bluuebunny/crossref_metadata_2025 huggingface dataset:
Aspects of adaptive host response in periodontitis
Authors: Berglundh Tord , Donati Mauro
Published: August 2005

Objective: To review host response in periodontitis with respect to cellular composition of lesions, T cell receptor (TCR) gene expression, cytokine profiles of T‐helper (Th) cells and autoimmune components.

Material and methods: The studies included were confined to human material (biopsies, gingival crevicular fluid, blood from subjects with periodontitis).

Results and conclusions: In periodontitis lesions, plasma cells are the most common cell type and represent about 50% of all cells, while B cells comprise about 18%. The proportion of B cells is larger than that of T cells and Th cells occur in larger numbers than T cytotoxic cells. Polymorphonuclear cells and macrophages are found in fractions of less than 5% of all cells. Lesions in aggressive and chronic forms of periodontitis exhibit similar cellular composition. Differences in disease severity, however, may reflect increases in plasma cell and B cell densities. B cells serve as important antigen‐presenting cells in periodontitis. The periodontitis lesion expresses a unique TCR gene repertoire that is different from that in blood. The role of superantigens in periodontitis is unclear. There are few studies using comparative designs and unbiased quantitative methods regarding Th‐1 and Th‐2 cells in periodontitis. The relative dominance of B cells and plasma cells in periodontitis lesions cannot entirely be explained by enhanced Th‐2 functions but maybe because of an imbalance between Th‐1 and Th‐2. Autoimmune reactions are evident in periodontitis lesions. The role of auto‐antibodies in the regulation of host response in periodontitis, however, needs to be clarified. Auto‐reactive B cells occur in larger proportions in subjects with periodontitis than in healthy controls.
Oral health‐related quality of life for 8–10‐year‐old children: an assessment of a new measure
Authors: Humphris Gerry , Freeman Ruth , Gibson Barry , Simpson Kirk , Whelton Helen
Published: August 2005

Abstract –  Objectives:  The aim of the study was to assess the reliability and construct validity of the Child Oral Health‐Related Quality of Life for 8–10‐year‐olds (COHRQoL [8–10]) using confirmatory factor analysis (CFA) and to test the measurement properties of latent variables believed to define the multidimensional construct of OHRQoL.

Methods:  A convenience sample of 270, year 4 children from six schools was obtained. The administered questionnaire included the 25‐item COHRQoL [8–10] and the Coopersmith Self‐Esteem Inventory‐School Form. The analytical method was based upon CFA using maximum likelihood estimation. A second‐order factoring approach was applied to determine the extent that the latent variables tapped a single over‐arching domain of quality of life.

Results:  Seven items were withdrawn for low endorsement and poor association with resultant factors. The COHRQoL [8–10] was confirmed to measure a single construct of three latent variables invariant to gender. Internal consistency of the three scales derived comprising a total of 18 retained items was acceptable. Associations with self‐esteem and with a single question on the extent that the mouth was a problem were confirmed and strengthened the construct validity of the COHRQoL [8–10] measure.

Conclusions:  Reliability and construct validity were demonstrated for COHRQoL [8–10] and supported the scale for adoption as an epidemiological and scientific tool for group comparisons. CFA showed that the three constructs or latent variables underlying the overall COHRQoL ratings were discrete measures that can be reliably assessed in children. Further model testing with additional data will increase generalization of these findings.
Discrimination of functional capacity for oral hygiene in elderly Spanish people by the Barthel General Index
Authors: Ruiz‐Medina Pilar , Bravo Manuel , Gil‐Montoya José Antonio , Montero Javier
Published: August 2005

Abstract –  Objectives:  To explore, among the institutionalized elderly in Spain, the association between functional dependence in manipulating aids used in oral self‐care (oral hygiene dependence) and general functional capacities, as measured by the Index of Activities of Daily Oral Hygiene (ADOH) and the Barthel Index (BI), respectively.

Methods:  A cross‐sectional study was performed in 2002 on 390 Spanish residents of a residential home for the elderly aged, 65–101 years. All study subjects underwent a oral examination and their ADOH and BI scores assessed. The association between the index scores was studied and the discriminant capacity of BI for oral hygiene dependence was calculated.

Results:  The mean number of decayed, missing, or filled permanent teeth (±SD) was 26.6 ± 7.3. The mean BI score was 68.31 (95% CI 64.35–72.27), and 172 individuals (44.1%; 95% CI 39.2–49.0%) were independent in all BI‐measured functions. The mean ADOH score was 2.43 (95% CI 2.11–2.75), and 238 individuals (61.0%; 95% CI 56.2–65.9%) were independent for oral hygiene, 39 (10.0%; 95% CI 7.2–13.4%) required assistance (assistive devices), and 113 (29.0%; 95% CI 24.5–33.5%) were completely dependent. The BI scores were significantly correlated with the ADOH scores (r = −0.80, P < 0.001). The BI showed a high discriminant capacity to identify the individuals who were dependent for oral hygiene in this population (area under the ROC curve ± SE = 0.929 ± 0.013). Using the optimal cut‐off point according to the Youden Index (<61), the sensitivity was 0.87 ± 0.03 and specificity 0.87 ± 0.02.

Conclusion:  There is a close association between BI and ADOH in this population, which could be useful to identify elderly individuals who are dependent for oral hygiene.
Periodontal health and oral mucosal lesions as related to occupational exposure to acid mists
Authors: Vianna Maria Isabel Pereira , Santana Vilma Sousa , McKelvey Wendy
Published: August 2005

Abstract –  Objectives:  The association between exposure to acid mists and periodontal changes and oral mucosal lesions was measured using data from an Oral Health Promotion Program in a large metal plant. The role of sociodemographic factors, lifestyle, and oral health behavior in relation to these outcomes was also examined.

Methods:  This is a cross‐sectional study of 665 active male workers who volunteered to participate in the oral health program. A job exposure matrix was constructed with industrial hygienist scores and job titles to estimate years of exposure to acid mists. Oral health outcomes were identified during standardized dental examinations. Unconditional logistic regression models were utilized in the analysis.

Results:  Duration of exposure to acid mists exposure was positively associated with oral mucosal lesions among workers without lip sealing. Only age, low salaries and oral hygiene‐related variables were associated with periodontal changes, and estimates varied according to lip sealing.

Conclusions:  Results suggest that long‐term occupational exposure to acid mists is associated with oral mucosal lesions, and that absence of lip sealing may increase the intensity of exposure.
“Voices of the broken body.” The resumption of non‐professional female players' sports careers after anterior cruciate ligament injury. The female player's dilemma: is she willing to run the risk?
Authors: Thing L. F.
Published: August 2005

The article takes as its starting point the lived experiences of female sports patients in rehabilitation. The research data are semi‐structured qualitative interviews (N=17) with non‐professional female players as patients, having anterior cruciate ligament injuries (ACL‐injuries). Injury narratives have been conducted, with a focus upon how female handball players managed the injured situation. Ethnographic research was taken in a private physiotherapy clinic over a period of more than 1 ½ years. The narratives show the impact of risk management – the individual coping strategy of the players. The handball her‐player has choices to make regarding the resumption of the career. The options and possibilities of playing or not playing after an ACL‐injury are connected to the trust in the capacity of the body. The concept of bodily risk reflexive coping strategy is constructed to understand the question of the resumption of the career. The individualistic self‐care management indicates a manageable body with a desire to act as worthy of being a full part of the sporting society. This strategy is adding to the sense of accomplishment and to the continuing development of self‐identity. The study shows that there is a need for guidance in the injury process. Playing is connected with pleasurable feelings and excitements, but the her‐player does care for the bodily self and her risk assessment is so far not a “misuse” or a consumption of sports medicine in the name of sporting achievements.
A Novel Mammalian Retromer Component, Vps26B
Authors: Kerr Markus C. , Bennetts Jennifer S. , Simpson Fiona , Thomas Elaine C. , Flegg Cameron , Gleeson Paul A. , Wicking Carol , Teasdale Rohan D.
Published: August 2005

The mammalian retromer protein complex, which consists of three proteins – Vps26, Vps29, and Vps35 – in association with members of the sorting nexin family of proteins, has been implicated in the trafficking of receptors and their ligands within the endosomal/lysosomal system of mammalian cells. A bioinformatic analysis of the mouse genome identified an additional transcribed paralog of the Vps26 retromer protein, which we termed Vps26B. No paralogs were identified for Vps29 and Vps35. Phylogenetic studies indicate that the two paralogs of Vps26 become evident after the evolution of the chordates. We propose that the chordate Vps26‐like gene published previously be renamed Vps26A to differentiate it from Vps26B. As for Vps26A, biochemical characterization of Vps26B established that this novel 336 amino acid residue protein is a peripheral membrane protein. Vps26B co‐precipitated with Vps35 from transfected cells and the direct interaction between these two proteins was confirmed by yeast 2‐hybrid analysis, thereby establishing Vps26B as a subunit of the retromer complex. Within HeLa cells, Vps26B was found in the cytoplasm with low levels at the plasma membrane, while Vps26A was predominantly associated with endosomal membranes. Within A549 cells, both Vps26A and Vps26B co‐localized with actin‐rich lamellipodia at the cell surface. These structures also co‐localized with Vps35. Total internal reflection fluorescence microscopy confirmed the association of Vps26B with the plasma membrane in a stable HEK293 cell line expressing cyan fluorescent protein (CFP)‐Vps26B. Based on these observations, we propose that the mammalian retromer complex is located at both endosomes and the plasma membrane in some cell types.
Do custom‐made mouth guards have negative effects on aerobic performance capacity of athletes?
Authors: Keçeci Ayşe Diljin , Çetin Cem , Eroǧlu Erdal , Baydar Metin Lütfi
Published: August 2005

Abstract –  Mouth guards are considered an essential part of equipment for athletes participating in contact sports. The purpose of this study was to evaluate the effect of custom‐made mouth guards on the ventilatory gas exchange effects of taekwondo athletes. The subjects were 22 elite athletes aged between 14 and 17 years. To determine the effect of mouth guard use during exercise, oxygen consumption (VO2) was measured with a portable gas analysis system while an exercise tolerance test with a shuttle run test protocol was performed. Values with and without mouth guard were compared. Wilcoxon ranks test was used for the statistical analysis. The results show that wearing mouth guards has no significant effect on maximal oxygen uptake (VO2max), minute ventilation (VE), tidal volume (VT) and respiratory exchange ratio (RER) while performing maximal exercise (P > 0.05). In conclusion, taekwondo athletes can use custom‐made mouth guards without negative effects on their aerobic performance capacity.
Diabetic embryopathy: Studies using a rat embryo culture system and an animal model
Authors: Akazawa Shoichi
Published: August 2005

ABSTRACT  The mechanism of diabetic embryopathy was investigated using in vitro experiments in a rat embryo culture system and in streptozotocin‐induced diabetic pregnant rats. The energy metabolism in embryos during early organogenesis was characterized by a high rate of glucose utilization and lactic acid production (anaerobic glycolysis). Embryos uninterruptedly underwent glycolysis. When embryos were cultured with hypoglycemic serum, such embryos showed malformations in association with a significant reduction in glycolysis.

In a diabetic environment, hyperglycemia caused an increased glucose flux into embryonic cells without a down‐regulation of GLUT1 and an increased metabolic overload on mitochondria, leading to an increased formation of reactive oxygen species (ROS). Activation of the hexamine pathway, subsequently occurring with increased protein carbonylation and increased lipid peroxidation, also contributed to the increased generation of ROS. Hyperglycemia also caused a myo‐inositol deficiency with a competitive inhibition of ambient glucose, which might have been associated with a diminished phosphoinositide signal transduction. In the presence of low activity of the mitochondrial oxidative glucose metabolism, the ROS scavenging system in the embryo was not sufficiently developed. Diabetes further weakened the antioxidant system, especially, the enzyme for GSH synthesis, γ‐GCS, thereby reducing the GSH concentration. GSH depletion also disturbed prostaglandin biosynthesis. An increased formation of ROS in a diminished GSH‐dependent antioxidant system may, therefore, play an important role in the development of embryonic malformations in diabetes.
Population‐based case–control study of mebendazole in pregnant women for birth outcomes
Authors: Ács Nándor , Bánhidy Ferenc , Puhó Erzsébet , Czeizel Andrew E.
Published: August 2005

ABSTRACT  The objectives of the study was to check the embryotoxic‐teratogenic and fetotoxic effect of mebendazole (Vermox; Richter, Budapest, Hungary) treatment during pregnancy. Mebendazole use during pregnancy was evaluated in mothers of babies born with congenital abnormalities and in matched control mothers of babies born without congenital abnormalities in the population‐based data set of the Hungarian Case–Control Surveillance of Congenital Abnormalities between 1980 and 1996.

Of 22 843 women who had newborns or fetuses with congenital abnormalities, 14 were found to have been treated with mebendazole for intestinal nematoda infections/diseases during pregnancy (crude POR: 1.8 with 95% CI: 0.7–4.2). Of 38 151 women who had newborns without any defects (controls), the same number (14) were found to have been treated with mebendazole during pregnancy. Six different congenital abnormality groups were evaluated and a higher prevalence of mebendazole use in these mothers throughout pregnancy was not found. Gestational age and birth weight were analyzed in control infants born to mothers with or without mebendazole treatment.  The  mean  gestational  age  was  somewhat  longer  and mean birth weight was larger in newborn infants born to mothers with mebendazole treatment. Thus, treatment with mebendazole during pregnancy did not indicate a teratogenic and fetotoxic risk to the embryo or fetus, though the numbers of treated cases and controls in this study were limited.
Iniencephaly and chromosome mosaicism: A report of two cases
Authors: Halder Ashutosh , Agarwal Savita , Pandey Amita
Published: August 2005

ABSTRACT  We report here two iniencephaly fetuses with chromosome mosaicism. The first fetus (22 weeks) was male with mosaic trisomy 13, and the second fetus (24 weeks) was female with mosaic monosomy X. The first fetus had anencephaly, facial clefting, left‐sided rocker bottom foot, equinovarous deformity, bilateral simian crease of hands and horseshoe kidney in addition to iniencephaly. The second fetus had hydrops fetalis with cystic hygroma in addition to iniencephaly. Because the fetuses were sent in formalin, conventional chromosomal analysis was not possible in spite of strong indication. Interphase fluorescence in situ hybridization (FISH) was carried out for targeted aneuploidy analysis. This is fourth published report of chromosomal abnormality in iniencephaly.
Probing the determinants of substrate specificity of a feruloyl esterase, AnFaeA, from Aspergillus niger
Authors: Faulds Craig B. , Molina Rafael , Gonzalez Ramón , Husband Fiona , Juge Nathalie , Sanz‐Aparicio Julia , Hermoso Juan A.
Published: August 2005

Feruloyl esterases hydrolyse phenolic groups involved in the cross‐linking of arabinoxylan to other polymeric structures. This is important for opening the cell wall structure making material more accessible to glycoside hydrolases. Here we describe the crystal structure of inactive S133A mutant of type‐A feruloyl esterase from Aspergillus niger (AnFaeA) in complex with a feruloylated trisaccharide substrate. Only the ferulic acid moiety of the substrate is visible in the electron density map, showing interactions through its OH and OCH3 groups with the hydroxyl groups of Tyr80. The importance of aromatic and polar residues in the activity of AnFaeA was also evaluated using site‐directed mutagenesis. Four mutant proteins were heterologously expressed in Pichia pastoris, and their kinetic properties determined against methyl esters of ferulic, sinapic, caffeic and p‐coumaric acid. The kcat of Y80S, Y80V, W260S and W260V was drastically reduced compared to that of the wild‐type enzyme. However, the replacement of Tyr80 and Trp260 with smaller residues broadened the substrate specificity of the enzyme, allowing the hydrolysis of methyl caffeate. The role of Tyr80 and Trp260 in AnFaeA are discussed in light of the three‐dimensional structure.
Acute activation of Erk1/Erk2 and protein kinase B/akt proceed by independent pathways in multiple cell types
Authors: Chiu Doris , Ma Kewei , Scott Alexander , Duronio Vincent
Published: August 2005

We used two inhibitors of the signaling enzyme phosphatidylinositol 3‐kinase (PtdIns3K), wortmannin and LY294002, to evaluate the potential involvement of PtdIns3K in the activation of the MAP kinases (MAPK), Erk1 and Erk2. In dose–response studies carried out on six different cell lines and a primary cell culture, we analyzed the ability of the inhibitors to block phosphorylation of protein kinase B/akt (PKB/akt) at Ser473 as a measure of PtdIns3K activity, or the phosphorylation of Erk1/2 at activating Thr/Tyr sites as a measure of the extent of activation of MAPK/Erk kinase (MEK/Erk). In three different hemopoietic cell lines stimulated with cytokines, and in HEK293 cells, stimulated with serum, either wortmannin or LY294002, but never both, could partially block phosphorylation of Erks. The same observations were made in a B‐cell line and in primary fibroblasts. In only one cell type, the A20 B cells, was there a closer correlation between the PtdIns3K inhibition by both inhibitors, and their corresponding effects on Erk phosphorylation. However, this stands out as an exception that gives clues to the mechanism by which cross‐talk might occur. In all other cells, acute activation of the pathway leading to Erk phosphorylation could proceed independently of PtdIns3K activation. In a biological assay comparing these two pathways, the ability of LY294002 and the MEK inhibitor, U0126, to induce apoptosis were tested. Whereas LY294002 caused death of cytokine‐dependent hemopoietic cells, U0126 had little effect, but both inhibitors together had a synergistic effect. The data show that these two pathways are regulating very different downstream events involved in cell survival.
Hyperactive antifreeze protein in flounder species
Authors: Gauthier Sherry Y. , Marshall Christopher B. , Fletcher Garth L. , Davies Peter L.
Published: August 2005

The recent discovery of a large hyperactive antifreeze protein in the blood plasma of winter flounder has helped explain why this fish does not freeze in icy seawater. The previously known, smaller and much less active type I antifreeze proteins cannot by themselves protect the flounder down to the freezing point of seawater. The relationship between the large and small antifreezes has yet to be established, but they do share alanine‐richness (> 60%) and extensive α‐helicity. Here we have examined two other righteye flounder species for the presence of the hyperactive antifreeze, which may have escaped prior detection because of its lability. Such a protein is indeed present in the yellowtail flounder judging by its size, amino acid composition and N‐terminal sequence, along with the previously characterized type I antifreeze proteins. An ortholog is also present in American plaice based on the above criteria and its high specific antifreeze activity. This protein was purified and shown to be almost fully α‐helical, highly asymmetrical, and susceptible to denaturation at room temperature. It is the only detectable antifreeze protein in the blood plasma of the American plaice. Because this species appears to lack the smaller type I antifreeze proteins, the latter may have evolved by descent from the larger antifreeze.
Second messenger function and the structure–activity relationship of cyclic adenosine diphosphoribose (cADPR)
Authors: Guse Andreas H.
Published: August 2005

Cyclic ADP‐ribose (cADPR) is a Ca2+ mobilizing second messenger found in various cell types, tissues and organisms. Receptor‐mediated formation of cADPR may proceed via transmembrane shuttling of the substrate NAD and involvement of the ectoenzyme CD38, or via so far unidentified ADP‐ribosyl cyclases located within the cytosol or in internal membranes. cADPR activates intracellular Ca2+ release via type 2 and 3 ryanodine receptors. The exact molecular mechanism, however, remains to be elucidated. Possibilities are the direct binding of cADPR to the ryanodine receptor or binding via a separate cADPR binding protein. In addition to Ca2+ release, cADPR also evokes Ca2+ entry. The underlying mechanism(s) may comprise activation of capacitative Ca2+ entry and/or activation of the cation channel TRPM2 in conjunction with adenosine diphosphoribose. The development of novel cADPR analogues revealed new insights into the structure–activity relationship. Substitution of either the northern ribose or both the northern and southern ribose resulted in much simpler molecules, which still retained significant biological activity.
Poly(ADP‐ribose)
Authors: Bürkle Alexander
Published: August 2005

One of the most drastic post‐translational modification of proteins in eukaryotic cells is poly(ADP‐ribosyl)ation, catalysed by a family enzymes termed poly(ADP‐ribose) polymerases (PARPs). In the human genome, 18 different genes have been identified that all encode PARP family members. Poly(ADP‐ribose) metabolism plays a role in a wide range of biological structures and processes, including DNA repair and maintenance of genomic stability, transcriptional regulation, centromere function and mitotic spindle formation, centrosomal function, structure and function of vault particles, telomere dynamics, trafficking of endosomal vesicles, apoptosis and necrosis. In this article, the most recent advances in this rapidly growing field are summarized.
Tet repressor mutants with altered effector binding and allostery
Authors: Henßler Eva‐Maria , Bertram Ralph , Wisshak Stefanie , Hillen Wolfgang
Published: August 2005

To learn about the correlation between allostery and ligand binding of the Tet repressor (TetR) we analyzed the effect of mutations in the DNA reading head–core interface on the effector specific TetRi2 variant. The same mutations in these subdomains can lead to completely different activities, e.g. the V99G exchange in the wild‐type leads to corepression by 4‐ddma‐atc without altering DNA binding. However, in TetRi2 it leads to 4‐ddma‐atc dependent repression in combination with reduced DNA binding in the absence of effector. The thermodynamic analysis of effector binding revealed decreased affinities and positive cooperativity. Thus, mutations in this interface can influence DNA binding as well as effector binding, albeit both ligand binding sites are not in direct contact to these altered residues. This finding represents a novel communication mode of TetR. Thus, allostery may not only operate by the structural change proposed on the basis of the crystal structures.
The Effects of Superoxide Anion Generators on Responses to Exogenous Nitric Oxide and Non‐Adrenergic, Non‐Cholinergic Nerve Stimulation in Rat Isolated Penile Bulb
Authors: Ozakman Selda , Uma Serdar
Published: August 2005

Abstract: The effects of the superoxide anion generators, pyrogallol and hydroquinone on relaxations induced by electrical field stimulation (70 V, 0.7 msec., 0.5–8 Hz for 5 sec.) and exogenous nitric oxide donor sodium nitroprusside, were investigated in rat penile bulb precontracted with phenylephrine (10−4 M). Pyrogallol (10−4 M, 3×10−4 M) and hydroquinone (3×10−4 M) reduced the relaxations induced by sodium nitroprusside, but had no effect on relaxations elicited by nitrergic nerve stimulation. After treatment with diethyldithiocarbamate (3×10−3 M), an inhibitor of Cu/Zn superoxide dismutase, both agents reduced the relaxations induced by electrical field stimulation. Superoxide dismutase, at 300 U/ml, significantly reversed the inhibitory action of pyrogallol and hydroquinone on responses to sodium nitroprusside. This concentration of superoxide dismutase failed to reverse the inhibitory action of pyrogallol on responses to electrical field stimulation observed in the presence of diethyldithiocarbamate, while at 600 U/ml it significantly prevented the reduction in relaxations. However, even at 600 U/ml, superoxide dismutase did not alter the decrease in responses to electrical field stimulation evoked by hydroquinone in tissues pretreated with diethyldithiocarbamate. These results suggest that the nitrergic transmitter in rat penile bulb is protected against superoxide anions by endogenous Cu/Zn superoxide dismutase in a manner similar to gastric fundus and anococcygeus muscles.
An Antithrombotic Agent, NQ301, Inhibits Thromboxane A2 Receptor and Synthase Activity in Rabbit Platelets
Authors: Jin Yong‐Ri , Cho Mi‐Ra , Lee Kyung‐Sup , Lee Jung‐Jin , Lim Yong , Han Xiang‐Hua , Oh Ki‐Wan , Hong Jin‐Tae , Yoo Hwan‐Soo , Yun Yeo‐Pyo
Published: August 2005

Abstract: In previous studies we have reported that NQ301, a synthetic 1,4‐naphthoquinone derivative, displays a potent antithrombotic activity, and that this might be due to antiplatelet effect, which was mediated by the inhibition of cytosolic Ca2+ mobilization in activated platelets. In the present study, the effect of NQ301 on arachidonic acid cascade in activated platelets has been examined. NQ301 concentration‐dependently inhibited washed rabbit platelet aggregation induced by collagen (10 μg/ml), arachidonic acid (100 μM) and U46619 (1 μM), a thromboxane A2 receptor agonist, with IC50 values of 0.60±0.02, 0.78±0.04 and 0.58±0.04 μM, respectively. NQ301 also produced a shift to the right of the concentration‐effect curve of U46619, indicating a competitive type of antagonism on thromboxane A2/prostaglandin H2 receptor. NQ301 slightly inhibited collagen‐induced arachidonic acid liberation. In addition, NQ301 potently suppressed thromboxane B2 formation by platelets that were exposed to arachidonic acid in a concentration‐dependent manner, but had no effect on the production of prostaglandin D2, indicating an inhibitory effect on thromboxane A2 synthase. This was supported by thromboxane A2 synthase activity assay that NQ301 concentration‐dependently inhibited thromboxane B2 formation converted from prostaglandin H2. Moreover, NQ301 concentration‐dependently inhibited 12‐hydroxy‐5,8,10,14‐eicosatetraenoic acid formation by platelets that were exposed to arachidonic acid. Taken together, these results suggest that NQ301 has a potential to inhibit thromboxane A2 synthase activity with thromboxane A2/prostaglandin H2 receptor blockade, and modulate arachidonic acid liberation as well as 12‐hydroxy‐5,8,10,14‐eicosatetraenoic acid formation in platelets. This may also be a convincing mechanism for the antithrombotic action of NQ301.
Assessment of CYP1A2 Activity in Clinical Practice: Why, How, and When?
Authors: Faber Mirko S. , Jetter Alexander , Fuhr Uwe
Published: August 2005

Abstract: The cytochrome P450 enzyme CYP1A2 mediates the rate‐limiting step in the metabolism of many drugs including theophylline, clozapine, and tacrine as well as in the bioactivation of procarcinogens. CYP1A2 activity shows both pronounced intra‐ and interindividual variability, which is, among other factors, related to smoking causing enzyme induction, to drug intake and to dietary factors which may result in induction or inhibition. In contrast to these exogenous factors, genetic influences on enzyme activity seem to be less pronounced. Therefore, phenotyping of CYP1A2, i.e. the determination of the actual activity of the enzyme in vivo, represents a useful approach both for scientific and clinical applications. CYP1A2 is almost exclusively expressed in the liver. Since liver tissue cannot be obtained for direct phenotyping, a probe drug which is metabolized by CYP1A2 has to be given. Proposed probe drugs include caffeine, theophylline, and melatonin. Caffeine is most often used because of the predominating role of CYP1A2 in its overall metabolism and the excellent tolerability. Various urinary, plasma, saliva, and breath based CYP1A2 caffeine metrics have been applied. While caffeine clearance is considered as the gold standard, the salivary or plasma ratio of paraxanthine to caffeine in a sample taken approximately 6 hr after a defined dose of caffeine is a more convenient, less expensive but also fully validated CYP1A2 phenotyping metric. CYP1A2 phenotyping is applied frequently in epidemiologic and drug‐drug interaction studies, but its clinical use and usefulness remains to be established.
Consumption of Charcoal‐Broiled Meat as an Experimental Tool for Discerning CYP1A2‐Mediated Drug Metabolism in vivo
Authors: Larsen John Teilmann , Brøsen Kim
Published: August 2005

Abstract: Cytochrome P450 1A2 (CYP1A2) is a major drug‐metabolising enzyme. Polycyclic aromatic hydrocarbons, present in high concentrations in tobacco smoke and charcoal‐broiled meat, are known to induce CYP1A2. The purpose of the present study was to validate enzyme induction by consumption of charcoal‐broiled meat as an experimental tool for discerning CYP1A2‐mediated drug metabolism in vivo. Twenty‐four healthy, non‐smoking men, all extensive metabolisers of sparteine (CYP2D6), participated in the study. All participants were genotyped for a putative CYP1A2‐inducibility genotype. In the study diet period charcoal‐broiled meat was served for lunch and dinner for five consecutive days. All participants were tested with probe reactions for CYP1A2 (caffeine) and CYP2C19 (proguanil) before and after consuming the study diet. Further, in three subgroups, they were tested with either the CYP1A2‐substrate tacrine or probe reactions for CYP3A4 (quinidine) or CYP2C9 (tolbutamide). Neither probe reactions for CYP1A2, CYP2C9, CYP2C19 or CYP3A4 were affected by consumption of charcoal‐broiled meat as practised in this study. No modifying role of the CYP1A2‐inducibility genotype was evident. A number of experimental limitations are discussed, among them the lack of standardisation of exposure, the timing of phenotyping, and the choice of probe reactions. In conclusion, consumption of charcoal‐broiled meat as practised in the present study appears not to be a useful experimental tool for discerning CYP1A2‐mediated metabolism in vivo.
Open‐Field Behavioural Alterations in Liver‐Impaired and Sham‐Operated Rats after Acute Exposure to the Antidepressant Venlafaxine
Authors: Kugelberg Fredrik C. , Apelqvist Gustav , Wikell Cecilia , Bengtsson Finn
Published: August 2005

Abstract: Patients with chronic liver impairment often display symptoms of affective psychiatric nature where the choice for antidepressant treatment is rational. Since caution is recommended when these drugs are used in such patients, a dose reduction is usually performed. We have previously reported that a dose reduction to liver‐impaired portacaval shunted rats has resulted in similar brain concentrations of venlafaxine as compared to sham‐operated control rats that received a two times higher dose. The main aim of the present study was therefore to investigate if this “normalisation” in pharmacokinetics of the portacaval‐shunted rats also was true for the pharmacodynamic response in terms of drug effect on spontaneous open‐field behaviour. Thus, portacaval‐shunted rats received a single reduced dose (5 mg/kg) of venlafaxine or saline, whereas sham‐operated rats received either 10 mg/kg or saline. Thereafter, central and peripheral arena locomotor and rearing activities were recorded during 60 min. The venlafaxine‐treated portacaval‐shunted and sham rats displayed reduced and unchanged overall behavioural activities compared with corresponding controls, respectively. However, the ratios between centrally and peripherally performed behavioural activities were higher in the venlafaxine‐treated sham rats, indicating an increase in central arena activity as compared to the sham‐saline and portacaval‐shunted rats. The present study indicates that, despite a 50% dose reduction, caution still is necessary when antidepressants are used in liver insufficient subjects. This study also shows the importance of detailed open‐field behavioural studies in which both central and peripheral activities are recorded for measurement of open‐field behavioural drug effects.
Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with ISA‐like properties
Authors: Jerng Henry H. , Kunjilwar Kumud , Pfaffinger Paul J.
Published: August 2005

Kv4 pore‐forming subunits are the principal constituents of the voltage‐gated K+ channel underlying somatodendritic subthreshold A‐type currents (ISA) in neurones. Two structurally distinct types of Kv4 channel modulators, Kv channel‐interacting proteins (KChIPs) and dipeptidyl‐peptidase‐like proteins (DPLs: DPP6 or DPPX, DPP10 or DPPY), enhance surface expression and modify functional properties. Since KChIP and DPL distributions overlap in the brain, we investigated the potential coassembly of Kv4.2, KChIP3 and DPL proteins, and the contribution of DPLs to ternary complex properties. Immunoprecipitation results show that KChIP3 and DPP10 associate simultaneously with Kv4.2 proteins in rat brain as well as heterologously expressing Xenopus oocytes, indicating Kv4.2 + KChIP3 + DPP10 multiprotein complexes. Consistent with ternary complex formation, coexpression of Kv4.2, KChIP3 and DPP10 in oocytes and CHO cells results in current waveforms distinct from the arithmetic sum of Kv4.2 + KChIP3 and Kv4.2 + DPP10 currents. Furthermore, the Kv4.2 + KChIP3 + DPP10 channels recover from inactivation very rapidly (τrec∼18–26 ms), closely matching that of native ISA and significantly faster than the recovery of Kv4.2 + KChIP3 or Kv4.2 + DPP10 channels. For comparison, identical triple coexpression experiments were performed using DPP6 variants. While most results are similar, the Kv4.2 + KChIP3 + DPP6 channels exhibit inactivation that slows with increasing membrane potential, resulting in inactivation slower than that of Kv4.2 + KChIP3 + DPP10 channels at positive voltages. In conclusion, the native neuronal subthreshold A‐type channel is probably a macromolecular complex formed from Kv4 and a combination of both KChIP and DPL proteins, with the precise composition of channel α and auxiliary subunits underlying tissue and regional variability in ISA properties.
Transient cutaneous vasodilatation and hypotension after drinking in dehydrated and exercising men
Authors: Kamijo Yoshi‐Ichiro , Okumoto Tadashi , Takeno Yoshiaki , Okazaki Kazunobu , Inaki Mitsuharu , Masuki Shizue , Nose Hiroshi
Published: August 2005

We examined whether oropharyngeal stimulation by drinking released the dehydration‐induced suppression of cutaneous vasodilatation and decreased mean arterial pressure (MAP) in exercising subjects, and assessed the effects of hypovolaemia or hyperosmolality alone on these responses. Seven young males underwent four hydration conditions. These were two normal plasma volume (PV) trials: normal plasma osmolality (Posmol, control trial) and hyperosmolality (ΔPosmol=+11 mosmol (kg H2O)−1); and two low PV trials: isosmolality (ΔPV =−310 ml) and hyperosmolality (ΔPV =−345 ml; ΔPosmol=+9 mosmol (kg H2O)−1), attained by combined treatment with furosemide (frusemide), hypertonic saline and/or 24 h water restriction. In each trial, the subjects exercised at 60% peak aerobic power for ∼50 min at 30°C atmospheric temperature and 50% relative humidity. When oesophageal temperature (Toes) reached a plateau after ∼30 min of exercise, the subjects drank 200 ml water at 37.5°C within a minute. Before drinking, forearm vascular conductance (FVC), calculated as forearm blood flow divided by MAP, was lowered by 20–40% in hypovolaemia, hyperosmolality, or both, compared with that in the control trial, despite increased Toes. After drinking, FVC increased by ∼20% compared with that before drinking (P < 0.05) in both hyperosmotic trials, but it was greater in normovolaemia than in hypovolaemia (P < 0.05). However, no increases occurred in either isosmotic trial. MAP fell by 4–8 mmHg in both hyperosmotic trials (P < 0.05) after drinking, but more rapidly in normovolaemia than in hypovolaemia. PV and Posmol did not change during this period. Thus, oropharyngeal stimulation by drinking released the dehydration‐induced suppression of cutaneous vasodilatation and reduced MAP during exercise, and this was accelerated when PV was restored.
Single channel properties of hyperpolarization‐activated cation currents in acutely dissociated rat hippocampal neurones
Authors: Simeone T. A. , Rho J. M. , Baram T. Z.
Published: August 2005

The hyperpolarization‐activated cation current (Ih), mediated by HCN channels, contributes to intrinsic neuronal properties, synaptic integration and network rhythmicity. Recent studies have implicated HCN channels in neuropathological conditions including epilepsy. While native HCN channels have been studied at the macroscopic level, the biophysical characteristics of individual neuronal HCN channels have not been described. We characterize, for the first time, single HCN currents of excised inside‐out patches from somata of acutely dissociated rat hippocampal CA1 pyramidal cells. Hyperpolarization steps elicited non‐inactivating channel openings with an apparent conductance of 9.7 pS, consistent with recent reports of native and recombinant HCN channels. The voltage‐dependent Po had a V1/2 of −81 ± 1.8 mV and slope −13.3 ± 1.9 mV. Blockers of macroscopic Ih, ZD7288 (50 μm) and CsCl (1 mm), reduced the channel conductance to 8 pS and 8.4 pS, respectively. ZD7288 was slightly more effective in reducing the Po at depolarized potentials, whereas CsCl was more efficacious at hyperpolarized potentials. The unitary neuronal HCN channels had voltage‐dependent latencies to first channel opening and two open states. As expected, ZD7288 and CsCl increased latencies and decreased the properties of both open states. The major endogenous positive modulator of macroscopic Ih is cAMP. Application of 8Br‐cAMP (10 μm) did not affect conductance (9.4 pS), but did increase Po and short and long open times. Thus, sensitivity to Ih modulators supports the single h‐channel identity of these unitary currents. Detailed biophysical analysis of unitary Ih conductances is likely to help distinguish between homomeric and heteromeric expression of these channels – findings that may be relevant toward the pathophysiology of diseases such as epilepsy.
Involvement of Src tyrosine kinase and mitogen‐activated protein kinase in the facilitation of calcium channels in rat nucleus of the tractus solitarius by angiotensin II
Authors: Endoh Takayuki
Published: August 2005

It is recognized that brain contains all the components of the renin–angiotensin systems (RAS). The nucleus of the tractus solitarius (NTS) is known to play a major role in the regulation of cardiovascular, respiratory, gustatory, hepatic and swallowing functions. Voltage‐dependent Ca2+ channels (VDCCs) serve as crucial mediators of membrane excitability and Ca2+‐dependent functions such as neurotransmitter release, enzyme activity and gene expression. The purpose of this study was to investigate the effects of angiotensin II (Ang II) on VDCC currents (ICa) in the NTS using patch‐clamp recording methods. An application of Ang II caused facilitation of L‐type ICa in a concentration‐dependent manner with an EC50 of 167 nm and a Hill coefficient of 1.73. AT1 receptor antagonist losartan antagonized the Ang II‐induced facilitation of ICa. Intracellular dialysis of the Gαi‐protein antibody attenuated the Ang II‐induced facilitation of ICa. Both Src tyrosine kinase inhibitor and mitogen‐activated protein kinase (MAPK) inhibitor attenuated the Ang II‐induced facilitation of ICa. p38 MAPK inhibitor also attenuated the Ang II‐induced facilitation of ICa. These results indicate that Ang II facilitates L‐type VDCCs via Gαi‐proteins involving Src tyrosine kinase and p38 MAPK kinase mediated by AT1 receptors in NTS.
Vesicles in snake motor terminals comprise one functional pool and utilize a single recycling strategy at all stimulus frequencies
Authors: Lin Michael Y. , Teng Haibing , Wilkinson Robert S.
Published: August 2005

At a variety of fast chemical synapses, spent synaptic vesicles are recycled via a large ‘reserve’ vesicle pool at high stimulus frequencies, and via fast ‘local cycling’ near release sites (e.g. ‘kiss and run’ transmitter release) at low stimulus frequencies. We have investigated recycling at the snake neuromuscular junction (NMJ), specifically seeking evidence for local cycling. Activity‐dependent staining and destaining of the endocytic probe FM1‐43 were directly compared to transmitter release over a range of stimulus frequencies. We found a fixed proportionality between staining/destaining and summed endplate potentials (EPPs) representing total transmitter release. There was no direct dependence of staining or destaining on stimulus frequency, as would be expected if local cycling (and consequent altered FM1‐43 retention) were more prevalent at one frequency than another. In other experiments the drug vesamicol was used to abolish refilling of vesicles with transmitter, thereby blocking EPPs contributed by recycled vesicles. Control and vesamicol‐treated NMJs had identical quantal content for the first 10 min of 1 Hz stimulation. Afterwards EPP amplitudes at vesamicol‐treated NMJs declined at a rate consistent with use of a large pool containing ∼130 000 vesicles. Finally, calibrated paired stimulations show that regenerated vesicles have poorer than random probability of re‐release. Our findings are inconsistent with local cycling and suggest that the snake motor terminal utilizes exclusively a single large vesicle pool.
Computers in Education: Activities, Contributions, and Future Trends
Authors: Khosrowjerdi Mohammad , Kinzel Gary L. , Rosen David W.
Published: August 2005

The Computers In Education (CIEd) technical committee focuses on educational issues and advances related to the usage of computing technologies in mechanical engineering courses and curricula. This paper provides a retrospective on CIEd activities, issues, and advances beginning with its formal start in 1983 and continuing through the present. Throughout the years, many different topics were explored, new technologies emerged while others disappeared, and many issues were investigated. Current CIEd activities are in six areas: CAD in higher education, robotics in higher education, software tools in the classroom, mechatronics and data acquisition, multimedia for higher education, and the role of the internet in higher education. The first four areas date from 1983, while the last two emerged in the late 1990’s. Future trends and issues are proposed to stimulate further investigations.
A Framework for Computational Design Synthesis: Model and Applications
Authors: Cagan Jonathan , Campbell Matthew I. , Finger Susan , Tomiyama Tetsuo
Published: August 2005

The field of computational design synthesis has been an active area of research for almost half a century. Research advances in this field have increased the sophistication and complexity of the designs that can be synthesized, and advances in the speed and power of computers have increased the efficiency with which those designs can be generated. Some of the results of this research have begun to be used in industrial practice, yet many open issues and research challenges remain. This paper provides a model of the automated synthesis process as a context to discuss research in the area. The varied works of the authors are discussed as representative of the breadth of methods and results that exist under the field of computational design synthesis. Furthermore, some guidelines are presented to help researchers and designers find approaches to solving their particular design problems using computational design synthesis.
Phenotypic Diversity, Population Growth, and Information in Fluctuating Environments
Authors: Kussell Edo , Leibler Stanislas
Published: August 2005

Organisms in fluctuating environments must constantly adapt their behavior to survive. In clonal populations, this may be achieved through sensing followed by response or through the generation of diversity by stochastic phenotype switching. Here we show that stochastic switching can be favored over sensing when the environment changes infrequently. The optimal switching rates then mimic the statistics of environmental changes. We derive a relation between the long-term growth rate of the organism and the information available about its fluctuating environment.
The Global Reach of the 26 December 2004 Sumatra Tsunami
Authors: Titov Vasily , Rabinovich Alexander B. , Mofjeld Harold O. , Thomson Richard E. , González Frank I.
Published: August 2005

Numerical model simulations, combined with tide-gauge and satellite altimetry data, reveal that wave amplitudes, directionality, and global propagation patterns of the 26 December 2004 Sumatra tsunami were primarily determined by the orientation and intensity of the offshore seismic line source and subsequently by the trapping effect of mid-ocean ridge topographic waveguides.