bluuebunny/crossref_metadata_2025 huggingface dataset:
A double-blind atropine trial for active learning of autonomic function
Authors: Fry Jeffrey R. , Burr Steven A.
Published: December 2011

Here, we describe a human physiology laboratory class measuring changes in autonomic function over time in response to atropine. Students use themselves as subjects, generating ownership and self-interest in the learning as well as directly experiencing the active link between physiology and pharmacology in people. The class is designed to concomitantly convey the importance of bias in experimentation by adopting a double-blind placebo-controlled approach. We have used this class effectively in various forms with ∼600 students receiving atropine over the last 16 yr. This class has received favorable feedback from staff and students of medicine, pharmacy, and neuroscience, and we recommend it for such undergraduates. The learning objectives that students are expected to achieve are to be able to 1) know the ethical, safety, and hygiene requirements for using human volunteers as subjects; 2) implement and explain a double-blind placebo-controlled trial; 3) design, agree, and execute a protocol for making (and accurately recording) precise reproducible measurements of pulse rate, pupil diameter, and salivary flow; 4) evaluate the importance of predose periods and measurement consistency to detect effects (including any reversibility) after an intervention; 5) experience direct cause-and-effect relationships integrating physiology with pharmacology in people; 6) calculate appropriate summary statistics to describe the data and determine the data's statistical significance; 7) recognize normal variability both within and between subjects in baseline physiological parameters and also recognize normal variability in response to pharmacological treatment; 8) infer the distribution and role of muscarinic receptors in the autonomic nervous system with respect to the heart, eye, and mouth; 9) identify and explain the clinical significance of differences in effect due to the route and formulation of atropine; 10) produce and deliver a concise oral presentation of experimental findings; and 11) produce a written report in the form of a short scientific research article. The results of a typical study are presented, which demonstrate that the administration of atropine by a subcutaneous injection elicited a significant increase in pulse rate and pupil diameter and a significant decrease in salivary flow, whereas administration of atropine in an oral liquid elicited significant effects on pulse rate and salivary flow, and an oral solid format elicited a significant alteration in salivary flow alone. More detailed analysis of the salivary flow data demonstrated clear differences between the routes of administration and formulation in the onset and magnitude of action of atropine.
Endogenous cannabinoid system regulates intestinal barrier function in vivo through cannabinoid type 1 receptor activation
Authors: Zoppi Silvia , Madrigal José L. M. , Pérez-Nievas Beatriz G. , Marín-Jiménez Ignacio , Caso Javier R. , Alou Luis , García-Bueno Borja , Colón Arturo , Manzanares Jorge , Luisa Gómez-Lus M. , Menchén Luis , Leza Juan C.
Published: December 2011

The deleterious effects of stress on the gastrointestinal tract seem to be mainly mediated by the induction of intestinal barrier dysfunction and subsequent subtle mucosal inflammation. Cannabinoid 1 receptor (CB1R) is expressed in the mammalian gut under physiological circumstances. The aim of this investigation is to study the possible role of CB1R in the maintenance of mucosal homeostasis after stress exposure. CB1R knockout mice (CB1R−/−) and their wild-type (WT) counterparts were exposed to immobilization and acoustic (IA) stress for 2 h per day during 4 consecutive days. Colonic protein expression of the inducible forms of the nitric oxide synthase and cyclooxygenase (NOS2 and COX2), IgA production, permeability to 51Cr-EDTA, and bacterial translocation to mesenteric lymph nodes were evaluated. Stress exposure induced greater expression of proinflammatory enzymes NOS2 and COX2 in colonic mucosa of CB1R−/− mice when compared with WT animals. These changes were related with a greater degree of colonic barrier dysfunction in CB1R−/− animals determined by 1) a significantly lower IgA secretion, 2) higher paracellular permeability to 51Cr-EDTA, and 3) higher bacterial translocation, both under basal conditions and after IA stress exposure. Pharmacological antagonism with rimonabant reproduced stress-induced increase of proinflammatory enzymes in the colon described in CB1R−/− mice. In conclusion, CB1R exerts a protective role in the colon in vivo through the regulation of intestinal secretion of IgA and paracellular permeability. Pharmacological modulation of cannabinoid system within the gastrointestinal tract might be therapeutically useful in conditions on which intestinal inflammation and barrier dysfunction takes place after exposure to stress.
Interleukin-18 facilitates neutrophil transmigration via myosin light chain kinase-dependent disruption of occludin, without altering epithelial permeability
Authors: Lapointe Tamia K. , Buret Andre G.
Published: December 2011

Compromised epithelial barrier function and tight junction alterations are hallmarks of a number of gastrointestinal disorders, including inflammatory bowel disease (IBD). Increased levels of IL-18 have been observed in mucosal samples from Crohn's disease and ulcerative colitis patients. Remarkably, several reports have demonstrated that immunological or genetic blockage of IL-18 ameliorates the severity of colitis in multiple in vivo models of IBD. Nevertheless, the effects of IL-18 on intestinal epithelial barrier function remain unclear. We hypothesized that IL-18 could disrupt intestinal epithelial barrier structure and function, thus contributing to tissue damage in the context of IBD. The aims of the present study were to determine the effects of IL-18 on epithelial barrier structure and function and to characterize the mechanisms involved in these modulatory properties. Human colonic epithelial Caco-2 monolayers were coincubated with IL-18 for 24 h and processed for immunocytochemistry, immunoblotting, quantitative PCR, and permeability measurements (transepithelial resistance, FITC-dextran fluxes, and bacterial translocation). Our findings indicate that IL-18 selectively disrupts tight junctional occludin, without affecting the distribution pattern of claudin-4, claudin-5, zonula occludens-1, or E-cadherin. This effect coincided with a significant increase in myosin light chain kinase (MLCK) protein levels and activity. Pharmacological inhibition of MLCK and NF-κB prevented IL-18-induced loss of occludin. Although too subtle to alter paracellular permeability, these fine changes correlated with an MLCK-dependent increase in neutrophil transepithelial migration. In conclusion, our data suggest that IL-18 may potentiate inflammation in the context of IBD by facilitating neutrophil transepithelial migration via MLCK-dependent disruption of tight junctional occludin.
Adipose stromal vascular fraction cell construct sustains coronary microvascular function after acute myocardial infarction
Authors: LeBlanc Amanda J. , Touroo Jeremy S. , Hoying James B. , Williams Stuart K.
Published: December 2011

A three-dimensional tissue construct was created using adipose-derived stromal vascular fraction (SVF) cells and evaluated as a microvascular protection treatment in a myocardial infarction (MI) model. This study evaluated coronary blood flow (BF) and global left ventricular function after MI with and without the SVF construct. Fischer-344 rats were separated into four groups: sham operation (sham), MI, MI Vicryl patch (no cells), and MI SVF construct (MI SVF). SVF cells were labeled with green fluorescent protein (GFP). Immediately postinfarct, constructs were implanted onto the epicardium at the site of ischemia. Four weeks postsurgery, the coronary BF reserve was significantly decreased by 67% in the MI group and 75% in the MI Vicryl group compared with the sham group. The coronary BF reserve of the sham and MI SVF groups in the area at risk was not significantly different (sham group: 83 ± 22% and MI SVF group: 57 ± 22%). Griffonia simplicifolia I and GFP-positive SVF immunostaining revealed engrafted SVF cells around microvessels in the infarct region 4 wk postimplant. Overall heart function, specifically ejection fraction, was significantly greater in MI SVF hearts compared with MI and MI Vicryl hearts (MI SVF: 66 ± 4%, MI: 37 ± 8%, and MI Vicryl: 29 ± 6%). In conclusion, adipose-derived SVF cells can be used to construct a novel therapeutic modality for treating microvascular instability and ischemia through implantation on the epicardial surface of the heart. The SVF construct implanted immediately after MI not only maintains heart function but also sustains microvascular perfusion and function in the infarct area by sustaining the coronary BF reserve.
Angiotensin-(1–7) attenuates angiotensin II-induced cardiac remodeling associated with upregulation of dual-specificity phosphatase 1
Authors: McCollum LaTronya T. , Gallagher Patricia E. , Ann Tallant E.
Published: December 2011

Chronic hypertension induces cardiac remodeling, including left ventricular hypertrophy and fibrosis, through a combination of both hemodynamic and humoral factors. In previous studies, we showed that the heptapeptide ANG-(1–7) prevented mitogen-stimulated growth of cardiac myocytes in vitro, through a reduction in the activity of the MAPKs ERK1 and ERK2. In this study, saline- or ANG II-infused rats were treated with ANG-(1–7) to determine whether the heptapeptide reduces myocyte hypertrophy in vivo and to identify the signaling pathways involved in the process. ANG II infusion into normotensive rats elevated systolic blood pressure >50 mmHg, in association with increased myocyte cross-sectional area, ventricular atrial natriuretic peptide mRNA, and ventricular brain natriuretric peptide mRNA. Although infusion with ANG-(1–7) had no effect on the ANG II-stimulated elevation in blood pressure, the heptapeptide hormone significantly reduced the ANG II-mediated increase in myocyte cross-sectional area, interstitial fibrosis, and natriuretic peptide mRNAs. ANG II increased phospho-ERK1 and phospho-ERK2, whereas cotreatment with ANG-(1–7) reduced the phosphorylation of both MAPKs. Neither ANG II nor ANG-(1–7) altered the ERK1/2 MAPK kinase MEK1/2. However, ANG-(1–7) infusion, with or without ANG II, increased the MAPK phosphatase dual-specificity phosphatase (DUSP)-1; in contrast, treatment with ANG II had no effect on DUSP-1, suggesting that ANG-(1–7) upregulates DUSP-1 to reduce ANG II-stimulated ERK activation. These results indicate that ANG-(1–7) attenuates cardiac remodeling associated with a chronic elevation in blood pressure and upregulation of a MAPK phosphatase and may be cardioprotective in patients with hypertension.
Increased arterial smooth muscle Ca2+ signaling, vasoconstriction, and myogenic reactivity in Milan hypertensive rats
Authors: Linde Cristina I. , Karashima Eiji , Raina Hema , Zulian Alessandra , Wier Withrow G. , Hamlyn John M. , Ferrari Patrizia , Blaustein Mordecai P. , Golovina Vera A.
Published: December 2011

The Milan hypertensive strain (MHS) rats are a genetic model of hypertension with adducin gene polymorphisms linked to enhanced renal tubular Na+ reabsorption. Recently we demonstrated that Ca2+ signaling is augmented in freshly isolated mesenteric artery myocytes from MHS rats. This is associated with greatly enhanced expression of Na+/Ca2+ exchanger-1 (NCX1), C-type transient receptor potential (TRPC6) protein, and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) compared with arteries from Milan normotensive strain (MNS) rats. Here, we test the hypothesis that the enhanced Ca2+ signaling in MHS arterial smooth muscle is directly reflected in augmented vasoconstriction [myogenic and phenylephrine (PE)-evoked responses] in isolated mesenteric small arteries. Systolic blood pressure was higher in MHS (145 ± 1 mmHg) than in MNS (112 ± 1 mmHg; P < 0.001; n = 16 each) rats. Pressurized mesenteric resistance arteries from MHS rats had significantly augmented myogenic tone and reactivity and enhanced constriction to low-dose (1–100 nM) PE. Isolated MHS arterial myocytes exhibited approximately twofold increased peak Ca2+ signals in response to 5 μM PE or ATP in the absence and presence of extracellular Ca2+. These augmented responses are consistent with increased vasoconstrictor-evoked sarcoplasmic reticulum (SR) Ca2+ release and increased Ca2+ entry, respectively. The increased SR Ca2+ release correlates with a doubling of inositol 1,4,5-trisphosphate receptor type 1 and tripling of SERCA2 expression. Pressurized MHS arteries also exhibited a ∼70% increase in 100 nM ouabain-induced vasoconstriction compared with MNS arteries. These functional alterations reveal that, in a genetic model of hypertension linked to renal dysfunction, multiple mechanisms within the arterial myocytes contribute to enhanced Ca2+ signaling and myogenic and vasoconstrictor-induced arterial constriction. MHS rats have elevated plasma levels of endogenous ouabain, which may initiate the protein upregulation and enhanced Ca2+ signaling. These molecular and functional changes provide a mechanism for the increased peripheral vascular resistance (whole body autoregulation) that underlies the sustained hypertension.
Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system
Authors: Bhandary Yashodhar P. , Shetty Shwetha K. , Marudamuthu Amarnath S. , Gyetko Margaret R. , Idell Steven , Gharaee-Kermani Mehrnaz , Shetty Rashmi S. , Starcher Barry C. , Shetty Sreerama
Published: December 2011

Alveolar type II (ATII) cell apoptosis and depressed fibrinolysis that promotes alveolar fibrin deposition are associated with acute lung injury (ALI) and the development of pulmonary fibrosis (PF). We therefore sought to determine whether p53-mediated inhibition of urokinase-type plasminogen activator (uPA) and induction of plasminogen activator inhibitor-1 (PAI-1) contribute to ATII cell apoptosis that precedes the development of PF. We also sought to determine whether caveolin-1 scaffolding domain peptide (CSP) reverses these changes to protect against ALI and PF. Tissues as well as isolated ATII cells from the lungs of wild-type (WT) mice with BLM injury show increased apoptosis, p53, and PAI-1, and reciprocal suppression of uPA and uPA receptor (uPAR) protein expression. Treatment of WT mice with CSP reverses these effects and protects ATII cells against bleomycin (BLM)-induced apoptosis whereas CSP fails to attenuate ATII cell apoptosis or decrease p53 or PAI-1 in uPA-deficient mice. These mice demonstrate more severe PF. Thus p53 is increased and inhibits expression of uPA and uPAR while increasing PAI-1, changes that promote ATII cell apoptosis in mice with BLM-induced ALI. We show that CSP, an intervention targeting this pathway, protects the lung epithelium from apoptosis and prevents PF in BLM-induced lung injury via uPA-mediated inhibition of p53 and PAI-1.
Activation of calpains mediates early lung neutrophilic inflammation in ventilator-induced lung injury
Authors: Liu Dejie , Yan Zhibo , Minshall Richard D. , Schwartz David E. , Chen Yuguo , Hu Guochang
Published: December 2011

Lung inflammatory responses in the absence of infection are considered to be one of primary mechanisms of ventilator-induced lung injury. Here, we determined the role of calpain in the pathogenesis of lung inflammation attributable to mechanical ventilation. Male C57BL/6J mice were subjected to high (28 ml/kg) tidal volume ventilation for 2 h in the absence and presence of calpain inhibitor I (10 mg/kg). To address the isoform-specific functions of calpain 1 and calpain 2 during mechanical ventilation, we utilized a liposome-based delivery system to introduce small interfering RNAs targeting each isoform in pulmonary vasculature in vivo. Mechanical ventilation with high tidal volume induced rapid (within minutes) and persistent calpain activation and lung inflammation as evidenced by neutrophil recruitment, production of TNF-α and IL-6, pulmonary vascular hyperpermeability, and lung edema formation. Pharmaceutical calpain inhibition significantly attenuated these inflammatory responses caused by lung hyperinflation. Depletion of calpain 1 or calpain 2 had a protective effect against ventilator-induced lung inflammatory responses. Inhibition of calpain activity by means of siRNA silencing or pharmacological inhibition also reduced endothelial nitric oxide (NO) synthase (NOS-3)-mediated NO production and subsequent ICAM-1 phosphorylation following high tidal volume ventilation. These results suggest that calpain activation mediates early lung inflammation during ventilator-induced lung injury via NOS-3/NO-dependent ICAM-1 phosphorylation and neutrophil recruitment. Inhibition of calpain activation may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury.
Acute running stimulates hippocampal dopaminergic neurotransmission in rats, but has no influence on brain-derived neurotrophic factor
Authors: Goekint Maaike , Bos Inge , Heyman Elsa , Meeusen Romain , Michotte Yvette , Sarre Sophie
Published: December 2011

Hippocampal brain-derived neurotrophic factor (BDNF) protein is increased with exercise in rats. Monoamines seem to play a role in the regulation of BDNF, and monoamine neurotransmission is known to increase with exercise. The purpose of this study was to examine the influence of acute exercise on monoaminergic neurotransmission and BDNF protein concentrations. Hippocampal microdialysis was performed in rats that were subjected to 60 min of treadmill running at 20 m/min or rest. Two hours postexercise, the rats were killed, and the hippocampus was dissected. In experiments without microdialysis, hippocampus and serum samples were collected immediately after exercise. Exercise induced a twofold increase in hippocampal dopamine release. Noradrenaline and serotonin release were not affected. Hippocampal BDNF levels were not influenced, whether they were measured immediately or 2 h after the exercise protocol. Serum BDNF levels did not change either, but serum BDNF was negatively correlated to peripheral corticosterone concentrations, indicating a possible inhibitory reaction to the stress of running. Sixty minutes of exercise enhances dopamine release in the hippocampus of the rat in vivo. However, this increase is not associated with changes in BDNF protein levels immediately nor 2 h after the acute exercise bout. An increased corticosterone level might be the contributing factor for the absence of changes in BDNF.
Modeling mechanical strains and stresses in soft tissues of the shoulder during load carriage based on load-bearing open MRI
Authors: Hadid Amir , Epstein Yoram , Shabshin Nogah , Gefen Amit
Published: December 2011

Shoulder strain is a major limiting factor associated with load carriage. Despite advances in backpack designs, there are still reports of shoulder discomfort, loss of sensorimotor functions, and brachial plexus syndrome. The current study is aimed at characterizing mechanical loading conditions (strains and stresses) that develop within the shoulder's soft tissues when carrying a backpack. Open MRI scans were used for reconstructing a three-dimensional geometrical model of an unloaded shoulder and for measuring the soft tissue deformations caused by a 25-kg backpack; subsequently, a subject-specific finite element (FE) model for nonlinear, large-deformation stress-strain analyses was developed. Skin pressure distributions under the backpack strap were used as reference data and for verifying the numerical solutions. The parameters of the model were adjusted to fit the calculated tissue deformations to those obtained by MRI. The MRI scans revealed significant compression of the soft tissues of the shoulder, with substantial deformations in the area of the subclavian muscle and the brachial plexus. The maximal pressure values exerted by a 25-kg load were substantial and reached ∼90 kPa. In the muscle surrounding the brachial plexus, the model predicted maximal compressive strain of 0.14 and maximal tensile strain of 0.13, which might be injurious for the underlying neural tissue. In conclusion, the FE model provided some insights regarding the potential mechanisms underlying brachial plexus injuries related to load carriage. The large tissue deformations and pressure hotspots that were observed are likely to result in tissue damage, which may hamper neural function if sustained for long time exposures.
Respiratory effect of the lower rib displacement produced by the diaphragm
Authors: De Troyer André
Published: December 2011

The diaphragm acting alone causes a cranial displacement of the lower ribs and a caudal displacement of the upper ribs. The respiratory effect of the lower rib displacement, however, is uncertain. In the present study, two sets of experiments were performed in dogs to assess this effect. In the first, all the inspiratory intercostal muscles were severed, so that the diaphragm was the only muscle active during inspiration, and the normal inspiratory cranial displacement of the lower ribs was suppressed at regular intervals. In the second experiment, the animals were given a muscle relaxant to abolish respiratory muscle activity, and external, cranially oriented forces were applied to the lower rib pairs to simulate the action of the diaphragm on these ribs. The data showed that 1) holding the lower ribs stationary during spontaneous, isolated diaphragm contraction had no effect on the change in lung volume during unimpeded inspiration and no effect on the fall in pleural pressure (Ppl) during occluded breaths; 2) the procedure, however, caused an increase in the caudal displacement of the upper ribs; and 3) pulling the lower rib pairs cranially induced a cranial displacement of the upper ribs and a small fall in Ppl. These observations indicate that the force applied on the lower ribs by the diaphragm during spontaneous contraction, acting through the interdependence of the ribs, is transmitted to the upper ribs and has an inspiratory effect on the lung. However, this effect is very small compared to that of the descent of the dome.
Alert: An Adaptive Low-Latency Event-Driven MAC Protocol for Wireless Sensor Networks
Authors: Namboodiri Vinod , Keshavarzian Abtin
Published: December 2011

Collection of rare but delay-critical messages from a group of sensor nodes is a key process in many wireless sensor network applications. This is particularly important for security-related applications like intrusion detection and fire alarm systems. An event sensed by multiple sensor nodes in the network can trigger many messages to be sent simultaneously. We present Alert, a MAC protocol for collecting event-triggered urgent messages from a group of sensor nodes with minimum latency and without requiring any cooperation or prescheduling among the senders or between senders and receiver during protocol execution. Alert is designed to handle multiple simultaneous messages from different nodes efficiently and reliably, minimizing the overall delay to collect all messages along with the delay to get the first message. Moreover, the ability of the network to handle a large number of simultaneous messages does not come at the cost of excessive delays when only a few messages need to be handled. We analyze Alert and evaluate its feasibility and performance with an implementation on commodity hardware. We further compare Alert with existing approaches through simulations and show the performance improvement possible through Alert.
Evaluation of the BD GeneOhm MRSA and VanR Assays as a Rapid Screening Tool for Detection of Methicillin-ResistantStaphylococcus aureusand Vancomycin-Resistant Enterococci in a Tertiary Hospital in Saudi Arabia
Authors: Hassan H. , Shorman M.
Published: December 2011

Objectives. The aim of this study was to evaluate the diagnostic performance of BD GeneOhm VanR Assay, a rapid PCR test that detects the presence ofvanAand/orvanBgenes and the performance of BDGeneOhm MRSA Assay which detects the staphylococcal cassette chromosomemec (SCCmeccassette) carrying themecAgene andStaphylococcus aureusspecific sequence located within theorfXgene.Methods. 300 duplicate rectal swabs collected consecutively were analyzed for the presence of VRE by culture and BD PCR. 2267 duplicate swabs were collected (728 nasal and 1539 groin swabs) and analyzed for the presence of MRSA by culture method and BD PCR.Results. Compared to culture, the BD GeneOhm VanR Assay showed a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100%, 91.1%, 23.5%, and 100%, respectively. The BD GeneOhm MRSA Assay revealed sensitivity, specificity, PPV, and NPV of 97.2%, 99.4%, 89.7%, and 99.9%, respectively, for nasal swabs. For groin swabs, it was 100%, 98.7%, 61.5% and 100%, respectively.Conclusion. The BD GeneOhm vanR Assay is a good screening test for rapid exclusion of VRE carriers in hospitals. The BD GeneOhm MRSA Assay represents a reliable screening test. The true strength of the BD GeneOhm Assay for MRSA and VRE is its exceptionally high NPV making the test an ideal tool for rapid exclusion of MRSA and VRE carriers in hospitals. As a consequence, this would dramatically shorten the patient isolation time.
Pathogenesis of Metastatic Calcification and Acute Pancreatitis in Adult T-Cell Leukemia under Hypercalcemic State
Authors: Senba Masachika , Kawai Kioko , Mori Naoki
Published: December 2011

Human T-cell leukemia virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL). Hypercalcemia is common in patients with ATL. These patients rarely develop metastatic calcification and acute pancreatitis. The underlying pathogenesis of this condition is osteoclast hyperactivity with associated overproduction of parathyroid hormone-related protein, which results in hypercalcemia in association with bone demineralization. The discovery of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL), its receptor RANK, and its decoy receptor osteoprotegerin (OPG), enhanced our understanding of the mechanisms of ATL-associated hypercalcemia. Macrophage inflammatory protein-1-α, tumor necrosis factor-α, interleukin-1, and interleukin-6 are important molecules that enhance the migration and differentiation of osteoclasts and the associated enhanced production of RANKL for osteoblast formation. In this paper, we focus on metastatic calcification and acute pancreatitis in ATL, highlighting recent advances in the understanding of the molecular role of the RANKL/RANK/OPG system including its interaction with various cytokines and calciotropic hormones in the regulation of osteoclastogenesis for bone resorption in hypercalcemic ATL patients.
The Importance of Relationships in Patients with Irritable Bowel Syndrome: A Review
Authors: Gerson Mary-Joan , Gerson Charles D.
Published: December 2011

Chronic illnesses such as irritable bowel syndrome are not experienced by patients in isolation. They live in a context of relationships, including spouses and partners, other family members, friends and business associates. Those relationships can have an effect, both positive and negative, on the course of illness and may also be affected by the experience of living with a chronic illness like IBS. We review the general literature regarding the effect of relationship factors on chronic illness followed by a focus on IBS symptomatology. We then discuss the challenges experienced by partners of IBS patients, followed by the effects of spousal violence, the particular relationship of mothers with IBS and their children, the effects of social support, and the importance of family dynamics and IBS. The final segment includes conclusions and recommendations. The topic, relationships and IBS, may have a significant effect on the lives of IBS patients and deserves more attention than it has received.
Mitochondrial Dysregulation in the Pathogenesis of Diabetes: Potential for Mitochondrial Biogenesis-Mediated Interventions
Authors: Joseph Anna-Maria , Joanisse Denis R. , Baillot Richard G. , Hood David A.
Published: December 2011

Muscle mitochondrial metabolism is a tightly controlled process that involves the coordination of signaling pathways and factors from both the nuclear and mitochondrial genomes. Perhaps the most important pathway regulating metabolism in muscle is mitochondrial biogenesis. In response to physiological stimuli such as exercise, retrograde signaling pathways are activated that allow crosstalk between the nucleus and mitochondria, upregulating hundreds of genes and leading to higher mitochondrial content and increased oxidation of substrates. With type 2 diabetes, these processes can become dysregulated and the ability of the cell to respond to nutrient and energy fluctuations is diminished. This, coupled with reduced mitochondrial content and altered mitochondrial morphology, has been directly linked to the pathogenesis of this disease. In this paper, we will discuss our current understanding of mitochondrial dysregulation in skeletal muscle as it relates to type 2 diabetes, placing particular emphasis on the pathways of mitochondrial biogenesis and mitochondrial dynamics, and the therapeutic value of exercise and other interventions.
Antifungal Resistance and New Strategies to Control Fungal Infections
Authors: Vandeputte Patrick , Ferrari Selene , Coste Alix T.
Published: December 2011

Despite improvement of antifungal therapies over the last 30 years, the phenomenon of antifungal resistance is still of major concern in clinical practice. In the last 10 years the molecular mechanisms underlying this phenomenon were extensively unraveled. In this paper, after a brief overview of currently available antifungals, molecular mechanisms of antifungal resistance will be detailed. It appears that major mechanisms of resistance are essential due to the deregulation of antifungal resistance effector genes. This deregulation is a consequence of point mutations occurring in transcriptional regulators of these effector genes. Resistance can also follow the emergence of point mutations directly in the genes coding antifungal targets. In addition we further describe new strategies currently undertaken to discover alternative therapy targets and antifungals. Identification of new antifungals is essentially achieved by the screening of natural or synthetic chemical compound collections. Discovery of new putative antifungal targets is performed through genome-wide approaches for a better understanding of the human pathogenic fungi biology.
Food Production and Processing Considerations of Allergenic Food Ingredients: A Review
Authors: Alvarez Pedro A. , Boye Joyce I.
Published: December 2011

Although most consumers show no adverse symptoms to food allergens, health consequences for sensitized individuals can be very serious. As a result, the Codex General Standard for the Labelling of Prepackaged Foods has specified a series of allergenic ingredients/substances requiring mandatory declaration when present in processed prepackaged food products. Countries adhering to international standards are required to observe this minimum of eight substances, but additional priority allergens are included in the list in some countries. Enforcement agencies have traditionally focused their effort on surveillance of prepackaged goods, but there is a growing need to apply a bottom-up approach to allergen risk management in food manufacturing starting from primary food processing operations in order to minimize the possibility of allergen contamination in finished products. The present paper aims to review food production considerations that impact allergen risk management, and it is directed mainly to food manufacturers and policy makers. Furthermore, a series of food ingredients and the allergenic fractions identified from them, as well as the current methodology used for detection of these allergenic foods, is provided.
IFNβ Produced by TLR4-Activated Tumor Cells Is Involved in Improving the Antitumoral Immune Response
Authors: Núñez Nicolás Gonzalo , Andreani Virginia , Crespo María Inés , Nocera David Andrés , Breser María Laura , Morón Gabriel , Dejager Lien , Libert Claude , Rivero Virginia , Maccioni Mariana
Published: December 2011

Toll-like receptor (TLR) ligands may be a valuable tool to promote antitumor responses by reinforcing antitumor immunity. In addition to their expression in immune cells, functional TLRs are also expressed by many cancer cells, but their significance has been controversial. In this study, we examined the action of TLR ligands on tumor pathophysiology as a result of direct tumor cell effects. B16 murine melanoma cells were stimulated in vitro with a TLR4 ligand (LPS-B16) prior to inoculation into TLR4-deficient mice (Tlr4 lps-del). Under such conditions, B16 cells yielded smaller tumors than nonstimulated B16 cells. The apoptosis/proliferation balance of the cells was not modified by TLR ligand treatment, nor was this effect compromised in immunocompromised nude mice. Mechanistic investigations revealed that IFNβ was the critical factor produced by TLR4-activated tumor cells in mediating their in vivo outgrowth. Transcriptional analysis showed that TLR4 activation on B16 cells induced changes in the expression of type I IFN and type I IFN-related genes. Most importantly, culture supernatants from LPS-B16 cells improved the maturation of bone marrow–derived dendritic cells (BMDC) from TLR4-deficient mice, upregulating the expression of interleukin-12 and costimulatory molecules on those cells. BMDC maturation was blunted by addition of an IFNβ-neutralizing antibody. Moreover, tumor growth inhibition observed in LPS-B16 tumors was abrogated in IFNAR1-deficient mice lacking a functional type I IFN receptor for binding IFN. Together, our findings show that tumor cells can be induced through the TLR4 pathway to produce IFN and positively contribute to the antitumoral immune response. Cancer Res; 72(3); 592–603. ©2011 AACR.
Arsenic Trioxide Treatment Decreases the Oxygen Consumption Rate of Tumor Cells and Radiosensitizes Solid Tumors
Authors: Diepart Caroline , Karroum Oussama , Magat Julie , Feron Olivier , Verrax Julien , Calderon Pedro Buc , Grégoire Vincent , Leveque Philippe , Stockis Julie , Dauguet Nicolas , Jordan Bénédicte F. , Gallez Bernard
Published: December 2011

Arsenic trioxide (As2O3) is an effective therapeutic against acute promyelocytic leukemia and certain solid tumors. Because As2O3 inhibits mitochondrial respiration in leukemia cells, we hypothesized that As2O3 might enhance the radiosensitivity of solid tumors by increasing tumor oxygenation [partial pressure of oxygen (pO2)] via a decrease in oxygen consumption. Two murine models of radioresistant hypoxic cancer were used to study the effects of As2O3. We measured pO2 and the oxygen consumption rate in vivo by electron paramagnetic resonance oximetry and 19fluorine-MRI relaxometry. Tumor perfusion was assessed by Patent blue staining. In both models, As2O3 inhibited mitochondrial respiration, leading to a rapid increase in pO2. The decrease in oxygen consumption could be explained by an observed decrease in glutathione in As2O3-treated cells, as this could increase intracellular reactive oxygen species that can disrupt mitochondrial membrane potential. When tumors were irradiated during periods of As2O3-induced augmented oxygenation, radiosensitivity increased by 2.2-fold compared with control mice. Notably, this effect was abolished when temporarily clamped tumors were irradiated. Together, our findings show that As2O3 acutely increases oxygen consumption and radiosensitizes tumors, providing a new rationale for clinical investigations of As2O3 in irradiation protocols to treat solid tumors. Cancer Res; 72(2); 482–90. ©2011 AACR.
Genetic Determinants for Promoter Hypermethylation in the Lungs of Smokers: A Candidate Gene-Based Study
Authors: Leng Shuguang , Stidley Christine A. , Liu Yushi , Edlund Christopher K. , Willink Randall P. , Han Younghun , Landi Maria Teresa , Thun Michael , Picchi Maria A. , Bruse Shannon E. , Crowell Richard E. , Van Den Berg David , Caporaso Neil E. , Amos Christopher I. , Siegfried Jill M. , Tesfaigzi Yohannes , Gilliland Frank D. , Belinsky Steven A.
Published: December 2011

The detection of tumor suppressor gene promoter methylation in sputum-derived exfoliated cells predicts early lung cancer. Here, we identified genetic determinants for this epigenetic process and examined their biologic effects on gene regulation. A two-stage approach involving discovery and replication was used to assess the association between promoter hypermethylation of a 12-gene panel and common variation in 40 genes involved in carcinogen metabolism, regulation of methylation, and DNA damage response in members of the Lovelace Smokers Cohort (N = 1,434). Molecular validation of three identified variants was conducted using primary bronchial epithelial cells. Association of study-wide significance (P < 8.2 × 10−5) was identified for rs1641511, rs3730859, and rs1883264 in TP53, LIG1, and BIK, respectively. These single-nucleotide polymorphisms (SNP) were significantly associated with altered expression of the corresponding genes in primary bronchial epithelial cells. In addition, rs3730859 in LIG1 was also moderately associated with increased risk for lung cancer among Caucasian smokers. Together, our findings suggest that genetic variation in DNA replication and apoptosis pathways impacts the propensity for gene promoter hypermethylation in the aerodigestive tract of smokers. The incorporation of genetic biomarkers for gene promoter hypermethylation with clinical and somatic markers may improve risk assessment models for lung cancer. Cancer Res; 72(3); 707–15. ©2011 AACR.
BAP1tism of a Tumor Suppressor
Authors: Woodman Scott E.
Published: December 2011

Driving cancer cells into a more differentiated state is a rational therapeutic approach. Primary uveal melanoma cells with a propensity to metastasize have less-differentiated features than their less aggressive counterparts. Treatment of uveal melanoma cells with histone deacetylase inhibitors induces a more differentiated phenotype with resultant lower growth capacity. Clin Cancer Res; 18(2); 323–5. ©2011 AACR.
Progression of Prostate Carcinogenesis and Dietary Methyl Donors: Temporal Dependence
Authors: Shabbeer Shabana , Williams Simon A. , Simons Brian W. , Herman James G. , Carducci Michael A.
Published: December 2011

Insufficient dose of dietary methyl groups are associated with a host of conditions ranging from neural tube defects to cancer. On the other hand, it is not certain what effect excess dietary methyl groups could have on cancer. This is especially true for prostate cancer, a disease that is characterized by increasing DNA methylation changes with increasing grade of the cancer. In this three-part study in animals, we look at (i) the effect of excess methyl donors on the growth rate of prostate cancer in vivo, (ii) the ability of 5-aza-2′-deoxycytidine (AdC), a demethylating agent, to demethylate in the presence of excess dietary methyl donors, and (iii) the effect of in utero feeding of excess methyl donors to the later onset of prostate cancer. The results show that when mice are fed a dietary excess of methyl donors, we do not see (i) an increase in the growth rate of DU-145 and PC-3 xenografts in vivo, or (ii) interference in the ability of AdC to demethylate the promoters of androgen receptor or Reprimo of prostate cancer xenografts but (iii) a protective effect on the development of higher grades of prostate cancer in the “Hi-myc” mouse model of prostate cancer which were fed the increased methyl donors in utero. We conclude that the impact of dietary methyl donors on prostate cancer progression depends upon the timing of exposure to the dietary agents. When fed before the onset of cancer, that is, in utero, excess methyl donors can have a protective effect on the progression of cancer. Cancer Prev Res; 5(2); 229–39. ©2011 AACR.
Randomized Phase II Trial of Lyophilized Strawberries in Patients with Dysplastic Precancerous Lesions of the Esophagus
Authors: Chen Tong , Yan Fei , Qian Jiaming , Guo Mingzhou , Zhang Hongbing , Tang Xiaofei , Chen Fang , Stoner Gary D. , Wang Xiaomin
Published: December 2011

Dysplasia is a histologic precursor of esophageal squamous cell carcinoma (SCC). We previously showed that dietary freeze-dried, or lyophilized, strawberry powder inhibits N-nitrosomethylbenzylamine-induced SCC in the rat esophagus. On the basis of this observation, we conducted a randomized (noncomparative) phase II trial in China to investigate the effects of two doses of freeze-dried strawberries in patients with esophageal dysplastic lesions in a high-risk area for esophageal cancer. We randomly assigned 75 patients identified by endoscopy to have dysplastic esophageal premalignant lesions to receive freeze-dried strawberry powder at either 30 g/d (37 patients) or 60 g/d (38 patients) for six months; the powder was mixed with water and drunk. After six months, we assessed the changes in histologic grade of these lesions (primary endpoint) in a blinded fashion. The dose of 30 g/d, did not significantly affect histology or any other measured parameter. The dose of 60 g/d, however, reduced the histologic grade of dysplastic premalignant lesions in 29 (80.6%) of the 36 patients at this dose who were evaluated for histology (P < 0.0001). The strawberry powder was well tolerated, with no toxic effects or serious adverse events. Strawberries (60 g/d) also reduced protein expression levels of inducible nitric oxide synthase (iNOS) by 79.5% (P < 0.001), cyclooxygenase-2 (COX-2) by 62.9% (P < 0.001), phospho-nuclear factor kappa B (NFκB)-p65 (pNFκB-p65) by 62.6% (P < 0.001), and phospho-S6 (pS6) by 73.2% (P < 0.001). Freeze-dried strawberries (60 g/d) also significantly inhibited the Ki-67 labeling index by 37.9% (P = 0.023). Our present results indicate the potential of freeze-dried strawberry powder for preventing human esophageal cancer, supporting further clinical testing of this natural agent in this setting. Cancer Prev Res; 5(1); 41–50. ©2011 AACR.
The Effect of HIV and HPV Coinfection on Cervical COX-2 Expression and Systemic Prostaglandin E2 Levels
Authors: Fitzgerald Daniel W. , Bezak Karl , Ocheretina Oksana , Riviere Cynthia , Wright Thomas C. , Milne Ginger L. , Zhou Xi Kathy , Du Baoheng , Subbaramaiah Kotha , Byrt Erin , Goodwin Matthew L. , Rafii Arash , Dannenberg Andrew J.
Published: December 2011

Human immunodeficiency virus (HIV-1) infection causes chronic inflammation. COX-2–derived prostaglandin E2 (PGE2) has been linked to both inflammation and carcinogenesis. We hypothesized that HIV-1 could induce COX-2 in cervical tissue and increase systemic PGE2 levels and that these alterations could play a role in AIDS-related cervical cancer. Levels of cervical COX-2 mRNA and urinary PGE-M, a biomarker of systemic PGE2 levels, were determined in 17 HIV-negative women with a negative cervical human papilloma virus (HPV) test, 18 HIV-infected women with a negative HPV test, and 13 HIV-infected women with cervical HPV and high-grade squamous intraepithelial lesions on cytology. Cervical COX-2 levels were significantly associated with HIV and HPV status (P = 0.006 and 0.002, respectively). Median levels of urinary PGE-M were increased in HIV-infected compared with uninfected women (11.2 vs. 6.8 ng/mg creatinine, P = 0.02). Among HIV-infected women, urinary PGE-M levels were positively correlated with plasma HIV-1 RNA levels (P = 0.003). Finally, levels of cervical COX-2 correlated with urinary PGE-M levels (P = 0.005). This study shows that HIV-1 infection is associated with increased cervical COX-2 and elevated systemic PGE2 levels. Drugs that inhibit the synthesis of PGE2 may prove useful in reducing the risk of cervical cancer or systemic inflammation in HIV-infected women. Cancer Prev Res; 5(1); 34–40. ©2011 AACR.
Changes of Body Mass Index among Young Men in Brazil over Two Decades
Authors: Marra César , dos Santos Barbosa Flávia , Sichieri Rosely
Published: December 2011

Aim: To evaluate changes in the body mass index (BMI) of young Brazilian men in two regions of Brazil at opposing socioeconomic extremes in order to determine whether the changes in BMI distribution had different patterns over two decades. Methods: We selected a sample of 6,706,386 males as the study population, aged 18 years, from individuals that were conscripted into the army from 1980 to 2005. The percentiles of the BMI distribution from 1980 to 2005 were calculated. For each percentile, the slope of a linear regression curve was tested for increases or decreases over time (p < 0.05). Results: The secular trends in BMI showed the largest increases at the upper ends of the distributions. However, the lower values of the percentiles in both regions did not change over time. The 10th percentile for the southeast region and the 20th percentile in the northeast did not change. Conclusion: No significant differences in the lower percentile values were found for the BMI distribution of young Brazilian males during the period 1980–2005, suggesting that around 10% of young Brazilian males living in the most developed regions, such as the southeast, are protected against obesity.
Inverse Association between trans Isomeric and Long-Chain Polyunsaturated Fatty Acids in Pregnant Women and Their Newborns: Data from Three European Countries
Authors: Decsi T. , Campoy C. , Demmelmair H. , Szabó É. , Marosvölgyi T. , Escolano M. , Marchal G. , Krauss-Etschmann S. , Cruz M. , Koletzko B.
Published: December 2011

Background:trans unsaturated fatty acids are thought to interfere with essential fatty acid metabolism. To extend our knowledge of this phenomenon, we investigated the relationship between trans isomeric and long-chain polyunsaturated fatty acids (LCPUFA) in mothers during pregnancy and in their infants at birth. Methods: Fatty acid composition of erythrocyte phosphatidylcholine (PC) and phosphatidylethanolamine (PE) was determined in Spanish (n = 120), German (n = 78) and Hungarian (n = 43) women at the 20th and 30th week of gestation, at delivery and in their newborns. Results: At the 20th week of gestation, the sum of trans fatty acids in PE was significantly (p < 0.01) lower in Hungarian [0.73 (0.51), % wt/wt, median (IQR)] than in Spanish [1.42 (1.36)] and German [1.30 (1.21)] women. Docosahexaenoic acid (DHA) values in PE were significantly (p < 0.01) higher in Hungarian [5.65 (2.09)] than in Spanish [4.37 (2.60)] or German [4.39 (3.3.2)] women. The sum of trans fatty acids significantly inversely correlated to DHA in PCs in Spanish (r = –0.37, p < 0.001), German (n = –0.77, p < 0.001) and Hungarian (r = –0.35, p < 0.05) women, and in PEs in Spanish (r = –0.67, p < 0.001) and German (r = –0.71, p < 0.001), but not in Hungarian (r = –0.02) women. Significant inverse correlations were seen between trans fatty acids and DHA in PEs at the 30th week of gestation (n = 241, r = –0.52, p < 0.001), at delivery (n = 241, r = –0.40, p < 0.001) and in cord lipids (n = 218, r = –0.28, p < 0.001). Conclusion: Because humans cannot synthesize trans isomeric fatty acids, the data obtained in the present study support the concept that high maternal trans isomeric fatty acid intake may interfere with the availability of LCPUFA both for the mother and the fetus.