bluuebunny/crossref_metadata_2025 huggingface dataset:
Mortality and cancer incidence among alachlor manufacturing workers 1968–99
Authors: Acquavella J F , Delzell E , Cheng H , Lynch C F , Johnson G
Published: July 2004

Background:Alachlor is the active ingredient in pre-emergent herbicide formulations that have been used widely on corn, soybeans, and other crops. It has been found to cause nasal, stomach, and thyroid tumours in rodent feeding studies at levels that are much higher than likely human exposures.

Aims:To evaluate mortality rates from 1968 to 1999 and cancer incidence rates from 1969 to 1999 for alachlor manufacturing workers at a plant in Muscatine, Iowa.

Methods:Worker mortality and cancer incidence rates were compared to corresponding rates for the Iowa state general population. Analyses addressed potential intensity and duration of exposure.

Results:For workers with any period of high alachlor exposure, mortality from all causes combined was lower than expected (42 observed deaths, SMR 64, 95% CI 46 to 86) and cancer mortality was slightly lower than expected (13 observed deaths, SMR 79, 95% CI 42 to 136). Cancer incidence for workers with potential high exposure was similar to that for Iowa residents, both overall (29 observed cases, SIR 123, 95% CI 82 to 177) and for workers exposed for five or more years and with at least 15 years since first exposure (eight observed cases, SIR 113, 95% CI 49 to 224). There were no cases of nasal, stomach, or thyroid cancer.

Conclusions:There were no cancers of the types found in toxicology studies and no discernible relation between cancer incidence for any site and years of alachlor exposure or time since first exposure. Despite the small size of this population, the findings are important because these workers had chronic exposure potential during extended manufacturing campaigns, while use in agriculture is typically limited to a few days or weeks each year.
Evaluation of the protective effectiveness of gloves from occupational exposure to 2-methoxyethanol using the biomarkers of 2-methoxyacetic acid levels in the urine and plasma
Authors: Chang H-Y , Lin C-C , Shih T-S , Chan H , Chou J-S , Huang Y-S
Published: July 2004

Aims:To evaluate the protective effectiveness of gloves from occupational exposure to 2-methoxyethanol (2-ME); and to examine the association of 2-methoxyacetic acid (MAA) in urine and plasma collected simultaneously from low 2-ME exposure and high 2-ME exposure workers in a semiconductor copper laminate circuit board manufacturing plant.

Methods:Eight hour time weighted breathing zone monitoring was performed to verify the 2-ME exposure classification between workers in regular and special operations. Urine and plasma samples were simultaneously collected from 74 exposed and 80 non-exposed workers. MAA concentrations in the urine (UMAA) and plasma (PMAA) were measured using previously published methods. Three types of gloves worn by workers (cotton, rubber, and no gloves) were recorded by direct observations in the workplace and validated by person-to-person interview. Protective effectiveness indices (PEI) were used to evaluate the glove effectiveness.

Results:There was no detectable 2-ME/MAA in the air, or in urine and plasma samples in non-exposed workers. The average UMAA and PMAA in special operations were 72.63 mg/g Cr. and 29.72 mg/l, significantly higher than values in regular operations (5.44 mg/g Cr. and 2.58 mg/l, respectively). PMAA showed satisfactory correlation to UMAA in all participants from both regular and special operations. The rubber gloves provided significant reduction in 2-ME uptake, whereas cotton gloves provided little protection with fluctuating effectiveness, based on PEI estimates.

Conclusions:PMAA, similar to UMAA, could serve as a specific biomarker for 2-ME exposure. Wearing impermeable rubber gloves during high risk tasks can reduce major 2-ME exposure. Other improvements, including engineering control, should be provided to diminish worker exposure to 2-ME in occupational environments.
No association between the use of cellular or cordless telephones and salivary gland tumours
Authors: Hardell L , Hallquist A , Hansson Mild K , Carlberg M , Gertzén H , Schildt E-B , Dahlqvist Å
Published: July 2004

Aim:To investigate the association between the use of cellular or cordless telephones and the risk for salivary gland tumours.

Methods:Cases were assessed from the six regional cancer registries in Sweden. Four controls matched for sex and age in five year age groups were selected for each case. A total of 293 living cases and 1172 controls were included.

Results:There were 267 (91%) participating cases and 1053 (90%) controls. Overall no significantly increased risk was found. Odds ratios were 0.92 (95% CI 0.58 to 1.44) for use of analogue phones, 1.01 (95% CI 0.68 to 1.50) for use of digital phones, and 0.99 (95% CI 0.68 to 1.43) for use of cordless phones. Similar results were found for different salivary gland localisations. No effect of tumour induction period or latency was seen, although few subjects reported use for more than 10 years.

Conclusions:No association between the use of cellular or cordless phones and salivary gland tumours was found, although this study does not permit conclusions for long term heavy use.
Assessing and intervening on OSH programmes: effectiveness evaluation of the Wellworks-2 intervention in 15 manufacturing worksites
Authors: LaMontagne A D , Barbeau E , Youngstrom R A , Lewiton M , Stoddard A M , McLellan D , Wallace L M , Sorensen G
Published: July 2004

Aims:(1) To develop a transparent and broadly applicable method for assessing occupational safety and health (OSH) programmes or management systems; (2) to assess OSH programmes in a sample of manufacturing worksites; and (3) to determine whether a management focused occupational health intervention results in greater improvement in OSH programmes compared to minimal intervention controls.

Methods:OSH programmes were assessed using an adaptation of the US Occupational Safety & Health Administration’s 1995 Program Evaluation Profile. Scores were generated from 91 binary indicator variables grouped under four “Essential Elements”. Essential Element scores were weighted to contribute to an overall programme score on a 100 point scale. Seventeen large manufacturing worksites were assessed at baseline; 15 sites completed the 16 month intervention and follow up assessments.

Results:There was considerable variation in Essential Element scores across sites at baseline as judged by our instrument, particularly in “management commitment and employee participation” and “workplace analysis”. Most sites scored highly on “hazard prevention and control” and “training and education”. For overall OSH programme scores, most sites scored in the 60–80% range at baseline, with four sites scoring below 60%, suggesting weak programmes. Intervention sites showed greater improvements than controls in the four programme elements and in overall programme scores, with significantly greater improvements in “management commitment and employee participation”.

Conclusions:The OSH programme assessment method used is broadly applicable to manufacturing work settings, and baseline profiles suggest needs for improvement in OSH programmes in most such worksites. Despite a small sample size, results showed that sustained management focused intervention can result in improvement in these OSH programme measures.
Asymptomatic sensitisation to grapes in a sample of workers in the wine industry: Table 1
Authors: Kalogeromitros D , Rigopoulos D , Gregoriou S , Mousatou V , Lyris N , Papaioannou D , Katsarou-Katsari A
Published: July 2004

Aims:To assess the prevalence of sensitisation to grapes (Vitis viniferavar.agiorghitiko) in a population with repeated exposure to grape allergens through direct cutaneous contact as well as through the gastrointestinal tract.

Methods:One hundred and twenty subjects were enrolled in each of four groups: grape harvesters, winery workers in selection of grapes, winery workers operating de-stemming/crushing/pressing machines, and administrative personnel. Sensitisation to grapes was examined by skin prick-to-prick tests with fresh fruit and juice.

Results:Eight harvesters and five workers in grape selection had positive reaction to the grapes tested. No machine operators or administrative personnel had positive tests. The likelihood of sensitisation was estimated at 3.7% per year of occupation by logistic regression analysis. None of the employees reported symptoms associated with sensitisation to grapes.

Conclusion:Asymptomatic sensitisation to grapes was detected only in workers handling the fruit, suggesting that sensitisation is more likely to occur through cutaneous exposure and/or minor wounding than through the gastrointestinal tract. Prevalence rates were high and the clinical impact needs to be further investigated.
REDESIGNING LEGACY SYSTEMS INTO THE OBJECT-ORIENTED PARADIGM
Authors: WONG W. ERIC , LI JENNY
Published: July 2004

Object-oriented languages support many modern programming concepts such as information hiding, inheritance, polymorphism, and dynamic binding. As a result, software systems implemented in OO languages are in general more reusable and reliable than others. Many legacy software systems, created before OO programming became popular, need to be redesigned and updated to OO programs. The process of abstracting OO designs from the procedural source code has often been done with limited assistance from program structural diagrams. Most reengineering focuses on the functionality of the original program, and the OO redesign often results in a completely new design based on the designers' understanding of the original program. Such an approach is not sufficient because it may take a significant amount of time and effort for designers to comprehend the original program. This paper presents a computer-aided semi-automatic method that abstracts OO designs from the original procedural source code. More specifically, it is a method for OO redesign based on program structural diagrams, visualization, and execution slices. We conducted a case study by applying this method to an inventory management software system. Results indicate that our method can effectively and efficiently abstract an appropriate OO design out of the original C code. In addition, some of the code from the original system can be automatically identified and reused in the new OO system.
AN ONTOLOGY FOR THE MANAGEMENT OF SOFTWARE MAINTENANCE PROJECTS
Authors: RUIZ FRANCISCO , VIZCAÍNO AURORA , PIATTINI MARIO , GARCÍA FELIX
Published: July 2004

Different proposals exist to represent the software maintenance process. However most of them are very informal or too focussed on a specific goal. We have developed a semi-formal ontology where the main concepts, according to the literature related to software maintenance, have been described. This ontology, besides representing static aspects, also represents dynamic issues related to the management of software maintenance projects. In order to develop an ontology a suitable methodology should also be followed. REFSENO was the methodology used in this work. The ontology that this work presents is not a preliminary idea but it has already been used in software maintenance environments, such as MANTIS, which is currently working successfully.
WHAT WILL AFFECT SOFTWARE REUSE: A CAUSAL MODEL ANALYSIS
Authors: LI GANG , DAI HONGHUA
Published: July 2004

Software reuse is an important topic due to its potential benefits in increasing product quality and decreasing cost. Although more and more people are aware that not only technical issues, but also nontechnical issues are important to the success of software reuse, people are still not certain which factors will have direct effect on the success of reuse. In this paper, we applied a causal discovery algorithm to the software reuse survey data [2]. Ensemble strategy is incorporated to locate a probable causal model structure for software reuse, and find all those factors which have direct effect on the success of reuse. Our discovery results reinforced some conclusions of Morisio et al. and found some new conclusions which might significantly improve the odds of a reuse project succeeding.
DESIGN OF OBJECT MODEL REUSE SYSTEM BY CBR IN SYSTEM ANALYSIS
Authors: KIM YOUNG JUN , KIM CHUNG TAE
Published: July 2004

This study aimed to design a software reuse system by case-based reasoning (CBR) in order to reuse object models in system analysis. We developed a system including the methods and procedures for reusing object models, and also proposed how to express the cases of object models by CBR. Moreover, this expressed the rules for retrieving, reusing and modifying object models in accordance with the new problems. Furthermore, this study confirmed its adequacy through applying the system for reusing object models to the real-world business cases; and verified the assumed hypotheses that are related to this system.
NANOSCOPIC BUILDING BLOCKS FROM POLYMERS, METALS, AND SEMICONDUCTORS FOR HYBRID ARCHITECTURES
Authors: KNOLL WOLFGANG , HAN MING-YONG , LI XINHENG , HERNANDEZ-LOPEZ JOSE-LUIS , MANNA ABHIJIT , MÜLLEN KLAUS , NAKAMURA FUMIO , NIU LIFANG , ROBELEK RUDOLF , SCHMID EVELYNE L. , TAMADA KAORU , ZHONG XINHUA
Published: July 2004

This paper describes some of our efforts in the area of nanostructured thin film architectures. The resulting interfacial hybrid assemblies are built from (1) organic/polymeric objects based on dendrimer systems, from (2) surface-functionalized Au nanoparticles, and (3) from a variety of semiconducting quantum dots. Dendrimers as polymeric building blocks with a strictly monodisperse particle size distribution in the nanometer range can be functionalized in the core, the scaffold, or at the periphery, thus offering interesting hybrid materials for a wide range of applications. The combination with Au clusters and their local surface plasmon resonances suggests new strategies for optoelectronic devices or unconventional bio-sensor platforms. The possibility of tuning the luminescent properties of semiconducting nanoparticles by size or compositional bandgap engineering complements the assembly kit with building blocks for supramolecular thin film nanocomposite materials.
GALERKIN FINITE ELEMENT SCHEME WITH BAYLISS–GUNZBURGER–TURKEL-LIKE BOUNDARY CONDITIONS FOR VECTORIAL OPTICAL MODE SOLVER
Authors: URANUS H. P. , HOEKSTRA H. J. W. M. , VAN GROESEN E.
Published: July 2004

A Galerkin finite element scheme furnished with 1st-order Bayliss–Gunzburger–Turkel-like boundary conditions is formulated to compute both the guided and leaky modes of anisotropic channel waveguides of non-magnetic materials with diagonal permittivity tensor. The scheme is formulated using transverse components of magnetic fields for nodal-based quadratic triangular elements. Results for some structures will be presented. The effectiveness of the boundary conditions will be illustrated using a step-index optical fiber with computational boundaries positioned near to the core, and the leaky modes computation of a leaky rib structure. In addition, a leaky mode solving of a six-hole "photonic crystal fiber" will be demonstrated. The computed results agree with their exact values (for optical fibers) and published results (for other structures).
TWO NOVEL INTEGRATED OPTICAL SENSOR TYPES FOR MEASURING CHEMICAL CONCENTRATIONS, BASED ON CHEMICALLY INDUCED CHANGES OF MODAL FIELD PROFILES
Authors: LAMBECK PAUL V. , HOEKSTRA HUGO J. W. M. , VAN LITH JORIS , VAN ELZAKKER GIJS
Published: July 2004

Two novel principles of sensing chemical concentrations by integrated optical sensors are presented. Both sensors are of the refractive type implying that a change of chemical concentration manifests itself as a change of the refractive index of a material located within the field profile of a guided mode. In contrast to common practice it is not the induced change of the effective refractive index N eff , but the change of the modal field profiles that is utilized for sensing, and here the changes of the refractive index finally show up as changes of the attenuation of a propagating mode. In the segmented waveguide sensor (SWS) the dependence of the modal transfer at the transition between two adjacent channel segments on the refractive index distributions of both segments is exploited while the second one relies on changes of the modal absorption as a result of a change of the penetration of the modal field into an absorptive region.

Sensitivity and resolution-potential of both principles have been analyzed theoretically also taking into account the properties of peripheral equipment. Based on structures producible with SiON technology a SWS with a refractive index resolution of 5×10-7 can be easily designed. In an implementation of the second principle suited for immuno-sensing, a resolution in the thickness of the immuno-layer better than 10-4 nm is shown to be theoretically feasible. A SWS sensor has been realized; theoretically and experimentally obtained performance corresponds well to each other.
DYNAMICS OF SPATIAL SOLITONS AT PHASE-MISMATCH INTERFACES
Authors: BARONIO FABIO , DE ANGELIS COSTANTINO , PIOGER PAUL-HENRI , COUDERC VINCENT , BARTHÉLÉMY ALAIN , MIN YOOHONG , QUIRING VICTOR , SOHLER WOLFGANG
Published: July 2004

We studied the dynamics of spatial solitons at a phase-mismatch interface in quadratic nonlinear waveguides. We present here a simple formalism to analyze intensity-dependent reflection, refraction and emission of beams. Experimental demonstrations at a phase-mismatch PPLN/LiNbO3 interface are reported.
OPTICAL LIMITING STUDIES OF NEW CARBON NANOCOMPOSITES AND AMORPHOUS SixNy OR AMORPHOUS SiC COATED MULTI-WALLED CARBON NANOTUBES
Authors: ELIM HENDRY IZAAC , CHEN WEIZHE , JI WEI , ZHONG ZIYI , LIN JIANYI , MENG GWEE CHEN , CHIN K. C. , GOHEL A. , WEE A. T. S. , CHEN G. X. , HONG M. H.
Published: July 2004

By using fluence-dependent transmission measurement with nanosecond laser pulses, we have studied optical limiting (OL) properties of new carbon nanocomposites as well as amorphous Si x N y or amorphous SiC coated carbon nanotubes suspended in distilled water. The observed nonlinearity at 532 nm contributed to OL performance of the carbon nanocomposites or carbon nanoballs (CNBs) is suggested to have its origin in the optically induced heating or scattering effects. It is found that when the linear transmittance of the CNBs is less than or equal to 70%, the intensity-dependent transmission of the CNBs is comparable to that of C 60. While at 80% linear transmittance, CNBs possess better OL behavior than that of C 60. These findings strongly support a potential application of CNBs for all laser protection devices. We have also observed OL effects in the amorphous silicon nitride ( a - Si x N y) and amorphous silicon carbide ( a - SiC ) coated multi-walled carbon nanotubes (MWNTs) at wavelengths of 532 and 1064 nm, and found that their OL performances are slightly poorer than that of their parent MWNTs. The possible sources of thickness-dependent OL effects of a - Si x N y and a - SiC coated MWNTs are discussed.
L-BAND EDFA WITH INJECTION OF C-BAND ASE
Authors: HARUN S. W. , AHMAD H.
Published: July 2004

The effect of injecting of C-band amplified spontaneous emission (ASE) from C-band erbium-doped fiber amplifier (EDFA) on the performance of L-band EDFA is demonstrated using a circulator and broadband fiber Bragg grating (FBG). Injecting a large amount of ASE (VOA=0 dB) clamps the gain at 15.2 dB from -40 to -10 dBm with a gain variation of less than 0.3 dB. Injecting a small amount of ASE (attenuation of 20 dB and above) improves the small signal gain with a negligible noise figure penalty compared to that of an amplifier without the ASE injection. A maximum gain improvement of 3.5 dB is obtained at an attenuation of 20 dB. These results show that the ASE injection technique can be used either for gain improvement or gain clamping in L-band EDFA.
SATURATION OF NONLINEAR SUSCEPTIBILITY
Authors: NURHUDA MUHAMMAD , SUDA AKIRA , MIDORIKAWA KATSUMI
Published: July 2004

The nonlinear susceptibility of atoms interacting with an intense laser field has been investigated using numerical solution of the time-dependent Schrödinger equation. It was found that the behavior of nonlinear susceptibility strongly depends on the intensity; it increases linearly in low intensity regime (Kerr nonlinearity), then saturates at higher intensity. Furthermore, it has also been found that the nonlinear susceptibility is substantially influenced by the onset of ionization.
Oxysterols from human bile induce apoptosis of canine gallbladder epithelial cells in monolayer culture
Authors: Seo Dong Wan , Choi Ho-Soon , Lee Sum P. , Kuver Rahul
Published: July 2004

Oxysterols have been detected in various mammalian organs and blood. Biliary epithelium is exposed to high concentrations of cholesterol, and we have identified three keto-oxysterols (cholest-4-en-3-one, cholesta-4,6-dien-3-one, cholesta-3,5-dien-7-one) in human bile and gallstones. Because the effects of oxysterols on biliary physiology are not well defined, we investigated their biological effects on dog gallbladder epithelial cells. Enriched medium (culture medium containing taurocholate and lecithin and cholesterol ± various oxysterols) was applied to confluent monolayers of dog gallbladder epithelial cells in culture. Cytotoxicity and apoptosis were studied by morphological analysis and flow cytometry. Oxysterols in the mitochondrial fraction were identified by gas chromatography/mass spectrometry, whereas release of cytochrome c from mitochondria was assayed by spectrophotometry and Western blot analysis. Compared with cells treated with culture medium or with enriched medium containing cholesterol, oxysterol-treated cells showed significantly increased apoptosis ( P < 0.05). Exogenously applied oxysterols were recovered from the mitochondrial fraction. Cytochrome c release from mitochondria was increased significantly by cholest-4-en-3-one, cholesta-4,6-dien-3-one, and 5β-cholestan-3-one (all P < 0.05). Thus oxysterols recovered from human bile and gallstones induce apoptosis of biliary epithelium via a mitochondrial-dependent pathway and may play a role in the pathogenesis of chronic inflammation and carcinogenesis in the gallbladder.
Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats
Authors: Okajima Kenji , Harada Naoaki , Uchiba Mitsuhiro , Mori Masakazu
Published: July 2004

We previously reported that nitric oxide (NO) derived from endothelial NO synthase (NOS) increased endothelial prostacyclin (PGI2) production in rats subjected to hepatic ischemia-reperfusion (I/R). The present study was undertaken to determine whether neutrophil elastase (NE) decreases endothelial production of PGI2, thereby contributing to the development of I/R-induced liver injury by decreasing hepatic tissue blood flow in rats. Hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2, were transiently increased and peaked at 1 h after reperfusion, followed by a gradual decrease until 3 h after reperfusion. Sivelestat sodium hydrochloride and L-658,758, two NE inhibitors, reduced I/R-induced liver injury. These substances inhibited the decreases in hepatic tissue levels of 6-keto-PGF1αat 2 and 3 h after reperfusion but did not affect the levels at 1 h after reperfusion. These NE inhibitors significantly increased hepatic tissue blood flow from 1 to 3 h after reperfusion. Both hepatic I/R-induced increases in the accumulation of neutrophils and the microvascular permeability were inhibited by these two NE inhibitors. Protective effects induced by the two NE inhibitors were completely reversed by pretreatment with nitro-l-arginine methyl ester, an inhibitor of NOS, or indomethacin. Administration of iloprost, a stable derivative of PGI2, produced effects similar to those induced by NE inhibitors. These observations strongly suggest that NE might play a critical role in the development of I/R-induced liver injury by decreasing endothelial production of NO and PGI2, leading to a decrease in hepatic tissue blood flow resulting from inhibition of vasodilation and induction of activated neutrophil-induced microvascular injury.
Regulated production of the chemokine CCL28 in human colon epithelium
Authors: Ogawa Hiroyuki , Iimura Mitsutoshi , Eckmann Lars , Kagnoff Martin F.
Published: July 2004

The chemokine CCL28 is constitutively expressed by epithelial cells at several mucosal sites and is thought to function as a homeostatic chemoattractant of subpopulations of T cells and IgA B cells and to mediate antimicrobial activity. We report herein on the regulation of CCL28 in human colon epithelium by the proinflammatory cytokine IL-1, bacterial flagellin, and n-butyrate, a product of microbial metabolism. In vivo, CCL28 was markedly increased in the epithelium of pathologically inflamed compared with normal human colon. Human colon and small intestinal xenografts were used to model human intestinal epithelium in vivo. Xenografts constitutively expressed little, if any, CCL28 mRNA or protein. After stimulation with the proinflammatory cytokine IL-1, CCL28 mRNA and protein were significantly increased in the epithelium of colon but not small intestinal xenografts, although both upregulated the expression of another prototypic chemokine, CXCL8, in response to the identical stimulus. In studies of CCL28 regulation using human colon epithelial cell lines, proinflammatory stimuli, including IL-1, bacterial flagellin, and bacterial infection, significantly upregulated CCL28 mRNA expression and protein production. In addition, CCL28 mRNA expression and protein secretion by those cells were significantly increased by the short-chain fatty acid n-butyrate, and IL-1- or flagellin-stimulated upregulation of CCL28 by colon epithelial cells was synergistically increased by pretreatment of cells with n-butyrate. Consistent with its upregulated expression by proinflammatory stimuli, CCL28 mRNA expression was attenuated by pharmacological inhibitors of NF-κB activation. These findings indicate that CCL28 functions as an “inflammatory” chemokine in human colon epithelium and suggest the notion that CCL28 may act to counterregulate colonic inflammation.
Agonist-induced polarized trafficking and surface expression of the adenosine 2b receptor in intestinal epithelial cells: role of SNARE proteins
Authors: Wang Lixin , Kolachala Vasantha , Walia Baljit , Balasubramanian Srividya , Hall Randy A. , Merlin Didier , Sitaraman Shanthi V.
Published: July 2004

Adenosine, acting through the A2b receptor, induces vectorial chloride and IL-6 secretion in intestinal epithelia and may play an important role in intestinal inflammation. We have previously shown that apical or basolateral adenosine receptor stimulation results in the recruitment of the A2b receptor to the plasma membrane. In this study, we examined domain specificity of recruitment and the role of soluble N-ethylmaleimide (NEM) attachment receptor (SNARE) proteins in the agonist-mediated recruitment of the A2b receptor to the membrane. The colonic epithelial cell line T84 was used because it only expresses the A2b-subtype adenosine receptor. Cell fractionation, biotinylation, and electron microscopic studies showed that the A2b receptor is intracellular at rest and that apical or basolateral adenosine stimulation resulted in the recruitment of the receptor to the apical membrane. Upon agonist stimulation, the A2b receptor is enriched in the vesicle fraction containing vesicle-associated membrane protein (VAMP)-2. Furthermore, in cells stimulated with apical or basolateral adenosine, we demonstrate a complex consisting of VAMP-2, soluble NEM-sensitive factor attachment protein (SNAP)-23, and A2b receptor that is coimmunoprecipitated in cells stimulated with adenosine within 5 min and is no longer detected within 15 min. Inhibition of trafficking with NEM or nocodazole inhibits cAMP synthesis induced by apical or basolateral adenosine by 98 and 90%, respectively. cAMP synthesis induced by foskolin was not affected, suggesting that generalized signaling is not affected under these conditions. Collectively, our data suggest that 1) the A2b receptor is intracellular at rest; 2) apical or basolateral agonist stimulation induces recruitment of the A2b receptor to the apical membrane; 3) the SNARE proteins, VAMP-2 and SNAP-23, participate in the recruitment of the A2b receptor; and 4) the SNARE-mediated recruitment of the A2b receptor may be required for its signaling.
Involvement of mast cells in basal and neurotensin-induced intestinal absorption of taurocholate in rats
Authors: Gui Xianyong , Carraway Robert E.
Published: July 2004

Neurotensin (NT), a hormone released from intestine by ingested fat, facilitates lipid digestion by stimulating pancreatic secretion and slowing the movement of chyme. In addition, NT can contract the gall bladder and enhance the enterohepatic circulation (EHC) of bile acids to promote micelle formation. Our recent finding that NT enhanced and an NT antagonist inhibited [3H]taurocholate ([3H]TC) absorption from proximal rat small intestine indicated a role for endogenous NT in the regulation of EHC. Here, we postulate the involvement of intestinal mast cells in the TC uptake process and in the stimulatory effect of NT. In anesthetized rats with the bile duct cannulated for bile collection, infusion of NT (10 pmol·kg−1·min−1) enhanced the [3H]TC recovery rate from duodenojejunum by 2.2-fold. This response was abolished by pretreatment with mast cell stabilizers (cromoglycate, doxantrazole) and inhibitors of mast cell mediators (diphenhydramine, metergoline, zileuton). In contrast, mast cell degranulators (compound 48/80, substance P) and mast cell mediators (histamine, leukotriene C4) reproduced the effect of NT. NG-nitro-l-arginine methyl ester enhanced and l-arginine inhibited basal and NT-induced TC uptake, consistent with the known inhibitory effect of nitric oxide (NO) on mast cell reactivity. These results argue that basal and NT-stimulated TC uptake in rat jejunum are similarly dependent on mast cells, are largely mediated by release of mast cell mediators, and are subject to regulation by NO.
IFN-γ/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1
Authors: Jaruga Barbara , Hong Feng , Kim Won-Ho , Gao Bin
Published: July 2004

We have previously shown that IFN-γ/STAT1 plays an essential role in concanavalin A (ConA)-induced T cell hepatitis via activation of apoptotic signaling pathways. Here we demonstrate that IFN-γ/STAT1 also plays a crucial role in leukocyte infiltration into the liver in T cell hepatitis. After injection of ConA, leukocytes were significantly infiltrated into the liver, which was suppressed in IFN-γ−/−and STAT1−/−mice. Disruption of the IFN regulatory factor-1 (IRF-1) gene, a downstream target of IFN-γ/STAT1, abolished ConA-induced liver injury and suppressed leukocyte infiltration into the liver. Additionally, ConA injection induced expression of a wide variety of chemokines and adhesion molecules in the liver. Among them, expression of ICAM-1, VCAM-1, monokine induced by IFN-γ (Mig), CC chemokine ligand-20, epithelial cell-derived neutrophil-activating peptide (ENA)-78, IFN-inducible T cell-α chemoattractant (I-TAC), and IFN-inducible protein-10 (IP-10) was markedly attenuated in IFN-γ−/−, STAT1−/−, and IRF-1−/−mice. In primary mouse hepatocytes, Kupffer cells, and endothelial cells, in vitro treatment with IFN-γ activated STAT1, STAT3, and IRF-1, and induced expression of VCAM-1, ICAM-1, Mig, ENA-78, I-TAC, and IP-10 mRNA. Induction of these chemokines and adhesion molecules was markedly diminished in STAT1−/−and IRF-1−/−hepatic cells compared with wild-type hepatic cells. These findings suggest that in addition to induction of apoptosis, previously well documented, IFN-γ also stimulated hepatocytes, sinusoidal endothelial cells, and Kupffer cells partly via an STAT1/IRF-1-dependent mechanism to produce multiple chemokines and adhesive molecules responsible for promoting infiltration of leukocytes and, ultimately, resulting in hepatitis.
Gastrointestinal nitric oxide generation in germ-free and conventional rats
Authors: Sobko Tanja , Reinders Claudia , Norin Elisabeth , Midtvedt Tore , Gustafsson Lars E. , Lundberg Jon O.
Published: July 2004

Nitric oxide (NO) is a central mediator of various physiological events in the gastrointestinal tract. The influence of the intestinal microflora for NO production in the gut is unknown. Bacteria could contribute to this production either by stimulating the mucosa to produce NO, or they could generate NO themselves. Using germ-free and conventional rats, we measured gaseous NO directly in the gastrointestinal tract and from the luminal contents using a chemiluminescence technique. Mucosal NO production was studied by using an NO synthase (NOS) inhibitor, and to evaluate microbial contribution to the NO generation, nitrate was given to the animals. In conventional rats, luminal NO differed profoundly along the gastrointestinal tract with the greatest concentrations in the stomach [>4,000 parts per billion (ppb)] and cecum (≈200 ppb) and lower concentrations in the small intestine and colon (≤20 ppb). Cecal NO correlated with the levels in incubated luminal contents. NOS inhibition lowered NO levels in the colon, without affecting NO in the stomach and in the cecum. Gastric NO increased greatly after a nitrate load, proving it to be a substrate for NO generation. In germ-free rats, NO was low (≤30 ppb) throughout the gastrointestinal tract and absent in the incubated luminal contents. NO also remained low after a nitrate load. Our results demonstrate a pivotal role of the intestinal microflora in gastrointestinal NO generation. Distinctly compartmentalized qualitative and quantitative NO levels in conventional and germ-free rats reflect complex host microbial cross talks, possibly making NO a regulator of the intestinal eco system.
TGF-β1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70S6k
Authors: Lechuga Carmen G. , Hernández-Nazara Zamira H. , Rosales José-Alfredo Domínguez , Morris Elena R. , Rincón Ana Rosa , Rivas-Estilla Ana María , Esteban-Gamboa Andrés , Rojkind Marcos
Published: July 2004

Transforming growth factor-β1 (TGF-β1), the main cytokine involved in liver fibrogenesis, induces expression of the type I collagen genes in hepatic stellate cells by a transcriptional mechanism, which is hydrogen peroxide and de novo protein synthesis dependent. Our recent studies have revealed that expression of type I collagen and matrix metalloproteinase-13 (MMP-13) mRNAs in hepatic stellate cells is reciprocally modulated. Because TGF-β1 induces a transient elevation of α1(I) collagen mRNA, we investigated whether this cytokine was able to induce the expression of MMP-13 mRNA during the downfall of the α1(I) collagen mRNA. In the present study, we report that TGF-β1 induces a rapid decline in steady-state levels of MMP-13 mRNA at the time that it induces the expression of α1(I) collagen mRNA. This change in MMP-13 mRNA expression occurs within the first 6 h postcytokine administration and is accompanied by a twofold increase in gene transcription and a fivefold decrease in mRNA half-life. This is followed by increased expression of MMP-13 mRNA, which reaches maximal values by 48 h. Our results also show that this TGF-β1-mediated effect is de novo protein synthesis-dependent and requires the activity of p38MAPK, phosphatidylinositol 3-kinase, AKT, and p70S6k. Altogether, our data suggest that regulation of MMP-13 by TGF-β1 is a complex process involving transcriptional and posttranscriptional mechanisms.
Role of primary sensorimotor cortex and supplementary motor area in volitional swallowing: a movement-related cortical potential study
Authors: Satow Takeshi , Ikeda Akio , Yamamoto Jun-ichi , Begum Tahamina , Thuy Dinh Ha Duy , Matsuhashi Masao , Mima Tatsuya , Nagamine Takashi , Baba Koichi , Mihara Tadahiro , Inoue Yushi , Miyamoto Susumu , Hashimoto Nobuo , Shibasaki Hiroshi
Published: July 2004

We investigated the role of the cerebral cortex, particularly the face/tongue area of the primary sensorimotor (SMI) cortex (face/tongue) and supplementary motor area (SMA), in volitional swallowing by recording movement-related cortical potentials (MRCPs). MRCPs with swallowing and tongue protrusion were recorded from scalp electrodes in eight normal right-handed subjects and from implanted subdural electrodes in six epilepsy patients. The experiment by scalp EEG in normal subjects revealed that premovement Bereitschaftspotentials (BP) activity for swallowing was largest at the vertex and lateralized to either hemisphere in the central area. The experiment by epicortical EEG in patients confirmed that face/tongue SMI and SMA were commonly involved in swallowing and tongue protrusion with overlapping distribution and interindividual variability. BP amplitude showed no difference between swallowing and tongue movements, either at face/tongue SMI or at SMA, whereas postmovement potential (PMP) was significantly larger in tongue protrusion than in swallowing only at face/tongue SMI. BP occurred earlier in swallowing than in tongue protrusion. Comparison between face/tongue SMI and SMA did not show any difference with regard to BP and PMP amplitude or BP onset time in either task. The preparatory role of the cerebral cortex in swallowing was similar to that in tongue movement, except for earlier activation in swallowing. Postmovement processing of swallowing was lesser than that of tongue movement in face/tongue SMI; probably suggesting that the cerebral cortex does not play a significant role in postmovement processing of swallowing. SMA plays a supplementary role to face/tongue SMI both in swallowing and tongue movements.
CD4+T cells from IL-10-deficient mice transfer susceptibility to NSAID-inducedRagcolitis
Authors: Blum Arthur M. , Metwali Ahmed , Elliott David E. , Berg Daniel J. , Weinstock Joel V.
Published: July 2004

Products of arachidonic acid metabolism are important for mucosal homeostasis, because blockade of this pathway with an NSAID triggers rapid onset of severe colitis in the IL-10 knockout (IL-10−/−) model of IBD. Rag mice do not make T or B cells. This study determined whether reconstitution of Rag mice with T cells from IL-10−/−mice transferred NSAID colitis susceptibility. Rag mice were reconstituted by intraperitoneal injection with splenocytes from wild-type (WT) or IL-10−/−animals. Colitis was induced by using piroxicam and was graded histologically. Isolated lamina propria mononuclear cells (LPMC), lamina propria T cells, and LPMC depleted of T cells from reconstituted Rag mice were studied for cytokine production. Only animals reconstituted with IL-10−/−CD4+T cells and administered piroxicam developed severe colitis. LPMC from these colitic animals made IFN-γ, whose production was dependent on T cells. Some IL-10 was produced but only from non-T cells. LPMC from the healthy Rag mice that were reconstituted with WT T cells and were piroxicam resistant made much more IL-10. This was mostly T cell dependent. In conclusion, only CD4+T cells from IL-10−/−animals leave Rag mice susceptible to NSAID-induced, Th1 colitis. Lamina propria T cells normally make large quantities of IL-10, suggesting that IL-10 from T cells may be protective.
Role of caveolae in ouabain-induced proliferation of cultured vascular smooth muscle cells of the synthetic phenotype
Authors: Liu Lijun , Abramowitz Joel , Askari Amir , Allen Julius C.
Published: July 2004

We have shown earlier that low concentrations of ouabain that do not perturb the ionic milieu can initiate proliferation of vascular smooth muscle cells (VSMCs) in the synthetic phenotype from three different species: canine, rodent, and human. This effect occurs by activation of Src and the epidermal growth factor receptor (EGFR), and thus supports the concept of an additional, nonionic, transducing function of the Na pump. The present study presents data suggesting that such activation occurs through specific Na pump sites localized to the caveolae, and subsequent interactions with selected signaling proteins resident within the same membrane microdomain. Our data show that at rest, 30% of the total number of Na pumps are concentrated within the caveolae. When the various VSMCs were treated with proliferating concentrations of ouabain, the key protein content in isolated caveolae was increased. However, the recruited proteins were different between the different tissues. Thus ouabain activated the recruitment of both the Na pump α1-subunit and EGFR in the caveolae from rat A7r5 cells, whereas in both human and canine cells, ouabain activated the recruitment of Src, with the caveolar content of the other proteins remaining constant. These data demonstrate that ouabain interacts with the α1-subunit of the Na pump that resides within the caveolar domain, and such interaction selectively recruits signal transducing proteins to this microdomain resulting in their activation, which is necessary for the initiation of the proliferative cascade.
Doxycycline inducible expression of SERCA2a improves calcium handling and reverts cardiac dysfunction in pressure overload-induced cardiac hypertrophy
Authors: Suarez Jorge , Gloss Bernd , Belke Darrell D. , Hu Ying , Scott Brian , Dieterle Thomas , Kim Yun-Kyung , Valencik Maria L. , McDonald John A. , Dillmann Wolfgang H.
Published: July 2004

Delayed cardiac relaxation in failing hearts has been attributed to reduced activity and/or expression of sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a). Although constitutive overexpression of SERCA2a has proven effective in preventing cardiac dysfunction, it is unclear whether increasing SERCA2a expression in hearts with preexisting hypertrophy will be therapeutic. To test this hypothesis, we generated a binary transgenic (BTG) system that allows tetracycline-inducible, cardiac-specific SERCA2a expression. In this system (tet-on SERCA2a), a FLAG-tagged SERCA2a transgene is expressed in the presence of doxycycline (Dox) but not in the absence of Dox (2.3-fold more mRNA, 45% more SERCA2a protein). Calcium transients measured in isolated cardiac myocytes from nonbanded Dox-treated BTG mice showed an accelerated calcium decline and an increased systolic Ca2+ peak. Sarcoplasmic reticulum (SR) calcium loading was increased by 45% in BTG mice. In the presence of pressure overload (aortic banding), echocardiographic analysis revealed that expression of SERCA2a-FLAG caused an improvement in fractional shortening. SERCA2a-FLAG expression alleviated the resultant cardiac dysfunction. This was illustrated by an increase in the rate of decline of the calcium transient. Cell shortening and SR calcium loading were also improved in cardiac myocytes isolated from banded BTG mice after SERCA2a overexpression. In conclusion, we generated a novel transgenic mouse that conditionally overexpresses SERCA2a. This model is suitable for both long- and short-term studies of the effects of controlled SERCA2a expression on cardiac function. In addition, inducible overexpression of SERCA2a improved cardiac function and calcium handling in mice with established contractile dysfunction.
Acetaminophen and myocardial infarction in dogs
Authors: Merrill Gary F. , Rork Tyler H. , Spiler Norell M. , Golfetti Roseli
Published: July 2004

The hypothesis that acetaminophen can reduce necrosis during myocardial infarction was tested in male dogs. Two groups were studied: vehicle- ( n = 10) and acetaminophen-treated ( n = 10) dogs. All dogs were obtained from the same vendor, and there were no significant differences in their ages (18 ± 2 mo), weights (24 ± 1 kg), or housing conditions. Selected physiological data, e.g., coronary blood flow, nonspecific collateral flow, epicardial temperature, heart rate, systemic mean arterial pressure, left ventricular developed pressure, the maximal first derivative of left ventricular developed pressure, blood gases, and pH, were collected at baseline and during regional myocardial ischemia and reperfusion. There were no significant differences in coronary blood flow, nonspecific collateral flow, epicardial temperature, heart rate, systemic mean arterial pressure, or blood gases and pH between the two groups at any of the three time intervals, even though there was a trend toward improved function in the presence of acetaminophen. Infarct size, the main objective of the investigation, was markedly and significantly reduced by acetaminophen. For example, when expressed as a percentage of ventricular wet weight, infarct size was 8 ± 1 versus 3 ± 1%( P < 0.05) in vehicle- and acetaminophen-treated hearts, respectively. When infarct size was expressed as percentage of the area at risk, it was 35 ± 3 versus 13 ± 2% ( P < 0.05) in vehicle- and acetaminophen-treated groups, respectively. When area at risk was expressed as percentage of total ventricular mass, there were no differences in the two groups. Results reveal that the recently reported cardioprotective properties of acetaminophen in vitro can now be extended to the in vivo arena. They suggest that it is necessary to add acetaminophen to the growing list of pharmaceuticals that possess cardioprotective efficacy in mammals.
Viscoelasticity of human alveolar epithelial cells subjected to stretch
Authors: Trepat Xavier , Grabulosa Mireia , Puig Ferranda , Maksym Geoffrey N. , Navajas Daniel , Farré Ramon
Published: July 2004

Alveolar epithelial cells undergo stretching during breathing and mechanical ventilation. Stretch can modify cell viscoelastic properties, which may compromise the balance of forces in the alveolar epithelium. We studied the viscoelasticity of alveolar epithelial cells (A549) subjected to equibiaxial distention with a novel experimental approach. Cells were cultured on flexible substrates and subjected to stepwise deformations of up to 17% with a device built on an inverted microscope. Simultaneously, cell storage (G′) and loss (G″) moduli were measured (0.1–100 Hz) with optical magnetic twisting cytometry. G′ and G″ increased with strain up to 64 and 30%, respectively, resulting in a decrease in G″/G′ (15%). This stretch-induced response was inhibited by disruption of the actin cytoskeleton with latrunculin A. G′ increased with frequency following a power law with exponent α = 0.197. G″ increased proportionally to G′ but exhibited a more marked frequency dependence at high frequencies. Stretching (14%) caused a fall in α (13%). At high stretching amplitudes, actual cell strain (14.4%) was lower than the applied substrate strain (17.3%), which could indicate a partial cell detachment. These data suggest that cytoskeletal prestress modulates the elastic and frictional properties of alveolar epithelial cells in a coupled manner, according to soft glassy rheology. Stretch-induced cell stiffening could compromise the balance of forces at the cell-cell and cell-matrix adhesions.