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Biomedical subjects

J M Vossen

Publications and source records attributed to J M Vossen.

At least 19 recordsLinked to original sources

Mobile surrogate mothers and the development of exploratory behavior and radius of action in infant long-tailed macaques (Macaca fascicularis).

One of the effects of rearing young monkeys on surrogate mothers is a delay in the development of exploratory behavior. An important question is which difference between mother and surrogate mother caused this delay. We hypothesized that the mothers' carrying the infant through the environment promotes the development of exploratory behavior and the radius of action of infant macques. Using surrogate mothers, we reared 9 infants in a peer group with immobile surrogates and 10 infants in another peer group with mobile surrogates. During the 3rd to the 6th month, we observed each infant for 30 min weekly, collecting observational data on several behavioral parameters and on time spent in several areas in the cage. Results showed that exploratory behavior and an increase in radius of action developed more rapidly in the mobile-reared infants.

Age Factors

Restricted utilization of germ-line VH3 genes and short diverse third complementarity-determining regions (CDR3) in human fetal B lymphocyte immunoglobulin heavy chain rearrangements.

Twenty-one independent immunoglobulin heavy chain VH3DJH rearrangements were cloned and sequenced from livers of human fetuses at 7, 13 and 18 weeks of gestation. The VH elements expressed were not somatically mutated. Eight out of the estimated 30 VH3 elements were utilized with a preference for five of them. One of these VH3 sequences, designated FL13-28, represented a thus-far unknown VH3 gene segment. From the six functional JH elements the JH3 and JH4 segments were utilized preferentially and from the estimated 30 D segments the DQ52 element and the Dxp family were found to rearrange frequently. D elements were utilized both in normal and inverted orientation, as single copies or in D to D fusions. Addition of N nucleotides, removal of nucleotides from the coding sequences and utilization of DIR elements (D genes with irregular recombination signals) further expanded the third complementarity-determining region (CDR3) diversity. One fourth of the fetal CDR3 regions lacked N regions. Due to utilization of DQ52, the relative absence of N regions and extensive exonuclease activity operating on the D elements, the fetal CDR3 regions were significantly shorter than those found in adult B lymphocytes.

Amino Acid Sequence

Genetics of spike-wave discharges in the electroencephalogram (EEG) of the WAG/Rij inbred rat strain: a classical mendelian crossbreeding study.

The WAG inbred strain might be an animal model for human absence epilepsy. To study the inheritance pattern of absence epilepsy, WAG rats were crossbred, in a classical Mendelian way, with inbred ACI rats which show no signs of epilepsy. In the parental strains, reciprocal F1 hybrids, F2, B1, and B2 generations, the number and duration of spike-wave discharges were determined. One hundred percent of the F1 animals showed spike-wave discharges, while the percentages for the F2, B1, and B2 generations were 79, 95, and 37%, respectively. These results suggest that the occurrence of spike-wave discharges is determined by one gene with a dominant mode of inheritance. Cavalli's least-squares fitting procedure suggested different genetic models for the two parameters (number and duration) during the two periods (dark and light). These results confirm our previous findings (Peeters et al., Behav. Genet. 20, 453-460, 1990) that a number of genes are involved in absence epilepsy. One dominant gene appears to determine the occurrence, however, while others manipulate the number and duration of epileptic phenomena during the two periods dark and light.

Animals

Intensification of GVHD prophylaxis interferes with the effects of pretransplant herpes virus serology on the occurrence of grades II-IV acute graft-versus-host disease.

The effects of pretransplant herpes virus serology on the occurrence of grades II-IV acute graft-versus-host disease (GVHD) were studied in 262 recipients and their HLA-identical family donors. In 131 recipients on standard GVHD prophylaxis (either methotrexate or cyclosporin A) significant effects were observed for donor HSV serology (seropositivity associated with increased risk for GVHD) and donor EBV serology (seronegativity associated with increased risk). However, these effects were nonsignificant in the other 131 recipients on intensified GVHD prophylaxis (i.e., methotrexate combined with cyclosporin A, in vivo anti-T-cell monoclonal antibodies, or various procedures to reduce the T-cell numbers in the transplants.

Acute Disease

Epstein-Barr virus infection in allogeneic marrow grafting: lessons for transplant physicians and virologists.

The relationship between Epstein-Barr virus (EBV) and the host is profoundly disturbed by allogeneic bone marrow transplantation (BMT) because EBV resides in the recipient's hematopoietic system, which has to be destroyed in the majority of cases, and in the donor's hematopoietic system, i.e., the marrow graft. We have shown that EBV may be eradicated from some BMT recipients and that the virus may be transferred with the marrow graft. During the immediate post-transplant period oropharyngeal EBV excretion may occur which, by infecting passing B lymphocytes, may act as co-factor for acute graft-versus-host disease and help the virus to survive, despite the temporary depletion of its reservoir. The coexistence of totally different EBV strains in BMT recipients but not in healthy, untransfused controls, suggests that superinfection may by possible in case of immunodeficiency; alternatively, transfer of the virus by the reservoir itself (the B lymphocytes) might be the only effective route for superinfection. The generation of 'variant' strains during viral replication may form the basis of the vast polymorphism between wild-type EBV isolates in the population.

Adolescent

Problem-solving behaviour in apomorphine-susceptible and unsusceptible rats.

Pharmacogenetically selected apomorphine-susceptible (APO-SUS) and apomorphine-unsusceptible (APO-UNSUS) rats were trained in a discrimination learning paradigm. After the initial discrimination task was solved, reinforcement contingencies were reversed. No differences between APO-SUS and APO-UNSUS animals were found in the rate of learning. However, negative transfer from the initial discrimination to its reversal was less for the APO-SUS rats than for the APO-UNSUS rats. Moreover, the APO-SUS rats responded more to the relevant dimension (light) than the APO-UNSUS rats in the last 100 trials before solving the initial problem as well as the reversal. During overtraining on the first problem, APO-SUS animals responded less to an irrelevant dimension (position of the lever) than APO-UNSUS animals. In the first 100 trials of the reversal APO-SUS rats responded more to another irrelevant dimension (noise) than APO-UNSUS rats. The data show that APO-SUS and APO-UNSUS rats used the various dimensions (visual, auditory, and spatial) differently in the chosen discrimination learning paradigm. It is concluded that the interline differences found are the consequences of the interline differences in the dopaminergic activity of the ventral and dorsal striatum.

Acoustic Stimulation

Effects of loreclezole on epileptic activity and on EEG and behaviour in rats with absence seizures.

The antiepileptic profile of loreclezole, a new putative antiepileptic compound, has been determined in rats of the WAG/Rij strain, a genetic model of generalized absence epilepsy. In addition, the effects of 0, 5, 10 and 20 mg/kg loreclezole on the spectral content of the background EEG and on spontaneous behaviour of rats were investigated. Both the number of spike-wave discharges and their total duration dose-dependently decreased following administration of loreclezole. Furthermore, the behaviour of the animals was not markedly influenced and significant changes in the background EEG were not noticed after administration. These data suggest that the broad-spectrum antiepileptic loreclezole can be a valuable new drug in the treatment of absence epilepsy.

Animals

Transfer of specific immunity from donor to recipient of an allogeneic bone marrow graft: evidence for donor origin of the antibody producing cells.

A rapid recovery of specific humoral immunity in the recipient of an allogeneic bone marrow transplantation (BMT) can be observed after immunization of the donor before graft sampling. This has been attributed to transfer of specific immunity from donor to recipient. However, to maintain the concept of transfer the origin of the antibody producing cells in the recipient after BMT must be demonstrated. To this end, donor-recipient pairs with differences in Gm-allotypes were selected and immunized before BMT with the neo-antigen Helix pomatia haemocyanin (HPH) according to three immunization protocols. Additionally, the recipients were immunized at day 42 after BMT. Serum samples were weekly obtained from the recipients in the first 100 d after BMT. The origin of HPH-specific antibody producing cells was assessed by two approaches: (1) determination of the Gm-allotypes of anti-HPH antibodies within a distinct IgG subclass, (2) analysis of anti-HPH antibody spectrotypes by isoelectric focusing combined with immunoblotting. The results obtained with these two approaches show concordance in most instances and led to the conclusion that the antibody producing cells are of donor origin.

Adult

Transfer of specific immunity from donor to recipient of an allogeneic bone marrow graft: effect of conditioning on the specific immune response of the graft recipient.

Transfer of specific immunity was investigated in a group of 28 paediatric and adult leukaemia patients during the first 100 d after allogeneic bone marrow transplantation (BMT). These patients and/or their donors were immunized 7-13 d before transplantation with the recall antigen tetanus toxoid (TT) and the neo-antigen Helix pomatia haemocyanin (HPH). The recipients were booster immunized with both antigens at day 42 after transplantation. Transfer of a primary IgM and IgG response to HPH was successful in most paediatric and adult patients, but transfer of a secondary response to TT was established in only a few paediatric recipients. After booster immunization at day 42 most paediatric recipients responded with a rise in serum antibody titre to HPH as opposed to only two of 18 adult recipients. This incapability of the adult recipients to mount a secondary immune response may be related to their conditioning regimen which included Campath-IG in vivo. The results from this study indicate that transfer of immunity against recall- and neo-antigens is possible. However, the establishment of long-term memory may be affected by the regimen used to condition the graft recipient.

Adolescent

Validation of a serum-free growth factor-replenished in vitro culture system for hematopoietic progenitor cells in healthy donors and recipients of an allogeneic bone marrow graft.

The in vitro colony formation of hematopoietic progenitor cells of bone marrow samples, taken before and early after allogeneic bone marrow transplantation (BMT), was investigated prospectively. In order to circumvent culture-related and sample-related variations, a serum-free recombinant growth factor-replenished culture system was developed using T cell- and monocyte-depleted bone marrow samples. Samples of healthy bone marrow donors were used to validate the technique. The standardized culturing technique gave reproducible results, with numbers of colonies above those in conventional conditioned-medium technique. Colony formation in vitro of myelomonocytic precursor cells was found decreased in graft recipients, also after addition of growth factors, in comparison with healthy donors. The growth-promoting effect of the combination of IL-3 + GM-CSF was superior to that of either growth factor alone or conditioned medium. No effect was observed of T lymphocytes and monocytes on in vitro colony formation after bone marrow transplantation, probably as a result of functional impairment of these cells at that period after transplantation.

Bone Marrow Cells

[Quantitative and qualitative stock-taking of scientific research in pediatrics in The Netherlands (1986-1990)].

All Dutch academic and non-academic pediatric training centres were requested to give a survey of all scientific publications produced from 1986 to 1990. The initiative came from the board of the Dutch Pediatric Association. During the observation period (1986-1990) the number of international publications with an external reference system was twice when compared with 1981-1985. The quality of the publications was similar. In at least four of the participating academic pediatric hospitals most publications came from the subspecialty area of metabolic diseases, oncology/hematology, immunology/infectious diseases, and cardiology, both during the first and the second observation period. From 1986 to 1990 the total number of theses in which a pediatrician was the main promoter or promoter in charge came to 84.

Academic Medical Centers

Experimental and clinical gnotobiotics: influence of the microflora on graft-versus-host disease after allogeneic bone marrow transplantation.

One of the major complications of allogeneic bone marrow transplantation (BMT) is graft-versus-host disease (GvHD), which is caused by donor type lymphocytes which react against the recipient's tissues. An important factor which influences GvHD is the recipient's gastrointestinal microflora. This was originally observed in gnotobiotic mice. Infusion of 10(7) H-2 incompatible bone marrow cells into lethally irradiated (9.0 Gy X-rays) conventional mice results in a late onset type GvHD which causes the death of the majority of the recipients during the first two months after BMT. This mortality can be completely prevented if the recipients are germfree mice, or when they are conventional animals which have been subjected to complete or selective gastrointestinal decontamination (GID). In a mouse model, the mechanism responsible for the influence of the microflora on GvHD after allogeneic BMT was investigated. These studies indicate that GvHD can be induced by activated T-lymphocytes from donor origin reacting against bacterial antigens which might be cross-reactive with the recipient's epithelial tissue antigens. Activation of these T-lymphocytes is confined to antigens of certain bacterial species of the recipient which are not present in the indigenous microflora of the donor mice. These bacteria most likely belong to the anaerobic flora of the recipient. The latter hypothesis is strongly supported by the observation in human patients that, in contrast to complete GID, selective decontamination of the gastrointestinal tract did not have any beneficial effect on moderately severe to severe GvHD after transplantation with MHC-matched sibling donor bone marrow grafts.

Animals

Study of possible correlations between in vitro growth of bone marrow stromal and hematopoietic precursor cells early after allogeneic bone marrow transplantation.

Growth characteristics of stromal cells, assessed as adherent cells in long-term bone marrow cultures, and of hematopoietic progenitor cells, prior to and shortly after allogeneic bone marrow transplantation (BMT), were investigated, more specifically with regard to their possible correlations. The main constituent cells of the bone marrow stroma, that is, endothelial cells, reticular cells/fibroblasts, and monocytes/macrophages, showed an as yet inexplicable increased growth in samples taken from recipients prior to BMT, as compared with the growth in samples from their healthy donors and those taken after BMT. In the third week after BMT the in vitro outgrowth of hematopoietic precursors was severely depressed, but cell numbers in the adherent layer were normal. No relationship between in vitro growth of hematopoietic precursor cells and stromal cells was observed at that time. Probably the precursor cells growing in vitro are committed progenitor cells, relatively independent of stromal influences. In the eight week after grafting, endothelial cell outgrowth in vitro was highly correlated with granulocyte-macrophage colony-forming unit (CFU-GM) colony formation and to a lesser extent with mixed-lineage colony-forming unit (CFU-Mix) colony formation. This may indicate the reappearance of cytokine-mediated influences or the reappearance of a direct interaction, for example, by cell-cell contact between stromal cells and hematopoietic progenitor cells at that time.

Bone Marrow

Interaction of two different disorders in the beta-globin gene cluster associated with an increased hemoglobin F production: a novel deletion type of (G) gamma + ((A) gamma delta beta)(0)-thalassemia and a delta(0)-hereditary persistence of fetal hemoglobin determinant.

We report two different disorders of the beta-globin gene cluster segregating in a Belgian family: a novel deletion that results in (G) gamma + ((A) gamma delta beta)(0)-thalassemia (thal) and a heterocellular hereditary persistence of foetal hemoglobin of the Swiss type linked to a delta(0)-thal gene (delta (0)-HPFH). Heterozygosity for the heterocellular HPFH brings about a moderate (3.4% to 8.24%) increase of hemoglobin (Hb) F having a G gamma/A gamma ratio of 4:1, whereas carriers of the G gamma + ((A) gamma delta beta)(0)-thal deletion show in their peripheral blood a considerably higher (15%) percentage of Hb F. Both defects interact in the compound heterozygotes for G gamma + ((A) gamma delta beta)(0)-thal and delta(0)-HPFH producing a further increase (up to 24%) of fetal Hb consisting entirely of G gamma chains. Molecular characterization of the (G) gamma + ((A) gamma delta beta)(0)-thal by means of Southern analysis showed that the deletion spans about 50 kb, removing the 3' end of the A gamma-gene, the psi beta-, delta-, and beta-genes. A number of possible mechanisms leading to the overproduction of Hb F in HPFH and (G) gamma + ((A) gamma delta beta)(0)-thal will be discussed.

Adult

Strain differences in rats with respect to speed of conflict resolution.

Speed of conflict resolution was studied in a conditioned punishment paradigm in a Skinner box and a straight runway. In both experimental situations speed of conflict resolution was defined as the latency to gain food during an approach-avoidance conflict. In the Skinner box Tryon Maze Bright rats were faster in speed of conflict resolution than Tryon Maze Dull rats, and Roman Low Avoidance rats were faster than Roman High Avoidance rats. In the runway situation, Wistar Kyoto rats were faster in solving the conflict than randomly bred Wistar Wu rats and Brown Norway rats were faster than Wistar Wu rats. Differences between the strains in speed of conflict resolution could not be consistently explained from strain differences in approach or avoidance behavior, measured separately. It is, therefore, suggested that speed of conflict resolution is a unique parameter.

Animals

Responses to novelty in phobic and non-phobic cynomolgus monkeys: the role of subject characteristics and object features.

In two previous studies it has been shown that most surrogate-reared cynomolgus monkeys became phobic of a harmless object (a big paper bag) while most mother-reared monkeys approached that object. Results of the first study seemed to indicate that the phobic reaction was restricted to the bag. Barnett and Cowan (Interdisciplinary Science Review, 1, 43-62, 1976) and Suomi (Anxiety disorder in childhood, pp. 1-23, 1986), however, reported that subjects (respectively rats and monkeys) that avoided a first novel object also avoided subsequent novel objects. In the present study we exposed phobic (bag-avoiding) and non-phobic (bag-approaching) monkeys from the study by Röder, Timmermans and Vossen (Behaviour Research and Therapy, 27, 221-231, 1989) to several big and small novel objects. Our results show that, irrespective of their rearing conditions, subjects that were phobic also avoided big novel objects while subjects that were non-phobic approached big novel objects. The reaction to small novel objects was independent of the previous reaction to the bag.

Animals

Arousal, performance and absence seizures in rats.

Rats of the WAG/Rij strain show bilateral symmetrical spontaneous spike-wave discharges in the EEG, with clinical concomitants. The present experiment investigated whether, during a learning task, the number of discharges would be diminished compared to a period of rest. Additionally, it was investigated whether behavioural differences would be noticed within the task in trials with and without spike-wave discharges. The length of the post reinforcement pause in a fixed interval task was used as a performance index. Eleven rats were extensively trained to press a lever for food in a fixed (60 sec) interval task until a stable response pattern emerged: a post-reinforcement pause of about half the interval. Next, EEG electrodes were implanted and baseline EEGs were made, before and after the first and fifth test sessions. In addition, the behavior of the animals in the task was monitored when an EEG was recorded. During the task, a significantly smaller number of spike-wave discharges was found, compared to the preceding and succeeding baseline hours. This reduction is probably related to a higher level of vigilance during the task compared to the rest hour. Furthermore, the post-reinforcement pause was significantly enhanced in trials with spike-wave discharges compared to trials without discharges, indicating a clear change in performance. Both results are in agreement with what could be expected in patients with absence epilepsy and provide further evidence for the validation of the spike-wave discharges as genuine epileptic phenomena.

Action Potentials