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21.
Incomplete rescue of cystic fibrosis transmembrane conductance regulator deficient mice by the human CFTR cDNA 总被引:2,自引:2,他引:2
Rozmahel R; Gyomorey K; Plyte S; Nguyen V; Wilschanski M; Durie P; Bear CE; Tsui LC 《Human molecular genetics》1997,6(7):1153-1162
We have used a mouse model to study the ability of human CFTR to correct
the defect in mice deficient of the endogenous protein. In this model,
expression of the endogenous Cftr gene was disrupted and replaced with a
human CFTR cDNA by a gene targeted 'knock-in' event. Animals homozygous for
the gene replacement failed to show neither improved intestinal pathology
nor survival when compared to mice completely lacking CFTR. RNA analyses
showed that the human CFTR sequence was transcribed from the targeted
allele in the respiratory and intestinal epithelial cells. Furthermore, in
vivo potential difference measurements showed that basal CFTR chloride
channel activity was present in the apical membranes of both nasal and
rectal epithelial cells in all homozygous knock-in animals examined. Ussing
chamber studies showed, however, that the cAMP-mediated chloride channel
function was impaired in the intestinal tract among the majority of
homozygous knock-in animals. Hence, failure to correct the intestinal
pathology associated with loss of endogenous CFTR was related to
inefficient functional expression of the human protein in mice. These
results emphasize the need to understand the tissue- specific expression
and regulation of CFTR function when animal models are used in gene therapy
studies.
相似文献
22.
Human MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases 总被引:5,自引:5,他引:5
The expansion of trinucleotide repeat sequences is associated with several
neurodegenerative diseases. The mechanism of this expansion is unknown but
may involve slipped-strand structures where adjacent rather than perfect
complementary sequences of a trinucleotide repeat become paired. Here, we
have studied the interaction of the human mismatch repair protein MSH2 with
slipped-strand structures formed from a triplet repeat sequence in order to
address the possible role of MSH2 in trinucleotide expansion. Genomic
clones of the myotonic dystrophy locus containing disease-relevant lengths
of (CTG)n x (CAG)n triplet repeats were examined. We have constructed two
types of slipped-strand structures by annealing complementary strands of
DNA containing: (i) equal numbers of trinucleotide repeats (homoduplex
slipped structures or S-DNA) or (ii) different numbers of repeats
(heteroduplex slipped intermediates or SI-DNA). SI-DNAs having an excess of
either CTG or CAG repeats were structurally distinct and could be separated
electrophoretically and studied individually. Using a band-shift assay, the
MSH2 was shown to bind to both S-DNA and SI-DNA in a structure- specific
manner. The affinity of MSH2 increased with the length of the repeat
sequence. Furthermore, MSH2 bound preferentially to looped-out CAG repeat
sequences, implicating a strand asymmetry in MSH2 recognition. Our results
are consistent with the idea that MSH2 may participate in trinucleotide
repeat expansion via its role in repair and/or recombination.
相似文献
23.
The LHRH antagonist cetrorelix: a review 总被引:7,自引:0,他引:7
Reissmann T Schally AV Bouchard P Riethmiiller H Engel J 《Human reproduction update》2000,6(4):322-331
In those clinical situations in which an immediate and profound suppression of gonadotrophins is desired, LHRH agonists have the disadvantage of producing an initial stimulatory effect on hormone secretion. Therefore, the use of GnRH antagonists which cause an immediate and dose-related inhibition of LH and FSH by competitive blockade of the receptors is much more advantageous. One of the most advanced antagonist produced to date is Cetrorelix, a decapeptide which has been shown to be safe and effective in inhibiting LH and sex-steroid secretion in a variety of animal species and in clinical studies as well. Clinical trials in patients suffering from advanced carcinoma of the prostate, benign prostate hyperplasia, and ovarian cancer are currently in progress and have already shown the usefulness of this new treatment modality. In particular, the concept that a complete suppression of sex-steroids may not be necessary in indications such as uterine fibroma, endometriosis and benign prostatic hyperplasia represents a promising novel perspective for treatment of these diseases. Following completion of phase III trials in controlled ovarian stimulation for IVF regimens, Cetrorelix was given marketing approval and, thus, became the first LHRH antagonist available clinically. 相似文献
24.
To-Nga Dao Jean Mathieu Jean-Pierrs Bouchard Marc De Braekeleer 《Clinical genetics》1992,42(5):234-239
Myotonic dystrophy (MD) is an autosomal dominant disorder that has a high prevalence in Saguenay-Lac-St-Jean. A case-control study, based on a population register, of 373 MD patients who married in this region between 1855 and 1971 was conducted to determine whether their fertility was affected by the disorder. Six demographic parameters, that is the number of children, the age at marriage, the ages at the time of birth of the first and the last child, the interval between the marriage and the birth of the first child, and the interval between consecutive births, were analyzed. The mean number of children born to MD and control individuals was not different (P > 0.05). However, MD males had more children than MD females although they have started delaying their marriage since 1921. Fertility fell significantly in both the MD and control groups during the period of observation. This change reflects the decline in fertility of French Canadians in general during this period, but mainly after 1940. 相似文献
25.
Rongières-Bertrand C Olivennes F Righini C Fanchin R Taïeb J Hamamah S Bouchard P Frydman R 《Human reproduction (Oxford, England)》1999,14(3):683-688
Natural cycles were abandoned in in-vitro fertilization (IVF) embryo transfer, due to premature luteinizing hormone (LH) surges--and subsequent high cancellation rates. In this study, we investigated the administration of a new gonadotrophin-releasing hormone antagonist (Cetrorelix) in the late follicular phase of natural cycles in patients undergoing IVF and intracytoplasmic sperm injection (ICSI). A total of 44 cycles from 33 healthy women [mean age 34.1 +/- 1.4 (range 26-36) years] were monitored, starting on day 8 by daily ultrasound and measurement of serum concentrations of oestradiol, LH, follicle stimulating hormone (FSH) and progesterone. When plasma oestradiol concentrations reached 100-150 pg/ml, with a lead follicle between 12-14 mm diameter, a single injection (s.c.) of 0.5 mg (19 cycles) or 1 mg (25 cycles) Cetrorelix was administered. Human menopausal gonadotrophin (HMG; 150 IU) was administered daily at the time of the first injection of Cetrorelix, and repeated thereafter until human chorionic gonadotrophin (HCG) administration. Four out of 44 cycles were cancelled (9.0%). No decline in follicular growth or oestradiol secretion was observed after Cetrorelix administration. A total of 40 oocyte retrievals leading to 22 transfers (55%) was performed. In 10 cycles (25%), no oocyte was obtained. Fertilization failure despite ICSI occurred in six cycles (15%). In two patients the embryo was arrested at the 2 pronuclear (PN) stage. The stimulation was minimal (4.7 +/- 1.4 HMG ampoules). A total of seven clinical pregnancies was obtained (32.0% per transfer, 17.5% per retrieval), of which five are ongoing. Thus, a spontaneous cycle and the GnRH antagonist Cetrorelix in single dose administration could represent a first-choice IVF treatment with none of the complications and risks of current controlled ovarian hyperstimulation protocols, and an acceptable success rate. 相似文献
26.
Albuisson J Pêcheux C Carel JC Lacombe D Leheup B Lapuzina P Bouchard P Legius E Matthijs G Wasniewska M Delpech M Young J Hardelin JP Dodé C 《Human mutation》2005,25(1):98-99
Kallmann syndrome (KAL) combines hypogonadotropic hypogonadism and anosmia. Hypogonadism is due to Gonadotropin Releasing Hormone (GnRH) deficiency and anosmia is related to hypoplasia of the olfactory bulbs. Occasional symptoms include renal agenesis, bimanual synkinesia, cleft lip palate, dental agenesis. KAL is genetically heterogeneous and two genes have so far been identified, namely KAL1 (Xp22.3) and FGFR1/KAL2 (8p12), which underlie the X chromosome‐linked form and an autosomal dominant form of the disease, respectively. We studied a cohort of 98 unrelated Caucasian KAL patients. We identified KAL1 mutations in 14 patients, of which 7 (c.3G>A (p.M1?), g.IVS1+1G>T, c.570_571insA (p.R191fsX14), c.784G>C (p.R262P), c.958G>T (p.E320X), c.1651_1654delinsAGCT (p.P551_E552delinsSX), c.1711T>A (p.W571R)) have not been previously reported. In addition, we found FGFR1 mutations in 7 patients, namely c.303G>A (p.V102I), C.385A>C (p.D129A), c.810G>A (p.V273M), c.1093_1094delAG (p.R365fsX41), c.1561G>A (p.A520T), c.1836_1837insT (p.Y613fsX42), c.2190C>G (p.Y730X), all of which were novel mutations. In this study, unilateral renal agenesis and bimanual synkinesia were exclusively found associated with KAL1mutations, cleft palate and dental agenesia with FGFR1mutations. © 2004 Wiley‐Liss, Inc. 相似文献
27.
Submaximal power output in adopted and biological siblings 总被引:2,自引:0,他引:2
C Bouchard G Lortie J A Simoneau C Leblanc G Thériault A Tremblay 《Annals of human biology》1984,11(4):303-309
Submaximal power output was determined in relative steady state on a bicycle ergometer at a heart rate of 150 beats per minute (PWC150). PWC150 was measured in 880 individuals, 9 to 26 years of age, belonging to 46 sibships of adopted sibs, 66 sibships of unrelated individuals including adoptees, 33 sibships of first-degree cousins, 225 sibships of biological sibs, 56 sibships of DZ twins and 54 sibships of MZ twins. PWC150, PWC150/kg of body weight, PWC150/kg lean body mass, PWC150/cm of height and PWC150/m2 of body surface area were submitted to analysis of variance and correlation analysis after statistical control over age and sex of subjects. Few significant resemblances were found in PWC measurements for adoptive siblings, unrelated sibs and cousins. Sibling resemblance was, however, significant for the sibships of biological sibs, and of DZ and MZ twins. Interclass correlations reached significance only in pairs of biological brothers and sisters, and in pairs of DZ and MZ twins. Estimates of total genetic effect in PWC150/kg in a population of free-living children, adolescents and young adults vary from 0.30 to 0.48. It is concluded that submaximal power output is only moderately affected by the genotype. 相似文献
28.
Franois Trudeau Roy J. Shephard Stephane Bouchard Louis Laurencelle 《American journal of human biology》2003,15(2):187-191
This study evaluated intraindividual child–adult and interindividual child–parent relationships of body mass index (BMI) using data from the Trois‐Rivières semilongitudinal study of growth and development. Intraindividual correlations between age 12 and 35 years were substantial (r2 = 36% of variance in women, 30% of variance in men). Interindividual child–parent correlations for mothers and fathers age 36.6 ± 0.4 and 39.5 ± 0.4 years, respectively, were very low to low for daughters age 12 years (r = 0.09, NS and 0.34, P < 0.001 vs. father and mother, respectively) but all very low for sons age 12 years (r = 0.07, NS and 0.16, NS vs. father and mother, respectively). A multiple regression analysis predicted adult BMI from the individual's BMI at 10, 11, 12 years plus the maternal and paternal BMIs as calculated from self‐reported heights and weights. The BMI at age 12 years was a better predictor of adult BMI than the parental BMI in both men and women (P < 0.001) and multivariate analysis revealed that this index at age 12 years was the sole significant predictor of adult BMI for both men and women. The results from our study do not support the hypothesis that parental BMI is a stronger predictor of adult BMI than childhood BMI. However, useful information for the prediction and prevention of adult overweight can be obtained from the BMI at age 12 years. Our results suggest that environmental influences may be the major factor in the present obesity epidemic. Am. J. Hum. Biol. 15:187–191, 2003. © 2003 Wiley‐Liss, Inc. 相似文献
29.
Michelle D Fortier Peter T Katzmarzyk Claude Bouchard 《Revue canadienne de physiologie appliquée》2002,27(5):449-462
Associations among baseline physical activity, aerobic fitness, changes in physical activity, and 7-y changes in adiposity were determined. The sample consisted of 602 males and 644 females, aged 20-69 y, from the 1981 Canada Fitness Survey and the 1988 Campbell's Survey. Questionnaire-derived measures of physical activity level consisted of activity energy expenditure (AEE) and time spent on physical activity. Participants were grouped into physical activity level categories by AEE and physical activity intensity (based on MET values), and physical activity level changes were determined from movement between tertiles of AEE from baseline to follow-up. Aerobic fitness levels at baseline were determined using the Canadian Aerobic Fitness Test. Changes in body mass, the sum of five skinfolds (SF5), and waist circumference (WC) were used as indicators of adiposity change. ANCOVA and multiple regression analyses indicated that neither baseline physical activity levels, intensity, physical activity change categories, nor aerobic fitness levels were significant predictors of changes in adiposity. In conclusion, physical activity was not predictive of 7-y changes in indicators of adiposity in this sample. 相似文献
30.
Skin conductance responses to a series of loud tones were measured bilaterally in 121 pairs of adult twins, 53 pairs reared together and 68 pairs reared apart. Subjects were given an absorbing task on which to focus their attention and instructed to ignore the meaningless tones. Rangecorrection eliminated hand and sex differences in SCR amplitude and also the correlation with age of this variable. For the combined group of 79 pairs of monozygotic (MZ) twins, the within-pair correlations for Y-intercept, the slope of the habituation curve, and the number of trials to habituation were near the limits of retest reliability for these variables. After range-correction, the correlation for Y-intercept for the 42 pairs of dizygotic (DZ) twins was about half the MZ value, suggesting that initial electrodermal reactivity is strongly genetic and can be interpreted according to a polygenic-additive model. Biometric model testing indicated that stable individual differences in uncorrected SCR amplitude and in habituation slope are primarily determined by non-additive genetic factors. About 40% of the total variance (and most of the stable variance) in number of trials to habituation is genetically determined. Co-twins of MZ twins who were electrodermal nonresponders tended also to be hyporesponsive while co-twins of DZ nonresponders tended to be normoresponsive. 相似文献