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A Jacobs

Publications and source records attributed to A Jacobs.

At least 163 records · Page 9Linked to original sources
PubMed1991

Detection of two-component mixtures of lognormal distributions in grouped, doubly truncated data: analysis of red blood cell volume distributions.

We have examined the statistical requirements for the detection of mixtures of two lognormal distributions in doubly truncated data when the sample size is large. The expectation-maximization algorithm was used for parameter estimation. A bootstrap approach was used to test for a mixture of distributions using the likelihood ratio statistic. Analysis of computer simulated mixtures showed that as the ratio of the difference between the means to the minimum standard deviation increases, the power for detection also increases and the accuracy of parameter estimates improves. These procedures were used to examine the distribution of red blood cell volume in blood samples. Each distribution was doubly truncated to eliminate artifactual frequency counts and tested for best fit to a single lognormal distribution or a mixture of two lognormal distributions. A single population was found in samples obtained from 60 healthy individuals. Two subpopulations of cells were detected in 25 of 27 mixtures of blood prepared in vitro. Analyses of mixtures of blood from 40 patients treated for iron-deficiency anemia showed that subpopulations could be detected in all by 6 weeks after onset of treatment. To determine if two-component mixtures could be detected, distributions were examined from untransfused patients with refractory anemia. In two patients with inherited sideroblastic anemia a mixture of microcytic and normocytic cells was found, while in the third patient a single population of microcytic cells was identified. In two family members previously identified as carriers of inherited sideroblastic anemia, mixtures of microcytic and normocytic subpopulations were found. Twenty-five patients with acquired myelodysplastic anemia were examined. A good fit to a mixture of subpopulations containing abnormal microcytic or macrocytic cells was found in two. We have demonstrated that with large sample sizes, mixtures of distributions can be detected even when distributions appear to be unimodal. These statistical techniques provide a means to characterize and quantify alterations in erythrocyte subpopulations in anemia but could also be applied to any set of grouped, doubly truncated data to test for the presence of a mixture of two lognormal distributions.

Adolescent↗
PubMed1991

Regulation of intestinal iron absorption and mucosal iron kinetics in hereditary hemochromatosis.

In hereditary hemochromatosis (HH), increased intestinal iron absorption leads to the development of iron overload. To examine the abnormal regulation of iron absorption in this disorder, we analyzed mucosal iron kinetics in six patients with HH and in five normal subjects by using a compartmental model of intestinal iron absorption and systemic ferrokinetics. Subjects were given simultaneous oral and intravenous tracer doses of iron 59-labeled citrate and iron 55-labeled transferrin, respectively. Plasma and whole-body radioactive iron levels were then monitored serially during the next 2 weeks, and mucosal iron transport rate constants were estimated by non-linear least-squares fit of the model to these data. Iron absorption was inversely related to serum ferritin concentration in both normal subjects and patients with HH but was higher in relation to serum ferritin level among the latter (p less than 0.0002). Analysis of mucosal iron kinetics demonstrated a similar inverse relationship between the rate constant for mucosal iron uptake and serum ferritin among all subjects combined, but the mean uptake rate constant in patients with HH did not differ from that of normal subjects (p = 0.71). The mean rate constant for incorporation of iron into the mucosal storage pool in patients with HH also was comparable to that of normal subjects (p = 0.94). In contrast, the rate constant for transfer of mucosal iron to the plasma was higher in patients with HH than in normal subjects for any given serum ferritin level (p less than 0.0001), and the transfer rate constant accounted for 87% of the variability in iron absorption among all subjects. We conclude that the increased iron absorption in HH is mediated primarily by an increase in the rate constant for transfer of mucosal iron to the plasma.

Ferritins↗
PubMed1990

Plant chromosome/marker gene fusion assay for study of normal and truncated T-DNA integration events.

During Agrobacterium tumefaciens infection, the T-DNA flanked by 24 bp imperfect direct repeats is transferred and stably integrated into the plant chromosome at random positions. Here we measured the frequency with which a promoterless reporter gene is activated after insertion into the Nicotiana tabacum SR1 genome. When adjacent to the right or left T-DNA border sequences, at least 35% of the transformants express the marker gene, suggesting preferential T-DNA insertion (greater than 70%) in transcriptionally active regions of the plant genome. When the promoterless neomycin phosphotransferase II (nptII) gene is located internally in the T-DNA, the activation frequency drops to 1% since gene activation requires T-DNA truncation. These truncation events in the nptII upstream region occur independently of the nature of the upstream sequence and of the T-DNA length. Deletion of the right border region prevents the detection of activated marker genes. Therefore, T-DNA truncation probably occurs after synthesis of a normal T-DNA intermediate during the transfer and/or integration process. In the absence of border regions, expression of the nptII selectable marker directed by the nopaline synthase promoter was detected in 1 out of 10(5) regenerated calli, suggesting the possibility that any DNA sequence from the Ti plasmid can be transformed into the plant genome, albeit at a low frequency.

Base Sequence↗
PubMed1990

Consolidating the role of *I-MIBG-scintigraphy in childhood neuroblastoma: five years of clinical experience.

In recent years, *I-MIBG (*I-metaiodobenzylguanidine), which is transported and stored in the chromaffin cells, has been shown to allow good visualization of neuroblastomas in children. This paper deals with 30 *I-MIBG-scans performed in 20 children: 16 with neuroblastoma, 3 with retinoblastoma, and 1 with a malignant paraganglioma. A high detection rate was found for both primary and secondary sites of neuroblastoma. *I-MIBG was generally superior to 99mTc-MDP bone scintigraphy in the detection of bone metastases. Our experience illustrates the unique place of *I-MIBG-scintigraphy compared with other imaging techniques: it makes it possible to define the nature of the tumour, particularly in cases with normal catecholamine levels; to establish how extensive the lesions are at the time of diagnosis; and to confirm complete remission. No abnormal *I-MIBG uptake was noted in the 3 cases of retinoblastoma.

3-Iodobenzylguanidine↗
PubMed1990

Clonal growth of haemopoietic progenitor cells from myelodysplastic marrow in response to recombinant haemopoietins.

The growth factor requirements of granulocyte-macrophage (GM) and erythroid marrow progenitor cells from 12 myelodysplastic (MDS) patients have been analysed. GM progenitors from two of six patients who grew normal numbers of colonies in response to conditioned medium + erythropoietin (5637CM + Epo) showed defective responses to either GMCSF and/or IL-3. Of all the recombinant factors tested (IL-3, IL-1, GCSF, GMCSF, MCSF), GMCSF was the strongest stimulator of myeloid clonal growth, inducing normal numbers of GM colonies from marrow of six patients (two of whom were neutropenic). Erythroid colonies were low in 5637CM + Epo-supplemented cultures of marrow from all but one patient and remained poor in the presence of any of the haemopoietins. tested. Supraoptimal doses (for normal marrow) of these haemopoietins improved colony growth in only one patient (GM colonies in response to IL-3). Combinations of factors were also largely ineffective at raising myeloid or erythroid colony numbers. These data indicate that the defective response of MDS progenitor cells to growth factors is not amenable to experimental manipulation of recombinant factor levels or combinations. Clonal assays might suggest a role for GMCSF therapy in a subpopulation of neutropenic MDS patients but their potential now needs to be evaluated in association with clinical trials.

Adult↗
PubMed1990

Glutathione-s-transferase pi expression in leukaemia: a comparative analysis with mdr-1 data.

Drug resistance in haemopoietic cells may be partly related to the expression of the glutathione-s-transferase (GST) pi and mdr-1 genes. We have used RNA slot blotting techniques to investigate the expression of GST pi in peripheral blood and bone marrow of eleven normal subjects, nine patients with myelodysplastic syndrome (MDS), eighteen patients with acute myeloblastic leukaemia (AML), and thirty-two patients with chronic lymphocyte leukaemia (CLL). We found increased expression of GST pi in 8 of 9 MDS, (7 peripheral blood, 1 bone marrow) 12 of 18 AML (5 peripheral blood, 7 bone marrow; 4 of 5 untreated, 1 of 5 secondary, 7 of 11 relapse or refractory) and in the peripheral blood of 24 of 32 CLL (3 of 7 untreated, 21 of 25 treated) relative to normal controls. Increased expression of GST pi can occur at any stage of disease and shows no clear relation to mdr-1 expression except, possibly, in CLL. In 3 AML patients GST pi transcript levels were the same or lower on relapse compared to presentation. Upregulation of the GST pi gene could not be demonstrated in 2 CLL patients in response to treatment with intermittent chlorambucil.

Adult↗
PubMed1990

FMS mutations in myelodysplastic, leukemic, and normal subjects.

The FMS gene encodes the functional cell surface receptor for colony-stimulating factor 1, the macrophage- and monocyte-specific growth factor. Codons 969 and 301 have been identified as potentially involved in promoting the transforming activity of FMS. Mutations at codon 301 are believed to lead to neoplastic transformation by ligand independence and constitutive tyrosine kinase activity of the receptor. The tyrosine residue at codon 969 has been shown to be involved in a negative regulatory activity, which is disrupted by amino acid substitutions. This study reports on the frequency of point mutations at these codons, in vivo, in human myeloid malignancies and in normal subjects. We studied 110 patients [67 with myelodysplasia (MDS) and 48 with acute myeloblastic leukemia (AML)], 5 patients being studied at the MDS and the later AML stage of the disease. There was a total incidence of 12.7% (14/110) with mutations in codon 969 and 1.8% (2/110) with mutations in codon 301. Two patients had mutations in the AML stage of the disease but not in the preceding MDS and one had a mutation in the MDS stage but not upon transformation of AML. This is consistent with the somatic origin of these mutations. FMS mutations were most prevalent (20%) in chronic myelomonocytic leukemia and AML type M4 (23%), both of which are characterized by monocytic differentiation. One of 51 normal subjects had a constitutional codon 969 mutation, which may represent a marker for predisposition to myeloid malignancy.

Anemia↗
PubMed1990

Unusual Tc-99m MDP and I-123 MIBG images in focal pyelonephritis.

A 6-year-old boy presented with an inflammatory syndrome. Because Tc-99m MDP bone scintigraphy revealed increased tracer uptake at the upper pole of the right kidney, further studies were oriented towards a diagnosis of renal or adrenal pathology. I-123 metaiodobenzylguanidine (MIBG) accumulated at the site of the abnormal MDP uptake. The diagnosis of neuroblastoma or allied disorder was excluded on the basis of other investigations and further evaluation, suggesting that the MIBG uptake was a false-positive. Findings on clinical imaging, laboratory findings, Tc-99m DMSA imaging, sonography, and CT scanning were highly suggestive of acute focal pyelonephritis.

3-Iodobenzylguanidine↗
PubMed1990

Clonal karyotype abnormalities and clinical progress in the myelodysplastic syndrome.

Clonal karyotype abnormalities in 124 patients with myelodysplastic syndrome are reviewed. 36% of patients had abnormalities at referral, the most common being 5q-, +8 and lesions of chromosomes 7 and 20. Reduced survival was associated with the presence of either single or multiple clonal abnormalities at referral, abnormalities of chromosome 7 or 8 (either alone or with other lesions) and exclusively abnormal metaphases. The presence of 5q- alone did not appear to affect survival. Sequential studies were carried out in 77 patients of whom 12 showed karyotypic evolution. Reduced survival was observed in patients with an evolving karyotype but appeared to be due almost entirely to evolution in those patients whose initial karyotype was normal. Leukaemic transformation occurred more commonly in patients with an abnormal karyotype, particularly those with multiple abnormalities, and in patients with an evolving karyotype. Although the first appearance of an abnormal karyotype or an apparent evolution are important phenomena, it is probable that in some cases they merely represent expansion of a previously existing clone that has escaped detection. The distinction between true karyotypic evolution or clonal expansion and statistical variations due to small sample size and variability of samples may be difficult but needs to be taken into account in considering clinical significance.

Adult↗
PubMed1990

Expression of the multiple drug resistance gene (mdr-1) and epitope masking in chronic lymphatic leukaemia.

Resistance to cytotoxic agents is a common clinical problem in the treatment of chronic lymphatic leukaemia (CLL). The multidrug resistant (MDR) phenotype characterized by increased levels of a specific cell membrane p-glycoprotein, confers cross resistance to a wide range of structurally dissimilar antineoplastic drugs. We have studied the expression of this p-glycoprotein in chronic lymphatic leukaemia measured by immunofluorescence using a monoclonal antibody MRK 16 by flow cytometry. Initial results showed that only 12% of lymphocyte samples from CLL patients showed increased p-glycoprotein, conflicting with a previous observation that 53% of CLL patients had an increased level of mdr-1 mRNA. Treatment of the cells with neuraminidase to remove sialic acid residues increased the proportion of patients showing increased p-glycoprotein to 52%. This suggest that in a subset of CLL patients post translational modification of the protein occurs masking the epitope recognized by MRK 16. Abnormal sialylation patterns associated with malignancy are a well-recognized phenomenon.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Serum erythropoietin and erythropoiesis in patients with myelodysplastic syndromes.

Ineffective erythropoiesis is an early feature of the myelodysplastic syndromes (MDS), usually accompanying an hypercellular marrow. In a previous study, concentrations of serum erythropoietin (EPO) in MDS have been shown to correlate inversely both with haemoglobin concentration and with % bone marrow erythroblasts. We have measured erythroid production using a radioisotopic technique in 20 patients with MDS. Although haemoglobin concentration shows a weak inverse relationship with serum EPO concentration there is considerable variation in EPO concentration at a given haemoglobin level. There is no correlation between serum EPO and total erythroid production, though there is a weak correlation with effective erythropoiesis. The data suggests that control mechanisms of erythropoiesis in patients with MDS are complex.

Bone Marrow↗
PubMed1990

Porphyria cutanea tarda and haemochromatosis: a family study.

A female patient aged 73 presented with a history of general malaise and hyperpigmentation. Iron studies in the patient and immediate family members indicated that the proband was homozygous for haemochromatosis, but subsequent investigations revealed that porphyria cutanea tarda was responsible for her signs and symptoms. Venesection of four units of blood brought her symptoms under control. The interplay between porphyria cutanea tarda and excess iron deposition is discussed as is the role of extending investigations to first and second degree relatives when either haemochromatosis or porphyria cutanea tarda is suspected.

Aged↗
PubMed1990

Erythroid colony growth from peripheral blood and bone marrow in polycythaemia.

Erythroid colony growth in the presence and absence of erythropoietin was compared in 23 patients with primary proliferative polycythaemia (PPP), nine with idiopathic erythrocytosis, 10 with secondary polycythaemia, 15 with pseudopolycythaemia and in 76 normal subjects. Erythroid colonies growing without erythropoietin stimulation (endogenous erythroid colonies) from peripheral blood (BFU-E) were found in 20 of 22 patients with PPP and in two of seven with idiopathic erythrocytosis. None was found in secondary polycythaemia, pseudopolycythaemia, or in normal subjects. Small numbers of endogenous colony forming units-erythroid (CFU-E) (though not BFU-E) were cultured from the bone marrow of three of 24 normal subjects, suggesting that peripheral blood cultures provide a more specific indicator of clonal erythropoiesis. Peripheral blood endogenous erythroid colony growth is an effective and convenient means of distinguishing patients with clonal erythrocytosis and may be of particular value when iron deficiency obscures the diagnosis of PPP on conventional criteria.

Adolescent↗
PubMed1990

A family study of congenital X linked sideroblastic anaemia.

We report on the cytogenetic findings in a family study of pyridoxine responsive, X linked sideroblastic anaemia. An increase in the number of X chromosomes was observed in a small proportion of metaphases prepared from five female members, but these findings did not strictly correlate with the carrier status of the condition. No consistent cytogenetic abnormality could be identified or associated with this rare familial condition. The diagnosis and counselling of carriers of this condition is discussed.

Adolescent↗
PubMed1990

Is the mdr 1 gene relevant in chronic lymphocytic leukemia?

Chronic lymphocytic leukemia (CLL) is a progressive disease in which chemotherapy may result in temporary suppression of the peripheral blood lymphocyte count, but cure is not usually possible. Drug resistance mechanisms and the multidrug resistant (MDR) phenotype may be relevant to the therapeutic response. We have studied 34 patients with CLL (seven untreated, 27 treated), screening both DNA and RNA with the mdr 1 gene probe. In pure lymphocyte populations from 10 normal subjects, low levels of mdr 1 RNA expression were found. Eighteen CLL patients (four untreated, 14 treated) had levels of mdr 1 RNA expression above the normal range. No evidence of mdr 1 gene amplification could be found in these patients. Sequential estimations of RNA levels in three patients suggest that malignant lymphocytes in CLL can increase mdr 1 expression in response to chemotherapy and return to basal levels on withdrawal of the treatment. Such data raise important questions about the type of timing of cytotoxic therapy in CLL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

RAS mutations in patients following cytotoxic therapy for lymphoma.

The occurrence of Myelodysplastic Syndrome (MDS) and Acute Myeloblastic Leukaemia (AML) following cytotoxic therapy for neoplastic disease is well recognised. RAS mutations are common in patients with MDS and AML. To determine whether these lesions are found as early markers of secondary disease, we have studied the incidence of RAS mutations in the peripheral blood of 70 patients in complete remission from lymphoma. Patients were treated by standard chemotherapy regimes and/or localised radiotherapy. Treatment had been given 6 months to 14 1/2 years previously and no patient showed any sign of residual disease. Genomic DNA from peripheral blood leukocytes was amplified in vitro at target codons of N, K and H RAS genes, and mutations detected by hybridisation with oligonucleotide probes. RAS mutations were detected in 9 subjects. One patient with an N12 valine (Val) substitution had been in complete remission from Hodgkin's disease (HD) for 9 years. DNA from this patient registered in a nude mouse tumorigenicity assay (NMT). The N12 Val mutation was not detected in the original tumour tissue from the same patient. A second patient in remission from HD showed evidence of co-existent N12 cysteine (Cys) and N13 valine (Val) substitutions which were not detected in presentation material or unaffected tissues. All patients are currently haematologically normal, indicating that clones of mutant RAS bearing cells may be detected prior to any overt sign of disease.

Animals↗