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Biomedical subjects

T Langer

Publications and source records attributed to T Langer.

At least 73 records · Page 4Linked to original sources
PubMed1997

CNS late effects after ALL therapy in childhood. Part I: Neuroradiological findings in long-term survivors of childhood ALL--an evaluation of the interferences between morphology and neuropsychological performance. The German Late Effects Working Group.

The effect of cranial irradiation on possible therapy-induced morphological central nervous system (CNS) side effects of children cured from acute lymphoblastic leukemia (ALL) is controversially discussed. In a retrospective multicenter study, 118 former ALL patients in first continuous remission were investigated using cranial computerised tomography (CCT) or magnetic resonance imaging (MRI) scans to evaluate CNS related impairments. Corresponding to the different kinds of CNS prophylaxis, the patient sample was divided: group A (n = 39) receiving intrathecal methotrexate (ITMTX) and systemical medium-high-dose methotrexate (SMHDMTX), group B (n = 41) cranial irradiated (in mean 16.8 Gy) and administering ITMTX and SMHDMTX, group C (n = 38) irradiated (in mean 17.1 Gy) and getting ITMTX. Pathologic scans showed atrophy, leukoencephalopathy, calcifications or grey matter changes. These findings were compared with the neuropsychological test results. Abnormal MRI or CCI scans were found in 61/118 patients (51.7%). Fifteen belonged to group A (38.5%), 23 to B (56.1%) and 23 to C (60.5%). Patients with definite CNS changes show reduced neuropsychological test results. The prevalence of brain alterations seems to appear twice increased after lengthening the posttherapeutic interval in irradiated patients as in nonirradiated patients. Irradiated patients as an age younger than 2 years at diagnosis may show a lower prevalence for developing CNS alterations. CNS alterations are not sex-related. Children treated with cranial irradiation in combination with SMHDMTX and/or ITMTX were at greater risk of developing morphological brain alterations than patients with chemotherapy alone. These alterations are partly correlated with reduced neuropsychological performances and seem to stay with a longer posttherapeutic interval.

Adolescent↗
PubMed1997

CNS late effects after ALL therapy in childhood. Part II: Conventional EEG recordings in asymptomatic long-term survivors of childhood ALL--an evaluation of the interferences between neurophysiology, neurology, psychology, and CNS morphology. German Late Effects Working Group.

Monitoring of therapy-related late effects after acute lymphoblastic leukemia (ALL) therapy in childhood has become an increasingly important area in posttherapeutic patient surveillance. The usefulness of conventional electro-encephalographic (EEG) investigations as part of these attempts is controversially discussed. However, EEG recordings have become a popular approach for judgement on the functional integrity of the central nervous system in this subject group. The present report focuses on this problem and discusses the question whether and to what extent conventional EEG recordings were correlated with further measures of central nervous system (CNS) integrity and therapeutic differences. EEGs were recorded in 110 subjects, asymptomatic long-term survivors of ALL in childhood, during a large retrospective multicenter study evaluating CNS late sequelae following antileukemic therapy in Germany and Austria. EEG findings were correlated with demographic data, illness- and treatment-related parameters, as well as with data on the morphological, neurological and psychological status of the participating subjects. At the time of follow-up the EEG was abnormal in 47 cases (42.7%). The most frequent EEG abnormalities observed were disturbances of the background activity (n = 45, 95.8%), followed by hypersynchrone activities (n = 1.0, 21.3%) and interhemispheric differences/focal slowing (n = 6, 12.8%). With exception of age at diagnosis, none of the observed EEG abnormalities showed a correlation with any of the aforementioned illness- or treatment-related parameters. Eighty percent of the observed EEG abnormalities were found in children younger than 5 years at diagnosis. Children less than 2 years of age as well as those above 5 years at onset of disease showed a significantly reduced prevalence of EEG disturbances compared to subjects between 2 and 5 years at diagnosis. Neither the degree of illness nor therapy-specific differences showed any relationship to EEG outcome. There was no specific EEG finding for a specific morphological substrate, neurological or psychological deficiency and vice versa. Overall, there was no beneficial effect of routine EEG testing in children following therapy for ALL. According to our data, the evaluation of conventional EEG recordings of otherwise asymptomatic ALL long-term survivors is not a very helpful measure for predicting the degree of behavioral deficiencies, neurological disturbances, or morphological CNS abnormalities, which may be present or will develop in this special subject group.

Adolescent↗
PubMed1997

Neurophysiological findings in long-term survivors of acute lymphoblastic leukaemia in childhood treated with the BFM protocol 81 SR-A/B.

UNLABELLED: Monitoring of therapy-related late effects after acute lymphoblastic leukaemia (ALL) therapy in childhood has become an increasingly important field in posttherapeutic patient surveillance. The usefulness of neurophysiological investigations (e.g. EEG, evoked potentials (EP)) as part of these attempts is controversial. The present report focuses on this problem and the question whether and to what extent routinely performed EEG recordings and visual evoked potentials (VEP) were correlated with further measures of CNS integrity. EEGs and VEPs were recorded in 163 asymptomatic long-term survivors of ALL in childhood during a large retrospective multicentre study evaluating CNS late sequelae following antileukaemic therapy. Fifty-two ALL long-term survivors (4.5-10.6 years after end of therapy, median: 8.8 years), who had been treated according to BFM-81 SR-A (n = 30) or SR-B (n = 22) were selected for this analysis focusing on therapy-related CNS late effects. Therapy protocols differed with regard to the mode for CNS prophylaxis: SR-A, cranial irradiation with intrathecal methotrexate; SR-B, intrathecal and iv methotrexate. Neurophysiological findings were correlated with illness- and treatment-related parameters, as well as with data on the morphological, neurological and psychological status of the CNS. At the time of follow-up neurophysiological measures were abnormal in 28/52 cases (53.8%). Neither illness- nor therapy-specific differences in CNS prophylaxis showed any relationship to EEG/VEP outcome any relationship to EEG/VEP outcome in this reduced group of the whole study population. Children with EEG/VEP abnormalities showed a significantly higher incidence of structural CNS disturbances compared to those with inconspicuous neurophysiological recordings (60.9% vs 31.8%). However, in this special subject group there was no specific neurophysiological finding for a specific morphological substrate, neurological or psychological deficiency and vice versa. CONCLUSION: Routinely performed EEG/VEP investigations are not very helpful measures to predict the presence or degree of behavioural deficiencies, neurological disturbances, or morphological CNS abnormalities. Patients who received cranial irradiation or systemic methotrexate applications showed the same incidence of neurophysiological disturbances without evidence for specific neurotoxic correlates.

Adolescent↗
PubMed1996

Regulated protein degradation in mitochondria.

Various adenosine triphosphate (ATP)-dependent proteases were identified within mitochondria which mediate selective mitochondrial protein degradation and fulfill crucial functions in mitochondrial biogenesis. The matrix-localized PIM1 protease, a homologue of the Escherichia coli Lon protease, is required for respiration and maintenance of mitochondrial genome integrity. Degradation of non-native polypeptides by PIM1 protease depends on the chaperone activity of the mitochondrial Hsp70 system, posing intriguing questions about the relation between the proteolytic system and the folding machinery in mitochondria. The mitochondrial inner membrane harbors two ATP-dependent metallopeptidases, the m- and the i-AAA protease, which expose their catalytic sites to opposite membrane surfaces and cooperate in the degradation of inner membrane proteins. In addition to its proteolytic activity, the m-AAA protease has chaperone-like activity during the assembly of respiratory and ATP-synthase complexes. It constitutes a quality control system in the inner membrane for membrane-embedded protein complexes.

Adenosine Triphosphate↗
PubMed1996

Molecular basis of peripheral vs central benzodiazepine receptor selectivity in a new class of peripheral benzodiazepine receptor ligands related to alpidem.

Alpidem (1), the anxiolytic imidazopyridine, has nanomolar binding affinity for both the central benzodiazepine receptor (CBR) and the peripheral benzodiazepine receptor (PBR). A novel class of PBR ligands related to alpidem has been designed by comparing the interaction models of alpidem with PBR and CBR. Several compounds in this class have shown high selectivity for PBR vs CBR, and the selectivity has been discussed in terms of interaction models. The binding behavior of the three selected compounds was extensively studied by competition and saturation assays, and the results suggest that they are capable of recognizing two sites labeled by [3H]PK11195. The molecular structure of one of the most active compounds (4e) has been determined by X-ray diffraction and compared with that of alpidem. Molecular modeling studies suggest that the bioactive conformation of 4e is likely to be very similar to the conformation found in the crystal.

Animals↗
PubMed1996

On the bioisosteric potential of diazines: diazine analogues of the combined thromboxane A2 receptor antagonist and synthetase inhibitor Ridogrel.

In this SAR study the bioisosteric potential of diazines in the field of combined antithrombotic thromboxane A2 synthetase inhibitors and receptor antagonists was investigated. In this context, two series of (E)- and (Z)-omega-[[(aryldiazinylmethylene)amino]oxy]alkanoic acids were synthesized of which pentanoic acid derivatives with a 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl group were found to exhibit this dual activity, while 4-pyrimidinyl as well as 3-pyridazinyl analogues showed only receptor antagonistic activity and 2-pyrimidinyl congeners were inactive. In the series of diazine analogues of Ridogrel (1), replacement of the 3-pyridyl group by a 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl moiety led to compounds that inhibit thromboxane A2 synthetase in gel-filtered human platelets comparable to 1 (IC50 of 0.006, 0.016, and 0.039 microM, respectively, versus 0.007 microM). Radioligand-binding studies with [3H]SQ 29,548 in washed human platelets revealed that these diazine analogues block the thromboxane A2 receptor with an IC50 of 11, 6.0, and 1.5 microM, respectively. This compares well with the IC50 = 1.7 microM of 1. Finally, testing of inhibition of collagen-induced platelet aggregation in human platelet aggregation in human platelet-rich plasma with 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl congeners of Ridogrel indicated that these heteroaromatic moieties may serve as bioisosteric substitutes of a 3-pyridyl group in dual-acting antiplatelet agents.

Blood Platelets↗
PubMed1996

AAA proteases with catalytic sites on opposite membrane surfaces comprise a proteolytic system for the ATP-dependent degradation of inner membrane proteins in mitochondria.

The mechanism of selective protein degradation of membrane proteins in mitochondria has been studied employing a model protein that is subject to rapid proteolysis within the inner membrane. Protein degradation was mediated by two different proteases: (i) the m-AAA protease, a protease complex consisting of multiple copies of the ATP-dependent metallopeptidases Yta1Op (Afg3p) and Yta12p (Rcalp); and (ii) by Ymelp (Ytallp) that also is embedded in the inner membrane. Ymelp, highly homologous to Yta1Op and Yta12p, forms a complex of approximately 850 kDa in the inner membrane and exerts ATP-dependent metallopeptidase activity. While the m-AAA protease exposes catalytic sites to the mitochondrial matrix, Ymelp is active in the intermembrane space. The Ymelp complex was therefore termed 'i-AAA protease'. Analysis of the proteolytic fragments indicated cleavage of the model polypeptide at the inner and outer membrane surface and within the membrane-spanning domain. Thus, two AAA proteases with their catalytic sites on opposite membrane surfaces constitute a novel proteolytic system for the degradation of membrane proteins in mitochondria.

ATP-Dependent Proteases↗
PubMed1996

The YTA10-12 complex, an AAA protease with chaperone-like activity in the inner membrane of mitochondria.

The mitochondrial members of the highly conserved AAA family, Yta10p and Yta12p, constitute a membrane-embedded complex of about 850 kDa. As an ATP dependent metallopeptidase (AAA protease), the YTA10-12 complex mediates the degradation of nonassembled inner membrane proteins. In contrast to nucleotide-dependent complex formation and substrate binding, proteolysis of bound polypeptides depends on the hydrolysis of ATP and the metallopeptidase activity of both subunits. Independent of its proteolytic function, the chaperone-like activity of the YTA10-12 complex is required for assembly of the membrane-associated ATP synthase. We propose that proteolytic and chaperone-like activities in the YTA10-12 complex mediate assembly and degradation processes of membrane protein complexes and thereby exert key functions in the maintenance of membrane integrity.

Adenosine Triphosphatases↗
PubMed1996

Substitution of PIM1 protease in mitochondria by Escherichia coli Lon protease.

PIM1 protease in mitochondria belongs to a conserved family of ATP-dependent proteases, which includes the Escherichia coli Lon protease. Yeast cells lacking PIM1 are largely defective in degrading misfolded proteins in the mitochondrial matrix, are respiratory deficient, and lose integrity of mitochondrial DNA. In order to analyze whether E. coli Lon protease is functionally equivalent to mitochondrial PIM1 protease, yeast cells lacking the PIM1 gene were transformed with a construct consisting of a mitochondrial targeting sequence fused onto the Lon protease. In these cells, the fusion protein was expressed and imported into mitochondria, and the targeting sequence was removed. In the absence of PIM1 protease, the E. coli Lon protease mediated the degradation of misfolded proteins in the matrix space in cooperation with the mitochondrial hsp70 system. These cells maintained the integrity of the mitochondrial genome and the respiratory function at 30 degrees C but not at 37 degrees C. Stabilization of mitochondrial DNA in Deltapim1 cells depended on protein degradation by the E. coli Lon protease, as a proteolytically inactive Lon variant was not capable of substituting for a loss of PIM1 protease. These results demonstrate functional conservation of Lon-like proteases from prokaryotes to eukaryotes and shed new light on the role of Lon-like proteases in mitochondrial biogenesis.

ATP-Dependent Proteases↗
PubMed1996

Role of the mitochondrial DnaJ homologue, Mdj1p, in the prevention of heat-induced protein aggregation.

The role of the mitochondrial Hsp70 system in the prevention of heat-induced protein aggregation was studied in isolated mitochondria from Saccharomyces cerevisiae. Firefly luciferase was employed as a thermolabile tester protein. After shift to 40 degrees Celsius transient increase of mt-Hsp70/luciferase complex was observed, which required functional Mdj1p and Mge1p, the mitochondrial homologues of DnaJ and GrpE. The kinetics of luciferase aggregation, however, were not influenced by mutations in either mt-Hsp70 or Mge1p. Only the absence of Mdj1p led to enhanced protein aggregation. Thus, a central role in the transient protection against heat stress is attributed to this mitochondrial DnaJ homologue.

Bacterial Proteins↗
PubMed1996

Molecular structure and dynamics of some potent 5-HT3 receptor antagonists. Insight into the interaction with the receptor.

The molecular structure and the dynamic behaviour of some potent 5-HT3 antagonists structurally related to quipazine have been investigated by NMR spectroscopy and by computational methods in order to gain insight into the structure-activity relationships at a molecular level. The role of the different dynamic behaviour of these compounds in the binding to 5-HT3 receptors is discussed. A model of ligand-receptor interaction has been developed on the basis of molecular orbital calculations and on the reference ligands quipazine, ondansetron and LY278584. The interaction model proposed herein rationalizes the observed agonist-antagonist shift between quipazine and investigated compounds with the assumption of different but overlapping binding domains for antagonists and agonists at the 5-HT3 receptor.

Affinity Labels↗
PubMed1996

Quantitative EEG in long-term survivors of acute lymphoblastic leukemia.

Conventional and quantitative aspects of electroencephalographic recordings obtained during a follow-up surveillance study in long-term survivors of acute lymphoblastic leukemia in childhood were investigated with respect to differences in central nervous system prophylaxis given during antileukemic therapy and compared with data derived from healthy controls. Central nervous system prophylaxis consisted either of cranial irradiation (18 Gray, group A, n = 8) or intermediate high-dose methotrexate (2000 mg/m2; group B, n = 5), each combined with intrathecal methotrexate. Conventional electroencephalographic analysis revealed comparable results in all three study groups. However, quantitative electroencephalography showed significantly increased absolute power scores for all frequency bands in both long-term survivor groups. Relative power estimates revealed a significant increase in delta/tau activities in both prophylaxis groups compared to healthy controls, which were countered by decreased percentage power scores in the alpha-range. Quantitative electroencephalographic comparisons between both central nervous system prophylaxis groups revealed only small differences in quantity, not quality, of the observed power disturbances with slightly higher deviations in irradiated long-term survivors than in nonirradiated ones. Topographical distributions of spectral band power were comparable between all three study groups without evidence for therapy-related topographical differences.

Adolescent↗
PubMed1996

A competitive enzyme immunoassay for the pyrrolizidine alkaloids of the senecionine type.

We developed an immunoassay with antibodies against retrorsine to detect the closely related senecionine, the main alkaloid in various Asteraceae. Sensitivity is about 23 pg (68 fmol) for senecionine. Cross reactivity of monocrotalin, retrorsine N-oxide, senkirkine (< 0.1%), and seneciphylline (3.6-34.5%) was resolved. The alkaloid content in leaves of Petasites hybridus (Asteraceae) was determined to be 3.86 ppm, calculated as senecionine, which was far less than in rhizomes (104.8 ppm). Additionally, we proved specificity by taking immunograms from different parts of Petasites hybridus. The test is a suitable tool for assessing the toxic potential of medicinal plants containing senecionine.

Animals↗
PubMed1996

Visual-evoked potentials in long-term survivors of acute lymphoblastic leukemia in childhood. The German Late Effects Working Group.

Visual-evoked potentials (VEPs) were studied in 92 asymptomatic long-term survivors of acute lymphoblastic leukemia (ALL) in first complete remission 6-7 years after cessation of therapy in order to detect therapy-related disturbances in conduction velocity capacities within central nerve fibers. Subjects were grouped with respect to CNS prophylaxis: a) ith. MTX and 18 GY cranial irradiation (group A, n = 58), b) ith. MTX and iv. MHD-MTX, no cranial irradiation (group B, n = 34). At follow-up VEPs were abnormal in 10 subjects (10.9%) with comparable rates in both CNS prophylaxis groups (A: 7/58 [12.1%], B: 3/34 [8.8%]; p = 0.56). Participants with radiological signs of leukodystrophy (n = 14), all within the irradiated CNS prophylaxis group showed significantly prolonged P100 latencies and had a 6.1-fold increased relative risk to develop VEP disturbances. No correlation could be established between VEP outcome and illness- or treatment-related parameters. VEP outcome was not correlated with age at diagnosis or gender. Thus, VEP recordings showed a close relationship with radiation-induced CNS white-matter disturbances. However, their value for clinical practice, routinely performed follow-up evaluations or standardized posttreatment surveillance studies is negligible.

Age of Onset↗
PubMed1996

The molecular chaperone Hsp78 confers compartment-specific thermotolerance to mitochondria.

Hsp78, a member of the family of Clp/Hsp100 proteins, exerts chaperone functions in mitochondria of S. cerevisiae which overlap with those of mitochondrial Hsp70. In the present study, the role of Hsp78 under extreme stress was analyzed. Whereas deletion of HSP78 does not affect cell growth at temperatures up to 39 decrees C and cellular thermotolerance at 50 degrees C, Hsp78 is crucial for maintenance of respiratory competence and for mitochondrial genome integrity under severe temperature stress (mitochondrial thermotolerance). Mitochondrial protein synthesis is identified as a thermosensitive process. Reactivation of mitochondrial protein synthesis after heat stress depends on the presence of Hsp78, though Hsp78 does not confer protection against heat-inactivation to this process. Hsp78 appears to act in concert with other mitochondrial chaperone proteins since a conditioning pretreatment of the cells to induce the cellular heat shock response is required to maintain mitochondrial functions under severe temperature stress. When expressed in the cytosol, Hsp78 can substitute for the homologous heat shock protein Hsp104 in mediating cellular thermotolerance, suggesting a conserved mode of action of the two proteins. Thus, proteins of the Clp/Hsp100-family located in the cytosol and within mitochondria confer compartment-specific protection against heat damage to the cell.

Cell Compartmentation↗