bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytokines, Obesity, and Cancer: New Insights on Mechanisms Linking Obesity to Cancer Risk and Progression
Authors: Gilbert Candace A. , Slingerland Joyce M.
Published: November 2012

Obesity is a problem of epidemic proportions in many developed nations. Increased body mass index and obesity are associated with a significantly worse outcome for many cancers. Breast cancer risk in the postmenopausal setting and poor disease outcome for all patients is significantly augmented in overweight and obese individuals. The expansion of fat tissue involves a complex interaction of endocrine factors known as adipokines and cytokines. High cytokine levels in primary breast cancers and in the circulation of affected patients have been associated with poor outcome. This review summarizes the how cytokine production in obese adipose tissue creates a chronic inflammatory microenvironment that favors tumor cell motility, invasion, and epithelial-mesenchymal transition to enhance the metastatic potential of tumor cells. Many of the cytokines associated with a proinflammatory state are not only upregulated in obese adipose tissue but may also stimulate the self-renewal of cancer stem cells. Thus, enhanced cytokine production in obese adipose tissue may serve both as a chemoattractant for invading cancers and to augment their malignant potential. These new mechanistic insights suggest that the current obesity epidemic will presage a significant increase in cancer incidence, morbidity, and mortality in the next few decades.
Reduced-Intensity Hematopoietic Stem Cell Transplants for Malignancies: Harnessing the Graft-Versus-Tumor Effect
Authors: Gill Saar , Porter David L.
Published: November 2012

Allogeneic hematopoietic cell transplantation combines the power of cytotoxic chemo/radiotherapy with the ability of the new immune system to seek out and destroy tumor cells. However, administration of such myeloablative transplants is fraught with risks, some of which are related to the intensive conditioning regimens. Reductions in the intensity of the administered cytotoxic therapy have demonstrated that under some circumstances, the burden of fighting tumor and enhancing stem cell engraftment can be shouldered mostly by the transplanted immune system. Reduced intensity has allowed a potentially curative therapy for hematologic malignancies to be offered to an expanded patient population. Ongoing research seeks to enhance the safety and power of this form of allogeneic immunotherapy.
Pathological and Molecular Advances in Pediatric Low-Grade Astrocytoma
Authors: Rodriguez Fausto J. , Lim Kah Suan , Bowers Daniel , Eberhart Charles G.
Published: November 2012

Pediatric low-grade astrocytomas are the most common brain tumors in children. They can have similar microscopic and clinical features, making accurate diagnosis difficult. For patients whose tumors are in locations that do not permit full resection, or those with an intrinsically aggressive biology, more effective therapies are required. Until recently, little was known about the molecular changes that drive the initiation and growth of pilocytic and other low-grade astrocytomas beyond the association of a minority of cases, primarily in the optic nerve, with neurofibromatosis type 1. Over the past several years, a wide range of studies have implicated the BRAF oncogene and other members of this signaling cascade in the pathobiology of pediatric low-grade astrocytoma. In this review, we attempt to summarize this rapidly developing field and discuss the potential for translating our growing molecular knowledge into improved diagnostic and prognostic biomarkers and new targeted therapies.
Diagnostic Applications of High-Throughput DNA Sequencing
Authors: Boyd Scott D.
Published: November 2012

Advances in DNA sequencing technology have allowed comprehensive investigation of the genetics of human beings and human diseases. Insights from sequencing the genomes, exomes, or transcriptomes of healthy and diseased cells in patients are already enabling improved diagnostic classification, prognostication, and therapy selection for many diseases. Understanding the data obtained using new high-throughput DNA sequencing methods, choices made in sequencing strategies, and common challenges in data analysis and genotype-phenotype correlation is essential if pathologists, geneticists, and clinicians are to interpret the growing scientific literature in this area. This review highlights some of the major results and discoveries stemming from high-throughput DNA sequencing research in our understanding of Mendelian genetic disorders, hematologic cancer biology, infectious diseases, the immune system, transplant biology, and prenatal diagnostics. Transition of new DNA sequencing methodologies to the clinical laboratory is under way and is likely to have a major impact on all areas of medicine.
Pathogenesis of the Viral Hemorrhagic Fevers
Authors: Paessler Slobodan , Walker David H.
Published: November 2012

Four families of enveloped RNA viruses, filoviruses, flaviviruses, arenaviruses, and bunyaviruses, cause hemorrhagic fevers. These viruses are maintained in specific natural cycles involving nonhuman primates, bats, rodents, domestic ruminants, humans, mosquitoes, and ticks. Vascular instability varies from mild to fatal shock, and hemorrhage ranges from none to life threatening. The pathogenic mechanisms are extremely diverse and include deficiency of hepatic synthesis of coagulation factors owing to hepatocellular necrosis, cytokine storm, increased permeability by vascular endothelial growth factor, complement activation, and disseminated intravascular coagulation in one or more hemorrhagic fevers. The severity of disease caused by these agents varies tremendously; there are extremely high fatality rates in Ebola and Marburg hemorrhagic fevers, and asymptomatic infection predominates in yellow fever and dengue viral infections. Although ineffective immunity and high viral loads are characteristic of several viral hemorrhagic fevers, severe plasma leakage occurs at the time of viral clearance and defervescence in dengue hemorrhagic fever.
Employee Recruitment
Authors: Breaugh James A.
Published: November 2012

The way an organization recruits can influence the type of employees it hires, how they perform, and their retention rate. This article provides a selective review of research that has addressed recruitment targeting, recruitment methods, the recruitment message, recruiters, the organizational site visit, the job offer, and the timing of recruitment actions. These and other topics (e.g., the job applicant's perspective) are discussed in terms of their potential influence on prehire (e.g., the quality of job applicants) and posthire (e.g., new employee retention) recruitment outcomes. In reviewing research, attention is given to the current state of scientific knowledge, limitations of previous research, and important issues meriting future investigation.
The guggulsterone derivative GG-52 inhibits NF-κB signaling in gastric epithelial cells and ameliorates ethanol-induced gastric mucosal lesions in mice
Authors: Kim Jung Mogg , Kim Su Hyun , Ko Su Hyuk , Jung Jireh , Chun Jaeyoung , Kim Nayoung , Jung Hyun Chae , Kim Joo Sung
Published: November 2012

Gastric mucosal inflammation can develop after challenge with noxious stimuli such as alcohol. Specially, alcohol stimulates the release of inflammatory cytokines but does not increase gastric acid secretion, leading to gastric mucosal damage. The plant sterol guggulsterone and its novel derivative GG-52 have been reported to inhibit nuclear factor-κB (NF-κB) signaling in intestinal epithelial cells and experimental colitis. In the present study, we investigated the anti-inflammatory effects of GG-52 on gastric epithelial cells and on ethanol-induced gastric mucosal inflammation in mice. GG-52 inhibited the expression of interleukin-8 (IL-8) in gastric epithelial AGS and MKN-45 cell lines stimulated with tumor necrosis factor (TNF)-α in a dose-dependent manner. Pretreatment with GG-52 suppressed TNF-α-induced activation of IκB kinase (IKK) and NF-κB signaling in MKN-45 cells. In contrast, the inactive analog GG-46 did not produce significant changes in IL-8 expression or NF-κB activation. In a model of ethanol-induced murine gastritis, administration of GG-52 significantly reduced the severity of gastritis, as assessed by macroscopic and histological evaluation of gastric mucosal damage. In addition, the ethanol-induced upregulation of chemokine KC, a mouse homolog of IL-8, and phosphorylated p65 NF-κB signals were significantly inhibited in murine gastric mucosa pretreated with GG-52. These results indicate that GG-52 suppresses NF-κB activation in gastric epithelial cells and ameliorates ethanol-induced gastric mucosal lesions in mice, suggesting that GG-52 may be a potential gastroprotective agent.
Oxidative modification of the intestinal mucus layer is a critical but unrecognized component of trauma hemorrhagic shock-induced gut barrier failure
Authors: Fishman Jordan E. , Levy Gal , Alli Vamsi , Sheth Sharvil , Lu Qu , Deitch Edwin A.
Published: November 2012

Recent studies demonstrate that mechanisms underlying gut barrier failure include systemic processes and less studied luminal processes. We thus tested the hypothesis that mucus layer oxidation is a component of trauma/hemorrhagic shock-induced gut injury and dysfunction. Male Sprague-Dawley rats underwent trauma/hemorrhagic shock. Controls underwent trauma only. Mucus from the terminal 30 cm of the ileum was collected, processed, and analyzed for reactive nitrogen intermediates (RNI)-mediated damage, reactive oxygen species (ROS)-induced damage, and total antioxidant capacity. The distal ileum was stained to quantify the mucus layer; gut permeability was assessed physiologically. A time course study was conducted to determine the temporal sequence of mucus layer damage. The role of free radical-mediated damage to the gut barrier was investigated by the effect of the free radical scavenger dimethyl sulfoxide on trauma/hemorrhagic shock-induced changes on the mucus and on gut permeability. Trauma/hemorrhagic shock increased intestinal permeability, which was associated with evidence of loss of the unstirred mucus layer. These changes correlated with increased ROS- and RNI-mediated mucus damage and loss of mucus total antioxidant capacity. Based on the time course study, ROS-mediated mucus damage and loss of total antioxidant capacity were present immediately following shock, whereas RNI-mediated damage was delayed for 3 h. Dimethyl sulfoxide ameliorated gut barrier loss, ROS-mediated changes to the mucus layer, and loss of total antioxidant capacity. There was no change in RNI-induced changes to the mucus layer. These results support the hypothesis that trauma/hemorrhagic shock leads to mucus damage and gut dysfunction through the generation of free radical species.
Critical role of interleukin-17A in murine intestinal ischemia-reperfusion injury
Authors: Lee H. Thomas , Kim Mihwa , Kim Joo Yun , Brown Kevin M. , Ham Ahrom , D'Agati Vivette D. , Mori-Akiyama Yuko
Published: November 2012

Intestinal ischemia-reperfusion (I/R) injury causes severe illness frequently complicated by remote multiorgan dysfunction and sepsis. Recent studies implicated interleukin-17A (IL-17A) in regulating inflammation, autoimmunity, and I/R injury. Here, we determined whether IL-17A is critical for generation of intestinal I/R injury and subsequent liver and kidney injury. Mice subjected to 30 min of superior mesenteric artery ischemia not only developed severe small intestinal injury (necrosis, apoptosis, and neutrophil infiltration) but also developed significant renal and hepatic injury. We detected large increases in IL-17A in the small intestine, liver, and plasma. IL-17A is critical for generating these injuries, since genetic deletion of IL-17A- or IL-17A-neutralizing antibody treatment markedly protected against intestinal I/R injury and subsequent liver and kidney dysfunction. Intestinal I/R caused greater increases in portal plasma and small intestine IL-17A, suggesting an intestinal source for IL-17A generation. We also observed that intestinal I/R caused rapid small intestinal Paneth cell degranulation and induced murine α-defensin cryptdin-1 expression. Furthermore, genetic or pharmacological depletion of Paneth cells significantly attenuated the intestinal I/R injury as well as hepatic and renal dysfunction. Finally, Paneth cell depletion significantly decreased small intestinal, hepatic, and plasma IL-17A levels after intestinal I/R. Taken together, we propose that Paneth cell-derived IL-17A may play a critical role in intestinal I/R injury as well as extraintestinal organ dysfunction.
The hepatic bile acid transporters Ntcp and Mrp2 are downregulated in experimental necrotizing enterocolitis
Authors: Cherrington Nathan J. , Estrada Teresa E. , Frisk Harrison A. , Canet Mark J. , Hardwick Rhiannon N. , Dvorak Bohuslav , Lux Katie , Halpern Melissa D.
Published: November 2012

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of premature infants and is characterized by an extensive hemorrhagic inflammatory necrosis of the distal ileum and proximal colon. We have previously shown that, during the development of experimental NEC, the liver plays an important role in regulating inflammation in the ileum, and accumulation of ileal bile acids (BA) along with dysregulation of ileal BA transporters contributes to ileal damage. Given these findings, we speculated that hepatic BA transporters would also be altered in experimental NEC. Using both rat and mouse models of NEC, levels of Cyp7a1, Cyp27a1, and the hepatic BA transporters Bsep, Ntcp, Oatp2, Oatp4, Mrp2, and Mrp3 were investigated. In addition, levels of hepatic BA transporters were also determined when the proinflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-18, which are both elevated in NEC, are neutralized during disease development. Ntcp and Mrp2 were decreased in NEC, but elevated ileal BA levels were not responsible for these reductions. However, neutralization of TNF-α normalized Ntcp, whereas removal of IL-18 normalized Mrp2 levels. These data show that the hepatic transporters Ntcp and Mrp2 are downregulated, whereas Cyp27a1 is increased in rodent models of NEC. Furthermore, increased levels of TNF-α and IL-18 in experimental NEC may play a role in the regulation of Ntcp and Mrp2, respectively. These data suggest the gut-liver axis should be considered when therapeutic modalities for NEC are developed.
Development and characterization of a 3D multicell microtissue culture model of airway smooth muscle
Authors: West Adrian R. , Zaman Nishat , Cole Darren J. , Walker Matthew J. , Legant Wesley R. , Boudou Thomas , Chen Christopher S. , Favreau John T. , Gaudette Glenn R. , Cowley Elizabeth A. , Maksym Geoffrey N.
Published: November 2012

Airway smooth muscle (ASM) cellular and molecular biology is typically studied with single-cell cultures grown on flat 2D substrates. However, cells in vivo exist as part of complex 3D structures, and it is well established in other cell types that altering substrate geometry exerts potent effects on phenotype and function. These factors may be especially relevant to asthma, a disease characterized by structural remodeling of the airway wall, and highlights a need for more physiologically relevant models of ASM function. We utilized a tissue engineering platform known as microfabricated tissue gauges to develop a 3D culture model of ASM featuring arrays of ∼0.4 mm long, ∼350 cell “microtissues” capable of simultaneous contractile force measurement and cell-level microscopy. ASM-only microtissues generated baseline tension, exhibited strong cellular organization, and developed actin stress fibers, but lost structural integrity and dissociated from the cantilevers within 3 days. Addition of 3T3-fibroblasts dramatically improved survival times without affecting tension development or morphology. ASM-3T3 microtissues contracted similarly to ex vivo ASM, exhibiting reproducible responses to a range of contractile and relaxant agents. Compared with 2D cultures, microtissues demonstrated identical responses to acetylcholine and KCl, but not histamine, forskolin, or cytochalasin D, suggesting that contractility is regulated by substrate geometry. Microtissues represent a novel model for studying ASM, incorporating a physiological 3D structure, realistic mechanical environment, coculture of multiple cells types, and comparable contractile properties to existing models. This new model allows for rapid screening of biochemical and mechanical factors to provide insight into ASM dysfunction in asthma.
CD40-Mediated Activation of Chronic Lymphocytic Leukemia Cells Promotes Their CD44-Dependent Adhesion to Hyaluronan and Restricts CCL21-Induced Motility
Authors: Girbl Tamara , Hinterseer Elisabeth , Grössinger Eva Melanie , Asslaber Daniela , Oberascher Karin , Weiss Lukas , Hauser-Kronberger Cornelia , Neureiter Daniel , Kerschbaum Hubert , Naor David , Alon Ronen , Greil Richard , Hartmann Tanja Nicole
Published: November 2012

Microenvironmental interactions are crucial for the survival and proliferation of chronic lymphocytic leukemia (CLL) cells. CD4+ T cells that express CD40 ligand (CD40L), along with other accessory immune and stromal cells within CLL lymph nodes, provide signals needed for activation and outgrowth of the tumor clone. Furthermore, correct positioning of CLL cells within lymphoid subcompartments is essential for the transmission of these supportive signals. Thereby, interstitial cell migration and adhesion events, influenced by activational stimuli, determine CLL cell localization. CD44 has been implicated in cell activation, migration, and tissue retention via binding to its extracellular matrix ligand hyaluronan (HA). In this study, we investigated the role of CD44–HA interactions for CLL positioning and interaction with supportive microenvironments in peripheral lymph nodes, focusing on its regulation via CD40L-dependent, T-cell–mediated activation of CLL cells. We found that hyaluronan triggered a robust CCL21-induced motility of resting CLL cells. However, CD40L stimulation promoted the firm, CD44-mediated adhesion of CLL cells to hyaluronan, antagonizing their motile behavior. N-linked glycosylations of CD44, particularly associated with the variant isoform CD44v6 after CD40L activation, seemed to facilitate hyaluronan recognition by CD44. We propose that the CD40L–CD40 signaling axis provides a stop signal to motile CLL cells within lymph node compartments by inducing high avidity CD44–HA adhesion. This might retain CLL cells close to T-cell stimuli and facilitate essential interactions with hyaluronan-bearing stromal cells, collectively promoting CLL cell proliferation and survival. Cancer Res; 73(2); 561–70. ©2012 AACR.
ABL Regulation by AXL Promotes Cisplatin Resistance in Esophageal Cancer
Authors: Hong Jun , Peng DunFa , Chen Zheng , Sehdev Vikas , Belkhiri Abbes
Published: November 2012

Esophageal adenocarcinoma (EAC) is characterized by resistance to chemotherapy and poor outcome. Although cisplatin (CDDP) has been used as a first-line therapy in patients with EAC, resistance remains a major clinical problem. The AXL receptor tyrosine kinase, originally isolated as a transforming gene from leukemia, is overexpressed in several solid tumors. Herein, we assessed AXL protein expression in human EACs and examined its role in CDDP resistance in human EAC cells. AXL overexpression was detected in more than 50% of tumors examined. Elevating AXL in nonoverexpressing cells doubled the CDDP IC50 and increased cell survival three-fold, while attenuating AXL in overexpressing cells reduced survival two-fold. The effects of AXL modulation on cell survival were associated with changes in cellular and molecular markers of apoptosis. Mechanistic investigations revealed that AXL blocked CDDP-induced activation of endogenous p73β (TP73), reducing its protein half-life, and inhibited CDDP-induced levels of p-c-ABL(Y412) and p-p73β(Y99). These changes were associated with a disruption of c-ABL/p73β protein interactions due to association with c-ABL in the cytoplasm, thereby blocking nuclear accumulation of c-ABL and phosphorylation of p73β in response to DNA damage. Together, our results establish that AXL promotes CDDP resistance in esophageal adenocarcinoma and argue that therapeutic targeting of AXL may sensitize these cancers to DNA-damaging drugs. Cancer Res; 73(1); 331–40. ©2012 AACR.
Androgen Receptor Splice Variants Mediate Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cell Lines
Authors: Li Yingming , Chan Siu Chiu , Brand Lucas J. , Hwang Tae Hyun , Silverstein Kevin A.T. , Dehm Scott M.
Published: November 2012

Persistent androgen receptor (AR) transcriptional activity underlies resistance to AR-targeted therapy and progression to lethal castration-resistant prostate cancer (CRPC). Recent success in retargeting persistent AR activity with next generation androgen/AR axis inhibitors such as enzalutamide (MDV3100) has validated AR as a master regulator during all stages of disease progression. However, resistance to next generation AR inhibitors limits therapeutic efficacy for many patients. One emerging mechanism of CRPC progression is AR gene rearrangement, promoting synthesis of constitutively active truncated AR splice variants (AR-V) that lack the AR ligand-binding domain. In this study, we show that cells with AR gene rearrangements expressing both full-length and AR-Vs are androgen independent and enzalutamide resistant. However, selective knock-down of AR-V expression inhibited androgen-independent growth and restored responsiveness to androgens and antiandrogens. In heterogeneous cell populations, AR gene rearrangements marked individual AR-V–dependent cells that were resistant to enzalutamide. Gene expression profiling following knock-down of full-length AR or AR-Vs showed that AR-Vs drive resistance to AR-targeted therapy by functioning as constitutive and independent effectors of the androgen/AR transcriptional program. Further, mitotic genes deemed previously to be unique AR-V targets were found to be biphasic targets associated with a proliferative level of signaling output from either AR-Vs or androgen-stimulated AR. Overall, these studies highlight AR-Vs as key mediators of persistent AR signaling and resistance to the current arsenal of conventional and next generation AR-directed therapies, advancing the concept of AR-Vs as therapeutic targets in advanced disease. Cancer Res; 73(2); 483–9. ©2012 AACR.
Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler (ECLIPse): A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Han Sang Won , Lee Sung-Soo , Kim Seo Hyun , Lee Jun Hong , Kim Gyu Sik , Kim Ok-Joon , Koh Im-Seok , Lee Jong Yun , Suk Seung-Han , Lee Sung Ik , Nam Hyo Suk , Kim Won-Joo , Yong Seok Woo , Lee Kyung-Yul , Park Jae Hyeon
Published: November 2012

Background: This study is intended to evaluate the propensities of cilostazol to reduce the pulsatility index (PI) in patients with acute lacunar infarction using the serial transcranial Doppler (TCD) examinations. Methods: In a multicenter, randomized, double-blind, placebo-controlled trial, patients were randomly assigned to receive either placebo or 100 mg cilostazol twice a day as well as aspirin 100 mg a day. The primary outcomes were the changes of middle cerebral artery (MCA) and basilar artery (BA) PIs at 14 and 90 days from the baseline TCD study. This study is registered with ClinicalTrials.gov (NCT00741286). Results: Trial medication was given to 203 patients, with 100 receiving cilostazol and 103 receiving placebo, and 164 were included in the per-protocol analysis of the primary outcome. Results from the linear mixed model showed that significant effects were obtained for time-by-group interactions (p = 0.008 in right MCA, p = 0.015 in left MCA, p = 0.002 in BA), suggesting that changes of PIs from the baseline to the 90-day study were different across the groups. Conclusions: Cilostazol further decreased TCD PIs at 90 days from baseline compared to placebo in acute lacunar infarction. This result may be related to pleiotropic effects, such as vasodilation, beyond its antiplatelet activity.
painDETECT Questionnaire and Lumbar Epidural Steroid Injection for Chronic Radiculopathy
Authors: Rados Ivan , Sakic Zdravcevic Katarina , Hrgovic Zlatko
Published: November 2012

Background: The painDETECT questionnaire (PD-Q) is a fast and uncomplicated way to ascertain the percentage of neuropathic pain in ‘total pain’ and is designed to detect neuropathic pain components in back pain. The purpose of this randomized, prospective study is to compare, with the assessment of the PD-Q, the efficacy of interlaminar (IL) and transforaminal (TF) steroid injections in patients with unilateral chronic lumbar radicular pain. Methods: Patients were treated fluoroscopically with epidural steroids, using the IL or TF method and with confirmation of the epidural space by contrast, using random computerized classification. The patients received a series of three IL or TF epidural steroid injections (ESI) at 2-week intervals. The patients were monitored for 6 months from the first steroid injection. Results: By analyzing the average values of the total sum of points in the PD-Q a dropping trend is confirmed for both groups. The trend equation (y = –1.1393x + 25.269) for the TF ESI shows a faster recovery than the IL ESI (y = –0.8089x + 26.654). The statistically significant difference in the two groups is proved between the first and the sixth visit (IL ESI, p = 0.014; TF ESI, p = 0.001). There is no statistically significant difference in the efficiency of the two dosages and the volumes of steroids between the IL and TF distribution of steroids. Conclusions: Steroids are efficient; besides alleviating the overall pain, they also reduce the neuropathic component in chronic lumbar radicular pain, whether it is distributed epidurally by the IL or TF approach.
Effects of Nasal High Flow on Ventilation in Volunteers, COPD and Idiopathic Pulmonary Fibrosis Patients
Authors: Bräunlich Jens , Beyer Denise , Mai David , Hammerschmidt Stefan , Seyfarth Hans-Jürgen , Wirtz Hubert
Published: November 2012

Background: A high flow of air applied by large bore nasal cannulae has been suggested to improve symptoms of chronic respiratory insufficiency. In pediatric patients, nasal high-flow (nHF) ventilation was similarly effective compared to noninvasive ventilation with a face mask. Objectives: The aim of this study was to describe changes in respiratory parameters. Methods: We measured pressure amplitudes during the respiratory cycle and mean pressures in patients with idiopathic pulmonary fibrosis (IPF) and COPD. In order to achieve tidal volume and minute volume measurements, we used a polysomnography device. Capillary blood was taken for blood gas analysis before and after nHF breathing (8 h). Results: nHF led to an increase in pressure amplitude and mean pressure in healthy volunteers and in patients with COPD and IPF in comparison with spontaneous breathing. In COPD, nHF increased tidal volume, while no difference in tidal volume was observed in patients with IPF. Interestingly, tidal volume decreased in healthy volunteers. Breathing rates and minute volumes were reduced in all groups. Capillary pCO2 decreased in patients with IPF and COPD. Conclusions: nHF resulted in significant effects on respiratory parameters in patients with obstructive and restrictive pulmonary diseases. The rise in pressure amplitude and mean pressure and the decrease in breathing rate and minute volume will support inspiratory efforts, helps to increase effectiveness of ventilation and will contribute to a reduction in the work of breathing. A CO2 wash-out effect in the upper airway part of the anatomical dead space may contribute to the beneficial effects of the nHF instrument.
Decline in Gait Performance Detected by an Electronic Walkway System in 907 Older Adults of the Population-Based KORA-Age Study
Authors: Autenrieth Christine S. , Karrasch Stefan , Heier Margit , Gorzelniak Lukas , Ladwig Karl-Heinz , Peters Annette , Döring Angela
Published: November 2012

Background: Gait changes at older ages are a strong predictor of a decline in lower extremity functions. However, large population-based studies assessing gait parameters in various gait tasks are lacking. Objective: We investigated the relationship of age, the use of mobility aids and being fitted with an endoprosthesis with selected gait parameters, assessed in different walking tasks. Methods: In the population-based KORA-Age study, data from 907 men and women aged 65-91 years were obtained using the validated electronic walkway system GAITRite, which quantifies spatiotemporal gait parameters in the measurement range of a 488 × 61 cm walkway mat. Participants completed three walking tasks at different speeds (normal, slow and fast) and a fourth walking task at normal speed with the additional task of counting backwards (dual-task walking). Additionally, the impact of endoprostheses (hip or knee) and mobility aids was assessed. Results: The highest relative age-related decline for velocity was observed during dual-task walking (26.1% for men and 23.4% for women) and for step length during fast walking (20.2 and 14.4%) when comparing participants aged <70 years with those aged ≥85 years. Weaker performances for velocity, cadence and step length were observed among women with knee or hip endoprostheses (fast walking speed) (p < 0.05). Across all walking tasks, significant differences between mobility aid users and nonusers were observed for velocity and step length among both men and women (p < 0.05). Conclusion: A decline in gait performance is most notable in fast speed and dual-task walking, in age-related endoprosthesis and mobility aid analyses. The marked relative decrease in gait parameters in these difficult gait tasks may be attributed to lacking resources for compensation among the elderly.
Hashimoto’s Encephalopathy as a Treatable Adult-Onset Cerebellar Ataxia Mimicking Spinocerebellar Degeneration
Authors: Matsunaga Akiko , Ikawa Masamichi , Fujii Akihiro , Nakamoto Yasunari , Kuriyama Masaru , Yoneda Makoto
Published: November 2012

Background: Hashimoto’s encephalopathy (HE) presents with a variety of neurologic and neuropsychiatric features. In this study, we investigated the clinical and immunological profiles of the cerebellar ataxic form of HE. Methods: The clinical features, treatments, laboratory features, brain imaging, and serum anti-NH2-terminal of α-enolase autoantibodies (anti-NAE Abs), a useful diagnostic marker for HE, were investigated in 13 patients who presented with sporadic adult-onset cerebellar ataxia and fulfilled the HE diagnostic criteria (antithyroid Abs and responsiveness to immunotherapy). Results: All of the patients presented with truncal ataxia, but nystagmus was uncommon (17%). Eight patients had an insidious onset that mimicked spinocerebellar degeneration (SCD), but brain imaging showed little or no cerebellar atrophy in all of the patients. Those patients with serum anti-NAE Abs (n = 8) did not have nystagmus and tended to respond better to immunotherapy than the anti-NAE Ab-negative patients. Conclusion: The present study suggests that insidious adult-onset and truncal ataxia are common in the cerebellar ataxic form of HE, which mimics SCD, but that nystagmus and severe cerebellar atrophy are uncommon. Antithyroid and anti-NAE Abs may be useful for diagnosing cerebellar ataxic HE.
Prospective Evaluation of Duodenogastroesophageal Reflux in Gastroesophageal Reflux Disease Patients Refractory to Proton Pump Inhibitor Therapy
Authors: Kunsch S. , Neesse A. , Linhart T. , Nell C. , Gress T.M. , Ellenrieder V.
Published: November 2012

Background: Duodenogastroesophageal reflux (DGER) is considered an independent risk factor for complicated reflux disease (gastroesophageal reflux disease; GERD). However, the role of DGER in GERD patients refractory to proton pump inhibitors (PPI) remains poorly understood. Methods: 85 patients with clinical reflux symptoms and a history of ineffective response to PPIs were enrolled in the study. Patients with elevated reflux measurement (pH and/or Bilitec measurement; n = 47) received pantoprazole 80 mg for 8 weeks. Clinical outcome was defined as response (≤2 symptoms/week) or nonresponse (≥3 symptoms/week). Results: Of the 47 patients with elevated reflux measurement, 30 were classified as responders and 17 as nonresponders. Treatment with pantoprazole resulted in a significant reduction of acidic reflux in both PPI responders and PPI nonresponders. In contrast, DGER was only significantly reduced in the PPI responder group (22.8 ± 22.8 vs. 6.6 ± 10.8%; p < 0.05) but not in the PPI nonresponder group (24.5 ± 18.6 vs. 22.2 ± 12.7%; p > 0.05). Conclusions: The presented study firstly describes that nonresponsiveness to PPI is associated with a limited effect of PPIs on reducing DGER. Thus, persistent DGER may play a key role in mediating reflux symptoms refractory to high-dose PPIs.
Gender Differences in Alcohol Choice among Russians: Evidence from a Quantitative Study
Authors: Minagawa Yuka
Published: November 2012

Aims: Qualitative studies find that men and women in Russia have different preferences for alcoholic beverages, but quantitative evidence for gender differences in beverage type choice remains scarce. The purpose of this article is to test numerically whether and to what extent men and women in Russia differ in terms of preferences for type of drink, such as vodka, wine and beer. Methods: Results are based on multinomial logistic regression and ordinary least squares regression analyses of the Russian Longitudinal Monitoring Survey-Higher School of Economics 2008 data. Results: We observed significant gender differences in preferences for alcoholic beverages. Men have strong preferences for vodka, and they drink it in much larger amounts in comparison with women. Women are more likely to either refrain from drinking or drink mild types of alcoholic beverages, such as wine and beer. Gender differences remain statistically significant even when sociodemographic factors are well accounted for. Conclusions: The present study confirms the previous research findings about gender differences in drinking practices among Russians. Our results provide quantitative evidence of the pronounced differences in beverage types consumed by men and women.
Risk Factors for Resistance to Proton Pump Inhibitor Maintenance Therapy for Reflux Esophagitis in Japanese Women over 60 Years
Authors: Watanabe Akira , Iwakiri Ryuichi , Yamaguchi Daisuke , Higuchi Toru , Tsuruoka Nanae , Miyahara Koichi , Akutagawa Kayo , Sakata Yasuhisa , Fujise Takehiro , Oda Yasutomo , Shimoda Ryo , Sakata Hiroyuki , Fujimoto Kazuma
Published: November 2012

Aim: The aim of this study was to evaluate risk factors for proton pump inhibitor (PPI) resistance in older Japanese female patients with reflux esophagitis evaluated by physicians. Methods: The study included 462 Japanese female patients aged over 60 years with reflux esophagitis who received PPI maintenance therapy for more than 6 months. Results: The characteristics of all 462 patients were: age: 76.4 ± 7.6 years, height: 147.2 ± 6.1 cm, weight: 49.9 ± 8.4 kg and body mass index: 24.0 ± 3.5. The reflux esophagitis grades were A in 69.5%, B in 15.8%, C in 9.1% and D in 5.6%. Helicobacter pylori was positive in 60.6%. Regarding PPI maintenance therapy for clinical symptoms evaluated by the attending physicians, 66.7% were ‘good control’, 26.8% were ‘reasonable control’ and 6.5% were ‘bad control: resistant’. PPI maintenance therapy was less effective in patients with more severe reflux esophagitis of grades C and D (OR: 0.027; 95% CI: 0.010–0.077) and negative H. pylori infection status (OR: 4.470; 95% CI: 1.631–12.247). Lumbar kyphosis and hiatus hernia were risk factors for severity grading of reflux esophagitis. Conclusions: PPI maintenance therapy evaluated by attending physicians indicated that reflux esophagitis severity and negative H. pylori status were risk factors for treatment resistance.
Ischemic Preconditioning Reduces Right Ventricular Infarct Size through Opening of Mitochondrial Potassium Channels
Authors: Andersen Asger , Povlsen Jonas Agerlund , Bøtker Hans Erik , Nielsen-Kudsk Jens Erik
Published: November 2012

Objectives: We investigated whether ischemic preconditioning (IPC) protects the right ventricular (RV) myocardium against ischemic injury in hearts treated with the specific mitochondrial ATP-sensitive potassium (KATP) channel blocker 5-hydroxydecanoate (5-HD). Methods: Hearts from male Wistar rats (300 g, n = 39) were isolated and perfused with Krebs-Henseleit buffer and randomized to no IPC (control, n = 16), IPC (n = 16) or IPC preceded by addition of 5-HD (100 µm, n = 7). IPC consisted of 2 × 5 min of global ischemia followed by 40 min of global ischemia and 120 min of reperfusion. The effect of IPC on RV myocardial infarct size was evaluated by measurement of the infarct size/area-at-risk ratio (RVIS/AAR). Postischemic RV function was evaluated by RV pressures. Results: IPC produced a marked decrease in RVIS/AAR (24.4 ± 8.1 vs. 42.6 ± 10.6%, p < 0.0001) and improved hemodynamic recovery of RV contractile function compared with the control group. We found no difference in RVIS/AAR (45.2 ± 4.4 vs. 42.6 ± 10.6, p > 0.05) or hemodynamic recovery between IPC + 5-HD and control hearts. Blockade of mitochondrial KATP channels by 5-HD abolished the cardioprotective response to IPC. Conclusion: IPC reduces RV myocardial infarct size and improves postischemic RV contractile function in the isolated rat heart, possibly through opening of the mitochondrial KATP channel.
Levetiracetam versus Carbamazepine in Patients with Late Poststroke Seizures: A Multicenter Prospective Randomized Open-Label Study (EpIC Project)
Authors: Consoli D. , Bosco D. , Postorino P. , Galati F. , Plastino M. , Perticoni G.F. , Ottonello G.A. , Passarella B. , Ricci S. , Neri G. , Toni D. ,   on behalf of EPIC Study
Published: November 2012

Background: Strokes are the leading cause of epileptic seizures in adults and account for 50% of seizures in those over the age of 65 years. The use of antiepileptic drugs to prevent recurrent poststroke seizures is recommended. Methods: One hundred and twenty-eight patients with poststroke seizures were randomly allocated to treatment with either levetiracetam (LEV) or sustained-release carbamazepine (CBZ) in a multicenter randomized open-label study. After a titration study phase (2 weeks), the optimal individual dose of trial medication was determined and treatment was continued for another 52 weeks. The primary endpoint was defined as the proportion of seizure-free patients; the secondary endpoints were: evaluation of time recurrence to the first seizure, EEG tracings, cognitive functions and side effects. Results: Of 128 patients, 22 discontinued the trial prematurely; thus a total of 106 patients (52 treated with LEV and 54 treated with CBZ) were included in the analysis. The results of the study were as follows: no significant difference in number of seizure-free patients between LEV and CBZ (p = 0.08); time to the first recurrence tended to be longer among patients on LEV; there was no correlation between the therapeutic effect and the EEG findings in either treatment group; LEV caused significantly fewer (p = 0.02) side effects than CBZ; attention deficit, frontal executive functions and functional scales (Activities of Daily Living and Instrumental Activities of Daily Living indices) were significantly worse in the CBZ group. Conclusions: This trial suggests that LEV may be a valid alternative to CBZ in poststroke seizures, particularly in terms of efficacy and safety. In addition, our results show that LEV has significant advantages over CBZ on cognitive functions. This trial also indicates that LEV in monotherapy is a safe and effective therapeutic option in elderly patients who have suffered epileptic seizures following a stroke.
Human Chorionic Gonadotropin Induces Human Macrophages to Form Intracytoplasmic Vacuoles Mimicking Hofbauer Cells in Human Chorionic Villi
Authors: Yamaguchi Munekage , Ohba Takashi , Tashiro Hironori , Yamada Gen , Katabuchi Hidetaka
Published: November 2012

The most characteristic morphological feature of macrophages in the stroma of placental villi, known as Hofbauer cells, is their highly vacuolated appearance. They also show positive immunostaining for human chorionic gonadotropin (hCG) and express messenger ribonucleic acid of the luteinizing hormone/chorionic gonadotropin receptor with a deletion of exon 9 (LH/CG-R Δ9). Maternal hCG enters fetal plasma through the mesenchyme of the placental villi and promotes male sexual differentiation in early pregnancy; therefore, excess hCG may induce aberrant genital differentiation and hCG must be adjusted at the fetomaternal interface. We hypothesized that hCG is regulated by Hofbauer cells and that their peculiar vacuoles are involved in a cell-specific function. To assess the morphological modification and expression of LH/CG-R Δ9 in human macrophages after hCG exposure, the present study examined phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells, a human monocyte-macrophage cell line. hCG induced transient vacuole formation in PMA-treated THP-1 cells, morphologically mimicking Hofbauer cells. Immunocytochemistry showed that PMA-treated THP-1 cells incorporated hCG but not luteinizing hormone or follicle-stimulating hormone. Western blotting analyses demonstrated that PMA-treated THP-1 cells expressed an immunoreactive 60-kDa protein, designated as endogenous LH/CG-R Δ9. hCG induced a transient reduction in the LH/CG-R Δ9, which was synchronous with the appearance of cytoplasmic vacuoles. In conclusion, human macrophages regulating hCG via cytoplasmic LH/CG-R Δ9 mimic the morphological characteristics of Hofbauer cells. Their vacuoles may be associated with their cell-specific function to protect the fetus from exposure to excess maternal hCG during pregnancy.
Morphogenesis of Rete Ridges in Human Oral Mucosa: A Pioneering Morphological and Immunohistochemical Study
Authors: Wu Tianfu , Xiong Xuepeng , Zhang Wenfeng , Zou Haixiao , Xie Haiyan , He Sangang
Published: November 2012

Objective: One of the major impediments in tissue-engineered oral mucosa (TEOM) is the lack of rete ridge (RR) structures that can weaken the connection between the epidermis and dermis. This study aimed to investigate the native morphology of RRs as well as the expression of extracellular signal-regulated kinase 1/2 (ERK1/2), Ki67, and keratin-19, which are related to cell mechanotransduction, proliferation, and stemness in the oral epidermis, respectively. Methods: RR characteristics, including type, density, length, and width, were analyzed in the masticatory mucosa (Mm) and lining mucosa (Lm) sites of 52 specimens. The expression of ERK1/2, Ki67, and keratin-19 was assessed by immunohistochemistry. ERK1/2 activation by masticatory stimuli was confirmed in vitro by loading pressure onto cultured keratinocytes isolated from the specimens. Results: Three types of RR were found. The RRs in the Mm and Lm differed. The length and percentage of ERK1/2-positive (%ERK1/2+) basal layer cells had a negative correlation (p = 0.004), whereas the length and %Ki67+ basal layer cells had a positive correlation (p = 0.013). The %ERK1/2+ basal layer cells and %keratin-19+ basal layer cells had a negative relationship (p = 0.011). ERK1/2 activation in the oral epithelium was induced by pressure and propagated in cultured keratinocytes. Conclusion: RRs are longer in the Mm, which may result from the topical basal cell proliferation and migration induced by masticatory pressure via ERK1/2 activation. Our findings preliminarily interpret RR histomorphology as influenced by oral masticatory pressure. Results may benefit future studies on RR development and reconstruction in TEOM models to enhance the epidermis-dermis connection.
Mannheim Carotid Intima-Media Thickness and Plaque Consensus (2004–2006–2011)
Authors: Touboul P.-J. , Hennerici M.G. , Meairs S. , Adams H. , Amarenco P. , Bornstein N. , Csiba L. , Desvarieux M. , Ebrahim S. , Hernandez Hernandez R. , Jaff M. , Kownator S. , Naqvi T. , Prati P. , Rundek T. , Sitzer M. , Schminke U. , Tardif J.-C. , Taylor A. , Vicaut E. , Woo K.S.
Published: November 2012

Intima-media thickness (IMT) provides a surrogate end point of cardiovascular outcomes in clinical trials evaluating the efficacy of cardiovascular risk factor modification. Carotid artery plaque further adds to the cardiovascular risk assessment. It is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. The scientific basis for use of IMT in clinical trials and practice includes ultrasound physics, technical and disease-related principles as well as best practice on the performance, interpretation and documentation of study results. Comparison of IMT results obtained from epidemiological and interventional studies around the world relies on harmonization on approaches to carotid image acquisition and analysis. This updated consensus document delineates further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT. Standardized methods will foster homogenous data collection and analysis, improve the power of randomized clinical trials incorporating IMT and plaque measurements and facilitate the merging of large databases for meta-analyses. IMT results are applied to individual patients as an integrated assessment of cardiovascular risk factors. However, this document recommends against serial monitoring in individual patients.
Pretreatment Parameters Obtained from Peripheral Blood Sample Predicts Invasiveness of Bladder Carcinoma
Authors: Can C. , Baseskioglu B. , Yılmaz M. , Colak E. , Ozen A. , Yenilmez A.
Published: November 2012

Purpose: To predict the invasiveness of urothelial bladder carcinoma using a logistic regression model on preoperative peripheral blood samples. Patients and Methods: Hospital data of patients operated for urothelial carcinoma were reviewed retrospectively. Preoperative blood samples were collected before the first cystoscopic examination. Any kind of infection or inflammation was an exclusion criterion. Patients were grouped as having a non-muscle-invasive or muscle-invasive urothelial carcinoma. The mean age was 69 years and was determined as the cut-off value. According to receiver operating characteristic curves, threshold points were determined for lymphocytes, neutrophil count, neutrophil-to-lymphocyte ratio (NLR), thrombocytes and mean platelet volume. Demographic specialties, parameters obtained from blood samples, tumor size and multiplicity were evaluated and significant parameters were put into a logistic regression model. Results: The study group consisted of 80 non-muscle-invasive and 102 muscle-invasive patients. Age (≤69 vs. >69), female gender, NLR (2.57), mean platelet volume (7.9/fl) and platelet count (400,000/µl) were significant parameters and put in a model. Using odds ratios, the probability of tumor invasiveness was calculated by a formula. Conclusion: Age, female gender, NLR and platelet count were found to be the predictors of invasiveness of urothelial carcinoma.