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J J Janssen

Publications and source records attributed to J J Janssen.

At least 19 recordsLinked to original sources
PubMed2004

[The Dutch Health Council report on haemopoietic stem cells].

The Dutch Health Council advised the government on the use of haemopoietic stem cells in clinical medicine in September 2003. Most stem cell transplantations (SCTs) are performed in closely co-operating centres for haematological intensive care, and these centres are required to have a license from the government. The introduction of non-myeloablative SCT, exploiting the immunological effects of donor T cells, extends the variety of diseases for which SCT is a useful treatment option, as well as extending the age limits. The capacity of the centres appears to be sufficient, but their finances are not. This, together with strict adherence to accepted indications, is probably one of the main reasons why the number of SCTs performed in the Netherlands is rather low as compared to other European countries. The Council stresses that the harvesting and handling of umbilical cord stem cells is a public rather than a private matter, with the purpose of creating a bank for these preparations from which patients may benefit if the need so dictates. The Council pleads for support to advance the basic research on stem cells and the immunological aspects of stem cell transplantation.

Critical Care↗
PubMed2003

[Ulcers on the legs and feet: a seldom recognised side effect of hydroxyurea].

Three male patients aged 52, 49 and 74 years who were treated with hydroxyurea for chronic myeloid leukaemia (CML) or essential thrombocytosis developed severely painful ulcers on the lower legs and feet after an interval varying from 4 months to 2.5 years. These ulcers only healed after discontinuation of the drug. This is an adverse effect of hydroxyurea that is not infrequently seen but is difficult to recognise. The precise pathogenesis is still unclear but micro-circulatory disorders and a direct cytostatic effect on the epidermal cells probably play a role. Often, the drug has already been used for several years before the ulcers develop. They are resistant to treatment unless the hydroxyurea is stopped. Alternatives to hydroxyurea are imatinib for the treatment of CML and interferon alpha-2a or anagrelide for essential thrombocytosis.

Aged↗
PubMed2001

Characterization of a dehydrogenase activity responsible for oxidation of 11-cis-retinol in the retinal pigment epithelium of mice with a disrupted RDH5 gene. A model for the human hereditary disease fundus albipunctatus.

In the vertebrate retina, the final step of visual chromophore production is the oxidation of 11-cis-retinol to 11-cis-retinal. This reaction is catalyzed by 11-cis-retinol dehydrogenases (11-cis-RDHs), prior to the chromophore rejoining with the visual pigment apo-proteins. The RDH5 gene encodes a dehydrogenase that is responsible for the majority of RDH activity. In humans, mutations in this gene are associated with fundus albipunctatus, a disease expressed by delayed dark adaptation of both cones and rods. In this report, an animal model for this disease, 11-cis-rdh-/- mice, was used to investigate the flow of retinoids after a bleach, and microsomal membranes from the retinal pigment epithelium of these mice were employed to characterize remaining enzymatic activities oxidizing 11-cis-retinol. Lack of 11-cis-RDH leads to an accumulation of cis-retinoids, particularly 13-cis-isomers. The analysis of 11-cis-rdh-/- mice showed that the RDH(s) responsible for the production of 11-cis-retinal displays NADP-dependent specificity toward 9-cis- and 11-cis-retinal but not 13-cis-retinal. The lack of 13-cis-RDH activity could be a reason why 13-cis-isomers accumulate in the retinal pigment epithelium of 11-cis-rdh-/- mice. Furthermore, our results provide detailed characterization of a mouse model for the human disease fundus albipunctatus and emphasize the importance of 11-cis-RDH in keeping the balance between different components of the retinoid cycle.

Alcohol Oxidoreductases↗
PubMed2001

Null mutation in the human 11-cis retinol dehydrogenase gene associated with fundus albipunctatus.

PURPOSE: Recent studies show that mutations in the gene encoding 11-cis retinol dehydrogenase are associated with fundus albipunctatus. The authors wanted to investigate whether additional, more severe, mutations in the 11-cis retinol dehydrogenase gene might be responsible for more severe forms of hereditary retinal diseases. DESIGN: Case-control molecular genetics study. PARTICIPANTS AND CONTROLS: Two index patients, 7 relatives, and 50 control individuals. METHODS: The authors screened two index patients diagnosed with fundus albipunctatus for mutations in exons 2 to 5 and exon/intron boundaries of the 11-cis retinol dehydrogenase gene by direct sequencing. Control individuals were screened for the presence of the mutations using allele-specific oligonucleotide hybridization. MAIN OUTCOME MEASURES: Mutations in exons 2 to 5 and exon/intron boundaries of the 11-cis retinol dehydrogenase gene. RESULTS: In a compound heterozygote, two novel mutations were found: a 4 bp insertion in exon 2 and a missense mutation Cys267Trp in exon 5. In a second pedigree, a homozygous frameshift mutation in codon 43 (Arg42ct[1-bpdel]) was detected. In both families, the mutations segregate with the disease. The mutations were not found in 50 control individuals. CONCLUSIONS: On the basis of our observations, it is unlikely that mutations in the 11-cis retinol dehydrogenase gene are associated with other, possibly more severe, retinal pathologic conditions/dystrophies or syndromic diseases in which the retina is also affected.

Adult↗
PubMed2001

Cystatin M/E expression is restricted to differentiated epidermal keratinocytes and sweat glands: a new skin-specific proteinase inhibitor that is a target for cross-linking by transglutaminase.

Using serial analysis of gene expression on cultured human keratinocytes we found high expression levels of genes putatively involved in host protection and defense, such as proteinase inhibitors and antimicrobial proteins. One of these expressed genes was the recently discovered cysteine proteinase inhibitor cystatin M/E that has not been characterized so far at the protein level with respect to tissue distribution and additional biologic properties. Here we report that cystatin M/E has a tissue-specific expression pattern in which high expression levels are restricted to the stratum granulosum of normal human skin, the stratum granulosum/spinosum of psoriatic skin, and the secretory coils of eccrine sweat glands. Low expression levels were found in the nasal cavity. The presence of cystatin M/E in skin and the lack of expression in a variety of other tissues was verified both at the protein level by immunohistochemistry or western blotting, and at the mRNA level by reverse transcriptase polymerase chain reaction or northern blotting. Using biotinylated hexapeptide probes we found that cystatin M/E is an efficient substrate for tissue type transglutaminase and for transglutaminases extracted from stratum corneum, and that it acts as an acyl acceptor but not as an acyl donor. Western blot analysis showed that recombinant cystatin M/E could be cross-linked to a variety of proteins extracted from stratum corneum. In vitro, we found that cystatin M/E expression in cultured keratinocytes is upregulated at the mRNA and protein level, upon induction of differentiation. We demonstrate that cystatin M/E, which has a putative signal peptide, is indeed a secreted protein and is found in vitro in culture supernatant and in vivo in human sweat by enzyme-linked immunosorbent assay or western blotting. Cystatin M/E showed moderate inhibition of cathepsin B but was not active against cathepsin C. We speculate that cystatin M/E is unlikely to be a physiologically relevant inhibitor of intracellular lysosomal cysteine proteinases but rather functions as an inhibitor of self and nonself cysteine proteinases that remain to be identified.

Cell Differentiation↗
PubMed2001

A model to determine the initial phase space of a clinical electron beam from measured beam data.

Advanced electron beam dose calculation models for radiation oncology require as input an initial phase space (IPS) that describes a clinical electron beam. The IPS is a distribution in position, energy and direction of electrons and photons in a plane in front of the patient. A method is presented to derive the IPS of a clinical electron beam from a limited set of measured beam data. The electron beam is modelled by a sum of four beam components: a main diverging beam, applicator edge scatter, applicator transmission and a second diverging beam. The two diverging beam components are described by weighted sums of monoenergetic diverging electron and photon beams. The weight factors of these monoenergetic beams are determined by the method of simulated annealing such that a best fit is obtained with depth-dose curves measured for several field sizes at two source-surface distances. The resulting IPSs are applied by the phase-space evolution electron beam dose calculation model to calculate absolute 3D dose distributions. The accuracy of the calculated results is in general within 1.5% or 1.5 mm; worst cases show differences of up to 3% or 3 mm. The method presented here to describe clinical electron beams yields accurate results, requires only a limited set of measurements and might be considered as an alternative to the use of Monte Carlo methods to generate full initial phase spaces.

Biophysical Phenomena↗
PubMed2000

Retinoic acid delays transcription of human retinal pigment neuroepithelium marker genes in ARPE-19 cells.

The effect of retinoic acid on the differentiation of a human retinal pigment epithelium-derived cell line ARPE-19 was studied. Differentiation of ARPE-19 cells is delayed by retinoic acid. The minimum all-trans-retinoic acid concentration needed for delay of ARPE-19 differentiation is 1 microM. A delay of differentiation was also observed using 1 microM 9-cis or 13-cis-retinoic acid. Differentiation at the molecular level was studied by analyzing transcription of two RPE-marker genes, RPE65 and peropsin. In the presence of 1 microM retinoic acid the onset of transcription of both genes was delayed by 2-3 weeks. We conclude that all-trans-, 9-cis-, and 13-cis-retinoic acid delay differentiation of ARPE-19 cells into cells that phenotypically resemble cells from the human retinal pigment epithelium.

Actins↗
PubMed2000

Mobilisation of haemopoietic progenitors in CML: a second course of intensive chemotherapy does not improve Ph-negativity in stem cell harvests.

We collected peripheral blood stem cells (PBSC) in 19 early chronic phase CML patients following each of two consecutive cycles of intensive chemotherapy (CT) to evaluate whether an additional cycle of CT would increase Philadelphia (Ph)-negativity of the PBSC harvest. Autologous SCT (autoSCT) was performed if a major cytogenetic response (MCR) of the PBSC harvest was obtained. CT consisted of cytarabine 200 mg/ m2/day (days 1-7)/idarubicin 12 mg/m2/day (days 1-2) (cycle one) and cytarabine 2000 mg/m2/day (days 1-6)/amsacrine 120 mg/m2/day (days 1-3) (cycle two). One patient died of fungal pneumonia after the first cycle. Stem cells were harvested in 18 patients after cycle one and in 16 patients after cycle two. After the first cycle, all patients showed a cytogenetic response of their graft (MCR in eight patients: three complete, five partial), after cycle two, seven patients obtained an MCR (one complete, six partial). Seven patients became eligible for autoSCT. All patients proceeded with IFNalpha maintenance. Currently, 16 patients are alive. At the latest cytogenetic examination of bone marrow, four patients showed an MCR and four a minor response. In conclusion, although a second cycle of CT may contribute to elimination of leukemia residing in the patient, it appeared to be ineffective in improving the Ph-negativity of the PBSC graft.

Adult↗
PubMed2000

Disruption of the 11-cis-retinol dehydrogenase gene leads to accumulation of cis-retinols and cis-retinyl esters.

To elucidate the possible role of 11-cis-retinol dehydrogenase in the visual cycle and/or 9-cis-retinoic acid biosynthesis, we generated mice carrying a targeted disruption of the 11-cis-retinol dehydrogenase gene. Homozygous 11-cis-retinol dehydrogenase mutants developed normally, including their retinas. There was no appreciable loss of photoreceptors. Recently, mutations in the 11-cis-retinol dehydrogenase gene in humans have been associated with fundus albipunctatus. In 11-cis-retinol dehydrogenase knockout mice, the appearance of the fundus was normal and punctata typical of this human hereditary ocular disease were not present. A second typical symptom associated with this disease is delayed dark adaptation. Homozygous 11-cis-retinol dehydrogenase mutants showed normal rod and cone responses. 11-cis-Retinol dehydrogenase knockout mice were capable of dark adaptation. At bleaching levels under which patients suffering from fundus albipunctatus could be detected unequivocally, 11-cis-retinol dehydrogenase knockout animals displayed normal dark adaptation kinetics. However, at high bleaching levels, delayed dark adaptation in 11-cis-retinol dehydrogenase knockout mice was noticed. Reduced 11-cis-retinol oxidation capacity resulted in 11-cis-retinol/13-cis-retinol and 11-cis-retinyl/13-cis-retinyl ester accumulation. Compared with wild-type mice, a large increase in the 11-cis-retinyl ester concentration was noticed in 11-cis-retinol dehydrogenase knockout mice. In the murine retinal pigment epithelium, there has to be an additional mechanism for the biosynthesis of 11-cis-retinal which partially compensates for the loss of the 11-cis-retinol dehydrogenase activity. 11-cis-Retinyl ester formation is an important part of this adaptation process. Functional consequences of the loss of 11-cis-retinol dehydrogenase activity illustrate important differences in the compensation mechanisms between mice and humans. We furthermore demonstrate that upon 11-cis-retinol accumulation, the 13-cis-retinol concentration also increases. This retinoid is inapplicable to the visual processes, and we therefore speculate that it could be an important catabolic metabolite and its biosynthesis could be part of a process involved in regulating 11-cis-retinol concentrations within the retinal pigment epithelium of 11-cis-retinol dehydrogenase knockout mice.

Alcohol Oxidoreductases↗
PubMed2000

Plasmacytoma of the mastoid bone: solitary and systemic.

Plasma cell tumours of the mastoid are rare malignancies of haematological origin. Two patients are described with a plasma cell tumour in the mastoid bone. In one patient it concerned a solitary plasmacytoma of the bone and in the other a focus in the mastoid of a recently diagnosed multiple myeloma. Symptoms in these patients were non-specific. Computed tomography (CT) and magnetic resonance image (MRI) scanning showed a non-specific space-occupying lesion in the mastoid. The diagnosis was made on immunohistological examination, that showed diffuse sheets of monoclonal plasma cells in a clear matrix. When a plasmacytoma lesion is found multiple myeloma should always be excluded. Treatment in case of solitary plasmacytoma of the mastoid bone consists of radiotherapy. In case of localization in the mastoid of multiple myeloma the treatment consists of palliative chemotherapy.

Aged↗
PubMed1999

Retinoic acid receptors and retinoid X receptors in the mature retina: subtype determination and cellular distribution.

PURPOSE: In the mature retina retinoic acid (RA) biosynthesis was reported to be regulated by light. RA is of vital importance for proper function of the retina. RA activity is mediated by interaction with nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). The purpose of this study was to determine if and which RARs and RXRs are present in the mature retina, and to determine their location within the retina. METHODS: The reverse transcriptase polymerase chain reaction (RT-PCR) was used to amplify cDNA fragments encoding RARalpha, RARbeta, RARgamma, RXRalpha, RXRbeta, and RXRgamma from human retinal RNA. RT-PCR products were cloned, sequenced, and used in Northern blot experiments. Antibodies directed against each receptor subtype were used for immunocytochemical analysis. RESULTS: RT-PCR and Northern blot analysis indicated that all RAR and RXR subtypes are present in the mature retina. Western blot analysis, using a cytoplasmic protein fraction isolated from the bovine and human neural retina, showed the presence of RXRalpha. Immunocytochemical analysis of the human, bovine, and rat retina showed that RARalpha is highly expressed in the outer segments of cone photoreceptor cells. RXRalpha expression was observed in the rod inner segment layer. RXRgamma was detected in the nuclei and outer segments of cone photoreceptor cells. CONCLUSIONS: The retinal expression pattern of RARs and RXRs is heterogeneous. The observation that RXRalpha is present in rods whereas RARalpha is present in cones, suggests a mechanism by which RA that is produced upon bleaching, could generate different responses in the two photoreceptor cell subtypes.

Animals↗
PubMed1998

The visual cycle retinol dehydrogenase: possible involvement in the 9-cis retinoic acid biosynthetic pathway.

The 11-cis-retinol dehydrogenase (11-cis-RoDH) gene encodes the short-chain alcohol dehydrogenase responsible for 11-cis-retinol oxidation in the visual cycle. The structure of the murine 11-cis-RoDH gene was used to reinvestigate its transcription pattern. An 11-cis-RoDH gene transcript was detected in several non-ocular tissues. The question regarding the substrate specificity of the enzyme was therefore addressed. Recombinant 11-cis-RoDH was found capable of oxidizing and reducing 9-cis-, 11-cis- and 13-cis-isomers of retinol and retinaldehyde, respectively. Dodecyl-beta-1-maltoside used to solubilize the enzyme was found to affect the substrate specificity. This is the first report on a visual cycle enzyme also present in non-retinal ocular and non-ocular tissues. A possible role in addition to its role in the visual cycle is being discussed.

Alcohol Oxidoreductases↗
PubMed1998

Comparison between the effects of amlodipine and lisinopril on proteinuria in nondiabetic renal failure: a double-blind, randomized prospective study.

Double-blind, randomized controlled studies of longer than 1 week in duration comparing the antiproteinuric potential of long-acting dihydropyridine calcium channel blockers with that of angiotensin converting enzyme (ACE) inhibitors are lacking. Therefore, we performed such a study in patients with nondiabetic renal disease and proteinuria. After a 4-week wash-out period in which patients did not use any medication known to affect proteinuria, 21 patients were randomized in a double-blind fashion to receive either the calcium channel blocker amlodipine (Amlo, 5 to 10 mg) or the ACE-inhibitor lisinopril (Lis, 5 to 10 mg). Throughout the 16-week study period, blood pressure, creatinine clearances, and proteinuria were measured every 2 weeks. In addition, device-measured blood pressure and renal hemodynamic studies were performed at the start and end of the study. Systolic blood pressure fell in the Lis group from 163+/-7 (SEM) to 140+/-8 mm Hg (P < .01) and from 157+/-10 to 147+/-6 mm Hg in the Amlo group; diastolic blood pressure fell from 101+/-3 to 86+/-7 mm Hg in the Lis group and from 98+/-3 to 91+/-2 mm Hg in the Amlo group. Renal hemodynamics were not affected by amlodipine treatment, whereas a fall in glomerular filtration rate (GFR) was seen in lisinopril-treated patients (from 55+/-11 to 50+/-10 mL/min; P < .01). Amlodipine did not significantly affect proteinuria. Lisinopril induced a decline in the protein-creatinine ratio with a maximal effect reached after 12 to 16 weeks of therapy (from 0.39+/-0.17 to 0.26 +/-0.11 g/mmol; P < .009). In conclusion, we could not demonstrate an antiproteinuric effect of the long-acting dihydropyridine calcium channel blocker amlodipine, whereas therapy with the ACE-inhibitor lisinopril resulted in a decrease in proteinuria. Amlodipine did not affect renal hemodynamics, whereas lisinopril induced a fall in GFR.

Adolescent↗
PubMed1997

Cloning and structural analysis of the murine GCN5L1 gene.

We recently cloned the murine 11-cis retinol dehydrogenase gene. A second gene, the murine GCN5L1 gene, was found to be situated upstream of the murine 11-cis retinol dehydrogenase gene. We have isolated and sequenced the complete coding sequence of the murine GCN5L1 gene. The distance between the 3'-end of the murine GCN5L1 gene and the 5'-end of the 11-cis retinol dehydrogenase gene is only 776 nt. The murine GCNSL1 gene consists of four exons encompassing approximately 3.5 kb of genomic DNA. Intron/exon splice sites conform to the GT/AG rule. The open reading frame consists of 375 nucleotides encoding a 14 kDa protein. The murine GCN5L1, like the human GCN5L1 protein, displays weak homology (27%) to yeast GCN5. The distance between the murine, human and bovine GCN5L1 and 11-cis retinol dehydrogenase genes appeared to be conserved.

Alcohol Oxidoreductases↗
PubMed1997

Numerical calculation of energy deposition by high-energy electron beams: III-B. Improvements to the 6D phase space evolution model.

The phase space evolution model of Huizenga and Storchi, Morawska-Kaczyńska and Huizenga and Janssen et al has been modified to (i) allow application on currently available computer equipment with limited memory (128 Megabytes) and (ii) allow 3D dose calculations based on 3D computer tomographic patient data. This is a further development aimed at the use of the phase space evolution model in radiotherapy electrons beam treatment planning. The first modification regards the application of depth evolution of the phase space state combined with an alternative method to transport back-scattered electrons. This depth evolution method requires of the order of 15 times less computer memory than the energy evolution method. Results of previous and new electron transport methods are compared and show that the new electron transport method for back-scattered electrons hardly affects the accuracy of the calculated dose distributions. The second modification regards the simulation of electron transport through tissues with varying densities by applying distributed electron transport through similarly composed media with a limited number of fixed densities. Results of non-distributed and distributed electron transport are compared and show that the distributed electron transport method hardly affects the accuracy of the calculated dose distributions. It is also shown that the results of the new dose distribution calculations are still in good agreement with and require significantly less computation time than results obtained with the EGS4 Monte Carlo method.

Electrons↗
PubMed1996

Outcome of ICU treatment in invasive aspergillosis.

OBJECTIVE: To assess the outcome of intensive care treatment in invasive aspergillosis. DESIGN: Retrospective study. SETTING: University Hospital, Medical Intensive Care Unit (ICU). PATIENTS: Twenty-five patients with invasive aspergillosis who were admitted to the medical ICU in a 5 1/2 year period. Twenty-two had received high-dose chemotherapy for (mainly hematologic) malignancies, one had been treated with cyclosporine and prednisolone for systemic lupus erythematosus, one with high-dose methylprednisolone for polyarteritis nodosa and one had an ARDS after near-drowning. MEASUREMENTS AND RESULTS: The medical records were reviewed for patient and disease characteristics, outcome, reasons for admission to the ICU, supportive care and antifungal therapy as well as for the results of cultures and autopsy. Out of 25 patients, a definite ante mortem diagnosis could be established in seven. When autopsied patients were included, a total of 15 suffered from proven invasive aspergillosis. Although standard antifungal treatment and maximal available supportive care were given, 23 of 25 patients (92%) died after a mean of 15 (1-51) days in the ICU. Both patients who recovered had received high-dose chemotherapy for hematologic malignancy and showed bone marrow recovery and/or had a localized pulmonary infection. CONCLUSIONS: In patients with highly suspected or proven invasive aspergillosis, admission to an ICU and mechanical ventilation should be considered in cases of localized infection and obvious signs of hematologic recovery. In most other circumstances ICU admission for mechanical ventilation does not seem to improve survival.

Adolescent↗
PubMed1996

Phase space evolution distribution functions for high energy electron beams.

The phase space evolution (PSE) model is a 3D electron beam dose calculation model for radiation oncology. The PSE model is based upon the transport of electrons with a specific energy and direction over short distances (typically 0.3-1 cm). The result of the transport of these electrons is described by an energy and direction distribution of the electrons, which is stored in a database. The database is used by the PSE model at the time of the actual electron transport simulation. A good agreement between dose distributions calculated by the PSE model and EGS4 Monte Carlo code for mono-energetic, mono-directional electron beams was found. The differences in point dose are within 1-2% of the maximum dose. These differences can be caused by errors in the database used, or by assumptions made in the PSE model. The aim of this paper is to get more insight into the possible errors introduced by the database. Results show that the data in the database are in good agreement with EGS4 calculated data. Also the influence of the database on a PSE calculated dose distribution has been investigated. The differences between a PSE calculated dose distribution and an EGS4 calculated dose distribution can be reduced to < 0.5% if the database is replaced by a database partly created by EGS4. This shows that small errors in the database have a distinct effect on the dose distribution, and that this dose distribution can be calculated accurately by the PSE model if the right database is used.

Computer Simulation↗