bluuebunny/crossref_metadata_2025 huggingface dataset:
Citizens in the Making: Youth and Citizenship Education in Europe
Authors: Georgi Viola B.
Published: July 2008

ABSTRACT—
This article explores the relationship between citizenship education and European citizenship in the light of increasingly diverse European societies. It raises the question of whether nation‐state models of citizenship need to be rethought to accommodate a supranationally conceptualized European citizenship and asks what kind of citizenship education complies with the demands of this new citizenship. In doing so, the article highlights the challenge of integrating a European dimension into citizenship education and reviews new European programs intended to promote citizenship among young people in particular. The article also presents data on young people’s knowledge about, and attitudes toward, the Europe Union. Finally, the article examines the rather meager evidence base of citizenship education in Europe by discussing recent comparative studies. It concludes that citizenship education in Europe, and the implementation of programs to develop it, require further scientific grounding.
Toward a New Public Education: Making Globalization Work for Us All
Authors: Moss Peter
Published: July 2008

ABSTRACT—
Globalization is a long‐term, multidimensional process. If it is to benefit humankind rather than ruining the planet, a number of threats must be urgently addressed, and many global processes must be better managed. This article proposes that managing globalization for the common good requires, inter alia, an enhanced role for democracy, a role supported by a new public education that is inscribed with 6 key values—democracy, critical thinking, relational ethics, creativity, social justice, and solidarity—and is based on a particular image of the child and the school. The article concludes by asking how this new public education might gain ground in the face of strong obstacles and proposes democratic experimentalism and “glocal” networks (the global linking of local experiences) as important elements of positive change that is radical in direction but piecemeal in form.
The Development of Gaze Following
Authors: Moore Chris
Published: July 2008

ABSTRACT—
Gaze following is a fundamental component of object‐focused social interaction that researchers have studied as a manifestation of early psychological understanding. This article reviews recent research on manipulations of gaze cues, target salience, spatial layout, and social‐interactive context. The development of gaze following through infancy is a dynamic system that should be studied using a combination of empirical and modeling approaches.
A KLEINIAN THEORY OF SEXUALITY
Authors: Lubbe Trevor
Published: July 2008

abstract  The author examines claims made some years ago by Green (1995), but still referenced today by others, that the theoretical and clinical emphasis given by British Object Relations theorists – Balint, Fairbairn, Winnicott and especially Klein – to the pregenital dimension of the mother–infant relationship has reduced the importance of sexuality in psychoanalysis resulting in a desexualization of classical theory and practice. The author notes that, except for Parsons (2000) and Litowitz (2002), these charges have gone unchallenged and he wishes to contribute to this ‘debate’ by presenting a Kleinian theory of sexuality. Meltzer's (1973) book Sexual States of Mind will be used as a primer for such a theory since the explicit goal of this text is a structural revision of psychoanalytic sexual theory from an Object Relations perspective. Through Meltzer's concept of ‘sexual states of mind’, and his sub‐theory of ‘aesthetic reciprocity’ as a theory of primal seduction, the author will demonstrate how the diverse features of infantile and adult sexuality are given a very detailed, comprehensive understanding within an Object Relations paradigm. In fact, if there has been a turning away from sexuality in psychoanalysis, as Green and others contend, it is not because of Object Relations theory but because of the great complexity brought to our understanding of sexuality by Object Relations paradigms. The author presents this paper as a tribute to Donald Meltzer who died in August 2004.
ASSESSMENT IN SUPERVISION: AN ANALYTIC PERSPECTIVE
Authors: Driver Christine
Published: July 2008

abstract  The art and science of assessment in supervision are considered in relation to all the dimensions of the supervisory matrix. Issues relating to assessing the patient and the supervisee are considered along with the interactive dynamics between patient and supervisee and supervisee and supervisor that influence this process. The paper considers criteria that the supervisee can utilize in relation to the assessment of the patient and the supervisee and includes issues relating to supervisee development. The complex process of assessment in supervision is also considered in relation to the many interactive layers and conscious and unconscious processes inherent within supervision.
METAPHOR IN PSYCHOANALYTIC PSYCHOTHERAPY: A COMPARATIVE STUDY OF FOUR CASES BY A PRACTITIONER–RESEARCHER
Authors: Long Philippa Shadrach , Lepper Georgia
Published: July 2008

abstract Twelve transcripts, three from each of four patients, taken from the early, mid and late phases of open‐ended, long‐term psychoanalytic psychotherapy with the same therapist, were analysed for metaphor. Metaphors were categorized into key, novel and conventional. Using grounded theory metaphors were categorized by theme and function. It was found that all metaphors – novel, conventional and key – could be representative of key concepts such as the self, others/relationships and therapy/self transformation and diagnosis or psychopathology; chart change; indicate mentalization (Fonagyet al.2004). In addition use of metaphors by different patients showed different patterns that co‐occurred with good or bad outcome.
Hepatocyte growth factor gene transfer with naked plasmid DNA ameliorates dimethylnitrosamine‐induced liver fibrosis in rats
Authors: Kanemura Hironari , Iimuro Yuji , Takeuchi Masaharu , Ueki Takahiro , Hirano Tadamichi , Horiguchi Kiyoshi , Asano Yasukane , Fujimoto Jiro
Published: July 2008

Aim:  Hepatocyte growth factor (HGF) has various biological properties, including antifibrogenic activity. In the present study, we tested the efficacy of HGF gene therapy using naked plasmid DNA in dimethylnitrosamine (DMN)‐induced liver fibrosis in a rat model.

Methods:  Naked plasmid DNA encoding human HGF was injected once, together with a hypertonic solution, into the hepatic artery after DMN treatment on three consecutive days per week for 3 weeks. Naked plasmid DNA encoding β‐galactosidase was injected similarly in the DMN‐treated control rats. DMN treatment was continued once weekly after gene transfer for additional 3 weeks.

Results:  The human HGF protein expression was detected in livers transfected with human HGF naked plasmid DNA, gradually decreasing by day 21. The expression of the endogenous rat HGF protein was also upregulated after human HGF gene transfer. Phosphorylation of c‐Met, a HGF receptor, was detected only in livers transfected with human HGF plasmid DNA. Fibrosis was attenuated significantly in livers transfected with the human HGF plasmid. Attenuation wasaccompanied by decreased expression of α‐smooth muscle actin. Increased portal vein pressure after treatment with DMN was suppressed significantly by HGF gene transfer. The upregulated hepatic protein expression of transforming growth factor‐β (TGF‐β) in response to DMN was markedly attenuated by HGF gene transfer accompanied by the increased protein expression for matrix metalloproteinases (MMP)‐3 and ‐13.

Conclusion:  The hepatic arterial injection of human naked plasmid HGF DNA was effective in suppressing liver fibrosis induced in rats by DMN. The mechanisms by which HGF expression attenuated liver fibrosis may include the suppression of hepatic TGF‐β expression and the induction of MMP expression.
Cell survival, activation and apoptosis of hepatic stellate cells: modulation by extracellular matrix proteins
Authors: Priya Sulochana , Sudhakaran Perumana R.
Published: July 2008

Aim:  Cytokines and growth factors released by various hepatic cells exert both paracrine and autocrine effects on hepatic stellate cell (HSC) activation during liver injury. The aim of the present study was to examine whether the surrounding extracellular matrix (ECM) influences the activation, transdifferentiation and survival of HSCs.

Methods:  An in vitro model system of isolated HSCs maintained in culture on different matrix protein substrata was employed.

Results:  The rate of loss of HSC‐specific retinol uptake activity and gain of myofibroblast‐like activity such as 35[S] proteoglycan synthesis varied in cells maintained on different matrix proteins and was in the order collagen I > collagen IV ≥ laminin. 3[H]‐thymidine incorporation by HSCs maintained on different matrix proteins varied and was in the order collagen I > collagen IV > laminin. MTT assay revealed that the growth inhibition in response to curcumin was significantly low in cells maintained on collagen I. Apoptotic marker activities such as DNA fragmentation, 4′,6′‐diamidino‐2‐phenylindole dihydrochloride (DAPI) staining, annexin staining and caspase‐3 activities showed that cells maintained on collagen I showed minimal apoptosis than those maintained on collagen IV, laminin and polylysine, showing the influence of ECM on HSC apoptosis. Experiments using blocking antibodies showed that the collagen I effect was mediated through α2β1 integrin.

Conclusions:  These results indicate that ECM influences activation, transdifferentiation and survival of HSCs, and suggest that apart from diffusible factors, the surrounding ECM also influences HSC behavior critical in both the progression of the fibrosis and the restitution of the liver during recovery after hepatic injury.
Recent status of drug‐induced liver injury
Authors: Takikawa Hajime
Published: July 2008

Drug‐induced liver injury is an major cause of acute liver injury and the incidence of drug‐induced liver injury seems to be increasing with an increase in the number of new drugs available. The diagnostic scale of drug‐induced liver injury was been modified by the International Consensus Meeting during Digestive Disease Week, Japan 2004, which includes the score of the drug‐lymphocyte stimulation test and eosinophilia. Although the modified diagnostic scale is useful, and widely used in Japan, there will be many issues to be investigated in the future. According to a recent survey of drug‐induced liver injury cases in Japan, drug‐induced liver injury from dietary supplements are increasing, as has been observed in foreign countries. More research is needed to elucidate the mechanisms of drug metabolism and the pathophysiology of liver injury by various drugs to prevent drug‐induced liver injury.
Nitric oxide–cGMP–protein kinase G pathway negatively regulates vascular transient receptor potential channel TRPC6
Authors: Takahashi Shinichi , Lin Hai , Geshi Naomi , Mori Yasuo , Kawarabayashi Yasuhiro , Takami Noboru , Mori Masayuki X. , Honda Akira , Inoue Ryuji
Published: July 2008

We investigated the inhibitory role of the nitric oxide (NO)–cGMP–protein kinase G (PKG) pathway on receptor‐activated TRPC6 channels in both a heterologous expression system (HEK293 cells) and A7r5 vascular myocytes. Cationic currents due to TRPC6 expression were strongly suppressed (by ∼70%) by a NO donor SNAP (100 μm) whether it was applied prior to muscarinic receptor stimulation with carbachol (CCh; 100 μm) or after G‐protein activation with intracellular perfusion of GTPγS (100 μm). A similar extent of suppression was also observed with a membrane‐permeable analogue of cGMP, 8Br‐cGMP (100 μm). The inhibitory effects of SNAP and 8Br‐cGMP on TRPC6 channel currents were strongly attenuated by the presence of inhibitors for guanylyl cyclase and PKG such as ODQ, KT5823 and DT3. Alanine substitution for the PKG phosphorylation candidate site at T69 but not at other sites (T14A, S28A, T193A, S321A) of TRPC6 similarly attenuated the inhibitory effects of SNAP and 8Br‐cGMP. SNAP also significantly reduced single TRPC6 channel activity recorded in the inside‐out configuration in a PKG‐dependent manner. SNAP‐induced PKG activation stimulated the incorporation of32P into wild‐type and S321A‐mutant TRPC6 proteins immunoprecipitated by TRPC6‐specific antibody, but this was greatly attenuated in the T69A mutant. SNAP or 8Br‐cGMP strongly suppressed TRPC6‐like cation currents and membrane depolarization evoked by Arg8‐vasopressin in A7r5 myocytes. These results strongly suggest that TRPC6 channels can be negatively regulated by the NO–cGMP–PKG pathway, probably via T69 phosphorylation of the N‐terminal. This mechanism may be physiologically important in vascular tissues where NO is constantly released from vascular endothelial cells or nitrergic nerves.
Cessation of daily exercise dramatically alters precursors of hepatic steatosis in Otsuka Long‐Evans Tokushima Fatty (OLETF) rats
Authors: Rector R. Scott , Thyfault John P. , Laye Matthew J. , Morris R. Tyler , Borengasser Sarah J. , Uptergrove Grace M. , Chakravarthy Manu V. , Booth Frank W. , Ibdah Jamal A.
Published: July 2008

The purpose of this study was to delineate potential mechanisms initiating the onset of hepatic steatosis following the cessation of daily physical activity. Four‐week‐old, hyperphagic/obese Otsuka Long‐Evans Tokushima Fatty rats were given access to voluntary running wheels for 16 weeks to prevent the development of hepatic steatosis. The animals were then suddenly transitioned to a sedentary condition as wheels were locked (wheel lock; WL) for 5 h (WL5), 53 h (WL53) or 173 h (WL173). Importantly after the cessation of daily exercise (5–173 h), no changes occurred in body weight, fat pad mass (omental and retroperitoneal), food intake, serum insulin, hepatic triglycerides or in the exercise‐suppressed hepatic stearoyl‐CoA desaturase‐1 and peroxisome proliferator‐activated receptor‐γ protein content. However, complete hepatic fatty acid oxidation and mitochondrial enzyme activities were highest at WL5 and WL53 and dropped significantly to SED levels by WL173. In addition, cessation of daily exercise quickly increased the hepatic protein contents of fatty acid synthase and acetyl‐coenzyme A carboxylase (ACC), reduced ACC phosphorylation status, and dramatically increased hepatic malonyl‐CoA concentration. This study is the first to show that the sudden cessation of daily exercise in a hyperphagic/obese model activates a subgroup of precursors and processes known to initiate hepatic steatosis, including decreased hepatic mitochondrial oxidative capacity, increased hepatic expression of de novo lipogenesis proteins, and increased hepatic malonyl CoA levels; each probably increasing the susceptibility to non‐alcoholic fatty liver disease.
Aldosterone increases KCa1.1 (BK) channel‐mediated colonic K+ secretion
Authors: Sørensen Mads V. , Matos Joana E. , Sausbier Matthias , Sausbier Ulrike , Ruth Peter , Praetorius Helle A. , Leipziger Jens
Published: July 2008

Mammalian K+ homeostasis results from highly regulated renal and intestinal absorption and secretion, which balances the unregulated K+ intake. Aldosterone is known to enhance both renal and colonic K+ secretion. In mouse distal colon K+ secretion occurs exclusively via luminal KCa1.1 (BK) channels. Here we investigate if aldosterone stimulates colonic K+ secretion via BK channels. Luminal Ba2+ and iberiotoxin (IBTX)‐sensitive electrogenic K+ secretion was measured in Ussing chambers. In vivo aldosterone was augmented via a high K+ diet. High K+ diet led to a 2‐fold increase of luminal Ba2+ and IBTX‐sensitive short‐circuit current in distal mouse colonic mucosa. This effect was absent in BK α‐subunit‐deficient (BK−/−) mice. The resting and diet‐induced K+ secretion was stimulated by luminal ionomycin. In BK−/− mice luminal ionomycin did not stimulate K+ secretion. In vitro addition of aldosterone likewise triggered a 2‐fold increase in K+ secretion, which was inhibited by the mineralocorticoid receptor antagonist spironolactone and the BK channel blocker IBTX. Semi‐quantification of mRNA from colonic crypts showed up‐regulation of BK α‐ and β2‐subunits in high K+ diet mice. The BK channel could be detected luminally in colonic crypt cells by immunohistochemistry. The expression level of the channel in the luminal membrane was strongly up‐regulated in K+‐loaded animals. Taken together, these data strongly suggest that aldosterone‐induced K+ secretion occurs via increased expression of luminal BK channels.
Mechanisms of response homeostasis during retinocollicular map formation
Authors: Shah Ruchir D. , Crair Michael C.
Published: July 2008

The mechanisms of Hebbian synaptic plasticity have been widely hypothesized to play a role in the activity‐dependent development of neural circuits. However, these mechanisms are inherently unstable and would lead to the runaway excitation or depression of circuits if left unchecked. In the last decade, a number of elegant studies have demonstrated that homeostatic plasticity mechanisms exist to stabilize neural networks and maintain the constancy of neuronal output in response to changes in activity levels. These include synaptic scaling, sliding threshold models of synaptic plasticity, dynamic regulation of the number and strength of synapses, and bidirectional control of intrinsic excitability. Recently, we showed that the total synaptic input onto individual neurons of the mouse superior colliculus is preserved regardless of the size of their visual receptive fields, a phenomenon we term ‘response homeostasis’. Here, we argue that regulating the capacity for synaptic plasticity and controlling the number and strength of retinocollicular inputs can preserve collicular neuron output, and we present evidence that changes in intrinsic excitability are not associated with response homeostasis. We also review findings from a number of different mutant mice and discuss whether and how different cellular mechanisms may underlie response homeostasis. Combined with other studies, our work reveals an important role for homeostatic mechanisms in regulating functional connectivity during the construction of receptive fields and the refinement of topographic maps.
Regulation of CD45 Alternative Splicing by Heterogeneous Ribonucleoprotein, hnRNPLL
Authors: Oberdoerffer Shalini , Moita Luis Ferreira , Neems Daniel , Freitas Rui P. , Hacohen Nir , Rao Anjana
Published: July 2008

The transition from naïve to activated T cells is marked by alternative splicing of pre-mRNA encoding the transmembrane phosphatase CD45. Using a short hairpin RNA interference screen, we identified heterogeneous ribonucleoprotein L-like (hnRNPLL) as a critical inducible regulator of CD45 alternative splicing. HnRNPLL was up-regulated in stimulated T cells, bound CD45 transcripts, and was both necessary and sufficient for CD45 alternative splicing. Depletion or overexpression of hnRNPLL in B and T cell lines and primary T cells resulted in reciprocal alteration of CD45RA and RO expression. Exon array analysis suggested that hnRNPLL acts as a global regulator of alternative splicing in activated T cells. Induction of hnRNPLL during hematopoietic cell activation and differentiation may allow cells to rapidly shift their transcriptomes to favor proliferation and inhibit cell death.
Suppressing Spin Qubit Dephasing by Nuclear State Preparation
Authors: Reilly D. J. , Taylor J. M. , Petta J. R. , Marcus C. M. , Hanson M. P. , Gossard A. C.
Published: July 2008

Coherent spin states in semiconductor quantum dots offer promise as electrically controllable quantum bits (qubits) with scalable fabrication. For few-electron quantum dots made from gallium arsenide (GaAs), fluctuating nuclear spins in the host lattice are the dominant source of spin decoherence. We report a method of preparing the nuclear spin environment that suppresses the relevant component of nuclear spin fluctuations below its equilibrium value by a factor of ∼70, extending the inhomogeneous dephasing time for the two-electron spin state beyond 1 microsecond. The nuclear state can be readily prepared by electrical gate manipulation and persists for more than 10 seconds.
Quantum Gas of Deeply Bound Ground State Molecules
Authors: Danzl Johann G. , Haller Elmar , Gustavsson Mattias , Mark Manfred J. , Hart Russell , Bouloufa Nadia , Dulieu Olivier , Ritsch Helmut , Nägerl Hanns-Christoph
Published: July 2008

Molecular cooling techniques face the hurdle of dissipating translational as well as internal energy in the presence of a rich electronic, vibrational, and rotational energy spectrum. In our experiment, we create a translationally ultracold, dense quantum gas of molecules bound by more than 1000 wave numbers in the electronic ground state. Specifically, we stimulate with 80% efficiency, a two-photon transfer of molecules associated on a Feshbach resonance from a Bose-Einstein condensate of cesium atoms. In the process, the initial loose, long-range electrostatic bond of the Feshbach molecule is coherently transformed into a tight chemical bond. We demonstrate coherence of the transfer in a Ramsey-type experiment and show that the molecular sample is not heated during the transfer. Our results show that the preparation of a quantum gas of molecules in specific rovibrational states is possible and that the creation of a Bose-Einstein condensate of molecules in their rovibronic ground state is within reach.
British American Tobacco and the “insidious impact of illicit trade” in cigarettes across Africa
Authors: LeGresley E , Lee K , Muggli M E , Patel P , Collin J , Hurt R D
Published: July 2008

Objectives:

To provide an overview of the complicity of British American Tobacco (BAT) in the illicit trade of cigarettes across the African continent in terms of rationale, supply routes and scale.

Methods:

Analysis of internal BAT documents and industry publications.

Results:

BAT has relied on illegal channels to supply markets across Africa since the 1980s. Available documents suggest smuggling has been an important component of BAT’s market entry strategy in order to gain leverage in negotiating with governments for tax concessions, compete with other transnational tobacco companies, circumvent local import restrictions and unstable political and economic conditions and gain a market presence. BAT worked through distributors and local agents to exploit weak government capacity to gain substantial market share in major countries.

Conclusions:

Documents demonstrate that the complicity of BAT in cigarette smuggling extends to Africa, which includes many of the poorest countries in the world. This is in direct conflict with offers by the company to contribute to stronger international cooperation to tackle the illicit tobacco trade.
Adaptive HNE-Nrf2-HO-1 pathway against oxidative stress is associated with acute gastric mucosal lesions
Authors: Ueda Kazuki , Ueyama Takashi , Yoshida Ken-ichi , Kimura Hiroko , Ito Takao , Shimizu Yasuhito , Oka Masashi , Tsuruo Yoshihiro , Ichinose Masao
Published: July 2008

Disturbance of the microcirculation and generation of reactive oxygen species are crucial in producing acute gastric mucosal lesions (AGML). To understand the protective mechanism against mucosal injury and oxidative stress in the stomach, we investigated sequential expression and localization of a product of lipid peroxidation and a chemical mediator of the oxidative response array, 4-hydroxynonenal (HNE), transcriptional factor, NF-E2-related factor (Nrf2), and the inducible heme oxygenase (HO-1) in the injured stomach. AGML was produced by intragastric administration of 0.6 N HCl in male rats. Expression and localization of HNE, Nrf2, and HO-1 were investigated by Western blotting, immunohistochemistry, real-time RT-PCR, and in situ hybridization histochemistry. Mucosal lesions and expression of HNE and HO-1 were assessed by prior treatment with the PGI2analog beraprast or after sensory denervation by pretreatment with capsaicin. Mucosal lesions were assessed by prior treatment with a HO-1 inhibitor, zinc protoporphyrin (ZnPP). After AGML, increased generation of HNE was observed in the injured mucosa and the surrounding submucosa, followed by nuclear translocation of Nrf2 and upregulation of HO-1 in the macrophages located in the margin of the injured mucosa and in the submucosa. Pretreatment with beraprost attenuated AGML and downregulated the expression of HNE and HO-1, while sensory denervation aggravated AGML and upregulated the expression of HNE and HO-1. Pretreatment with ZnPP also aggravated AGML. The sequential HNE-Nrf2-HO-1 pathway in the gastric mucosal cells and the macrophages is involved in an adaptive mechanism against oxidative stress after AGML.
Sodium tungstate decreases sucrase and Na+/d-glucose cotransporter in the jejunum of diabetic rats
Authors: Miró-Queralt Montserrat , Guinovart Joan J. , Planas Joana M.
Published: July 2008

Sodium tungstate reduces glycemia and reverts the diabetic phenotype in several induced and genetic animal models of diabetes. Oral administration of this compound has recently emerged as an effective treatment for diabetes. Here we examined the effects of 30 days of oral administration of tungstate on disaccharidase and Na+/d-glucose cotransporter (SGLT1) activity in the jejunum of control and streptozotocin-induced diabetic rats. Diabetes increased sucrase-specific activity in the jejunal mucosa but did not affect the activity of lactase, maltase, or trehalase. The abundance and the maximal rate of transport of SGLT1 in isolated brush-border membrane vesicles also increased. Tungstate decreased sucrase activity and normalized SGLT1 expression and activity in the jejunum of diabetic rats. Furthermore, tungstate did not change the affinity of SGLT1 for d-glucose and had no effect on the diffusional component. In control animals, tungstate had no effect on disaccharidases or SGLT1 expression. Northern blot analysis showed that the amount of specific SGLT1 mRNA was the same in the jejunum from all experimental groups, thereby indicating that changes in SGLT1 abundance are due to posttranscriptional mechanisms. We conclude that the antidiabetic effect of tungstate is partly due to normalization of the activity of sucrase and SGLT1 in the brush-border membrane of enterocytes.
Differences in activity and phosphorylation of MAPK enzymes in esophageal squamous cells of GERD patients with and without Barrett's esophagus
Authors: Zhang Hui Ying , Zhang Xi , Chen Xi , Thomas Deena , Hormi-Carver Kathy , Elder Frederick , Spechler Stuart J. , Souza Rhonda F.
Published: July 2008

We hypothesized that, in esophageal squamous epithelial cells, there are differences among individuals in the signal transduction pathways activated by acid reflux that might underlie the development of Barrett's esophagus. To explore that hypothesis, we immortalized nonneoplastic, esophageal squamous cells from patients with gastroesophageal reflux disease (GERD) with (NES-B3T) and without (NES-G2T) Barrett's esophagus and used those cells to study acid effects on MAPK proteins. During endoscopy in patients with GERD with and without Barrett's esophagus, we took biopsy specimens from the distal squamous esophagus to study MAPK proteins before and after esophageal perfusion with 0.1 N HCl. We used immunoblotting and Western blotting to study MEK1/2 phosphorylation at two activating sites (serines 217/221), MEK1 phosphorylation at an inhibitory site (threonine 286), and MEK1/2 activity. After acid exposure, both cell lines exhibited increased MEK1/2 phosphorylation at the activating sites; the NES-B3T cells had higher levels of MEK1 phosphorylation at the inhibitory site, however, and only the NES-G2T cells showed an acid-induced increase in MEK1/2 activity. Similarly, in the squamous epithelium of patients with GERD with and without Barrett's esophagus, acid perfusion increased MEK1/2 phosphorylation at the activating sites in both patient groups; the Barrett's patients had higher levels of MEK1 phosphorylation at the inhibitory site, however, and only the patients without Barrett's demonstrated an acid-induced increase in ERK1/2 phosphorylation. In esophageal squamous cell lines and biopsies from patients with GERD with and without Barrett's esophagus, we have found differences in MAPK pathways activated by acid exposure. We speculate that these differences might underlie the development of Barrett's metaplasia.
High body mass alters colonic sensory-motor function and transit in humans
Authors: Delgado-Aros Silvia , Camilleri Michael , Garcia Montse Andreu , Burton Duane , Busciglio Irene
Published: July 2008

There is increased prevalence of abdominal pain and diarrhea and decreased gastric sensation with increased body mass index (BMI). Our hypothesis is that increased BMI is associated with increased colonic motility and sensation. The study aim was to assess effect of BMI on colonic sensory and motor functions and transit. We used a database of colonic tone, compliance, and perception of distensions measured by intracolonic, barostat-controlled balloon, and gastrointestinal transit was measured by validated scintigraphy in healthy obese and nonobese subjects. Regression analysis was applied to assess the association of BMI with colonic sensory and motor functions. We included adjustments for sex differences, age, height, balloon volumes during distension, and psychological stress. Among 165 participants (87 women, 78 men), increased BMI was associated with decreased colonic compliance ( P < 0.006, adjusted), decreased pain rating during distensions ( P = 0.02, adjusted), and a higher threshold for pain ( P = 0.042, adjusted). Sensation for gas, colonic tone, and contraction after meal ingestion were not significantly associated with BMI. Transit was assessed in 72 participants (41 women, 31 men); colonic transit was faster with BMI >30 kg/m2 ( P = 0.003 unadjusted, P = 0.08 adjusted for gender). In conclusion, BMI >25 kg/m2 is associated with decreased colonic compliance and pain sensation; colonic transit is accelerated particularly with BMI >30 kg/m2 in women. These data suggest that colonic dysfunction may contribute to diarrhea, but the cause of increased abdominal pain in obesity is not explained by the studies of colonic sensation and requires further study of afferent, spinal, and central mechanisms.
Inhibition of vascular smooth muscle cell proliferation by chronic hemin treatment
Authors: Chang Tuanjie , Wu Lingyun , Wang Rui
Published: July 2008

Hemin, an oxidized form of heme, is an essential regulator of gene expression and cell cycle progression. Our laboratory previously reported ( 34 ) that chronic hemin treatment of spontaneously hypertensive rats reversed the eutrophic inward remodeling of small peripheral arteries. Whether long-term treatment of cultured vascular smooth muscle cells (VSMCs) with hemin alters the proliferation status of these cells has been unknown. In the present study, hemin treatment at 5 μM for 4, 7, 14, and 21 days significantly inhibited the proliferation of cultured rat aortic VSMCs (A-10 cells) by arresting cells at G0/G1 phases so as to decelerate cell cycle progression. Heme oxygenase (HO) activity and inducible HO-1 protein expression were significantly increased by hemin treatment. HO inhibitor tin protoporphyrin IX (SnPP) abolished the effects of hemin on cell proliferation and HO activity. Interestingly, hemin-induced HO-1 expression was further increased in the presence of SnPP. Hemin treatment had no significant effect on the expression of constitutive HO-2. Expression of p21 protein and the level of reactive oxygen species (ROS) were decreased by hemin treatment, which was reversed by application of SnPP. After removal of hemin from culture medium, inhibited cell proliferation and increased HO-1 expression in VSMCs were returned to control level within 1 wk. Transfection with HO-1 small interfering RNA significantly knocked down HO-1 expression and decreased HO activity, but had no effect on HO-2 expression, in cells treated with or without hemin for 7 days. The inhibitory effect of hemin on cell proliferation was abolished in HO-1 silenced cells. It is concluded that induction of HO-1 and, consequently, increased HO activity are responsible for the chronic inhibitory effect of hemin on VSMC proliferation. Changes in the levels of p21 and ROS might also participate in the cellular effects of hemin.
Contrasting effects of isocapnic and hypocapnic hyperventilation on orthostatic circulatory control
Authors: Thijs Roland D. , van den Aardweg Joost G. , Reijntjes Robert H. A. M. , van Dijk J. Gert , van Lieshout Johannes J.
Published: July 2008

The effects of hyperventilation (HV) on mean arterial pressure (MAP) are variable. To identify factors affecting the MAP response to HV, we dissected the effects of hypocapnic HV (HHV) and isocapnic HV (IHV) and evaluated the effects of acute vs. prolonged HHV. In 11 healthy subjects the cardio- and cerebrovascular effects of HHV and IHV vs. normal ventilation were examined for 15 min in the supine position and also for 15 min during 60° head-up tilt. The end-tidal CO2 of the HHV condition was set at 15–20 mmHg. With HHV in the supine position, mean cerebral blood flow velocity (mCBFV) declined [95% confidence interval (CI) −43 to −34%], heart rate (HR) increased (95% CI 7 to 16 beats/min), but MAP did not change (95% CI −1 to 6 mmHg). However, an augmentation of the supine MAP was observed in the last 10 min of HHV compared with the first 5 min of HHV (95% CI 2 to 12 mmHg). During HHV in the tilted position mCBFV declined (95% CI −28 to −12%) and MAP increased (95% CI 3 to 11 mmHg) without changes in HR. With supine IHV, mCBFV decreased (95% CI −14 to −4%) and MAP increased (95% CI 1 to 13 mmHg) without changes in HR. During IHV in the tilted position MAP was further augmented (95% CI 11 to 20 mmHg) without changes in CBFV or HR. Preventing hypocapnia during HV resulted in a higher MAP, suggesting two contrasting effects of HV on MAP: hypocapnia causing vasodepression and hyperpnea without hypocapnia acting as a vasopressor.
Effect of hydration state on resistance exercise-induced endocrine markers of anabolism, catabolism, and metabolism
Authors: Judelson Daniel A. , Maresh Carl M. , Yamamoto Linda M. , Farrell Mark J. , Armstrong Lawrence E. , Kraemer William J. , Volek Jeff S. , Spiering Barry A. , Casa Douglas J. , Anderson Jeffrey M.
Published: July 2008

Hypohydration (decreased total body water) exacerbates the catabolic hormonal response to endurance exercise with unclear effects on anabolic hormones. Limited research exists that evaluates the effect of hypohydration on endocrine responses to resistance exercise; this work merits attention as the acute postexercise hormonal environment potently modulates resistance training adaptations. The purpose of this study was to examine the effect of hydration state on the endocrine and metabolic responses to resistance exercise. Seven healthy resistance-trained men (age = 23 ± 4 yr, body mass = 87.8 ± 6.8 kg, body fat = 11.5 ± 5.2%) completed three identical resistance exercise bouts in different hydration states: euhydrated (EU), hypohydrated by ∼2.5% body mass (HY25), and hypohydrated by ∼5.0% body mass (HY50). Investigators manipulated hydration status via controlled water deprivation and exercise-heat stress. Cortisol, epinephrine, norepinephrine, testosterone, growth hormone, insulin-like growth factor-I, insulin, glucose, lactate, glycerol, and free fatty acids were measured during euhydrated rest, immediately preceding resistance exercise, immediately postexercise, and during 60 min of recovery. Body mass decreased 0.2 ± 0.4, 2.4 ± 0.4, and 4.8 ± 0.4% during EU, HY25, and HY50, respectively, supported by humoral and urinary changes that clearly indicated subjects achieved three distinct hydration states. Hypohydration significantly 1) increased circulating concentrations of cortisol and norepinephrine, 2) attenuated the testosterone response to exercise, and 3) altered carbohydrate and lipid metabolism. These results suggest that hypohydration can modify the hormonal and metabolic response to resistance exercise, influencing the postexercise circulatory milieu.
The airway response to deep inspirations decreases with COPD severity and is associated with airway distensibility assessed by computed tomography
Authors: Scichilone Nicola , La Sala Alba , Bellia Maria , Fallano Katherine , Togias Alkis , Brown Robert H. , Midiri Massimo , Bellia Vincenzo
Published: July 2008

In patients with mild chronic obstructive pulmonary disease (COPD), the effect of deep inspirations (DIs) to reverse methacholine-induced bronchoconstriction is largely attenuated. In this study, we tested the hypothesis that the effectiveness of DI is reduced with increasing disease severity and that this is associated with a reduction in the ability of DI to distend the airways. Fifteen subjects [Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I–II: n = 7; GOLD stage III–IV: n = 8] underwent methacholine bronchoprovocation in the absence of DI, followed by DI. The effectiveness of DI was assessed by their ability to improve inspiratory vital capacity and forced expiratory volume in 1 s (FEV1). To evaluate airway distensibility, two sets of high-resolution computed tomography scans [at residual volume (RV) and at total lung capacity] were obtained before the challenge. In addition, mean parenchymal density was calculated on the high-resolution computed tomography scans. We found a strong correlation between the response to DI and baseline FEV1 %predicted ( r2 = 0.70, P < 0.0001) or baseline FEV1/forced vital capacity ( r2 = 0.57, P = 0.001). RV %predicted and functional residual capacity %predicted correlated inversely ( r2 = 0.33, P = 0.02 and r2 = 0.32, P = 0.03, respectively), and parenchymal density at RV correlated directly ( r2 = 0.30, P = 0.03), with the response to DI. Finally, the effect of DI correlated to the change in large airway area from RV to total lung capacity ( r2 = 0.44, P = 0.01). We conclude that loss of the effects of DI is strongly associated with COPD severity and speculate that the reduction in the effectiveness of DI is due to the failure to expand the lungs because of the hyperinflated state and/or the parenchymal damage that prevents distension of the airways with lung inflation.
Human cerebral arteriovenous vasoactive exchange during alterations in arterial blood gases
Authors: Peebles Karen C. , Richards A. Mark , Celi Leo , McGrattan Ken , Murrell Carissa J. , Ainslie Philip N.
Published: July 2008

Cerebral blood flow (CBF) is highly regulated by changes in arterial Pco2and arterial Po2. Evidence from animal studies indicates that various vasoactive factors, including release of norepinephrine, endothelin, adrenomedullin, C-natriuretic peptide (CNP), and nitric oxide (NO), may play a role in arterial blood gas-induced alterations in CBF. For the first time, we directly quantified exchange of these vasoactive factors across the human brain. Using the Fick principle and transcranial Doppler ultrasonography, we measured CBF in 12 healthy humans at rest and during hypercapnia (4 and 8% CO2), hypocapnia (voluntary hyperventilation), and hypoxia (12 and 10% O2). At each level, blood was sampled simultaneously from the internal jugular vein and radial artery. With the exception of CNP and NO, the simultaneous quantification of norepinephrine, endothelin, or adrenomedullin showed no cerebral uptake or release during changes in arterial blood gases. Hypercapnia, but not hypocapnia, increased CBF and caused a net cerebral release of nitrite (a marker of NO), which was reflected by an increase in the venous-arterial difference for nitrite: 57 ± 18 and 150 ± 36 μmol/l at 4% and 8% CO2, respectively (both P < 0.05). Release of cerebral CNP was also observed during changes in CO2(hypercapnia vs. hypocapnia, P < 0.05). During hypoxia, there was a net cerebral uptake of nitrite, which was reflected by a decreased venous-arterial difference for nitrite: −96 ± 14 μmol/l at 10% O2( P < 0.05). These data indicate that there is a differential exchange of NO across the brain during hypercapnia and hypoxia and that CNP may play a complementary role in CO2-induced CBF changes.
Characterization of Proteases, Proteins, and Eicosanoid-Like Substances in Soluble Extracts from Allergenic Pollen Grains
Authors: Gunawan Hendra , Takai Toshiro , Kamijo Seiji , Wang Xiao Ling , Ikeda Shigaku , Okumura Ko , Ogawa Hideoki
Published: July 2008

Background: Pollen is an important trigger of seasonal rhinitis, conjunctivitis, and/or allergic asthma, and an exacerbating factor in atopic dermatitis. Pollen grains contain allergen proteins, enzymes, and bioactive lipid mediators, the latter two possibly involved in the pathogenesis of allergic diseases through IgE-independent mechanisms. Methods: We analyzed the patterns of release of endopeptidases from allergenic pollen of Japanese cedar, Japanese cypress, and Rocky mountain juniper, which belong to the Cupressaceae/Taxodiaceae family, and birch, ragweed, and two grasses, Kentucky blue and cultivated rye, using synthetic substrates, class-specific inhibitors, and zymography. The proteins released were analyzed by gel electrophoresis. Eicosanoid-like substances were measured by enzyme-linked immunosorbent assays for prostaglandin E2 and leukotriene B4. Results: Major fractions of proteins, eicosanoid-like substances, and at least one molecular species of serine endopeptidase were released into phosphate-buffered saline from the pollen grains at 37°C within 25 min or 60 min without sonication. In the Cupressaceae/Taxodiaceae family, sonication was necessary for the release of other proteins and another serine endopeptidase. In birch, ragweed, and the grasses, most of the serine and cysteine endopeptidases were released without sonication. Proteases released within 25 min digested gelatin and/or casein differently among plant species. Conclusions: Grains of allergenic pollen release proteases, which can digest not only short synthetic substrates but also protein substrates, along with eicosanoid-like substances and proteins. The release of these components could contribute to the formation of a microenvironment optimum for initiation of the sensitization or the exacerbation of pollen allergy in tissues exposed to pollen grains.
Mal d 2, the Thaumatin-Like Allergen from Apple, Is Highly Resistant to Gastrointestinal Digestion and Thermal Processing
Authors: Smole Ursula , Bublin Merima , Radauer Christian , Ebner Christof , Breiteneder Heimo
Published: July 2008

Background: The stability of food allergens to proteolysis and thermal denaturation contributes considerably to their allergenicity. Methods: Mal d 2, an allergenic thaumatin-like protein (TLP) from apple, was isolated and purified by anion exchange chromatography. Its IgE reactivity was tested by ELISA and immunoblotting using sera from apple allergic patients. The proteolytic stability of Mal d 2 was investigated using two in vitro digestion models. Effects of thermal treatment at different pH values on the secondary structure of the protein were recorded by circular dichroism. The level and IgE reactivity of Mal d 2 present in industrially prepared foods were assessed. Results: Purified Mal d 2 consisted of two isoforms. Both harbored carbohydrate moieties and bound serum IgE from apple allergic individuals. Mal d 2 showed remarkable stability to proteolysis and thermal treatments. The allergen remained intact after 2 h each of gastric and subsequent duodenal digestion retaining its full IgE-binding capacity. Mal d 2 was unfolded at neutral and acidic pH at 70°C. Refolding after cooling was only observed at acidic pH. Mal d 2 detected by an anti-TLP antibody in cloudy apple juice did not bind IgE of a serum pool of apple allergic patients. Conclusion: Our findings suggest that Mal d 2 maintains its structure in the gastrointestinal tract, a feature essential for sensitizing the mucosal immune system and provoking allergic reactions.
Tumor Necrosis Factor-α Develops Late Anaphylactic Reaction through Cytosolic Phospholipase A2 Activation
Authors: Kang Nam-In , Kim Hae-Kyoung , Ko Hyun-Mi , Kim Jae-Hong , You Hye-Jin , Choi Il-Whan , Im Suhn-Young , Lee Hern-Ku
Published: July 2008

Background: We have recently reported that tumor necrosis factor (TNF)-α plays an important role in the development of a late anaphylactic reaction, but the downstream pathway beyond TNF-α remains unclear. Objective: It was the aim of this study to examine whether TNF-α induces late-phase anaphylaxis via the activation of cytosolic phospholipase A2 (cPLA2). Methods: Using a murine model of active systemic anaphylaxis to penicillin V, the induction of the late phase of anaphylaxis was quantified by measuring the increase in hematocrit value as well as the plasma level of platelet-activating factor in TNF-α knockout mice. Phosphorylation of mitogen-activated protein kinases (MAPKs) and cPLA2 was measured by immunoprecipitation. cPLA2 activity was assessed by using 1-stearoyl-2-[1-14C] arachidonyl-sn-glycero-3-phosphocholine as the substrate. Results: Phosphorylation and enzymatic activity of cPLA2, and phosphorylation of the 3 known MAPKs, i.e. p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase, were markedly increased in a TNF-α-dependent way in the lungs of mice undergoing anaphylaxis. A specific cPLA2 inhibitor significantly attenuated the late anaphylactic symptoms. Either p38 or an ERK inhibitor significantly attenuated not only cPLA2 phosphorylation and activity, but also the late-phase anaphylaxis. Conclusion: TNF-α-induces cPLA2 activation through the pathway involving p38 MAPK and ERK activation and appears to be the key mechanism leading to the development of late-phase anaphylaxis.
Intranasal Mometasone Furoate Alleviates the Ocular Symptoms Associated with Seasonal Allergic Rhinitis: Results of a Post Hoc Analysis
Authors: Anolik Robert , Nathan Robert A. , Schenkel Eric , Danzig Melvyn R. , Gates Davis , Varghese Santosh
Published: July 2008

Background: Burdensome symptoms of allergic rhinitis (AR) include nasal and ocular symptoms such as itching, tearing and redness. Intranasal corticosteroids are efficacious in the treatment of nasal symptoms of AR. Objective: It was the aim of this study to determine the efficacy of the intranasal corticosteroid mometasone furoate nasal spray (MFNS) in relieving ocular symptoms associated with seasonal AR (SAR). Methods: Ocular symptom data were analyzed for subjects ≧12 years of age, randomized to MFNS 200 µg q.d. (n = 176) or placebo (n = 177) in a placebo-controlled, double-blind clinical trial. Post hoc efficacy analysis assessed the mean change from baseline in subject-reported total ocular symptom scores (TOSS) averaged over the treatment period. Results: Mean baseline TOSS was 4.91 for the MFNS group and comparable (5.05) for the placebo group – combined average for individual symptoms such as itching, tearing and redness ranged from 0 (no symptoms) to 9 (all symptoms, severe). Mean change from baseline in TOSS averaged over days 1–15 was –1.42 for the MFNS group and –0.94 for the placebo group (p = 0.02), for an observed treatment difference of 0.49 (statistical data rounded to 2 decimal positions). Improvement in individual symptoms (eye itching, tearing and redness) contributed to this treatment effect; the greatest improvement occurred with tearing, which decreased –0.52 from the baseline score 1.59 in the MFNS group and –0.31 from 1.67 in those receiving placebo (p < 0.01), for an observed treatment difference of 0.21. Treatment with MFNS was safe and well tolerated. Conclusion: MFNS is effective in reducing ocular symptoms of SAR, in addition to its established efficacy in reducing nasal symptoms of SAR.