalling provides a platform useful to frustrate an effective anti-tumour response and to increase melanoma migration and metastatic dissemination of this cancer.



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Photophysical properties, singlet oxygen generation efficiency and cytotoxic effects of aloe emodin as a blue light photosensitizer for photodynamic therapy in dermatological treatment

Photochem. Photobiol. Sci., 2017, Accepted Manuscript
DOI: 10.1039/C6PP00453A, Paper

Lixin Zang, Huimin Zhao, Xueyu Ji, Wenwu Cao, Zhiguo Zhang, Peisong Meng
Conventional photodynamic therapy (PDT) uses red light for deeper penetration. A natural compound, aloe emodin (AE) with anticancer and photosensitising capabilities, excited by blue light, is proposed to treat superficial...
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Successful Treatment of Allergic Bronchopulmonary Aspergillosis With Isavuconazole: Case Report and Review of the Literature

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Isavuconazole is a new triazole that is approved for primary therapy of invasive aspergillosis. We provide the first report of a patient with allergic bronchopulmonary aspergillosis (ABPA) who was successfully treated with isavuconazole with marked improvement and minimal adverse effects. We further review the literature on antifungal management of ABPA.</span>

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Predictors of Dengue-Related Mortality and Disease Severity in a Tertiary Care Center in North India

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>There is lack of reliable predictors of disease severity and mortality in dengue. The present study was carried out to identify these predictors during the 2015 outbreak in India.<div class="boxTitle">Methods.</div>This prospective observational study included confirmed adult dengue patients hospitalized between August and November 2015 in a tertiary care centre in New Delhi, India. Appropriate statistical tests were used to compare clinicolaboratory characteristics, derive predictors of severe disease and mortality, and compute a predictive score for mortality. Serotyping was done.<div class="boxTitle">Results.</div>Data of 369 patients were analyzed (mean age, 30.9 years; 67% males). Of these, 198 (54%) patients had dengue fever, 125 (34%) had dengue hemorrhagic fever (grade 1 or 2), and 46 (12%) developed dengue shock syndrome (DSS). Twenty-two (6%) patients died. Late presentation to the hospital (≥5 days after onset) and dyspnea at rest were identified as independent predictors of severe disease. Age ≥24 years, dyspnea at rest and altered sensorium were identified as independent predictors of mortality. A clinical risk score was developed (12*age + 14*sensorium + 10*dyspnea), which, if ≥22, predicted mortality with a high sensitivity (81.8%) and specificity (79.2%). The predominant serotypes in Delhi (2015) were dengue virus DENV2 and DENV4.<div class="boxTitle">Conclusion.</div>Age ≥24 years, dyspnea at rest, and altered sensorium were identified as independent predictors of mortality. Platelet counts did not determine outcome in dengue patients. Timely referral/access to healthcare is important. The clinical risk score for mortality prediction that was developed in this study can be used in all healthcare settings, after validation in larger cohorts.</span>

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Ovarian Endometrioma Superinfected With Salmonella : Case Report and Review of the Literature

<span class="paragraphSection"><div class="boxTitle">Abstract</div>We present the case of a 28-year-old woman with <span style="font-style:italic;">Salmonella</span> serovar Schwarzengrund gastroenteritis acquired during foreign travel. Her case was complicated by superinfection of a pre-existing ovarian endometrioma with a quinolone-resistant organism; the resultant ovarian abscess ultimately required surgical removal for resolution. We review the key features of this case and the previous literature on <span style="font-style:italic;">Salmonella</span> ovarian abscess. This report highlights (1) the potential for metastatic spread of <span style="font-style:italic;">Salmonella</span> to the ovary in women with pre-existing cysts or endometriomas and (2) the increasing worldwide burden of quinolone-resistant <span style="font-style:italic;">Salmonella</span>.</span>

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Zinc Acetate Lozenges May Improve the Recovery Rate of Common Cold Patients: An Individual Patient Data Meta-Analysis

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>A previous meta-analysis of 3 zinc acetate lozenge trials estimated that colds were on average 40% shorter for the zinc groups. However, the duration of colds is a time outcome, and survival analysis may be a more informative approach. The objective of this individual patient data (IPD) meta-analysis was to estimate the effect of zinc acetate lozenges on the rate of recovery from colds.<div class="boxTitle">Methods.</div>We analyzed IPD for 3 randomized placebo-controlled trials in which 80–92 mg/day of elemental zinc were administered as zinc acetate lozenges to 199 common cold patients. We used mixed-effects Cox regression to estimate the effect of zinc.<div class="boxTitle">Results.</div>Patients administered zinc lozenges recovered faster by rate ratio 3.1 (95% confidence interval, 2.1–4.7). The effect was not modified by age, sex, race, allergy, smoking, or baseline common cold severity. On the 5th day, 70% of the zinc patients had recovered compared with 27% of the placebo patients. Accordingly, 2.6 times more patients were cured in the zinc group. The difference also corresponds to the number needed to treat of 2.3 on the 5th day. None of the studies observed serious adverse effects of zinc.<div class="boxTitle">Conclusions.</div>The 3-fold increase in the rate of recovery from the common cold is a clinically important effect. The optimal formulation of zinc lozenges and an ideal frequency of their administration should be examined. Given the evidence of efficacy, common cold patients may be instructed to try zinc acetate lozenges within 24 hours of onset of symptoms.</span>

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A Report of Adult Human Adenovirus Infections in a Tertiary Hospital

<span class="paragraphSection"><div class="boxTitle">Abstract</div>We describe a review of human adenovirus (HAdV) infections occurring among adults in a tertiary hospital in Singapore from February to May 2013. A similar increase in cases was observed among children and military personnel during the same time period. The majority of isolates were identified as HAdV-7, likely an emerging pathogen in Asia.</span>

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Infections in Hematopoietic Cell Transplant Recipients: Results From the Organ Transplant Infection Project, a Multicenter, Prospective, Cohort Study

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Infection is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Our object was to better define the epidemiology and outcomes of infections after HCT.<div class="boxTitle">Methods.</div>This was a prospective, multicenter cohort study of HCT recipients and conducted from 2006 to 2011. The study included 4 US transplant centers and 444 HCT recipients. Data were prospectively collected for up to 30 months after HCT using a standardized data collection tool.<div class="boxTitle">Results.</div>The median age was 53 years, and median follow up was 413 (range, 5–980) days. The most common reason for HCT was hematologic malignancy (87%). The overall crude mortality was 52%. Death was due to underlying disease in 44% cases and infection in 21%. Bacteremia occurred in 231 (52%) cases and occurred early posttransplant (median day 48). Gram-negative bloodstream infections were less frequent than Gram-positive, but it was associated with higher mortality (45% vs 13%, <span style="font-style:italic;">P</span> = .02). <span style="font-style:italic;">Clostridium difficile</span> infection developed in 148 patients (33%) at a median of 27 days post-HCT. There were 53 invasive fungal infections (IFIs) among 48 patients (11%). The median time to IFI was 142 days. Of 155 patients with cytomegalovirus (CMV) infection, 4% had CMV organ involvement. Varicella zoster infection (VZV) occurred in 13 (4%) cases and was disseminated in 2. Infection with respiratory viruses was seen in 49 patients. <span style="font-style:italic;">Pneumocystis jirovecii</span> pneumonia was rare (1%), and there were no documented cases of nocardiosis, toxoplasmosis, endemic mycoses, or mycobacterial infection. This study lacked standardized antifungal and antiviral prophylactic strategies.<div class="boxTitle">Conclusions.</div>Infection remains a significant cause of morbidity and mortality after HCT. Bacteremias and <span style="font-style:italic;">C difficile</span> infection are frequent, particularly in the early posttransplant period. The rate of IFI is approximately 10%. Organ involvement with CMV is infrequent, as are serious infections with VZV and herpes simplex virus, likely reflecting improved prevention strategies.</span>

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Fecal Microbiota Transfer for Multidrug-Resistant Gram-Negatives: A Clinical Success Combined With Microbiological Failure

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Combined fecal microbiota transfer and antibiotic treatment prevented recurrences of urinary tract infections with multidrug-resistant (MDR) <span style="font-style:italic;">Pseudomonas aeruginosa</span>, but it failed to eradicate intestinal colonization with MDR <span style="font-style:italic;">Escherichia coli</span>. Based on microbiota analysis, failure was not associated with distinct diminished microbiota diversity.</span>

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Clinical Impact of Nucleic Acid Amplification Testing in the Diagnosis of Mycobacterium Tuberculosis : A 10-Year Longitudinal Study

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Nucleic acid amplification (NAA) testing for <span style="font-style:italic;">Mycobacterium tuberculosis</span> (MTB) offers improved diagnostic accuracy, compared with smear microscopy, in differentiating MTB from other mycobacteria. We aimed to evaluate the reliability and projected impact of NAA testing in patients with acid-fast bacilli (AFB) smear-positive respiratory samples.<div class="boxTitle">Methods.</div>We identified a retrospective cohort of all patients with AFB smear-positive respiratory specimens at Henry Ford Hospital from January 1, 2001 through December 31, 2011. We examined the association between patients’ sociodemographic factors and clinical comorbidities with the likelihood of being diagnosed with MTB. We evaluated the projected change in duration of airborne isolation and unnecessary MTB treatment with introducing NAA testing into clinical decision making for AFB smear-positive patients.<div class="boxTitle">Results.</div>One hundred thirty patients had AFB smear-positive respiratory specimens, 80 of these patients had a positive NAA test result, and 82 patients grew MTB on culture. Nucleic acid amplification testing had a sensitivity and specificity of 97.6% and 100%, respectively. Integrating NAA testing into clinical decision making for patients with AFB-positive smears was associated with a significantly shorter time in airborne isolation (6.0 ± 7.6 vs 23.1 ± 38.0, <span style="font-style:italic;">P</span> < .001) and 9.5 ± 11.32 fewer days of unnecessary MTB treatment in patients with negative NAA test.<div class="boxTitle">Conclusions.</div>Nucleic acid amplification testing provided a rapid and accurate test in the diagnosis of MTB while significantly reducing the duration of isolation and unnecessary medications in patients with negative NAA test.</span>

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Microbiological Etiology and Treatment of Complicated Skin and Skin Structure Infections in Diabetic and Nondiabetic Patients in a Population-Based Study

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Diabetes is a major risk factor for skin and skin structure infection (SSSI), and the global burden of diabetics with SSSI is enormous. The more complex microbiology of diabetic foot infection (DFI) is well established, but it is not known whether microbiological etiology differs between diabetics and nondiabetics in other disease entities under the umbrella of complicated SSSI (cSSSI).<div class="boxTitle">Methods.</div>This retrospective, population-based study included patients with cSSSI, and it was conducted in 2 Nordic cities with a low prevalence of antimicrobial resistance. In analyses, patients (<span style="font-style:italic;">N</span> = 460) were separated into 3 groups: diabetics (<span style="font-style:italic;">n</span> = 119), nondiabetics (<span style="font-style:italic;">n</span> = 271), and patients with DFI (<span style="font-style:italic;">n</span> = 70).<div class="boxTitle">Results.</div>After exclusion of patients with DFI, there was no difference in the microbiological etiology or initial antimicrobial treatment of cSSSI between diabetics and nondiabetics. Gram-positive bacteria encountered 70% of isolations in diabetics and 69% in nondiabetics, and the empirical treatment covered initial pathogens in 81% and 86% of patients, respectively. However, diabetes was the only background characteristic in the propensity score-adjusted analysis associated with broad-spectrum antimicrobial use and longer antibiotic treatment duration. Patients with DFI had Gram-negative and polymicrobial infection more often than nondiabetics.<div class="boxTitle">Conclusions.</div>These observations suggest that diabetics without DFI are not different in the causative agents of cSSSI, although they are more exposed to antimicrobial therapy of inappropriate extended spectrum and long duration. Broad-spectrum coverage was clearly needed only in DFI. A clear opportunity for antimicrobial stewardship was detected in the rapidly growing population of diabetic patients with cSSSI.</span>

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Use of Carbapenems, Polymyxins, and Tigecycline in United States Children’s Hospitals, 2010–2014

<span class="paragraphSection"><div class="boxTitle">Abstract</div>We characterized use of the carbapenems, polymyxins, and tigecycline in United States children’s hospitals between 2010 and 2014. We found substantial variability in use across hospitals and overall decreased use over time. Most polymyxin and tigecycline use occurred in cystic fibrosis patients, and appendectomy was a common indication for carbapenem therapy.</span>

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Rapid Emergence of a New Clone Impacts the Population at Risk and Increases the Incidence of Type emm89 Group A Streptococcus Invasive Disease

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Invasive group A <span style="font-style:italic;">Streptococcus</span> (iGAS) disease caused by type <span style="font-style:italic;">emm89</span> strains has been increasing worldwide, driven by the emergence of an epidemic clonal variant (clade 3 <span style="font-style:italic;">emm89</span>). The clinical characteristics of patients with <span style="font-style:italic;">emm89</span> iGAS disease, and in particular with clade 3 <span style="font-style:italic;">emm89</span> iGAS disease, are poorly described.<div class="boxTitle">Methods.</div>We used population-based iGAS surveillance data collected in metropolitan Toronto, Ontario, Canada during the period 2000–2014. We sequenced the genomes of 105 <span style="font-style:italic;">emm89</span> isolates representing all <span style="font-style:italic;">emm89</span> iGAS disease cases in the area during the period and 138 temporally matched <span style="font-style:italic;">emm89</span> iGAS isolates collected elsewhere in Ontario.<div class="boxTitle">Results.</div>Clades 1 and 2 and clade O, a newly discovered <span style="font-style:italic;">emm89</span> genetic variant, caused most cases of <span style="font-style:italic;">emm89</span> iGAS disease in metropolitan Toronto before 2008. After rapid emergence of new clade 3, previously circulating clades were purged from the population and the incidence of <span style="font-style:italic;">emm89</span> iGAS disease significantly increased from 0.14 per 100000 in 2000–2007 to 0.22 per 100000 in 2008–2014. Overall, <span style="font-style:italic;">emm89</span> organisms caused significantly more arthritis but less necrotizing fasciitis than strains of the more common type <span style="font-style:italic;">emm1</span>. Other clinical presentations were soft tissue and severe respiratory tract infections. Clinical outcomes did not differ significantly between <span style="font-style:italic;">emm89</span> clades overall. However, clade 3 <span style="font-style:italic;">emm89</span> iGAS disease was more common in youth and middle-aged individuals.<div class="boxTitle">Conclusions.</div>The rapid shift in <span style="font-style:italic;">emm89</span> iGAS strain genetics in metropolitan Toronto has resulted in a significant increase in the incidence of <span style="font-style:italic;">emm89</span> iGAS disease, with noticeably higher rates of clade 3 disease in younger patients.</span>

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Central Nervous System Infection Diagnosis by Next-Generation Sequencing: A Glimpse Into the Future?

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Japanese encephalitis virus was detected by deep sequencing for the first time in urine of a 16-year-old boy with encephalitis. Seroconversion and polymerase chain reaction analysis confirmed the metagenomics finding. Urine is useful for diagnosis of flaviviral encephalitis, whereas deep sequencing can be a panpathogen assay for the diagnosis of life-threatening infectious diseases.</span>

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Pulmonary Histoplasma Infection After Allogeneic Hematopoietic Stem Cell Transplantation: Case Report and Review of the Literature

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Histoplasmosis causes a wide spectrum of clinical illness, including disseminated infection in the immunocompromised. We report a case of pulmonary histoplasmosis in an allogeneic stem cell transplant recipient and review the literature on this topic. Histoplasmosis in this patient population is uncommon, but it is associated with poor outcome.</span>

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Sensitive Molecular Diagnostics for Cutaneous Leishmaniasis

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Rapid diagnosis of cutaneous leishmaniasis (CL) and identification of <span style="font-style:italic;">Leishmania</span> species is highly important for the disease management. In Israel, CL is caused mainly by <span style="font-style:italic;">Leishmania major</span> and <span style="font-style:italic;">Leishmania tropica</span> species.<div class="boxTitle">Methods.</div>We established an easy to handle point of care lesion-swabbing, combined with a highly sensitive multiplex real time PCR (multiplex qPCR) for accurate and rapid diagnosis of <span style="font-style:italic;">Leishmania</span> species.<div class="boxTitle">Results.</div>Using three probes: one general for: Leishmania species, and two specific for <span style="font-style:italic;">L major</span>, and <span style="font-style:italic;">L tropica</span>, we screened 1783 clinical samples collected during two years. <span style="font-style:italic;">Leishmania</span> species was found in 1086 individuals, 1008 <span style="font-style:italic;">L major</span>, and 70 <span style="font-style:italic;">L tropica</span>. Eight samples positive for <span style="font-style:italic;">Leishmania</span> species only, were further tested using a second set of multiplex qPCR developed, and were found positive for <span style="font-style:italic;">Leishmania braziliensis</span> and <span style="font-style:italic;">Leishmania infantum/donovani</span> (2 and 6 samples, concomitantly).<div class="boxTitle">Conclusions.</div>Taken together, the test enabled diagnostics and better treatment of <span style="font-style:italic;">Leishmania</span> infections from the Old World (1078 samples) and the New World (8 samples), and the subtyping of the dominant strains in the region, as well as in returning travelers’.</span>

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Comparative Sensitivity of Transthoracic and Transesophageal Echocardiography in Diagnosis of Infective Endocarditis Among Veterans With Staphylococcus aureus Bacteremia

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Echocardiography is fundamental for diagnosing infective endocarditis (IE) in patients with <span style="font-style:italic;">Staphylococcus aureus</span> bacteremia (SAB), but whether all such patients require transesophageal echocardiography (TEE) is controversial.<div class="boxTitle">Methods.</div>We identified SAB cases between February 2008 and April 2012. We compared sensitivity and specificity of transthoracic echocardiography (TTE) and TEE for evidence of IE, and we determined impacts of IE risk factors and TTE image quality on comparative sensitivities of TTE and TEE and their impact on clinical decision making.<div class="boxTitle">Results.</div>Of 215 evaluable SAB cases, 193 (90%) had TTE and 130 (60%) had TEE. In 119 cases with both tests, IE was diagnosed in 29 (24%), for whom endocardial involvement was evident in 25 (86%) by TEE, vs only 6 (21%) by TTE (<span style="font-style:italic;">P</span> < .001). Transesophageal echocardiography was more sensitive than TTE regardless of risk factors. Even among the 66 cases with adequate or better quality TTE images, sensitivity was only 4 of 17 (24%) for TTE, vs 16 of 17 (94%) for TEE (<span style="font-style:italic;">P</span> < .001). Among 130 patients with TEE, the TEE results, alone or with TTE results, influenced treatment duration in 56 (43%) cases and led to valve surgery in at least 4 (6%). It is notable that, despite vigorous efforts to obtain both tests routinely, TEE was not done in 86 cases (40%) for various reasons, including pathophysiological contraindications (14%), patient refusal or other patient-related factors (16%), and provider declination or system issues (10%).<div class="boxTitle">Conclusions.</div>Patients with SAB should undergo TEE when possible to detect evidence for IE, especially if the results might affect management.</span>

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Risk Factors for Surgical Site Infection After Cholecystectomy

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>There are limited data on risk factors for surgical site infection (SSI) after open or laparoscopic cholecystectomy.<div class="boxTitle">Methods.</div>A retrospective cohort of commercially insured persons aged 18–64 years was assembled using <span style="font-style:italic;">International Classification of Diseases, 9th Revision, Clinical Modification</span> (ICD-9-CM) procedure or Current Procedural Terminology, 4th edition codes for cholecystectomy from December 31, 2004 to December 31, 2010. Complex procedures and patients (eg, cancer, end-stage renal disease) and procedures with pre-existing infection were excluded. Surgical site infections within 90 days after cholecystectomy were identified by ICD-9-CM diagnosis codes. A Cox proportional hazards model was used to identify independent risk factors for SSI.<div class="boxTitle">Results.</div>Surgical site infections were identified after 472 of 66566 (0.71%) cholecystectomies; incidence was higher after open (n = 51, 4.93%) versus laparoscopic procedures (n = 421, 0.64%; <span style="font-style:italic;">P</span> < .001). Independent risk factors for SSI included male gender, preoperative chronic anemia, diabetes, drug abuse, malnutrition/weight loss, obesity, smoking-related diseases, previous <span style="font-style:italic;">Staphylococcus aureus</span> infection, laparoscopic approach with acute cholecystitis/obstruction (hazards ratio [HR], 1.58; 95% confidence interval [CI], 1.27–1.96), open approach with (HR, 4.29; 95% CI, 2.45–7.52) or without acute cholecystitis/obstruction (HR, 4.04; 95% CI, 1.96–8.34), conversion to open approach with (HR, 4.71; 95% CI, 2.74–8.10) or without acute cholecystitis/obstruction (HR, 7.11; 95% CI, 3.87–13.08), bile duct exploration, postoperative chronic anemia, and postoperative pneumonia or urinary tract infection.<div class="boxTitle">Conclusions.</div>Acute cholecystitis or obstruction was associated with significantly increased risk of SSI with laparoscopic but not open cholecystectomy. The risk of SSI was similar for planned open and converted procedures. These findings suggest that stratification by operative factors is important when comparing SSI rates between facilities.</span>

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Association Between Cytomegalovirus Reactivation and Clinical Outcomes in Immunocompetent Critically Ill Patients: A Systematic Review and Meta-Analysis

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>The aim of our systematic review was to investigate the association between cytomegalovirus (CMV) reactivation and outcomes in immunocompetent critically ill patients.<div class="boxTitle">Methods.</div>We searched electronic databases and gray literature for original studies and abstracts published between 1990 and October 2016. The review was limited to studies including critically ill immunocompetent patients. Cytomegalovirus reactivation was defined as positive polymerase chain reaction, pp65 antigenemia, or viral culture from blood or bronchoalveolar lavage. Selected patient-centered outcomes included mortality, duration of mechanical ventilation, need for renal replacement therapy (RRT), and nosocomial infections. Health resource utilization outcomes included intensive care unit and hospital lengths of stay.<div class="boxTitle">Results.</div>Twenty-two studies were included. In our primary analysis, CMV reactivation was associated with increased ICU mortality (odds ratio [OR], 2.55; 95% confidence interval [CI], 1.87–3.47), overall mortality (OR, 2.02; 95% CI, 1.60–2.56), duration of mechanical ventilation (mean difference 6.60 days; 95% CI, 3.09–10.12), nosocomial infections (OR, 3.20; 95% CI, 2.05–4.98), need for RRT (OR, 2.37; 95% CI, 1.31–4.31), and ICU length of stay (mean difference 8.18 days; 95% CI, 6.14–10.22). In addition, numerous sensitivity analyses were performed.<div class="boxTitle">Conclusions.</div>In this meta-analysis, CMV reactivation was associated with worse clinical outcomes and greater health resource utilization in critically ill patients. However, it remains unclear whether CMV reactivation plays a causal role or if it is a surrogate for more severe illness.</span>

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Treatment Outcomes Among Older Human Immunodeficiency Virus-Infected Adults in Nigeria

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Older age at initiation of combination antiretroviral therapy (cART) has been associated with poorer clinical outcomes. Our objectives were to compare outcomes between older and younger patients in our clinical cohort in Jos, Nigeria.<div class="boxTitle">Methods.</div>This retrospective cohort study evaluated patients enrolled on cART at the Jos University Teaching Hospital, Nigeria between 2004 and 2012. We compared baseline and treatment differences between older (≥50 years) and younger (15–49 years) patients. Kaplan-Meier analysis and Cox proportional hazard models estimated survival and loss to follow-up (LTFU) and determined factors associated with these outcomes at 24 months.<div class="boxTitle">Results.</div>Of 8352 patients, 643 (7.7%) were aged ≥50 years. The median change in CD4 count from baseline was 151 vs 132 (<span style="font-style:italic;">P</span> = .0005) at 12 months and 185 vs 151 cells/mm³ (<span style="font-style:italic;">P</span> = .03) at 24 months for younger and older patients, respectively. A total of 68.9% vs 71.6% (<span style="font-style:italic;">P</span> = .13) and 69.6% vs 74.8% (<span style="font-style:italic;">P</span> = .005) of younger and older patients achieved viral suppression at 12 and 24 months, with similar incidence of mortality and LTFU. In adjusted hazard models, factors associated with increased risk of mortality were male sex, World Health Organization (WHO) stage III/IV, and having a gap in care, whereas being fully suppressed was protective. The risk of being LTFU was lower for older patients, those fully suppressed virologically and with adherence rates >95%. Male sex, lack of education, WHO stage III/IV, body mass index <18.5 kg/m², and having a gap in care independently predicted LTFU.<div class="boxTitle">Conclusions.</div>Older patients achieved better viral suppression, and older age was not associated with increased mortality or LTFU in this study.</span>

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Relationship of Human Immunodeficiency Virus Viral Load in Cerebrospinal Fluid and Plasma in Patients Co-infected With Cryptococcal Meningitis

<span class="paragraphSection"><div class="boxTitle">Abstract</div>We measured human immunodeficiency virus (HIV) ribonucleic acid (RNA) in paired cerebrospinal fluid (CSF) and plasma samples in a prospective study of 91 HIV-infected, antiretroviral therapy-naive patients with cryptococcal meningitis. Cerebrospinal fluid HIV RNA was lower than in plasma (median 4.7 vs 5.2 log₁₀ copies/mL, <span style="font-style:italic;">P</span> < .0001) and positively correlated with plasma HIV RNA, peripheral CD4⁺ T-cell percentage, and CSF CXCL10. Plasma/CSF ratio of HIV RNA ranged widely from 0.2 to 265.5 with a median of 2.6. Cerebrospinal fluid quantitative cryptococcal culture positively correlated with CSF CCL2 and CCL3. CSF-plasma viral discordance was not associated with cryptococcal-associated immune reconstitution inflammatory syndrome.</span>

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eConsultations to Infectious Disease Specialists: Questions Asked and Impact on Primary Care Providers’ Behavior

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Since 2010, the Champlain BASE (Building Access to Specialist Advice through eConsultation) has allowed primary care providers (PCPs) to submit clinical questions to specialists through a secure web service. The study objectives are to describe questions asked to Infectious Diseases specialists through eConsultation and assess impact on physician behaviors.<div class="boxTitle">Methods.</div>eConsults completed through the Champlain BASE service from April 15, 2013 to January 29, 2015 were characterized by the type of question asked and infectious disease content. Usage data and PCP responses to a closeout survey were analyzed to determine eConsult response time, change in referral plans, and change in planned course of action.<div class="boxTitle">Results.</div>Of the 224 infectious diseases eConsults, the most common question types were as follows: interpretation of a clinical test 18.0% (41), general management 16.5 % (37), and indications/goals of treating a particular condition 16.5% (37). The most frequently consulted infectious diseases were as follows: tuberculosis 14.3% (32), Lyme disease 14.3% (32), and parasitology 12.9% (29). Within 24 hours, 63% of cases responded to the questions, and 82% of cases took under 15 minutes to complete. In 32% of cases, a face-to-face referral was originally planned by the PCP but was no longer needed. In 8% of cases, the PCP referred the patient despite originally not planning to make a referral. In 55% of cases, the PCP either received new information or changed their course of action.<div class="boxTitle">Conclusions.</div>An eConsult service provides PCPs with timely access to infectious disease specialists’ advice that often results in a change in plans for a face-to-face referral.</span>

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Kinematic Design of a Seven-Bar Linkage with Optimized Centrodes for Pure-Rolling Cutting

A novel method for designing a seven-bar linkage based on the optimization of centrodes is presented in this paper. The proposed method is applied to the design of a pure-rolling cutting mechanism, wherein close interrelation between the contacting lines and centrodes of two pure-rolling bodies is formulated and the genetic optimization algorithm is adopted for the dimensional synthesis of the mechanism. The optimization is conducted to minimize the error between mechanism centrodes and the expected trajectories, subject to the design requirements of the opening distance, the maximum amount of overlap error, and peak value of shearing force. An optimal solution is obtained and the analysis results show that the horizontal slipping and standard deviation of the lowest moving points of the upper shear blade have been reduced by 78.0% and 80.1% and the peak value of shear stress decreases by 29%, which indicate better cutting performance and long service life.

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Serum Alanine Aminotransferase Levels within Normal Range Have Different Associations with Augmentation Index and Other Cardiometabolic Risk Factors in Nondrinkers and Drinkers: A Chinese Community-Based Analysis

Background. To investigate whether serum alanine aminotransferase (ALT) levels within normal range were associated with augmentation index (AIx) and cardiometabolic risk factors in nondrinkers and drinkers in Chinese community-dwelling population. Methods. There were 4165 participants with serum ALT levels within normal range. Results. Alcohol drinking was observed in 1173 participants (28.2%). In multivariate analysis, serum ALT levels of nondrinkers were independently associated with age, sex, body mass index (BMI), hypertension, diabetes mellitus, diastolic blood pressure, triglyceride, low-density lipoprotein-cholesterol (LDL-c), and AIx, while serum ALT levels of drinkers were independently associated with age, sex, BMI, triglyceride, and LDL-c ( for all). Conclusions. Associations of serum ALT levels within normal range with age, sex, body height and weight, and blood lipid were simultaneously present in participants with and without alcohol drinking, while associations of serum ALT levels within normal range with AIx, blood pressure, and glucose were seen in nondrinkers rather than in drinkers. These findings not only provide the evidence that serum ALT levels, even within the normal range, have different associations with arteriosclerosis and cardiometabolic risk factors in nondrinkers and drinkers but also are helpful in understanding the underlying pathophysiologic mechanisms linking the hepatic function to arteriosclerosis and cardiometabolic risk factors.

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Electronic Tongue Combined with Chemometrics to Provenance Discrimination for a Green Tea (Anji-White Tea)

This paper aims to provide a stable instrumental method for provenance discrimination of Anji-White tea by its distinctive taste. 180 authentic and 60 counterfeit white tea samples were collected for specific geographical origins detection; all of them were measured by electronic tongue coupled with 7 independent sensors. Therefore, chemometrics methods, principal component analysis (PCA), and partial least squares discriminant analysis (PLSDA) were performed in classification. The PCA distribution shows that, in provenance analysis, PCA is a simple and reliable tool for small sample sets, but for sets with large objects, PCA seems powerless in classification. Therefore, PLSDA was applied to develop a classification model. The prediction sensitivity and specificity of PLSDA, respectively, reached 0.917 and 0.950. This study demonstrates the potential of combining electronic tongue system and chemometrics as an effective tool for specific geographical origins detection in Anji-White tea.

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Nonlinear Dynamic Analysis of Macrofiber Composites Laminated Shells

This work presents the nonlinear dynamical analysis of a multilayer piezoelectric macrofiber composite (MFC) laminated shell. The effects of transverse excitations and piezoelectric properties on the dynamic stability of the structure are studied. Firstly, the nonlinear dynamic models of the MFC laminated shell are established. Based on known selected geometrical and material properties of its constituents, the electric field of MFC is presented. The vibration mode-shape functions are obtained according to the boundary conditions, and then the Galerkin method is employed to transform partial differential equations into two nonlinear ordinary differential equations. Next, the effects of the transverse excitations on the nonlinear vibration of MFC laminated shells are analyzed in numerical simulation and moderating effects of piezoelectric coefficients on the stability of the system are also presented here. Bifurcation diagram, two-dimensional and three-dimensional phase portraits, waveforms phases, and Poincare diagrams are shown to find different kinds of periodic and chaotic motions of MFC shells. The results indicate that piezoelectric parameters have strong effects on the vibration control of the MFC laminated shell.

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QoS Based Cooperative Communications and Security Mechanisms for Ad Hoc Sensor Networks

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Lightweight Data Aggregation Scheme against Internal Attackers in Smart Grid Using Elliptic Curve Cryptography

Recent advances of Internet and microelectronics technologies have led to the concept of smart grid which has been a widespread concern for industry, governments, and academia. The openness of communications in the smart grid environment makes the system vulnerable to different types of attacks. The implementation of secure communication and the protection of consumers’ privacy have become challenging issues. The data aggregation scheme is an important technique for preserving consumers’ privacy because it can stop the leakage of a specific consumer’s data. To satisfy the security requirements of practical applications, a lot of data aggregation schemes were presented over the last several years. However, most of them suffer from security weaknesses or have poor performances. To reduce computation cost and achieve better security, we construct a lightweight data aggregation scheme against internal attackers in the smart grid environment using Elliptic Curve Cryptography (ECC). Security analysis of our proposed approach shows that it is provably secure and can provide confidentiality, authentication, and integrity. Performance analysis of the proposed scheme demonstrates that both computation and communication costs of the proposed scheme are much lower than the three previous schemes. As a result of these aforementioned benefits, the proposed lightweight data aggregation scheme is more practical for deployment in the smart grid environment.

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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.

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Bifurcation of a Delayed SEIS Epidemic Model with a Changing Delitescence and Nonlinear Incidence Rate

This paper is concerned with a delayed SEIS (Susceptible-Exposed-Infectious-Susceptible) epidemic model with a changing delitescence and nonlinear incidence rate. First of all, local stability of the endemic equilibrium and the existence of a Hopf bifurcation are studied by choosing the time delay as the bifurcation parameter. Directly afterwards, properties of the Hopf bifurcation are determined based on the normal form theory and the center manifold theorem. At last, numerical simulations are carried out to illustrate the obtained theoretical results.

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Some New Existence and Uniqueness Results for an Integral Boundary Value Problem of Caputo Fractional Differential Equations

In this work, we consider an integral boundary value problem of Caputo fractional differential equations. Based on a fixed-point theorem of generalized concave operators, we obtain the existence and uniqueness of positive solutions. As applications of main results, we give two examples in the end.

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Locally Advanced Thyroglossal Duct Cyst Carcinoma Presenting as a Neck Mass

Thyroglossal duct cyst carcinoma is rare and occurs in just 1% of cases with thyroglossal duct cysts. It is not always possible to distinguish a thyroglossal cyst harboring malignancy from its benign counterparts unless biopsied, thus posing the dilemma. Currently there is no clear consensus on the optimal management of thyroglossal duct cyst carcinoma. Here we present the case of a 69-year-old female who presented with a midline neck mass and dysphagia and was found to have papillary thyroid cancer in the biopsy specimen of the neck mass. She underwent excision of the mass and the thyroglossal duct cyst along with total thyroidectomy; however, the thyroidectomy specimen showed no malignancy. Her lymph node mapping was negative and she is awaiting radioactive iodine treatment.

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Stabilisation of Collagen Sponges by Glutaraldehyde Vapour Crosslinking

Glutaraldehyde is a well-recognised reagent for crosslinking and stabilising collagens and other protein-based materials, including gelatine. In some cases, however, the use of solutions can disrupt the structure of the material, for example, by causing rapid dispersion or distortions from surface interactions. An alternative approach that has been explored in a number of individual cases is the use of glutaraldehyde vapour. In this study, the effectiveness of a range of different glutaraldehyde concentrations in the reservoir providing vapour, from 5% to 25% (w/v), has been explored at incubation times from 5 h to 48 h at room temperature. These data show the effectiveness of the glutaraldehyde vapour approach for crosslinking collagen and show that materials with defined, intermediate stability could be obtained, for example, to control resorption rates in vivo.

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The Influence of Temperature on the Formation of Cubic Structured CdO Nanoparticles and Their Thin Films from Bis(2-hydroxy-1-naphthaldehydato)cadmium(II) Complex via Thermal Decomposition Technique

Recently, researchers have developed a great interest in the synthesis of metal oxide nanoparticles due to their potential applications in various fields of science and industry, especially in catalysis, due to their high activity. Bis(2-hydroxy-1-naphthaldehydato)cadmium(II) complexes were prepared and used as precursors for the synthesis of cadmium oxide nanoparticles via thermal decomposition method using HDA as a stabilizing agent. The prepared complexes were also used as single source precursors to prepare CdO thin films onto the glass substrates by spin coating and were annealed at 250, 300, and 350°C, respectively. The precursors were characterized by Fourier transform infrared (FTIR) spectroscopy, elemental analysis, nuclear magnetic resonance (NMR), and thermogravimetric analysis (TGA). The synthesized CdO nanoparticles and CdO thin films were characterized by ultraviolet-visible (UV-vis) spectroscopy, photoluminescence (PL), X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM).

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Photophysicochemical characterization of mycosporine-like amino acids in micellar solutions

Photochem. Photobiol. Sci., 2017, Accepted Manuscript
DOI: 10.1039/C7PP00051K, Paper

Dalila E. Orallo, Sonia Graciela Bertolotti, Maria Sandra Churio
Properties and photochemical and photophysical behavior of the mycosporine-like amino acids (MAAs) shinorine and porphyra-334 were experimentally evaluated in solutions of direct ionic micelles as simple biomimicking environments. The preferential...
The content of this RSS Feed (c) The Royal Society of Chemistry

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Mesoporous Silicon Hollow Nanocubes Derived from Metal–Organic Framework Template for Advanced Lithium-Ion Battery Anode

ACS Nano

DOI: 10.1021/acsnano.7b01185

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Sulfur Vapor-Infiltrated 3D Carbon Nanotube Foam for Binder-Free High Areal Capacity Lithium–Sulfur Battery Composite Cathodes

ACS Nano

DOI: 10.1021/acsnano.7b01437

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Chinese Abstracts – Volume 5 Issue 2 *

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Ascites, refractory ascites and hyponatremia in cirrhosis

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Ascites is the most common complication related to cirrhosis and is associated with increased morbidity and mortality. Ascites is a consequence of the loss of compensatory mechanisms to maintain the overall effective arterial blood volume due to worsening splanchnic arterial vasodilation as a result of clinically significant portal hypertension. In order to maintain effective arterial blood volume, vasoconstrictor and antinatriuretic pathways are activated, which increase overall sodium and fluid retention. As a result of progressive splanchnic arterial vasodilation, intestinal capillary pressure increases and results in the formation of protein-poor fluid within the abdominal cavity due to increased capillary permeability from the hepatic sinusoidal hypertension. In some patients, the fluid can translocate across diaphragmatic fenestrations into the pleural space, leading to hepatic hydrothorax. In addition, infectious complications such as spontaneous bacterial peritonitis can occur. Eventually, as the liver disease progresses related to higher portal pressures, loss of a compensatory cardiac output and further splanchnic vasodilation, kidney function becomes compromised from worsening renal vasoconstriction as well as the development of impaired solute-free water excretion and severe sodium retention. These mechanisms then translate into significant clinical complications, such as refractory ascites, hepatorenal syndrome and hyponatremia, and all are linked to increased short-term mortality. Currently, liver transplantation is the only curative option for this spectrum of clinical manifestations but ongoing research has led to further insight on alternative approaches. This review will further explore the current understanding on the pathophysiology and management of ascites as well as expand on two advanced clinical consequences of advanced liver disease, refractory ascites and hyponatremia.</span>

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Renal dysfunction in cirrhosis: acute kidney injury and the hepatorenal syndrome

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Renal dysfunction is a common complication of liver cirrhosis and of utmost clinical and prognostic relevance. Patients with cirrhosis are more prone to developing acute kidney injury (AKI) than the non-cirrhotic population. Pre-renal AKI, the hepatorenal syndrome type of AKI (HRS-AKI, formerly known as ‘type 1’) and acute tubular necrosis represent the most common causes of AKI in cirrhosis. Correct differentiation is imperative, as treatment differs substantially. While pre-renal AKI usually responds well to plasma volume expansion, HRS-AKI and ATN require different specific approaches and are associated with substantial mortality. Several paradigms, such as the threshold of 2.5 mg/dL for diagnosis of HRS-AKI, have recently been abolished and novel urinary biomarkers are being investigated in order to facilitate early and correct diagnosis and treatment of HRS-AKI and other forms of AKI in patients with cirrhosis. This review summarizes the current diagnostic criteria, as well as pathophysiologic and therapeutic concepts for AKI and HRS-AKI in cirrhosis.</span>

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