Biomedical subjects

J Kiefer

Publications and source records attributed to J Kiefer.

At least 55 records · Page 3Linked to original sources

PubMed1995

Degradation of lamin B1 precedes oligonucleosomal DNA fragmentation in apoptotic thymocytes and isolated thymocyte nuclei.

Chromatin condensation and nuclear envelope breakdown are characteristic features of apoptotic cell death, but the mechanisms underlying these phenomena have not been identified. Solubilization of nuclear lamin is responsible for both events in mitosis. In this work, we report that glucocorticoids stimulate rapid degradation of lamin B1 that occurs before oligonucleosomal DNA fragmentation in apoptotic thymocytes. Protease inhibitors and the Ca2+ buffering agent BAPTA-AM block lamin degradation and DNA fragmentation, indicating that the processes are regulated by similar or identical mechanisms. Incubation of isolated thymocyte nuclei with Ca2+ stimulates lamin degradation before the detection of oligonucleosomal DNA fragments. However, in contrast to lamin dissolution during mitosis and some other forms of apoptosis, glucocorticoid-induced degradation of lamin B1 in thymocytes is not accompanied by dephosphorylation-mediated activation of cdc2. Our results demonstrate that lamin degradation is an early feature of apoptosis in thymocytes and suggest that chromatin condensation and breakdown of the nuclear envelope may occur as a result of disruption of nuclear lamina architecture.

Animals↗

PubMed1995

Induction of HPRT- mutants in Chinese hamster V79 cells after heavy ion exposure.

The induction of resistance to 6-thioguanine by heavy ion exposure was investigated with various accelerated ions (oxygen-uranium) up to linear energy transfer (LET) values of about 15,000 keV/microns. Survival curves are exponential with fluence; mutation induction shows a linear dependence. Cross-sections (sigma i: inactivation, sigma m: mutation) were derived from the respective slopes. Generally, sigma i rises over the whole LET range, but separates into different declining curves for single ions with LET values above 200 keV/microns. Similar behaviour is seen for sigma m. The new SIS facility at GSI, Darmstadt, makes it possible to study the effects of ions with the same LET but very different energies and track structures. Experiments using nickel and oxygen ions (up to 400 MeV/u) showed that inactivation cross-sections do not depend very much on track structure, i.e. similar values are found with different ions at the same LET. This is not the case for mutation induction, where very energetic ions display considerably smaller induction cross-sections, compared with low-energy ions of identical LET. Preliminary analyses using the polymerase chain reaction (PCR) demonstrate that even heavy ions cause "small alterations" (small deletions or base changes). The proportion of the total deletions seems to increase with LET.

Animals↗

PubMed1995

Heavy ion-induced DNA double-strand breaks with yeast as a model system.

Cells of diploid yeast, Saccharomyces cerevisiae, were exposed to a variety of energetic heavy ions (provided by the UNILAC facility at the Gesellschaft für Schwerionenforschung, GSI), 241Am alpha-particles and 80-keV x-rays after which they were assessed for DNA double-strand breaks (DSB) using either the neutral sedimentation or the pulsed-field gel electrophoresis (PFGE) technique. Both yielded comparable results. The DSB production cross-sections are compared with inactivation studies performed for the same cells under identical conditions. The measurements show that with lighter ions DSB induction cross-sections increase with linear energy transfer (LET), but the situation is less clear with the heavier ions. A close parallelism was found between DSB induction and cell inactivation in these yeast cells.

Alpha Particles↗

PubMed1995

Ambulatory blood pressure monitoring in healthy schoolchildren.

Ambulatory blood pressure monitoring (ABPM) was performed in 564 healthy schoolchildren during normal circadian activities. The data of two cohorts (155 boys and 139 girls aged 9-13 years and 184 boys and 168 girls with a body height between 120 and 155 cm) are presented. From the age of 9 to 13 years the mean 24-h systolic/diastolic blood pressure (SBP/DBP) increases from 107 +/- 9/66 +/- 7 mmHg to 115 +/- 13/68 +/- 9 mmHg in boys and from 104 +/- 5/64 +/- 6 mmHg to 109 +/- 8/65 +/- 9 mmHg in girls. When related to body height the values rise from 105 +/- 6/64 +/- 6 mmHg at 120 cm to 113 +/- 8/67 +/- 7 mmHg at 155 cm in boys and from 100 +/- 7/65 +/- 7 mmHg to 112 +/- 9/66 +/- 9 mmHg in girls. In comparison with the causal blood pressure data obtained from European studies, the presented ABPM values (daytime BP) are higher throughout, which may be explained by the increased activity during daytime with ABPM. There is a mean difference of 4.4 mmHg in boys and of 3.0 mmHg in girls for SBP and of 10.8 mmHg in boys and of 9.0 mmHg in girls for DBP when related to age. In relation to body height, there is a mean difference of 4.4 mmHg in boys and of 3.5 mmHg in girls for SBP and of 10.9 mmHg in boys and of 10.5 mmHg in girls for DBP. We conclude that standards derived from causal blood pressure measurements should not be used for the evaluation of ABPM data.

Adolescent↗

PubMed1995

Sleep disturbances in the demented elderly: treatment in ambulatory care.

We report the results of a representative survey in Lower Saxony, Germany, that focused on the treatment of sleep disturbances in the moderately demented elderly. Two written sample case histories (vignettes) described either a vascular demented patient suffering from nocturnal wandering or an Alzheimer's-type demented patient without apparent psychotic or behavioral (sleep) disorder. These were randomly assigned and presented to 145 family physicians and 14 neuropsychiatrists working in private practice by a trained investigator, who then conducted a standardized interview with the physicians. The study was representative of physicians (response rate: 83.2%). In response to the question concerning how they would treat the patient's sleep disturbances, about 20% of the physicians (with respect to both versions) answered that they would not choose drugs. More than 40% considered neuroleptics to be the drugs of choice. Benzodiazepines, antidepressants and other substances were seldom considered. No significant difference was noted in the response to the two different case histories. The results allow for the conclusion that non-drug treatments, which (at least initially) should be the treatment of choice, are mainly disregarded by the majority of the ambulatory care physicians. The reason for this seems to be a lack of education in sleep medicine and also in geriatric medicine.

Aged↗

PubMed1995

Killing and mutation of Chinese hamster V79 cells exposed to accelerated oxygen and neon ions.

Mutation induction by accelerated heavy ions to 6-thioguanine resistance (HPRT system) in Chinese hamster V79 cells was investigated using oxygen and neon ions with energies between 1.9 and 400 MeV/mu, corresponding to LET values between 18 and 754 keV/microns, respectively. Because of technical limitations most experiments could be performed only once. Inactivation and mutation induction cross sections, sigma i and sigma m, were obtained from the slopes of the exponential survival and the linear mutation induction curves, respectively. Both parameters increased with LET up to about 200 keV/microns, where the curves separated for the two types of ions. Calculated RBEs were higher for mutation induction than for killing for all LET values.

Animals↗

PubMed1995

Reasons for prescribing cognition enhancers in primary care. Results of a representative survey in Lower Saxony, Germany.

With regard either to the controversial debate about the efficacy of cognition enhancers (CEs) or to the high costs which the frequent prescription of these drugs causes the German health system's economy, we wanted to know what physicians expect from a therapy with these drugs. We performed a representative survey (response rate 83.2%) in Lower Saxony, Germany from February to July 1993. We designed two written case vignettes which described either a patient with slight memory problems or a moderately demented patient who also suffers from common systemic disorders. In a face-to-face interview 145 general practitioners and primary care internists (family physicians) and 14 community neuropsychiatrists answered the question, whether they would prescribe CEs to each of the patients described and what they would expect from this therapy. 70.4% of all physicians would prescribe a cognition enhancer to the slightly impaired patient and 63.5% to the multimorbid moderately demented patient, respectively. More than 50% of the family physicians would not expect any positive therapeutic effect in both patients, while the neuropsychiatrists did so in 57.1% in the patient with slight memory disturbances and in 35.7% in the moderately demented patient. A positive effect on cognition was expected by 28.2% of all physicians in the slight and by 18.3% in the moderately impaired patient, respectively. Other reasons mentioned were amelioration of cerebral perfusion and drive, as well as effects on disease progression. In conclusion, the results of this study clearly demonstrate that cognition enhancers are prescribed in spite of major doubts in their efficacy.

Aged↗

PubMed1994

Isolation and chromosomal localization of a novel human G-protein-coupled receptor (GPR3) expressed predominantly in the central nervous system.

Degenerate oligonucleotide primers designed against known G-protein-coupled receptors were used in polymerase chain reaction amplification to isolate a novel receptor sequence (R4) from a rat insulinoma cell line and its human homolog (GPR3) from a human neuroblastoma cDNA library. The novel human receptor sequence is expressed in low abundance predominantly in the central nervous system and at low levels in the lung and kidney. The gene encoding GPR3 is intronless within the coding region, contains at least one intron in the 5'-untranslated region, and has been localized to chromosome 1p34.3. The activating ligand for the homologous receptors R4 and GPR3 is not known, but sequence similarity with the closely related orphan rat receptor R334 [FEBS Lett. 292:243 (1991)] suggests that R334 and the homologous receptors R4 and GPR3 probably represent two discrete molecular subtypes that interact with the same or closely related ligands.

Amino Acid Sequence↗

PubMed1994

[Ambulatory treatment of sleep disorders in the aged].

An enquiry into the handling by medical practitioners of sleeping problems among elderly patients was conducted in southern Lower Saxony by personal interview, combined with a standard questionnaire. A typical case report had been drafted concerning a 70-year-old, previously healthy widow: her complaints were "nonspecific" and could be classified as an example of either depression, of the onset of senile dementia or as within normal limits for age. This case report was presented by two interviewers to 145 general practitioners (GPs) and 14 neurologists in private practice (response rate of 83.2%) who were asked how they would have treated the patient's sleeping disorder. 30.3% of the GPs and 14.3% of the neurologists would initially not have prescribed medication. Only GPs (19.5%) mentioned possible herbal medication. Sedative neuroleptics were preferred by 57.1% of neurologists and 26.2% of GPs, while benzodiazepines would have been given by 14% of both groups. Antidepressive drugs and chloral hydrate were chosen less often (5.7% and 2.5%, respectively). These data support the finding of a high frequency of neuroleptic prescriptions given to the elderly. They also make clear that the possibility of treatment without drugs is usually not sufficiently explored.

Aged↗

PubMed1994

Repair of radiation induced genetic damage under microgravity.

The influence of microgravity on the repair of radiation induced genetic damage in a temperature-conditional repair mutant of the yeast Saccharomyces cerevisiae (rad 54-3) was investigated onboard the IML-1 mission (January 22nd-30th 1992, STS-42). Cells were irradiated before the flight, incubated under microgravity at the permissive (22 degrees C) and restrictive (36 degrees C) temperature and afterwards tested for survival. The results suggest that repair may be reduced under microgravity.

Cell Survival↗

PubMed1994

Diagnosis of dementia in primary care: results of a representative survey in lower Saxony, Germany.

To investigate whether an early diagnosis of dementia is established, whether a differentiation is made between vascular and primary degenerative etiology, and whether treatable causes of dementia are considered in primary care, we performed a survey using three written sample case histories describing slight memory impairment (case 1) or moderate dementia (case 2a: vascular dementia; case 2: degenerative dementia of Alzheimer type). The combinations 1 and 2a or 1 and 2b were randomly assigned and presented to ambulatory-care physicians (145 general practitioners and primary care internists and 14 neuropsychiatrists in private practice) in Göttingen and rural surroundings by a trained investigator who then performed a standardized interview. The study was representative (response rate 83.2%). For the sample case with slight memory complaints 13.8% of all physicians arrived at a primary diagnosis of depression and 44.0% considered depression for differential diagnosis. Senile dementia of Alzheimer type was considered less often. In the sample cases with moderate dementia according to established scientific criteria, there was a striking under-diagnosis of dementia, and in both cases an over-diagnosis of underlying vascular etiology. Treatable causes of dementia, such as possible drug interactions and substance abuse, were considered only by a minority of physicians. In conclusion, memory deficits seem to be regarded mainly as consequences of disturbed cerebral perfusion, and dementia as well as depression and drug adverse effects seem to be under-diagnosed in primary care.

Aged↗

PubMed1994

Mutation induction by heavy ions.

Mutation induction by heavy ions is compared in yeast and mammalian cells. Since mutants can only be recovered in survivors the influence of inactivation cross sections has to be taken into account. It is shown that both the size of the sensitive cellular site as well as track structure play an important role. Another parameter which influences the probability of mutation induction is repair: Contrary to naive assumptions primary radiation damage does not directly lead to mutations but requires modification to reconstitute the genetic machinery so that mutants can survive. The molecular structure of mutations was analyzed after exposure to deuterons by amplification with the aid of polymerase chain reaction. The results--although preliminary--demonstrate that even with densely ionizing particles a large fraction does not carry big deletions which suggests that point mutations may also be induced by heavy ions.

Animals↗

PubMed1994

Mutation induction in yeast by very heavy ions.

Resistance to canavanine was studied in haploid yeast after exposure to heavy ions (argon to uranium) of energies between 1 and 10 MeV/u covering a LET-range up to about 10000 keV/micrometer. Mutations were found in all instances but the induction cross sections increased with ion energy. This is taken to mean that the contribution of penumbra electrons plays an important role. The probability to recover surviving mutants is highest if the cell is not directly hit by the particle. The experiments demonstrate that the geometrical dimensions of the target cell nucleus as well as its sensitivity in terms of survival have a critical influence on mutation induction with very heavy ions.

Argon↗

PubMed1994

Issues and problems for radiobiological research in space.

The uniqueness of the space radiation field creates specific problems in the evaluation of hazards to men and materials. Comprehensive measurements of all physical parameters are necessary but not sufficient. Particular attention has to be paid to variables like solar flares by applying fast-responding active dosimetry. The assessment of biological consequences poses even more problems. There are no human data for the kinds of particles seen in space and they will presumably never be available. The only reasonable approach is therefore to use the information obtained for other radiations and check their applicability for the space situation. This involves both the study of fundamental processes in ground experiments as well as their verification in space missions. Special emphasis has to be laid on the modification of radiation effects by flight-dynamic factors and microgravity. Radiation protection guidelines for space flights cannot simply be transformed from existent regulations designed for radiation workers on earth but have to be tailored to the specific situation in space.

Aerospace Medicine↗

PubMed1994

DNA double-strand break measurement in mammalian cells by pulsed-field gel electrophoresis: an approach using restriction enzymes and gene probing.

DNA samples prepared from human SP3 cells, which had been exposed to various doses of X-ray, were treated with NotI restriction endonuclease before being run in a contour-clamped homogeneous electrophoresis system. The restriction enzyme cuts the DNA at defined positions delivering DNA sizes which can be resolved by pulsed-field gel electrophoresis (PFGE). In order to investigate only one of the DNA fragments, a human lactoferrin cDNA, pHL-41, was hybridized to the DNA separated by PFGE. As a result, only the DNA fragment which contains the hybridized gene was detected resulting in a one-band pattern. The decrease of this band was found to be exponential with increasing radiation dose. From the slope, a double-strand break induction rate of (6.3 +/- 0.7) x 10(-3)/Mbp/Gy was deduced for 80 kV X-rays.

DNA↗

PubMed1994

Increasing melanoma incidence: putatively explainable by retrotransposons. Experimental contributions of the xiphophorine Gordon-Kosswig melanoma system.

The worldwide accelerating increase of neoplasia in humans is difficult to explain. We use the Xiphophorus tumor model to approach this problem by melanoma provocation with X-rays. Melanoma develops following inappropriate expression of x-erb B-conducted developmental genes and their controllers. These oncodeterminants are inherited according to Mendelian rules. We detected a new type of oncodeterminants that, following a single treatment of embryos with X-rays, generates a self-generating non-Mendelian melanoma transmission and accelerating increase of its incidence in succeeding generations (e.g., 0-->18-->33-->52%). To localize these oncodeterminants, we crossed nonirradiated fish having half of their chromosomes irradiated with nonirradiated fish having none of, half of, or all of their chromosomes irradiated. Because tumor rate and expression in the following generations correspond to the rates of treated chromosomes, we conclude that the new oncodeterminants are distributed over the chromosomes of the fish, where they may increase in the changing generations. By means of xiphophorine-specific retroviral DNA, we isolated two retrotransposons that behave hereditarily like the new transgenerational oncodeterminants. Sequence analysis revealed three ORFs flanked by LTRs containing motives of regulatory sequences typical for known retroviral and retrotransposal LTRs. Pol- and env-resembling sequences are lacking. Southern and in situ hybridization showed their multiple and repetitive nature distributed throughout the chromosomes and indications for their capability to increase in number without further treatment. Their transcripts are expressed in concert with those of most of the other known xiphophorine tumor determinants. Their expression is extremely high in cell cultures from tumorous embryos derived from ancestors treated as embryos with X-rays.

Animals↗

PubMed1994

[Immunoscintigraphy of carcinomas in the area of the head-neck with technetium-99m marked monoclonal antibody 174H.64. A new diagnostic procedure].

Twenty-one patients with squamous cell carcinomas of the head and neck were studied by immunoscintigraphy and immunoemission, computed tomography (ECT) using monoclonal antibody 174H.64 (Biomira Edminton) labelled with 99Tcm (Schwartz Method). Immunoscintigraphic results were compared with routine clinical assessments, including CT and ultrasonography, and were controlled by histopathological examination after surgery. All primary localizations (pT1 = 3, pT2 = 3, pT3 = 7, pT4 = 5; oropharynx 7, larynx 5, hypopharynx 3, oral cavity 3, lymph nodes 3) could be visualized, while 15 out of 18 neck lesions from tumor metastases could also be visualized (pN1 = 8, pN2 = 8, pN3 = 2). In one case with micrometastases in lymph nodes that could not be demonstrated by other methods, staging was upgraded by the immunoscintigraphic results. Three other micrometastases in lymph nodes could not be visualized. Distant metastases were suspected in 5 cases, three of which were confirmed either histologically or by radiography. Two of the cases with distant metastases were detected by the immunoscintigraphy. The present results indicate that immunoscintigraphy in combination with immuno-ECT can improve preoperative staging of head and neck carcinomas, especially with regard to metastatic neck disease, tumor recurrences and some cases of distant metastases.

Antibodies, Monoclonal↗

PubMed1994

Measurement of DNA double-strand breaks in mammalian cells by pulsed-field gel electrophoresis: a new approach using rarely cutting restriction enzymes.

A new method is presented for measuring DNA double-strand breaks (DSBs) which combines the technique of pulsed-field gel electrophoresis (PFGE) with the idea of velocity sedimentation. Purified DNA samples were treated with restriction enzymes, which results in DNA of sizes which can be separated by PFGE. After electrophoresis, unirradiated DNA shows a size distribution (obtained with the help of a specially developed software program) similar to that obtained with the sedimentation technique; with X irradiation, this distribution is shifted to lower molecular weight with increasing dose. The rate of DSB induction was calculated by comparing the curves obtained experimentally with theoretical distributions (based on the assumption that breaks are formed according to Poisson statistics). The method was tested by measuring X-ray-induced DSBs in P3 (derived from human epithelial teratoma) cells. The induction of DSBs was found to be linear with dose and a rate of 5.4 x 10(-3)/Mbp/Gy was obtained.

DNA↗