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Biomedical subjects

A Jacobs

Publications and source records attributed to A Jacobs.

At least 37 records · Page 2Linked to original sources
PubMed1995

Occupational and environmental exposures and myelodysplasia: a case-control study.

A case-control study of newly diagnosed myelodysplastic syndrome patients investigated lifetime exposures through occupation, environment or hobby by questionnaire, structured and semi-structured interview. The exposure histories of 400 individually matched pairs were compared. Increased or possibly increased odds ratios were observed for radiation (2.05, 95% confidence interval 1.16-3.76), halogenated organics (1.57, 0.97-2.57), metals (1.40, 0.99-2.00), several specific radiation exposures and individual chemicals and for childlessness (1.46, 1.01-2.11). Since myelodysplasia generally carries a poor prognosis, whether or not individuals convert to leukaemia or to other cancer, these findings add to previous reports of exposures implicated in the aetiology of leukaemia and add to the case for minimizing exposures to radiation and halogenated organics.

Adolescent↗
PubMed1995

Upregulation of p21 RAS levels in HL-60 cells during differentiation induction with DMSO, all-trans-retinoic acid and TPA.

The role of p21 RAS in the proliferation and differentiation of myeloid cells has been studied by analysing the changes in the level of expression of p21 RAS proteins by flow cytometry upon differentiation down the granulocytic and monocytic pathways. Differentiation resulted in upregulated p21 RAS expression despite a marked decline in the number of dividing cells. On the other hand, growth inhibition, without differentiation, resulted in a decline in expression. Cell cycle analysis showed that the increase in p21 RAS occurred throughout the cell cycle. These results suggest that p21 RAS has a role in the process of myeloid differentiation.

Cell Cycle↗
PubMed1995

A screen for RAS mutations in individuals at risk of secondary leukaemia due to occupational exposure to petrochemicals.

Occupational exposure to petrochemicals, in particular benzene, has been identified as a risk factor in the development of acute leukaemia. A cohort of exposed (n = 44) and non-exposed individuals (n = 19) from the same petrochemical installation were screened by polymerase chain reaction (PCR) followed by oligonucleotide hybridization (ONH) for the presence of mutations in the H, K, and NRAS cellular proto-oncogenes. A KRAS mutation was detected in one individual from the exposed group who was haematologically normal at the time of sampling. The presence of this mutation was confirmed by nude mouse tumorigenicity assay and positively identified as a K13 Gly-Asp substitution by cloning and sequencing.

Adult↗
PubMed1995

Regional cerebral hypoperfusion in long-term type 1 (insulin-dependent) diabetic patients: relation to hypoglycaemic events.

Regional distribution of cerebral blood flow was determined semi-quantitatively with 99Tcm-HMPAO brain SPET under basal conditions in Type 1 (insulin-dependent) diabetic patients of recent onset and longer disease duration, and related to metabolic control and history of hypoglycaemic events. Long-term diabetic patients showed significantly more alterations in regional cerebral blood flow than diabetics of recent onset and healthy controls. Regional hypoperfusion, predominantly localized in the fronto-temporal cortex, was almost exclusively observed in patients with long-term diabetes. The latter finding was related to lower HbA1c levels (i.e. better metabolic control) and to the frequency of impending hypoglycaemia, but not to age of the patient, duration of diabetes or to chronic diabetes complications. The incidence of hypoperfusion was comparable in patient groups with or without a medical history of hypoglycaemic coma. However, regions of hypoperfusion were larger in the patients who had experienced hypoglycaemic coma. It is concluded that regional cerebral hypoperfusion in long-term Type 1 (insulin-dependent) diabetics, as evidenced by HMPAO-SPET can be related to the frequency and degree of hypoglycaemic events and to tight metabolic control, which is however at the expense of an increased risk of recurrent hypoglycaemia.

Adult↗
PubMed1995

Amino acid uptake in ischemically compromised brain tissue.

BACKGROUND AND PURPOSE: Multitracer positron emission tomography (PET) was used to investigate local amino acid accumulation in brain tissue surrounding focal ischemia. METHODS: PET using 15O-labeled oxygen and water for measuring cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF), C15O for determination of blood volume (CBV) and calculation of oxygen extraction fraction, and L-[11C]methylmethionine (11C-MET) for the assessment of amino acid accumulation was applied in 14 patients (mean age, 52 +/- 9.1 years) with acute ischemic hemispheric stroke. Two multitracer PET studies were completed, the first 8 to 24 hours after onset of neurological symptoms and the follow-up study 14 +/- 1 days after the ischemic attack. Functional changes were compared with morphological damage on cranial CT or MRI. Three-dimensional matching and volume of interest evaluation procedures were used to study 11C-MET accumulation in relation to various physiological variables in infarcted and noninfarcted tissue. RESULTS: Compared with contralateral mirror regions, initially increased regional 11C-MET uptake (21.2 +/- 10.9%, P < .001) was found in patchy areas in the immediate vicinity of infarction as well as in distant areas within the same hemisphere. In those areas, regional CBF (-11.4 +/- 21.2%, P < .01) and oxygen extraction fraction (2.8 +/- 29.1%, P = NS) were highly variable, and regional CMRO2 was preserved or slightly reduced (-12.4 +/- 16.0%, P < .001). CBF data comprised severely ischemic as well as high values (14.6 to 64.2 mL/100 g per minute). Cranial CT and coregistered MRI in five patients demonstrated preserved morphology. In all peri-infarct areas (n = 62), the 11C-MET uptake showed a positive correlation with delta CMRO2 as the relative improvement of ipsilateral CMRO2 between the two PET studies (r = .378, P < .01). Particularly in areas with increased oxygen extraction fraction (n = 42), the 11C-MET uptake showed a mild correlation with CMRO2 at follow-up measurement (r = .31, P < .05). In all peri-infarct areas, 11C-MET uptake showed a negative correlation with oxygen extraction fraction (r = -.672, P < .001) and a positive correlation with CBF (r = .4, P = .001). In all infarcted and peri-infarct areas, normalized initial 11C-MET uptake was positively correlated with CMRO2 at follow-up (r = .603, P < .001). CONCLUSIONS: Focal increases of 11C-MET uptake seen in this study were generally mild. They might be seen in the core of ischemia, indicating breakdown of the blood-brain barrier with poor tissue prognosis, but they also frequently occurred during or after ischemic compromise in surviving brain tissue surrounding focal cerebral infarction, perhaps representing alterations of amino acid transport or protein synthesis in brain tissue with a favorable prognosis.

Adult↗
PubMed1995

RAS and FMS mutations following cytotoxic therapy for childhood acute lymphoblastic leukaemia.

Patients who have received cytotoxic therapy for primary neoplastic disease are at an increased risk of developing secondary (therapy-related) acute myeloid leukaemia (AML) or myelodysplasia (MDS). RAS and FMS mutations have been observed in patients with AML and MDS. It has been suggested that the mutational status within these genes may be predictive of early secondary leukaemic disease. In this study we have screened 50 haematologically normal patients in complete remission from childhood acute lymphoblastic leukaemia (ALL) for activating point mutations in the RAS and FMS proto-oncogenes. Such patients may be considered at risk of therapy-related disease. Codons 12, 13 and 61 were screened in RAS and codon 969 in FMS using the polymerase chain reaction (PCR) followed by oligonucleotide hybridization (ONH). Three of the 50 patients (6%) were found to harbour N12 RAS mutations. One of these three patients (2%) had both a N12 RAS and FMS 969 mutation. Upon sequencing the RAS mutations, substitutions of serine, cysteine and aspartic acid for glycine were identified. The FMS 969 mutation was also confirmed, by sequencing, as a histidine substitution. RAS mutations were not detected in presentation samples indicating that these lesions have been somatically acquired presumably subsequent to cytotoxic therapy for the primary disease. Continued follow-up of these patients may indicate a role for these mutations in the development of secondary malignancies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

The activation of Escherichia coli aspartate transcarbamylase by ATP. Specific involvement of helix H2' at the hydrophobic interface between the two domains of the regulatory chains.

The regulatory chain of E. coli aspartate transcarbamylase (E.C. 2.1.3.2) is folded into two domains. The allosteric domain harbours the regulatory site where the activator ATP and the inhibitors CTP and UTP bind competitively. The zinc domain ensures the contact with the catalytic chains. The interface between these two domains is hydrophobic, and involves the carboxy-terminal part of the helix H2' of the allosteric domain and several residues of the zinc domain. This structural feature mediates the transmission of the ATP regulatory signal. In the present work, site-directed mutagenesis and molecular modelling were used to investigate the role of specific amino acid residues in this process. The modifications of the hydrophobic core which are expected to alter the position of helix H2' reduce or abolish the sensitivity of the enzyme to ATP. The properties of the mutants and the results of modelling are fully consistent and suggest that a movement of helix H2' is part of the mechanism of activation by ATP. A model is proposed to account for the transmission of the ATP signal from the regulatory site to the interface between the regulatory and catalytic chains.

Adenosine Triphosphate↗
PubMed1994

HMPAO SPET and FDG PET in Alzheimer's disease and vascular dementia: comparison of perfusion and metabolic pattern.

Positron emission tomography (PET) of 18F-2-fluoro-2-deoxy-D-glucose (FDG) and single-photon emission tomography (SPET) of 99mTc-hexamethylpropylene amine oxime (HMPAO) were performed under identical resting conditions within 3 h in 20 patients with probable Alzheimer's disease (AD), 12 patients with vascular dementia (VD) and 13 normal persons. In the temporoparietal association cortex similar impairment of relative regional cerebral glucose metabolism (rCMRGl) and relative HMPAO uptake (rCBF) was found. In addition PET showed hypometabolism in the occipital association cortex. The functional pattern was condensed to a ratio of regional values of association areas divided by regional values of structures that are typically less affected by AD. In normals this ratio was significantly related to age for PET metabolic data (r = -0.66, P = 0.01). The ratio was significantly lower in AD than in VD and controls for both rCMRGl and rCBF. In AD only, the metabolic ratio was related to severity of dementia (r = 0.54, P = 0.003) and age (r = 0.64, P = 0.003). Metabolic differences between normals and AD patients were less obvious in old age. In contrast, there were no significant correlations between the perfusion ratio and severity of dementia or age. Comparing the metabolic and perfusion ratio by receiver operating characteristic curves, PET differentiated AD from normals only marginally better than SPET. Differentiation between AD and VD was much better achieved by PET. Our results suggest that both PET and SPET can distinguish AD patients from controls, whereas for differentiation between AD and VD SPET is of little value.

Aged↗
PubMed1994

Quality assurance in general practice: the state of the art in Europe.

Quality assurance' (QA) is an important new development in general practice. In order to describe the state of the art in this field a preliminary survey was performed by the WONCA European Working Party on Quality in General Practice (EQuiP) in 17 European countries. The results revealed considerable differences in the systems and organization of general practice care [such as practice form, list size, the role of the general practitioner (GP), remuneration], which will have an impact on setting up QA. The preliminary findings demonstrated that most countries are only just beginning the implementation of QA. Nevertheless, there are many valuable developments and experiments concerned with the methodology, procedures and structures for it. In order to accelerate the speed of adoption of QA and to avoid the repetition of mistakes, policy makers and GPs from different parts of Europe should study examples in their fellow countries. A clearing house of QA projects in general practice can help to inform them on valuable developments.

Europe↗
PubMed1994

Atypical progression of multiple myeloma with extensive extramedullary disease.

Multiple myeloma is a neoplastic disorder caused by the proliferation of a transformed B lymphoid progenitor cell that gives rise to a clone of immunoglobulin-secreting cells. Other plasma cell tumours include solitary plasmacytoma of bone (SPB) and extramedullary plasmacytomas (EMP). Despite an apparent common origin there exist pathological and clinical differences between these neoplasms and the association between them is not completely understood. A case of IgG multiple myeloma that presented with typical clinical and laboratory features, including a bone marrow infiltrated by well differentiated plasma cells, is reported. The tumour had an unusual evolution, with the development of extensive extramedullary disease while maintaining mature histological features.

Aged↗
PubMed1994

Extended cytogenetic follow-up and clinical progress in patients with myelodysplastic syndromes (MDS).

198 patients with MDS were followed cytogenetically for up to 90 months. There were significant differences in survival between patients with a normal karyotype, single abnormalities (p < 0.05) and multiple abnormalities (p < 0.0001). Survival differences were also seen in each of the FAB sub-types but were only significant in RAEB/RAEB-t and CMML (p = 0.001) where a normal karyotype was associated with prolonged survival. Single and multiple abnormalities of chromosomes 7 and 8 but only multiple abnormalities of chromosome 5 were also associated with reduced survival. 126 patients were successfully investigated on more than one occasion. Karyotype evolution occurred in 15 and was associated with reduced overall survival in those patients who had previously been karyotypically normal (p < 0.05). Median survival following evolution was only 10 months. 29 patients developed leukaemia. The incidence of transformation was significantly higher in patients with multiple abnormalities than in those with a normal karyotype (p < 0.05) or single abnormalities (p < 0.05).

Adult↗
PubMed1994

An interactive technique for three-dimensional image registration: validation for PET, SPECT, MRI and CT brain studies.

UNLABELLED: A multipurpose three-dimensional registration technique was validated with PET, SPECT, CT and MRI scans, which had been obtained under normal clinical conditions. In contrast to fully automated procedures, this coregistration method is highly interactive, which has the advantage that it does not impose rigid restrictions by data type and by alterations in normal anatomy or brain function resulting from disease. METHODS: Basically, a computer program provides a variety of tools to examine the accuracy of coregistration visually and to specify necessary translations and rotations in all three dimensions. Tools and criteria to accept coregistration were applied according to a standardized protocol. Reproducibility was assessed with five independent users on nine pairs of image sets. In two pairs of these image sets, coregistration was repeated three times by each user. RESULTS: Depending on the resolution of the images involved, the reproducibility of translation distances ranged from 0.32 to 2.22 mm (s.d.) and of rotation angles from 0.32 to 1.70 degrees. It was always much smaller than the point-spread full-width half maximum of the device with the lower resolution. The accuracy of coregistration was examined using two arbitrarily misplaced image sets. Interindividual and intraindividual variance were similar, which suggested that the influence of subjectivity was not significant. Average displacements after coregistration were 0.43 and 0.29 mm or less for PET and MRI data, respectively, which indicated the absence of a systematic bias. CONCLUSION: The results indicate the high reproducibility and accuracy of this three-dimensional coregistration technique, which is comparable or superior to those of automated techniques and methods based on external artificial landmarks.

Brain↗
PubMed1994

Non-dysplastic myelodysplasia?

Patients successfully treated for a malignancy with cytotoxic therapy have an increased risk of developing secondary myelodysplasia (MDS) and acute myeloid leukemia (AML). We report a patient in remission from Hodgkin's disease (HD) who remains hematologically normal 4 years after combination chemotherapy, but who has biological and genetic abnormalities characteristic of myelodysplasia. X-inactivation analysis using a 5' phosphoglycerate kinase (PGK) probe demonstrates polyclonal hematopoiesis, but cytogenetic analysis reveals a clonal population with a minority of metaphases having a 7q-deletion. NRAS mutations are not detectable 1 year after treatment, but are present in two separate clones (at codons 12 and 15) analyzed by single-stranded conformational polymorphism (SSCP), followed by cloning and sequencing 4 years after treatment. The presence of an activated NRAS with the same codon 12 mutation was independently confirmed by the nude mouse tumorigenicity assay. In vitro peripheral blood granulocyte-macrophage colony-forming units (CFU-GM) have changed from normal to undetectable levels while erythroid burst forming units (BFU-E) were significantly reduced on two occasions during the period of observation. These abnormalities are characteristic of MDS. Continued clinical follow-up will determine whether these evolving genetic and biological abnormalities pre-date the onset of clinical and morphological features of MDS.

Adult↗
PubMed1994

Prospective evaluation of technetium-99m-HMPAO SPECT in mild and moderate traumatic brain injury.

UNLABELLED: We prospectively evaluated the contribution of 99mTc-HMPAO SPECT in patients who have sustained acute, mild or moderate head trauma. METHODS: Forty-two patients formed the first subgroup of moderate trauma (ModTr) and 25 patients formed the second subgroup of mild trauma (MilTr). All 67 patients underwent an initial SPECT (Tinit) within 4 wk after a closed cranial trauma. After a mean interval of 3 mo from the time of Tinit, all patients were clinically re-evaluated; those with an abnormal Tinit underwent a repeat SPECT (Trpt) as well. All SPECT studies were visually graded by agreement of three observers adjudging a score ranging from 0 (no lesions) to 4. RESULTS: For the group as a whole (ModTr + MilTr), the following results could be derived: (1) in 32/33 Tinit negative cases, clinical symptoms had resolved; (2) the positive predictive value of Tinit was only 20/34 (59%); (3) the sensitivity for the repeat SPECT was 19/20 (95%). CONCLUSION: Our results show that: (1) SPECT alterations correlate well with the severity of the trauma; (2) a negative initial SPECT study is a reliable predictor of a favorable clinical outcome; (3) in cases with a positive initial SPECT, a follow-up consisting of a combination of SPECT and clinical data is necessary; (4) in patients suffering from postconclusive symptoms, SPECT offers an instrument to objective sequelae.

Adolescent↗
PubMed1994

A randomized phase II study of low-dose cytosine arabinoside (LD-AraC) plus granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in myelodysplastic syndromes (MDS) with a high risk of developing leukemia. EORTC Leukemia Cooperative Group.

In a randomized phase II study, patients with myelodysplastic syndromes (MDS) with 10-30% blasts in the bone marrow and hematopoietic failure were treated with low-dose Ara C (2 x 10 mg/m2 subcutaneously (s.c.) days 1-14) and rhGM-CSF (fully glycosylated, Sandoz/Schering-Plough, 2 x 150 micrograms protein/day s.c.) given either following Ara C (days 15-21) or simultaneously (days 8-14) for 1-5 cycles. 108 patients with a median age of 65 years, range 17-80 years and refractory anemia with an excess of blasts (RAEB, n = 54), RAEB with transformation (RAEBt, n = 50) or with chronic myelomonocytic leukemia (CMML, n = 4) were evaluable. Complete remission was achieved in 15 cases (14%), 11 had a partial response (10%), and 16 a minor response (15%). Stable disease was reached in 35 cases (32%). There were 16 cases of toxic death (15%), progression occurred in 15 patients (14%). No differences existed between the two treatment arms with respect to response and duration of response. Prognostic factors for poor response included the presence of cytogenetic abnormalities and a history of previous blood transfusions. Major adverse events during treatment were hemorrhage (55%), infections (54%), and fever associated with GM-CSF administration (40%). The overall response rate ws 39%, median duration was 12.5 months from start of treatment which allowed responding patients to lead good quality life without further therapy. The question whether the combination is indeed superior to LD-Ara C alone is not settled but will be evaluated in an ongoing clinical trial.

Acute Disease↗
PubMed1993

Assembly of an antibody and its derived antibody fragment in Nicotiana and Arabidopsis.

The yield and assembly of an IgG1 antibody and its derived F(ab) fragment were compared in Nicotiana and Arabidopsis. The results obtained showed a lot of interclonal variability. For 45% of the primary transgenic calluses, antigen-binding entities represented less than 0.1% of the total soluble protein (TSP). Only two of the 103 analysed transformants contained more than 1% of antigen-binding protein, with 1.26% being the highest yield. Analogous amounts of complete antibody and F(ab) accumulated in primary callus tissue. Moreover, yields were in the same range for both species as far as primary callus tissue is concerned. However, the accumulation of the F(ab) fragment in leaf tissue of regenerated plants differed significantly between Nicotiana and Arabidopsis. The F(ab) fragment accumulated to only 0.044% of TSP in Nicotiana leaves but up to 1.3% in Arabidopsis leaves. Furthermore, both species showed differences in the assembly pattern of the complete antibody. Whereas Arabidopsis contained primarily fully assembled antibodies of 150 kDa, Nicotiana showed an abundance of fragments in the 50 kDa range.

Animals↗
PubMed1993

Semiquantitative analysis of cerebral blood flow by means of 99Tcm-HMPAO SPECT in individuals before and after a high altitude Himalayan expedition.

Nine members of the 'Belgian Tibet Expedition 1991' underwent a 99Tcm-hexamethylpropyleneamine oxime (HMPAO) brain single photon emission computed tomographic study before and after their stay at high altitude. Cerebral and cerebellar activity were analysed in three circumference profiles, representing the lower, middle and upper transaxial sections of the brain. The count value of each volume element (VE) was normalized to the maximum cerebellar value. In order to compare individual regional cerebral blood flow (rCBF) before and after the expedition, the relative differences in rCBF were calculated for each VE as: rel delta (%) = 100 x (value after expedition - value before expedition)/value before expedition. In 4/9 cases regional rel delta values were negative in most cortical regions; in 3/9 individuals nonsignificant changes were found and 2/9 climbers showed a positive rel delta value in most cortical regions. For the group as a whole there was (1) a mean decrease of 1.7% in global cortical CBF and (2) a significantly (P < 0.01) diminished rCBF was observed in both temporal and the left frontotemporal areas.

Adult↗