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C Fidler

Publications and source records attributed to C Fidler.

At least 37 records · Page 2Linked to original sources
PubMed1998

Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma.

BACKGROUND: The ability to determine fetal RhD Status noninvasively is useful in the treatment of RhD-sensitized pregnant women whose partners are heterozygous for the RhD gene. The recent demonstration of fetal DNA in maternal plasma raises the possibility that fetal RhD genotyping may be possible with the use of maternal plasma. METHODS: We studied 57 RhD-negative pregnant women and their singleton fetuses. DNA extracted from maternal plasma was analyzed for the RhD gene with a fluorescence-based polymerase-chain-reaction (PCR) test sensitive enough to detect the RhD gene in a single cell. Fetal RhD status was determined directly by serologic analysis of cord blood or PCR analysis of amniotic fluid. RESULTS: Among the 57 RhD-negative women, 12 were in their first trimester of pregnancy, 30 were in their second trimester, and 15 were in their third trimester. Thirty-nine fetuses were RhD-positive, and 18 were RhD-negative. In the samples obtained from women in their second or third trimester of pregnancy, the results of RhD PCR analysis of maternal plasma DNA were completely concordant with the results of serologic analysis. Among the maternal plasma samples collected in the first trimester, 2 contained no RhD DNA, but the fetuses were RhD-positive; the results in the other 10 samples were concordant (7 were RhD-positive, and 3 RhD-negative). CONCLUSIONS: Noninvasive fetal RhD genotyping can be performed rapidly and reliably with the use of maternal plasma beginning in the second trimester of pregnancy.

Blood Grouping and Crossmatching↗
PubMed1998

Molecular cytogenetic delineation of the critical deleted region in the 5q- syndrome.

The 5q- syndrome is a distinct type of myelodysplastic syndrome (MDS) characterised by refractory anaemia, morphological abnormalities of megakaryocytes, and del(5q) as the sole cytogenetic abnormality. In contrast to patients with therapy-related MDS with 5q deletions, 5q- syndrome patients have a favourable prognosis and a low rate of transformation to acute leukaemia. We have previously delineated a common deleted region of 5.6 Mb between the gene for fibroblast growth factor acidic (FGF1) and the subunit of interleukin 12 (IL12B) in two patients with 5q- syndrome and small deletions, del(5)(q31q33). The present study used fluorescence in situ hybridisation (FISH) analysis of these and a third 5q- syndrome patient with a small deletion, del(5)(q33q34), to refine further the critical deleted region. This resulted in the narrowing of the common deleted region within 5q31.3-5q33 to approximately 3 Mb, flanked by the adrenergic receptor beta 2 (ADRB2) and IL/2B genes. The common region of loss in these three 5q- syndrome patients includes the macrophage colony-stimulating factor-1 receptor (CSF1R), secreted protein, acidic, cysteine-rich (SPARC), and glutamate receptor (GR1A1) genes. This 5q- syndrome critical region is telomeric to and distinct from the other critical regions on 5q associated with MDS and acute myeloid leukaemia.

Adult↗
PubMed1997

Novel genes mapping to the critical region of the 5q- syndrome.

The 5q- syndrome is a myelodysplastic syndrome with specific hematological features and a good prognosis. Using molecular mapping techniques, we have previously defined the critical region of gene loss of the 5q- chromosome in the 5q- syndrome as the approximately 5-Mb region at 5q31-q33 flanked by the genes for FGF1 and IL12B. This region is completely represented by a series of overlapping YACs, and we are currently generating a transcription map with the aim of identifying the tumor-suppressor gene associated with the development of the 5q- syndrome. In this study two techniques have been used: first, the screening of full-length cDNA libraries with radiolabeled YACs and second, the mapping of chromosome 5-specific expressed sequence tags (ESTs) to a YAC contig. A 1-Mb YAC contig encompassing the CSF1R gene has been used to screen a fetal brain cDNA library, and this has resulted in the identification of two genes comprising one known gene previously localized to the region (ADRB2) and one known gene previously unlocalized. Six of 135 chromosome 5-specific ESTs were localized by PCR screening to the YAC contig mapping to the critical region of the 5q- syndrome. IMAGE cDNA clones for each of the six ESTs have been obtained. These seven (excluding ADRB2) newly assigned cDNA clones were subjected to further analysis. The expression patterns of each of the cDNA clones have been established in a range of human tissues, including bone marrow. Six of seven cDNAs are expressed in human bone marrow. Six of seven cDNAs have no known homology to any deposited human sequences, and one (C29) is dihydropyrimidinase-related protein-3, a member of a novel gene family. Genomic localization and expression patterns would suggest that these newly assigned cDNAs represent potential candidate genes for the 5q- syndrome.

Chromosome Deletion↗
PubMed1997

Telomere length in myelodysplastic syndromes.

We have studied telomere length in the bone marrow cells or the granulocyte and lymphocyte cell fractions of 54 patients with myelodysplastic syndromes (MDS) by Southern blot hybridization using the (TTAGGG)4 probe. The average telomere length expressed as the peak telomere repeat array (TRA) in the peripheral blood, or bone marrow samples obtained from a group of 21 healthy age-matched controls (26-89 years old, mean age 55), ranged between 7.5 and 9.5 kb (mean peak TRA 8.6 kb). Twenty-four patients with refractory anemia (RA) were studied; 10/24 (42%) had telomere reduction (<7.5 kb) relative to age-matched controls and the mean peak TRA was 7.5 kb (range 4.0-9.0 kb). Eleven patients with RA with excess blasts (RAEB) were studied; 5/11 (45%) had reduced telomeres relative to age-matched controls and the mean peak TRA was 7.1 kb (range 5.0-9.0 kb). Eighteen patients with MDS in transformation to AML, comprising 15 with RAEB in transformation (RAEBt) and 3 with CMML in transformation (CMMLt), were also studied. Thirteen of eighteen patients (72%) had telomere reduction relative to age-matched controls and the mean peak TRA was 6.1 kb (range 3.5-9.0 kb). Thirty-six patients included in the study had either a normal karyotype or a simple karyotype (1 karyotypic change) and 20/36 (55%) of these had telomere reduction and the mean peak TRA was 7.1 kb (range 4.3-9.0 kb); 8 patients had a complex karyotype (3 or more karyotypic changes) and 5/8 (62%) of these had telomere reduction and the mean peak TRA was 6.1 kb (range 3.5-9.0 kb). We conclude, firstly that there is heterogeneity of telomere length in MDS and that this is observed throughout the spectrum of FAB-subtypes. Secondly, these data show that a marked reduction in telomere length in MDS if often associated with leukemic transformation and with the presence of complex karyotypic abnormalities.

Adult↗
PubMed1996

Molecular characterization of the 7q deletion in myeloid disorders.

Deletion of the long arm of chromosome 7 is a common karyotypic finding in myeloid disorders and in particular is found in association with secondary leukaemias. We have used restriction fragment length polymorphisms and gene dosage experiments to assess the loss or retention of sequences localized to chromosome 7q in five patients with clonal myeloid disorders and a 7q deletion. The deletion was interstitial in all cases with retention of the anonymous marker pS194 located at 7q36-qter. Three out of five cases also retained the more proximal gene T-cell receptor beta (TCR beta) located at 7q35. The proximal breakpoints of all five cases were localized to 7q22 by cytogenetic analysis. In two cases the proximal breakpoint lay between the genes for elastin (ELN) and collagen type 1 alpha (COL1A2) and in three cases distal to this region between the genes for erythropoietin (EPO) and acetylcholinesterase (ACHE). The genes of ACHE, plasminogen activator inhibitor 1 (PLANH1), CCAAT displacement protein (CUTL1) and Met proto-oncogene (MET) were deleted in all cases. Molecular analysis of the 7q deletion in myeloid leukaemias demonstrates heterogeneity of the breakpoints, supporting a recessive mechanism of tumourigenesis.

Adult↗
PubMed1996

Amplification of mitochondrial DNA in acute myeloid leukaemia.

There is a long-standing interest in the possible role of mitochondria in malignancy. We sought to discover whether amplification of mitochondrial DNA (mtDNA) occurred in leukaemia, and found it was often remarkably amplified in the blast cells of acute myeloid leukaemia (AML). We used gene dosage experiments to quantify the amount of mtDNA relative to nuclear DNA. DNA extracted from peripheral blood leucocytes or bone marrow of healthy individuals or patients was simultaneously hybridized with a probe for the mitochondrial genome and a control probe for the renin gene on human chromosome 1. Comparative densitometric ratios of approximately 1 were obtained between the two signals in 20 normal control peripheral blood samples. In contrast, comparative ratios in the range of 2-50 were observed in 25 AML samples and 13 of these showed 8-fold or greater amplification of mtDNA relative to normal peripheral blood controls. An additional four cases of AML were investigated at both presentation and remission and showed 3-10-fold amplification of mtDNA at presentation, but no amplification when in clinical remission. 18 cases of chronic granulocytic leukaemia (CGL) were also studied in chronic phase and showed mtDNA dosage levels equivalent to normal peripheral blood controls. However, 8/9 CGL patients showed mtDNA amplification during transformation from chronic phase. We conclude that amplification of mtDNA is an invariable feature of acute myeloid leukaemia and that it may be a useful marker for detecting transformation of CGL.

Acute Disease↗
PubMed1995

Chromosomal deletions in myelodysplasia.

There are two major classes of genes implicated in human tumorigenesis, the oncogenes and the tumour suppressor genes. In haematological malignancies most emphasis has been placed upon the recurring translocations in which the juxtaposition of two gene sequences has resulted in the activation of an oncogene. Chromosomal loss rather than translocation is the most frequent karyotypic abnormality in the myelodysplastic syndromes, a heterogeneous group of clonal malignant blood disorders characterised by dyshaematopoiesis and/or impaired maturation of haemopoietic cells with frequent evolution to acute leukaemia. Recent attention has focused on the loss of genetic material as a result of chromosomal monosomy or deletion in the myelodysplastic syndromes. The most frequently reported deletions in these myeloid syndromes are of chromosomes 5, 20 and 7. Deletions of chromosomes 11, 12, and 13, although more rarely observed, are also characteristics of the myelodysplastic syndromes. It is probable that the deleted chromosomal bands give the location for as yet unidentified myeloid specific tumour suppressor loci and there is considerable interest in the cloning of these genes. This review discusses the three most frequently observed deletions in MDS; 7q deletion, 5q deletion and 20q deletion taking into account recent evidence on the respective critical regions of gene loss and the role of candidate genes.

Animals↗
PubMed1994

Molecular mapping of uncharacteristically small 5q deletions in two patients with the 5q- syndrome: delineation of the critical region on 5q and identification of a 5q- breakpoint.

Molecular mapping techniques have defined the region of gene loss in two patients with the 5q- syndrome and uncharacteristically small 5q deletions (5q31-q33). The allelic loss of 10 genes localized to 5q23-qter (centromere-CSF2-EGR1-FGFA-GRL-ADRB2-CS F1R-SPARC-GLUH1-NKSF1-FLT4-telomere) was investigated in peripheral blood cell fractions. Gene dosage experiments demonstrated that CSF2, EGR1, NKSF1, and FLT4 were retained on the 5q- chromosome in both patients and that FGFA was retained in one patient, thus placing these genes outside the critical region. GRL, ADRB2, CSF1R, SPARC, and GLUH1 were shown to be deleted in both patients. The proximal breakpoint is localized between EGR1 and FGFA in one patient and between FGFA and ADRB2 in the other, and the distal breakpoint is localized between GLUH1 and NKSF1 in both patients. Pulsed-field gel electrophoresis was used to map the 5q deletion breakpoints, and breakpoint-specific fragments were detected with FGFA in the granulocyte but not the lymphocyte fraction of one patient. This study has established the critical region of gene loss of the 5q- chromosome in the 5q- syndrome, giving the location for a putative tumor-suppressor gene in the 5.6-Mb region between FGFA and NKSF1.

Adult↗
PubMed1993

Allelic loss of IRF1 in myelodysplasia and acute myeloid leukemia: retention of IRF1 on the 5q- chromosome in some patients with the 5q- syndrome.

Acquired interstitial deletions of the long arm of chromosome 5 occur frequently in the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Recently IRF1, a putative tumor suppressor gene localized to the long arm of chromosome 5, has been shown to be deleted from the 5q- chromosome in a group of patients with MDS and AML. It has been suggested that the loss of IRF1 may be critical to the development of the 5q- syndrome. We have investigated the allelic loss of IRF1 in a group of 12 patients with MDS and a 5q deletion and 2 patients with AML and a 5q deletion. Gene dosage experiments demonstrated that 12 of 14 patients had loss of one allele of the IRF1 gene but no evidence of homozygous loss and that 2 patients with 5q- syndrome retained both copies of the gene. The retention of IRF1 on the 5q- chromosome in these two cases has been confirmed by fluorescent in situ hybridization localization using an IRF1 cosmid. Pulsed field gel electrophoresis was used to determine whether there was any evidence for structural rearrangement in the region encompassing the IRF1 gene in these two patients. No aberrant bands were detected with a range of rare cutter enzyme digests. We conclude that IRF1 maps outside the commonly deleted segment of the 5q- chromosome and that loss of IRF1 is not solely responsible for the development of the 5q- syndrome.

Adult↗
PubMed1993

Pulsed field gel electrophoresis on single murine hemopoietic colonies.

We report a technique which allows for the direct molecular analysis of single whole murine hemopoietic colonies by pulsed field gel electrophoresis (PFGE). Murine bone marrow cells were plated out in semi-solid agarose and gave rise to macroscopic colonies after 11 days in culture. Single colonies were excised from the agarose using a sterile blade and embedded without further manipulation in molten low-melting-temperature agarose. The leucocyte DNA contained within the agarose plug was subjected to restriction enzyme digestion and PFGE. Sufficient high molecular weight DNA is afforded by this method to achieve a hybridization signal with a single copy probe. This method will make PFGE directly applicable to the clonal analysis of chromosomal aberrations in hemopoietic stem and progenitor cells.

Animals↗
PubMed1992

Vigabatrin in adults with poorly-controlled epilepsy and learning disabilities.

Twenty-two adult patients with uncontrolled epilepsy and severe learning difficulties were included in an open study of vigabatrin. Patients were all in residential care and had experienced at least 12 seizures during the previous 12 months despite all attempts to optimize antiepileptic drug (AED) treatment. Following a 4 month baseline period, vigabatrin 500 mg twice daily was added to the current AED treatment and the dose increased according to response, up to a maximum of 4 g/day. Ten patients achieved a reduction in seizure frequency of more than 50% during this 4 month dose titration phase. Two patients had no seizures during the baseline period. For the 30 patients with seizures during the baseline period the median improvement in seizure frequency with the addition of vigabatrin was 49% (P = 0.014). The response rate was higher for patients with partial seizures than for those with generalized seizures. Ten patients continued with vigabatrin while the dose of one of their other AEDs was gradually reduced and successfully withdrawn in three patients. Adverse events were reported in 20 patients during the 64 week study period. The most frequently reported events were sedation (8 patients), aggression (4 patients), agitation (3 patients) and ataxia (3 patients). No patients were withdrawn from the study as a consequence of adverse events. Vigabatrin was therefore an effective add-on therapy in 45% of these difficult-to-treat patients and allowed reduction of other AED treatment in a small number.

Adolescent↗
PubMed1991

Multicenter, crossover study of the efficacy and tolerability of terfenadine, 120 mg, versus cetirizine, 10 mg, in perennial allergic rhinitis.

In this 3-week randomized, double-blind, double-dummy multicenter, crossover study terfenadine, 120 mg, was compared with cetirizine, 10 mg, both given once daily in the treatment of perennial allergic rhinitis in sixty patients. Compared with the investigators' pretreatment assessment, both terfenadine and cetirizine significantly reduced the severity of all five symptoms (P less than .001). The two treatments were equally effective in controlling eye irritation, sneezing, nasal congestion and itchy nose, throat and palate, but cetirizine improved rhinorrhea more than terfenadine (P less than .05). Daily symptom assessments by the patients for the last 14 days of each treatment period showed no difference in efficacy between the two drugs for any of the symptoms. There were also no differences between the two drugs for overall assessments of efficacy or patient preference. Adverse events were recorded more frequently while taking cetirizine, with 14 attributable events compared with only five with terfenadine. Four of the cetirizine-related events were drowsiness or tiredness, but none was reported while patients were taking terfenadine. There was a tendency to increased weight (greater than 1 kg) with both treatments.

Adult↗
PubMed1990

Multicentre, double-blind comparison of terfenadine and cetirizine in patients with seasonal allergic rhinitis.

This double-blind, multicentre study was designed to compare the efficacy and tolerability of terfenadine 120 mg with cetirizine 10 mg, each taken once daily, in the treatment of seasonal allergic rhinitis. Two hundred and eighty-five patients were recruited to the study by nine general practice centres in the south of England during the 1989 hay-fever season. Symptom severity was assessed daily by the patient and before and after the one-week treatment period by the investigator. At the second clinic visit both patient and investigator assessed the overall response to treatment. The two treatment groups were well matched for all demographic variables and baseline symptom scores. Improvement in all seven symptoms (nasal congestion, sneezing, rhinorrhoea, itching nose, itching eyes, watery eyes and red eyes) and overall response to treatment were similar in both treatment groups. Adverse events were mainly of mild to moderate severity and were reported by 14 patients on terfenadine and 21 patients treated with cetirizine (p = 0.317). This study confirmed terfenadine's role as the treatment of choice in hayfever. A single 120 mg dose in the morning effectively reduced symptoms by 43 to 70 per cent of baseline values, with an acceptably low incidence of side effects. Cetirizine at a single dose of 10 mg displayed equal efficacy in controlling hayfever symptoms but, in common with other studies, had a significantly greater incidence of drowsiness (p = 0.046).

Adult↗
PubMed1990

Treatment of seasonal allergic rhinitis: a comparison of a combination tablet of terfenadine and pseudoephedrine with the individual ingredients.

This single-centre, double-blind, parallel randomised study of one week's duration compared terfenadine 40 mg, pseudoephedrine 60 mg and a combination of the two (40 mg/60 mg) given three times a day in the management of hayfever. Of 88 known hayfever sufferers recruited during the 1988 season 86 were evaluable for efficacy. Demographic data were similar, but some significant differences in baseline symptom values made direct comparison of post-treatment scores difficult to interpret. Nevertheless, comparisons of improvements from baseline show that all three treatments provide good control of the individual seven symptoms (nasal block, sneezing, runny nose, itchy nose, watery eyes, red eyes, itchy eyes). Terfenadine provided a statistically greater improvement in mean total symptom score than pseudoephedrine alone. Overall assessments favoured terfenadine and the combination, and rhinoscopy examination showed a trend in favour of terfenadine alone. Adverse events were recorded more frequently in the combination group: 45% of patients versus 21% in the terfenadine group and 26% in the pseudoephedrine group. In this group of patients, terfenadine, pseudoephedrine or a combination provide good relief of hayfever symptoms, including nasal block, with terfenadine and the combination being preferred to pseudoephedrine in the treatment of this condition. However, the combination can be expected to cause a greater incidence of side-effects.

Adolescent↗
PubMed1990

A comparative study of terfenadine at two dose levels in the management of hayfever.

One hundred and twenty patients with hayfever were enrolled in a single-centre, double-blind crossover study designed to compare the efficacy and safety of terfenadine at doses of 60 mg bd and 120 mg bd. A two-week placebo run-in period was followed by the two treatment periods, each lasting two weeks. Assessments of hayfever symptoms were made daily by patients and at each clinic visit by the investigator. Adverse events were recorded at the end of each treatment period. At the end of the study both investigator and patient rated the overall efficacy and the patient recorded treatment preference. The data were examined by analysis of variance (ANOVA) for treatment, period and crossover effects. Pollen counts were recorded for the duration of the study. Seventy-four patients completed the study, the majority of withdrawals occurring during the placebo phase. There was no significant difference in symptom relief between the two doses of terfenadine. The number of adverse events, including drowsiness, was similar for the two treatments and for placebo. Mean and peak pollen counts both correlated well with symptom severity. These data show that terfenadine 60 mg bd is an adequate dose for the treatment of hayfever symptoms.

Adult↗