bluuebunny/crossref_metadata_2025 huggingface dataset:
Administrative Record Linkage as a Tool for Public Health Research
Authors: Jutte Douglas P. , Roos Leslie L. , Brownell Marni D.
Published: March 2011

Linked administrative databases offer a powerful resource for studying important public health issues. Methods developed and implemented in several jurisdictions across the globe have achieved high-quality linkages for conducting health and social research without compromising confidentiality. Key data available for linkage include health services utilization, population registries, place of residence, family ties, educational outcomes, and use of social services. Linking events for large populations of individuals across disparate sources and over time permits a range of research possibilities, including the capacity to study low-prevalence exposure-disease associations, multiple outcome domains within the same cohort of individuals, service utilization and chronic disease patterns, and life course and transgenerational transmission of health. Limited information on variables such as individual-level socioeconomic status (SES) and social supports is outweighed by strengths that include comprehensive follow-up, continuous data collection, objective measures, and relatively low expense. Ever advancing methodologies and data holdings guarantee that research using linked administrative databases will make increasingly important contributions to public health research.
Toward a Fourth Generation of Disparities Research to Achieve Health Equity
Authors: Thomas Stephen B. , Quinn Sandra Crouse , Butler James , Fryer Craig S. , Garza Mary A.
Published: March 2011

Achieving health equity, driven by the elimination of health disparities, is a goal of Healthy People 2020. In recent decades, the improvement in health status has been remarkable for the U.S. population as a whole. However, racial and ethnic minority populations continue to lag behind whites with a quality of life diminished by illness from preventable chronic diseases and a life span cut short by premature death. We examine a conceptual framework of three generations of health disparities research to understand (a) data trends, (b) factors driving disparities, and (c) solutions for closing the gap. We propose a new, fourth generation of research grounded in public health critical race praxis, utilizing comprehensive interventions to address race, racism, and structural inequalities and advancing evaluation methods to foster our ability to eliminate disparities. This new generation demands that we address the researcher's own biases as part of the research process.
Ecological Models Revisited: Their Uses and Evolution in Health Promotion Over Two Decades
Authors: Richard Lucie , Gauvin Lise , Raine Kim
Published: March 2011

Since the 1980s, ecological models of health promotion have generated a great deal of enthusiasm among researchers and interventionists. These models emerged from conceptual developments in other fields, and only selected elements of the ecological approach have been integrated into them. In this article, we describe the tenets of the ecological approach and highlight those aspects that have been integrated into ecological models used in health promotion. We also analyze how ecological models have been applied to the study of two important public health issues, namely physical activity promotion and the increased consumption of fruits and vegetables, by conducting an archival study of published research. Finally, we make a statement regarding the usefulness of ecological models for research and practice and propose recommendations for future research, program planning, and evaluation.
The Health Effects of Economic Decline
Authors: Catalano Ralph , Goldman-Mellor Sidra , Saxton Katherine , Margerison-Zilko Claire , Subbaraman Meenakshi , LeWinn Kaja , Anderson Elizabeth
Published: March 2011

Political pronouncements and policy statements include much conjecture concerning the health and behavioral effects of economic decline. We both summarize empirical research concerned with those effects and suggest questions for future research priorities. We separate the studies into groups defined by questions asked, mechanisms invoked, and outcomes studied. We conclude that although much research shows that undesirable job and financial experiences increase the risk of psychological and behavioral disorder, many other suspected associations remain poorly studied or unsupported. The intuition that mortality increases when the economy declines, for example, appears wrong. We note that the research informs public health programming by identifying risk factors, such as job loss, made more frequent by economic decline. The promise that the research would identify health costs and benefits of economic policy choices, however, remains unfulfilled and will likely remain so without stronger theory and greater methodological agreement.
The U.S. Healthy People Initiative: Its Genesis and Its Sustainability
Authors: Green Lawrence W. , Fielding Jonathan
Published: March 2011

Unlike most government initiatives in health, the Healthy People initiative of the U.S. federal government was crafted and sustained not as a federal initiative, but as a “national initiative” eliciting participation from nongovernmental national organizations, state health agencies, professional associations, multiple agencies of the U.S. Department of Health and Human Services, and other federal agencies, such as Agriculture, and increasingly engaging academia and state and local stakeholders in adapting the objectives for their own efforts to enact and evaluate state and local policies and programs. The quantified objectives at the center of the initiative were a product of continuous balancing of changing science and political or social concerns and priorities along with national and state or special population needs. The evolution from the first decade's objectives to each subsequent set of objectives reflected changing societal concerns, evidence-based technologies, theories, and discourses of those decades. Such accommodations changed the contours of the initiative over time in attempts to make it more relevant to specific partners and other stakeholders.
Promoting Global Population Health While Constraining the Environmental Footprint
Authors: McMichael A.J. , Butler C.D.
Published: March 2011

Populations today face increasing health risks from human-induced regional and global environmental changes and resultant ecological nonsustainability. Localized environmental degradation that has long accompanied population growth, industrialization, and rising consumerism has now acquired a global and often systemic dimension (e.g., climate change, disrupted nitrogen cycling, biodiversity loss). Thus, the economic intensification and technological advances that previously contributed to health gains have now expanded such that humanity's environmental (and ecological) footprint jeopardizes global population health. International data show, in general, a positive correlation of a population's health with level of affluence and size of per-person footprint. Yet, beyond a modest threshold, larger footprints afford negligible health gain and may impair health (e.g., via the rise of obesity). Furthermore, some lower-income countries have attained high levels of health. Many changes now needed to promote ecological (and social) sustainability will benefit local health. Continued improvement of global health could thus coexist with an equitably shared global environmental footprint.
Sodium Intake and Cardiovascular Disease
Authors: Morrison Alanna C. , Ness Roberta B.
Published: March 2011

Sodium consumption is a target for prevention of cardiovascular disease (CVD). The relationship between sodium intake and blood pressure (BP) is well-established, but the relationship with CVD is less clear. This review focuses on studies investigating the association between sodium intake and CVD within five principal subgroups: age, underlying BP, gender, body size, and ethnicity. We conclude that sodium reduction results in decreased CVD risk in the general population, and some susceptible subgroups may especially benefit from preventive efforts. Older individuals, those with underlying elevated BP, and those with increased body size may benefit most, but men and women of all ages, ethnicities, and normotensives also experience reduced CVD risk in relation to lowered sodium intake. Public health policy to reduce sodium intake in the United States would have significant cost-savings, far greater than the cost of intervention, and would also result in a significant gain in quality-adjusted life years.
Prospects for a Cardiovascular Disease Prevention Polypill
Authors: Dabhadkar Kaustubh C. , Kulshreshtha Ambar , Ali Mohammed K. , Venkat Narayan K.M.
Published: March 2011

Cardiovascular diseases (CVD) account for one-third of annual global mortality. The aggregated benefits of concurrently controlling common CVD risk factors, such as dyslipidemia and hypertension, in people at overall risk for CVD is postulated to be more efficient than treating each individual risk factor to target. Administration of a polypill consisting of cholesterol-lowering (statins), antihypertensive, and antiplatelet agents together would simultaneously lower multiple risk factors, and applying such a population risk-reduction strategy would drastically reduce CVD incidence. This idea has generated much controversy and debate over the past decade. A few studies have emerged providing early evidence about the safety and efficacy of such a pill, and the results of ongoing and planned studies of outcome are eagerly anticipated. In this article, we review and interpret the existing evidence as well as explore the potential of a polypill for primary and secondary prevention of CVD.
The Growing Impact of Globalization for Health and Public Health Practice
Authors: Labonté Ronald , Mohindra Katia , Schrecker Ted
Published: March 2011

In recent decades, public health policy and practice have been increasingly challenged by globalization, even as global financing for health has increased dramatically. This article discusses globalization and its health challenges from a vantage of political science, emphasizing increased global flows (of pathogens, information, trade, finance, and people) as driving, and driven by, global market integration. This integration requires a shift in public health thinking from a singular focus on international health (the higher disease burden in poor countries) to a more nuanced analysis of global health (in which health risks in both poor and rich countries are seen as having inherently global causes and consequences). Several globalization-related pathways to health exist, two key ones of which are described: globalized diseases and economic vulnerabilities. The article concludes with a call for national governments, especially those of wealthier nations, to take greater account of global health and its social determinants in all their foreign policies.
Prenatal Famine and Adult Health
Authors: Lumey L.H. , Stein Aryeh D. , Susser Ezra
Published: March 2011

We review human studies on the relation between acute exposures to prenatal famine and adult physical and mental health. These studies are observational and include exposures to a famine environment by natural or man-made causes or, more commonly, from the interplay between natural and human factors. These natural experiments provide an opportunity to examine long-term outcomes after famine exposures by comparing exposed and nonexposed individuals.

The studies show consistent associations between prenatal famine and adult body size, diabetes, and schizophrenia. For other measures of adult health, findings are less robust. A relation between prenatal famine and some reported epigenetic changes may provide a potential mechanism to explain specific associations. Much progress can be made if current separate studies are further analyzed with comparable definitions of exposures and outcomes and using common analytic strategies.
Social Determinants and the Decline of Cardiovascular Diseases: Understanding the Links
Authors: Harper Sam , Lynch John , Smith George Davey
Published: March 2011

This article reviews the historical declines in cardiovascular mortality and provides an overview of the contribution of social and economic factors to disease change. We document the magnitude of declines in cardiovascular diseases and the major role of changes in conventional risk factors, and we review the contributions of social determinants to changes in disease rates. We conclude by arguing that understanding patterns and trends of social inequalities in cardiovascular disease and its risk factors requires consideration of the specific intersections of health and social exposures acting across the life course in different settings, in both time and place.
Advances and Current Themes in Occupational Health and Environmental Public Health Surveillance
Authors: Shire Jeffrey D. , Marsh Gary M. , Talbott Evelyn O. , Sharma Ravi K.
Published: March 2011

The essential purpose of public health surveillance is to monitor important health outcomes and risk factors and provide actionable information to practitioners, policy makers, researchers, and the public to prevent or ameliorate exposure, disease, and death. Although separate 1970s-era acts of Congress made possible the creation of modern occupational health and environmental public health surveillance, these acts also led to fragmented responsibilities and unconnected data across federal agencies. Having a well-defined purpose for systematically collecting relevant data is key, and state and local programs play a crucial role in conducting meaningful surveillance and connecting it with evidence-based outreach and interventions. Congress has directed monies to environmental public health surveillance and capacity has improved, yet no analagous funding has occurred to address the fragmentation found within occupational health surveillance. This article provides a review of the advances and important themes within occupational health and environmental public health surveillance over the past decade.
Prematurity: An Overview and Public Health Implications
Authors: McCormick Marie C. , Litt Jonathan S. , Smith Vincent C. , Zupancic John A.F.
Published: March 2011

The high rate of premature births in the United States remains a public health concern. These infants experience substantial morbidity and mortality in the newborn period, which translate into significant medical costs. In early childhood, survivors are characterized by a variety of health problems, including motor delay and/or cerebral palsy, lower IQs, behavior problems, and respiratory illness, especially asthma. Many experience difficulty with school work, lower health-related quality of life, and family stress. Emerging information in adolescence and young adulthood paints a more optimistic picture, with persistence of many problems but with better adaptation and more positive expectations by the young adults. Few opportunities for prevention have been identified; therefore, public health approaches to prematurity include assurance of delivery in a facility capable of managing neonatal complications, quality improvement to minimize interinstitutional variations, early developmental support for such infants, and attention to related family health issues.
From Serendipity to Therapy
Authors: Neufeld Elizabeth F.
Published: March 2011

My postdoctoral training in the biosynthesis of plant polysaccharides at the University of California, Berkeley, led me, rather improbably, to study mucopolysaccharide storage disorders in the intramural program of the National Institutes of Health (NIH). I have traced the path from studies of mucopolysaccharide turnover in cultured cells to the development of therapy for patients. The key experiment started as an accident, i.e., the mixing of cells of different genotypes, resulting in correction of their biochemical defect. This serendipitous experiment led to identification of the enzyme deficiencies in the Hurler and Hunter syndromes, to an understanding of the biochemistry of lysosomal enzymes in general, and to the cell biology of receptor-mediated endocytosis and targeting to lysosomes. It paved the way for the development of enzyme replacement therapy with recombinant enzymes. I have also included studies performed after I moved to the University of California, Los Angeles (UCLA), including a recent unexpected finding in a neurodegenerative mucopolysaccharide storage disease, the Sanfilippo syndrome, with implications for therapy.
Insect Transgenesis: Current Applications and Future Prospects
Authors: Fraser Malcolm J.
Published: March 2011

The ability to manipulate the genomes of many insects has become a practical reality over the past 15 years. This has been led by the identification of several useful transposon vector systems that have allowed the identification and development of generalized, species-specific, and tissue-specific promoter systems for controlled expression of gene products upon introduction into insect genomes. Armed with these capabilities, researchers have made significant strides in both fundamental and applied transgenics in key model systems such as Bombyx mori, Tribolium casteneum, Aedes aegypti, and Anopheles stephensi. Limitations of transposon systems were identified, and alternative tools were developed, thus significantly increasing the potential for applied transgenics for control of both agricultural and medical insect pests. The next 10 years promise to be an exciting time of transitioning from the laboratory to the field, from basic research to applied control, during which the full potential of gene manipulation in insect systems will ultimately be realized.
Thermodynamics and Mechanics of Membrane Curvature Generation and Sensing by Proteins and Lipids
Authors: Baumgart Tobias , Capraro Benjamin R. , Zhu Chen , Das Sovan L.
Published: March 2011

Research investigating lipid membrane curvature generation and sensing is a rapidly developing frontier in membrane physical chemistry and biophysics. The fast recent progress is based on the discovery of a plethora of proteins involved in coupling membrane shape to cellular membrane function, the design of new quantitative experimental techniques to study aspects of membrane curvature, and the development of analytical theories and simulation techniques that allow a mechanistic interpretation of quantitative measurements. The present review first provides an overview of important classes of membrane proteins for which function is coupled to membrane curvature. We then survey several mechanisms that are assumed to underlie membrane curvature sensing and generation. Finally, we discuss relatively simple thermodynamic/mechanical models that allow quantitative interpretation of experimental observations.
Coherent Nonlinear Optical Imaging: Beyond Fluorescence Microscopy
Authors: Min Wei , Freudiger Christian W. , Lu Sijia , Xie X. Sunney
Published: March 2011

The quest for ultrahigh detection sensitivity with spectroscopic contrasts other than fluorescence has led to various novel approaches to optical microscopy of biological systems. Coherent nonlinear optical imaging, especially the recently developed nonlinear dissipation microscopy (including stimulated Raman scattering and two-photon absorption) and pump-probe microscopy (including excited-state absorption, stimulated emission, and ground-state depletion), provides new image contrasts for nonfluorescent species. Thanks to the high-frequency modulation transfer scheme, these imaging techniques exhibit superb detection sensitivity. By directly interrogating vibrational and/or electronic energy levels of molecules, they offer high molecular specificity. Here we review the underlying principles and excitation and detection schemes, as well as exemplary biomedical applications of this emerging class of molecular imaging techniques.
Underinsurance in the United States: An Interaction of Costs to Consumers, Benefit Design, and Access to Care
Authors: Lavarreda Shana Alex , Brown E. Richard , Bolduc Claudie Dandurand
Published: March 2011

Underinsurance is most commonly defined as the state in which people with medical coverage are still exposed to financial risk. We argue that the adequacy of health insurance coverage should also be assessed in terms of the adequacy of specific benefits coverage and access to care. Underinsurance can be understood conceptually as comprising three separate domains: (a) the economic features of health insurance, (b) the benefits covered, and (c) access to health services. The literature provides ample evidence that people who are underinsured have high financial risk and face barriers in access to care similar to those who are completely uninsured. In response to the growing recognition of the problems associated with underinsurance, the Patient Protection and Affordable Care Act of 2010 includes numerous provisions designed to limit costs to consumers, to assure a minimum set of benefits, and to enhance access to care, especially primary care.
Hypoxia. 5. Hypoxia and hematopoiesis
Authors: Yoon Donghoon , Ponka Prem , Prchal Josef T
Published: March 2011

Our understanding of organismal responses to hypoxia has stemmed from studies of erythropoietin regulation by hypoxia that led to the discovery of the master regulator of the hypoxic response, i.e., hypoxia-inducible factor (HIF). This is a transcription factor that is now known to induce the expression of a battery of genes in response to hypoxia. HIF-1 and HIF-2 regulate many genes that are involved in erythropoiesis and iron metabolism, which are essential for tissue oxygen delivery.
Real-time dynamic movement of caveolin-1 during smooth muscle contraction of human colon and aged rat colon transfected with caveolin-1 cDNA
Authors: Somara Sita , Bashllari Daniela , Gilmont Robert R. , Bitar Khalil N.
Published: March 2011

Caveolin-1 (cav-1) plays a key role in PKC-α and RhoA signaling pathways during acetylcholine (ACh)-induced contraction of colonic smooth muscle cells (CSMC). Aged rat CSMC showed sluggish contractility, concomitant with reduced expression of cav-1 with an associated reduction in activation of PKC-α and RhoA signaling pathway. Real-time monitoring of live human CSMC transfected with yellow fluorescent protein-tagged wild-type caveolin 1 cDNA (YFP-wt-cav-1) cDNA in the present study suggests that cav-1 cycles within and along the membrane in a synchronized, highly organized cytoskeletal path. These studies provide, for the first time, the advantages of real-time monitoring of the dynamic movement of caveolin in living cells. Rapid movement of cav-1 in response to ACh suggests its dynamic role in CSMC contraction. Human CSMC transfected with YFP-ΔTFT-cav-1 dominant negative cDNA show fluorescence in the cytosol of the CSMC and no movement of fluorescent cav-1 in response to ACh mimicking the response shown by aged rat CSMC. Transfection of CSMC from aged rat with YFP-wt-cav-1 cDNA restored the physiological contractile response to ACh as well as the dynamic movement of cav-1 along the organized cytoskeletal path observed in normal adult CSMC. To study the force generation by CSMC, three-dimensional colonic rings were bioengineered. Colonic bioengineered rings from aged CSMC showed reduced force generation compared with colonic bioengineered rings from adult CSMC. Colonic bioengineered rings from aged CSMC transfected with wt-cav-1 cDNA showed force generation similar to colonic bioengineered rings from adult rat CSMC. The data suggest that contraction in CSMC is dependent on cav-1 reorganization dynamics, which restores the physiological contractile response in aged CSMC. We hypothesize that dynamic movement of cav-1 is essential for physiological contractile response of colonic smooth muscle.
Effects of luminal thymol on epithelial transport in human and rat colon
Authors: Kaji Izumi , Karaki Shin-ichiro , Kuwahara Atsukazu
Published: March 2011

Gut lumen is continually exposed to a great variety of agents, including noxious compounds. Chemical receptors that detect the luminal environment are thought to play an important role as sensors and to modulate gastrointestinal functions. Recently, it has been reported that odorant receptors (ORs) are expressed in the small intestinal mucosa and that odorants stimulate serotonin secretion. However, ion transport in the responses to odorants has rarely been discussed, particularly in relation to the large intestine. In the present study, we examined the effects of the OR ligand thymol on ion transport in human and rat colonic epithelia using an Ussing chamber. In the mucosal-submucosal preparations, the mucosal addition of thymol evoked anion secretion concentration dependently. In addition, dextran (4 kDa) permeability was enhanced by the mucosal treatment with thymol. The response to thymol was not affected by tetrodotoxin (TTX) or piroxicam treatments in human or rat colon. Thymol-evoked electrogenic anion secretion was abolished under Ca2+-free conditions or mucosal treatment with transient receptor potential (TRP) A1 blocker (HC-030031). Pretreatment of thymol did not affect electrical field stimulation-evoked anion secretion but significantly attenuated short-chain fatty acid-evoked secretion in a concentration-dependent manner. OR1G1 and TRPA1 expression was investigated in isolated colonic mucosa by RT-PCR. The present results provide evidence that the OR ligand thymol modulates epithelial permeability and electrogenic anion secretion in human and rat colon. The anion secretion by luminal thymol is most likely mediated by direct activation of TRPA1 channel. We suggest that the sensing and responding to odorants in the colon also plays a role in maintaining intestinal homeostasis.
The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives
Authors: Bourque Stephane L. , Davidge Sandra T. , Adams Michael A.
Published: March 2011

Nitric oxide (NO) and endothelin-1 (ET-1) are natural counterparts in vascular function, and it is becoming increasingly clear that an imbalance between these two mediators is a characteristic of endothelial dysfunction and is important in the progression of vascular disease. Here, we review classical and more recent data that suggest that ET-1 should be regarded as an essential component of NO signaling. In particular, we review evidence of the role of ET-1 in models of acute and chronic NO synthase blockade. Furthermore, we discuss the possible mechanisms by which NO modulates ET-1 activity. On the basis of these studies, we suggest that NO tonically inhibits ET-1 function, and in conditions of diminished NO bioavailability, the deleterious effects of unmitigated ET-1 actions result in vasoconstriction and eventually lead to vascular remodeling and dysfunction.
Exercise ameliorates high-fat diet-induced metabolic and vascular dysfunction, and increases adipocyte progenitor cell population in brown adipose tissue
Authors: Xu Xiaohua , Ying Zhekang , Cai Ming , Xu Zhaobin , Li Yuanjing , Jiang Silis Y. , Tzan Kevin , Wang Aixia , Parthasarathy Sampath , He Guanglong , Rajagopalan Sanjay , Sun Qinghua
Published: March 2011

A high-fat diet (HFD) is associated with adipose inflammation, which contributes to key components of metabolic syndrome, including obesity and insulin resistance. The increased visceral adipose tissue mass associated with obesity is the result of hyperplasia and hypertrophy of adipocytes. To investigate the effects of exercise on HFD-induced metabolic disorders, male C57BL/6 mice were divided into four groups: SED (sedentary)-ND (normal diet), EX (exercise)-ND, SED-HFD, and EX-HFD. Exercise was performed on a motorized treadmill at 15 m/min, 40 min/day, and 5 day/wk for 8 wk. Exercise resulted in a decrease in abdominal fat contents and inflammation, improvements in glucose tolerance and insulin resistance, and enhancement of vascular constriction and relaxation responses. Exercise with or without HFD increased putative brown adipocyte progenitor cells in brown adipose tissue compared with groups with the same diet, with an increase in brown adipocyte-specific gene expression in brown and white adipose tissue. Exercise training enhanced in vitro differentiation of the preadipocytes from brown adipose depots into brown adipocytes and enhanced the expression of uncoupling protein 1. These findings suggest that exercise ameliorates high-fat diet-induced metabolic disorders and vascular dysfunction, and increases adipose progenitor cell population in brown adipose tissue, which might thereby contribute to enhanced functional brown adipose.
n-3 Fatty acids block TNF-α-stimulated MCP-1 expression in rat mesangial cells
Authors: Diaz Encarnacion Montserrat M. , Warner Gina M. , Cheng Jingfei , Gray Catherine E. , Nath Karl A. , Grande Joseph P.
Published: March 2011

Monocyte chemoattractant protein 1 (MCP-1) is a CC cytokine that fundamentally contributes to the pathogenesis of inflammatory renal disease. MCP-1 is highly expressed in cytokine-stimulated mesangial cells in vitro and following glomerular injury in vivo. Interventions to limit MCP-1 expression are commonly effective in assorted experimental models. Fish oil, an abundant source of n-3 fatty acids, has anti-inflammatory properties, the basis of which remains incompletely defined. We examined potential mechanisms whereby fish oil reduces MCP-1 expression and thereby suppresses inflammatory responses to tissue injury. Cultured mesangial cells were treated with TNF-α in the presence of the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); equimolar concentrations of the n-6 fatty acids LA and OA served as controls. MCP-1 mRNA expression was assessed by Northern blotting, and transcriptional activity of the MCP-1 promoter was assessed by transient transfection. The involvement of the ERK and NF-κB pathways was evaluated through transfection analysis and the use of the MEK inhibitor U0126. DHA and EPA decreased TNF-α-stimulated MCP-1 mRNA expression by decreasing transcription of the MCP-1 gene. DHA and EPA decreased p-ERK expression and nuclear translocation of NF-κB, both of which are necessary for TNF-α-stimulated MCP-1 expression. Both NF-κB and AP-1 sites were involved in transcriptional regulation of the MCP-1 gene by DHA and EPA. We conclude that DHA and EPA inhibit TNF-α-stimulated transcription of the MCP-1 gene through interaction of signaling pathways involving ERK and NF-κB. We speculate that such effects may contribute to the salutary effect of fish oil in renal and vascular disease.
Glycated and carbamylated albumin are more “nephrotoxic” than unmodified albumin in the amphibian kidney
Authors: Gross M.-L. , Piecha G. , Bierhaus A. , Hanke W. , Henle T. , Schirmacher P. , Ritz E.
Published: March 2011

There is increasing evidence that proteins in tubular fluid are “nephrotoxic.” In vivo it is difficult to study protein loading of tubular epithelial cells in isolation, i.e., without concomitant glomerular damage or changes of renal hemodynamics, etc. Recently, a unique amphibian model has been described which takes advantage of the special anatomy of the amphibian kidney in which a subset of nephrons drains the peritoneal cavity (open nephrons) so that intraperitoneal injection of protein selectively causes protein storage in and peritubular fibrosis around open but not around closed tubules. There is an ongoing debate as to what degree albumin per se is nephrotoxic and whether modification of albumin alters its nephrotoxicity. We tested the hypothesis that carbamylation and glycation render albumin more nephrotoxic compared with native albumin and alternative albumin modifications, e.g., lipid oxidation and lipid depletion. Preparations of native and modified albumin were injected into the axolotl peritoneum. The kidneys were retrieved after 10 days and studied by light microscopy as well as by immunohistochemistry [transforming growth factor (TGF)-β, PDGF, NF-κB, collagen I and IV, RAGE], nonradioactive in situ hybridization, and Western blotting. Two investigators unaware of the animal groups evaluated and scored renal histology. Compared with unmodified albumin, glycated and carbamylated albumin caused more pronounced protein storage. After no more than 10 days, selective peritubular fibrosis was seen around nephrons draining the peritoneal cavity (open nephrons), but not around closed nephrons. Additionally, more intense expression of RAGE, NF-κB, as well as PDGF, TGF-β, EGF, ET-1, and others was noted by histochemistry and confirmed by RT-PCR for fibronectin and TGF-β as well as nonradioactive in situ hybridization for TGF-β and fibronectin. The data indicate that carbamylation and glycation increase the capacity of albumin to cause tubular cell damage and peritubular fibrosis.
A mathematical model of diffusional shunting of oxygen from arteries to veins in the kidney
Authors: Gardiner Bruce S. , Smith David W. , O'Connor Paul M. , Evans Roger G.
Published: March 2011

To understand how arterial-to-venous (AV) oxygen shunting influences kidney oxygenation, a mathematical model of oxygen transport in the renal cortex was created. The model consists of a multiscale hierarchy of 11 countercurrent systems representing the various branch levels of the cortical vasculature. At each level, equations describing the reactive-advection-diffusion of oxygen are solved. Factors critical in renal oxygen transport incorporated into the model include the parallel geometry of arteries and veins and their respective sizes, variation in blood velocity in each vessel, oxygen transport (along the vessels, between the vessels and between vessel and parenchyma), nonlinear binding of oxygen to hemoglobin, and the consumption of oxygen by renal tissue. The model is calibrated using published measurements of cortical vascular geometry and microvascular Po2. The model predicts that AV oxygen shunting is quantitatively significant and estimates how much kidney V̇o2 must change, in the face of altered renal blood flow, to maintain cortical tissue Po2 at a stable level. It is demonstrated that oxygen shunting increases as renal V̇o2 or arterial Po2 increases. Oxygen shunting also increases as renal blood flow is reduced within the physiological range or during mild hemodilution. In severe ischemia or anemia, or when kidney V̇o2 increases, AV oxygen shunting in proximal vascular elements may reduce the oxygen content of blood destined for the medullary circulation, thereby exacerbating the development of tissue hypoxia. That is, cortical ischemia could cause medullary hypoxia even when medullary perfusion is maintained. Cortical AV oxygen shunting limits the change in oxygen delivery to cortical tissue and stabilizes tissue Po2 when arterial Po2 changes, but renders the cortex and perhaps also the medulla susceptible to hypoxia when oxygen delivery falls or consumption increases.
Gender difference in antidiuretic response to desmopressin
Authors: Juul Kristian Vinter , Klein Bjarke Mirner , Sandström Rikard , Erichsen Lars , Nørgaard Jens Peter
Published: March 2011

Increased age and female gender are well-known risk factors for the development of desmopressin-induced hyponatremia. However, little focus has been on exploring gender differences in the antidiuretic response to desmopressin. Based on an exploratory analysis from three clinical trials, we report a significant gender difference in the effects of desmopressin on nocturnal urine volume that could not be explained by pharmacokinetic differences. Mean desmopressin concentration profiles were tested for covariates, and age and gender were not statistically significant and only weight was significant for log(Cmax) ( P = 0.0183) and borderline significant for log(AUC) ( P = 0.0571). The decrease in nocturnal urine volume in nocturia patients treated with desmopressin over 28 days was significantly larger for women at the lower desmopressin melt doses of 10 and 25 μg than for men. The ED50 for men was modeled to be 43.2 μg and 16.1 μg for women, with the ED50 men/women estimated to be 2.7 (1.3–8.1 95% CI), corresponding to significantly higher sensitivity to desmopressin in women. An increasing incidence of hyponatremia with increasing dose was found, and at the highest dose level of 100 μg decreases in serum sodium were approximately twofold greater in women over 50 yr of age than in men. A new dose recommendation stratified by gender is suggested in the treatment of nocturia: for men, 50- to 100-μg melt is an efficacious and safe dose, while for women a dose of 25 μg melt is recommended as efficacious with no observed incidences of hyponatremia. Areas for further research are proposed to uncover pathophysiological mechanism(s) behind these gender differences.
Early life exposure to noise alters the representation of auditory localization cues in the auditory space map of the barn owl
Authors: Efrati Adi , Gutfreund Yoram
Published: March 2011

The auditory space map in the optic tectum (OT) (also known as superior colliculus in mammals) relies on the tuning of neurons to auditory localization cues that correspond to specific sound source locations. This study investigates the effects of early auditory experiences on the neural representation of binaural auditory localization cues. Young barn owls were raised in continuous omnidirectional broadband noise from before hearing onset to the age of ∼65 days. Data from these birds were compared with data from age-matched control owls and from normal adult owls (>200 days). In noise-reared owls, the tuning of tectal neurons for interaural level differences and interaural time differences was broader than in control owls. Moreover, in neurons from noise-reared owls, the interaural level differences tuning was biased towards sounds louder in the contralateral ear. A similar bias appeared, but to a much lesser extent, in age-matched control owls and was absent in adult owls. To follow the recovery process from noise exposure, we continued to survey the neural representations in the OT for an extended period of up to several months after removal of the noise. We report that all the noise-rearing effects tended to recover gradually following exposure to a normal acoustic environment. The results suggest that deprivation from experiencing normal acoustic localization cues disrupts the maturation of the auditory space map in the OT.
Leg muscle vibration modulates bodily self-consciousness: integration of proprioceptive, visual, and tactile signals
Authors: Palluel Estelle , Aspell Jane Elizabeth , Blanke Olaf
Published: March 2011

Behavioral studies have used visuo-tactile conflicts between a participant's body and a visually presented fake or virtual body to investigate the importance of bodily perception for self-consciousness (bodily self-consciousness). Illusory self-identification with a fake body and changes in tactile processing—modulation of visuo-tactile cross-modal congruency effects (CCEs)—were reported in previous findings. Although proprioceptive signals are deemed important for bodily self-consciousness, their contribution to the representation of the full body has not been studied. Here we investigated whether and how self-identification and tactile processing (CCE magnitude) could be modified by altering proprioceptive signals with 80-Hz vibrations at the legs. Participants made elevation judgments of tactile cues (while ignoring nearby lights) during synchronous and asynchronous stroking of a seen fake body. We found that proprioceptive signals during vibrations altered the magnitude of self-identification and mislocalization of touch (CCE) in a synchrony-dependent fashion: we observed an increase of self-identification and CCE magnitude during asynchronous stroking. In a second control experiment we studied whether proprioceptive signals per se, or those from the lower limbs in particular, were essential for these changes. We applied vibrations at the upper limbs (which provide no information about the position of the participant's body in space) and in this case observed no modulation of bodily self-consciousness or tactile perception. These data link proprioceptive signals from the legs that are conveyed through the dorsal column-medial lemniscal pathway to bodily self-consciousness. We discuss their integration with bodily signals from vision and touch for full-body representations.
miR-34a Induces the Downregulation of BothE2F1andB-MybOncogenes in Leukemic Cells
Authors: Zauli Giorgio , Voltan Rebecca , di Iasio Maria Grazia , Bosco Raffaella , Melloni Elisabetta , Sana Maria Elena , Secchiero Paola
Published: March 2011

Purpose: To elucidate new molecular mechanisms able to downregulate the mRNA levels of key oncogenes, such as B-Myb and E2F1, in a therapeutic perspective.

Experimental Design: B-Myb and E2F1 mRNA levels were evaluated in primary B chronic lymphocytic leukemia (B-CLL, n = 10) and acute myeloid leukemia (AML, n = 5) patient cells, in a variety of p53wild-type and p53mutated/deleted leukemic cell lines, as well as in primary endothelial cells and fibroblasts. Knockdown experiments with siRNA for p53 and E2F1 and overexpression experiments with miR34a were conducted to elucidate the role of these pathways in promoting B-Myb downregulation.

Results: In vitro exposure to Nutlin-3, a nongenotoxic activator of p53, variably downregulated the expression of B-Myb in primary leukemic cells and in p53wild-type myeloid (OCI, MOLM) and lymphoblastoid (SKW6.4, EHEB) but not in p53mutated (NB4, BJAB, MAVER) or p53deleted (HL-60) leukemic cell lines. The transcriptional repression of B-Myb was also observed in primary normal endothelial cells and fibroblasts. B-Myb downregulation played a critical role in the cell-cycle block in G1 phase induced by Nutlin-3, as shown by transfection experiments with specific siRNA. Moreover, we have provided experimental evidence suggesting that miR-34a is a central mediator in the repression of B-Myb both directly and through E2F1.

Conclusions: Owing to the role of B-Myb and E2F1 transcription factors in controlling cell-cycle progression of leukemic cells, the downregulation of these oncogenes by miR-34a suggests the usefulness of therapeutic approaches aimed to modulate the levels of miR-34a. Clin Cancer Res; 17(9); 2712–24. ©2011 AACR.
Targeting the Hedgehog Pathway in Cancer: Can the Spines Be Smoothened?
Authors: Ailles Laurie , Siu Lillian L.
Published: March 2011

Aberrant Hedgehog (Hh) pathway signaling has been suggested to play a role in the development of multiple solid tumors and hematologic malignancies. GDC-0449 is a novel first-in-human, first-in-class smoothened (SMO) inhibitor, which has completed its phase I evaluation and achieved proof of concept in tumors with Hh pathway mutations. Clin Cancer Res; 17(8); 2071–3. ©2011 AACR.
Chemoprevention of Azoxymethane/Dextran Sodium Sulfate–Induced Mouse Colon Carcinogenesis by Freeze-Dried YamSanyakuand Its Constituent Diosgenin
Authors: Miyoshi Noriyuki , Nagasawa Tomoki , Mabuchi Ryota , Yasui Yumiko , Wakabayashi Keiji , Tanaka Takuji , Ohshima Hiroshi
Published: March 2011

The effects of sanyaku, a traditional Chinese medicine [freeze-dried powder of the yam tuber (Dioscorea)], and its major steroidal saponin constituent, diosgenin, on colon carcinogenesis were investigated. Male ICR mice were subjected to a single intraperitoneal injection of azoxymethane (AOM; 10 mg/kg body weight) followed by administration of 1.5% dextran sodium sulfate (DSS) in drinking water for 7 days to establish carcinogenesis. Commercial diosgenin or sanyaku, which contained diosgenin at 63.8 ± 1.2 mg/kg dry weight, was given in the diet at 20, 100, or 500 mg/kg for 17 weeks. Groups of mice that received diosgenin or sanyaku at all doses yielded significantly less number of colon tumors compared with the AOM/DSS-treated mice. Occurrence of colonic mucosal ulcer and dysplastic crypt induced by AOM/DSS treatment was also significantly decreased by the administration of diosgenin and sanyaku, which was in accordance with the significant reduction of AOM/DSS-mediated increases in expression of inflammatory cytokines such as IL-1β by diosgenin and sanyaku. Furthermore, elevated levels of serum triglyceride in the AOM/DSS-treated mice tended to be reduced in mice given diosgenin and sanyaku. Microarray and real-time reverse transcriptase PCR analyses revealed that diosgenin administration increased 12-fold the expression of lipoprotein lipase, which may contribute to reduced serum triglyceride levels. Other genes altered by diosgenin included those associated with antioxidative stress responses and apoptosis, such as heme oxygenase-1, superoxide dismutase-3, and caspase-6. Our results imply that the Chinese medicine sanyaku and the tubers of various yams containing diosgenin as food could be ingested to prevent colon carcinogenesis in humans. Cancer Prev Res; 4(6); 924–34. ©2011 AACR.
Association of Prostate Cancer Risk Loci with Disease Aggressiveness and Prostate Cancer–Specific Mortality
Authors: Pomerantz Mark M. , Werner Lillian , Xie Wanling , Regan Meredith M. , Lee Gwo-Shu Mary , Sun Tong , Evan Carolyn , Petrozziello Gillian , Nakabayashi Mari , Oh William K. , Kantoff Philip W. , Freedman Matthew L.
Published: March 2011

Genome-wide association studies have detected more than 30 inherited prostate cancer risk variants. While clearly associated with risk, their relationship with clinical outcome, particularly prostate cancer–specific mortality, is less well known. We investigated whether the risk variants are associated with various measures of disease aggressiveness and prostate cancer–specific mortality. In a cohort of 3,945 men of European ancestry with prostate cancer, we genotyped 36 single nucleotide polymorphisms (SNP): 35 known prostate cancer risk variants and one SNP (rs4054823) that was recently reported to be associated with prostate cancer aggressiveness. The majority of subjects had a diagnosis of prostate cancer between 1995 and 2004, and the cohort included a total of 580 prostate cancer–specific deaths. We evaluated associations between the 36 polymorphisms and prostate cancer survival, as well as other clinical parameters including age at diagnosis, prostate-specific antigen (PSA) at diagnosis, and Gleason score. Two SNPs, rs2735839 at chromosome 19q13 and rs7679673 at 4q24, were associated with prostate cancer–specific survival (P = 7 × 10−4 and 0.014, respectively). A total of 12 SNPs were associated with other variables (P < 0.05): age at diagnosis, PSA at diagnosis, Gleason score, and/or disease aggressiveness based on D'Amico criteria. Genotype status at rs4054823 was not associated with aggressiveness or outcome. Our results identify two common polymorphisms associated with prostate cancer–specific mortality. Cancer Prev Res; 4(5); 719–28. ©2011 AACR.
Role of GSTM1 and GSTT1 Polymorphism: Susceptibility to Oral Submucous Fibrosis in the North Indian Population
Authors: Agrawal Deepa , Gupta Shalini , Agarwal Deepti , Gupta Om Prakash , Agarwal Mohit
Published: March 2011

Molecular epidemiological studies have provided evidence that individual susceptibility to cancer is mediated by both genetic and environmental factors. Several allelic variants of polymorphic glutathione s-transferases (GSTs) show impaired enzyme activity and are suspected to increase the host’s susceptibility to various cancers. To determine the association of GST variants with the risk of oral submucous fibrosis (OSF), the distribution of polymorphisms in GSTM1 and GSTT1 was studied in 90 OSF patients and 130 healthy controls. Genotypic analysis was performed by multiplex PCR. The relationship between the null genotypes and the risk of OSF was assessed by means of odds ratios (OR) with 95% confidence intervals (CI) calculated by logistic regression. The frequency of both the GSTM1 and GSTT1 null genotypes was higher in the OSF cases than in the controls. The prevalence of the GSTM1 null genotype in the OSF cases was 46.6% as compared to 29.2% in the controls (OR 2.12, 95% CI 1.2–3.9) and GSTT1 null was 24.4% in the OSF cases versus 10.7% in the controls (OR 2.68, 95% CI 1.22–5.96). There was evidence of an increased risk with the absence of both genotypes (7.5-fold; OR 7.5, 95% CI 2.3–24). Our findings suggest that the GSTM1 and GSTT1 null genotypes, separately or in combination, increase the risk of developing OSF in the North Indian population.