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Biomedical subjects

S Langlois

Publications and source records attributed to S Langlois.

At least 19 recordsLinked to original sources
PubMed2000

Comparative genomic hybridization: a new approach to screening for intrauterine complete or mosaic aneuploidy.

In the practice of clinical genetics chromosomal aneuploidy in both mosaic and nonmosaic forms has long been recognized as a cause of abnormal prenatal and postnatal development. Traditionally, cytogenetic analysis of cultured lymphocytes has been used as a standard test for detection of constitutional aneuploidies. As lymphocytes represent only one lineage, chromosomal mosaicism expressed in other tissues often remains undetected. The purpose of this study was to assess the utilization of molecular cytogenetic analysis for detection of chromosomal aneuploidy in placental tissues. Using placentas from 100 pregnancies with viable nonmalformed livebirths, both trophoblast and chorionic stroma were analyzed using comparative genomic hybridization (CGH). In all cases with an indication of chromosomal imbalance by CGH, fluorescence in situ hybridization (FISH) analysis was performed to confirm the presence of aneuploidy. To differentiate between constitutional aneuploidy and confined placental mosaicism (CPM), amniotic membrane was analyzed by CGH and FISH techniques. Our results demonstrated five placentas with CPM for chromosomes 2, 4, 12, 13, and 18, respectively, and two constitutional nonmosaic aneuploidies (47,XXX and 47,XXY). Molecular cytogenetic studies of human placental tissues enables easy analysis of both embryonic (amnion) and extraembryonic (chorion) cell lineages. Detection at birth of chromosomal defects affecting intrauterine placental and fetal development is important because these chromosomal defects may continue to have an influence on postnatal development.

Amnion↗
PubMed2000

A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation.

Hyperkalemic periodic paralysis (HyperKPP) is an autosomal dominant skeletal muscle disorder caused by single mutations in the SCN4A gene, encoding the human skeletal muscle voltage-gated Na(+) channel. We have now identified one allele with two novel mutations occurring simultaneously in the SCN4A gene. These mutations are found in two distinct families that had symptoms of periodic paralysis and malignant hyperthermia susceptibility. The two nucleotide transitions predict phenylalanine 1490-->leucine and methionine 1493-->isoleucine changes located in the transmembrane segment S5 in the fourth repeat of the alpha-subunit Na(+) channel. Surprisingly, this mutation did not affect fast inactivation parameters. The only defect produced by the double mutant (F1490L-M1493I, expressed in human embryonic kidney 293 cells) is an enhancement of slow inactivation, a unique behavior not seen in the 24 other disease-causing mutations. The behavior observed in these mutant channels demonstrates that manifestation of HyperKPP does not necessarily require disruption of slow inactivation. Our findings may also shed light on the molecular determinants and mechanism of Na(+) channel slow inactivation and help clarify the relationship between Na(+) channel defects and the long-term paralytic attacks experienced by patients with HyperKPP.

Adult↗
PubMed1999

Clinical and molecular findings in two patients with russell-silver syndrome and UPD7: comparison with non-UPD7 cases.

The clinical presentation of prenatal and postnatal growth deficiency, triangular face, relative macrocephaly, and body asymmetry is frequently diagnosed as Russell-Silver syndrome (RSS). Maternal uniparental disomy (UPD) of chromosome 7 was reported previously in a small subset of individuals with RSS phenotype or primordial growth retardation. The primary purpose of this study was to identify RSS patients with UPD7 and determine whether or not they present phenotypic findings that distinguish them from RSS patients without UPD7. UPD7 testing was performed in 40 patients with unexplained growth retardation, including 21 patients with a diagnosis of RSS. In addition, a subset of patients was screened with markers spanning chromosome 7 to detect potential microdeletions or segmental uniparental disomy. Two of the RSS cases were identified to have maternal UPD7; no cases with deletion or partial UPD were detected. Together with previously published studies, UPD7 was identified in 11/120 (9%) of individuals with classical RSS phenotype. Our patients with UPD7 and those previously published had a classical RSS phenotype and were not clinically distinguishable from other children diagnosed with RSS.

Abnormalities, Multiple↗
PubMed1999

MRI geometric distortion: a simple approach to correcting the effects of non-linear gradient fields.

We present a method to correct intensity variations and voxel shifts caused by non-linear gradient fields in magnetic resonance images. The principal sources of distortion are briefly discussed, as well as the methods of correction currently in use. The implication of the gradient field non-linearities on the signal equations are described in a detailed way for the case of two- and three-dimensional Fourier imaging. A model of these non-linearities, derived from the geometry of the gradient coils, is proposed and then applied in post-processing to correct any images regardless of the acquisition sequence. Initial position errors, as large as 4 mm (i.e., four voxels of 1 x 1 x 1.4 mm3) before correction, are reduced to less than the voxel sizes after correction.

Humans↗
PubMed1999

Month of birth in deficit and non-deficit schizophrenic patients.

In order to test the hypothesis that an excess of summer births is a risk factor for deficit syndrome, the month of birth was studied in 53 deficit schizophrenic patients compared to 158 non-deficit patients. No significant difference in terms of month of birth or season of birth was observed between deficit and non-deficit patients, suggesting that summer births might not be a risk factor for deficit schizophrenia.

Adult↗
PubMed1999

Thalassemia carrier screening and prenatal diagnosis among the British Columbia (Canada) population of Chinese descent.

The goal of thalassemia screening is the identification, prior to the conception or birth of an affected child, of couples where both partners are thalassemia carriers. When both partners are identified as carriers for alpha- or beta-thalassemia, the risk of having a fetus who is homozygous or compound heterozygous for the abnormal gene is 25%. A study was performed to identify whether routine screening for thalassemia is indicated for the Chinese population in British Columbia (BC). In a population of 783 subjects, studied either prospectively or retrospectively, 5.0% were alpha-thalassemia carriers and 1.7% were beta-thalassemia carriers. In addition, a review of all BC cases of prenatal diagnosis for thalassemia over a 6-year period indicated that 26% of couples were identified as alpha-thalassemia carriers because of a second or third trimester diagnosis of fetal hydrops, and 17% of couples referred for beta-thalassemia already had an affected child. The experience with prenatal diagnosis shows that a significant proportion of at-risk couples are not identified prior to or early in a pregnancy. The prevalence of carriers for thalassemia would warrant a program of education and routine screening for this condition in the BC Asian population.

British Columbia↗
PubMed1999

Confirmation of linkage in X-linked infantile spasms (West syndrome) and refinement of the disease locus to Xp21.3-Xp22.1.

The syndrome of infantile spasms, hypsarrhythmia, and mental retardation (West syndrome) is a classical form of epilepsy, occurring in early infancy, which is etiologically heterogeneous. In rare families, West syndrome is an X-linked recessive condition, mapped to Xp11.4-Xpter (MIM 308350). We have identified a multi-generation family from Western Canada with this rare syndrome of infantile spasms, seen exclusively in male offspring from asymptomatic mothers, thereby confirming segregation as an X-linked recessive trait. Using highly polymorphic microsatellite CA-repeat probes evenly distributed over the entire X chromosome, linkage to markers DXS7110, DXS989, DXS1202, and DXS7106 was confirmed, with a maximum LOD score of 3.97 at a theta of 0.0. The identification of key recombinants refined the disease-containing interval between markers DXS1226 and the adrenal hypoplasia locus (AHC). This now maps the X-linked infantile spasms gene locus to chromosome Xp21.3-Xp22.1 and refines the interval containing the candidate gene to 7.0 cM. Furthermore, this interval overlaps several loci previously linked with either syndromic or non-syndromic X-linked mental retardation (XLMR), including one recognized locus implicated in neuroaxonal processing (radixin, RDXP2). Collectively, these studies lend strong support for the presence of one or more genes intrinsic to brain development and function, occurring within the critical interval defined between Xp21.3-Xp22.1.

Chromosome Mapping↗
PubMed1999

The spectrum of mutations in UBE3A causing Angelman syndrome.

Angelman syndrome (AS) is characterized by mental retardation, absence of speech, seizures and motor dysfunction. AS is caused by maternal deletions for chromosome 15q11-q13, paternal uniparental disomy (UPD), imprinting defects or loss-of-function mutations in the UBE3A locus which encodes E6-AP ubiquitin-protein ligase. The UBE3A gene is imprinted with paternal silencing in human brain and similar silencing of the Ube3a locus in Purkinje cells and hippocampal neurons in the mouse. We have sequenced the major coding exons for UBE3A in 56 index patients with a clinical diagnosis of AS and a normal DNA methylation pattern. The analysis identified disease-causing mutations in 17 of 56 patients (30%) including 13 truncating mutations, two missense mutations, one single amino acid deletion and one stop codon mutation predicting an elongated protein. Mutations were identified in six of eight families (75%) with more than one affected case, and in 11 of 47 isolated cases (23%); no mutation was found in one family with two siblings, one with a typical and one with an atypical phenotype. Mutations were de novo in nine of the 11 isolated cases. An amino acid polymorphism of threonine substituted for alanine at codon 178 was identified, and a 3 bp length polymorphism was found in the intron upstream of exon 8. In all informative cases, phenotypic expression was consistent with imprinting with a normal phenotype when a mutation was on the paternal chromosome and an AS phenotype when a mutation was on the maternal chromosome. Laboratory diagnosis and genetic counseling for AS are complex, and mutation analysis is valuable in clinically typical AS patients with a normal methylation analysis.

Angelman Syndrome↗
PubMed1998

Acute exposure to aliphatic hydrocarbons: an unusual cause of acute tubular necrosis.

Acute tubular necrosis is not an uncommon phenomenon, but it rarely results from environmental factors. We describe a patient in whom acute renal failure developed 2 times after overexposure to aliphatic hydrocarbons and discuss some potential pathophysiological mechanisms. This association has rarely been reported in the literature. Considering the wide availability of aliphatic hydrocarbons in diesel fuel and solvents, associated renal toxicity is probably underrecognized. We stress the importance of identifying environmental and professional factors as causes of acute tubular necrosis.

Adult↗
PubMed1998

Linkage of malignant hyperthermia and hyperkalemic periodic paralysis to the adult skeletal muscle sodium channel (SCN4A) gene in a large pedigree.

Hyperkalemic periodic paralysis (HPP) is caused by mutations of the adult skeletal muscle sodium channel (SCN4A) gene on chromosome 17. Malignant hyperthermia (MH) is a genetically heterogeneous autosomal-dominant disorder occurring in association with various neuromuscular diseases or without other apparent abnormalities. In some families, MH is associated with mutations of a calcium release channel (RYR1) gene on chromosome 19. In other families, linkage of this disorder to the SCN4A gene on chromosome 17 has been suggested. We report on linkage analysis in a family in which both HPP and MH are inherited as autosomal-dominant traits. Two polymorphisms within the SCN4A locus, an RFLP and a (C-A)n repeat, were typed on multiple family members. The findings were consistent with linkage of the polymorphic markers within the SCN4A gene to both HPP (Zmax = 6.79 at theta = 0.0) and MH (Zmax = 1.76 at theta = 0) in this family. Our data provide further evidence that MH is linked to the SCN4A locus in some families.

Adult↗
PubMed1998

Maternal meiosis I non-disjunction of chromosome 15: dependence of the maternal age effect on level of recombination.

Non-disjoined chromosomes 15 from 115 cases of uniparental disomy (ascertained through Prader-Willi syndrome) and 13 cases of trisomy of maternal origin were densely typed for microsatellite loci spanning chromosome 15q. Of these 128 cases a total of 97 meiosis I (MI) errors, 19 meiosis II (MII) errors and 12 mitotic errors were identified. The genetic length of a map created from the MI errors was 101 cM, as compared with a maternal length of 137 cM based on CEPH controls. No significant differences were detected in the distribution of recombination events along the chromosome arm and a reduction was seen for most of the chromosome 15 intervals examined. It was estimated that 21% of tetrads leading to MI non-disjunction were achiasmate, which may account for most or all of the reduction in recombination noted. The mean age of mothers of cases involving MI errors which showed no transitions from heterodisomy to isodisomy was significantly lower (32.7) than cases showing one or more observable transitions (36.3) (P < 0.003, t -test). However, even among chiasmate pairs the highest mean maternal age was seen for multiple exchange tetrads. Chromosome-specific differences in maternal age effects may be related to the normal distribution of exchanges (and their individual susceptibilities) for each chromosome. However, they may also reflect the presence of multiple factors which act to ensure normal segregation, each affected by maternal age in a different way and varying in importance for each chromosome.

Chromosomes, Human, Pair 15↗
PubMed1998

Clinical and radiological predictors of complete excision in breast-conserving surgery for primary breast cancer.

BACKGROUND: Local recurrence after conservative surgery for breast cancer usually results from growth of residual cancer adjacent to the excised primary tumour or from multicentric disease. Complete local excision (CLE) confirmed histologically is essential to ensure that the risk of local recurrence is minimal. This study was undertaken to determine that clinical or radiological factors may assist the surgeon at the time of surgery to achieve this aim. METHODS: A retrospective review of 101 cases treated by conservative surgery identified 70 cases of CLE and 31 of incomplete local excision (ILE). Clinical, surgical and histopathological data were taken from hospital records. Mammographic features and those of specimen X-rays were evaluated without knowledge of the histopathological outcome of surgery. RESULTS: Complete excision was significantly associated with type of operation (lumpectomy vs wide local excision/quadrantectomy, P < 0.003), absence of calcification (P < 0.03) and the presence of a mass on mammography (P = 0.05). Tumour size (> 2.5 cm) and the presence of extensive ductal carcinoma in situ (DCIS) were associated with incomplete excision (P = 0.0005). No relationship was demonstrated with patient age, breast size, breast density, tumour grade, receptor status, axillary nodal status or spicules on X-ray and completeness of excision. Specimen X-ray had a positive predictive value of 94% with CLE. CONCLUSIONS: Clinical and pre-operative mammographic parameters are important for predicting CLE for breast cancers treated by breast-conserving surgery. Specimen radiology for palpable lesions can confirm excision of the cancer and permit re-excision of breast tissue at the time of initial surgery. Its role in determining CLE should be further evaluated.

Adult↗
PubMed1998

Hemodynamic and hormonal changes during erythropoietin therapy in hemodialysis patients.

To better understand the mechanism of recombinant human erythropoietin (rhEPO)-induced increase in BP, hemodynamic parameters, body fluid volumes, and the hormones implicated in BP regulation were studied in 32 anemic hemodialysis patients before and after 3 to 4 mo of rhEPO therapy. Hemoglobin levels increased from 83 +/- 1.5 to 119 +/- 2.3 g/L (P < 0.01) after rhEPO therapy (25 to 43 U/kg) administered subcutaneously three times weekly. Mean 24-h systolic and diastolic ambulatory BP were significantly increased by 14 +/- 3 and 10 +/- 2 mmHg, respectively (P < 0.01 for both groups). Systemic vascular resistance consistently increased by 28 +/- 5% (P < 0.01), whereas cardiac output was decreased by 6 +/- 3% (P < 0.05). Red blood cell mass increased by 510 +/- 35 ml (P < 0.01), whereas plasma volume decreased by 420 +/- 66 ml (P < 0.01), which resulted in a nonsignificant increase in total blood volume. Extracellular fluid volume and exchangeable sodium were decreased by 873 +/- 255 ml (P < 0.01) and 125 mmol (P < 0.01), respectively. There was a positive correlation between the changes in exchangeable sodium and in systolic BP (r = 0.41, P < 0.05). Furthermore, a greater increase in 24-h systolic BP was observed in patients in whom exchangeable sodium increased or remained unchanged (n = 10) compared with patients (n = 22) with decreased exchangeable sodium (20 +/- 4 mmHg versus 8 +/- 2 mmHg, respectively, P < 0.01). Plasma catecholamines, plasma renin concentration, plasma atrial natriuretic peptide, and plasma endothelin-1 did not significantly change with rhEPO treatment, whereas plasma aldosterone increased significantly (P < 0.01). Although volume-independent mechanisms may contribute to rhEPO-induced BP increase, the results presented here suggest the importance of optimally reducing extracellular fluid volume to prevent, at least in part, the development of hypertension often observed with improved uremic anemia in these patients.

Adolescent↗
PubMed1998

Plasma and peritoneal endothelin levels and blood pressure in CAPD patients with or without erythropoietin replacement therapy.

The aim of the study was to determine the ET-1 concentration in peritoneal dialysate fluid and to investigate the relationship between peritoneal and plasma ET-1 levels and blood pressure in stable continuous ambulatory peritoneal dialysis (CAPD) patients with and without human recombinant erythropoietin (r-HuEPO) replacement therapy. Twenty-seven stable CAPD patients were investigated. They completed their overnight exchange at the Dialysis Centre. Blood pressure was recorded and a blood sample was drawn. Biochemical parameters and ET-1 were measured in plasma and peritoneal dialysate fluid. Mean plasma ET-1 levels were increased by about four-fold in CAPD patients. ET-1 was detectable in peritoneal dialysate fluid and a significant correlation was observed between plasma and peritoneal ET-1 concentrations (r = 0.65, p < 0.01). The peritoneal clearance of ET-1 was lower than the creatinine clearance (1.69 +/- 0.08 ml/min vs. 3.96 +/- 0.15 ml/min, p < 0.01). There was also a significant correlation between the time (months) on dialysis and plasma (r = 0.68, p < 0.01) or peritoneal dialysate ET-1 levels (r = 0.46, p < 0.05). Mean blood pressure was higher in patients treated with r-HuEPO than in untreated patients (97 +/- 4 mmHg vs. 81 +/- 4 mmHg, p < 0.01). Plasma and peritoneal dialysate ET-1 concentrations were comparable in the two groups with or without r-HuEPO replacement therapy and plasma ET-1 values correlated significantly with mean blood pressure only in r-HuEPO-treated patients (r = 0.63, p < 0.05 vs. r = 0.10, N.S. in untreated patients). In conclusion, plasma ET-1 concentrations are elevated in CAPD patients and the levels appear to increase with time on dialysis. ET-1 is cleared by the peritoneal membrane but at a much lower rate than creatinine. Blood pressure is higher in CAPD patients or r-HuEPO replacement therapy and blood pressure correlates with plasma ET-1 levels in these patients.

Ascitic Fluid↗
PubMed1997

Frequency of fetal cells in sorted subpopulations of nucleated erythroid and CD34+ hematopoietic progenitor cells from maternal peripheral blood.

Fetal cells that circulate in maternal peripheral blood (PB) during pregnancy offer a potential source of nucleated fetal material for noninvasive prenatal diagnosis. Fluorescence-activated cell sorting was used to target two populations of fetal cells: nucleated erythroid cells (NECs; CD71/glycophorin-A+ CD45(lo-int) CD34-) and hematopoietic progenitor cells (CD34+ cells; CD34++ CD71/glycophorin-A- CD45(int)). Fetal cells were detected by fluorescence in situ hybridization (FISH) using directly conjugated chromosome X and Y probes in 65% (13 of 20) of the maternal PBs (fetal karyotype 46,XY). The frequency of fetal cells isolated from the NEC and CD34+ fractions was, respectively, 0 to 14 and 0 to 7 cells per 2 x 10(7) previously frozen maternal cells (approximately 20 mL of blood). In nonfrozen samples, the yield and recovery of fetal cells was moderately improved. Culturing the CD34+ sorted fractions in serum-free media with cytokines improved the quality of the FISH preparations and resulted in a slight expansion in detectable fetal cells. The frequency of fetal cells isolated from cultured CD34+ fractions was 0 to 35 and 0 to 93 cells per 2 x 10(7) previously frozen and nonfrozen maternal PB cells, respectively. These results document the isolation, characterization, and enumeration of fetal cells from the maternal periphery that appear to be present in most, but not all, samples analyzed.

Antigens, CD34↗