Showing papers by "Laval University published in 2002"

Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.

Abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. PARP-1 is also a mediator of cell death after ischemia-reperfusion injury, glutamate excitotoxicity, and various inflammatory processes. We show that PARP-1 activation is required for translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and that AIF is necessary for PARP-1–dependent cell death. N -methyl- N ′-nitro- N -nitrosoguanidine, H2O2, and N -methyl-d-aspartate induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP-1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP-1–dependent cytotoxicity. These data support a model in which PARP-1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.

Intravenous zoledronic acid in postmenopausal women with low bone mineral density.

Abstract: Background Bisphosphonates are effective agents for the management of osteoporosis. Their low bioavailability and low potency necessitate frequent administration on an empty stomach, which may reduce compliance. Gastrointestinal intolerance limits maximal dosing. Although intermittent intravenous treatments have been used, the optimal doses and dosing interval have not been systematically explored. Methods We studied the effects of five regimens of zoledronic acid, the most potent bisphosphonate, on bone turnover and density in 351 postmenopausal women with low bone mineral density in a one-year, randomized, double-blind, placebo-controlled trial. Women received placebo or intravenous zoledronic acid in doses of 0.25 mg, 0.5 mg, or 1 mg at three-month intervals. In addition, one group received a total annual dose of 4 mg as a single dose, and another received two doses of 2 mg each, six months apart. Lumbar-spine bone mineral density was the primary end point. Results There were similar increases in bone ...

Midthigh Muscle Cross-Sectional Area Is a Better Predictor of Mortality than Body Mass Index in Patients with Chronic Obstructive Pulmonary Disease

Abstract: This study was undertaken to test the hypothesis that a reduction in midthigh muscle cross-sectional area obtained by CT scan (MTCSACT) is a better predictor of mortality in chronic obstructive pulmonary disease (COPD) than low body mass index (BMI). We also wished to evaluate whether anthropometric measurements could be used to estimate MTCSACT. One hundred forty-two patients with COPD (age = 65 ± 9 years, mean ± SD, 26 F, BMI = 26 ± 6 kg/m2, FEV1 = 42 ± 16% predicted) were recruited from September 1995 to April 2000 with a mean follow-up of 41 ± 18 months. The primary end-point was all-cause mortality during the study period. A Cox proportional hazards regression model was used to predict mortality using the following independent variables: age, sex, daily use of corticosteroid, FEV1, DlCO, BMI, thigh circumference, MTCSACT, peak exercise workrate, PaO2, and PaCO2. Only MTCSACT and FEV1 were found to be significant predictors of mortality (p = 0.0008 and p = 0.01, respectively). A second analysis was al...

Innate immunity: the missing link in neuroprotection and neurodegeneration?

Abstract: Innate immunity was previously thought to be a nonspecific immunological programme that was engaged by peripheral organs to maintain homeostasis after stress and injury. Emerging evidence indicates that this highly organized response also takes place in the central nervous system. Through the recognition of neuronal fingerprints, the long-term induction of the innate immune response and its transition to an adaptive form might be central to the pathophysiology and aetiology of neurodegenerative disorders. Paradoxically, this response also protects neurons by favouring remyelination and trophic support afforded by glial cells.

Marriage Market, Divorce Legislation, and Household Labor Supply

Abstract: This paper provides a theoretical framework for analyzing the impact of the marriage market and divorce legislation on household labor supply. In our approach, the sex ratio in the marriage market and the rules governing divorce are examples of “distribution factors.” These factors are defined as variables that affect the household members’ bargaining position but not preferences or the joint budget set. We extend the collective labor supply model developed by Chiappori to allow for distribution factors. We show that our model imposes new restrictions on the labor supply functions and eases the identification of individual preferences and the intrahousehold decision process. The model is estimated using PSID data for the year 1988. Our results do not reject the restrictions imposed by the model. Also, the sex ratio and divorce laws deemed favorable to women are found to affect labor supply behavior and the decision process in the directions predicted by the theory and to have sizable effects.

Hybrid choice models : Progress and challenges

Abstract: We discuss the development of predictive choice models that go beyond the random utility model in its narrowest formulation. Such approaches incorporate several elements of cognitive process that have been identified as important to the choice process, including strong dependence on history and context, perception formation, and latent constraints. A flexible and practical hybrid choice model is presented that integrates many types of discrete choice modeling methods, draws on different types of data, and allows for flexible disturbances and explicit modeling of latent psychological explanatory variables, heterogeneity, and latent segmentation. Both progress and challenges related to the development of the hybrid choice model are presented.

The effect of sex, age and race on estimating percentage body fat from body mass index: The Heritage Family Study.

Abstract: Objective To study the effects of sex, age and race on the relation between body mass index (BMI) and measured percent body fat (%fat) Design Cross-sectional validation study of sedentary individuals Subjects The Heritage Family Study cohort of 665 black and white men and women who ranged in age from 17 to 65 y Measurements Body density determined from hydrostatic weighing Percentage body fat determined with gender and race-specific, two-compartment models BMI determined from height and weight, and sex and race in dummy coded form Results Polynomial regression showed that the relationship between %fat and BMI was quadratic for both men and women A natural log transformation of BMI adjusted for the non-linearity Test for homogeneity of log transformed BMI and gender showed that the male-female slopes were within random variance, but the intercepts differed For the same BMI, the %fat of females was 104% higher than that of males General linear models analysis of the women's data showed that age, race and race-by-BMI interaction were independently related to %fat The same analysis applied to the men's data showed that %fat was not just a function of BMI, but also age and age-by-BMI interaction Multiple regression analyses provided models that defined the bias Conclusions These data and results published in the literature show that BMI and %fat relationship are not independent of age and gender These data showed a race effect for women, but not men The failure to adjust for these sources of bias resulted in substantial differences in the proportion of subjects defined as obese by measured %fat

Synthesis of high performance PM motors with concentrated windings

Abstract: The windings concentrated around the teeth offer obvious advantages for the electrical machines with radial air-gap, because the volume of copper used in the end-windings can be reduced. The Joule losses are decreased, and the efficiency is improved. These machines are still limited to applications of sub-fractional power and they generally present a reduced number of phases. In the three-phase machines, the concentrated winding is too often restricted to a winding with a short pitch of 120 electrical degrees, i.e., to a winding with performances reduced compared to the traditional structures. But there is a significant number of three-phase structures which can support a concentrated winding if the number of poles is increased. In this article, the authors present a synthesis of the structures of three-phase machines with concentrated windings. (1) In the first part, the structures with a regular distribution of the slots are presented. A systematic method is proposed to determine the windings and the performances are discussed. (2) In the second part, the authors present original structures of three-phase machines with concentrated windings which use an irregular distribution of the slots. A specific method to identify these structures is described, and a comparative analysis of the performances of the original and traditional structures is performed by using a field calculation software.

N-Acylhomoserine Lactones Undergo Lactonolysis in a pH-, Temperature-, and Acyl Chain Length-Dependent Manner during Growth of Yersinia pseudotuberculosis and Pseudomonas aeruginosa

Abstract: In gram-negative bacterial pathogens, such as Pseudomonas aeruginosa and Yersinia pseudotuberculosis, cell-to-cell communication via the N-acylhomoserine lactone (AHL) signal molecules is involved in the cell population density-dependent control of genes associated with virulence. This phenomenon, termed quorum sensing, relies upon the accumulation of AHLs to a threshold concentration at which target structural genes are activated. By using biosensors capable of detecting a range of AHLs we observed that, in cultures of Y. pseudotuberculosis and P. aeruginosa, AHLs accumulate during the exponential phase but largely disappear during the stationary phase. When added to late-stationary-phase, cell-free culture supernatants of the respective pathogen, the major P. aeruginosa [N-butanoylhomoserine lactone (C4-HSL) and N-(3-oxododecanoyl)homoserine lactone (3-oxo-C12-HSL)] and Y. pseudotuberculosis [N-(3-oxohexanoyl)homoserine lactone (3-oxo-C6-HSL) and N-hexanoylhomoserine lactone (C6-HSL)] AHLs were inactivated. Short-acyl-chain compounds (e.g., C4-HSL) were turned over more extensively than long-chain molecules (e.g., 3-oxo-C12-HSL). Little AHL inactivation occurred with cell extracts, and no evidence for inactivation by specific enzymes was apparent. This AHL turnover was discovered to be due to pH-dependent lactonolysis. By acidifying the growth media to pH 2.0, lactonolysis could be reversed. By using carbon-13 nuclear magnetic resonance spectroscopy, we found that the ring opening of homoserine lactone (HSL), N-propionyl HSL (C3-HSL), and C4-HSL increased as pH increased but diminished as the N-acyl chain was lengthened. At low pH levels, the lactone rings closed but not via a simple reversal of the ring opening reaction mechanism. Ring opening of C4-HSL, C6-HSL, 3-oxo-C6-HSL, and N-octanoylhomoserine lactone (C8-HSL), as determined by the reduction of pH in aqueous solutions with time, was also less rapid for AHLs with more electron-donating longer side chains. Raising the temperature from 22 to 37°C increased the rate of ring opening. Taken together, these data show that (i) to be functional under physiological conditions in mammalian tissue fluids, AHLs require an N-acyl side chain of at least four carbons in length and (ii) that the longer the acyl side chain the more stable the AHL signal molecule.

Virological Features and Clinical Manifestations Associated with Human Metapneumovirus: A New Paramyxovirus Responsible for Acute Respiratory-Tract Infections in All Age Groups

Abstract: The virological features and clinical findings associated with the new human metapneumovirus (HMPV) were examined retrospectively in Canadian patients hospitalized for various respiratory conditions since 1993 Thirty-eight previously unidentified respiratory viruses isolated from rhesus monkey kindey (LLC-MK2) cells were found to be positive for HMPV by reverse-transcription polymerase chain reaction, and those strains clustered in 2 phylogenetic groups Children aged 65 years represented 351% and 459% of the HMPV-infected cases, respectively In hospitalized children, the most frequent diagnoses were pneumonitis (667%) and bronchiolitis (583%), whereas bronchitis and/or bronchospasm (60%) and pneumonitis (40%) were most commonly seen in elderly subjects Of the 15 patients with pneumonitis, 4 (267%) had immunosuppressive conditions and 6 (40%) were infants aged <15 months These findings suggest that HMPV can be associated with severe lower-respiratory-tract infections in very young children, the elderly, and immunocompromised patients

Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone.

Abstract: Paget disease of bone (PDB) is a common disorder characterized by focal and disorganized increases of bone turnover. Genetic factors are important in the pathogenesis of PDB. We and others recently mapped the third locus associated with the disorder, PDB3, at 5q35-qter. In the present study, by use of 24 French Canadian families and 112 unrelated subjects with PDB, the PDB3 locus was confined to ∼300 kb. Within this interval, two disease-related haplotype signatures were observed in 11 families and 18 unrelated patients. This region encoded the ubiquitin-binding protein sequestosome 1 (SQSTM1/p62), which is a candidate gene for PDB because of its association with the NF-κB pathway. Screening SQSTM1/p62 for mutations led to the identification of a recurrent nonconservative change (P392L) flanking the ubiquitin-associated domain (UBA) (position 394–440) of the protein that was not present in 291 control individuals. Our data demonstrate that two independent mutational events at the same position in SQSTM1/p62 caused PDB in a high proportion of French Canadian patients.

The Dodo Bird Verdict Is Alive and Well—Mostly

Abstract: We examined 17 meta-analyses of comparisons of active treatments with each other, in contrast to the more usual comparisons of active treatments with controls. These meta-analyses yielded a mean uncorrected absolute effect size for Cohen's d of .20, which is small and non-significant (an equivalent Pearson's r would be. 10). The smallness of this effect size confirms Rosenzweig's supposition in 1936 about the likely results of such comparisons. In the present sample, when such differences were corrected for the therapeutic allegiance of the researchers involved in comparing the different psychotherapies, these differences tend to become even further reduced in size and significance, as shown previously by Luborsky, Diguer, Seligman, et al. (1999).

Colorimetric and Fluorometric Detection of Nucleic Acids Using Cationic Polythiophene Derivatives

Abstract: Simple and reliable sequence-specific methods are needed for the rapid detection of oligonucleotides, to diagnose infections and various genetic diseases. In this regard, interesting optical and electrochemical DNA-hybridization sensors have been proposed.[1±5] The recognition capabilities of DNA are well established but, to transduce the recognition event into a physically measurable value, a fluorescent or electroactive tag is often bound to the analyte. Electrochemical and optical sensors based on conjugated polymers have also been reported[6±9] and some oligonucleotide-functionalized conjugated polymers can also transduce hybridization events into an electrical signal without labeling of the oligonucleotide target.[10±12] The detection relies on a modTo our knowledge this is the first report on the use of singlemolecule atomic-force spectroscopy to study the reduction pathway of multiple disulfide bonds in proteins and to evaluate the distributions of intermediates obtained under different reducing conditions without separating them and without any blocking and fractionation steps. The characterization of these intermediates has so far been accomplished by first blocking them with reagents such as alkylalkanethiosulfonates and then by fractionation by ion-exchange chromatography, 2D or capillary gel electrophoresis, or gel filtration.[11] The determination of thiol groups and disulfide bonds in a polythiol systems has always been a very challenging problem.[12] The single-molecule force-spectroscopy data presented here show: 1) how a redox environment can modulate the mechanical properties of angiostatin; 2) how this modulation relies, at the single-molecule level, on the extent of reduction of the disulfide bonds; and 3) how, at the level of a large sample of molecules, the distribution of the different thiol/ disulfide intermediates after reduction can be estimated by statistical analysis of the force curves.

Model of Thalamocortical Slow-Wave Sleep Oscillations and Transitions to Activated States

Abstract: During natural slow-wave sleep (SWS) in nonanesthetized cats, silent (down) states alternate with active (up) states; the down states are absent during rapid-eye-movement sleep and waking. Oscillations (<1 Hz) in SWS and transformation to an activated awake state were investigated with intracellular recordings in vivo and with computational models of the corticothalamic system. Occasional summation of the miniature EPSPs during the hyperpolarized (silent) phase of SWS oscillation activated the persistent sodium current and depolarized the membrane of cortical pyramidal (PY) cells sufficiently for spike generation. In the model, this triggered the active phase, which was maintained by lateral PY–PY excitation and persistent sodium current. Progressive depression of the excitatory interconnections and activation of Ca2+-dependent K+ current led to termination of the 20–25 Hz activity after 500–1000 msec. Including thalamocortical (TC) and thalamic reticular neurons in the model increased the duration of the active epochs up to 1–1.5 sec and introduced waning spindle sequences. An increase in acetylcholine activity, which is associated with activated states, was modeled by the reduction in the K+ leak current in PY and TC cells and by a decrease in intracortical PY–PY synaptic conductances. These changes eliminated the hyperpolarizing phases of network activity and transformed cortical neurons to tonic firing at 15–20 Hz. During the transition from SWS to the activated state, the input resistance of cortical neurons gradually increased and, in a fully activated state, reached the same or even higher values as during silent phases of SWS oscillations. The model describes many essential features of SWS and activated states in the thalamocortical system as well as the transition between them.

Newly generated neurons in the amygdala and adjoining cortex of adult primates

Abstract: The subventricular zone remains mitotically active throughout life in rodents. Studies with tritiated thymidine, which is incorporated into the DNA of mitotic cells, have revealed that the rodent subventricular zone produces neuroblasts that migrate toward the olfactory bulb along the rostral migratory stream. A similar migratory stream has been documented in monkeys by using the thymidine analogue BrdUrd. The same approach showed that neurogenesis occurred in the dentate gyrus of adult primates, including humans. In the present study, experiments combining injections of BrdUrd and the dye 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindo-carbocyanine, with the immunostaining for molecular markers of neurogenesis (polysialylated neural cell adhesion molecule, β-tubulin-III, collapsin response mediator protein-4, neuronal nuclear protein) in New World (Saimiri sciureus) and Old World (Macaca fascicularis) monkeys have revealed that new neurons are produced in the amygdala, piriform cortex, and adjoining inferior temporal cortex in adult primates. These newborn neurons expressed the antiapoptotic protein Bcl-2 and formed a more-or-less continuous pathway that extended from the tip of the temporal ventricular horn to the deep portion of the temporal lobe. The production of newborn neurons in the amygdala, piriform cortex, and inferior temporal cortex seems to parallel the continuing addition of neurons in the olfactory bulb. These two concomitant phenomena may ensure structural stability and functional plasticity to the primate olfactory system and temporal lobe.

A stable isotope (δ13C, δ15N) model for the North Water food web: implications for evaluating trophodynamics and the flow of energy and contaminants

Abstract: The North Water Polynya is an area of high biological activity that supports large numbers of higher trophic-level organisms such as seabirds and marine mammals. An overall objective of the Upper Trophic-Level Group of the International North Water Polynya Study (NOW) was to evaluate carbon and contaminant flux through these high trophic-level (TL) consumers. Crucial to an evaluation of the role of such consumers, however, was the establishment of primary trophic linkages within the North Water food web. We used δ15N values of food web components from particulate organic matter (POM) through polar bears (Ursus maritimus) to create a trophic-level model based on the assumptions that Calanus hyperboreus occupies TL 2.0 and there is a 2.4‰ trophic enrichment in 15N between birds and their diets, and a 3.8‰ trophic enrichment for all other components. This model placed the planktivorous dovekie (Alle alle) at TL 3.3, ringed seal (Phoca hispida) at TL 4.5, and polar bear at TL 5.5. The copepods C. hyperboreus, Chiridius glacialis and Euchaeta glacialis formed a trophic continuum (TL 2.0–3.0) from primary herbivore through omnivore to primary carnivore. Invertebrates were generally sorted according to planktonic, benthic and epibenthic feeding groups. Seabirds formed three trophic groups, with dovekie occupying the lowest, black-legged kittiwake (Rissa tridactyla), northern fulmar (Fulmarus glacialis), thick-billed murre (Uria aalge), and ivory gull (Pagophilia eburnea) intermediate (TL 3.9–4.0), and glaucous gull (Larus hyperboreus) the highest (TL 4.6) trophic positions. Among marine mammals, walrus (Odobenus rosmarus) occupied the lowest (TL 3.2) and bearded seal (Erignathus barbatus), ringed seal, beluga whale (Delphinapterus leucas), and narwhal (Monodon monoceros) intermediate positions (TL 4.1–4.6). In addition to arctic cod (Boreogadus saida), we suggest that lower trophic-level prey, in particular the amphipod Themisto libellula, contribute fundamentally in transferring energy and carbon flux to higher trophic-level seabirds and marine mammals. We measured PCB 153 among selected organisms to investigate the behavior of bioaccumulating contaminants within the food web. Our isotopic model confirmed the trophic magnification of PCB 153 in this high-Arctic food web due to a strong correlation between contaminant concentration and organism δ15N values, demonstrating the utility of combining isotopic and contaminant approaches to food-web studies. Stable-carbon isotope analysis confirmed an enrichment in 13C between POM and ice algae (–22.3 vs. –17.7‰). Benthic organisms were generally enriched in 13C compared to pelagic species. We discuss individual species isotopic data and the general utility of our stable isotope model for defining carbon flux and contaminant flow through the North Water food web.

Chemopreventive and adjuvant therapeutic potential of pomegranate (Punica granatum) for human breast cancer.

Abstract: Fresh organically grown pomegranates (Punica granatum L.) of the Wonderful cultivar were processed into three components: fermented juice, aqueous pericarp extract and cold-pressed or supercritical CO2-extracted seed oil. Exposure to additional solvents yielded polyphenol-rich fractions ('polyphenols') from each of the three components. Their actions, and of the crude whole oil and crude fermented and unfermented juice concentrate, were assessed in vitro for possible chemopreventive or adjuvant therapeutic potential in human breast cancer. The ability to effect a blockade of endogenous active estrogen biosynthesis was shown by polyphenols from fermented juice, pericarp, and oil, which inhibited aromatase activity by 60-80%. Fermented juice and pericarp polyphenols, and whole seed oil, inhibited 17-beta-hydroxysteroid dehydrogenase Type 1 from 34 to 79%, at concentrations ranging from 100 to 1,000 microg/ml according to seed oil >> fermented juice polyphenols > pericarp polyphenols. In a yeast estrogen screen (YES) lyophilized fresh pomegranate juice effected a 55% inhibition of the estrogenic activity of 17-beta-estradiol; whereas the lyophilized juice by itself displayed only minimal estrogenic action. Inhibition of cell lines by fermented juice and pericarp polyphenols was according to estrogen-dependent (MCF-7) >> estrogen-independent (MB-MDA-231) > normal human breast epithelial cells (MCF-10A). In both MCF-7 and MB-MDA-231 cells, fermented pomegranate juice polyphenols consistently showed about twice the anti-proliferative effect as fresh pomegranate juice polyphenols. Pomegranate seed oil effected 90% inhibition of proliferation of MCF-7 at 100 microg/ml medium, 75% inhibition of invasion of MCF-7 across a Matrigel membrane at 10 microg/ml, and 54% apoptosis in MDA-MB-435 estrogen receptor negative metastatic human breast cancer cells at 50 microg/ml. In a murine mammary gland organ culture, fermented juice polyphenols effected 47% inhibition of cancerous lesion formation induced by the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). The findings suggest that clinical trials to further assess chemopreventive and adjuvant therapeutic applications of pomegranate in human breast cancer may be warranted.

Shape Memory Materials for Biomedical Applications

Abstract: Shape memory properties provide a very attractive insight into materials science, opening unexplored horizons and giving access to unconventional functions in every material class (metals, polymers, and ceramics). In this regard, the biomedical field, forever in search of materials that display unconventional properties able to satisfy the severe specifications required by their implantation, is now showing great interest in shape memory materials, whose mechanical properties make them extremely attractive for many biomedical applications. However, their biocompatibility, particularly for long-term and permanent applications, has not yet been fully established and is therefore the object of controversy. On the other hand, shape memory polymers (SMPs) show promise, although thus far, their biomedical applications have been limited to the exploration. This paper will first review the most common biomedical applications of shape memory alloys and SMPs and address their critical biocompatibility concerns. Finally, some engineering implications of their use as biomaterials will be examined.

Trapping of messenger RNA by Fragile X Mental Retardation protein into cytoplasmic granules induces translation repression

Abstract: Absence of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein, is responsible for the Fragile X syndrome, the most common form of inherited mental retardation. FMRP is a cytoplasmic protein associated with mRNP complexes containing poly(A)+mRNA. As a step towards understanding FMRP function(s), we have established the immortal STEK Fmr1 KO cell line and showed by transfection assays with FMR1-expressing vectors that newly synthesized FMRP accumulates into cytoplasmic granules. These structures contain mRNAs and several other RNA-binding proteins. The formation of these cytoplasmic granules is dependent on determinants located in the RGG domain. We also provide evidence that FMRP acts as a translation repressor following co-transfection with reporter genes. The FMRP-containing mRNPs are dynamic structures that oscillate between polyribosomes and cytoplasmic granules reminiscent of the Stress Granules that contain repressed mRNAs. We speculate that, in neurons, FMRP plays a role as a mRNA repressor in incompetent mRNP granules that have to be translocated from the cell body to distal locations such as dendritic spines and synaptosomes.

Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38).

Abstract: 7-Ethyl-10-hydroxycamptothecin (SN-38) is the pharmacologically active metabolite of irinotecan, in addition to being responsible for severe toxicity. Glucuronidation is the main metabolic pathway of SN-38 and has been shown to protect against irinotecan-induced gastrointestinal toxicity. The purpose of this study was to determine whether common polymorphic UDP-glucuronosyltransferase (UGT) affects SN-38 glucuronidation. First, kinetic characterization of SN-38-glucuronide (SN-38-G) formation was assessed for all known human UGT1A and UGT2B overexpressed in human embryonic kidney 293 cells. To assess the relative activity of UGT isoenzymes for SN-38, rates of formation of SN-38-G were monitored by liquid chromatography/mass spectrometry analysis and normalized by level of UGT cellular expression. Determination of intrinsic clearances predicts that hepatic UGT1A1 and UGT1A9 and the extrahepatic UGT1A7 are major components in SN-38-G formation, whereas a minor role is suggested for UGT1A6, UGT1A8, and UGT1A10. In support of the involvement of UGT1A9, a strong coefficient of correlation was observed in the glucuronidation of SN-38 and a substrate, mainly glucuronidate, by UGT1A9 (flavopiridol) by human liver microsomes (coefficient of correlation, 0.905; p = 0.002). In vitro functional experiments revealed a negative impact of the UGT1A1 allelic variants. Residual activities of 49, 7, 8, and 11% were observed for UGT1A1*6 (G(71)R), UGT1A1*27 (P(229)Q), UGT1A1*35 (L(233)R), and UGT1A1*7 (Y(486)D), respectively. Common variants of UGT1A7, UGT1A7*3 (N(129)K;R(131)K;W(208)R), and UGT1A7*4 (W(208)R), displayed residual activities of 41 and 28% compared with the UGT1A7*1 allele. Taken together, these data provide the evidence that molecular determinants of irinotecan response may include the UGT1A polymorphisms studied herein and common genetic variants of the hepatic UGT1A9 isoenzyme yet to be described.

Multiphase catalytic reactors: a perspective on current knowledge and future trends

Abstract: Conventional and emerging processes that require the application of multiphase reactors are reviewed with an emphasis on catalytic processes. In the past, catalyst discovery and development preceded and drove the selection and development of an appropriate multiphase reactor type. This sequential approach is increasingly being replaced by a parallel approach to catalyst and reactor selection. Either approach requires quantitative models for the flow patterns, phase contacting, and transport in various multiphase reactor types. This review focuses on these physical parameters for various multiphase reactors. First, fixed-bed reactors are reviewed for gas-phase catalyzed processes with an emphasis on unsteady state operation. Fixed-bed reactors with two-phase flow are treated next. The similarities and differences are outlined between trickle beds with cocurrent gas–liquid downflow, trickle-beds with countercurrent gas–liquid flow, and packed-bubble columns where gas and liquid are contacted in coc...

Functional gastrointestinal disorders in Canada: first population-based survey using Rome II criteria with suggestions for improving the questionnaire

Abstract: The Rome II criteria and questionnaires developed to identify functional gastrointestinal disorders have not been evaluated. Our objectives were to determine the prevalence of functional gastrointestinal disorders in Canada, compare our results with data from other published studies, assess concordance of Rome I and Rome II criteria for irritable bowel syndrome, and suggest improvements in the Rome II questionnaire. An independent research firm was employed to conduct a random digit dial national survey, inviting household members ≥18 years of age to participate in a study examining personal health issues. Subjects recruited by telephone, who agreed to participate, were mailed a questionnaire, and the data were retrieved by a follow-up phone call. The Rome II questionnaire and algorithms were used and where possible Rome I algorithms were also applied. At least one functional gastrointestinal disorder occurred in 61.7% of 1149 respondents (65.6% female versus 57.6% male; P < 0.05). The most prevalent were the functional bowel disorders at 41.6% followed by esophageal disorders at 28.9%. Irritable bowel syndrome prevalence by Rome II and I criteria were 12.1% and 13.5%, respectively (kappa = 0.76). Because the Rome II criteria have added exclusion items that are not present in the Rome I criteria, the prevalence of esophageal, gastroduodenal, and anorectal disorders is lower than the figures from a US market survey. In conclusion, functional gastrointestinal disorders are highly prevalent in Canada, with a significantly higher rate in women. There is substantial agreement between Rome I and Rome II criteria for irritable bowel syndrome. Rome criteria and questionnaire remain works in progress.

The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis.

Abstract: This study evaluated the efficacy and tolerability of risedronate once a week (35 mg and 50 mg) compared with risedronate 5 mg once daily in women with osteoporosis. We conducted a randomized, double-blind, active-controlled, 2-year study; the primary efficacy assessment was performed after 1 year. Subjects were women aged 50 years or older who had been postmenopausal for at least 5 years, with either a bone mineral density (BMD) T-score of -2.5 or lower (lumbar spine or proximal femur) or a T-score lower than -2 and at least one prevalent vertebral fracture. Subjects received risedronate 5 mg once daily, 35 mg once a week or 50 mg once a week. All subjects also received 1 g daily of elemental calcium supplementation and supplemental vitamin D if the baseline serum levels were low. The primary efficacy measure was percent change in lumbar spine BMD at 12 months. A total of 1,456 women were randomized and received medication; 1,209 (83%) women completed 12 months. The mean percent change (SE) in lumbar spine BMD after 12 months was 4.0% (0.2%) in the 5 mg daily group, 3.9% (0.2%) in the 35 mg group, and 4.2% (0.2%) in the 50 mg group; each once-a-week treatment was determined to be as effective as the daily treatment. Outcomes of the secondary efficacy measurements and safety assessments were also similar in all 3 groups after 12 months. Risedronate 35 mg and 50 mg once a week provide the same efficacy and safety as the daily 5 mg regimen; therefore, the lower dose, 35 mg once a week, is considered optimal for women with postmenopausal osteoporosis who desire a once-a-week regimen.

Regulation of the Genes Encoding Interleukin‐6, Its Receptor, and gp130 in the Rat Brain in Response to the Immune Activator Lipopolysaccharide and the Proinflammatory Cytokine Interleukin‐1β

Abstract: Interleukin-6 (IL-6) is a pleiotropic cytokine believed to play key roles in the neuroimmune interactions. This molecule may act on the nervous system by interacting with its specific receptor subunit (IL-6R) and the signal transducer gp130. The purposes of the present study were to describe the central distribution of IL-6, IL-6R, and gp130 mRNAs under basal conditions and to verify the influence of the immune activator lipopolysaccharide (LPS) and the proinflammatory cytokine interleukin-1beta (IL-1beta) on the expression of IL-6 and its related genes throughout the rat brain. Rats were killed at multiple times after intraperitoneal injection of the bacterial endotoxin and intravenous administration of the recombinant rat IL-1beta (rrIL-1beta), and their brains were cut into 30-microm coronal sections from the olfactory bulb to the end of the medulla. Each transcript was localized by in situ hybridization histochemistry using 35S-labeled rat riboprobes. The results show that IL-6 mRNA was undetectable in the brain under basal conditions and following the injection of rrIL-1beta. Injection of LPS rapidly stimulated transcription of this gene in the choroid plexus and the sensorial circumventricular organs (CVOs), including the organum vasculosum laminae terminalis (OVLT), subfornical organ, median eminence, and area postrema. Conversely, IL-6R and gp130 mRNAs were heterogeneously distributed throughout the brain under basal conditions. The injection of LPS stimulated the biosynthesis of IL-6R in the CVOs, medial preoptic area, bed nucleus stria terminalis, central nucleus of the amygdala, hippocampus, hypothalamic paraventricular nucleus, cerebral cortex, and blood vessels. Increased levels of IL-6R mRNA were also observed in the microvasculature following rrIL-1beta injection. Finally, gp130 mRNA expression was increased in the OVLT and throughout the endothelium of brain capillaries of LPS-treated rats but remained unchanged after administration of rrIL-1beta. These results demonstrate that expression of the genes encoding IL-6, IL-6R, and gp130 can be up-regulated in selective regions of the brain in response to the bacterial endotoxin LPS and the proinflammatory cytokine IL-1beta (only for IL-6R expression). This fine genetic regulation might be of great importance in the neuroimmune interplay and provides the evidence that sensorial CVOs and microvasculature are in a privileged position to mediate the action of IL-6 of central and/or systemic origin in the brain of immune-challenged animals.