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Biomedical subjects

A Bakker

Publications and source records attributed to A Bakker.

At least 145 records · Page 8Linked to original sources
PubMed1992

Pharmaco-morbidity linkage: a feasibility study comparing morbidity in two pharmacy based exposure cohorts.

STUDY OBJECTIVES: The aims were (1) to compare discharge diagnoses and concurrent medication in a pharmacy based cohort of users of H2 receptor antagonists to those in a population of users of other drugs in the same period, who did not use H2 receptor antagonists; (2) to compare these results to those of a similar study performed with the Tayside record linkage scheme. DESIGN AND SETTING: The study was a retrospective cohort study. The morbidity data from the only hospital in one medium sized city (62,000 inhabitants) were linked to the dispensing data of all five community pharmacies on an individual basis (April 1, 1986-December 31, 1989). In the absence of a unique patient identification number, data from pharmacies and hospital were linked by the combination of date of birth, gender, and general practitioner code. For every user of H2 receptor antagonists two controls were obtained from all patients who had not used these drugs, and matched for age (within 5 years), gender, and general practitioner. All discharge diagnoses which followed this first prescription up to December 31, 1989, in a patient in the index cohort, and during the same period in his or her matched controls, were included in the study. MAIN RESULTS: In the index cohort (n = 2174) 341 persons were admitted (526 admissions) as against 398 persons (527 admissions) in the control cohort (n = 4348). There was increased morbidity in the index cohort, especially concerning the gastrointestinal system (peptic ulcers and malignancies, abdominal pain, gastrointestinal haemorrhage), but also concerning the musculoskeletal, respiratory, and circulatory systems. The morbidity in the last three groups corresponded with drugs used concomitantly by patients in the index cohort, so it was probably not causally related to the intake of H2 receptor antagonists but was rather an indicator of higher levels of morbidity in the index cohort. CONCLUSIONS: The figures were grossly comparable to those of the Tayside record linkage scheme. Probabilistic linking with the patient characteristics of gender, date of birth, and general practitioner code can facilitate the undertaking of postmarketing surveillance studies.

Chronic Disease↗
PubMed1992

Channelling of controlled release formulation of ketoprofen (Oscorel) in patients with history of gastrointestinal problems.

STUDY OBJECTIVE: The aim was to determine if a new controlled release formulation (Oscorel) of the non-steroidal anti-inflammatory drug (NSAID) ketoprofen has been preferentially prescribed in patients with prior history of gastro-intestinal disturbances. DESIGN: The study was a pharmacy records based comparison of the rates of prior prescribing of drugs indicated for peptic ulcer treatment in first recipients of Oscorel in 1989 versus recipients of other NSAID products. SETTING: A representative panel of Dutch community pharmacies serving approximately 425,000 people was used. MAIN RESULTS: Oscorel was launched in January 1989. Data on prescriptions dispensed in 1987-1988 to a total of 837 first users of Oscorel were analysed and compared with the dispensing history of a reference population including 30,787 patients who did not receive a prescription for Oscorel during 1989. Compared to the reference population, first users of Oscorel included a greater proportion of females, of patients 75 years and older, of heavy users of NSAIDs, and of patients switching among different NSAIDs. A total of 24.1% of first users of Oscorel had received peptic ulcer therapy in 1987-1988, versus 15.7% of the reference population. The rate ratio was 1.54, with 95% confidence interval of 1.36-1.74. Adjustment for stratifying variables caused only minor changes in the rate ratio, which remained stable on 1.5. CONCLUSIONS: Oscorel appears to have been channelled into use in patients with recognised risk factors for gastrointestinal toxicity. This preferential prescribing probably resulted from expectations and claims that this product has a lower risk of such toxicity.

Community Pharmacy Services↗
PubMed1992

[Detection of mitochondrial contact sites and creatine kinase activity in Ca(2+)-stimulated rat hearts].

Contact sites are created by fusion of the inner and outer mitochondrial membrane. They represent a dynamic microcompartment for creatine kinase activity. In this microenvironment the active sites of creatine kinase, oxidative phosphorylation, and ADP/ATP transport interact during basal and stimulated metabolism. Electron microscopic studies showed that the occurrence rate of contact sites was changing according to the energy state of the mitochondrion (Biermans et al., 1989). The aim of this study was to stimulate the metabolism of the rat heart by extracellular calcium and to investigate the formation of contact sites and creatine kinase activity. Isolated rat hearts were perfused with Krebs-Henseleit solution containing 1.6 mmol Ca. After 15 min stabilization the hearts were subjected to 0.6, 0.9, 1.8, 2.2, 2.6, or 3.6 mmol Ca for a period of 15 min. Stimulation of the isolated rat hearts with increasing calcium concentrations was physiologically manifested by enhanced dp/dt and LVP values. A higher frequency rate of mitochondrial contact sites was observed and these were associated with higher creatine kinase activity. We suppose that induction of contact site formation is related to the functional activity of the Ca stimulated rat heart and thus efficient production and transport of energy is provided. (Tab. 1, Fig. 6, Ref. 18.).

Animals↗
PubMed1991

Minor histocompatibility antigens, defined by graft-vs.-host disease-derived cytotoxic T lymphocytes, show variable expression on human skin cells.

Little is known on the effector mechanisms inducing the cutaneous lesions observed during acute graft-vs.-host disease (aGvHD) after allogeneic bone marrow transplantation (BMT). Histological findings have indicated that infiltrating CD8+ lymphocytes probably play a role. We addressed the question of whether host minor histocompatibility (mH) antigen-reactive cytotoxic T lymphocytes (CTL) could account for this phenomenon via direct lysis of the epidermal cell layer. Six CTL clones, obtained from peripheral blood lymphocytes of patients suffering from aGvHD, each recognizing a well-characterized MHC class I-restricted mH antigen epitope, were tested on cultured keratinocytes of nine MHC and mH antigen-typed donors. Four of six mH antigen-specific CTL clones lysed unstimulated MHC class I-expressing, as well as recombinant interferon-gamma (rIFN-gamma)-activated, ICAM-1, MHC class I- and II-expressing keratinocytes. Two strongly cytolytic CTL clones showed no recognition of keratinocytes of donors whose phytohemagglutinin-activated T cell lines were readily lysed. With respect to a GvHD, the results imply that some class I-restricted CTL obtained from peripheral blood lymphocytes of a GvHD patients have the in vitro potential to destroy resting as well as IFN-gamma-activated epidermal cells, whereas others do not. In other words, CTL-defined human mH antigens vary with respect to their expression in the skin. It is intriguing that those minor H antigens which cannot be detected on human keratinocytes in vitro are those known to be associated with the occurrence of GvHD.

Antibodies, Monoclonal↗
PubMed1991

A randomized trial of carboplatin versus iproplatin in untreated advanced ovarian cancer.

Between August 1984 and October 1987, 120 patients with stage IC to IV epithelial ovarian cancer were randomly assigned to receive carboplatin (400 mg/m2) or iproplatin (300 mg/m2) every 4 weeks as initial treatment. Stratification was made according to International Federation of Gynecology and Obstetrics (FIGO) stage and according to size of residual disease after surgery. Response was evaluated after six courses when patients were restaged, with laparoscopy or laparotomy in clinical complete responders or those with no assessable disease. Treatment was then stopped in surgically proven complete responders. Patients with partial (PR) or minor response (MR) received a further six courses of their original drug at a reduced dose (carboplatin 300 mg/m2, iproplatin 225 mg/m2). Patients with stable (SD), progressive (PD), or recurrent disease were treated with cyclophosphamide (1 g/m2). The response rates were 63% (95% confidence interval [CI], 50% to 74%) for carboplatin and 38% (95% CI, 26% to 51%) for iproplatin. Fifteen patients were not assessable for response. The median survival was 114 weeks (95% CI, 82 to 233 weeks) for carboplatin patients and 68 weeks (95% CI, 48 to 82 weeks) for iproplatin patients (P = .008). The amount of residual disease after initial laparotomy was a prognostic factor for survival. Myelosuppression was the main toxicity and was greater with iproplatin. This study shows carboplatin to be more active than iproplatin in the treatment of ovarian cancer and less toxic. Few responses to cyclophosphamide occurred following either drug, implying resistance to the alkylating agent.

Adult↗
PubMed1990

[Pharmaco-morbidity linking: a pilot study of its technical possibilities in The Netherlands].

The feasibility has been studied of linking pharmacy-based dispensing data and hospital-based morbidity data by using as a linkage key a combination of gender and birth date of the patient and of his general practitioner (GP) code. Firstly, the records of one pharmacy (14,686 patients) and those of one hospital (8475 admissions in 1987) were linked on the basis of date of birth and gender. This resulted in 3,715 matching record pairs. To a random sample of 1,713 of these pairs the GP code was added. Subsequently these pairs were validated by reference to the original medical and pharmaceutical records with a procedure that guaranteed that only the name and address of the patients could be compared without having access to the clinical or pharmaceutical record of an individual. We were able to link records with a sensitivity of 91.4% (95%-confidence interval: 88.8-94.0) and a specificity of 96.0% (95%-confidence interval: 94.5-97.5). In conclusion, probabilistic linkage of pharmaceutical and medical data with the combination of gender, date of birth and GP code facilitates successful record linkage.

Drug Therapy↗
PubMed1990

Contact site between inner and outer mitochondrial membrane: a dynamic microcompartment for creatine kinase activity.

Creatine kinase is involved in the integration of high-energy metabolism in various tissues. In this study the tissue-specific distribution of the mitochondrial isoform was investigated, both by electrophoresis of rat tissue extracts, and by ultrastructural localisation of creatine kinase activity. Furthermore, the influence of uncoupling of oxidative phosphorylation on mitochondrial creatine kinase activity associated with intermembrane contacts was investigated by enzyme cytochemistry and morphometric analysis. The results of the cytochemical survey indicate that contact sites are a prerequisite for creatine kinase to demonstrate enzymatic activity. Moreover, the extent of creatine kinase active membrane contacts depends on the metabolic state of the mitochondrion, as shown for heart mitochondria in vivo and in vitro, before and after treatment with dinitrophenol.

Animals↗
PubMed1990

Utilization patterns of non-steroidal anti-inflammatory drugs in an open Dutch population.

Non-steroidal anti-inflammatory drugs represent an important drug class in ambulatory care. A utilization study among half a million persons showed that 8.6% could be identified as having used one or more non-steroidal anti-inflammatory drugs (excluding salicylates) in 1987. Data were drawn from a representative sample of pharmacy records which comprise full medication histories of individual patients. Overall utilization of non-steroidal anti-inflammatory drugs was 10.8 defined daily doses/(1000 persons.day). Approximately three quarters of the patients are 'incidental' users and receive non-steroidal anti-inflammatory drugs for a relatively short time (30 days or less). Patients who were identified as 'regular' (31-210 days of therapy) and 'heavy' (greater than 210 days of therapy) users, accounted for 21.2% respectively 4.8% of all users. 'Heavy' users are responsible for 17.3% of all non-steroidal anti-inflammatory drug prescriptions. Especially the elderly and females are prone to be 'heavy' users. Five drugs account for 90.4% of all prescriptions (diclofenac, ibuprofen, naproxen, piroxicam, indomethacin). A total of 71.1% of the patients with more than one prescription for non-steroidal anti-inflammatory drugs switched in therapy. There are two classes of concomitant drug use especially relevant with respect to detecting non-steroidal anti-inflammatory drugs-associated risks: H2 blockers and antacids (belonging to anatomical therapeutic and chemical anatomic class A) and diuretics (belonging to anatomical therapeutical chemical anatomic class C). More than half of the 'heavy' users showed concomitant use of drugs in these classes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Induction of minor histocompatibility antigen-specific T-helper but not T-cytotoxic response is dependent on the source of antigen-presenting cell.

We studied the accessory cell requirements for triggering in vivo primed human major histocompatibility complex class I- and class II-restricted T cells specific for minor histocompatibility antigens. We compared the antigen-presenting capacities of peripheral blood lymphocytes (PBLs) and Epstein-Barr virus-transformed lymphoblastoid cell lines (EBV-LCLs), both derived from the same donor, to induce minor histocompatibility antigen-specific cytotoxic and proliferative T cells. PBLs and EBV-LCLs were equally effective as antigen-presenting cells to trigger cytotoxic-T-cell responses specific for minor histocompatibility antigens, some of which were reactive with B cells only. In contrast, a clear difference was found between the capacities of the two antigen-presenting cell types to induce minor histocompatibility antigen-specific T-helper-cell responses. PBLs as antigen-presenting cells could induce T-helper-cell lines reactive against minor histocompatibility antigens presented on PBLs, on EBV-LCLs, or on both cell types as stimulator cells. Unexpectedly, however, EBV-LCLs as antigen-presenting cells in all instances failed to induce T-helper-cell responses specific for minor histocompatibility antigens presented on PBLs or on both PBLs and EBV-LCLs as stimulator cells and could only trigger T-helper cells directed against B-cell-specific minor histocompatibility antigens. Our findings indicate a dichotomy in the capacity of EBV-LCLs to present minor histocompatibility antigens in the induction versus the effector phse of the in vitro T-helper-cell response. Furthermore, the results show different in vitro accessory cell requirements for major histocompatibility complex class I- and class II-restricted T-cell responses specific for human minor histocompatibility antigens.

Adolescent↗
PubMed1990

Effector mechanisms in graft-versus-host disease in response to minor histocompatibility antigens. I. Absence of correlation with cytotoxic effector cells.

Cell-mediated immunity against minor histocompatibility (mH) antigens is assumed to contribute to the development of graft-vs.-host disease in recipients of HLA-identical bone marrow grafts. To investigate the role of antihost-specific cytotoxic effector cells, we analyzed patients' T cell cultures after transplantation, in a chromium release assay using T lymphoblasts from patients and donors as target cells. Sixteen patients were studied between 1 and 25 months after grafting. Specific antihost cytotoxic T cell activity was detected in 4 of 5 patients with acute GVHD and in 5 of 5 patients with chronic GVHD, but also in 5 of 6 patients without any clinical signs of GVHD. Generally, the antihost Tc cell activity appeared within the first 3 months, increased to a maximum between 3 and 6 months, and gradually disappeared thereafter. This time effect was significant (P = 0.002). There was a suggestive trend in patients with chronic GVHD toward developing higher and more persistent levels of antihost Tc cell activity than in those without GVHD. Yet, these results can no longer support our earlier finding that the generation of antihost Tc cells is associated with the development of GVHD, since antihost Tc cells could be generally detected whether or not GVHD occurred. Our findings do not a priori exclude an effector cell role for Tc cells in GVHD but strongly indicate that other risk factors must be involved as well.

Adolescent↗
PubMed1990

Effector mechanisms in graft-versus-host disease in response to minor histocompatibility antigens. II. Evidence of a possible involvement of proliferative T cells.

To study helper T cell activation against minor histocompatibility (mH) antigens of the host after HLA-identical bone marrow transplantation, patients' lymphocytes collected longitudinally after transplantation were tested in a primed lymphocyte test using PBL from patients and donors as stimulator cells. Sixteen patients were studied between 1 and 25 months after grafting. Antihost Th cells were detected in 10 patients. Optimum levels of antihost activity were generally reached within the first 3 months, thereafter two patterns were identified; in some patients the antihost Th cell activity persisted for at least 2 years, whereas in other patients a decline was observed with time. Antihost Th cell activity developed in each of 5 patients with acute GVHD, in 3 out of 5 patients with chronic GVHD, but in only 2 out of 6 patients without GVHD. The average antihost Th cell activity in patients with acute GVHD was significantly higher than in patients without GVHD (P = 0.036) and was also higher, although not significantly, than in patients with chronic GVHD. These findings indicate that, in man, as was shown in studies in mice, helper T cells do participate in the response to mH antigens. Although other mechanisms may also be involved, we here propose that mH antigen-specific Th cells may be a risk factor for acute GVHD.

Adolescent↗
PubMed1990

Graft-versus-host disease associated T helper cell responses specific for minor histocompatibility antigens are mainly restricted by HLA-DR molecules.

Graft-versus-host reactions are mediated by subpopulations of donor T cells and can be attributed to host specific minor histocompatibility (mH) antigens. We isolated strong anti-host mH antigen proliferative T cell lines, LG2, PN2, and LH3, from three patients suffering from acute graft-versus-host disease (GVHD). To study the role of the different major histocompatibility complex (MHC) molecules in the anti-host mH antigen specific proliferative response, the reactivities of the three T cell lines were analysed in primed lymphocyte test (PLT) assays against panels of stimulator cells obtained from unrelated blood donors. LG2 and LH3 stimulating determinants were commonly detected in the unrelated panel, whereas the PN2 T cell line recognized a rare specificity. The responses were associated with the presence of self HLA-DR molecules on the stimulator cells, although not all DR sharing stimulator cells were recognized. The proliferative responses of LG2, LH3 and PN2 cells could be blocked by monoclonal antibodies (MoAbs) against HLA-DR, but not by MoAbs against HLA-A/B/Cw, HLA-DQ or -DP. At the responder cell level, depletion of CD4 cells as well as blocking with CD4 specific MoAbs abrogated the specific responses of the three T cell lines. Our findings suggest that anti-host Th cell responses activated in the acute phase of GVHD are directed against both frequent and rare mH antigens, are mediated by CD4 + ve class II restricted Th cells, and use the HLA-DR molecule as a common restriction element for mH antigen presentation.

Acute Disease↗
PubMed1990

Capping of Con A receptors and actin distribution are influenced by disruption of microtubules in Dictyostelium discoideum.

Capping of Concanavalin A (Con A) receptors can be inhibited in Dictyostelium by treatment of amoebae with the microtubular drug tubulozole. In cells that were incubated with Con A or with fluorescent Con A conjugate the capping process was completed in 30 min as could be demonstrated by fluorescence microscopy and Con A peroxidase labeling. In the presence of 10(-5) M tubulozole redistribution of the receptors did not proceed beyond a stage that can be characterized as patching. The effect of the drug on microtubule integrity was checked by electron microscopy and immunofluorescence of tubulin. Treatment resulted in shortening of the peripheral parts of the microtubules, in agreement with results described by other authors. Electron microscopy confirmed that the Con A receptor complexes remained on the plasma membrane and were not internalized. The distribution of F-actin in Con A-treated cells showed a pattern closely resembling that of Con A. Cells that were also treated with tubulozole remained spherical and did not resume significant directional movement until tubulozole was removed from the medium. It is concluded that microtubules are involved in the rearrangement of the microfilament network in moving cells.

Actins↗
PubMed1989

Methylation of GATC sites is required for precise timing between rounds of DNA replication in Escherichia coli.

We have used the Koppes and Nordstrøm (Cell 44:117-124, 1986) CsCl density transfer approach for analysis of DNA from exponentially growing, isogenic Escherichia coli dam+ and dam mutant cells to show that timing between DNA replication initiation events is precise in the dam+ cells but is essentially random in the dam cells. Thus, methylation of one or more GATC sites, such as those found in unusual abundance within the origin, oriC, is required for precise timing between rounds of DNA replication, and precise timing between initiation events is not required for cell viability. Both the dam-3 point mutant and the delta(dam)100 complete deletion mutant were examined. The results were independent of the mismatch repair system; E. coli mutH cells showed precise timing, whereas timing in the isogenic E. coli mutH delta(dam)100 double mutant was random. The mechanism is thus different from the role of Dam methylation in mismatch repair and probably involves conversion of hemimethylated GATC sites present in daughter origins just after initiation to a fully methylated state.

DNA Replication↗
PubMed1988

A gene for dihydrofolate reductase in a herpesvirus.

The enzyme dihydrofolate reductase (DHFR) is found ubiquitously in both prokaryotes and eukaryotes. It is essential for de novo synthesis of purines and of deoxythymidine monophosphate for DNA synthesis. Among viruses, however, only the T-even and T5 bacteriophage have been found to encode their own DHFR. In this study a gene for DHFR was found in a specific subgroup of the gamma or lymphotropic class of herpesviruses. DNA sequences for DHFR were found in herpesvirus saimiri and herpesvirus ateles but not in Epstein-Barr virus, Marek's disease virus, herpes simplex virus, varicella-zoster virus, herpesvirus tamarinus, or human cytomegalovirus. The predicted sequence of herpesvirus saimiri DHFR is 186 amino acids in length, the same length as human, murine, and bovine DHFR. The human and herpesvirus saimiri DHFRs share 83 percent positional identity in amino acid sequence. The herpesvirus saimiri DHFR gene is devoid of intron sequences, suggesting that it was acquired by some process involving reverse transcription. This is to our knowledge the first example of a mammalian virus with a gene for DHFR.

Amino Acid Sequence↗