Biomedical subjects

H Schroeder

Publications and source records attributed to H Schroeder.

At least 19 recordsLinked to original sources

PubMed1999

Allogeneic bone marrow transplantation in second remission of childhood acute lymphoblastic leukemia: a population-based case control study from the Nordic countries.

This study compares allogeneic BMT with conventional chemotherapy for childhood ALL in second remission. Seventy-five children were transplanted between July 1981 and December 1995. For each patient two control patients matching the following criteria were selected from the Nordic database of ALL: (1) time of diagnosis, (2) T vs. non-T ALL, (3) site of relapse, (4) initial risk group, (5) sex and (6) relapse < or > or =6 months after cessation of therapy. The minimal time of follow-up was 24 months. Mortality rate in CR2, leukemic relapse rate and the proportion in continued second remission were 16/75 (21%), 22/75 (29%) and 37/75 (50%), respectively. P2.-EFS for the BMT group was significantly better than that for the control group (0.40 vs. 0.23, P = 0.02). Children transplanted for bone marrow relapses in particular had a higher P2.-EFS (0.35 vs. 0.15 for the control group, P<0.01). Also, children grafted for early BM relapses had a higher P2.-EFS (0.32 vs. 0.11 for the control group P = 0.01). The outcome was similar when children were transplanted after early or late relapse. Also, there was no difference in outcome between the BMT and the chemotherapy group for children with late relapses. We conclude that allogeneic BMT with an HLA-identical sibling donor or other family donor should be performed in children relapsing in bone marrow during therapy or within 6 months of discontinuing therapy.

Adolescent↗

PubMed1998

The effect of pentylenetetrazol kindling on synaptic mechanisms of interacting glutamatergic and opioid system in the hippocampus of rats.

Endogenous opioids modulate processes of central excitability such as long-term potentiation and electrical kindling. Little is known about the neurochemical alterations in the interaction of the glutamatergic and opioid system in the development of pentylenetetrazol (PTZ) kindling in rats. Therefore, in the present study we investigated glutamate, DAMGO and naltrindole receptor binding, receptor protein expression by Western blot and ex vivo glutamate transmitter release in PTZ kindled rats. The specific 3H-DAMGO and -naltrindole binding to hippocampal membranes displayed no significant changes in kindled rats compared to controls. In contrast, the 3H-l-glutamate binding was significantly enhanced after completion of PTZ kindling. The expression of receptor protein for glutamate as well as the naloxone- and naltrindole-induced 3H-d-aspartate release from hippocampal slices did not alter in any case as a consequence of PTZ kindling. The PTZ induced enhancement of the glutamate binding sites in the hippocampus was downregulated to control level by natrindole treatment of rats prior to each PTZ application. Furthermore, naltrindole pretreatment of rats significantly inhibited the development of seizure susceptibility. In contrast, naloxone was not able to alter the seizure activity induced by PTZ as well as the transmitter receptor binding. The results are discussed in the light of a modulating role of delta-opioid receptors in PTZ kindling.

Animals↗

PubMed1998

Hypoxia/reoxygenation induces apoptosis through biphasic induction of protein synthesis in cultured rat brain neurons.

To investigate biochemical events accounting for the outcome of central neurons following hypoxia/reoxygenation, cultured neurons from fetal rat forebrain were exposed to hypoxia (95% N2/5% CO2) for 6 h, and then reoxygenated for up to 96 h. Time-dependent changes in macromolecular biosynthesis were analysed by incorporation of [3H]uridine and [3H]leucine and were coupled to cell viability and lactate dehydrogenase leakage. Morphological features of necrosis and apoptosis were scored following nuclear incorporation of the fluorescent dye 4,6-diamidino-2-phenylindole. Hypoxia led to a 36% reduction of cell viability at the end of the reoxygenation period, while 23% of the neurons exhibited apoptosis. A biphasic increase in the rates of protein synthesis was measured 1 h after the onset of hypoxia (77% above controls) and by 48-h postreoxygenation (72%). The presence of cycloheximide during hypoxia inhibited both peaks of synthesis and prevented the development of apoptosis. Protein electrophoresis outlined specific alterations in constitutive proteins, and immunohistochemistry revealed an overexpression of the pro-apoptotic gene products Bax and ICE. Therefore, hypoxia followed by reoxygenation would trigger sequential changes in synthesis of specific proteins, leading to delayed and mainly apoptotic neuronal death.

Animals↗

PubMed1998

Sensitivity and density of glutamate receptor subtypes in the hippocampal formation are altered in pentylenetetrazole-kindled rats.

Kindling induced by 13 intraperitoneal injections of 40 mg/kg pentylenetetrazole (PTZ) over a period of 4 weeks resulted in a significant long-lasting increase in both the convulsive susceptibility of animals to the convulsant and the density of the specific [3H]-L-glutamate binding sites in the hippocampus. The quisqualate- and kainate-sensitive [3H]-L-glutamate binding sites were increased 24 h after the final PTZ injection, whereas the N-methyl-D-aspartate (NMDA)-sensitive sites had only a tendency to be enhanced. Furthermore, we investigated [3H]-L-glutamate binding on metabotropic receptors and found a significant increase in the hippocampus following PTZ kindling. In addition, in hippocampal tissue of kindled rats (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD)-stimulated inositol phosphate formation is increased. It can be concluded that the increase in metabotropic glutamate receptor (mGluR) density may be the expression of a specific enhancement in susceptibility of the glutamatergic systems to this excitatory amino acid developing in the course of PTZ-induced kindling.

2-Amino-5-phosphonovalerate↗

PubMed1998

Simulation of psychosis by continuous delivery of phencyclidine from controlled-release polymer implants.

To simulate psychosis in rats we have developed a method for the continuous delivery of phencyclidine (PCP) using implantable controlled-release polymers. PCP polymer implants produced deficits in latent inhibition which do not occur after repeated bolus injections. PCP implanted rats were also devoid of any anxiogenic signs, motoric hyperactivity and learning acquisition which can be seen in rats receiving daily bolus injections of a comparable PCP dose. This behavioral double-dissociation of the two modes of PCP application was accompanied by respective neurochemical changes. PCP binding sites were reduced in both striatum and hippocampus, but in the hippocampus, loss of PCP binding sites was more severe following pulsatile PCP administration. Morphological assessment revealed a significant shrinkage of the CA3 region in hippocampus in both groups. Pharmacokinetic analysis showed that the maximum PCP concentration in the brain after bolus injections was 10-fold above the PCP implants.

Animals↗

PubMed1998

Clinical and pharmacokinetic risk factors for high-dose methotrexate-induced toxicity in children with acute lymphoblastic leukemia--a logistic regression analysis.

The clinical and pharmacokinetic risk factors for toxicity after high-dose methotrexate (MTX) in children with acute lymphoblastic leukemia were evaluated using a multivariate statistical analysis. Plasma samples were collected after 44 24-h infusions of MTX (5 or 8 g/m2) in 13 children (age 3.3-12.9 years) and subsequently analyzed by HPLC to determine the MTX and 7-hydroxymethotrexate (7-OHMTX) concentrations. Toxicity was evaluated according to the WHO criteria. Severe toxicity was not observed. Oral mucositis (WHO grade > or = 1) was significantly related to a high plasma MTX concentration at 28 h after starting the infusion (p = 0.013), a low ratio of plasma 7-OHMTX/MTX at 66 h after starting the infusion (p = 0.049), and a slow clearance of MTX (p = 0.048). The risk of leukopenia (WHO grade > or = 2) increased significantly with the number of courses (p = 0.02). Increasing age and a long exposure to a high MTX concentration in plasma (AUC) were significant risk factors (p = 0.047 and p = 0.009, respectively) for developing elevated liver enzymes (ALAT) (WHO grade > or = 2). This study shows how a statistical model can be used to identify clinical and pharmacokinetic factors that may influence MTX-induced toxicity. The therapeutic ratio could thereby potentially be improved.

Bone Marrow↗

PubMed1998

Salivary gland necrosis in dogs: a retrospective study of 19 cases.

Salivary gland necrosis has been described in dogs and is characterised by enlarged, hard, painful salivary glands, retching and vomiting or regurgitation. The cause has yet to be determined. A retrospective study of 19 dogs with the same clinical signs was undertaken for breed, age, gender, history and presenting signs, diagnostic evaluations and findings, treatment and outcome. An underlying association was identified in 16 of the 19 dogs. This included Spirocerca lupi infestation (seven dogs), megaoesophagus (three dogs) and oesophagitis, oesophageal diverticulum, giardiasis and suspected autoimmune sialadenitis. Almost all associated lesions involved the oesophagus. Where the associated disease was successfully treated, the salivary glands returned to normal and all clinical signs resolved. It is hypothesised that an afferent vagal reflex may be involved, and that the mechanism of disease is similar to the neural pathogenesis suggested for hypertrophic osteopathy; in this instance, the efferent targets are the salivary glands rather than the limbs.

Animals↗

PubMed1998

Long-term effects of early diazepam exposure on social differentiation in adult male rats subjected to the diving-for-food situation.

The present study was designed to investigate the consequences of a chronic diazepam (DZ) exposure (10 mg/kg/day) during the first 3 weeks of life on social behavior of adult male rats measured in a situation of restricted access to food, the diving-for-food model. The treatment had no long-term effects on the acquisition of social roles related to feeding. However, DZ-exposed rats were less efficient than controls in carrying food from the feeder to the cage during the 1st session but were able to adapt and improve their performances during the 2nd one. In the home cage, DZ-exposed rats were more aggressive toward conspecifics than controls and compensated for their deficit of food by stealing it from the others. These results suggest that an early DZ exposure has long-term consequences on social behavior of rats, possibly reflecting a reduction of the level of emotionality.

Animals↗

PubMed1997

S-Acylation and plasma membrane targeting of the farnesylated carboxyl-terminal peptide of N-ras in mammalian fibroblasts.

We have used a series of fluorescent lipid-modified peptides, based on the farnesylated C-terminal sequence of mature N-ras [-GCMGLPC(farnesyl)-OCH3], to investigate the membrane-anchoring properties of this region of the protein and its reversible modification by S-acylation in cultured mammalian fibroblasts. The farnesylated peptide associates with lipid bilayers (large unilamellar phospholipid vesicles) with high affinity but in a rapidly reversible manner. Additional S-palmitoylation of the peptide suppresses its ability to desorb from, and hence to diffuse between, lipid bilayers on physiologically significant time scales. NBD-labeled derivatives of the farnesylated N-ras C-terminal heptapeptide, when incubated with CV-1 cells in culture, are taken up by the cells and reversibly S-acylated in a manner similar to that observed previously for the parent protein. The S-acylation process is highly specific for modification of a cysteine rather than a serine residue but tolerates replacement of the peptide-linked farnesyl moiety by other hydrophobic groups. Fluorescence microscopy reveals that in CV-1 cells the S-acylated form of the peptide is localized preferentially to the plasma membrane, as has been observed for N-ras itself. This plasma membrane localization is unaffected by either reduced temperature (15 degrees C) or exposure to brefeldin A, treatments which inhibit various trafficking steps within the secretory pathway. These results suggest that in mammalian cells the plasma membrane localization of mature N-ras is maintained by a 'kinetic trapping' mechanism based on S-acylation of the protein at the level of the plasma membrane itself.

4-Chloro-7-nitrobenzofurazan↗

PubMed1997

Long-term consequences of neonatal exposure to diazepam on cerebral glucose utilization, learning, memory and anxiety.

The long-term consequences of neonatal exposure to diazepam (DZP) on behavioral abilities and local cerebral glucose utilization (LCGU) in 12 brain regions involved in the control of memory and anxiety were studied in adult rats. Rat pups received a daily subcutaneous injection of 10 mg/kg DZP or of the dissolution vehicle from postnatal day (P) 2 to 21. Learning and memory were tested in P60-P70 rats over 5 consecutive days in a T maze and an eight-arm maze while anxiety and reaction to novelty were tested in a two-compartment box with a two-step staircase on the enriched side. LCGU was measured in the P60 rat by the quantitative autoradiographic [14C]deoxyglucose method. In the T maze, when performed without delay between the two trials, the rate of alternation was significantly lower in DZP- than in vehicle-exposed rats on the first 2 days of testing and similar in both groups on days 3-5. In the procedure with a 30 s intertrial delay, the rate of alternation was similar in DZP- and vehicle-treated rats on all days of testing. In the eight-arm maze, DZP-treated rats were more active, i.e., entered more arms per minute than control animals. The number of arms entered before the first error was lower on day 1 and higher on day 3 in DZP- compared to vehicle-exposed rats. In the two-compartment box, DZP-treated rats crossed more often and spent more time than controls on the lower step of the staircase while control rats made more rearings and spent more time than DZP-exposed rats in the well protected corner of the box. LCGU were decreased by early DZP exposure in six regions which were mammillary body, septum, visual and prefrontal cortices, dorsomedian caudate nucleus and mediodorsal thalamus. In conclusion, postnatal DZP treatment induced at adulthood an increase in activity, a delay in task acquisition but no learning-memory impairment and reduced the level of anxiety allowing active responding to novelty. These quite subtle behavioral changes were accompanied by discrete metabolic decreases in regions mediating anxiety, reflecting a change in the level of anxiety and emotionality.

Animals↗

PubMed1997

Amphetamine induces hypermotility in MPTP-lesioned mice.

Two strains of mice (NMRI and C57B1/ 6) were treated with MPTP (within 8 h 4 x 30 mg/kg MPTP, IP) and motility was monitored 10 days later. An acute administration of amphetamine (2.5 mg/kg or 10.0 mg/kg) or apomorphine (0.5 mg/kg or 5.0 mg/kg) led to hypermotility and a dose-dependent increase of stereotyped behavior. Immunocytochemical investigations indicated a substantial loss of tyrosine-hydroxylase immunoreactivity in the basal ganglia which was accompanied by a 15% increase of 3H-spiroperidol binding to a striatal membrane preparation. No difference was found in biochemical and behavioral measures between both mice strains. Thus, MPTP-induced lesions in mice are probably followed by a denervation-like supersensitivity of the dopaminergic system, which might account for the finding that despite a severe degeneration of dopaminergic terminals amphetamine induces hypermotility.

Animals↗

PubMed1997

The role of striatal glutamatergic system in haloperidol-induced dopamine receptor supersensitivity and effects of monosialoganglioside GM1.

The mechanism underlying the action of ganglioside GM1 on the increase of haloperidol-induced dopamine receptor supersensitivity was studied using the method of chemically stimulated (3H)-D-aspartate release in rat striatal slices. After a 3-week chronic haloperidol treatment the transmitter release was reduced by about 30%, with a further reduction to 40% when GM1 was applied chronically as well. This suggests that the downregulation of the glutamatergic system by chronic haloperidol treatment is potentiated by gangliosides. The acute effect of gangliosides on the stimulated (3H)-D-aspartate release from striatal slices was tested by adding GM1 to the superfusion medium. When given at a concentration of 10(-4) M, GM1 did not alter the amino acid release itself. GM1 did, however, reduce the haloperidol-enhanced (3H)-D-aspartate release to control levels and elevated the glutamate-stimulated (3H)-D-aspartate release. Binding experiments indicate that gangliosides do not directly interact with glutamate or dopamine receptors. The data are discussed in view of earlier findings that GM1 potentiates the behavioral supersensitivity following chronic haloperidol treatment without directly altering dopamine receptor supersensitivity.

Animals↗

PubMed1997

Monitoring of methotrexate and 7-hydroxymethotrexate in saliva from children with acute lymphoblastic leukemia receiving high-dose consolidation treatment: relation to oral mucositis.

The purpose of the study was to find out if saliva concentrations of methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OHMTX), can predict oral mucositis in children with acute lymphoblastic leukemia (ALL) after treatment with high-dose consolidation therapy. We have also studied the relationship between the concentrations of MTX and 7-OHMTX in saliva and the unbound concentrations in plasma. Twelve patients (36 infusions) were studied during treatment with high-dose MTX as remission consolidation therapy (5-8 g/m2 by 24 h i.v. infusion followed by leucovorin rescue). Plasma and saliva concentrations of MTX and 7-OHMTX were determined concomitantly by HPLC at 20 h and at various times following infusion. Unbound plasma concentrations of MTX and 7-OHMTX were determined after ultrafiltration. Oral toxicity was graded according to the WHO criteria (grade 0-4). The concentrations of MTX and 7-OHMTX in saliva were not directly related to the development of mucositis. In patients with oral mucositis (WHO grade 1 or greater), the ratio to 7-OHMTX and MTX in saliva at 20 h was significantly lower than in patients without symptoms (p = 0.014, Mann Whitney rank sum test), but not at 42 and 66 h after starting the infusion. The salivary concentration of 7-OHMTX at 20 h ranged from undetectable (less than 1 nmol/l) to 1.6 micromol/l. No significant correlation was found between the unbound and total plasma concentrations of MTX and 7-OHMTX and the drug concentrations in saliva at different points in time. The concentrations of 7-OHMTX in saliva were 11, 23 and 13% of the unbound plasma concentrations at 20, 42 and 66 h, respectively, after starting the infusion. The respective median corresponding values for MTX were 1.6, 16.1 and 61.6%. The results suggest that determinations of saliva concentrations of MTX and 7-OHMTX may predict oral mucositis. This opens up the possibility of early identification of patients at high risk of developing oral mucositis in order to intensify topical or systemic treatment of these patients.

Child↗

PubMed1997

Suspected primary immunodeficiency syndrome in three related Irish wolfhounds.

Three related Irish wolfhound dogs less than one year old presented with a history of chronic nasal discharge and signs of lower respiratory tract disease. These responded well to treatment initially but were chronically recurring. Cursory evaluation of the immune system (full blood counts, globulin determination and fractionation, electrophoresis and lymphocyte blastogenesis) seemed to indicate a cell-mediated immunodeficiency which, because of the age of the patients, is strongly suspected to be primary.

Animals↗

PubMed1996

Methotrexate plasma pharmacokinetics: importance of assay method.

Intravenous methotrexate (MTX) therapy is widely used for treatment of various neoplastic diseases in children. The optimization of the MTX dose and/or the subsequent leucovorin rescue is based on pharmacokinetic data calculated from plasma concentrations collected after cessation of the MTX administration. The influence of the MTX assay method on the subsequent pharmacokinetic evaluation was studied in 13 children with acute lymphoblastic leukemia. Plasma samples were collected after administration of MTX (5-8 g/m2) as 24 h infusions. All samples were analyzed by five different analytical procedures, viz. liquid chromatography (LC), enzyme inhibition assay (EIA), two fluorescence polarization immunoassays (FPIA1 and FPIA2) and enzyme multiplied immunoassay (EMIT). Using measurements from the four non-chromatographic procedures, only about 50% of determined pharmacokinetic parameters (area under the plasma concentration time curve, calculated by the trapezoidal rule and from pharmacokinetic modelling, and the terminal half life time) were within the range 75-125% of the values obtained from LC data. We conclude that the clinical outcome of MTX therapy using estimated MTX pharmacokinetics as guidelines for proper dosing of MTX and/or leucovorin rescue might be affected by the lack of accuracy of non-chromatographic procedures for MTX analysis. There is still a need for improving the accuracy of the procedures aimed at therapeutic drug monitoring of MTX.

Adolescent↗

PubMed1996

Lipid-modified, cysteinyl-containing peptides of diverse structures are efficiently S-acylated at the plasma membrane of mammalian cells.

A variety of cysteine-containing, lipid-modified peptides are found to be S-acylated by cultured mammalian cells. The acylation reaction is highly specific for cysteinyl over serinyl residues and for lipid-modified peptides over hydrophilic peptides. The S-acylation process appears by various criteria to be enzymatic and resembles the S-acylation of plasma membrane-associated proteins in various characteristics, including inhibition by tunicamycin. The substrate range of the S-acylation reaction encompasses, but is not limited to, lipopeptides incorporating the motifs myristoylGC- and -CXC(farnesyl)-OCH3, which are reversibly S-acylated in various intracellular proteins. Mass-spectrometric analysis indicates that palmitoyl residues constitute the predominant but not the only type of S-acyl group coupled to a lipopeptide carrying the myristoylGC- motif, with smaller amounts of S-stearoyl and S-oleoyl substituents also detectable. Fluorescence microscopy using NBD-labeled cysteinyl lipopeptides reveals that the products of lipopeptide S-acylation, which cannot diffuse between membranes, are in almost all cases localized preferentially to the plasma membrane. This preferential localization is found even at reduced temperatures where vesicular transport from the Golgi complex to the plasma membrane is suppressed, strongly suggesting that the plasma membrane itself is the preferred site of S-acylation of these species. Uniquely among the lipopeptides studied, species incorporating an unphysiological N-myristoylcysteinyl- motif also show substantial formation of S-acylated products in a second, intracellular compartment identified as the Golgi complex by its labeling with a fluorescent ceramide. Our results suggest that distinct S-acyltransferases exist in the Golgi complex and plasma membrane compartments and that S-acylation of motifs such as myristoylGC- occurs specifically at the plasma membrane, affording efficient targeting of cellular proteins bearing such motifs to this membrane compartment.

Acylation↗

PubMed1996

Evaluation of clinical assays for measuring high-dose methotrexate in plasma.

Four routine assays commonly used for monitoring plasma methotrexate (MTX) during high-dose therapy were validated by HPLC as the comparison method. MTX and its main metabolite, 7-hydroxymethotrexate (7-OHMTX), were analyzed by HPLC with postcolumn derivatization and fluorometric detection. About 200 clinical plasma samples from 13 children with acute lymphoblastic leukemia who received 5-8 g/m2 MTX as 24-h infusions were analyzed. The fraction of measured concentrations of MTX that were within 75-125% of the values obtained by HPLC were 64.5% for enzyme inhibition assay, 56.4% for fluorescence polarization immunoassay with polyclonal antibodies (FPIA1; Abbott), 58.9% for FPIA2 (with monoclonal antibodies; Abbott), and 46.4% for enzyme-multiplied immunoassay (Emit; Syva). All nonchromatographic procedures were subject to interferences from MTX plasma metabolites or endogenous substances. The interference from 7-OHMTX was, however, somewhat less pronounced for FPIA2 (monoclonal) than for FPIA1 (polyclonal).

Child↗

PubMed1996

Allogeneic bone marrow transplantation in first remission for children with very high-risk acute lymphoblastic leukemia: a retrospective case-control study in the Nordic countries. Nordic Society for Pediatric Hematology and Oncology (NOPHO).

Among children with high-risk (HR) ALL there are subgroups with very-high-risk (VHR) features and poor prognosis despite developments in conventional chemotherapy for childhood ALL. We evaluated the outcome of VHR-ALL in children receiving allogeneic BMT (allo-BMT) in first remission (1CR) in a retrospective case-control study. In the population-based ALL material of the five Nordic countries, 22 children with VHR-ALL have undergone allo-BMT in 1CR between 1981-1991. We compared the outcome in these 22 children with 44 closely matched control patients who received conventional chemotherapy on HR-ALL protocols, as well as with a group of 405 children representing the remaining HR-ALL patients in the Nordic ALL database. The disease-free survival at 10 years was 73% in children receiving allo-BMT in 1CR, 50% in the matched controls (P = 0.02), and 59% in the remaining HR-ALL patients. The good prognosis of the allo-BMT group was due to a low relapse rate of 9%, as opposed to 41% in the group of matched controls. The superiority of allo-BMT as therapy in 1CR was mainly apparent in those with a very high WBC of > or = 100 x 10(9)/I at diagnosis; in the allo-BMT group 9/10 survived, as opposed to 8/20 of the matched controls (P = 0.03). We conclude that allo-BMT in 1CR should be seriously considered for children with a matched sibling donor and a VHR-ALL with WBC of > or = 100 and other established VHR criteria.

Adolescent↗