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Biomedical subjects

I Peake

Publications and source records attributed to I Peake.

At least 19 recordsLinked to original sources
PubMed1998

Late relapsing childhood lymphoblastic leukemia.

Childhood lymphoblastic leukemia (ALL) is usually assumed to have been permanently eradicated in patients in long-term remission, but occasionally can recur after many years. To learn more about the problem, we studied a group of children whose leukemia had been in remission for 10 or more years before relapse and tried to determine whether they had true recurrences or second malignancies. We studied children treated on Medical Research Council ALL protocols between 1970 and 1984 and followed up by the Clinical Trial Service Unit in Oxford. Detailed clinical and laboratory data was collected from the centers concerned on all who were reported to have had a recurrence of their leukemia after 10 or more years from the time of achieving first complete remission (CR1). To prove that the relapse was a true recurrence rather than a second or secondary leukemia, DNA extracted from archived marrow smears was subjected to polymerase chain reaction (PCR) analysis for the presence of an identical Ig heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement at initial diagnosis and subsequent relapse. A total of 1,134 of 2,746 children had survived 10 years or more (range, 10 to 24 years) in CR1 and of those, 12 (approximately 1%) had subsequently relapsed. Relapse blast cells were shown to express the common ALL antigen (CD 10) in all cases and an identical clonal IgH or TCR gene rearrangement was found on PCR analysis of DNA from diagnosis and relapse in all eight cases where DNA extraction was successful. A further program of therapy was successful in inducing a second CR in all patients, four of whom have succumbed to a second relapse after 12 to 27 months. The remaining eight are in continuing CR2 at a follow-up of 12 to 108 months (median, 52) from relapse. Although the risk of relapse of childhood ALL after 10 years in remission appears to be small (around 1%), it persists. This raises questions about how blasts can survive quiescent for so long and when we can truly be confident of cure, if ever.

Adult↗
PubMed1998

The molecular basis of haemophilia A.

The cloning and isolation of the human factor VIII (FVIII) gene in the mid-1980s has lead to 10 years of increasing understanding of the genetic and hence the molecular basis of haemophilia A. These studies are not only of enormous potential benefit for accurate carrier detection and prenatal diagnosis in families with haemophilia A, but provide insights into the relationships between genetic defects and their clinical manifestations. These latter studies not only explain and even predict the severity of the disease but may also help towards a better understanding of the basis of inhibitor development.

Factor VIII↗
PubMed1997

Clonal stability in late-relapsing childhood lymphoblastic leukaemia.

We report stability of a clonal immunoglobulin heavy chain (IgH) gene rearrangement in a case of childhood acute lymphoblastic leukaemia (ALL) relapsing 17 years after completion of first-line therapy. Clonal stability was shown by polymerase chain reaction amplification of the hypervariable CDRIII region of IgH gene. Identically sized products from the original diagnostic and the second presentation samples were obtained and direct sequencing confirmed complete sequence homology. Absence of clonal evolution together with recent reports of persistent minimal residual disease in patients in long-term complete remission, suggests that 'cure' of childhood ALL may be critically dependent on effective immune surveillance to keep such disease below clinically significant levels.

Adult↗
PubMed1996

A novel DNA inversion causing severe hemophilia A.

Almost half of all cases of severe hemophilia A are caused by recurrent DNA inversions, which disrupt the factor VIII (FVIII) gene. These inversions generally occur between a region of intron 22 (int22h) and one of two homologous copies of this region, located 300 to 400 kb telomeric to the FVIII gene. They are routinely detected by a Bcl I Southern blot assay in which the sizes of two of the three normal hybridization bands are characteristically altered. However, atypical hybridization patterns have been observed, and this report describes the first detailed analysis of a hemophilia A patient with such a pattern. The abnormal result was found to be caused by a novel FVIII inversion involving an extra copy of int22h from a site only 70 to 200 kb telomeric of the FVIII gene. Polymerase chain reaction (PCR) allowed one of the inversion junctions to be analyzed, showing that the int22h sequence at this inversion junction was truncated. This patient and his novel inversion provide further evidence that int22h is associated with instability in Xq28.

Base Sequence↗
PubMed1995

Factor VIII gene inversions in severe hemophilia A: results of an international consortium study.

Twenty-two molecular diagnostic laboratories from 14 countries participated in a consortium study to estimate the impact of Factor VIII gene inversions in severe hemophilia A. A total of 2,093 patients with severe hemophilia A were studied; of those, 740 (35%) had a type 1 (distal) factor VIII inversion, and 140 (7%) showed a type 2 (proximal) inversion. In 25 cases, the molecular analysis showed additional abnormal or polymorphic patterns. Ninety-eight percent of 532 mothers of patients with inversions were carriers of the abnormal factor VIII gene; when only mothers of nonfamilial cases were studied, 9 de novo inversions in maternal germ cells were observed among 225 cases (approximately 1 de novo maternal origin of the inversion in 25 mothers of sporadic cases). When the maternal grandparental origin was examined, the inversions occurred de novo in male germ cells in 69 cases and female germ cells in 1 case. The presence of factor VIII inversions is not a major predisposing factor for the development of factor VIII inhibitors; however, slightly more patients with severe hemophilia A and factor VIII inversions develop inhibitors (130 of 642 [20%]) than patients with severe hemophilia A without inversions (131 of 821 [16%]).

Blotting, Southern↗
PubMed1995

A chromogenic assay for activated protein C resistance.

Resistance to activated protein C (APC) diagnosed on the basis of prolongation of clotting time in an activated partial thromboplastin time (aPTT) assay is now considered a major cause of inherited thrombophilia. The majority of patients with APC resistance carry a factor V molecule with a point mutation at one APC cleavage site (Arg506Gln) which prevents the optimal inactivation of activated factor V by APC. To overcome the limitations of aPTT-based assays in the diagnosis of APC resistance, we have developed a chromogenic assay which is based on the capacity of APC to limit the generation of factor Xa by inactivating factor VIIIa in plasma. The ratio of the factor Xa amidolytic activity in a sample without APC to its factor Xa activity with the addition of APC reflects the response of the plasma coagulation system to APC. The normal range in 44 healthy individuals was 1.62-2.06. APC response ratios as measured by the chromogenic assay correlated with ratios measured by the aPTT assay and were below the normal range in 23/24 individuals with Arg506Gln mutant factor V from three different families with familial thrombosis and from 11 unrelated asymptomatic individuals. In reconstitution experiments, purified factor V corrected the decreased APC response in plasma samples from patients with the Arg506Gln mutation as well as with factor V deficiency, and increased the APC response in normal plasma, whereas the addition of activated factor V had no enhancing effect.

Anticoagulants↗
PubMed1995

Molecular genetics and counselling in haemophilia.

Genetic analysis of the human factor VIII and IX genes has resulted in accurate carrier detection and prenatal diagnosis based on either informative DNA polymorphisms or on causative mutations. By combined use of up to 10 polymorphisms within the factor IX gene, over 90% of families are informative. Within the factor VIII gene the multiallelic CA repeats in introns 13 and 22 can be analysed by multiplex PCR resulting also in over 80% of families being informative. Mutation detection has developed with advancing technology which can be used to identify mutations in the factor IX gene in practically all patients with haemophilia B and their relatives. Although this is more technically demanding for patients with haemophilia A because of the greater complexity of the factor VIII gene, the recent description of X-chromosome inversions as a cause of severe haemophilia A in almost 50% of patients has led to the ready detection of these inversions in such families with associated precise carrier detection.

DNA Mutational Analysis↗
PubMed1993

Detection of carriers and prenatal diagnosis of bleeding disorders.

Carrier detection and prenatal diagnosis in the three commonest bleeding disorders (hemophilia A and B and von Wilebrands disease) can be performed either phenotypically or genotypically. Phenotypic analysis for carrier detection results only in a probabilistic assessment whereas DNA analysis, either by direct defect detection or by DNA polymorphism based gene tracking, can result in an accuracy of effectively 100%. Direct defect detection is the method of choice but can be technically demanding. Polymorphism analysis is much simpler and is now being used in family studies world wide.

Genetic Carrier Screening↗