Showing papers by "Paris Descartes University published in 1997"
TL;DR: Results demonstrate that the addition of a third carboxylic group to ACPD can change its activity (from agonist to antagonist) and either increase or decrease its selectivity and/or affinity for the various mGluR subtypes.
Abstract: The four stereoisomers of 1-aminocyclopentane-1,3,4-tricarboxylic acid {ACPT-I (18) and -II (19), (3R, 4R)-III [(-)-20], and (3S,4S)-III [(+)-20]} have been synthesized and evaluated for their effects at glutamate receptors subtypes. ACPTs are ACPD analogues in which a third carboxylic group has been added at position 4 in the cyclopentane ring. None of the ACPT isomers showed a significant effect on ionotropic NMDA, KA, and AMPA receptors. On the other hand, ACPT-II (19) was found to be a general competitive antagonist for metabotropic receptors (mGluRs) and exhibited a similar affinity for mGluR1a (KB = 115 +/- 2 microM), mGluR2 (KB = 88 +/- 21 microM), and mGluR4a (KB = 77 +/- 9 microM), the representative members of group I, II and III mGluRs, respectively. Two other isomers, ACPT-I (18) and (+)-(3S,4S)-ACPT-III [(+)-20], were potent agonists at the group III receptor mGluR4a (EC50 = 7.2 +/- 2.3 and 8.8 +/- 3.2 microM) and competitive antagonists with low affinity for mGluR1a and mGluR2 (KB > 300 microM). Finally, (-)-(3R,4R)-ACPT-III [(-)-20] was a competitive antagonist with poor but significant affinity for mGluR4a (KB = 220 microM). These results demonstrate that the addition of a third carboxylic group to ACPD can change its activity (from agonist to antagonist) and either increase or decrease its selectivity and/or affinity for the various mGluR subtypes.
132 citations
TL;DR: To investigate the role of genomic sequences in instability, transgenic mice containing a 45-kb genomic segment with a 55-CTG repeat cloned from a mildly affected patient showed both intergenerational and somatic repeat instability.
Abstract: Myotonic dystrophy (DM) is associated with the expansion of a (CTG)n trinucleotide repeat in the 3′ untranslated region (UTR) of the DM protein kinase gene (DMPK)1. The (CTG)n repeat is polymorphic and varies in size between 5 and 37 repeats in unaffected individuals1 whereas in affected patients there are between 50 and 4,000 CTGs2,3. The size of the (CTG)n.repeat, which increases through generations, generally correlates with clinical severity and age of onset4. The instability of the CTG repeat appears to depend on its size as well as on the sex of the transmitting parent5–9. Moreover, mitotic instability analysis of different human DM tissues shows length mosaicism between different cell lineages3,6,10–14. The molecular mechanisms of triplet instability remain elusive. To investigate the role of genomic sequences in instability, we produced transgenic mice containing a 45-kb genomic segment with a 55-CTG repeat cloned from a mildly affected patient. In contrast to other mouse models containing CAG repeats within cDNAs, these mice showed both intergenerational and somatic repeat instability15–17
127 citations
TL;DR: The widespread distribution of the H2 receptor, namely in thalamic nuclei or in telencephalic areas such as most layers of the cerebral cortex, together with its excitatory role previously established in electrophysiological studies, support its alleged function in mediating the histamine-driven control of arousal mechanisms.
124 citations
119 citations
TL;DR: In the dura mater, as in peripheral tissues, sensory nerve fibers and mast cells actively synthesizing and releasing histamine form a short inhibitory feedback loop involving prejunctional H3 receptors that could regulate the release of pro-inflammatory mediators, thus limiting the extent of inflammatory reactions.
108 citations
TL;DR: In this article, Tretinoin solubility was dramatically enhanced by inclusion, especially in dimethyl β-cyclodextrin, and in every case, the dissolved products dissociated more or less rapidly leading to reprecipitation of free tretinin.
93 citations
TL;DR: It is shown that a specific and previously detected QTL of moderate or even small effect can be accurately mapped into a 1-cM interval in a program involving a total of no more than 1000 individuals and can serve as the ultimate genetic mapping procedure before the application of physical mapping tools for positional cloning of a QTL.
Abstract: A general experimental design that allows mapping of a quantitative trait locus (QTL) into a 1-cM interval is presented. The design consists of a series of strains, termed “interval-specific congenic strains (ISCS)”. Each ISCS is recombinant at a specific 1-cM sub-interval out of an ordered set of sub-intervals, which together comprise a wider interval, to which a QTL was previously mapped. It is shown that a specific and previously detected QTL of moderate or even small effect can be accurately mapped into a 1-cM interval in a program involving a total of no more than 1000 individuals. Consequently, ISCS can serve as the ultimate genetic mapping procedure before the application of physical mapping tools for positional cloning of a QTL.
92 citations
TL;DR: The moderate, but statistically significant difference, suggests that MHC genes partially control spontaneous NOD thyroiditis, which offers a unique opportunity of analyzing the factors leading to immune chronicity in a genetic context which promotes autoimmune endocrinopathies.
Abstract: Beside diabetes, non-obese diabetic (NOD) mice develop sporadic lymphoid infiltration of the thyroid gland, mimicking Hashimoto's thyroiditis. We have examined the prevalence of those manifestations in NOD mice, the influence of the major histocompatibility complex (MHC) and the association with autoantibodies. The incidence at 1 year is of 14.3% in wild-type NOD mice versus 19.6% in congenic NOD.H2k mice. The moderate, but statistically significant difference, based on the analysis of 161 NOD and 169 NOD.H2k mice, suggests that MHC genes partially control spontaneous NOD thyroiditis. Autoantibodies against thyroglobulin (Tg) are mouse specific and their presence correlates closely with thyroiditis. The strong correlation between cellular and humoral anomalies therefore resembles Hashimoto's thyroiditis. NOD and NOD.H2k mice actively immunized against Tg develop severe chronic lesions with epithelium necrosis and interstitial tissue fibrosis. Most interestingly, those lesions do not regress spontaneously as in CBA/J mice. Paradoxically, the response to Tg of lymph node cells from NOD mice is weaker both in proliferation and cytokine production. The defect is most evident for interferon-gamma-producing T cells and is reflected in the marked deficit in IgG2a antibodies. Thus a moderate anti-Tg response seems to favor chronicity of thyroiditis. In conclusion, NOD and NOD.H2k mice offer a unique opportunity of analyzing the factors leading to immune chronicity in a genetic context which promotes autoimmune endocrinopathies.
72 citations
TL;DR: It is shown that dissemination and poor prognosis are associated with lack of E‐cadherin expression on LCH cells, and Aggressive clinical evolution of LCH may be related to the loss of functions mediated by E‐ caderin.
Abstract: Langerhans' cell histiocytosis (LCH) often occurs in children as a cutaneous disease. The course of the disease is characterized by either spontaneous resolution or multivisceral dissemination with poor prognosis. The pathogenesis of LCH is not known. Since E-cadherin mediates homophilic adhesion of normal Langerhans' cells to keratinocytes and is also a ligand of the αEβ7 intraepithelial lymphocyte integrin, this study was undertaken to investigate whether its expression on LCH cells correlates with the clinical behaviour of the disease. Clinical records of 14 children with LCH, all of whom had cutaneous involvement, were retrospectively analysed. The expression of E-cadherin was studied by in situ immunohistochemistry on 22 frozen biopsy samples with two specific monoclonal antibodies. LCH cells of the seven children with only skin involvement were positive for E-cadherin. By contrast, LCH cells of the seven children who further developed extensive LCH disclosed a negative or low expression of E-cadherin. This study shows that dissemination and poor prognosis are associated with lack of E-cadherin expression on LCH cells. Aggressive clinical evolution of LCH may therefore be related to the loss of functions mediated by E-cadherin. © 1997 John Wiley & Sons, Ltd.
71 citations
TL;DR: Results suggest that the new CIEF assay can be competitive with HPLC for complete routine analysis of Hb variants, and were highly correlated between the two assays.
Abstract: We have developed two assays for complete analysis of hemoglobins (Hbs) in the field of hemoglobinopathies: a high-performance cation-exchange liquid chromatography (HPLC) assay on the weak cation-exchanger Poly Cat A and a two-step capillary isoelectric focusing (CIEF) assay on the neutral-coated capillary from Beckman in a narrow pH gradient. The resolution was satisfactory for both HPLC and CIEF and allowed separation of normal and common abnormal Hbs, i.e., Hb A, Hb F, Hb A2, Hb S, Hb C, and Hb E; slight differences were shown for the resolution of unusual variants such as Hb C-Harlem and Hb D-Punjab. The reproducibility of retention times was satisfactory as well for HPLC (CV 3.3%) and CIEF (CV 4.9%). The imprecision of quantification of Hb A2, evaluated at two concentrations, and of Hb F and Hb S was <5%, except for low concentrations of Hb A2quantified by CIEF. Quantitative data obtained for these three Hb forms were highly correlated between the two assays. These results suggest that the new CIEF assay can be competitive with HPLC for complete routine analysis of Hb variants.
65 citations
TL;DR: The model used to investigate the effect of selective genotyping on QTL mapping accuracy consists of a 100-cM chromosome with a single QTL located at its center and an infinite number of markers, represented in the simulations by a marker every 0.1 cM, is assumed.
Abstract: The detection of quantitative trait loci (QTL) requires large sample sizes to attain reasonable power (Soller et al. 1976). For reduction of the number of individuals needed to be genotyped in markerQTL linkage experiments, a procedure termed \"selective genotyping\" has been proposed for experimental species (Darvasi and Soller 1992; Lander and Botstein 1989; Lebowitz et al. 1987) and has been adapted for humans as well (Risch and Zhang 1995). With selective genotyping, only individuals from the high and low phenotypic extremes are genotyped. It has been shown that the number of individuals genotyped to attain a given power can be decreased significantly, at the expense of a moderate increase in the number of individuals phenotyped (Darvasi and Soller 1992). The major limitation of this approach is that if the experiment is aimed at analyzing a number of traits, then by selecting the extremes of each trait one would select most of the population and thus no reduction in genotyping can be obtained. Selective genotyping is thus most appropriate for the cases where only one trait is being analyzed. This conclusion is valid when selective genotyping is applied to QTL detection. However, after a QTL is detected, its map location will be estimated. In this case, additional markers at chromosomal regions of interest will be used to provide better estimation of QTL map location, since for QTL detection alone, relatively wide marker spacing is adequate (Darvasi and Soller 1994). These additional markers will be at a specific chromosomal region, and thus they will ordinarily concern a single specific QTL and a single specific trait only. Consequently, with respect to these markers, selective genotyping can be applied, even if the initial experimental population was used to map QTL affecting several traits. The proportion of the population selected for genotyping with the additional markers will be determined by the effect of selective genotyping on QTL mapping accuracy. This aspect of selective genotyping is the object of the present study. The model used to investigate the effect of selective genotyping on QTL mapping accuracy consists of a 100-cM chromosome with a single QTL located at its center. A backcross population, originating from crosses between two inbred lines with alternative alleles for all markers and for the QTL, is assumed. The quantitative trait is taken to have a normal distribution with equal variance, cr 2, for all QTL genotypes; and standardized gene effects of 0 and d for the QTL genotypes Qq and QQ respectively. Darvasi and colleagues (1993) have shown that QTL mapping accuracy when using an infinite number of markers is the same as that achieved by interval mapping using moderate marker spacing. Consequently, simulation results obtained on the assumption of an infinite number of markers apply for the actual experimental case where markers spaced at fairly wide intervals are used. On this basis and for simplicity of calculations only, an infinite number of markers, represented in the simulations by a marker every 0.1 cM, is assumed. Monte Carlo simulations were carried out according to the above model, and a maximum likelihood estimate (MLE) was obtained for QTL map location, as detailed in Darvasi and colleagues (1993). A 95% empirical confidence interval (CI) was obtained from 1000 replicated simulations for each parameter combination. Heron, CI is referred to as the length of the 95% confidence interval. The equivalence of various experimental designs (BC, F2, halfsibs) when using selective genotyping has also been presented (Darvasi and Soller 1992). Consequently, the present model serves as a close approximation to a wide range of actual experimental conditions. Previous studies have shown that CI is mainly a function of sample size, N, and gene effect, d (Darvasi et al. 1993). In order to explore the independent effect of N and d, six different parameter combinations of N and d were chosen: N = 500 with d = 2.0, 0.7 and 0.5; and N = 2000 with d = 1.0, 0.35 and 0.25. The values of d were chosen to provide similar CI with the two different sample sizes. Confidence intervals were estimated selecting a total proportion, p, of the population (p/2 at each phenotypic extreme). Figure 1 presents CI as a function of the proportion selected, p, for the six parameter combinations. As expected, CI increases when smaller proportions of the population are selected. It can be seen that population size and gene effect, independently, do not substantially affect the way CI changes as a function of p. That is, the influence of proportion selected on CI will be similar for any particular combination of d and N that determines the same CIs when selecting the entire population. Most importantly, it can be seen that in all cases, selecting more than 40-50% of the population does not reduce the CI.
TL;DR: The results show that histamine intervenes in resorption through both H1 and H2 receptors, however, the mechanisms triggered by these receptors were quite different: H1 receptors appeared to be more strategic, as no replenishment of the osteoclast population occurred after the initial depletion in precursors.
Abstract: We have previously postulated that mast cells (MC) may act as accessory cells in bone resorption. In this study we obtained evidence that histamine, the most abundant mediator released upon MC degranulation, is one of many factors modulating resorption. As the effect of histamine is mediated through different receptors, we tested the effects of mepyramine (1.5 mg/kg/day) and cimetidine (125 mg/kg/day), that antagonize H1 and H2 receptors, respectively. These effects were assessed morphometrically in a well-defined rat model of synchronized resorption at different stages of the process. On day 4 after induction (i.e., at the peak of resorption in this model), both agents reduced resorption significantly. Mepyramine acted by disturbing osteoclast activation and by reducing osteoclast activity (P < 0.01), while cimetidine principally reduced the size of the osteoclast population (P < 0.01). On day 6 (stage of declining resorption), the same resorption score as on day 4 was maintained in the mepyramine group, mainly through a marked increase in osteoclast activity (P < 0.01). In contrast, cimetidine continued to strongly reduce resorption (P < 0.01) and led to a further drop in the osteoclast population (P < 0.01). One day after induction, nonspecific esterase (NSE)-positive cells (putative osteoclast precursors) were significantly less numerous after treatment with the two agents. Significant changes in the MC population in the vicinity of the zone undergoing resorption occurred on days 4 and 6. The periosteal microvasculature adjacent to the reference bone zone was also markedly modified, especially in the cimetidine group. These results show that histamine intervenes in resorption through both H1 and H2 receptors. However, the mechanisms triggered by these receptors were quite different: H2 receptors appeared to be more strategic, as no replenishment of the osteoclast population occurred after the initial depletion in precursors. Histamine also appears to influence other neighbouring compartments, in which disturbances are probably linked to defective resorption. These findings support our hypothesis by which MC are accessory cells of resorption in this model.
TL;DR: To facilitate the mutationalAnalysis of the LDLR gene, and promote the analysis of the relationship between genotype and phenotype, a software package along with a computerized database have been created.
Abstract: The low-density lipoprotein receptor (LDLr) plays a pivotal role in cholesterol homeostasis. Mutations in the LDLr gene (LDLR), which is located on chromosome 19, cause familial hypercholesterolemia (FH), an autosomal dominant disorder characterized by severe hypercholesterolemia associated with premature coronary atherosclerosis. To date almost 300 mutations have been identified in the LDLR gene. To facilitate the mutational analysis of the LDLR gene, and promote the analysis of the relationship between genotype and phenotype, a software package along with a computerized database (currently listing 210 entries) have been created.
TL;DR: A bimodal distribution of the isoniazid acetylation MR was shown in children, with an antimode close to that described in the literature and a maturation of isoniaZid acetolation during the first 4 years.
Abstract: Isoniazid acetylation metabolic ratio (MR) was studied in 61 children with tuberculosis after administration of isoniazid. MR was calculated as the molar acetylisoniazid to isoniazid concentration ratio. MR was used as a probe for N-acetyltransferase activity and to determine the acetylation phenotype. MR had a bimodal distribution with an antimode between 0.48 and 0.77. MR and the percentage of fast acetylators increased significantly with age. The cumulative frequency of fast acetylators increased with age, with a plateau reached around 4 years. MR value was checked during treatment in 44 children. All children but one who initially appeared as fast acetylators remained in this group after repeated testing. Among the 30 slow acetylators, 12 became fast acetylators, and 10 showed a variable phenotyping at different ages. A bimodal distribution of the isoniazid acetylation MR was shown in children, with an antimode close to that described in the literature and a maturation of isoniazid acetylation during the first 4 years.
TL;DR: GH and SL cell activities seemed to be negatively correlated in starved fish and controlled by different mechanisms; GH appears to play a major role in the long-term survival of fasted eels; SL does not seem to be involved.
Abstract: European eels reaching the silver stage stop feeding in freshwater and during their spawning migration to the Sargasso sea (6000 km at least in the Ocean). The total duration of this exceptional fast is not well known. Few data are available on the general condition and the endocrine responses to starvation of migrating eels. In this study male (silver) and female (yellow and silver) eels were kept in freshwater without food for various lengths of time. Animals were killed after 7 months to 3 or 4 years. After a gradual decrease, the final body weight was reduced by 84% in males (52 months) and 67–69% in females (up to 4 years). The condition factor (K) followed a parallel curve. In the pituitary gland, GH cells were hypertrophied and highly stimulated. Their cross-sectional area was negatively correlated to K. Large GH cells remained well immunostained with an anti-eel GH serum after 7 to 12 months of starvation. In the leanest eels, the immunostaining was often reduced and many GH cells appeared degranulated, suggesting a low hormonal storage. In contrast, SL cells were reduced in size and number in the anterior half of the neurointermediate lobe (NIL), but showed a more heterogeneous picture in the caudal portion. GH and SL cell activities seemed to be negatively correlated in starved fish and controlled by different mechanisms. GH appears to play a major role in the long-term survival of fasted eels; SL does not seem to be involved.
TL;DR: The extent of alterations to the elastic fibre network in lesional skin areas of three patients with anetoderma was assessed by quantitative image analysis of tissue sections and compared with morphometric parameters from unaffected sites of the same individuals.
Abstract: Summary
The extent of alterations to the elastic fibre network in lesional skin areas of three patients with anetoderma was assessed by quantitative image analysis of tissue sections and compared with morphometric parameters from unaffected sites of the same individuals. In the anetodermic skins pre-elastic fibres were undetectable or extremely rare; the volume fraction (Vv%) occupied by these pre-elastic fibres was 0–0·3%, while in unaffected skins the Vv% occupied by pre-elastic fibres was 0·5–0·8%. A nearly complete absence of dermal elastic fibres in lesional skins from the three patients was evidenced (Vv%= 0·2–0·3%).
Organ cultures were performed using explants from skin with or without anetodermic lesions to quantify the expressions of elastase-type proteinases. All tissues from anetodermic lesions expressed proforms of gelatinases A and B and the activated form of gelatinase A: their levels increased with the culture time. In comparison, enzymatic activities on oligopeptide substrates specific for leucocyte elastase and fibroblast plasma membrane-associated metalloelastase were not detected in the conditioned media of any explants at any time of culture from 1 to 5 days. Increased production of progelatinases A and B and activation of progelatinase A could be mainly responsible for the degradation of skin elastic fibres demonstrated in anetodermic skins.
TL;DR: It is shown that the exposure of normal human dermal fibroblasts in culture to hydrogen peroxide and to oxygen free-radical generating systems decreased PKA activity, as well as cyclic AMP binding to the RI and RII regulatory subunits, to levels similar to those observed with psoriatic fibroBLasts, and that oxidative modification may serve as a mechanism to alter PKAactivity in human cells.
TL;DR: The authors compared the infant-directed speech of Wolof-speaking Senegalese mothers and French-speaking mothers living in Paris to relate infantdirected communicative acts to the value system of the society to which the speaker belongs, and describe the child's place in those societies.
Abstract: The infant-directed speech of Wolof-speaking Senegalese mothers and French-speaking mothers living in Paris were compared to relate infantdirected communicative acts to the value system of the society to which the speaker belongs, and to describe the child's place in those societies. Motherinfant linguistic interactions with 4-month-old infants were recorded (five dyads in the French group and four in the Wolof group). The discourse variables of the pragmatic and semantic categories in the mothers' speech were analysed. The cross-cultural analysis included a comparison of the conventional versus shifted use of person markers by the mothers in the two cultures. The results demonstrated some features common to both groups, namely, a high percentage of expressive speech acts and the importance of affect-related statements. Some culture-specific emphases and tendencies were also noted. Whereas the French mothers' conversational exchanges with their infants were dyadic in organisation and centred on the immedi...
TL;DR: The results indicate that the deterioration of blur discrimination performance with speed may be due to motion sharpening and not motion blur as has previously been suggested.
TL;DR: It is shown that the low levels of IFN-A11 gene expression are caused essentially by the lack of two inducible enhancer domains disrupted by the A−78 → G and the G−57 → C substitutions, and suggested that virus-induced factor may correspond to the primary transcription factor directly activated by virus that is involved in the initiation of IFn-A gene transcription.
TL;DR: In this article, the Hermite polynomial expansion of crossings of any level by a stationary Gaussian process is obtained under some assumptions on the spectral moments of the process, and the number of maxima in an interval is given.
TL;DR: It is demonstrated that adipogenesis is site-specifically controlled by the ovarian status in the rat and suggests that ovariectomy-induced obesity (mainly abdominal) could be related to changes in some of the signaling pathways controlling adipogenesis in intraabdominal preadipocytes.
Abstract: As ovariectomy induces obesity in rats, we have investigated the influence of ovariectomy and hormone replacement on the proliferation and differentiation capacities of rat cultured preadipocytes removed from different fat depots (femoral sc, parametrial, and perirenal). Ovariectomy induced increased proliferation and differentiation as well as high mitogen-activated protein (MAP) kinase activity and c-fos protein induction in both confluent and differentiated preadipocytes from perirenal fat depots. In parametrial preadipocytes, ovariectomy also increased proliferation and c-fos protein induction, but failed to alter the capacities of these cells to differentiate. Treatment of ovariectomized rats with estradiol and progesterone reversed the promoting effect of ovariectomy on proliferation, differentiation, and c-fos induction in perirenal preadipocytes, but not the MAP kinase activation observed during the proliferative phase. This treatment also reversed the promoting effect of ovariectomy on proliferation and c-fos induction seen in confluent parametrial preadipocytes. In contrast, sc preadipocytes were totally insensitive to ovarian status in terms of proliferation and differentiation capacities, MAP kinase activity, and c-fos induction. This study demonstrates that adipogenesis is site-specifically controlled by the ovarian status in the rat. It also suggests that ovariectomy-induced obesity (mainly abdominal) could be related to changes in some of the signaling pathways controlling adipogenesis in intraabdominal preadipocytes.
TL;DR: Sequential methods are particularly interesting when recruitment is difficult because they may allow a study to be stopped early while maintaining type I and II error rates.
Abstract: Background
Sequential methods are particularly interesting when recruitment is difficult because they may allow a study to be stopped early while maintaining type I and II error rates.
Methods
This placebo-controlled, randomized double-blind study was aimed at assessing the efficacy of metoclopramide (0.2 mg/kg three times daily during 14 days) on gastroesophageal reflux in infancy. The main end point was the relative variation of the percentage of time at pH <4 between inclusion (day 0) and evaluation (day 14) assessed on two 24-hour esophageal pH recordings. Statistical analysis was performed with use of a sequential method, the triangular test.
Results
The study was stopped after the seventh analysis (39 infants evaluated: 20 placebo and 19 metoclopramide) without showing the expected benefit. Improvement on the main end point was 30% ± 48% (mean ± SD). Corresponding unbiased median estimates were 22% for placebo and 39% for metoclopramide (p = 0.28, sequential analysis). On day 14, the percentage of time at pH 5 minutes was 3.0 ± 3.5 for placebo and 1.9 ± 3.0 for metoclopramide (p = 0.33, t test).
Conclusion
If a tendency for a superior improvement with metoclopramide than with placebo was observed on the main end point, it was lower than expected and the difference was not significant. Compared with the corresponding single-stage design, the triangular test allowed to stop the study with a 15% reduction in sample size.
Clinical Pharmacology & Therapeutics (1997) 61, 377–384; doi:
TL;DR: The results suggest that androgenic status affects adipogenesis from deep intraabdominal preadipocytes through alterations of some components of the MAP kinase cascade/Fos signaling pathways.
Abstract: In rats, castration induces a complete defective adipose conversion of preadipocytes from the epididymal fat depots (Lacasa, D., B. Agli, D. Noynarol, and Y. Giudicelli, 1995, Endocrine 3: 789–793). The aim of this study was to establish the eventual site-specificity of this effect as well as the mechanisms involved. Therefore, the influence of androgenic status on the Fos protein induction and the Raf/mitogen-activated protein (MAP) kinase kinase (MEK)/MAP cascade, which are all required for adipose conversion of preadipocytes, was compared in proliferating and differentiated preadipocytes from femoral sc and deep intraabdominal (epididymal and perirenal) fat depots. In epididymal and perirenal proliferating preadipocytes, increased proliferation due to castration is associated with increased MAP kinase activity. However, higher immunoreactive levels of the upstream activators of MAP kinase, Raf-1 and MEK, were observed only in epididymal cells. Moreover, in vivo testosterone treatment corrected the effe...
TL;DR: An original method to detect both mutations simultaneously, based upon PCR‐mediated, site‐directed mutagenesis and double restriction of a unique PCR product is reported.
Abstract: Familial ligand-defective apolipoprotein B-100 (FDB) is an autosomal dominant disorder leading to plasma LDL cholesterol elevation and coronary artery disease (CAD) Two specific mutations in the APOB gene—R3500Q and R3531C—induce FDB We report an original method to detect both mutations simultaneously, based upon PCR-mediated, site-directed mutagenesis and double restriction of a unique PCR product With this method we have investigated the prevalence of these mutations in 1,040 French patients The R3500Q mutation was found in five probands Genotypes were determined for 10 APOB polymorphic markers and were consistent with the common European ancestral haplotype previously reported The only exception was one FDB proband who did not harbor the 48 repeat allele of the 3′HVR Additionally, the first two R3531C mutations were identified in French probands Genotypes were consistent with a previously reported haplotype, suggesting that this is another mutation of European ancestry Hum Mutat 10:160–163, 1997 © 1997 Wiley-Liss, Inc
TL;DR: The authors investigated referent introductions in narratives produced by Spanish children of 6, 9 and 11 years and adults in two situations, where they either could assume mutual back ground knowledge of the narrated content (Situation MK) or could not make this assumption, while holding this content constant by means of a picture book and found that situation NMK elicits more indefinite first mentions than situation MK and this effect is more marked for the main characters than for the secondary ones.
Abstract: This study investigates referent introductions in narratives produced by Spanish children of 6, 9 and 11 years and adults in two situations, where they either could assume mutual back ground knowledge of the narrated content (Situation MK) or could not make this assumption (Situation NMK), while holding this content constant by means of a picture book. Overall, situation NMK elicits more indefinite first mentions than situation MK and this effect is more marked for the main characters than for the secondary ones. The developmental pattern indicates that 9 years is the critical age at which Spanish children begin to use more indefinite first mentions in both situations. For all animate referents, Spanish children's and adults' introductions occur significantly more often in VN clause structures than in NV ones. Situation NMK elicits more VN first mentions than situation MK, but this contrasted effect concerns only the main characters. For these referents, the dominant pattern is Indefinite/Non Subject/VN c...
TL;DR: A series of 17 ring-mono and -disubstituted D-phenylglycine derivatives was prepared in high enantiomeric purity by enzymatic hydrolysis and deracemisation of the corresponding DL-hydantoins, followed by diazotation of the resulting N -carbamyl D-amino acids.
Abstract: A series of 17 ring-mono and -disubstituted D-phenylglycine derivatives was prepared in high enantiomeric purity by enzymatic hydrolysis and deracemisation of the corresponding DL-hydantoins, using D-hydantoinase activities of microorganisms or purified enzymes, followed by diazotation of the resulting N -carbamyl D-amino acids. No significant L-hydantoinase activity was found to produce the corresponding L-enantiomers.
TL;DR: By preserving energy status, FK506 leads to fewer metabolic disturbances than CsA in the renal epithelial cell line LLC-PK1, demonstrating a minor potential nephrotoxicity.
Abstract: FK506 and cyclosporin A (CsA) are two potent immunosupressants with similar toxicity profile. Nephrotoxicity is the main adverse effect of both compounds. The aim of this study is to compare the in vitro nephrotoxic effects on renal epithelial cell line LLC-PK1 by measuring cell viability and energy status as evaluated by concentrations of ATP and ATP metabolites. Cell viability (expressed as IC50 was assessed via thiazolyl blue (MTT) assay after incubation for 4-24 h with FK506 or CsA. ATP and its metabolites were determined by HPLC after 4 and 6 h incubation with FK506 or CsA alone at the respective IC50. Both FK506 and CsA decreased cell viability to similar extents, in a dose- and time-dependent manner. After 4 h incubation, both drugs decreased ATP levels (-25%) and increased uric acid levels. However, the latter percentage increase was twofold higher with CsA (18%) than with FK506 (9%). The energy charge, calculated according to levels of adenine nucleotides, was decreased by 10% in FK506-treated cells and by 27% in CsA-treated cells. At the end of 6-h incubation, FK506-treated cells maintained ATP levels coupled with energy charge at near control levels whereas the levels were 32% lower in CsA treated cells. Compared to the 4 h-incubation, the increase in uric acid was similar for FK506 but was doubled with CsA. The decrease in cell integrity and ATP depletion induced by CsA in LLC-PK1 cells was only transiently observed with FK506. By preserving energy status, FK506 leads to fewer metabolic disturbances than CsA in the renal epithelial cell line LLC-PK1, demonstrating a minor potential nephrotoxicity.
TL;DR: There was no evidence of a significant relationship between early natural menopause at 45 years of age and factors relative to heavy physical work conditions and significant relationships existed statistically between the occurrence of early naturalMenopause and marital status, educational level, age at first childbirth and breast-feeding of children.
Journal Article•
TL;DR: Because aortic stenosis progresses rapidly in patients on chronic dialysis and thus quickly leads to irreversible cardiac failure, the operative risk, although high in this population, seems acceptable when only one valve is affected.
Abstract: Une enquete multicentrique retrospective, portant sur les 230 centres de dialyse chronique de France metropolitaine pendant la periode du 1 M janvier 1988 au 31 decembre 1992, a identifie 98 patients dont la severite de la valvulopathie justifiait une intervention chirurgicale. L'incidence annuelle a ete estimee entre 15 et 19 cas pour 10 000 dialyses. Les causes les plus frequentes etaient les valvulopathies calcifiees (69 %) et les endocardites (19 %). Les valvulopathies calcifiees entrainaient principalement une stenose aortique, tandis que les endocardites conduisaient le plus souvent a une insuffisance mitrale. Deux appareils valvulaires etaient leses chez 32 % des patients atteints d'endocardite et chez 9 % de ceux qui avaient une valvulopathie calcifiee. Soixante-et-un patients ont ete operes. La mediane de survie apres chirurgie etait de 25 ± 3.0 mois. Les patients operes pour une valvulopathie calcifiee, ou une stenose aortique ou ayant eu un seul remplacement valvulaire avaient une mediane de survie de 36 mois. Ceux qui ont ete operes pour une endocardite ou qui ont eu un remplacement de 2 valves avaient une mediane de survie inferieure a 12 mois. La survie actuarielle des patients operes differait significativement entre : a) les patients dont l'evaluation preoperatoire montrait une seule lesion severe et ceux qui avaient plusieurs lesions (p = 0,0021, b) les patients dont une seule valve a ete remplacee par rapport a ceux qui ont eu un autre type de chirurgie (p = 0,001), c) les patients dont seule la valve aortique a ete remplacee par rapport a ceux qui ont eu une autre intervention (p = 0,004). L'analyse multivariee (entre la cause, le nombre des lesions valvulaires severes et le type de chirurgie a montre que la survie dependait significativement seulement du nombre de lesions valvulaires severes (p = 0,0021 Cinq patients ayant un retrecissement aortique severe sont decedes avant que l'acte chirurgical programme ait pu etre realise. le retrecis-Ces donnees suggerent que, chez les patients dialyses, le retrecissement aortique calcifie est la plus frequente des valvulopathies. Du fait que, dans cette population, il progresse rapidement, donnant lieu precocement a une insuffissance cardiaque, le risque operatoire, bien qu'eleve, semble acceptable quand il n'y a pas de lesion valvulaire severe associee.