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Biomedical subjects

R G Gray

Publications and source records attributed to R G Gray.

At least 19 recordsLinked to original sources
PubMed2001

Immunological phenotyping of fibroblast cultures from patients with a mitochondrial respiratory chain deficit.

Conventional approaches to the diagnosis of mitochondrial respiratory chain diseases, using enzyme assays and histochemistry, are laborious and give limited information concerning the genetic basis of a deficiency. We have evaluated the diagnostic value of 12 monoclonal antibodies to subunits of the four respiratory chain enzyme complexes and F(1)F(0)-ATP synthase. Antibodies were used in immunological studies with skin fibroblast cultures derived from patients with diverse mitochondrial diseases, including patients in which the disease was caused by a nuclear genetic defect and patients known to harbor a heteroplasmic mutation in a mitochondrial tRNA gene. Immunoblotting experiments permitted the identification of specific enzyme assembly deficits and immunocytochemical studies provided clues regarding the genetic origin of the disease. The immunological findings were in agreement with the biochemical and genetic data of the patients. Our study demonstrates that characterization of the fibroblast cultures with the monoclonal antibodies provides a convenient technique to complement biochemical assays and histochemistry in the diagnosis of mitochondrial respiratory chain disorders.

Adult↗
PubMed2001

Intraoral molluscum contagiosum: a report of a case and a review of the literature.

Molluscum contagiosum (MC) occurring on the face, lips, and perioral region is a relatively common manifestation of this infectious disease. MC of the intraoral mucosa has been documented, but is rare. This report details the case of a 52-year-old HIV-seropositive man with MC of the gingiva. A review of the literature discloses only 4 previously reported cases of intraoral MC.

AIDS-Related Opportunistic Infections↗
PubMed2000

Cytochrome oxidase deficiency presenting as birth asphyxia.

Hypoxic-ischaemic encephalopathy (HIE) was diagnosed in an infant with acidosis. At 7 weeks of age further investigations revealed abnormal neuroimaging (CT and MRI scans) and a raised plasma and CSF lactate. A skeletal-muscle biopsy at 2 months of age confirmed the diagnosis of cytochrome oxidase deficiency. The course of the patient's disorder has taken that of a static encephalopathy (cerebral palsy). Inborn disorders of the respiratory chain should be considered in the differential diagnosis of HIE.

Acidosis, Lactic↗
PubMed2000

Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency.

Three patients have been reported with (putative) methylmalonic semialdehyde dehydrogenase (MMSDH) deficiency. The urine metabolic pattern was strikingly different in all, including beta-alanine, 3-hydroxypropionic acid, both isomers of 3-amino- and 3-hydroxyisobutyric acids in one and 3-hydroxyisobutyric and lactic acids in a second, and mild methylmalonic aciduria in a third patient. In an effort to clarify these disparate metabolite patterns, we completed the cDNA structure, and characterized the genomic structure of human MMSDH gene in order to undertake molecular analysis. Only the first patient had alterations in the MMSDH coding region, revealing homozygosity for a 1336G > A transversion, which leads to substitution of arginine for highly conserved glycine at amino acid 446. No abnormalities of the MMSDH cDNA were detected in the other patients. These data provide the first molecular characterization of an inborn error of metabolism specific to the L-valine catabolic pathway.

Aldehyde Oxidoreductases↗
PubMed1999

Severe adverse impact on sexual functioning and fertility of bone marrow transplantation, either allogeneic or autologous, compared with consolidation chemotherapy alone: analysis of the MRC AML 10 trial.

BACKGROUND: Data relating to the impact of bone marrow transplantation (BMT) on sexual functioning are equivocal; some studies have shown no major impact whereas others demonstrate a significant adverse effect on sexual health in patients treated with BMT. Further clarification is required to facilitate treatment choices and follow-up management of patients. METHODS: A cross-sectional study of sexual health and infertility was conducted in 479 patients with acute myeloid leukemia (AML) in first complete remission (CR) who were entered into the UK MRC AML 10 trial comparing allogeneic BMT (Allo-BMT), autologous BMT (A-BMT), and intensive consolidation chemotherapy (CCT). Assessment was made by patient questionnaire via the treating centers for completion and returned directly to the coordinating center. RESULTS: Both Allo-BMT and A-BMT were observed to have severe, highly significant adverse effects on the patients' sexual health. Significantly more BMT patients than CCT patients reported a decrease in interest in sex (48% vs. 24%), sexual activity (53% vs. 35%), pleasure from sex (36% vs. 18%), and ability to have sex (38% vs. 18%) (P < 0.001 in each case). Hormonal disorders and infertility also were more common in BMT patients than in CCT patients. These differences were more apparent in women and remained after adjustment for age. CONCLUSIONS: These results indicate a need to consider quality of life parameters when reviewing treatment options and to instigate effective proactive management strategies for dealing with sexual health problems in leukemia survivors.

Acute Disease↗
PubMed1999

Mitochondrial DNA depletion syndrome is expressed in amniotic fluid cell cultures.

Mitochondrial DNA depletion syndrome is an autosomal inherited disease associated with grossly reduced cellular levels of mitochondrial DNA in infancy. Most patients are born after a full and uncomplicated pregnancy, are normal at birth, but develop symptoms in the early neonatal period. These observations have led to the suggestion that the patients have a defect affecting the control of mitochondrial DNA copy number after birth. Using immunocytochemical techniques, we demonstrated that the disease is already expressed in amniotic fluid cells. Detection of mitochondrial DNA depletion in these fetal cells indicates that the defect may already be expressed early in embryological development.

Amniotic Fluid↗
PubMed1999

A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council's Adult and Childhood Leukaemia Working Parties.

Data on 1711 patients, aged up to 55 years, in the MRC AML 10 trial were used to create a prognostic index for use in risk-directed therapy decision making for younger patients with acute myeloid leukaemia (AML). Two parameters, response after course 1 and cytogenetics, were strongly predictive of outcome. For patients with complete remission, partial remission and resistant disease, 5-year survival from the start of course 2 was 53%, 44% and 22% and relapse rates were 46%, 48% and 69% respectively, and for patients with favourable, intermediate and adverse karyotypic abnormalities, survival was 72%, 43% and 17% and relapse rates were 34%, 51% and 75% respectively (all P < 0.0001). Patients with FAB type M3 but no cytogenetic t(15;17) also had a low relapse rate (29%). These three factors were combined to give three risk groups: good (favourable karyotype or M3, irrespective of response status or presence of additional abnormalities), standard (neither good nor poor), poor (adverse karyotype or resistant disease, and no good-risk features). Survival for these three groups was 70%, 48% and 15% respectively and relapse rates were 33%. 50% and 78% (both P < 0.0001). The index is simple (based on just three parameters), robust (derived from 1711 patients), highly discriminatory (55% survival difference between good and poor risk) and validated, so can be applied in the clinical setting to assist with therapeutic decisions as in the current AML 12 trial.

Acute Disease↗
PubMed1999

Identification and characterization of three novel missense mutations in mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene biosynthesis.

Mevalonic aciduria is a rare autosomal recessive metabolic disorder, characterized by psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. The disorder is caused by a deficient activity of mevalonate kinase due to mutations in the encoding gene. Thus far, only two disease-causing mutations have been identified. We now report four different missense mutations including three novel ones, which were identified by sequence analysis of mevalonate kinase cDNA from three mevalonic aciduria patients. All mutations affect conserved amino acids. Heterologous expression of the corresponding mutant mevalonate kinases as fusion proteins with glutathione S -transferase in Escherichia coli showed a profound effect of each of the mutations on enzyme activity. In addition, immunoblot analysis of fibroblast lysates from patients using specific antibodies against mevalonate kinase identified virtually no protein. These results demonstrate that the mutations affect not only the activity but also the stability of the mutant proteins.

Adolescent↗
PubMed1998

Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children's Leukaemia Working Parties.

BACKGROUND: Three strategies are used to prevent relapse in patients with acute myeloid leukaemia in first remission. Most of those with suitable donors are offered allogeneic haemopoietic-stem-cell transplant. Other patients may receive intensive chemotherapy or autologous transplantation; we undertook this randomised prospective trial to assess which is the better option. METHODS: After three courses of intensive chemotherapy, bone marrow was harvested from patients (<56 years of age) in remission who lacked an HLA-matched sibling donor. These patients were then randomised to receive, after one more course of chemotherapy, no further treatment (n=191) or an autologous bone-marrow transplant (BMT) after preparation with cyclophosphamide and total-body irradiation (n=190). Outcome comparisons were by intention to treat with adjustment for the most important risk factors for relapse. FINDINGS: 381 patients were randomised (38% of those eligible). Of the 190 patients allocated autologous BMT, 126 received it. On intention-to-treat analysis the number of relapses was substantially lower in the autologous BMT group than in the group assigned no further treatment (64/190 [37%] vs 101/191 [58%], p=0.0007), resulting in superior disease-free survival at 7 years (53 vs 40%; p=0.04). These benefits were observed in all risk groups and age-groups. There were more deaths in remission in the autologous BMT group than in the no further treatment group (22 [12%] vs 7 [4%], p=0008). In children (<15 years) and patients with good-risk disease, survival from relapse in the no further treatment group was 35% and 38% at 2 years. There was an overall survival advantage in the autologous BMT group at 7 years (57 vs 45%, p=0.2). INTERPRETATION: The addition of autologous BMT to four courses of intensive chemotherapy substantially reduces the risk of relapse in all risk groups, leading to improvement in long-term survival. The good chance of salvage for children or patients with good-risk disease who relapse from chemotherapy, and the mortality, morbidity, late effects, and expense of autologous BMT, suggest that delay of autograft until second remission in these two groups may be appropriate.

Acute Disease↗
PubMed1998

Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene.

X-linked liver glycogenosis (XLG) resulting from phosphorylase kinase (Phk) deficiency is one of the most common forms of glycogen storage disease. It is caused by mutations in the gene encoding the liver isoform of the Phk alpha subunit (PHKA2). In the present study, we address the issue of phenotypic and allelic heterogeneity in XLG. We have identified mutations in seven male patients. One of these patients represents the variant biochemical phenotype, XLG subtype 2 (XLG2), where Phk activity is low in liver but normal or even elevated in erythrocytes. He carries a K189E missense mutation, which adds to the emerging evidence that XLG2 is associated with missense mutations clustering at a few sites. Two patients display clinical phenotypes unusual for liver Phk deficiency, with dysfunction of the kidneys (proximal renal tubular acidosis) or of the nervous system (seizures, delayed cognitive and speech abilities, peripheral sensory neuropathy), respectively, in addition to liver glycogenosis. In the patient with kidney involvement, we have identified a missense mutation (P399S) and a trinucleotide deletion (2858del3) leading to the replacement of two amino acids by one new residue (N953/L954I), and a missense mutation has also been found in the patient with neurological symptoms (G1207W). These two cases demonstrate that PHKA2 mutations can also be associated with uncommon clinical phenotypes. Finally, in four typical XLG cases, we have identified three truncating mutations (70insT, R352X, 567del22) and an in-frame deletion of eight well-conserved amino acids (2452del24). Together, this study adds eight new mutations to the previously known complement of sixteen PHKA2 mutations. All known PHKA2 mutations but one are distinct, indicating pronounced allelic heterogeneity of X-linked liver glycogenosis with mutations in the PHKA2 gene.

Amino Acid Sequence↗
PubMed1998

Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial. MRC Childhood Leukaemia Working Party.

359 eligible children with acute myeloid leukaemia (AML) entered the MRC AML 10 trial between May 1988 and March 1995. Patients received four courses of intensive induction and consolidation chemotherapy, with or without subsequent autologous (A-BMT) or allogeneic (allo-BMT) bone marrow transplant. There were randomized comparisons of thioguanine versus etoposide in induction and of A-BMT versus not. Allo-BMT was recommended for patients with a HLA-matched sibling and was evaluated by donor versus no donor comparison. The complete remission rate was 92%. In first remission there were 20 deaths during consolidation chemotherapy and 11 after BMT (8/61 allo-BMTs. 1/60 A-BMTs and 2/4 matched unrelated donor transplants). The relapse rate was low, decreasing from 26% in the first year to 2% in the fourth. Long-term outcome was excellent with survival at 7 years from entry of 56% and event-free survival of 48%. There were no significant differences between thioguanine and etoposide, whereas both A-BMT and allo-BMT reduced relapse risk but did not produce a significant survival benefit. It appears that over half the children entered into AML 10 are cured, a result which compares favourably with other reported series. We conclude that four courses of intensive chemotherapy are an effective approach to the treatment of paediatric AML, which avoids the acute toxicity and long-term side-effects of BMT and also avoids the need for prolonged maintenance therapy or cranial irradiation.

Acute Disease↗
PubMed1998

A case of Ohtahara syndrome with cytochrome oxidase deficiency.

Ohtahara syndrome is a rare cause of epileptic seizures during the neonatal period. This is believed to be the first report of this syndrome with a specific metabolic defect. Defects in respiratory chain function may be more common than previously assumed in patients with this epilepsy syndrome.

Cytochrome-c Oxidase Deficiency↗
PubMed1998

Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkin's disease: a meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkin's Disease Collaborative Group.

PURPOSE: To assess the effect of more extensive radiotherapy and of adjuvant combination chemotherapy on long-term outcome of early-stage Hodgkin's disease. METHODS: In a collaborative worldwide systematic overview, individual patient data were centrally reviewed on 1,974 patients in eight randomized trials of more versus less extensive radiotherapy and on 1,688 patients in 13 trials of radiotherapy plus chemotherapy versus radiotherapy alone. Crude mortality data on 226 patients in two other trials of chemotherapy were also reviewed. RESULTS: More extensive radiotherapy reduced the risk of treatment failure (resistant or recurrent disease) at 10 years by more than one third (31.3% v 43.4% failures; P < .00001), but there was no apparent improvement in overall 10-year survival (77.1 % v 77.0% alive). The addition of chemotherapy to radiotherapy halved the 10-year risk of failure (15.8% v 32.7%; P < .00001), with a small, nonsignificant improvement in survival (79.4% v 76.5% alive). This involved a reduction of borderline significance for deaths from Hodgkin's disease (12.3% v 15.4% dead at 10 years; P = .07), which was partly counterbalanced by a nonsignificant excess of deaths from other causes (12.4% v 10.0% 10-year risk). CONCLUSION: More extensive radiotherapy fields or the addition of chemotherapy to radiotherapy in the initial treatment of early-stage Hodgkin's disease had a large effect on disease control, but only a small effect on overall survival. Recurrences could be prevented by more extensive radiotherapy or by additional chemotherapy. However, if chemotherapy had not been given initially, recurrences were generally salvageable by re-treatment with chemotherapy. Hence, less intensive primary treatment--particularly a reduction in radiotherapy fields--appears to achieve similar survival rates as more intensive treatment, although more randomized evidence is needed to confirm this.

Antineoplastic Agents↗
PubMed1997

Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council.

The relative efficacy and toxicity of the chemotherapeutic agents thioguanine (6TG) and etoposide (VP16) were assessed by a randomized comparison of the DAT (daunorubicin, cytarabine, thioguanine) versus ADE (daunorubicin, cytarabine, etoposide) regimens in the Medical Research Council's 10th acute myeloid leukaemia trial (MRC AML 10), which was open to patient entry from May 1988 to April 1995. In this, the largest reported trial of AML therapy to date, 1,857 eligible patients, mostly less than 56 years old, were randomized: 929 (including 143 children under 15 years old) were allocated to DAT and 928 (143 children) to ADE. The two groups were well matched for presentation features. The complete remission (CR) rate was 81% with DAT and 83% with ADE (P = .3). The percentages of remitters achieving remission after 1, 2, or more than 2 courses were 70%, 22%, and 8% for DAT and 74%, 21%, and 5% for ADE. The percentages failing to achieve a CR due to resistant disease were 11% with DAT versus 9% with ADE (P = .07). There was a slightly higher death rate in CR during consolidation chemotherapy with ADE (9%) than with DAT (6%) (P = .06). Patients receiving DAT took slightly but significantly longer to recover from neutropenia and thrombocytopenia but the median number of days in hospital were similar in each group. ADE patients experienced slightly more severe nonhematologic toxicity. There was also no significant difference between the groups in the longer-term measures of efficacy: disease-free survival at 6 years from CR was 42% (+/-4) for DAT and 43% (+/-4) for ADE (P = .8); relapse rate at 6 years was 50% (+/-4) for DAT and 49% (+/-5) for ADE (P = .6); survival at 6 years was 40% (+/-4) for both DAT and ADE (P = .9). Subgroup analysis failed to show any benefit for etoposide in patients with monocytic or myelomonocytic disease, or in any other diagnostic subgroup. In conclusion, DAT and ADE both achieve high remission rates and good long-term survival, and are equally effective chemotherapy regimens for the treatment of AML patients aged up to 55 years.

Acute Disease↗
PubMed1997

Ethylmalonic adipic aciduria--a treatable hepatomuscular disorder in two adult brothers.

An adult male presented at 28 years of age with muscle weakness and liver dysfunction. His brother had died suddenly 2 years earlier after presenting with Reye's syndrome. Urine organic acid analysis and muscle and cultured fibroblast fatty acid oxidation studies confirmed a diagnosis of ethylmalonic/adipic aciduria-an inherited defect of fatty acid oxidation. The patient responded favourably to treatment with a low fat/high carbohydrate diet supplemented with riboflavin. This case highlights the importance of considering inborn errors of metabolism, in particular fatty acid oxidation defects, in adults with liver disease, muscle disease or Reye's syndrome.

Adipates↗