bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgeons, Intensivists, and Discretion to Refuse Requested Treatments
Authors: Wicclair Mark R. , White Douglas B.
Published: October 2014

Physicians are expected to engage patients as partners in identifying the possible benefits and harms associated with treatment options and selecting from among medically appropriate treatment options, rather than simply dictating what treatments patients will and will not receive. This collaborative model reflects the recognition that citizens in multicultural societies have diverse values and are likely to have different views about whether the possible benefits of a medical intervention outweigh the possible harms. However, there are circumstances in which the collaborative process breaks down due to irresolvable disagreement. Especially challenging are cases in which patients are expected to die if they do not receive a treatment and either the patients or their surrogates insist on the treatment despite the physician's belief that providing it is ill advised. The source of disagreement is often differing appraisals of the risks and potential benefits. In such cases, physicians generally judge that there is insufficient likelihood or magnitude of benefit to justify the burdens or expense of treatment, while patients or surrogates believe that the small chance of preventing the patient's death is sufficient to justify the costs and potential burdens to the patient.

There is a perception that surgeons enjoy considerable discretion in deciding when the risks of a procedure outweigh the expected benefits. An important contrast can be drawn between surgeons and intensivists—physicians who specialize in the medical management of critically ill patients. We will argue that there are good reasons for subjecting the decisions of both surgeons and intensivists to some oversight. We begin by showing that, for many cases, major professional society guidelines for intensivists recommend oversight via a procedural mechanism rather than unilateral decision‐making by individual clinicians. Next, we present reasons for adopting a procedural approach to dispute resolution, and we argue that these reasons apply to situations in which intensivists believe that patients or surrogates are requesting inappropriate life support as well as to many disagreements between surgeons and surrogates. Finally, we present and respond to several objections.
“Pregnancy Is Not a Disease”
Authors: Brudney Daniel
Published: October 2014

In many American states, a health care worker has a legal right to immunity from employer sanction if she refuses to perform actions at odds with her conscience: she has a legal right to accommodation of her conscientious beliefs. A number of arguments have been advanced to defend or reject this right. These have tended to focus on the possibly conflicting interests of the health care worker and the patient. Recently, however, a new argument has been proposed to justify immunity from employer sanction. This argument rests on the premise that the scope of the very concepts of medicine and disease circumscribes the scope of proper medical practice. Procedures and activities that fall outside the scope of medicine and disease are not properly within the brief of health care personnel.

This argument is important because, in principle, it stands outside the balancing of interests. Its central claim is nonsectarian—namely, that a person ought to do her job but need not do what is not her job. This claim avoids taking any stand in the culture wars. It is merely a claim about the logic of the concept “professional.” The medical professional who refuses to perform a procedure is not asking for special treatment. On the contrary, she is asking to be treated normally—in accordance with the normal contours of her job.

Of course, other arguments also seek to justify health care providers’ immunity from employer sanction. Ultimately, these different arguments need to be prized apart and scrutinized one by one. This essay focuses on the argument from the concepts of medicine and disease, as a down payment on that larger project.
Neuroscience and Morality
Authors: Gert Bernard
Published: October 2014

In 2009 I participated in a symposium, “Toward a Common Morality,” held at the United Nations Building in New York, that reflected the growing interest among scientists and philosophers in showing that science—particularly neuroscience—provides a foundation, not only for understanding morality, but also for improving it. In this essay I shall examine three books that are part of this trend: Experiments in Ethics, by Kwame Anthony Appiah; The Moral Landscape: How Science Can Determine Human Values, by Sam Harris; and Braintrust: What Neuroscience Tells Us about Morality, by Patricia S. Churchland. These three books put forward quite different perspectives about the relationship between science and morality, which suggests that neuroscience has nothing to add to our understanding of morality as a code of conduct that everyone should follow. However, neuroscience may help explain why some people behave as they do in situations that call for moral decisions or judgments.
Affordable Access to Care for the Undocumented
Authors: Rosen Dennis
Published: October 2014

How do you tell a sick kid that nobody cares if he gets better? That's an exaggeration, of course, but it is the fundamental message our society sends when we tell him that, because he and his family are undocumented immigrants, we are unwilling to extend them access to affordable and reliable health insurance.

One major shortcoming of the Affordable Care Act is its specific exclusion of the almost twelve million undocumented immigrants—including millions of children—in this country from access to the state and federal insurance exchanges where coverage can be purchased. It is true that providing undocumented immigrants access to the exchanges and subsidies mandated by the ACA would require additional funding. However, a recent analysis in California has found that the costs of expanding state‐supported care to include undocumented immigrants would largely be offset by the increased state sales tax revenue paid by managed care organizations and by reduced spending at the county level on emergency‐room and hospital care of the uninsured.
Ethical Issues Raised by the Treatment of Gender‐Variant Prepubescent Children
Authors: Drescher Jack , Pula Jack
Published: October 2014

Transgender issues and transgender rights have become increasingly a matter of media attention and public policy debates. Reflecting changes in psychiatric perspectives, the diagnosis of “trans‐sexualism” first appeared in the International Statistical Classification of Diseases and Related Health Problems in 1975 and shortly thereafter, in 1980, in the Diagnostic and Statistical Manual of Mental Disorders. Since that time, international standards of care have been developed, and today those standards are followed by clinicians across diverse cultures. In many instances, treatment of older adolescents and adults is covered by national health care systems and, in some cases, by private health insurance. Most recently, the Medicare ban on coverage for gender reassignment surgery was lifted in 2014.

In contrast to the relative lack of controversy about treating adolescents and adults, there is no expert clinical consensus regarding the treatment of prepubescent children who meet diagnostic criteria for what was referred to in both DSM‐IV‐TR and ICD‐10 as gender identity disorder in children and now in DSM‐5 as gender dysphoria. One reason for the differing attitudes has to do with the pervasive nature of gender dysphoria in older adolescents and adults: it rarely desists, and so the treatment of choice is gender or sex reassignment. On the subject of treating children, however, as the World Professional Association for Transgender Health notes in their latest Standards of Care, gender dysphoria in childhood does not inevitably continue into adulthood, and only 6 to 23 percent of boys and 12 to 27 percent of girls treated in gender clinics showed persistence of their gender dysphoria into adulthood. Further, most of the boys’ gender dysphoria desisted, and in adulthood, they identified as gay rather than as transgender.

In an effort to clarify best treatment practices for transgender individuals, a recent American Psychiatric Association Task Force on the Treatment of Gender Identity outlined three differing approaches to treating prepubescent gender dysphoric children.
Reducing Health Disparities and Enhancing the Responsible Conduct of Research Involving LGBT Youth
Authors: Fisher Celia B. , Mustanski Brian
Published: October 2014

Although there is clearly a need for evidenced‐based behavioral or biomedical prevention or treatment programs for suicide, substance abuse, and sexual health targeted to members of the LGBT population under the age of eighteen, few such programs exist, due in substantial part to limited research knowledge. Ambiguities in regulations that govern human subjects protections and the related inconsistencies in institutional review board (IRB) interpretations of regulatory language are the key reason for the lack of rigorous clinical trial evidence to support treatment choices and prevention approaches to reducing health disparities for this population. Given the socially sensitive nature of suicide, substance abuse, and HIV and STI research in general and LGBT research specifically, in the absence of empirical data to guide their decisions, IRBs must often rely on subjective judgments of minimal risk, which can lead to overestimation of the magnitude and probability of psychological, social, and informational harms that might arise from LGBT youth participation in clinical trials. In addition, more than other youth, LGBT adolescents whose families are unaware of their sexual orientation or gender identity or whose families have victimized them on account of it may be reluctant to participate in studies that require guardian permission. This, in turn, intensifies problems of recruitment and unbiased sampling. However, many IRBs are reluctant to apply federal regulations permitting waiver of guardian permission under conditions in which such permission is clearly not “feasible” or “reasonable” to require. Consequently, many investigators have excluded LGBT individuals under eighteen years of age in health intervention research proposals because of anticipated or actual difficulties obtaining IRB approval. This situation is in conflict with current ethical discourse focusing on the right of youths to participate in trials that will protect them from receiving developmentally untested, inappropriate, and unsafe treatments. In this article, we describe these barriers and recommendations for providing LGBT youth safe and fair access to health research.
Legal and Ethical Concerns about Sexual Orientation Change Efforts
Authors: Powell Tia , Stein Edward
Published: October 2014

The United States has recently made significant and positive civil rights gains for LGB people, including expanded recognition of marriages between people of the same sex. Among the central tropes that have emerged in the struggle for the rights of LGB people are that they are “born that way,” that sexual orientations cannot change, and that one's sexual orientation is not affected by choice. Writer Andrew Sullivan put it this way: “[H]omosexuality is an essentially involuntary condition that can neither be denied nor permanently repressed.… [S]o long as homosexual adults as citizens insist on the involuntary nature of their condition, it becomes politically impossible to deny or ignore the fact of homosexuality.… [The strategy for obtaining LGB rights is to] seek full public equality for those who, through no fault of their own, happen to be homosexual.”

This idea of linking LGB rights to empirical claims about sexual orientations has become so central that casting doubt on these claims is, in many circles, tantamount to opposing LGB rights. Nonetheless, claims about innateness, immutability, and lack of choice about sexual orientation should not be the primary basis for LGB rights.
Moral Progress in the Public Safety Net: Access for Transgender and LGB Patients
Authors: Davis Stephan , Berlinger Nancy
Published: October 2014

As a population, people who self‐identify as lesbian, gay, bisexual, or transgender face significant risks to health and difficulty in obtaining medical and behavioral health care, relative to the general public. These issues are especially challenging in safety‐net health care institutions, which serve a range of vulnerable populations with limited access, limited options, and significant health disparities. Safety‐net hospitals, particularly public hospitals with fewer resources than academic medical centers and other nonprofit hospitals that also serve as safety nets, are under immense financial pressures. However, with the introduction in 2011 of standards for LGBT inclusion by The Joint Commission, showing progress on LGBT health care has become a compliance issue for hospitals. And because the health care community itself has contributed to LGBT health disparities through prejudice, disrespect, or inadequate knowledge that have made it difficult for LGB and especially T people to seek care or to obtain the care they need, there is a moral case for allocating scarce resources to this population: we owe them some investment in righting wrongs that the health care system itself has produced.

So, where to begin in the typical safety‐net hospital or clinic? Beyond staff training, which is essential and for which good models now exist, what does justice demand from a service‐utilization perspective? Given the range of health care services that an LGBT person in the safety net may need or want, how should we set priorities? And what can't we promise to do for this member of our community?
Ensuring Appropriate Care for LGBT Veterans in the Veterans Health Administration
Authors: Sharpe Virginia Ashby , Uchendu Uchenna S.
Published: October 2014

Within health care systems, negative perceptions of lesbian, gay, bisexual, and transgender persons have often translated into denial of services, denial of visitation rights to same‐sex partners, reluctance on the part of LGBT patients to share personal information, and failure of workers to assess and recognize the unique health care needs of these patients. Other bureaucratic forms of exclusion have included documents, forms, and policies that fail to acknowledge a patient's valued relationships because of, for example, a narrow definition of “spouse,” “parent,” or “family.” Bureaucratic exclusion has taken a particularly prominent form in the U.S. military. Until its repeal and termination in 2011, the “Don't Ask, Don't Tell” policy had for eighteen years barred openly gay men and lesbians from serving in the military. Among the effects of DADT is a dearth of information about the number and needs of LGBT service members who transition to the Veterans Health Administration for health care at the end of their military service. The long‐standing social stigma against LGBT persons, the silence mandated by DADT, and the often unrecognized bias built into the fabric of bureaucratic systems make the task of creating a welcoming culture in the VHA urgent and challenging.

The VHA has accepted a commitment to that task. Its Strategic Plan for fiscal years 2013 through 2018 stipulates that “[v]eterans will receive timely, high quality, personalized, safe, effective and equitable health care irrespective of geography, gender, race, age, culture or sexual orientation.” To achieve this goal, the VHA undertook a number of coordinated initiatives to create an environment and culture that is informed, welcoming, positive, and empowering for the LGBT veterans and families whom the agency serves.
Comfort Care as Denial of Personhood
Authors: Peace William J.
Published: October 2014

It is 2 a.m. I am very sick. I am not sure how long I have been hospitalized. The last two or three days have been a blur, a parade of procedures and people. I had a bloody debridement for a severe, large, and grossly infected stage four wound‐the first wound I have had since I was paralyzed in 1978. I know the next six months or longer are going to be exceedingly difficult. I will be bedbound for months, dependent upon others for the first time in my adult life. As these thoughts are coursing through my mind, a physician I have never met and the registered nurse on duty appear at my door. As they put on their gowns I am weary but hopeful. Surely there is something that can be done to stop the vomiting. The physician examines me with the nurse's help. Like many other hospitalists that have examined me, he is coldly efficient. At some point, he asks the nurse to get a new medication.

What transpired after the nurse exited the room has haunted me. Paralyzed me with fear. The hospitalist asked me if I understood the gravity of my condition. He grimly told me I would be bedbound for at least six months and most likely a year or more. That there was a good chance the wound would never heal. If this happened, I would never sit in my wheelchair. I would never be able to work again. Not close to done, he told me I was looking at a life of complete and utter dependence. He went on to tell me I was on powerful antibiotics that could cause significant organ damage. He informed me I had the right to forego any medication, including the lifesaving antibiotics. If I chose not to continue with the current therapy, I could be made very comfortable. I would feel no pain or discomfort at all. Although not explicitly stated, the message was loud and clear. I can help you die peacefully.
The Influenza Controversy: Should Limits Be Placed on Science?
Authors: Gostin Lawrence O.
Published: October 2014

Should government have the power to place limits on a scientific pursuit that holds the potential for both good and harm—on what is called “dual‐use research”? That is the highly charged question surrounding research to genetically modify influenza A (H5N1) to render it more easily transmissible from human to human. There is seldom a “right” answer to dual‐use research, but a fair, inclusive, and transparent process—building on the NSABB model—should improve decision‐making. A local institutional panel should evaluate dual‐use research based on the following structured ethical framework.
Whither the Affordable Care Act?
Authors: Latham Stephen R.
Published: October 2014

The U.S. Supreme Court has likely already decided how much, if any, of President Obama's signature Affordable Care Act it is going to strike down as unconstitutional; its holding will be published this summer. No matter what the Court decides, though, it will send state and federal legislators scrambling—either to implement the law or to deal with the consequences of its alteration. There are various decisions the Court might make, but it is still most apt either to leave the ACA standing, or to selectively invalidate some of its mandate‐related provisions. In either case, there will be exchanges to design and manage, subsidies to allocate, transparency standards to design and enforce. The Court's decision will thus mark the beginning, not the end, of health reform.
Predicting Our Future: Lessons from Winnie‐the‐Pooh
Authors: Wilfond Benjamin
Published: October 2014

In this issue, Greer Donley, Sara Chandros Hull, and Benjamin E. Berkman explore the implications of using whole genome sequencing in the prenatal context. They focus on how whole genome sequencing may refine pregnancy expectations, impact child‐rearing decisions, and foreclose children's desire not to know more about their future. Their paper inspired me to reimagine the predominant worldviews of genomics prediction. One worldview is characterized by woe: the world as we know it will be forever changed unless we avoid the perils of genomics. I found myself thinking of this as the Eeyore phenotype. The Tigger phenotype is a worldview characterized by confidence: the world as we know it is forever changed, and we should embrace our genomic future. Donley, Hull, and Berkman adopt a new phenotype, one that perhaps resembles Christopher Robin. This worldview is characterized by its commitment to moving forward, nurturing relationships, and deliberating thoughtfully: it applies the evidentiary model to whole genome sequencing. Like Christopher Robin, who accepted that growing up was inevitable, the authors appreciate that progress is inevitable. Their response is to offer recommendations for research that might help the Eeyores and Tiggers find common ground.
The Disasters of March 11th
Authors: Dwyer James , Hamano Kenzo , Hui Wei Hsuan
Published: October 2014

On March 11, 2011, one of the most powerful earthquakes ever recorded occurred off the northeast coast of Japan. It destroyed buildings, damaged infrastructure, and killed people in the Tohoku region. The associated tsunami was even more destructive, engulfing coastal areas and obliterating whole towns. The earthquake and the tsunami together occasioned a third disaster: the meltdown at the Fukushima nuclear power plant.

Like most people, Dr. Makoto Sato was horrified by the destruction and suffering that he saw. He wanted to help and felt that he should, but doing something appropriate and effective was not easy. He is a general internist and bioethicist at a university medical center in Hokkaido, the large island north of Tohoku.

What should Dr. Sato have done then? What should he do now?
Normalizing Atypical Genitalia: How a Heated Debate Went Astray
Authors: Johnston Josephine
Published: October 2014

In a series of essays and letters published in 2010, commentators in bioethics debated the ethics of two interventions that aim to prevent or treat a symptom of a genetic condition called congenital adrenal hyperplasia, which can cause “virilization” in affected baby girls—the development of atypical, sometimes masculine‐appearing, genitals. Surgeries are often performed to try to “normalize” both the appearance and the function of affected girls’ genitals, and a drug thought to prevent virilization is sometimes prescribed to pregnant women who are likeliest to be carrying an affected fetus. The CAH debates suggest that there is profound disagreement in the field about whether preventing or treating virilization is an appropriate goal of medicine—or, indeed, parenting. Of course, that disagreement has its roots in ongoing debates about how to understand and react to a range of anatomical and behavioral differences, from short stature to deafness to hyperactivity, as well as ongoing debates about the limits of autonomy—in this case, parental autonomy, which is all the more complex. These issues are at the heart of bioethics. Yet it can be very difficult for us to talk and write respectfully and clearly about them.

Here, I recount the debates, show how they lost focus, and attempt to explain why the question about how parents and physicians should respond to atypical genitalia in children is so important and difficult. I argue that it is not a question that should be answered based on a single principle or philosophical commitment. No one principle can do all of the work. For each individual or family that faces it, the question is shaped by details about particular interventions aimed at altering a particular difference and offered in a particular social and family context. Scholars in bioethics who hold an especially strong commitment to any one principle should advocate for their views, but they must also make room for and respect the kind of pragmatic, particularized decision‐making that parents sometimes engage in.
The Moral Status of Invasive Animal Research
Authors: Rollin Bernard E.
Published: October 2014

Historically, society has not had a robust, institutionalized ethic for how animals should be treated. Before the Animal Welfare Act, the only laws constraining animal use in society were the anticruelty laws forbidding sadistic, deviant, purposeless, deliberate, unnecessary infliction of pain and suffering on animals, or outrageous neglect. These laws, both by statute and by judicial interpretation, did not apply to socially accepted animal uses such as research or agriculture. Because the overwhelming use of animals in society was in agriculture, aimed at providing food, fiber, locomotion, and power, and because the key to agricultural success was having healthy animals, good husbandry and good care were enforced by the most powerful sanction, self‐interest; the anticruelty laws were only there for society to manage sadists and psychopaths unmoved by self‐interest. But with the emergence of new kinds of “normal” animal use—such as intensive agriculture and animal research, both of which caused animal pain and suffering that did not fall under the anticruelty ethic—society was forced to create a new ethic for animals that went “beyond cruelty.” The Animal Welfare Act was a start, but it did not address all of the ethical concerns that society has had about the treatment of animals. As evidence of the need for a new ethic for animals, thousands of bills pertaining to animal welfare have been promulgated across the United States in the last decade. The new ethic for animals essentially applies much of our social ethic for humans, mutatis mutandis, to the treatment of animals and embodies the desired protections in the legal system.
Interleukin‐1β/Iinterleukin‐1 receptor‐associated kinase 1 inflammatory signaling contributes to persistent Gankyrin activation during hepatocarcinogenesis
Authors: Su Bo , Luo Tao , Zhu Junjie , Fu Jing , Zhao Xiaofang , Chen Lei , Zhang Huilu , Ren Yibin , Yu Lexing , Yang Xiaojun , Wu Mengchao , Feng Gensheng , Li Shao , Chen Yao , Wang Hongyang
Published: October 2014

Hepatocellular carcinoma (HCC) is a prototype of inflammation‐associated cancer. Oncoprotein Gankyrin, which mostly increases in HCC, plays a critical role in HCC development and metastasis. However, the exact mechanism of Gankyrin up‐regulation in HCC remains unclear. A Gankyrin luciferase reporter was developed to screen a potential regulator for Gankyrin from a list of proinflammatory cytokines, and interleukin (IL)‐1β was found as one of its activators. In clinical premalignant and malignant liver disease samples, enhanced IL‐1β/interleukin‐1 receptor‐associated kinase 1 (IRAK‐1) signaling accompanied by increased Gankyrin was observed. Lower expression of Gankyrin and phospho‐IRAK‐1 are favorable prognostic markers for HCC. A similar correlation was observed in the diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. The results from Gankyrin reporter activity, real‐time polymerase chain reaction, or immunoblotting further confirmed the up‐regulation of Gankyrin by IL‐1β/IRAK‐1 inflammatory signaling. Moreover, a series of Gankyrin's truncated reporters were constructed, and electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) were performed to analyze the properties of Gankyrin promoter. Mechanistically, the core promoter of Gankyrin contains the binding site of nuclear factor Y (NF‐Y) family members, which can recruit histone acetyltransferase coactivator E1A‐binding protein p300 (p300) or CREB‐binding protein (CBP) to promote Gankyrin transcription. Conversely, knockdown of NF‐Y, p300, or CBP inhibits Gankyrin expression. IL‐1β stimulation causes sequential phosphorylation of IRAK‐1, c‐Jun N‐terminal kinase (JNK), and p300 and enhances recruitment of the p300/CBP/NF‐Y complex to Gankyrin promoter. Inhibition of phospho‐JNK impairs IL‐1β/IRAK‐1 signaling‐mediated up‐regulation of Gankyrin. Conclusion: The finding of IL‐1β/IRAK‐1 signaling promoting Gankyrin expression through JNK and NF‐Y/p300/CBP complex provides a fresh view on inflammation‐enhanced hepatocarcinogenesis. (Hepatology 2015;61:585‐597)
Hyponatremia and Fractures: Findings From the MrOS Study
Authors: Jamal Sophie A , Arampatzis Spyridon , Harrison Stephanie Litwack , Bucur Roxana C , Ensrud Kristine , Orwoll Eric S , Bauer Douglas C
Published: October 2014

Hyponatremia may be a risk factor for fracture. To determine the relationship between hyponatremia and fracture we conducted cross-sectional and longitudinal analyses using data from the Osteoporotic Fractures in Men (MrOS) study. The MrOS study enrolled 5122 community dwelling men aged ≥65 years from six centers across the United States. We excluded men taking bisphosphonates, those with unknown medication history, those without serum sodium measures, or those with out of range assays for serum sodium. Serum sodium was measured at study entry. Subjects were followed for fractures (nonspine [including hip], hip, incident morphometric, and prevalent morphometric) for up to 9 years. We used Cox proportional hazards models to analyze the association between serum sodium levels (<135 mmol/L versus ≥135 mmol/L) and risk of nonspine and hip fractures, with results presented as hazard ratios (HRs) and 95% confidence intervals (CIs). We examined the association between morphometric vertebral fractures and serum sodium using logistic regression models, presented as odds ratios (ORs) and 95% CI. Hyponatremia was observed in 64 men (1.2% of the cohort). After adjusting for age, BMI, study center, and other covariates, we found that, compared to men with serum sodium ≥135 mmol/L, those with serum sodium <135 mmol/L, had an increased risk of hip fracture (HR = 3.04; 95% CI, 1.37 to 6.75), prevalent morphometric spine fracture (OR = 2.46; 95% CI, 1.22 to 4.95), and incident morphometric spine fracture (OR = 3.53; 95% CI, 1.35 to 9.19), but not nonspine fracture (OR = 1.44; 95% CI, 0.85 to 2.44). Adjusting for bone mineral density (BMD) did not change our findings. Our data show that hyponatremia is associated with up to a doubling in the risk of hip and morphometric spine fractures, independent of BMD. Further studies, to determine how hyponatremia causes fractures and if correction of hyponatremia decreases fractures, are needed. © 2014 American Society for Bone and Mineral Research.
Fruit and Vegetable Intake and Risk of Hip Fracture: A Cohort Study of Swedish Men and Women
Authors: Byberg Liisa , Bellavia Andrea , Orsini Nicola , Wolk Alicja , Michaëlsson Karl
Published: October 2014

Dietary guidelines recommend a daily intake of 5 servings of fruits and vegetables. Whether such intakes are associated with a lower risk of hip fracture is at present unclear. The aim of the present study was to investigate the dose-response association between habitual fruit and vegetable intake and hip fracture in a cohort study based on 40,644 men from the Cohort of Swedish Men (COSM) and 34,947 women from the Swedish Mammography Cohort (SMC) (total n = 75,591), free from cardiovascular disease and cancer, who answered lifestyle questionnaires in 1997 (age 45 to 83 years). Intake of fruits and vegetables (servings/day) was assessed by food frequency questionnaire and incident hip fractures were retrieved from the Swedish Patient Register (1998 to 2010). The mean follow-up time was 14.2 years. One-third of the participants reported an intake of fruits and vegetables of >5 servings/day, one-third reported >3 to ≤5 servings/day, 28% reported >1 to ≤3 servings/day, and 6% reported ≤1 serving/day. During 1,037,645 person-years we observed 3644 hip fractures (2266 or 62% in women). The dose-response association was found to be strongly nonlinear (p < 0.001). Men and women with zero consumption had 88% higher rate of hip fracture compared with those consuming 5 servings/day; adjusted hazard ratio (HR) was 1.88 (95% CI, 1.53 to 2.32). The rate was gradually lower with higher intakes; adjusted HR for 1 versus 5 servings/day was 1.35 (95% CI, 1.21 to 1.58). However, more than 5 servings/day did not confer additionally lower HRs (adjusted HR for 8 versus 5 servings/day was 0.96; 95% CI, 0.90 to 1.03). Similar results were observed when men and women were analyzed separately. We conclude that there is a dose-response association between fruit and vegetable intake and hip fracture such that an intake below the recommended five servings/day confers higher rates of hip fracture. Intakes above this recommendation do not seem to further lower the risk. © 2014 American Society for Bone and Mineral Research.
Resveratrol Protects against Cigarette Smoke–Induced Oxidative Damage and Pulmonary Inflammation
Authors: Liu Hong , Ren JianZhuang , Chen Hongjie , Huang Yongjie , Li Haiyan , Zhang Zhao , Wang Jing
Published: October 2014

This study was carried out to investigate the effects of resveratrol on cigarette smoke (CS)–induced lung injury. Experimental mice were administrated with 1 mg/kg or 3 mg/ kg resveratrol orally, 1 h prior to CS exposure (five cigarettes a day for 3 consecutive days). Airway inflammation and gene expression changes were assessed. CS exposure increased the number of pulmonary inflammatory cells, coupled with elevated production of tumor necrosis factor α and interleukin‐6 in bronchoalveolar lavage fluids. Resveratrol treatment decreased CS‐induced lung inflammation. Resveratrol restored the activities of superoxide dismutase, GSH peroxidase, and catalase in CS‐treated mice. CS significantly enhanced the nuclear translocation of nuclear factor κB (NF‐κB) and NF‐κB DNA binding activity, which was impaired by resveratrol pretreatment. In addition, resveratrol promoted CS‐induced heme oxygenase‐1 (HO‐1) expression and activation. Our results collectively indicate that resveratrol attenuates CS‐induced lung oxidative injury, which involves decreased NF‐κB activity and the elevated HO‐1 expression and activity.
A Novel Role of Annexin A2 in Human Type I Collagen Gene Expression
Authors: Schäfer Georgia , Hitchcock Jessica K. , Shaw Tamlyn M. , Katz Arieh A. , Parker M. Iqbal
Published: October 2014

The fibrillar collagen scaffold of the extracellular matrix provides a structural framework for cells in tissues and regulates intercellular communication; its disregulation has been associated with tumour development and progression. Previous work has shown that expression of type I collagen, the most abundant mammalian extracellular matrix protein, is decreased in chemically or virally transformed cells. This negative regulation could be mapped to a proximal COL1A2 promoter element spanning a CME (Collagen Modulating Element) site in SV40‐transformed human fibroblasts (SV‐WI38) that binds an unknown repressing protein. By magnetic bead pull‐down, we observed a multi‐protein complex bound to the CME with preference for single‐stranded over conventional double‐stranded DNA. MALDI‐TOF mass spectrometry of the CME‐binding protein complex revealed involvement of nuclear annexin A2 (AnxA2) which was increased in SV40‐transformed cells. Further EMSA analysis demonstrated that AnxA2 did not directly bind to the DNA but stabilised the complex and led to an increase in protein binding to the CME in SV‐WI38 but not untransformed WI38 cells. Knockdown of AnxA2 by siRNA increased type I collagen production in both WI38 and SV‐WI38 cells; however, these effects were not mediated at the transcriptional level. Rather, our data indicate a novel functional role of AnxA2 in the negative post‐transcriptional regulation of type I collagen synthesis in human fibroblasts. In SV40‐transformed cells, AnxA2 is accumulated at the proximal COL1A2 promoter region, suggesting close association with the transcriptional machinery that possibly facilitates binding to the emerging mRNA, eventually contributing to overall repression of type I collagen protein synthesis. J. Cell. Biochem. 116: 408–417, 2015. © 2014 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals, Inc.
Cyclooxygenase‐2 Regulates NLRP3 Inflammasome‐Derived IL‐1β Production
Authors: Hua Kuo‐Feng , Chou Ju‐Ching , Ka Shuk‐Man , Tasi Yu‐Ling , Chen Ann , Wu Shih‐Hsiung , Chiu Hsiao‐Wen , Wong Wei‐Ting , Wang Yih‐Fuh , Tsai Change‐Ling , Ho Chen‐Lung , Lin Cheng‐Hsiu
Published: October 2014

The NLR family, pyrin domain‐containing 3 (NLRP3) inflammasome is a reactive oxygen species‐sensitive multiprotein complex that regulates IL‐1β maturation via caspase‐1. It also plays an important role in the pathogenesis of inflammation‐related disease. Cyclooxygenase‐2 (COX‐2) is induced by inflammatory stimuli and contributes to the pathogenesis of inflammation‐related diseases. However, there is currently little known about the relationship between COX‐2 and the NLRP3 inflammasome. Here, we describe a novel role for COX‐2 in regulating the activation of the NLRP3 inflammasome. NLRP3 inflammasome‐derived IL‐1β secretion and pyroptosis in macrophages were reduced by pharmaceutical inhibition or genetic knockdown of COX‐2. COX‐2 catalyzes the synthesis of prostaglandin E2 and increases IL‐1β secretion. Conversely, pharmaceutical inhibition or genetic knockdown of prostaglandin E2 receptor 3 reduced IL‐1β secretion. The underlying mechanisms for the COX‐2‐mediated increase in NLRP3 inflammasome activation were determined to be the following: (1) enhancement of lipopolysaccharide‐induced proIL‐1β and NLRP3 expression by increasing NF‐κB activation and (2) enhancement of the caspase‐1 activation by increasing damaged mitochondria, mitochondrial reactive oxygen species production and release of mitochondrial DNA into cytosol. Furthermore, inhibition of COX‐2 in mice in vivo with celecoxib reduced serum levels of IL‐1β and caspase‐1 activity in the spleen and liver in response to lipopolysaccharide (LPS) challenge. These findings provide new insights into how COX‐2 regulates the activation of the NLRP3 inflammasome and suggest that it may be a new potential therapeutic target in NLRP3 inflammasome‐related diseases. J. Cell. Physiol. 230: 863–874, 2015. © 2014 Wiley Periodicals, Inc.
Methods and Procedures in Adipose Stem Cells: State of the Art and Perspective for Translation Medicine
Authors: Nicoletti G. F. , De Francesco F. , D'Andrea F. , Ferraro G. A.
Published: October 2014

Stem cells have potential in the retrieval and repair of injured tissue and renovation of organ function. To date, several studies have been carried out to elucidate how differentiation of stem cells can be used in regenerative medicine applications. Adipose tissue is an abundant and accessible source of stem cell, useful for regenerative therapeutic use. Adipose stem cells (ASCs) are favorable for future translational research and can be applied in many clinical settings. Adipose tissue repair has been recently adopted in clinical trials to prove that ASCs can be successfully used in patients. Variability in cell culture procedures (isolation, characterization, and differentiation) may have an influence on the experimental outcome. In this report, we consider the selection mechanisms of ASCs using flow cytometry, cell culture, freezing/thawing, cell cycle evaluation, histochemistry/immunofluorescence, and differentiation of ASCs. Both researchers and regulatory institutions should consider a new policy for GMP procedures and protocols, paying special attention to stem cell bio‐physiology, to facilitate more clinically oriented studies. ASCs show angiogenic properties, with prospects of repairing tissue damaged by radiotherapy, as well as possessing the ability to heal chronic wounds. They can also be useful in surgical practice. We focus on the potential clinical application of ASCs that are currently available regarding translational medicine and the methods and procedures for their isolation, differentiation, and characterization. J. Cell. Physiol. 230: 489–495, 2015. © 2014 Wiley Periodicals, Inc., A Wiley Company
DNA‐PKcs Deficiency Inhibits Glioblastoma Cell‐Derived Angiogenesis After Ionizing Radiation
Authors: Liu Yang , Zhang Luwei , Liu Yuanyuan , Sun Chao , Zhang Hong , Miao Guoying , Di Cui Xia , Zhou Xin , Zhou Rong , Wang Zhenhua
Published: October 2014

DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs) plays a critical role in non‐homologous end‐joining repair of DNA double‐strand breaks (DSB) induced by ionizing radiation (IR). Little is known, however, regarding the relationship between DNA‐PKcs and IR‐induced angiogenesis; thus, in this study we aimed to further elucidate this relationship. Our findings revealed that lack of DNA‐PKcs expression or activity sensitized glioma cells to radiation due to the defective DNA DSB repairs and inhibition of phosphorylated AktSer473. Moreover, DNA‐PKcs deficiency apparently mitigated IR‐induced migration, invasion and tube formation of human microvascular endothelial cell (HMEC‐1) in conditioned media derived from irradiated DNA‐PKcs mutant M059J glioma cells or M059K glioma cells that have inhibited DNA‐PKcs kinase activity due to the specific inhibitor NU7026 or siRNA knockdown. Moreover, IR‐elevated vascular endothelial growth factor (VEGF) secretion was abrogated by DNA‐PKcs suppression. Supplemental VEGF antibody to irradiated‐conditioned media was negated enhanced cell motility with a concomitant decrease in phosphorylation of the FAKTry925 and SrcTry416. Furthermore, DNA‐PKcs suppression was markedly abrogated in IR‐induced transcription factor hypoxia inducible factor‐1α (HIF‐1α) accumulation, which is related to activation of VEGF transcription. These findings, taken together, demonstrate that depletion of DNA‐PKcs in glioblastoma cells at least partly suppressed IR‐inflicted migration, invasion, and tube formation of HMEC‐1 cells, which may be associated with the reduced HIF‐1α level and VEGF secretion. Inhibition of DNA‐PKcs may be a promising therapeutic approach to enhance radio‐therapeutic efficacy for glioblastoma by hindering its angiogenesis. J. Cell. Physiol. 230: 1094–1103, 2015. © 2014 Wiley Periodicals, Inc., A Wiley Company
A meta‐analysis comparing the efficacy of entecavir and tenofovir for the treatment of chronic hepatitis B infection
Authors: Zuo Shan‐Ru , Zuo Xiao‐Cong , Wang Chun‐Jiang , Ma Yu‐Tao , Zhang Hao‐Ye , Li Zuo‐Jun , Song Li‐Ying , Deng Zhen‐Zhen , Liu Shi‐Kun
Published: October 2014

The efficacy of entecavir and tenofovir in patients with chronic hepatitis B virus (HBV) is inconsistent. To address this issue, we conducted a meta‐analysis based on a current review of the literature addressing the efficacy and safety of entecavir and tenofovir. Electronic databases were searched through June 2014 for relevant clinical trials. We included 2 randomized controlled trials, 2 prospective cohort studies, and 7 case‐control studies that included 1,656 patients. In the entecavir group, 842 of 992 were nucleos(t)ide‐naïve chronic HBV patients, and in the tenofovir group 481 of 664 were nucleos(t)ide‐naïve. The virological response to tenofovir was superior to entecavir (RR: 0.82; 95%CI: 0.72–0.93), especially in nucleos(t)ide‐naïve chronic HBV patients at 48 weeks (RR: 0.78; 95%CI: 0.65–0.92). Additionally, there was no difference between entecavir and tenofovir for virological response at 24 weeks (RR: 0.87, 95%CI: 0.71–1.05). The alanine aminotransferase normalization rate, serological response, and adverse event rate were also not significantly different between entecavir and tenofovir at 24 or 48 weeks after treatment. These results suggest that tenofovir is a better choice to treat chronic HBV patients than entecavir as it is better able to suppress HBV viral load and has a similar safety profile.
Müllerian duct anomalies: Embryological development, classification, and MRI assessment
Authors: Robbins Jessica B. , Broadwell Christy , Chow Lawrence C. , Parry John P. , Sadowski Elizabeth A.
Published: October 2014

Müllerian duct anomalies (MDA) occur due to abnormal development of the uterus, cervix, and vagina, many times affecting a woman's ability to conceive and carry a pregnancy to term. The spectrum of possible abnormalities are related to the development of two separate Müllerian systems, which then fuse and subsequently undergo degeneration of the fused segments. This multiphasic development explains the multiple variations within the scheme of MDA classification. The purpose of this article is to review the embryologic development of the Müllerian ducts, relate the development to the most commonly used classification system, and review the magnetic resonance imaging (MRI) assessment of Müllerian duct anomalies. A brief review of the treatment options, as they relate to the imaging diagnosis, will be provided as well. J. Magn. Reson. Imaging 2015;41:1–12. © 2014 Wiley Periodicals, Inc.
Mechanism of mast cell adhesion to human tenocytes in vitro
Authors: Behzad Hayedeh , Tsai Shu‐Huei , Nassab Paulina , Mousavizadeh Rouhollah , McCormack Robert G. , Scott Alex
Published: October 2014

Mast cells and fibroblasts are two key players involved in many fibrotic and degenerative disorders. In the present study we examined the nature of binding interactions between human mast cells and tendon fibroblasts (tenocytes). In the mast cell‐fibroblast co‐culture model, mast cells were shown to spontaneously bind to tenocytes, in a process that was partially mediated by α5β1 integrin receptors. The same receptors on mast cells significantly mediated binding of these cells to tissue culture plates in the presence of tenocyte‐conditioned media; the tenocyte‐derived fibronectin in the media was shown to also play a major role in these binding activities. Upon binding to tenocytes or tissue culture plates, mast cells acquired an elongated phenotype, which was dependent on α5β1 integrin and tenocyte fibronectin. Additionally, tenocyte‐derived fibronectin significantly enhanced mRNA expression of the adhesion molecule, THY1, by mast cells. Our data suggests that α5β1 integrin mediates binding of mast cells to human tenocyte and to tenocyte‐derived ECM proteins, in particular fibronectin. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:9–16, 2015.
Preparation of two flavonoid glycosides with unique structures from barley seedlings by membrane separation technology and preparative high‐performance liquid chromatography
Authors: Chen Tao , Li Hong‐mei , Zou Deng‐Lang , Du Yu‐Zhi , Shen Yu‐Hu , Li Yulin
Published: October 2014

Barley seedlings are rich in flavones that can have positive effects on people with antihypoxia and antifatigue. Lutonarin and saponarin are two major flavonoid glycosides that have unique structures in barley seedlings. This study presents a new approach for the preparation of lutonarin and saponarin from barely seedlings by membrane separation technology and preparative high‐performance liquid chromatography. Preparative conditions of these two flavonoid glycosides by membrane separation technology were studied using response surface methodology. Under the optimized conditions, the total contents of these two flavonoid glycosides amounts to 17.0%.
Etiology and management of recurrent parotid pleomorphic adenoma
Authors: Witt Robert L. , Eisele David W. , Morton Randall P. , Nicolai Piero , Poorten Vincent Vander , Zbären Peter
Published: October 2014

The objective of this review study was to encompass the relevant literature and current best practice options for this challenging, sometimes incurable problem. The source of the data was Ovid MEDLINE from 1946 to 2014. Review methods consisted of articles with clinical correlates. The most important cause of recurrence is enucleation with rupture and incomplete tumor excision at operation. Incomplete pseudocapsule, extracapsular extension, pseudopods of pleomorphic adenoma tissue, and satellite pleomorphic beyond the pseudocapsule are also likely linked to recurrent pleomorphic adenoma. Most recurrent pleomorphic adenoma are multinodular. Magnetic resonance imaging is the imaging study of choice for recurrent pleomorphic adenoma. Nerve integrity monitoring may reduce morbidity for recurrent pleomorphic adenoma. Treatment of recurrent pleomorphic adenoma must be individualized. Total parotidectomy, given the multicentricity of recurrent pleomorphic adenoma, is appropriate in many patients, but may be inadequate to control recurrent pleomorphic. There is accumulating evidence from retrospective series that postoperative radiation therapy results in significantly better local control. Laryngoscope, 125:888–893, 2015