NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology

This is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2012 meeting in San Diego, California, on April 25, 2012. The symposium speakers summarized and critically evaluated our current understanding of the physiologic, pharmacological, and toxicological roles of NADPH-cytochrome P450 oxidoreductase (POR), a flavoprotein involved in electron transfer to microsomal cytochromes P450 (P450), cytochrome b(5), squalene mono-oxygenase, and heme oxygenase. Considerable insight has been derived from the development and characterization of mouse models with conditional Por deletion in particular tissues or partial suppression of POR expression in all tissues. Additional mouse models with global or conditional hepatic deletion of cytochrome b(5) are helping to clarify the P450 isoform- and substrate-specific influences of cytochrome b(5) on P450 electron transfer and catalytic function. This symposium also considered studies using siRNA to suppress POR expression in a hepatoma cell-culture model to explore the basis of the hepatic lipidosis phenotype observed in mice with conditional deletion of Por in liver. The symposium concluded with a strong translational perspective, relating the basic science of human POR structure and function to the impacts of POR genetic variation on human drug and steroid metabolism.

Reclaiming Indigenous Narratives through Critical Discourses and the Autonomy of the Trickster

How do prevailing narratives about Native Americans, particularly in the medium of film, conspire to promote the perspective of the dominant culture? What makes the appropriation of Indigenous images so metaphorically popular? In the past hundred years, little has changed in the forms of representation favored by Hollywood. The introductory chapter elucidates the problem and outlines the scope of this study. As each subsequent chapter makes clear, the problem is as relevant today as it has been throughout the entire course of filmic history. Chapter Two analyzes representational trends and defines each decade according to its favorite stereotype. The binary of the bloodthirsty savage is just as prevalent as it was during the 1920s and 30s. The same holds true for the drunken scapegoat and the exotic maiden, which made their cinematic debuts in the 1940s and 50s. But Hollywood has added new types as well. The visionary peacemaker and environmental activist have also made an appearance within the last forty years. What matters most is not the realism of these images, but rather the purposes to which they can be put toward validating whatever concerns the majority filmmakers wish to promote. Whether naïvely or not, such representations continue to evacuate Indigenous agency to the advantage of the majority. A brief historical overview confirms this legacy. Various disciplines have sought to interrogate this problem. Chapter three investigates the field of postcolonial studies, which makes inquiry into the various ways these narratives are produced, marketed, and consumed. It also raises the key questions of for whom, and by whom, these narratives are constructed. Additional consideration is given to their value as commodities in the mass marketplace. Typically the products of a boutique-multiculturalism, their storylines are apt to promote the prevailing point of view. Critical theory provides a foundational framework for chapter four. What is the blockbuster formula and how do the instruments of capital promote it? Concepts such as culture industry and repressive tolerance examine both the function and form of the master narrative, as well as its use to control the avenues of dissent. Moreover, the public sphere and its diminishment highlight the challenges inherent in the widespread promotion of an alternative set of narratives. Nonetheless, challenges to prevailing narratives do exist, particularly in the form of Trickster narratives. Often subject to persistent misrecognition, the Trickster demonstrates a potent form of agency that undeniably dismantles the hegemony of Western cinema. The final chapter examines some of the Trickster's more subtle and obscure productions. Usually subjugated to the realm of the mystical, rather than the mythical, these misinterpreted forms have the power to speak in circles around a majority audience. Intended for an Other audience, they are coded in a language that delivers a type of direction through indirection, promoting a poignant agency all their own.

The Control of the Grain Size of Tin.

The tin alloys of tellurium are extremely hard and have very great tensile strength. It was thought that the reduction of the rate of grain growth of tin with the addition of tellurium accompanied this hardening and strengthening and such way found to be true.

Guest Editorial: Racial and Ethnic Conflict and Violence

Racial and ethnic violence takes many forms. Genocides, ethnic cleansing, pogroms, civil wars, and violent separatist movements are the most obvious and extreme expressions, but less organized violence such as rioting, and hate crimes by individuals or small groups are products of racial and ethnic conflict as well. Also, the distribution of criminal violence within societies, which may or may not be aimed at members of another group, is in some places a by-product of ongoing conflicts between superior and subordinated racial or ethnic groups. Although estimates of the number of deaths attributable to ethnic violence vary widely, range of eleven to twenty million given for the period between 1945 and the early 1990s show the gravity of this type of conflict (Williams 1994, 50). So it comes as no surprise that scholars have paid increasing attention to such conflicts over the last decades.

Neonatal Fc receptor expression in dendritic cells mediates protective immunity against colorectal cancer

Cancers arising in mucosal tissues account for a disproportionately large fraction of malignancies. Immunoglobulin G (IgG) and the neonatal Fc receptor for IgG (FcRn) have an important function in the mucosal immune system that we have now shown extends to the induction of CD8(+) T cell-mediated antitumor immunity. We demonstrate that FcRn within dendritic cells (DCs) was critical for homeostatic activation of mucosal CD8(+) T cells that drove protection against the development of colorectal cancers and lung metastases. FcRn-mediated tumor protection was driven by DCs activation of endogenous tumor-reactive CD8(+) T cells via the cross-presentation of IgG complexed antigens (IgG IC), as well as the induction of cytotoxicity-promoting cytokine secretion, particularly interleukin-12, both of which were independently triggered by the FcRn-IgG IC interaction in murine and human DCs. FcRn thus has a primary role within mucosal tissues in activating local immune responses that are critical for priming efficient anti-tumor immunosurveillance.

New Journal, Same Ongoing Challenge: Advancing Policies that Promote the Health and Well-Being of Children and Families

The publication of the inaugural issue of the Journal of Applied Research on Children is a notable milestone for its sponsoring organization, CHILDREN AT RISK (www.childrenatrisk.org). With the release of “Volume 1, Number 1,” we as the Co-Editors in Chief would like to take the opportunity to thank the inaugural contributors whose articles follow and to answer the obvious question of “Why publish a new journal?”

Human Trafficking: Awareness, Data and Policy

The implications of the new research presented in Volume 2, Issue 1 (Human Trafficking) of the Journal of Applied Research on Children are explored, calling attention to the need for increased awareness, greater availability of data, and proactive policy solutions to combat child trafficking.

Migraine and vasodepressor syncope in a large family.

We evaluated a 47-year-old woman for recurrent migraine and syncope. The patient had 7 children (not examined by the authors), all of whom also experienced migraine and syncope. The patient's father, now deceased, had reportedly experienced migraine and episodes of feeling faint. All 5 of the patient's siblings reported migraine, and 4 of the 5 reported syncope. The case of our patient, which we discuss herein, suggests a genetic link between these 2 conditions, both of which include vascular dysregulation in their pathogenesis. To our knowledge, the medical literature contains no previous description of familial associations of combined migraine and syncope.

Teen Pregnancy: Ending the Cycle

The implications of the new research presented in Volume 2, Issue 2 (Teen Pregnancy) of the Journal of Applied Research on Children are explored, calling attention to proactive policy solutions to combat teen pregnancy.

New Name, New Format, New Publisher, Same Principles and Values

This issue of the Journal of Family Strengths is an opportunity for a fresh start, as the Family Preservation Journal is renewed and revived under a new name and a new format. Still keen on being a definitive record on developments in family strengths and parenting, the Journal is devoted to presenting theory, practice and evaluation articles on the strengths perspective in family preservation practice, all to assure and improve services and programs that promote and sustain family systems.

Food Insecurity and Children: Hunger?… In America?... How is that possible?

Despite being one of the wealthiest nations in the world, the United States continues to be plagued by the problem of food insecurity, especially at the child level. The editors' implications piece presents a call for greater urgency in addressing the problem of food insecurity in the United States.

Urinary diversion: how experts divert

OBJECTIVE To determine the rates of the available urinary diversion options for patients treated with radical cystectomy for bladder cancer in different settings (pioneering institutions, leading urologic oncology centers, and population based). METHODS Population-based data from the literature included all patients (n = 7608) treated in Sweden during the period 1964-2008, from Germany (n = 14,200) for the years 2008 and 2011, US patients (identified from National Inpatient Sample during 1998-2005, 35,370 patients and 2001-2008, 55,187 patients), and from Medicare (n = 22,600) for the years 1992, 1995, 1998, and 2001. After the International Consultation on Urologic Diseases-European Association of Urology International Consultation on Bladder Cancer 2012, the urinary diversion committee members disclosed data from their home institutions (n = 15,867), including the pioneering institutions and the leading urologic oncology centers. They are the coauthors of this report. RESULTS The receipt of continent urinary diversion in Sweden and the United States is <15%, whereas in the German high-volume setting, 30% of patients receive a neobladder. At leading urologic oncology centers, this rate is also 30%. At pioneering institutions up to 75% of patients receive an orthotopic reconstruction. Anal diversion is <1%. Continent cutaneous diversion is the second choice. CONCLUSION Enormous variations in urinary diversion exist for >2 decades. Increased attention in expanding the use of continent reconstruction may help to reduce these disparities for patients undergoing radical cystectomy for bladder cancer. Continent reconstruction should not be the exclusive domain of cystectomy centers. Efforts to increase rates of this complex reconstruction must concentrate on better definition of the quality-of-life impact, technique dissemination, and the centralization of radical cystectomy.

Multidisciplinary consensus on assessment of unruptured intracranial aneurysms: proposal of an international research group.

BACKGROUND AND PURPOSE To address the increasing need to counsel patients about treatment indications for unruptured intracranial aneurysms (UIA), we endeavored to develop a consensus on assessment of UIAs among a group of specialists from diverse fields involved in research and treatment of UIAs. METHODS After composition of the research group, a Delphi consensus was initiated to identify and rate all features, which may be relevant to assess UIAs and their treatment by using ranking scales and analysis of inter-rater agreement (IRA) for each factor. IRA was categorized as very high, high, moderate, or low. RESULTS Ultimately, 39 specialists from 4 specialties agreed (high or very high IRAs) on the following key factors for or against UIA treatment decisions: (1) patient age, life expectancy, and comorbid diseases; (2) previous subarachnoid hemorrhage from a different aneurysm, family history for UIA or subarachnoid hemorrhage, nicotine use; (3) UIA size, location, and lobulation; (4) UIA growth or de novo formation on serial imaging; (5) clinical symptoms (cranial nerve deficit, mass effect, and thromboembolic events from UIAs); and (6) risk factors for UIA treatment (patient age and life expectancy, UIA size, and estimated risk of treatment). However, IRAs for features rated with low relevance were also generally low, which underlined the existing controversy about the natural history of UIAs. CONCLUSIONS Our results highlight that neurovascular specialists currently consider many features as important when evaluating UIAs but also highlight that the appreciation of natural history of UIAs remains uncertain, even within a group of highly informed individuals.

The unruptured intracranial aneurysm treatment score: a multidisciplinary consensus.

OBJECTIVE We endeavored to develop an unruptured intracranial aneurysm (UIA) treatment score (UIATS) model that includes and quantifies key factors involved in clinical decision-making in the management of UIAs and to assess agreement for this model among specialists in UIA management and research. METHODS An international multidisciplinary (neurosurgery, neuroradiology, neurology, clinical epidemiology) group of 69 specialists was convened to develop and validate the UIATS model using a Delphi consensus. For internal (39 panel members involved in identification of relevant features) and external validation (30 independent external reviewers), 30 selected UIA cases were used to analyze agreement with UIATS management recommendations based on a 5-point Likert scale (5 indicating strong agreement). Interrater agreement (IRA) was assessed with standardized coefficients of dispersion (vr*) (vr* = 0 indicating excellent agreement and vr* = 1 indicating poor agreement). RESULTS The UIATS accounts for 29 key factors in UIA management. Agreement with UIATS (mean Likert scores) was 4.2 (95% confidence interval [CI] 4.1-4.3) per reviewer for both reviewer cohorts; agreement per case was 4.3 (95% CI 4.1-4.4) for panel members and 4.5 (95% CI 4.3-4.6) for external reviewers (p = 0.017). Mean Likert scores were 4.2 (95% CI 4.1-4.3) for interventional reviewers (n = 56) and 4.1 (95% CI 3.9-4.4) for noninterventional reviewers (n = 12) (p = 0.290). Overall IRA (vr*) for both cohorts was 0.026 (95% CI 0.019-0.033). CONCLUSIONS This novel UIA decision guidance study captures an excellent consensus among highly informed individuals on UIA management, irrespective of their underlying specialty. Clinicians can use the UIATS as a comprehensive mechanism for indicating how a large group of specialists might manage an individual patient with a UIA.

Measuring Success in Public Education: Whether Wanted or Not

Robert Sanborn and Angelo Giardino's introduction for Volume 3, Issue 2: Measuring Success in Public Education.