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Biomedical subjects

G J Mufti

Publications and source records attributed to G J Mufti.

At least 109 records · Page 6Linked to original sources
PubMed1991

Abnormal localization of immature precursors (ALIP) in the bone marrow of myelodysplastic syndromes: current state of knowledge and future directions.

It has been suggested that the occurrence of abnormal localization of immature precursors (ALIP) in the bone marrow biopsy (BMB) may be of diagnostic and prognostic significance in myelodysplastic syndromes (MDS). The recognition of ALIP has been based exclusively on bone marrow histological appearances. During the last decade technical advances have led to the widespread use of various immunophenotypic markers for the diagnostic and prognostic purposes which has contributed enormously in understanding the development of haemopoietic cells and the cellular origin of various haematological malignancies. In addition proliferation antigens, growth factors, oncogenes, anti-oncogenes and other biological discoveries have opened new vistas to our knowledge of the normal and neoplastic growth processes. Despite this, the precise nature of ALIP and their significance in relation to the aetiopathogenesis and evolution of MDS remains unclear. Indeed the diagnostic value of ALIP in MDS is debatable. Furthermore, the precise cell lineages which comprise ALIP are not defined. The purpose of this review is to address these issues and to incorporate our new findings on the histological and immunophenotypic characterization of immature cell aggregates.

Bone Marrow↗
PubMed1991

The cytokine receptor superfamily.

The binding of haemopoietic growth factors and cytokines to specific receptors triggers a cascade of intracellular events which results in cell proliferation and differentiation. The knowledge of ligand-receptor-signal pathways is not only important in understanding the pathophysiology of malignant disease but also essential for devising future therapeutic strategies. The advent of recombinant technology has made it possible to test the efficacy of selective differentiation therapy, and haemopoietic growth factors are undergoing clinical trials for a number of indications. In addition, increasingly the receptors for haemopoietic growth factors and cytokines have come under scientific scrutiny. Recently receptors for IL-2 alpha, IL-2 beta, IL-3, IL-4, IL-5, IL-6, IL-7, erythropoietin, G-CSF and GM-CSF have been isolated and cloned. It has become apparent that they have structural homology that is shared by receptors for growth hormone and prolactin, and this receptor group makes up the new cytokine receptor superfamily. The finding of sequence homology within these receptors suggests their evolutionary relationship. These receptors are transmembrane proteins 257-856 amino acids and their extracellular ligand-binding domain contains four conserved cysteine residues and a Trp-Ser-X-Trp-Ser motif. The secondary structure of the extracellular domain is made up of alpha-helices. High and low affinity binding forms exist for all these receptors. Binding affinity may depend on the formation of receptor heterodimers or multimers, association with other membrane proteins or differential glycosylation. Soluble receptor forms have been described for IL-2 alpha, IL-4, IL-5, IL-6 and IL-7. It is not known whether they are actively secreted or represent the degradation products of cell turnover. Their function may be to mop up excess cytokines and thereby confine the cytokine response. There is no sequence homology of the intracytoplasmic domains although several are rich in proline and serine residues, which may be important in mechanisms of signal transduction. No receptor in this superfamily functions as a receptor tyrosine kinase or has intrinsic protein tyrosine kinase activity. Detailed study of individual receptors holds clues to the regulation of receptor expression, ligand-receptor interactions and mechanisms involved in signal transduction. Such knowledge might explain the pleotropic effects cytokines may have on different cell types and their overlap in biological functions. Elevated levels of soluble IL-2 alpha receptor (Tac) are detected in hairy cell leukaemia, lymphomas and adult T-cell leukaemia (TL), and levels reflect tumour burden.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1991

Cross-lineage rearrangement of antigen receptor genes in atypical chronic myeloid leukemia.

The configuration of immunoglobulin (Ig) and T-cell receptor (TCR) genes was investigated in a case of atypical chronic myeloid leukemia (aCML) lacking a cytogenetically detectable Philadelphia chromosome and molecular evidence of breakpoint cluster region (bcr) rearrangement as determined by 5' and 3' bcr gene probes. Dual clonal rearrangement of Ig-heavy (H) and TCR-delta chain genes was identified. The genes for TCR-gamma and beta chain as well as Ig-kappa (k) chain were in germline configuration. These findings indicate transformation to have occurred in a hemopoietic stem cell with the capacity for antigen receptor gene rearrangement. The demonstration of cross-lineage rearrangement of both Ig and TCR genes lends support to evidence from G6PD alloenzyme studies that the target of transformation in aCML is an early stem cell not yet irreversibly committed to myeloid differentiation. Further studies are indicated to ascertain whether antigen receptor gene rearrangement constitutes a molecular marker useful in the diagnosis of aCML.

Aged↗
PubMed1990

The insertion of chronic indwelling central venous catheters (Hickman lines) in interventional radiology suites.

The insertion of Hickman central venous catheters for chronic venous access is a procedure usually conducted in the operating theatre under local or general anaesthesia. In a prospective study over a one year period we have assessed the feasibility of radiologists inserting central venous catheters for long term access. A subclavicular approach to the subclavian vein with prior digital subtraction angiography or video imaging of the vein was the technique of choice. Thirty-one Hickman catheters were inserted in 21 patients. All but two patients had a haematological malignancy. Ages ranged from 19 to 77 years. The mean time for insertion was 43 min (range 20-80 min). The catheters remained in situ for between 2 days and 242 days with a mean of 86 days. There was one documented line infection; nine patients had episodes of septicaemia with identified organisms, and a further six had pyrexias of unknown origin during the line indwelling period. There were four documented line and or ipsilateral subclavian vein thromboses, and one death occurred within 36 hours of the procedure. We conclude that radiological placement is an excellent alternative to 'blind' surgical placement. Screening during insertion provides immediate facilities for correction of malposition and monitoring of immediate complications. The time taken for catheter insertion did not impede the usual patient throughout in the interventional radiology suite.

Adult↗
PubMed1990

Randomized multicentre study of ciprofloxacin and azlocillin versus gentamicin and azlocillin in the treatment of febrile neutropenic patients.

In a randomized multicentre study ciprofloxacin combined with azlocillin was compared with gentamicin and azlocillin for the treatment of febrile episodes in neutropenic patients. In 147 evaluable episodes in 108 patients, 80 patients received ciprofloxacin/azlocillin and 67 received gentamicin/azlocillin. The two treatment groups were comparable in terms of age, underlying diagnosis, and duration of neutropenia. Microbiologically documented infections were the cause of fever in 34 (42.5%) and 29 (43.3%) episodes in the ciprofloxacin/azlocillin and gentamicin/azlocillin groups respectively. At the end of therapy, 46 patients (57.5%) receiving ciprofloxacin/azlocillin showed complete resolution compared with 30 (44.7%) for the gentamicin/azlocillin group (P = 0.14). The clinical response rate for microbiologically documented episodes was 58.8% and 48.3% respectively (P = 0.45). Among the microbiologically documented infections with follow-up cultures available, 24 (92.3%) of 26 isolates from patients receiving ciprofloxacin/azlocillin were eradicated, in comparison with 19 (86.4%) of 22 in the gentamicin/azlocillin group (P = 0.65). There were five superinfections, all in the gentamicin/azlocillin group. Significant resistance to the study drugs was not seen. Of all evaluable patients, including those subsequently withdrawn because of early modification of therapy, there were 12 deaths within the study period; six (6.8%) of these occurred in 88 patients randomized to the ciprofloxacin/azlocillin group, compared with two of 80 (2.5%) in the gentamicin/azlocillin group. Both treatments were generally well-tolerated; one patient in the ciprofloxacin/azlocillin group developed convulsions, probably related to ciprofloxacin. The combination of ciprofloxacin and azlocillin is as effective as gentamicin plus azlocillin and offers a useful alternative for the empirical treatment of febrile neutropenic patients.

Adolescent↗
PubMed1990

Clinicopathological features of acute undifferentiated leukaemia with a stem cell phenotype.

Over a 4 1/2-year period, 141 patients with acute leukaemia had morphologic, immunophenotypic and cytochemical studies performed at King's College Hospital. Seven cases were noted to have blast cells which did not express myeloid or lymphoid antigens or cytochemical staining indicative of differentiation but were HLA DR and CD 34 positive. Based on these criteria we have used the term stem cell acute leukaemia to denote these patients. There were five women and two men with a median age of 61 years (16-86). Presentation marrows were heavily infiltrated with blasts (greater than 95% in 6/7) which were usually pleomorphic. Type 2 blasts. Auer rods and dysplastic features were absent. Two of six cases studied showed clonal karyotypic abnormalities. Four patients were treated with high dose chemotherapy. Three of these achieved a complete remission but relapsed at 3, 6 and 7 months respectively. The median survival of the group was 7 months (2-12). We conclude that the stem cell acute leukaemias are a distinct clinicomorphological group which appear to have a poor prognosis with conventional chemotherapy.

Acute Disease↗
PubMed1990

Lead poisoning: clinical, biochemical, and haematological aspects of a recent outbreak.

The clinical, biochemical, and haematological aspects of a recent outbreak of lead poisoning, in which exposure was related to the oxyacetylene cutting of red lead painted ironwork, were investigated. Initial suspicion was raised when a blood film showed punctate basophilia which remains a simple and useful method of picking up lead toxicity. Estimations of blood lead concentration and conventional laboratory data confirmed the diagnosis. Although there was prominent punctate basophilia, spectrophotometric analysis showed only negligible accumulation of pyrimidine-5'-nucleotides despite severe suppression of pyrimidine-5'-nucleotidase activity. The pattern of the red cell glycolytic intermediates, investigated for the first time, suggested that lead may also affect glycolysis at the hexokinase step. Once the diagnosis was made intravenous chelation treatment was begun with a rapid improvement in symptoms. Long term follow up is required to assess any sequelae of intoxication. These cases emphasise the classic features of lead poisoning, and despite the currently available diagnostic tests, lead intoxication may still go unrecognised unless a thorough occupational history is taken.

5'-Nucleotidase↗
PubMed1990

Palmar-plantar erythema associated with combination chemotherapy.

We report three cases of a distinctive palmar-plantar erythema associated with the treatment of non-Hodgkin's lymphoma and acute myeloid leukaemia. The rash is characterized by a painful, sharply demarcated, intense erythema of the palms and/or soles followed by bulla formation, desquamation and healing. The eruption is self limiting in nature and did not adversely affect prognosis. Treatment need be neither altered nor stopped; only symptomatic measures are required.

Adult↗
PubMed1990

Mutation of the human FMS gene (M-CSF receptor) in myelodysplastic syndromes and acute myeloid leukemia.

We studied 41 patients with myelodysplastic syndromes or acute myeloid leukemia to assess the presence of point mutations in the human FMS gene (M-CSF receptor). Using the polymerase chain reaction and hybridization of oligonucleotide probes to the amplified sequences, we have detected mutations in eight of 41 patients, at codons 301 and 969. In vitro work has highlighted mutations at these codons as being oncogenic. We now report the detection of potentially activating mutations of the human FMS gene in vivo. The consequence of these mutations in the multistep pathogenesis of myeloid malignancy and their relevance to prognosis remains to be determined.

Alleles↗
PubMed1990

Multicentric reticulohistiocytosis. Detailed immunophenotyping confirms macrophage origin.

A case study of multicentric reticulohistiocytosis is presented with extensive immunohistochemical studies of the infiltrate in both paraffin and cryostat sections. These studies showed that the cells are of monocyte/macrophage origin. B- and T-cell gene rearrangement analysis of multicentric reticulohistiocytosis was also performed and showed a germline configuration.

Cell Line↗
PubMed1990

In vitro colony culture and chromosomal studies in hepatic and portal vein thrombosis--possible evidence of an occult myeloproliferative state.

We have studied the prevalence of an underlying myeloproliferative state in 20 patients with either hepatic or portal vein thrombosis. Using conventional clinical and laboratory criteria, an underlying myeloproliferative state was identified as the cause of the thrombosis in five patients (25%). A further 10 of the remaining 15 cases were found to have characteristic in vitro bone marrow culture studies and cytogenetic abnormalities suggestive of an underlying myeloproliferative disorder. Although none of these 10 cases have developed overt clinical and laboratory features of such a myeloproliferative disorder after a median observation period of two years, the presence of clonal karyotypic abnormalities in three cases, increased megakaryocyte colony growth in three cases and endogenous erythropoietin independent colony growth of the marrow erythroid progenitors in seven cases, argues strongly in favour of a primary haematological disorder. This has important therapeutic implications, particularly in cases being considered for orthotopic liver transplantation.

Adolescent↗