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Biomedical subjects

W Hofmann

Publications and source records attributed to W Hofmann.

At least 55 records · Page 3Linked to original sources
PubMed2002

Monte Carlo code for microdosimetry of inhaled alpha emitters.

A Monte Carlo code has been developed to calculate the local energy deposited by alpha emitters deposited on the inner surface in the lung airway. Developed to deal further with airway bifurcations, this code has been as a first step validated in a cylindrical airway configuration by comparison with well-established analytical codes in the case of contamination of bronchiolar airways with actinides. The code has then been applied to the study of uniform and non-uniform contamination of cylindrical bronchial airways by radon progeny in indoor and mine exposure conditions. In addition to the microdosimetric spectra, the average microdosimetric parameters (zp, n, z) have been evaluated. The work currently in progress consists in adapting this developed Monte Carlo code to the configuration of an airway bifurcation with realistic particles deposition.

Alpha Particles↗
PubMed2002

Local deposition distributions of inhaled radionuclides in the human tracheobronchial tree.

There is experimental evidence that bronchogenic carcinomas originate mainly at the carinal ridges of the large central airways, where primary hot spots of deposition have been found. However, current lung dosimetry models do not take into consideration the inhomogeneity of deposition within the airways. In this study, computed local distributions of deposited inhaled radionuclides such as radon progenies in morphologically realistic human airway bifurcation models are analysed for different flow rates and particle sizes. Then, local deposition enhancement factors, defined as the ratio of local to average deposition densities, are computed by scanning along the surface of the bifurcation with pre-specified surface area elements. Computed enhancement factors indicate that cells located at carinal ridges or at the inner sides of the progeny branches may receive localised doses which are two orders of magnitude higher than the average values.

Administration, Inhalation↗
PubMed2001

Constitutional genomic instability with inversions, duplications, and amplifications in 9p23-24 in BRCA2 mutation carriers.

Germ-line mutations of the BRCA2 gene (13q12-13) account for a large proportion of familial breast cancer cases in females and the majority of familial breast cancers in males. Recent studies provide evidence for a role of the BRCA2 protein in the maintenance of genomic integrity by involvement in DNA repair and recombination. In pursuit of identifying in humans genetic damage resulting from mutated BRCA2, we have analyzed constitutional karyotypes of BRCA2 mutation carriers. The present study establishes that constitutional distal 9p rearrangements without obvious additional gross chromosomal alterations are a recurrent feature of independently ascertained families. From our cytogenetic analyses we have no indication of additional gross rearrangements, but we cannot exclude more subtle recombinations in other genomic regions. We also show that the topography of the 9p rearrangements can differ among family members, even within an individual that can have cell populations with different 9p rearrangements. Collectively these results raise point to an association of mutant BRCA2 with genomic instability and gene alteration in 9p23-24 in at least a subset of BRCA2 mutation carriers.

Adult↗
PubMed2001

Mutational analysis of the peroxisome proliferator-activated receptor gamma gene in human malignancies.

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in adipocyte differentiation and is expressed in many human malignancies, including those from prostate, breast, as well as colon. It regulates differentiation and/or cell growth of these cells. However, expression of this nuclear hormone receptor in other types of cancer, especially in hematological malignancies, remains to be fully elucidated. The PPARgamma gene has been mapped to chromosome band 3p25, where chromosomal abnormalities are observed in a variety of human malignancies. Furthermore, a recent study revealed that the PPARgamma gene is functionally mutated in sporadic colon cancer cells. Therefore, PPARgamma could be an important tumor suppressor gene. This prompted us to investigate the expression and mutational status of the PPARgamma gene in cancers of a variety of tissues. A total of 159 samples were interrogated for their expression of PPARgamma as measured by reverse transcription-polymerase chain reaction and/or Western blot analysis. In each of the samples, expression of PPARgamma was detectable. In addition, a total of 397 clinical samples and cell lines including colon, prostate, breast and lung cancers, and leukemias were analyzed for mutations of the PPARgamma gene by either reverse transcription-polymerase chain reaction-single-strand conformation polymorphism or polymerase chain reaction-single-strand conformation polymorphism analysis. No abnormalities were detectable in any of the human malignancies. On the other hand, shifted bands were easily detectable when using positive controls, which harbored the same sequence alterations reported previously in colon cancer cells. Taken together, PPARgamma is expressed in a variety of cancers, and mutation of the PPARgamma gene is a very rare event in human malignancies.

Blotting, Western↗
PubMed2001

alpha1 Integrin cytoplasmic domain is involved in focal adhesion formation via association with intracellular proteins.

Integrins are heterodimeric adhesion receptors consisting of alpha- and beta-subunits capable of binding extracellular matrix molecules as well as other adhesion receptors on neighbouring cells. These interactions induce various signal transduction pathways in many cell types, leading to cytoskeletal reorganization, phosphorylation and induction of gene expression. Integrin ligation leads to cytoplasmic protein-protein interactions requiring both integrin cytoplasmic domains, and these domains are initiation points for focal adhesion formation and subsequent signal transduction cascades. In previous studies we have shown that the very short cytoplasmic alpha1 tail is required for post-ligand events, such as cell spreading as well as actin stress-fibre formation. In the present paper we report that cells lacking the cytoplasmic domain of the alpha1 integrin subunit are unable to form proper focal adhesions and that phosphorylation on tyrosine residues of focal adhesion components is reduced on alpha1beta1-specific substrates. The alpha1 cytoplasmic sequence is a specific recognition site for focal adhesion components like paxillin, talin, alpha-actinin and pp125FAK. It seems to account for alpha1-specific signalling, since when peptides that mimic the cytoplasmic domain of alpha1 are transferred into cells, they influence alpha1beta1-specific adhesion, presumably by competing for binding partners. For alpha1 integrin/protein binding, the conserved Lys-Ile-Gly-Phe-Phe-Lys-Arg motif and, in particular, the two lysine residues, are important.

Actinin↗
PubMed2001

Cofactor requirements for nuclear export of Rev response element (RRE)- and constitutive transport element (CTE)-containing retroviral RNAs. An unexpected role for actin.

Nuclear export of proteins containing leucine-rich nuclear export signals (NESs) is mediated by the export receptor CRM1/exportin1. However, additional protein factors interacting with leucine-rich NESs have been described. Here, we investigate human immunodeficiency virus type 1 (HIV-1) Rev-mediated nuclear export and Mason-Pfizer monkey virus (MPMV) constitutive transport element (CTE)-mediated nuclear export in microinjected Xenopus laevis oocytes. We show that eukaryotic initiation factor 5A (eIF-5A) is essential for Rev and Rev-mediated viral RNA export, but not for nuclear export of CTE RNA. In vitro binding studies demonstrate that eIF-5A is required for efficient interaction of Rev-NES with CRM1/exportin1 and that eIF-5A interacts with the nucleoporins CAN/nup214, nup153, nup98, and nup62. Quite unexpectedly, nuclear actin was also identified as an eIF-5A binding protein. We show that actin is associated with the nucleoplasmic filaments of nuclear pore complexes and is critically involved in export processes. Finally, actin- and energy-dependent nuclear export of HIV-1 Rev is reconstituted by using a novel in vitro egg extract system. In summary, our data provide evidence that actin plays an important functional role in nuclear export not only of retroviral RNAs but also of host proteins such as protein kinase inhibitor (PKI).

Actins↗
PubMed2001

Correlated hit probability and cell transformation in an effect-specific track length model applied to in vitro alpha irradiation.

In estimating the risk from low doses of alpha particles such as those emitted by radon progeny, it is important to consider the correlation between cellular inactivation and transformation that can exist at the cellular level. A phenomenological model of radiation-induced cellular inactivation and transformation at this level is presented here which incorporates aspects of a state vector model of radiation carcinogenesis and of correlated hit probabilities for inactivation and transformation. The general form of the model assumes that both inactivation and initial initiation damage are produced through the interaction of sublesions induced by radiation passing through cell nuclei, with the production of sublesions governed by hit probabilities and a characteristic probability-per-unit track length. The inactivation and initiation events are partially correlated through the use of hit probabilities. In addition, promotional events are incorporated for the case of cellular transformation based on a previously published state vector model. The model provides good fits to available data on the relationship between inactivation, transformation and LET for doses of alpha above 0.1 Gy in the range of LETs commonly produced by radon and progeny; by "good fits" we mean here the ability to yield the correct shapes of dose-response data using parameter values that vary smoothly with LET and using inactivation parameters that are applied consistently between inactivation and transformation assays. The resulting model correctly predicts recent findings indicating an increased transformation frequency per surviving cell when a population receives a distribution of hits compared to irradiation where all cells receive the same number of hits.

Animals↗
PubMed2001

Identification of a recurrent BRCA1 mutation in German breast-cancer and/or ovarian-cancer families.

Specific BRCA1 mutations have been reported to be common within particular populations. We have investigated German breast- and/or ovarian-cancer families and detected a recurrent carboxy-terminal BRCA1 mutation, 5622C > T, using PCR-based restriction assay and haplotype analysis. Unrelated families carrying this BRCA1 mutation shared two different disease-associated haplotypes, indicating two independent mutation events.

Breast Neoplasms↗
PubMed2001

Comparison of clearance of particles inhaled with bolus and extremely slow inhalation techniques.

Ten healthy nonsmokers inhaled 6-microm (aerodynamic diameter) Teflon particles labelled with 111In twice, once with the shallow bolus technique (volumetic lung depth 76+/-20 mL ([+/- SD]) and once with the extremely slow inhalation technique (0.05 L/s). The radioactivity in the lungs was measured at 1 and 24 hours as well as at 1, 2, and 3 weeks after both inhalations. The 24-hour lung retention a percentage of lung deposition was significantly lower for the bolus inhalation, 46%+/-9% (+/- SD) than for the extremely slow inhalation, 56%+/-11%. The retention after 21 days as a percentage of the 24-hour retention was 55%+/-9% for the shallow bolus inhalation and 56%+/-10% for the extremely slow inhalation. Also within the subjects, clearance was similar for the 2 modes of inhalation. Deposition of particles inhaled with the 2 modes of inhalation was calculated with 2 model, one being based on Monte (Carlo particle transport together with an asymmetric lung model. Deposition predicted with this model agreed well with the experimental data under the assumption that there are large retained fractions only in small ciliated airways (bronchioli) and not in large ones. For the bolus inhalation, the model predicted 43% to 50% deposition in the bronchial (BB) region of initial lung deposition, 33% to 38% in the bronchiolar (bb) region, and 16% to 22% in the alveolar region. For the extremely slow inhalation, the model predicted 31% to 34% deposition in the BB region, 45% to 47% in the bb region, and 21% to 22% in the alveolar region. In addition, it predicted about the same ratio between bb and alveolar depositions for the 2 modes of inhalation. Thus, both the experimental and theoretical data indicate that the shallow bolus particles to a considerable extent reach both the bb and the alveolar regions and that they do that at about the same extent as the particles inhaled extremely slow. This conclusion is concerning the experimental data based on the assumption that there are no large retained fractions in the BB region. Another interpretation of the similar clearance for the two modes of inhalation is that there are large retained fractions in both the BB and the bb regions and that individual charactristics of clearance of these fractions are of importance rather than the site of deposition.

Administration, Inhalation↗
PubMed2001

Significance of cell-cycle delay, multiple initiation pathways, misrepair and replication errors in a model of radiobiological effects.

PURPOSE: To advance a biomathematical model of radiocarcinogenesis by describing multiple pathways for initiation, a radiologically induced cell-cycle delay, misrepair and spontaneous DNA damages caused by replication. It was investigated whether the incorporation of these biological features would improve the fit of the model to data showing plateaus in in vitro irradiations of different cell lines and whether the fit parameters were then more biologically realistic. MATERIALS AND METHODS: A biomathematical submodel was developed based on a previous State-Vector Model that mathematically described enhanced DNA repair and radical scavenging following irradiation. RESULTS: With the two initiation pathways and cell-cycle delay, the simulations better explained the mouse data but not the rat data, and for both data sets the fit parameters were biologically more realistic than previously assumed. Inclusion of misrepair and replicational errors did not significantly affect the fit. CONCLUSIONS: A plateau in the dose-effect relationship for in vitro irradiation of different cell lines can be explained by radioprotective mechanisms. The plateau-type dose-response relationships point to a non-linear dose- effect relationship at low doses and indicate that linear extrapolation from moderate (or high) to low doses may not be justified for in vitro studies of these cell lines.

Animals↗
PubMed2001

Environmental tobacco smoke deposition in the human respiratory tract: differences between experimental and theoretical approaches.

Total deposition of environmental tobacco smoke (ETS) particles was measured in a group of 15 nonsmokers who inhaled ETS of count median diameter of 0.2 microm and geometric standard deviation of 1.6. A total deposition of 56.0 +/- 15.9% was observed for nasal breathing and 48.7 +/- 11.5% for oral breathing. In contrast, our stochastic deposition model predicted a total deposition of only 17.9% (male) and 15.7% (female) for nose breathing, and 13.4% (male) and 10.7% (female) for mouth breathing, if based on standard breathing conditions. Consideration of individual lung volumes and breathing parameters for each volunteer resulted in total deposition values of 16.9 +/- 2.2% for nose breathing and 12.1 +/- 2.1% for mouth breathing. The apparent discrepancy between experiment and modeling suggests that either single ETS particles increase substantially in size upon inhalation (up to an order of magnitude) and/or additional physical mechanisms must be invoked that are acting specifically upon ETS particles: (1) hygroscopic growth of ETS particles does not exceed 20-30%; (2) number concentrations in the ETS experiments (3.8 x 10(4), to 1.3 x 10(5) cm(-3)) are too low to increase particle size by coagulation; (3) cast experiments indicate that electrical charge (image forces) may play an important role, but theory predicts only an increase of 20-60%; and (4) cloud settling is unlikely to be a significant factor at such low number concentrations. In conclusion, estimates of the magnitudes of these potential effects demonstrate that none of these mechanisms alone can be responsible for the significantly higher total ETS deposition observed in the experiments. This suggests that a combination of all these mechanisms may be necessary to reconcile experimental and theoretical ETS deposition data, the most likely candidates being image forces and hygroscopic growth.

Biophysical Phenomena↗
PubMed2001

Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3(-/-) and wild-type mice.

Uncoupling protein-3 (UCP3) is a mitochondrial carrier protein of as yet undefined physiological function. To elucidate characteristics of its function, we studied the effects of fasting on resting metabolic rate, respiratory quotient, muscle Ucp3 expression, and mitochondrial proton leak in wild-type and Ucp3(-/-) mice. Also analyzed were the fatty acid compositions of skeletal muscle mitochondria in fed and fasted Ucp3(-/-) and wild-type mice. In wild-type mice, fasting caused significant increases in Ucp3 (4-fold) and Ucp2 (2-fold) mRNA but did not significantly affect mitochondrial proton leak. State 4 oxygen consumption was not affected by fasting in either of the two groups. However, protonmotive force was consistently higher in mitochondria of Ucp3(-/-) animals (P = 0.03), and fasting further augmented protonmotive force in Ucp3(-/-) mice; there was no effect in wild-type mitochondria. Resting metabolic rates decreased with fasting in both groups. Ucp3(-/-) mice had higher respiratory quotients than wild-type mice in fed resting states, indicating impaired fatty acid oxidation. Altogether, results show that the fasting-induced increases in Ucp2 and Ucp3 do not correlate with increased mitochondrial proton leak but support a role for UCP3 in fatty acid metabolism.

Animals↗
PubMed2000

Chromosomal aberrations of blood lymphocytes induced in vitro by radon-222 daughter alpha-irradiation.

Blood samples were irradiated in vitro with alpha-rays emitted from short-lived radon decay products dissolved in the culture medium at doses between 0.03 and 41.4 mGy. The data were collected from experiments conducted during the period 1984-1992 and comprise a total of about 64000 scored metaphases. For statistical reasons, only 60,022 metaphases were used for the subsequent analysis. The results for total chromosome aberrations and dicentrics indicate a linear dose dependence in the dose range above about 10 mGy, consistent with other experimental observations. At doses below about 10 mGy, aberration frequencies cannot be linearly extrapolated from higher doses, suggesting that there is no dependence on dose within a certain low-dose range. In addition, a statistically significant minimum has been observed at a dose of about 0.03 mGy, which is consistently lower than the related control values. The behavior of the aberration frequencies in the low-dose region seems to be influenced by the control values, which also depend on the environmental radiation burdens to the donors before blood sampling and thus were significantly affected by the Chernobyl fallout.

Alpha Particles↗
PubMed2000

[Pseudoaneurysm of the pediatric popliteal artery after arthroscopic meniscus resection].

Arterial injuries following arthroscopic procedures are extremely rare, but may have dramatic consequences without early diagnosis and appropriate treatment. We report a case of popliteal artery pseudo-aneurysm a following arthroscopic meniscectomy in a child. Non-invasive diagnostic workup included Doppler flow color imaging and computed tomography with contrast and 3D workup. The arterial lesion was repaired surgically by an posterior approach using a vein patch plasty. The popliteal artery is in close relationship to the posterior capsule of the knee joint. During knee flexion the vessel is positioned forward and placed even closer to the horn of the lateral meniscus. For this reason arthroscopic surgical manipulation in the posterior aspects of the knee joint must be performed under direct visualization. Indistinct swelling in the popliteal fossa and calf following arthroscopic surgery should arouse suspicion of an arterial injury.

Adolescent↗
PubMed2000

Intensive chemotherapy with idarubicin, ara-C, etoposide, and m-AMSA followed by immunotherapy with interleukin-2 for myelodysplastic syndromes and high-risk Acute Myeloid Leukemia (AML).

Intensive chemotherapy followed by treatment with interleukin-2 (IL-2) was evaluated in a prospective, randomized, multicenter trial including 18 patients with refractory anemia with excess of blasts in transformation (RAEB-T), 86 patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndromes, and six patients with secondary AML after previous chemotherapy. Median age was 58 years (range: 18-76 years). Forty-nine patients (45%) achieved a complete remission (CR) after two induction cycles with idarubicin, ara-C, and etoposide, 52% of them aged </=60 years and 35% aged >60 years (p=0.06). After two consolidation courses, patients were randomized to four cycles of either high- or low-dose IL-2. Patients aged up to 55 years with an HLA-identical sibling donor were eligible for allogeneic bone marrow transplantation. The median relapse-free survival was 12.5 months, with a probability of ongoing CR at 6.5 years of 19%. Overall survival of all patients was 8 months, and 21 months for the CR patients. Median survival was significantly longer among patients aged </=60 years than among the older patients (16 vs 6 months, p<0.001). Median duration of survival and relapse-free survival were not statistically different in the two IL-2 treatment arms.

Acute Disease↗
PubMed2000

BRCA1 and BRCA2--breast cancer susceptibility genes.

Genetic predisposition is responsible for 5% 10% of all breast cancer cases. Therefore, the inherited susceptibility to breast cancer has been intensively investigated during the last 10 years. In particular, the identification of the breast cancer susceptibility genes BRCA1 (breast cancer gene 1) and BRCA2 and the current genetic testing for mutations in both genes are the basis for estimating disease risks for women with a strong family history of breast cancer and will provide important information on the prevention and treatment of familial breast cancer.

BRCA2 Protein↗
PubMed2000

Human neutral brush border endopeptidase EC 3.4.24.11 in urine, its isolation, characterisation and activity in renal diseases.

Human neutral brush border endopeptidase (NEP) was purified from the urine of patients suffering from acute toxic tubulointerstitial nephropathy. An enzyme preparation with specific activity of 102 Ug(-1) protein was obtained. The urinary activities of neutral endopeptidase and alanine aminopeptidase were measured in patients with renal disease and in 30 control patients, resulting in a reference range from 0.1 to 0.7 Ug(-1) creatinine and 1.4-14.1 Ug(-1) creatinine, respectively. Urine enzyme activities were highest in patients with acute tubulotoxic renal diseases. Neutral endopeptidase and alanine aminopeptidase activities were found to be 6.5- and 10-fold higher than the upper value of the reference range, respectively. Smaller increases in the rate of excretion of these enzymes (2.5- and 3.5-fold), respectively, were observed in patients suffering from acute tubular insufficiency and even lower increases, 2- and 1.5-fold, respectively, were observed in patients with chronic renal diseases. In diabetics and kidney transplant patients the enzyme excretion rates were within the reference range. Assay of both transmembrane metalloproteinases in urine may prove valuable in serving as markers for renal toxicity. Together with beta-NAG these enzymes could be employed as differentiation markers between acute and chronic tubular insufficiency.

Chromatography, Ion Exchange↗