bluuebunny/crossref_metadata_2025 huggingface dataset:
Tillich on Salvation
Authors: Burch Sharon Peebles
Published: August 2006

Abstract:  Paul Tillich holds that it is the responsibility of every generation to free the received tradition from assumptions that limit the vitality of Christian concepts. Salvation is often held hostage to an exclusive view that limits it to the people who have had contact with Jesus Christ. Tillich holds that Jesus as the Christ as the New Being overcame existential estrangement, making salvation a dynamic power that contends with the anxiety that is the inevitable accompaniment of finitude. This has universal implications.
Liberation, Salvation, Enlightenment: An Exercise in Comparative Soteriology
Authors: Largen Kristin Johnston
Published: August 2006

Abstract:  This article is an exercise in what might be called “comparative soteriology.” It is both constructive and essential for Christians to examine non‐Christian expressions of soteriology that challenge their own, in order to see with new eyes what salvation can and perhaps should connotate. Thus, this article intends to lead the reader to a deeper appreciation of the Christian doctrine of salvation through the exploration of three different images of salvation: from Hinduism, the Nataraja—the Dancing Shiva; from Buddhism, the Bodhisattva of Compassion, Avalokiteshvara; and from Christianity, an icon of the crucifixion, the San Damiano Crucifix.
Behavioural adaptation ofCoquillettidia(Coquillettidia)richiardiilarvae to underwater life: environmental cues governing plant–insect interaction
Authors: Sérandour Julien , Rey Delphine , Raveton Muriel
Published: August 2006

Densely overgrown pre‐alpine permanent aquatic habitats are overrun by the mosquitoCoquillettidia (Coquillettidia) richiardii(Ficalbi) (Diptera: Culicidae). The invasive potential of this insect depends on the ability of its larvae to survive on the roots of emergent aquatic macrophytes. In order to characterize this particular ecological niche, which is out of reach for a direct investigation, environmental factors likely to influence the interaction between larvae and host plant roots were investigated using a simplified laboratory microcosm. Environmental light and oxygen concentrations appeared to be the main factors influencing larval attachment, a dark anoxic environment being significantly more favourable. Carbon dioxide produced by the root system of the host plant appeared to be an attractive cue for larval attachment. Knowledge of the hierarchy of these environmental factors may enable us to better understand the ecological traits of larvalC. richiardiiin deep water. With regard to their management, new ecological data are required to develop a long‐term control strategy againstCoquillettidiamosquitoes.
Sel1p/Ubx2p Participates in a Distinct Cdc48p‐Dependent Endoplasmic Reticulum‐Associated Degradation Pathway
Authors: Wilson Joshua D. , Liu Yiting , Bentivoglio Christine M. , Barlowe Charles
Published: August 2006

The endoplasmic reticulum (ER) serves a critical role in the biogenesis of secretory proteins. Folding of nascent polypeptides occurs in the ER before anterograde transport through the secretory pathway, whereas terminally misfolded secretory proteins are recognized and eliminated by ER‐associated degradation (ERAD). Here, we investigated the role of the ubiquitin regulatory X (UBX) domain‐containing protein Sel1p in ER quality control and transport. Mutant sel1Δ yeast displayed a constitutively active unfolded protein response and a mildly reduced rate of secretory protein transport from the ER. Immunoisolation of Sel1p from detergent‐solubilized ER microsomes revealed a protein complex containing both Cdc48p and Npl4p and suggested a direct role for Sel1p in ERAD. In cells that lack Sel1p, we observed a reduction in the level of Cdc48p bound to ER membranes and a decrease in the turnover rate of two model ERAD substrates, carboxypeptidase Y* and Ste6*. In addition, we found that Sel1p and a second UBX domain‐containing protein, Shp1p, associated with Cdc48p in a mutually exclusive manner. Interestingly, the association of Sel1p with Cdc48p was regulated by ATP, while the interaction of Shp1p with Cdc48p was not influenced by ATP. Based on these findings, we conclude that Sel1p operates in the ERAD pathway by coupling Cdc48p to ER membranes and that Shp1p acts in a distinct Cdc48p‐dependent protein degradation pathway.
Retrieved Implants from Irradiated Sites in Humans: A Histologic/Histomorphometric Investigation of Oral and Craniofacial Implants
Authors: Bolind Pia , Johansson Carina B. , Johansson Petra , Granström Gösta , Albrektsson Tomas
Published: August 2006

Purpose  The aim of this report was to quantitatively and qualitatively evaluate the tissue response to bone‐anchored implants retrieved from irradiated sites in patients.

Materials and Methods  The material consists of 23 consecutively received Brånemark® implants (Nobel Biocare AB, Göteborg, Sweden) placed in pre‐ or postoperatively irradiated sites. Twenty‐two of the 23 implants were suitable for histologic evaluation of undecalcified sections in the light microscope.

Results  The oral implants with shorter time in situ demonstrated sparse bone to implant contact with mainly dense connective tissue in the interface. However, for implants with longer time in situ, high amounts of bone‐implant contact and bone fill of threads were noted. The mean values of bone‐implant contact and bone area within the thread were calculated to 40% (16–94) and 70% (13–96), respectively. The craniofacial implants, with the exception of two implants lined with a capsular formation, demonstrated mature and newly formed bone at the bone‐implant interface. The mean value for bone‐metal contact was calculated to 45 and 53% for two specimens. The mean value for bone area within the thread ranged from 65 to 88% for three specimens.

Conclusion  The possibility to achieve bone anchorage of implants in irradiated tissue was supported by the findings in this study. However, due to limited material, conclusions with regard to radiation dose and bone tissue response to implants cannot be stated.
Soluble RANKL in Crevicular Fluid of Dental Implants: A Pilot Study
Authors: Monov Gabriel , Strbac Georg D. , Baron Monika , Kandler Barbara , Watzek Georg , Gruber Reinhard
Published: August 2006

Background  Receptor activator of NF‐κB ligand (RANKL), a member of the tumor necrosis factor superfamily, is a key mediator of osteoclast formation, activation, and survival. Thus, it is reasonable to hypothesize that there might be a functional relationship between RANKL expression and peri‐implantitis.

Purpose  This pilot study was performed to determine the reference levels for soluble RANKL (sRANKL) in peri‐implant crevicular fluid and to correlate them with the clinical parameters associated with inflammatory reactions and bone destruction.

Materials and Methods  The clinical parameters probing depth (PD), modified bleeding index (MBI), and modified plaque index (MPI) served as indicators for bone resorption and inflammation. Exclusion criteria for calculations were the detection limit of the immunoassay and the minimum acceptable crevicular volume for measurement. From the 84 collected samples of 16 patients, 30–84 years of age, with a total of 19 implants, 29 met these criteria. The absolute amount of sRANKL within crevicular fluid adsorbed to filter strips was a median of 0.18 femtomol (fmol; range, 0.08–0.53) and 0.26 nM (range, 0.09–1.21) when normalized by volume. PD was 4 mm in median and varied within a range between 2 and 12 mm.

Results  Absolute amounts of sRANKL showed no correlation with the adsorbed volume and the clinical parameters PD, MBI, and MPI. When sRANKL was normalized by volume, no correlation with the clinical parameters PD, MBI, and MPI was observed either. The patients’ age was not associated with total sRANKL and the concentration of RANKL within crevicular fluid. Absolute levels of sRANKL and sRANKL concentration did not show any differences based on the sampling sites buccal and lingual, or on the patients’ gender. A significant difference in sRANKL concentration was detectable when samples from maxillary implants (0.31 nM median; range, 0.12–1.21) were compared with samples from mandibular implants (0.21 nM median; range, 0.09–0.6) (p=.03). Absolute levels of sRANKL were not different between the maxilla and the mandible.

Conclusion  Given the limited sample size, our data provide a basis for future prospective longitudinal studies on the possible relevance of sRANKL as a prognostic marker in peri‐implantitis, and for an understanding of the pathophysiologic process of the disease as a prerequisite for the design of treatment strategies.
Design of Novispirin Antimicrobial Peptides by Quantitative Structure–Activity Relationship
Authors: Taboureau Olivier , Olsen Ole Hvilsted , Nielsen Jesper Duus , Raventos Dora , Mygind Per Holse , Kristensen Hans‐Henrik
Published: August 2006

Novispirin G10 is an α‐helical antimicrobial peptide designed in an effort to develop alternative treatments against multidrug‐resistant micro‐organisms. To further optimize the antimicrobial activity, 58 novispirin analogs were constructed and used to establish a quantitative structure–activity relationship model. A statistically significant model (r2 = 0.73, q2 = 0.61) was obtained using a set of 69 selected molecular descriptors. Among these, VolSurf and charged partial surface area descriptors played a dominant role. Analysis of the model indicated that hydrophobicity, amphipathicity and charge were the most important features influencing activity for this set of peptides. Furthermore, the ability of the quantitative structure–activity relationship model to predict bioactivity was evaluated by analyzing a set of 400 novispirin analogs designed by molecular modeling. Out of these 400, 16 new novispirins with a higher predicted antimicrobial activity were tested in the suicide expression system, and about three out of four appeared more potent than the parent novispirin G10. Combination of VolSurf and charged partial surface area descriptors seems relevant to depict the interaction between novispirin and its target(s), presumably the microbial cell membrane. The presented findings show that modeling and quantitative structure–activity relationship methods can be useful in the construction of and/or optimization of the bioactivity of antimicrobial peptides for further development as effective antibiotic therapeutics.
Law reform in the twenty-first century
Authors: Toulson Roger
Published: August 2006

In this paper, which is the text of a lecture given at the official launch of the Law School at the University of Bradford on 11 May 2006, the history of law reform in England is traced, the role of the Law Commission is analysed and future prospects are considered.
THE PHYLOGENETIC RELATIONSHIPS AND BIOGEOGRAPHY OF TRUE PORPOISES (MAMMALIA: PHOCOENIDAE) BASED ON MORPHOLOGICAL DATA
Authors: Fajardo‐Mellor Liliana , Berta Annalisa , Brownell Robert L. , Boy Claudia C. , Natalie P. Goodall R.
Published: August 2006

Abstract

Prior studies of phylogenetic relationships among phocoenids based on morphology and molecular sequence data conflict and yield unresolved relationships among species. This study evaluates a comprehensive set of cranial, postcranial, and soft anatomical characters to infer interrelationships among extant species and several well‐known fossil phocoenids, using two different methods to analyze polymorphic data: polymorphic coding and frequency step matrix. Our phylogenetic results confirmed phocoenid monophyly. The division of Phocoenidae into two subfamilies previously proposed was rejected, as well as the alliance of the two extinct generaSalumiphocaenaandPiscolithaxwithPhocoena dioptricaandPhocoenoides dalli. Extinct phocoenids are basal to all extant species. We also examined the origin and distribution of porpoises within the context of this phylogenetic framework. Phocoenid phylogeny together with available geologic evidence suggests that the early history of phocoenids was centered in the North Pacific during the middle Miocene, with subsequent dispersal into the southern hemisphere in the middle Pliocene. A cooling period in the Pleistocene allowed dispersal of the southern ancestor ofPhocoena sinusinto the North Pacific (Gulf of California).
Mechanisms underlying the temporal precision of sound coding at the inner hair cell ribbon synapse
Authors: Moser Tobias , Neef Andreas , Khimich Darina
Published: August 2006

Our auditory system is capable of perceiving the azimuthal location of a low frequency sound source with a precision of a few degrees. This requires the auditory system to detect time differences in sound arrival between the two ears down to tens of microseconds. The detection of these interaural time differences relies on network computation by auditory brainstem neurons sharpening the temporal precision of the afferent signals. Nevertheless, the system requires the hair cell synapse to encode sound with the highest possible temporal acuity. In mammals, each auditory nerve fibre receives input from only one inner hair cell (IHC) synapse. Hence, this single synapse determines the temporal precision of the fibre. As if this was not enough of a challenge, the auditory system is also capable of maintaining such high temporal fidelity with acoustic signals that vary greatly in their intensity. Recent research has started to uncover the cellular basis of sound coding. Functional and structural descriptions of synaptic vesicle pools and estimates for the number of Ca2+ channels at the ribbon synapse have been obtained, as have insights into how the receptor potential couples to the release of synaptic vesicles. Here, we review current concepts about the mechanisms that control the timing of transmitter release in inner hair cells of the cochlea.
ON direction‐selective ganglion cells in the mouse retina
Authors: Sun Wenzhi , Deng Qiudong , Levick William R. , He Shigang
Published: August 2006

Two types of ganglion cells (RGCs) compute motion direction in the retina: the ON–OFF direction‐selective ganglion cells (DSGCs) and the ON DSGCs. The ON DSGCs are much less studied mostly due to the low encounter rate. In this study, we investigated the physiology, dendritic morphology and synaptic inputs of the ON DSGCs in the mouse retina. When a visual stimulus moved back and forth in the preferred–null axis, we found that the ON DSGCs exhibited a larger EPSC when the visual stimulus moved in the preferred direction and a larger IPSC in the opposite, or null direction, similar to what has been found in ON–OFF DSGCs. This similar synaptic input pattern is in contrast to other well‐known differences, namely: profile of velocity sensitivity, distribution of preferred directions, and different central projection of the axons. Immunohistochemical staining showed that the dendrites of ON DSGCs exhibited tight cofasciculation with the cholinergic plexus. These findings suggest that cholinergic amacrine cells may play an important role in generating direction selectivity in the ON DSGCs, and that the mechanism for coding motion direction is probably similar for the two types of DSGCs in the retina.
Nicotinic modulation of network and synaptic transmission in the immature hippocampus investigated with genetically modified mice
Authors: Le Magueresse Corentin , Safiulina Victoria , Changeux Jean‐Pierre , Cherubini Enrico
Published: August 2006

The hippocampus, a key structure in learning and memory processes, receives a powerful cholinergic innervation from the septum and contains nicotinic acetylcholine receptors (nAChRs). Early in postnatal development, activation of nAChRs by nicotine or endogenous acetylcholine contributes to enhance synaptic signalling. Here, the patch‐clamp technique was used to assess the contribution of α7 and β2‐containing (α7* and β2*) nAChRs to nicotine‐elicited modulation of GABAergic and glutamatergic activity at the network and single‐cell level in the immature hippocampus of wild‐type (WT), α7−/− and β2−/− mice. We found that α7* and β2* nAChRs were sufficient to modulate nicotine‐induced increase in frequency of spontaneously occurring giant depolarizing potentials (GDPs), which are generated at the network level by the synergistic action of glutamate and depolarizing GABA, and thought to play a crucial role in neuronal wiring. However, α7* but not β2* receptors were essential in nicotine‐induced increase of interictal discharge frequency recorded after postnatal day 3 in the presence of bicuculline, when GABA shifted from the depolarizing to the hyperpolarizing direction. To correlate these observations with nicotine‐elicited changes in synaptic transmission, we recorded spontaneous GABAergic and glutamatergic postsynaptic currents in pyramidal cells and interneurons localized in stratum oriens, stratum pyramidale and stratum radiatum, in slices obtained from WT and knock‐out animals. We found that early in postnatal life α7* and β2* nAChRs exert a fine regional modulation of GABAergic and glutamatergic transmission that underlies nicotine‐elicited changes in network synchronization.
A case–control study of farming and prostate cancer in African-American and Caucasian men
Authors: Meyer Tamra E , Coker Ann L , Sanderson Maureen , Symanski Elaine
Published: August 2006

Objective:To determine the risk of prostate cancer associated with farming by duration, recency and specific activities among African-Americans and Caucasians.

Methods:This population-based case–control study had information on farming-related activities for 405 incident prostate cancer cases and 392 controls matched for age, race and region in South Carolina, USA, from 1999 to 2001. Cases with histologically confirmed, primary invasive prostate cancer who were aged between 65 and 79 years were ascertained through the South Carolina Central Cancer Registry. Appropriately matched controls were identified from the Health Care Financing Administration Medicare Beneficiary File. Data were collected using computer-assisted telephone interviewing, and adjusted odds ratios (aOR) were estimated using unconditional logistic regression.

Results:Farming was associated with increased risk of prostate cancer in Caucasians (aOR 1.8; 95% confidence interval (CI) 1.3 to 2.7) but not in African-Americans (aOR 1.0; 95% CI 0.6 to 1.6). Regarding specific farming activities, farmers who mixed or applied pesticides had a higher risk of prostate cancer (aOR 1.6; 95% CI 1.2 to 2.2). Increased risk of prostate cancer was observed only for those farming <5 years.

Conclusions:Increased risk of prostate cancer for farmers in this study may be attributable to pesticide exposure. Racial differences in the association between farming and prostate cancer may be explained by different farming activities or different gene–environment interactions by race.
A 3D SHAPE OPTIMIZATION PROBLEM IN HEAT TRANSFER: ANALYSIS AND APPROXIMATION VIA BEM
Authors: ABBÀ ANTONELLA , SALERI FAUSTO , D'ANGELO CARLO
Published: August 2006

In this paper an optimal shape control problem dealing with heat transfer in enclosures is studied. We have considered an enclosure heated by a flame surface (taking into account radiation, conduction and convection effects), and we look for an optimal flame shape which minimizes a cost functional defined on the temperature field. This kind of problem arises in industrial furnaces optimization, as temperature uniformity is one of the most important aspects in industrial plant analysis and design. Analytical results (smoothness of the control-to-state mapping, existence of an optimal shape in a certain admissible class) as well as numerical optimization results by the boundary element method have been obtained; we have employed the gradient method to optimize the flame shape, exploiting the adjoint equation associated with our state equation and cost functional.
MONITORING ASSERTION-BASED BUSINESS PROCESSES
Authors: AIELLO MARCO , LAZOVIK ALEXANDER
Published: August 2006

Business processes that span organizational borders describe the interaction between multiple parties working towards a common objective. They also express business rules that govern the behavior of the process and account for expressing changes reflecting new business objectives and new market situations.

We developed a service request language and support framework that allow users to formulate their requests against standard business processes.19 In this paper, we extend the approach by presenting a framework capable of automatically associating business rules with relevant processes involved in a user request. This framework plans and monitors the execution of the request and assertions against services underlying these processes. Definitions and classifications of business rules (named assertions in the paper) are given together with an assertion language for expressing them. The framework is able to handle the non-determinism typical for service-oriented computing environments and it is based on the interleaving of planning and execution. Interestingly, the language is able to express both functional and non-functional aspects of the assertions.
STIEFEL–WHITNEY CLASSES AND SYMPLECTIC LOCAL ROOT NUMBERS
Authors: FRANCO-FERNANDEZ MANUEL , SNAITH VICTOR
Published: August 2006

Let K be a p-adic local field where p is an odd prime and let A be the unique quaternion division algebra whose centre is K. By means of Stiefel–Whitney classes, we define an exponential homomorphism ϒK from the orthogonal representations of A*/K* to fourth roots of unity. We then evaluate this homomorphism in terms of the local root numbers of two-dimensional symplectic Galois representations of K, using the Langlands correspondence relating Galois representations to continuous representations of A*.
Carbon-Nitrogen Interactions in Terrestrial Ecosystems in Response to Rising Atmospheric Carbon Dioxide
Authors: Reich Peter B. , Hungate Bruce A. , Luo Yiqi
Published: August 2006

Interactions involving carbon (C) and nitrogen (N) likely modulate terrestrial ecosystem responses to elevated atmospheric carbon dioxide (CO2) levels at scales from the leaf to the globe and from the second to the century. In particular, response to elevated CO2 may generally be smaller at low relative to high soil N supply and, in turn, elevated CO2 may influence soil N processes that regulate N availability to plants. Such responses could constrain the capacity of terrestrial ecosystems to acquire and store C under rising elevated CO2 levels. This review highlights the theory and empirical evidence behind these potential interactions. We address effects on photosynthesis, primary production, biogeochemistry, trophic interactions, and interactions with other resources and environmental factors, focusing as much as possible on evidence from long-term field experiments.
Perception of Human Motion
Authors: Blake Randolph , Shiffrar Maggie
Published: August 2006

Abstract  Humans, being highly social creatures, rely heavily on the ability to perceive what others are doing and to infer from gestures and expressions what others may be intending to do. These perceptual skills are easily mastered by most, but not all, people, in large part because human action readily communicates intentions and feelings. In recent years, remarkable advances have been made in our understanding of the visual, motoric, and affective influences on perception of human action, as well as in the elucidation of the neural concomitants of perception of human action. This article reviews those advances and, where possible, draws links among those findings.
Energy expenditure adjusted for body composition differentiates constitutional thinness from both normal subjects and anorexia nervosa
Authors: Bossu Cécile , Galusca Bogdan , Normand Sylvie , Germain Natacha , Collet Philippe , Frere Delphine , Lang François , Laville Martine , Estour Bruno
Published: August 2006

Constitutional thinness (CT) is characterized by a low and stable body mass index (BMI) without any hormonal abnormality. To understand the weight steadiness, energetic metabolism was evaluated. Seven CT, seven controls, and six anorexia nervosa (AN) young women were compared. CT and AN had a BMI <16.5 kg/m2. Four criteria were evaluated: 1) energy balance including diet record, resting metabolic rate (RMR) (indirect calorimetry), total energy expenditure (TEE) (doubly labeled water), physical activity; 2) body composition (dual-energy X-ray absorptiometry); 3) biological markers (leptin, IGF-I, free T3); 4) psychological profile of eating behavior. The normality of free T3 (3.7 ± 0.5 pmol/l), IGF-I (225 ± 93 ng/ml), and leptin (8.3 ± 3.4 ng/ml) confirmed the absence of undernutrition in CT. Their psychological profiles revealed a weight gain desire. TEE (kJ/day) in CT (8,382 ± 988) was not found significantly different from that of controls (8,793 ± 845) and AN (8,001 ± 2,152). CT food intake (7,565 ± 908 kJ/day) was found similar to that of controls (7,961 ± 1,452 kJ/day) and higher than in AN (4,894 ± 703 kJ/day), thus explaining the energy metabolism balance. Fat-free mass (FFM) (kg) was similar in CT and AN (32.5 ± 2.9 vs. 34.1 ± 1.9) and higher in controls (37.8 ± 1.6). While RMR absolute values (kJ/day) were lower in CT (4,839 ± 473) than in controls (5,576 ± 209), RMR values adjusted for FFM were the highest in CT. TEE-to-FFM ratio was also higher in CT than in controls. Energetic metabolism balance maintains a stable low weight in CT. An increased energy expenditure-to-FFM ratio differentiates CT from controls and could account for the resistance to weight gain observed in CT.
Identification of key residues that cause differential gallbladder response to PACAP and VIP in the guinea pig
Authors: Wei Muxin , Fujiki Kotoyo , Ando Eiji , Zhang Sumin , Ozaki Tsuyoshi , Ishiguro Hiroshi , Kondo Takaharu , Nokihara Kiyoshi , Wray Victor , Naruse Satoru
Published: August 2006

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) have opposite actions on the gallbladder; PACAP induces contraction, whereas VIP induces relaxation. Here, we have attempted to identify key residues responsible for their interactions with PACAP (PAC1) and VIP (VPAC) receptors in the guinea pig gallbladder. We synthesized PACAP-27/VIP hybrid peptides and compared their actions on isolated guinea pig gallbladder smooth muscle strips using isotonic transducers. [Ala4]- and [Val5]PACAP-27 were more potent than PACAP-27 in stimulating the gallbladder. In contrast, [Ala4, Val5]- and [Ala4, Val5, Asn9]PACAP-27 induced relaxation similarly to VIP. [Asn9]-, [Thr11]-, or [Leu13]PACAP-27 had 20–70% contractile activity of PACAP-27, whereas [Asn24,Ser25,Ile26]PACAP-27 showed no change in the activity. All VIP analogs, including [Gly4,Ile5,Ser9]VIP, induced relaxation. In the presence of a PAC1receptor antagonist, PACAP(6–38), the contractile response to PACAP-27 was inhibited and relaxation became evident. RT-PCR analysis revealed abundant expressions of PAC1receptor, “hop” splice variant, and VPAC1and VPAC2receptor mRNAs in the guinea pig gallbladder. In conclusion, PACAP-27 induces contraction of the gallbladder via PAC1/hop receptors. Gly4and Ile5are the key NH2-terminal residues of PACAP-27 that distinguish PAC1/hop receptors from VPAC1/VPAC2receptors. However, both the NH2-terminal and α-helical regions of PACAP-27 are required for initiating gallbladder contraction.
Effect of Slc26a6 deletion on apical Cl−/HCO3− exchanger activity and cAMP-stimulated bicarbonate secretion in pancreatic duct
Authors: Ishiguro Hiroshi , Namkung Wan , Yamamoto Akiko , Wang Zhaohui , Worrell Roger T. , Xu Jie , Lee Min Goo , Soleimani Manoocher
Published: August 2006

The role of Slc26a6 (PAT1) on apical Cl−/HCO3− exchange and bicarbonate secretion in pancreatic duct cells was investigated using Slc26a6 null and wild-type (WT) mice. Apical Cl−/HCO3− exchange activity was measured with the pH-sensitive dye BCECF in microperfused interlobular ducts. The HCO3−-influx mode of apical [Cl−]i/[HCO3−]o exchange (where brackets denote concentration and subscripts i and o denote intra- and extracellular, respectively) was dramatically upregulated in Slc26a6 null mice ( P < 0.01 vs. WT), whereas the HCO3−-efflux mode of apical [Cl−]o/[HCO3−]i exchange was decreased in Slc26a6 null mice ( P < 0.05 vs. WT), suggesting the unidirectionality of the Slc26a6-mediated HCO3− transport. Fluid secretory rate in interlobular ducts were comparable in WT and Slc26a6 null mice ( P > 0.05). In addition, when pancreatic juice was collected from whole animal in basal and secretin-stimulated conditions, neither juice volume nor its pH showed differences between WT and Slc26a6 null mice. Semiquantitative RT-PCR demonstrated more than fivefold upregulation in Slc26a3 (DRA) expression in Slc26a6 knockout pancreas. In conclusion, these results point to the role of Slc26a6 in HCO3− efflux at the apical membrane and also suggest the presence of a robust Slc26a3 compensatory upregulation, which can replace the function of Slc26a6 in pancreatic ducts.
Lactobacillus caseiprevents the upregulation of ICAM-1 expression and leukocyte recruitment in experimental colitis
Authors: Angulo Sandra , Llopis Marta , Antolín María , Gironella Meritxell , Sans Miquel , Malagelada Juan Ramon , Piqué Josep Maria , Guarner Francisco , Panés Julián
Published: August 2006

Lactobacillus casei has been shown to attenuate the severity of experimental colitis. The objective of the present study was to determine whether the effects of L. casei on colitis are related to modulation of leukocyte recruitment into the inflamed intestine. Rats with a colonic segment excluded from fecal transit were surgically prepared. The segment was decontaminated with antibiotics and recolonized with normal flora isolated from the inflamed rat colon, associated or not to L. casei. Control and colitic [2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced] animals were studied. Leukocyte-endothelial cell interactions were characterized in the colonic microcirculation by intravital microscopy, and ICAM-1 and VCAM-1 expression was measured by the radiolabeled antibody technique. Compared with the noninflamed colonic segment, induction of colitis by TNBS provoked a marked increase in the number of leukocytes firmly adherent to the venular wall (0.5 ± 0.1 vs. 2.1 ± 0.6 leukocytes/100 μm, P < 0.01). Colonization with L. casei significantly reduced the number of adherent leukocytes (1.3 ± 0.4 leukocytes/100 μm; P < 0.05) but did not affect the increased rolling interactions associated with the induction of colitis. Compared with the noncolitic group, induction of colitis was associated with a marked increase in ICAM-1 expression (117 ± 4 vs. 180 ± 3 ng antibody/g tissue) that was abrogated when the colitic segment was colonized by L. casei (117 ± 3 ng antibody/g tissue, P < 0.05). However, L. casei administration did not modify VCAM-1 upregulation in colitic animals. L. casei attenuates leukocyte recruitment observed in experimental colitis induced by TNBS. This effect is possibly related to abrogation of ICAM-1 upregulation.
Lung injury after ozone exposure is iron dependent
Authors: Ghio Andrew J. , Turi Jennifer L. , Madden Michael C. , Dailey Lisa A. , Richards Judy D. , Stonehuerner Jacqueline G. , Morgan Daniel L. , Singleton Steven , Garrick Laura M. , Garrick Michael D.
Published: August 2006

We tested the hypothesis that oxidative stress and biological effect after ozone (O3) exposure are dependent on changes in iron homeostasis. After O3 exposure, healthy volunteers demonstrated increased lavage concentrations of iron, transferrin, lactoferrin, and ferritin. In normal rats, alterations of iron metabolism after O3 exposure were immediate and preceded the inflammatory influx. To test for participation of this disruption in iron homeostasis in lung injury following O3 inhalation, we exposed Belgrade rats, which are functionally deficient in divalent metal transporter 1 (DMT1) as a means of iron uptake, and controls to O3. Iron homeostasis was disrupted to a greater extent and the extent of injury was greater in Belgrade rats than in control rats. Nonheme iron and ferritin concentrations were higher in human bronchial epithelial (HBE) cells exposed to O3 than in HBE cells exposed to filtered air. Aldehyde generation and IL-8 release by the HBE cells was also elevated following O3 exposure. Human embryonic kidney (HEK 293) cells with elevated expression of a DMT1 construct were exposed to filtered air and O3. With exposure to O3, elevated DMT1 expression diminished oxidative stress (i.e., aldehyde generation) and IL-8 release. We conclude that iron participates critically in the oxidative stress and biological effects after O3 exposure.
Cigarette smoke upregulates pulmonary vascular matrix metalloproteinases via TNF-α signaling
Authors: Wright J. L. , Tai H. , Wang R. , Wang X. , Churg A.
Published: August 2006

Cigarette smoke exposure causes vascular remodeling and pulmonary hypertension by poorly understood mechanisms. To ascertain whether cigarette smoke exposure affects production of matrix metalloproteinases (MMPs) in the pulmonary vessels, we exposed C57Bl/6 (C57) mice or mice lacking TNF-α receptors (TNFRKO) to smoke daily for 2 wk or 6 mo. Using laser capture microdissection and RT-PCR analysis, we examined gene expression of MMP-2, MMP-9, MMP-12, MMP-13, and tissue inhibitor of metalloproteinase (TIMP-1) and examined protein production by immunohistochemistry for MMP-2, MMP-9, and MMP-12 in small intrapulmonary arteries. At 2 wk, mRNA levels of TIMP-1 and all MMPs were increased in the C57, but not TNFRKO, mice, and immunoreactive protein for MMP-2, MMP-9, and MMP-12 was also increased in the C57 mice. Increased gelatinase activity was identified by in situ and bulk tissue zymography. At 6 mo, only MMP-12 mRNA levels remained increased in the C57 mice, but at a much lower level; however, MMP-2 mRNA levels increased in the TNFRKO mice. We conclude that smoke exposure increases MMP production in the small intrapulmonary arteries but that, with the exception of MMP-12, increased MMP production is transient. MMPs probably play a role in smoke-induced vascular remodeling, as they do in other forms of pulmonary hypertension, implying that MMP inhibitors might be beneficial. MMP production is largely TNF-α dependent, further supporting the importance of TNF-α in the pathogenesis of cigarette smoke-induced lung disease.
Low-carbohydrate diets affect energy balance and fuel homeostasis differentially in lean and obese rats
Authors: Morens C. , Sirot V. , Scheurink A. J. W. , van Dijk G.
Published: August 2006

In parallel with increased prevalence of overweight people in affluent societies are individuals trying to lose weight, often using low-carbohydrate diets. Nevertheless, long-term metabolic consequences of those diets, usually high in (saturated) fat, remain unclear. Therefore, we investigated long-term effects of high-fat diets with different carbohydrate/protein ratios on energy balance and fuel homeostasis in obese ( fa/fa) Zucker and lean Wistar rats. Animals were fed high-carbohydrate (HC), high-fat (HsF), or low-carbohydrate, high-fat, high-protein (LC-HsF-HP) diets for 60 days. Both lines fed the LC-HsF-HP diet displayed reduced energy intake compared with those fed the HsF diet (Zucker, −3.7%) or the HC diet (Wistar rats, −12.4%). This was not associated with lower weight gain relative to HC fed rats, because of increased food efficiencies in each line fed HsF and particularly LC-HsF-HP food. Zucker rats were less glucose tolerant than Wistar rats. Lowest glucose tolerances were found in HsF and particularly in LC-HsF-HP-fed animals irrespective of line, but this paralleled reduced plasma adiponectin levels, elevated plasma resistin levels, higher retroperitoneal fat masses, and reduced insulin sensitivity (indexed by insulin-induced hypoglycemia) only in Wistar rats. In Zucker rats, however, improved insulin responses during glucose tolerance testing and tendency toward increased insulin sensitivities were observed with HsF or LC-HsF-HP feeding relative to HC feeding. Thus, despite adverse consequences of LC-HsF diets on blood glucose homeostasis, principal differences exist in the underlying hormonal regulatory mechanisms, which could have benefits for B-cell functioning and insulin action in the obese state but not in the lean state.
Gastrointestinal processing of Na+, Cl−, and K+during digestion: implications for homeostatic balance in freshwater rainbow trout
Authors: Bucking Carol , Wood Chris M.
Published: August 2006

The role of the gastrointestinal tract in maintaining ionic homeostasis during digestion, as well as the relative contribution of the diet for providing electrolytes, has been generally overlooked in many aquatic species. An experimental diet that contained an inert reference marker (lead-glass beads) was used to quantify the net transport of Na+, K+, and Cl−during the digestion and absorption of a single meal (3% ration) by freshwater rainbow trout ( Oncorhynchus mykiss). Secretion of Cl−into the stomach peaked at 8 and 12 h following feeding at a rate of 1.1 mmol·kg−1·h−1, corresponding to a theoretical pH of 0.6 in the secreted fluid (i.e., 240 mmol/l HCl). The majority (∼90%) of dietary Na+and K+was absorbed in the stomach, whereas subsequent large fluxes of Na+and Cl−into the anterior intestine corresponded to a large flux of water previously observed. The estimated concentration of Na+in fluids secreted into the anterior intestine was ∼155 mmol/l, equivalent to reported hepatic bile values, whereas the estimated concentration of Cl−(∼285 mmol/l) suggested seepage of HCl acid from the stomach in advance of the chyme front. Net absorption of K+in the stomach occurred following the cessation of Cl−secretion, providing indirect evidence of K+involvement with HCl acid production. Overall, 80–90% of the K+and Cl−contents of the meal were absorbed on a net basis, whereas net Na+absorption was negligible. Chyme-to-plasma ion concentration gradients were often opposed to the direction of ion transport, especially for Na+and Cl−.
Pifithrin-α, an inhibitor of p53 transactivation, alters the inflammatory process and delays tendon healing following acute injury
Authors: Marsolais David , Côté Claude H. , Frenette Jérôme
Published: August 2006

Transcription factor p53, which was initially associated with cancer, has now emerged as an important regulator of inflammation and extracellular matrix homeostasis, two processes highly relevant to tendon repair. The goal of this study was to evaluate the effect of a p53 transactivation inhibitor, namely, pifithrin-α, on the pathophysiological sequence following collagenase-induced tendon injury. Administration of pifithrin-α during the inflammatory phase reduced the accumulation of neutrophils and macrophages by 30 and 40%, respectively, on day 3 postinjury. Pifithrin-α failed to reduce the percentage of apoptotic cells following collagenase injection but delayed functional recovery. In uninjured Achilles tendons, pifithrin-α increased metalloprotease activity 2.4-fold. Accordingly, pifithrin-α reduced the collagen content in intact tendons as well as in injured tendons 7 days posttrauma compared with placebo. The effect of pifithrin-α on load to failure and stiffness was also evaluated. The administration of pifithrin-α during the inflammatory phase did not significantly decrease the functional deficit 3 days posttrauma. More importantly, load to failure and stiffness were significantly decreased in the pifithrin-α group from day 7 to day 28 compared with placebo. Overall, our results suggest that administration of pifithrin-α alters the inflammatory process and delays tendon healing. The present findings also support the concept that p53 can regulate extracellular matrix homeostasis in vivo.
Effects of progressive and maximal exercise on plasma levels of adhesion molecules in athletes with sickle cell trait with or without α-thalassemia
Authors: Monchanin Geraldine , Serpero Laura D. , Connes Philippe , Tripette Julien , Wouassi Dieudonné , Bezin Laurent , Francina Alain , Ngongang Jeanne , de la Peña Monica , Massarelli Raphael , Gozal David , Thiriet Patrice , Martin Cyril
Published: August 2006

The aim of the study was to examine the effects of exercise on soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) in sickle cell trait (SCT) athletes with or without α-thalassemia. Six athletes with SCT, seven athletes with both SCT and α-thalassemia (SCTAT), and seven control athletes (Cont) performed an incremental and maximal test on cycloergometer. Levels of sICAM-1 and sVCAM-1 were assessed at rest, immediately after the end of exercise, and 1, 2, and 24 h after exercise. Although Cont and SCTAT groups exhibited similar basal plasma levels of inflammatory and adhesion molecules, the SCT group had higher sVCAM-1 basal concentrations. Incremental exercise resulted in a significant increase of sVCAM-1 in all subjects, which remained elevated only in the SCT group during the recovery period. In conclusion, as sVCAM-1 increased with exercise and during the recovery period, our findings support the concept that SCT athletes might be at risk for microcirculatory disturbances and adhesive phenomena developing at rest and several hours after exercise. α-Thalassemia might be considered protective among exercising SCT subjects.
Emergence of Intrinsic Bursting in Trigeminal Sensory Neurons Parallels the Acquisition of Mastication in Weanling Rats
Authors: Brocard Frédéric , Verdier Dorly , Arsenault Isabel , Lund James P. , Kolta Arlette
Published: August 2006

There is increasing evidence that a subpopulation of neurons in the dorsal principal sensory trigeminal nucleus are not simple sensory relays to the thalamus but may form the core of the central pattern generating circuits responsible for mastication. In this paper, we used whole cell patch recordings in brain stem slices of young rats to show that these neurons have intrinsic bursting abilities that persist in absence of extracellular Ca2+. Application of different K+ channel blockers affected duration and firing rate of bursts, but left bursting ability intact. Bursting was voltage dependent and was abolished by low concentrations of Na+ channel blockers. The proportion of bursting neurons increased dramatically in the second postnatal week, in parallel with profound changes in several electrophysiological properties. This is the period in which masticatory movements appear and mature. Bursting was associated with the development of an afterdepolarization that depend on maturation of a persistent sodium conductance ( INaP). An interesting finding was that the occurrence of bursting and the magnitude of INaP were both modulated by the extracellular concentration of Ca2+. Lowering extracellular [Ca2+] increased both INaP and probability of bursting. We suggest that these mechanisms underlie burst generation in mastication and that similar processes may be found in other motor pattern generators.
Real-time Dose Adjustment of Cyclophosphamide in a Preparative Regimen for Hematopoietic Cell Transplant: A Bayesian Pharmacokinetic Approach
Authors: Salinger David H. , McCune Jeannine S. , Ren Aaron G. , Shen Danny D. , Slattery John T. , Phillips Brian , McDonald George B. , Vicini Paolo
Published: August 2006

Purpose: Dose-related toxicity of cyclophosphamide may be reduced and therapeutic efficacy may be improved by pharmacokinetic sampling and dose adjustment to achieve a target area under the curve (AUC) for two of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM). To facilitate real-time dose adjustment, we developed open-source code within the statistical software R that incorporates individual data into a population pharmacokinetic model.

Experimental Design: Dosage prediction performance was compared to that obtained with nonlinear mixed-effects modeling using NONMEM in 20 cancer patients receiving cyclophosphamide. Bayesian estimation of individual pharmacokinetic parameters was accomplished from limited (i.e., five samples over 0-16 hours) sampling of plasma HCY and CEPM after the initial cyclophosphamide dose. Conditional on individual pharmacokinetics, simulations of the AUC of both HCY and CEPM were provided for a range of second doses (i.e., 0-100 mg/kg cyclophosphamide).

Results: The results compared favorably with NONMEM and returned accurate predictions for AUCs of HCY and CEPM with comparable mean absolute prediction error and root mean square prediction error. With our method, the mean absolute prediction error and root mean square prediction error of AUC CEPM were 11.0% and 12.8% and AUC HCY were 31.7% and 44.8%, respectively.

Conclusions: We developed dose adjustment software that potentially can be used to adjust cyclophosphamide dosing in a clinical setting, thus expanding the opportunity for pharmacokinetic individualization of cyclophosphamide. The software is simple to use (requiring no programming experience), reads individual patient data directly from an Excel spreadsheet, and runs in less than 5 minutes on a desktop PC.
CpG Island Methylator Phenotype Redefines the Prognostic Effect of t(12;21) in Childhood Acute Lymphoblastic Leukemia
Authors: Roman-Gomez Jose , Jimenez-Velasco Antonio , Agirre Xabier , Castillejo Juan A. , Navarro German , Calasanz Maria J. , Garate Leire , San Jose-Eneriz Edurne , Cordeu Lucia , Prosper Felipe , Heiniger Anabel , Torres Antonio
Published: August 2006

Purpose: To examine cancer genes undergoing epigenetic inactivation in a set of ETV6/RUNX1-positive acute lymphoblastic leukemias in order to define the CpG island methylator phenotype (CIMP) in the disease and evaluate its relationship with clinical features and outcome.

Experimental Design: Methylation-specific PCR was used to analyze the methylation status of 38 genes involved in cell immortalization and transformation in 54 ETV6/RUNX1-positive samples in comparison with 190 ETV6/RUNX1-negative samples.

Results: ETV6/RUNX1-positive samples had at least one gene methylated in 89% of the cases. According to the number of methylated genes observed in each individual sample, 20 patients (37%) were included in the CIMP− group (0-2 methylated genes) and 34 (67%) in the CIMP+ group (>2 methylated genes). Remission rate did not differ significantly among either group of patients. Estimated disease-free survival and overall survival at 9 years were 92% and 100% for the CIMP− group and 33% and 73% for the CIMP+ group (P = 0.002 and P = 0.04, respectively). Multivariate analysis showed that methylation profile was an independent prognostic factor in predicting disease-free survival (P = 0.01) and overall survival (P = 0.05). A group of four genes (DKK3, sFRP2, PTEN, and P73) showed specificity for ETV6/RUNX1-positive subset of samples.

Conclusion: Our results suggest that methylation profile may be a potential new biomarker of risk prediction in ETV6/RUNX1-positive acute lymphoblastic leukemias.