scispace - formally typeset
Search or ask a question

Showing papers by "Université de Montréal published in 1998"


Journal ArticleDOI
TL;DR: It is concluded that this mathematical model of the human atrial AP reproduces a variety of observed AP behaviors and provides insights into the mechanisms of clinically important AP properties.
Abstract: The mechanisms underlying many important properties of the human atrial action potential (AP) are poorly understood. Using specific formulations of the K+, Na+, and Ca2+ currents based on data recorded from human atrial myocytes, along with representations of pump, exchange, and background currents, we developed a mathematical model of the AP. The model AP resembles APs recorded from human atrial samples and responds to rate changes, L-type Ca2+ current blockade, Na+/Ca2+ exchanger inhibition, and variations in transient outward current amplitude in a fashion similar to experimental recordings. Rate-dependent adaptation of AP duration, an important determinant of susceptibility to atrial fibrillation, was attributable to incomplete L-type Ca2+ current recovery from inactivation and incomplete delayed rectifier current deactivation at rapid rates. Experimental observations of variable AP morphology could be accounted for by changes in transient outward current density, as suggested experimentally. We conclude that this mathematical model of the human atrial AP reproduces a variety of observed AP behaviors and provides insights into the mechanisms of clinically important AP properties.

1,134 citations


Journal Article
TL;DR: A pivotal role for IL-17 is suggested in initiating and/or sustaining an inflammatory response to proinflammatory mediators by human macrophages in response to recombinant human (rh) IL- 17.
Abstract: IL-17 is a newly described, T cell-derived cytokine with ill-defined physiologic properties. As such, we examined the release of proinflammatory mediators by human macrophages in response to recombinant human (rh) IL-17. IL-1beta and TNF-alpha expression and synthesis were up-regulated by rhIL-17 in a dose (ED50 was 50 +/- 9 ng/ml)- and time-dependent fashion, with cytokine accumulation reaching a zenith after 9 h. Release of IL-6, PGE2, IL-10, IL-12, IL-1R antagonist, and stromelysin was also stimulated by rhIL-17. IL-1beta and TNF-alpha mRNA expression levels were controlled by rhIL-17 in a complex manner with an initial 30-min inhibitory phase, and then up-regulation beginning at 1 h and reaching a plateau at about 3 h. The latter expression pattern closely mirrored the nuclear accumulation of the transcription factor nuclear factor-kappaB. cAMP mimetics isobutyl-1-methylxanthine (IBMX), forskolin, PGE2, and cholera toxin reversed rhIL-17-induced release of TNF-alpha, but had no consistent effect on induced IL-1beta synthesis. Induced release of TNF-alpha was also inhibited by serine/threonine protein kinase inhibitors KT-5720 (protein kinase A) and Calphostin C (protein kinase C), mitogen-activated protein kinase kinase inhibitor PD098059, and a nonspecific tyrosine kinase inhibitor, genistein. Calphostin C alone abrogated the rhIL-17-induced release of IL-1beta. The antiinflammatory cytokines IL-4 (p < 0.01) and IL-10 (p < 0.02) completely reversed rhIL-17-stimulated IL-1beta release, while IL-13 and TGF-beta2 were partially effective (59 and 43% diminution, respectively). IL-10 exerted a significant suppressive effect on IL-17-induced TNF-alpha release (99%, p < 0.02), while the inhibitory effects of IL-4, IL-13, and TGF-beta2 on TNF-alpha secretion were partial (48, 10, and 23%, respectively). The data suggest a pivotal role for IL-17 in initiating and/or sustaining an inflammatory response.

1,040 citations


Journal ArticleDOI
TL;DR: Although FSH signaling is not essential for initiating spermatogenesis, it appears to be required for adequate viability and motility of the sperms and mice lacking FSH-R are generated by homologous recombination.
Abstract: Pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone stimulate the gonads by regulating germ cell proliferation and differentiation. FSH receptors (FSH-Rs) are localized to testicular Sertoli cells and ovarian granulosa cells and are coupled to activation of the adenylyl cyclase and other signaling pathways. Activation of FSH-Rs is considered essential for folliculogenesis in the female and spermatogenesis in the male. We have generated mice lacking FSH-R by homologous recombination. FSH-R-deficient males are fertile but display small testes and partial spermatogenic failure. Thus, although FSH signaling is not essential for initiating spermatogenesis, it appears to be required for adequate viability and motility of the sperms. FSH-R-deficient females display thin uteri and small ovaries and are sterile because of a block in folliculogenesis before antral follicle formation. Although the expression of marker genes is only moderately altered in FSH-R −/− mice, drastic sex-specific changes are observed in the levels of various hormones. The anterior lobe of the pituitary gland in females is enlarged and reveals a larger number of FSH- and thyroid-stimulating hormone (TSH)-positive cells. The phenotype of FSH-R −/− mice is reminiscent of human hypergonadotropic ovarian dysgenesis and infertility.

812 citations


Journal ArticleDOI
TL;DR: Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei to cause autosomal recessive OPMD.
Abstract: Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution. It usually presents in the sixth decade with progressive swallowing difficulties (dysphagia), eyelid drooping (ptosis) and proximal limb weakness. Unique nuclear filament inclusions in skeletal muscle fibres are its pathological hallmark. We isolated the poly(A) binding protein 2 gene (PABP2) from a 217-kb candidate interval on chromosome 14q11 (B.B. et al., manuscript submitted). A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened. More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele that is found in 2% of the population, whereas homozygosity for the (GCG)7 allele leads to autosomal recessive OPMD. Thus the (GCG)7 allele is an example of a polymorphism which can act either as a modifier of a dominant phenotype or as a recessive mutation. Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.

706 citations


Journal ArticleDOI
TL;DR: These studies demonstrate a selective collaboration between a member of the Hox family and one of its DNA‐binding partners in transformation of hemopoietic cells.
Abstract: Hoxa9, Meis1 and Pbx1 encode homeodomaincontaining proteins implicated in leukemic transformation in both mice and humans. Hoxa9, Meis1 and Pbx1 proteins have been shown to physically interact with each other, as Hoxa9 cooperatively binds consensus DNA sequences with Meis1 and with Pbx1, while Meis1 and Pbx1 form heterodimers in both the presence and absence of DNA. In this study, we sought to determine if Hoxa9 could transform hemopoietic cells in collaboration with either Pbx1 or Meis1. Primary bone marrow cells, retrovirally engineered to overexpress Hoxa9 and Meis1a simultaneously, induced growth factor-dependent oligoclonal acute myeloid leukemia in <3 months when transplanted into syngenic mice. In contrast, overexpression of Hoxa9, Meis1a or Pbx1b alone, or the combination of Hoxa9 and Pbx1b failed to transform these cells acutely within 6 months post-transplantation. Similar results were obtained when FDC-P1 cells, engineered to overexpress these genes, were transplanted to syngenic recipients. Thus, these studies demonstrate a selective collaboration between a member of the Hox family and one of its DNA-binding partners in transformation of hemopoietic cells.

680 citations


Journal ArticleDOI
01 Dec 1998-Ecology
TL;DR: The hypothesis that the impacts of grazers on plant species richness reverse under contrasting nutrient richness is tested, and it is suggested that species richness declines with high grazing in nutrient-poor ecosystems because a limitation of available resources prevents regrowth of species after grazing.
Abstract: To test the hypothesis that the impacts of grazers on plant species richness reverse under contrasting nutrient richness, we analyzed unpublished and published data from lake, stream, marine, grassland, and forest ecosystems. We analyzed data from 30 studies providing 44 comparisons of plant species richness under low vs. high grazing pressure in enriched or nutrient-rich and non-enriched or nutrient-poor ecosystems. All 19 comparisons from non-enriched or nutrient-poor ecosystems exhibited significantly lower species richness under high grazing than under low grazing. In contrast, 14 of 25 comparisons from enriched or nutrient-rich ecosystems showed significantly higher species richness under high grazing than under low grazing. However, nine of these 25 comparisons showed no significant impact of grazers on species richness, while two comparisons showed declines in species richness under high grazing. Based on all the comparisons, plant species richness decreases with high grazing in nutrient-poor ecosystems, while it increases with high grazing in nutrient-rich ecosystems. Although nutrient-rich ecosystems seemed to produce more variable responses to grazers than did nutrient-poor ecosystems, in rare cases high grazing produced a decline in species richness in nutrient-rich environments. We suggest that species richness declines with high grazing in nutrient-poor ecosystems because a limitation of available resources prevents regrowth of species after grazing, which may not be the case in nutrient-rich ecosystems. It is also possible that an increase in species richness under high grazing in nutrient-rich ecosystems may be due to an increase in the dominance of inedible species. Our observation of a grazer reversal of plant species richness under contrasting nutrient richness may have important implications for management of species diversity.

625 citations


Journal ArticleDOI
TL;DR: In this paper, the analysis of the X-ray photoelectron spectra (XPS) of the C 1s core level of pulsed laser deposited diamond-like carbon thin films, obtained at different laser intensities is presented.

608 citations


Journal ArticleDOI
TL;DR: Evidence supports the laryngeal mask and Combitube™ have proved to be effective in establishing and maintaining a patent airway in “cannot ventilate” situations and support integration of these devices into strategies to manage difficult airway as the new standard of care.
Abstract: Purpose To review the current literature and generate recommendations on the role of newer technology in the management of the unanticipated difficult airway.

607 citations


Journal ArticleDOI
17 Sep 1998-Nature
TL;DR: The results resolve a long-standing controversy in that they provide behavioural evidence that totally blind individuals have better auditory ability than sighted subjects, enabling them to compensate for their loss of vision.
Abstract: Do blind persons develop capacities of their remaining senses that exceed those of sighted individuals? Besides anecdotal suggestions, two views based on experimental studies have been advanced. The first proposes that blind individuals should be severely impaired, given that vision is essential to develop spatial concepts. The second suggests that compensation occurs through the remaining senses, allowing them to develop an accurate concept of space. Here we investigate how an ecologically critical function, namely three-dimensional spatial mapping, is carried out by early-blind individuals with or without residual vision. Subjects were tested under monaural and binaural listening conditions. We find that early-blind subjects can map the auditory environment with equal or better accuracy than sighted subjects. Furthermore, unlike sighted subjects, they can correctly localize sounds monaurally. Surprisingly, blind individuals with residual peripheral vision localized sounds less precisely than sighted or totally blind subjects, confirming that compensation varies according to the aetiology and extent of blindness. Our results resolve a long-standing controversy in that they provide behavioural evidence that totally blind individuals have better auditory ability than sighted subjects, enabling them to compensate for their loss of vision.

582 citations


Journal ArticleDOI
TL;DR: The adjusted odds ratio for ovarian cancer associated with any past use of oral contraceptives was 0.5 (95 percent confidence interval, 0.3 to 0.8), which decreased with increasing duration of use.
Abstract: Background Women with mutations in either the BRCA1 or the BRCA2 gene have a high lifetime risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they also protect against hereditary forms of ovarian cancer. Methods We enrolled 207 women with hereditary ovarian cancer and 161 of their sisters as controls in a case–control study. All the patients carried a pathogenic mutation in either BRCA1 (179 women) or BRCA2 (28 women). The control women were enrolled regardless of whether or not they had either mutation. Lifetime histories of oral-contraceptive use were obtained by interview or by written questionnaire and were compared between patients and control women, after adjustment for year of birth and parity. Results The adjusted odds ratio for ovarian cancer associated with any past use of oral contraceptives was 0.5 (95 percent confidence interval, 0.3 to 0.8). The risk decreased with increasing duration of use (P for trend, <0.001); use for six or...

570 citations


Journal ArticleDOI
TL;DR: In this paper, the authors examined turnout in 324 democratic national lower house elections held in 91 countries, between 1972 and 1995, and showed that the patterns that have been shown to prevail in studies dealing with more limited samples of countries generally hold when they look at a larger set of democracies.
Abstract: We examine turnout in 324 democratic national lower house elections held in 91 countries, between 1972 and 1995. We rely on Freedom House ratings of political rights to determine whether an election is democratic or not. We distinguish three blocs of factors that affect turnout: the socio-economic environment, institutions, and party systems. We show that turnout is influenced by a great number of factors and that the patterns that have been shown to prevail in studies dealing with more limited samples of countries generally hold when we look at a larger set of democracies. But we also show that the socio-economic environment, which has been downplayed in previous studies, has a substantial impact on turnout.

Journal ArticleDOI
TL;DR: In this paper, a rigorous formulation of the solvation forces associated with the electrostatic free energy calculated from numerical solutions of the linearized Poisson-Boltzmann equation on a discrete grid is described.

Journal ArticleDOI
TL;DR: Results indicate that the linkage of the aminoalkylsilane to the oxidized surface is stable and that bound proteins such alkaline phosphatase and albumin retain their enzymatic activity and antigenicity, respectively.
Abstract: The surface of implantable biomaterials is in di- rect contact with the host tissue and plays a critical role in determining biocompatibility. In order to improve the inte- gration of implants, it is desirable to control interfacial re- actions such that nonspecific adsorption of proteins is mini- mized and tissue-healing phenomena can be controlled. In this regard, our goal has been do develop a method to func- tionalize oxidized titanium surfaces by the covalent immo- bilization of bioactive organic molecules. Titanium first was chemically treated with a mixture of sulfuric acid and hy- drogen peroxide to eliminate surface contaminants and to produce a consistent and reproducible titanium oxide sur- face layer. An intermediary aminoalkylsilane spacer mol- ecule was then covalently linked to the oxide layer, followed by the covalent binding of either alkaline phosphatase or albumin to the free terminal NH2 groups using glutaralde- hyde as a coupling agent. Surface analyses following coating procedures consisted of X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and atomic force microscopy (AFM). Enzymatic activity of coupled al- kaline phosphatase was assayed colorimetrically, and sur- face coverage by bound albumin was evaluated by SEM visualization of colloidal gold immunolabeling. Our results indicate that the linkage of the aminoalkylsilane to the oxi- dized surface is stable and that bound proteins such alkaline phosphatase and albumin retain their enzymatic activity and antigenicity, respectively. The density of immunolabel- ing for albumin suggests that the binding and surface cov- erage obtained is in excess of what would be expected for inducing biological activity. In conclusion, this method of- fers the possibility of covalently linking selected molecules with known biological activity to oxidized titanium surfaces in order to guide and promote the tissue healing that occurs during implant integration in bone and soft tissues. © 1998 John Wiley & Sons, Inc. J Biomed Mater Res, 40, 324-335, 1998.

Journal ArticleDOI
TL;DR: The results show that emotional judgments are (a) highly consistent across subjects and resistant to brain damage; (b) determined by musical structure (mode and tempo); and (c) immediate.

Journal ArticleDOI
16 Oct 1998-Cell
TL;DR: The generation of Tg mice expressing selected HIV-1 gene(s) revealed that nef harbors a major disease determinant, suggesting that Nef may play a critical role in human AIDS, independently of its role in virus replication.

Journal ArticleDOI
TL;DR: These data confirm that, in selected patients, stents can safely be implanted without the use of systemic anticoagulation, provided optimal stent expansion is achieved.
Abstract: Objectives A study was set up to validate the safety and feasibility of intravascular ultrasound-guided stenting without subsequent anticoagulation, and its impact on the 6 months restenosis rate. Methods The study was designed to be multicentred, prospective, and observational. Results One hundred and sixty-one patients with stable angina and a de novo coronary artery lesion were enrolled. In four patients, the implantation of a Palmaz–Schatz (with spiral bridge) stent had failed. One of these four patients died 3 days following bypass surgery. In two other patients, intravascular ultrasound assessment was not performed. One hundred and twenty-five of the remaining 155 patients (81%) were treated with aspirin (100mg.day−1), because all three criteria for optimized stent expansion were met. Twenty-two of the remaining 38 patients (25%), in whom at least one criterion was not met were treated with aspirin and acenocoumarol (3 months, INR 2·5–3·5), while 16 patients only received aspirin. Stent thrombosis was documented in two patients (1·3%) for which repeat angioplasty was performed. During the hospital stay, there were no deaths or Q-wave myocardial infarctions. Five patients (3·2%) sustained a non-Q-wave myocardial infarction. During the follow-up period (198±38 days, complete for all patients, except one), one patient (0·6%) sustained a Q-wave myocardial infarction, one (0·6%) underwent bypass surgery, and repeat angioplasty was performed in nine patients (5·7%). In two of the nine patients, repeat angioplasty involved another lesion. Therefore, the target lesion revascularization rate during follow-up was 4·5% (seven patients).At quantitative coronary angiography, the minimal lumen diameter (mean±SD) increased from 1·12± 0·34mm before to 2·89±0·35mm after stenting. Repeat angiography at 6 months was performed in 144 patients (92%). The minimal lumen diameter at follow-up was 2·12±0·67mm. Restenosis (diameter stenosis of 50% or more) was documented in 12 patients or 8·3%. When the two patients with documented stent thrombosis are included, the restenosis rate amounts to 9·7%. Conclusions These data confirm that, in selected patients, stents can safely be implanted without the use of systemic anticoagulation, provided optimal stent expansion is achieved. The exact role of intravascular ultrasound in the achievement of these results needs to be established by appropriately designed studies. In the meantime, intra-vascular ultrasound coupled with the Palmaz–Schatz stent incorporating a spiral bridge, may have contributed considerably to the immediate angiographic outcome, which in turn may explain the favourable clinical and angiographic outcome at 6 months.

Journal ArticleDOI
TL;DR: Electrochemical properties and reactivities of the two mediators 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulfonate) (ABTS) and 1-hydroxybenzotriazole (HBT) were studied and their intermediates responsible for lignin oxidation were characterized.

Journal Article
TL;DR: Lithoprobe, Canada's national earth science research project, was established in 1984 to develop a comprehensive understanding of the evolution of the northern North American continent as discussed by the authors, and 10 study areas span the country and geological time.
Abstract: Lithoprobe, Canada’s national earth science research project, was established in 1984 to develop a comprehensive understanding of the evolution of the northern North American continent. With rocks representing 4 b.y. of Earth history, the Canadian landmass and offshore margins provide an exceptional opportunity to gain new perspectives on continental evolution. Lithoprobe’s 10 study areas span the country and geological time. A pan-Lithoprobe synthesis will bring the project to a formal conclusion in 2003. Each transect involves an integrated, collaborative, multidisciplinary scientific program. Two transects are highlighted here. The first, across southern British Columbia, illustrates elements of evolution of the Canadian Cordillera and the Cascadia subduction zone. A key result is that crustal rocks of accreted terranes are detached from their subducting lithosphere and attached as thin flakes to the craton. Accretion at Cascadia is characterized by both underplating and duplexing of old oceanic crust below the backstop and near-surface thrusting to form an accretionary wedge. The second, a lithospheric section across the southeastern Superior province of Quebec, provides direct evidence for plate tectonics in the Late Archean. Complementary studies indicate that the northdipping collisional subduction zone(s?) imaged by reflection data stepped southward with time. Postcollisional modification of the lower crust occurred across the southern part of the region. INTRODUCTION— THE LITHOPROBE PROJECT Canada, with its diverse geology spanning 4 b.y. of Earth history, is unique in providing the opportunity to investigate continental evolution over an immense time period. The country is a mosaic of tectonic elements forming a complex jigsaw puzzle representing continental growth, destruction, and reorganization. Lithoprobe is providing the opportunity to address fundamental questions, with global implications, on how the current continental configuration was established and what tectonic processes were involved. The project began in 1984 and will end in 2003. Understanding the tectonic development of northern North America requires collaborative application of multiple Earth Science disciplines to acquire comprehensive two-dimensional knowledge of units at the surface, as well as information in the third (depth) and fourth (time) dimensions. Lithoprobe brings together these ingredients in a series of 10 study areas (transects; Fig. 1), focused on geological features of Canada that represent globally significant tectonic processes. The study areas span the country from Vancouver Island to Newfoundland, from the northern United States to the Yukon and NorthLithoprobe Leads to New Perspectives on Continental Evolution Ron M. Clowes, Lithoprobe, University of British Columbia, 6339 Stores Road, Vancouver, BC V6T 1Z4, Canada, clowes@lithoprobe.ubc.ca Fred A. Cook, Department of Geology & Geophysics, University of Calgary, Calgary, AB T2N 1N4, Canada John N. Ludden, Centre de Recherches Pétrographiques et Géochimiques, Vandoeuvre-les-Nancy, Cedex, France CENTER SCTION SA Bkstore ewest Rleases Figure 1. Location of Lithoprobe transects on a simplified tectonic element map of northern North America; MRS is mid-continent rift system. Transects: SC—Southern Cordillera; AB—Alberta Basement; SNORCLE—Slave–Northern Cordillera Lithospheric Evolution; THOT—Trans-Hudson Orogen; WS—Western Superior; KSZ—Kapuskasing Structural Zone; GL—Great Lakes International Multidisciplinary Program on Crustal Evolution (GLIMPCE); AG—Abitibi-Grenville; LE—Lithoprobe East; and ECSOOT—Eastern Canadian Shield Onshore-Offshore. Cdillera Wopmay

Journal ArticleDOI
TL;DR: It is suggested that OPN is not essential for normal mouse development and osteogenesis, but can modulate osteoclast differentiation.
Abstract: We have used homologous recombination in embryonic stem cells to generate mice with a targeted disruption of the osteopontin (Opn, or Spp1, for secreted phosphoprotein 1) gene. Mice homozygous for this disruption fail to express osteopontin (OPN) as assessed at both the mRNA and protein level, although an N-terminal fragment of OPN is detectable at extremely low levels in the bones of -/- animals. The Opn -/- mice are fertile, their litter size is normal, and they develop normally. The bones and teeth of animals not expressing OPN are morphologically normal at the level of light and electron microscopy, and the skeletal structure of young animals is normal as assessed by radiography. Ultrastructurally, proteinaceous structures normally rich in OPN, such as cement lines, persist in the bones of the Opn-/- animals. Osteoclastogenesis was assessed in vitro in cocultures with a feeder layer of calvarial osteoblast cells from wild-type mice. Spleen cells from Opn-/- mice cells formed osteoclasts 3- to 13-fold more frequently than did control Opn+/+ cells, while the extent of osteoclast development from Opn -/- bone marrow cells was about 2- to 4-fold more than from the corresponding wild-type cells. Osteoclast development occurred when Opn-/- spleen cells were differentiated in the presence of Opn-/-osteoblasts, indicating that endogenous OPN is not required for this process. These results suggest that OPN is not essential for normal mouse development and osteogenesis, but can modulate osteoclast differentiation.

Journal ArticleDOI
TL;DR: An oligomerization-assisted enzyme reassembly strategy whereby fragments are covalently linked to independently folding and interacting domains whose interactions serve to promote efficient refolding and complementation of fragments, forming active enzyme.
Abstract: Reassembly of enzymes from peptide fragments has been used as a strategy for understanding the evolution, folding, and role of individual subdomains in catalysis and regulation of activity. We demonstrate an oligomerization-assisted enzyme reassembly strategy whereby fragments are covalently linked to independently folding and interacting domains whose interactions serve to promote efficient refolding and complementation of fragments, forming active enzyme. We show that active murine dihydrofolate reductase (E.C. 1.5.1.3) can be reassembled from complementary N- and C-terminal fragments when fused to homodimerizing GCN4 leucine zipper-forming sequences as well as heterodimerizing protein partners. Reassembly is detected by an in vivo selection assay in Escherichia coli and in vitro. The effects of mutations that disrupt fragment affinity or enzyme activity were assessed. The steady-state kinetic parameters for the reassembled mutant (Phe-31 --> Ser) were determined; they are not significantly different from the full-length mutant. The strategy described here provides a general approach for protein dissection and domain swapping studies, with the capacity both for rapid in vivo screening as well as in vitro characterization. Further, the strategy suggests a simple in vivo enzyme-based detection system for protein-protein interactions, which we illustrate with two examples: ras-GTPase and raf-ras-binding domain and FK506-binding protein-rapamycin complexed with the target of rapamycin TOR2.

Journal ArticleDOI
TL;DR: ASA and pANCA assays are highly disease specific for CD and UC, respectively, and may be useful in making therapeutic decisions in patients with IBD.

Journal ArticleDOI
TL;DR: Analysis of the ontogeny of gonadal GATA-4 expression by immunohistochemistry found that the Müllerian inhibiting substance promoter which harbors a conserved GATA element is a downstream target for Gata-4, indicating a new factor in the cascade of regulators that control gonadal development and sex differentiation in mammals.
Abstract: Mammalian gonadal development and sexual differentiation are complex processes that require the coordinated expression of a specific set of genes in a strict spatiotemporal manner. Although some of these genes have been identified, the molecular pathways, including transcription factors, that are critical for the early events of lineage commitment and sexual dimorphism, remain poorly understood. GATA-4, a member of the GATA family of transcription factors, is present in the gonads and may be a regulator of gonadal gene expression. We have analyzed the ontogeny of gonadal GATA-4 expression by immunohistochemistry. GATA-4 protein was detected as early as embryonic day 11.5 in the primitive gonads of both XX and XY mouse embryos. In both sexes, GATA-4 specifically marked the developing somatic cell lineages (Sertoli in testis and granulosa in ovary) but not primordial germ cells. Interestingly, abundant GATA-4 expression was maintained in Sertoli cells throughout embryonic development but was markedly down-regulated shortly after the histological differentiation of the ovary on embryonic day 13.5. This pattern of expression suggested that GATA-4 might be involved in early gonadal development and possibly sexual dimorphism. Consistent with this hypothesis, we found that the Mullerian inhibiting substance promoter which harbors a conserved GATA element is a downstream target for GATA-4. Thus, transcription factor GATA-4 may be a new factor in the cascade of regulators that control gonadal development and sex differentiation in mammals.

Journal ArticleDOI
TL;DR: Dr Lajeunesse provides a persuasive overview of this theory in his article, demonstrating that this tissue is more intimately related to the progression and/or the onset of OA, rather than being merely a consequence of this disease.

Journal ArticleDOI
TL;DR: The data suggest that L-NIL may act by reducing the activity of metalloproteases in cartilage and the production of IL-1beta by synovium, both of which are known to play a major role in the pathophysiology of OA structural changes.
Abstract: Objective To evaluate the in vivo therapeutic efficacy of N-iminoethyl-L-lysine (L-NIL), a selective inhibitor of inducible nitric oxide synthase (iNOS), on the progression of lesions in an experimental osteoarthritis (OA) dog model. The effect of L-NIL on metalloprotease activity, levels of interleukin-1beta (IL-1beta), prostaglandin E2 (PGE2), and nitrite/nitrate in synovial fluid was determined. Methods The OA model was created by sectioning the anterior cruciate ligament of the right stifle joint of mongrel dogs by a stab wound. Dogs were separated into experimental groups: Group 1 was made up of unoperated dogs that received no treatment, group 2 were operated dogs with no treatment, and group 3 were operated dogs that received oral L-NIL (10 mg/kg/twice daily) starting immediately after surgery. The OA dogs were killed at 10 weeks after surgery. Results Experiments showed that dog OA cartilage explants in culture produced an increased amount of NO (nitrite). Immunohistochemical study demonstrated that this was due to an increased level of iNOS in chondrocytes. OA dogs treated with L-NIL showed a reduction in the incidence of osteophytes compared with the untreated OA dogs (58% versus 92%) as well as in their size (mean +/- SEM 1.92 +/- 0.58 mm versus 5.08 +/- 0.66 mm). Macroscopically, L-NIL decreased the size of the cartilage lesions by approximately 50% both on condyles and plateaus. The histologic severity of both the cartilage lesions and synovial inflammation was significantly decreased in the L-NIL-treated dogs. Treatment with L-NIL also significantly decreased both collagenase and general metalloprotease activity in the cartilage and the levels of IL-1beta, PGE2, and nitrite/nitrate in synovial fluid. Conclusion This study demonstrated the effectiveness of a selective inhibitor of iNOS, L-NIL, in attenuating the progression of experimental OA. The data suggest that L-NIL may act by reducing the activity of metalloproteases in cartilage and the production of IL-1beta by synovium, both of which are known to play a major role in the pathophysiology of OA structural changes.

Journal ArticleDOI
TL;DR: Northern hybridization analysis showed strong expression of CYP1B1 in the anterior uveal tract, which is involved in secretion of the aqueous humor and in regulation of outflow facility, processes that could contribute to the elevated intraocular pressure characteristic of PCG.
Abstract: We recently reported three truncating mutations of the cytochrome P4501B1 gene (CYP1B1) in five families with primary congenital glaucoma (PCG) linked to the GLC3A locus on chromosome 2p21. This could be the first direct evidence supporting the hypothesis that members of the cytochrome P450 superfamily may control the processes of growth and differentiation. We present a comprehensive sequence analysis of the translated regions of the CYP1B1 gene in 22 PCG families and 100 randomly selected normal individuals. Sixteen mutations and six polymorphisms were identified, illustrating an extensive allelic heterogeneity. The positions affected by these changes were evaluated by building a three-dimensional homology model of the conserved C-terminal half of CYP1B1. These mutations may interfere with heme incorporation, by affecting the hinge region and/or the conserved core structures (CCS) that determine the proper folding and heme-binding ability of P450 molecules. In contrast, all polymorphic sites were poorly conserved and located outside the CCS. Northern hybridization analysis showed strong expression of CYP1B1 in the anterior uveal tract, which is involved in secretion of the aqueous humor and in regulation of outflow facility, processes that could contribute to the elevated intraocular pressure characteristic of PCG.

Journal ArticleDOI
TL;DR: The results suggest that most of the two-site I-PTH assays would cross-react with non-(1-84)PTH material, thus explaining about one-half of the 2-2.5 x higher I-pTH concentrations reported in uremic patients without bone involvement than in subjects without uremia.
Abstract: We have previously shown that the Nichols assay for intact parathyroid hormone (I-PTH) reacts with a non-(1–84) molecular form of PTH. This form behaves as a carboxy-terminal fragment and accumulates in renal failure, accounting for 40–60% of the measured immunoreactivity. We wanted to see whether this was a common event with other commercial two-site I-PTH assays. We thus compared the ability of three commercial kits [Nichols (NL), Incstar (IT), and Diagnostic System Laboratories (DSL)] to measure I-PTH in 112 renal failure patients and to detect hPTH(1–84) and non-(1–84)PTH on HPLC profiles of serum pools from uremic patients with I-PTH concentrations of 10–100 pmol/L. The behavior of synthetic hPTH(7–84), a fragment possibly related to non-(1–84)PTH was also compared with hPTH(1–84) in the three assays. The I-PTH concentrations measured with the three assays in the 112 uremic samples were highly related (r2 ≥ 0.89, P <0.0001), and the values measured with NL were, on average, 23% higher than IT. Values measured with DSL were 23% and 56% higher than IT for values less than and more than 40 pmol/L, respectively. The three assays detected two HPLC peaks on four different profiles corresponding to hPTH(1–84) and non-(1–84)PTH. This last peak represented 36 ± 8.4% of the immunoreactivity with NL, 24 ± 5.5% with IT, and 25 ± 2.8% with DSL (NL vs IT or DSL: P <0.05). These differences were confirmed by a 50% lower immunoreactivity to hPTH(7–84) compared with hPTH(1–84) for IT and DSL but not for NL. These results suggest that most of the two-site I-PTH assays would cross-react with non-(1–84)PTH material, thus explaining about one-half of the 2–2.5 × higher I-PTH concentrations reported in uremic patients without bone involvement than in subjects without uremia.

Journal ArticleDOI
TL;DR: The LDL concentrations achieved during treatment with pravastatin or placebo were associated with reduction in coronary events down to an LDL concentration of approximately 125 mg/dL, and triglyceride but not HDL concentrations during follow-up were weakly but significantly associated with the coronary event rate.
Abstract: Background—Although LDL lowering has been shown to reduce recurrent coronary events in patients with coronary heart disease, little direct information is available on the extent of LDL lowering required to achieve this outcome. Methods and Results—The Cholesterol and Recurrent Events (CARE) trial compared pravastatin and placebo in patients who had experienced myocardial infarction (MI) who had average concentrations of total cholesterol <240 mg/dL (baseline mean, 209 mg/dL) and LDL cholesterol (LDL) 115 to 174 mg/dL (mean, 139 mg/dL). Pravastatin reduced coronary death or recurrent MI by 24%. In multivariate analysis, the LDL concentration achieved during follow-up was a significant, although nonlinear, predictor of the coronary event rate (P=.007), whereas the extent of LDL reduction was not significant, whether expressed as an absolute amount (P=.97) or a percentage (P=.76). The coronary event rate declined as LDL decreased during follow-up from 174 to ≈125 mg/dL, but no further decline was seen in the...

Journal ArticleDOI
TL;DR: Epistasis studies revealed that C. albicans CST20, HST7, CEK1, andCPH1 gene products lie in an equivalent, canonical, MAPK cascade, and Cek1p acts as part of theMAPK cascade involved in starvation-specific hyphal development, it may also play independent roles in C.Albicans.
Abstract: Extracellular signal-regulated protein kinase (ERK, or mitogen-activated protein kinase [MAPK]) regulatory cascades in fungi turn on transcription factors that control developmental processes, stress responses, and cell wall integrity. CEK1 encodes a Candida albicans MAPK homolog (Cek1p), isolated by its ability to interfere with the Saccharomyces cerevisiae MAPK mating pathway. C. albicans cells with a deletion of the CEK1 gene are defective in shifting from a unicellular budding colonial growth mode to an agar-invasive hyphal growth mode when nutrients become limiting on solid medium with mannitol as a carbon source or on glucose when nitrogen is severely limited. The same phenotype is seen in C. albicans mutants in which the homologs (CST20, HST7, and CPH1) of the S. cerevisiae STE20, STE7, and STE12 genes are disrupted. In S. cerevisiae, the products of these genes function as part of a MAPK cascade required for mating and invasiveness of haploid cells and for pseudohyphal development of diploid cells. Epistasis studies revealed that the C. albicans CST20, HST7, CEK1, and CPH1 gene products lie in an equivalent, canonical, MAPK cascade. While Cek1p acts as part of the MAPK cascade involved in starvation-specific hyphal development, it may also play independent roles in C. albicans. In contrast to disruptions of the HST7 and CPH1 genes, disruption of the CEK1 gene adversely affects the growth of serum-induced mycelial colonies and attenuates virulence in a mouse model for systemic candidiasis.

Journal ArticleDOI
TL;DR: Research projects under development, and an assessment of the situation and of the problems encountered on the way to a commercial use of such transgenic plants are discussed in this review.

Journal ArticleDOI
TL;DR: In vivo investigation revealed that expanded GAA·TTC repeats from intron I of the FRDA gene inhibit transcription rather than post-transcriptional RNA processing and also interfere with replication, suggesting the molecular basis for these effects may be the formation of non-B DNA structures.