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Biomedical subjects

M Krämer

Publications and source records attributed to M Krämer.

At least 19 recordsLinked to original sources
PubMed2006

Rapid calculation of biological effects in ion radiotherapy.

We describe a method for fast calculation of biological effects after ion irradiation. It is an alternative derivative of the established local effect model (LEM) and has been integrated into GSI's TRiP98 treatment planning system. We show that deviations from our classic approach for treatment planning are less than 5% for therapeutical doses, but calculational speed can be improved by one to two orders of magnitude. This will allow sophisticated methods of treatment planning for ion irradiation, taking biological effects fully into account.

Body Burden↗
PubMed2004

The global gene expression response of Escherichia coli to L-phenylalanine.

We investigated the global gene expression changes of Escherichia coli due to the presence of different concentrations of phenylalanine or shikimate in the growth medium. The response to 0.5 g l(-1) phenylalanine primarily reflected a perturbed aromatic amino acid metabolism, in particular due to TyrR-mediated regulation. The addition of 5g l(-1) phenylalanine reduced the growth rate by half and elicited a great number of likely indirect effects on genes regulated in response to changed pH, nitrogen or carbon availability. Consistent with the observed gene expression changes, supplementation with shikimate, tyrosine and tryptophan relieved growth inhibition by phenylalanine. In contrast to the wild-type, a tyrR disruption strain showed increased expression of pckA and of tktB in the presence of phenylalanine, but its growth was not affected by phenylalanine at the concentrations tested. The absence of growth inhibition by phenylalanine suggested that at high phenylalanine concentrations TyrR-defective strains might perform better in phenylalanine production.

Bacterial Proteins↗
PubMed2004

Treatment planning for scanned ion beams.

Since 1997 a radiotherapy unit using fast carbon ions is operational at GSI. An intensity-controlled magnetic raster scanner together with a synchrotron allowing fast energy variation enable a unique method of purely active dose shaping in three dimensions. This contribution describes the necessary steps to establish a treatment planning system for this novel modality. We discuss the requirements for the physical beam model and the radiobiological model. Based on these we chose to implement a home-grown pencil beam model to describe the ion-tissue interaction and the Local Effect Model to calculate the RBE voxel-by-voxel. Given the large number of degrees of freedom biological dose optimization must be achieved by means of inverse treatment planning. All ion-related aspects are collected in our TRiP98 software. Biological dosimetry measuring cell survival in two dimensions turns out to be a good way to verify the model predictions as well as the actual irradiation procedure. We show a patient example and outline the future steps towards a dedicated clinic facility for all light ions.

Carbon↗
PubMed2004

Treatment planning for carbon ion radiotherapy in Germany: review of clinical trials and treatment planning studies.

The GSI carbon ion radiotherapy facility established the first completely active beam shaping system for heavy ions, using energy variation on the synchrotron and pencil beam scanning. The introduction of an active beam shaping system for carbon ions has considerable impact on the design of the treatment planning system (TPS). The TPS has to account for the capability of the beam delivery and the biological modelling, which is needed to calculate the RBE for the resulting varying depth dose modulation. The TPS used in clinical routine with carbon ions is described and its use in treatment planning studies are outlined. A clinical trial with carbon ion therapy as primary therapy for chordoma and chondrosarcoma of the base of skull has been completed in 2001. Currently, carbon ion therapy as a boost treatment together with conventional conformal photon therapy or IMRT is under investigation in clinical trials for adenoid cystic carcinoma, chordoma and chondrosarcoma of the cervical spine and sacrococcygeal chordoma. Treatment planning studies comparing carbon ion therapy with IMRT, using optimization of combination therapy, and optimization of beam-line design have already been completed. Analysis of uncertainties in treatment planning has been started with the investigation of range uncertainties stemming from CT imaging. Uncertainties coming from the beam delivery play only a minor role. An attempt to asses the uncertainties introduced in treatment plans by the biological modelling, was done, using phantom verification of calculated cell survival levels. The clinical trials and planning studies are of special importance for the upcoming new clinical ion facility of the Heidelberg university hospital.

Carbon↗
PubMed2003

Biological dosimetry of complex ion radiation fields.

We report on a set of cell survival experiments performed in complex field combinations of therapeutic 12C ion beams. CHO cells were exposed to the superposition of two or three fields of 12C ions arranged in a similar way to real patient treatments. Two-dimensional survival distributions were measured and compared with the predictions of the TRiP98 treatment planning system. Good agreement was found in general. In particular the method of tissue sparing using dose ramps could be verified.

Animals↗
PubMed2003

Three-dimensional dose verification with x-ray films in conformal carbon ion therapy.

A three-dimensional dose verification with photographic emulsions (x-ray films) was realized within the tumour therapy project at GSI Darmstadt, using carbon ions. We present Bragg-peak measurements for 88, 100 and 200 MeV/u carbon ion beams as the simplest case of dose verification. An actual patient treatment plan, composed by the superposition of Bragg-peaks having different energies and intensities, was used to perform a three-dimensional dose verification of an irregularly formed target volume. The shape of the measured dose distribution from film closely matches the intended irradiation volume. Furthermore, the calculated and measured optical density distribution is in good agreement with a maximum deviation of less than 10%.

Carbon Radioisotopes↗
PubMed2003

The increased biological effectiveness of heavy charged particles: from radiobiology to treatment planning.

The increased biological effectiveness of heavy charged particle beams like e.g., carbon ions in the tumor volume in comparison to the lower effectiveness in the surrounding healthy tissue represents one of the major rationales for their application in tumor therapy. This increased effectiveness also characterizes the advantage of heavier ions compared to proton beams. The increased effectiveness has to be taken into account in treatment planning in order to estimate the corresponding photon equivalent doses in normal and tumor tissues, thus allowing a link e.g., to normal tissue dose limits in conventional photon therapy. Due to the complex dependencies of RBE on parameters like dose, beam energy, LET, atomic number and cell or tissue type, the relevant RBEs cannot be solely determined from experimental data. Therefore, within the framework of the pilot project of tumor therapy with carbon ions performed at GSI Darmstadt, treatment planning is based on a biophysical model, which has been extensively tested. The paper first summarizes the essential systematic dependencies of RBE on different parameters like e.g., dose, LET, atomic number and cell type. The basic principle of the biophysical model is then introduced, and special emphasis is given to the application of the model to in vivo and clinical endpoints. Model predictions are compared to experimental data in vitro and in vivo. Finally, the implementation of the biophysical model in the treatment planning procedure is presented. The biological verification of the whole treatment planning procedure is explained and examples of patient treatment plans are given.

Animals↗
PubMed2003

Effects of acute prolactin manipulation on sexual drive and function in males.

The neuroendocrine response to sexual activity in humans is characterized by a pronounced orgasm-dependent increase of plasma levels of prolactin. In contrast to the well-known inhibitory effects of chronic hyperprolactinemia on sexual drive and function, the impact of acute prolactin alterations on human sexual physiology is unknown. Therefore, this study was designed to investigate the effects of acute manipulation of plasma prolactin on sexual behavior. Ten healthy males participated in a single-blind, placebo-controlled, balanced cross-over design. Prolactin levels were pharmacologically increased to high levels (protirelin, 50 micro g i.v.) or reduced to low physiological concentrations (cabergoline, 0.5 mg p.o.). Sexual arousal and orgasm were then induced by an erotic film and masturbation. In addition to continuous neuroendocrine and cardiovascular recordings, the quality and intensity of the acute sexual drive, arousal, orgasm and refractory period were assessed by extensive psychometric measures. Administration of cabergoline decreased prolactin levels and significantly enhanced all parameters of sexual drive (P<0.05), function (P<0.01) and positive perception of the refractory period (P<0.01). Administration of protirelin increased prolactin concentrations and produced small, but not significant reductions of sexual parameters. The sexual effects observed from cabergoline were completely abrogated by coadministration of protirelin. Although different pharmacological sites of action of prolactin-altering drugs have to be considered, these data demonstrate that acute changes in prolactin plasma levels may be one factor modulating sexual drive and function. Therefore, besides a neuroendocrine reproductive reflex, a post-orgasmic prolactin increase may represent one factor modulating central nervous system centers controlling sexual drive and behavior. These findings may offer a new pharmacological approach for the treatment of sexual disorders.

Adult↗
PubMed2002

Calculation of the x-ray film response to heavy charged particle irradiation.

A model was developed to calculate the response of films to heavy ion irradiation as a function of particle type and energy. It is based on the local effect model and was extended to be applied to the non-homogeneous target of photographic emulsions. The calculation was performed for protons and carbon ions in the energy range from 2 to 430 MeV u(-1). The calculated film responses are in very good agreement with experimental data. Based on this model calculation a data base of film responses was set up. This enables a three-dimensional dose verification with films in the heavy ion tumour therapy project at GSI, Darmstadt.

Carbon↗
PubMed2002

Macroscopic dynamics of a trapped Bose-Einstein condensate in the presence of 1D and 2D optical lattices.

The hydrodynamic equations of superfluids for a weakly interacting Bose gas are generalized to include the effects of periodic optical potentials produced by stationary laser beams. The new equations are characterized by a renormalized interaction coupling constant and by an effective mass accounting for the inertia of the system along the laser direction. For large laser intensities the effective mass is directly related to the tunneling rate between two consecutive wells. The predictions for the frequencies of the collective modes of a condensate confined by a magnetic harmonic trap are discussed for both 1D and 2D optical lattices and compared with recent experimental data.

Journal Article↗
PubMed2002

Absence of orgasm-induced prolactin secretion in a healthy multi-orgasmic male subject.

In several studies we have recently demonstrated that orgasm induces prolactin secretion in healthy males and females. This suggests that prolactin may form a feedback regulator of the refractory period following orgasm. To examine this position we investigated the prolactin response of a healthy multi-orgasmic male subject. Blood was drawn continuously during masturbation-induced orgasm. The prolactin response of the case-subject was compared with that of nine healthy adult men with a normal refractory period. The case-subject showed no prolactin response to three orgasms. Data from this multi-orgasmic subject support the hypothesized role of plasma prolactin in contributing to sexual-satiation mechanisms.

Adult↗
PubMed2001

Higgs radiation off top quarks at the Tevatron and the LHC.

Higgs bosons can be searched for in the channels pp macro/pp-->tt macro H + X at the Fermilab Tevatron and the Cern Large Hadron Collider (LHC). We have calculated the QCD corrections to these processes in the standard model at next-to-leading order. The higher-order corrections reduce the renormalization and factorization scale dependence considerably and stabilize the theoretical predictions for the cross sections. At the central scale mu = (2m(t)+M(H))/2 the properly defined K factors are slightly below unity for the Tevatron (K approximately 0.8) and slightly above unity for the LHC (K approximately 1.2).

Journal Article↗
PubMed2001

Metabolic engineering for microbial production of aromatic amino acids and derived compounds.

Metabolic engineering to design and construct microorganisms suitable for the production of aromatic amino acids and derivatives thereof requires control of a complicated network of metabolic reactions that partly act in parallel and frequently are in rapid equilibrium. Engineering the regulatory circuits, the uptake of carbon, the glycolytic pathway, the pentose phosphate pathway, and the common aromatic amino acid pathway as well as amino acid importers and exporters that have all been targeted to effect higher productivities of these compounds are discussed.

Amino Acids, Aromatic↗
PubMed2001

Experimental investigations of the response of films to heavy-ion irradiation.

The response of films to heavy-ion irradiation was investigated systematically by recording dose-response curves for protons and carbon ions in an energy range of 8-430 MeV u(-1). In order to allow for an objective comparison of different experimental results, a practicable method was developed to decouple the value of the net optical density from the film's processing conditions and a precise definition of the film response was deduced. A qualitative explanation of the strong variation of the film response depending on particle type and energy is given, based on the particle's track structure. The data presented here form the basis for using films for dosimetry in mixed particle radiation fields and their application in the heavy-ion therapy project at GSI, Darmstadt.

Carbon↗
PubMed2001

Treatment planning for heavy ion radiotherapy: clinical implementation and application.

The clinical implementation and application of a novel treatment planning system (TPS) for scanned ion beams is described, which is in clinical use for carbon ion treatments at the German heavy ion facility (GSI). All treatment plans are evaluated on the basis of biologically effective dose distributions. For therapy control, in-beam positron emission tomography (PET) and an online monitoring system for the beam intensity and position are used. The absence of a gantry restricts the treatment plans to horizontal beams. Most of the treatment plans consist of two nearly opposing lateral fields or sometimes orthogonal fields. In only a very few cases a single beam was used. For patients with very complex target volumes lateral and even distal field patching techniques were applied. Additional improvements can be achieved when the patient's head is fixed in a tilted position, in order to achieve sparing of the organs at risk. In order to test the stability of dose distributions in the case of patient misalignments we routinely simulate the effects of misalignments for patients with critical structures next to the target volume. The uncertainties in the range calculation are taken into account by a margin around the target volume of typically 2-3 mm, which can, however, be extended if the simulation demonstrates larger deviations. The novel TPS developed for scanned ion beams was introduced into clinical routine in December 1997 and was used for the treatment planning of 63 patients with head and neck tumours until July 2000. Planning strategies and methods were developed for this tumour location that facilitate the treatment of a larger number of patients with the scanned heavy ion beam in a clinical setting. Further developments aim towards a simultaneous optimization of the treatment field intensities and more effective procedures for the patient set-up. The results demonstrate that ion beams can be integrated into a clinical environment for treatment planning and delivery.

Brain Neoplasms↗
PubMed2001

Treatment planning for heavy-ion radiotherapy: biological optimization of multiple beam ports.

A crucial task in radiotherapy is dose conformation to the prescribed target volume whilst sparing the surrounding healthy tissue around as much as possible. One of the best approaches so far is active dose shaping in three dimensions using scanned beams of charged particles, like carbon ions. Besides their inverse dose profile and minimal lateral scattering, carbon ions have the advantage that their RBEs increase towards the end of their range. An active beam-delivery system for intensity-modulated carbon-ion beams has been operational at GSI since December, 1997. In order to ensure dose conformation, inverse treatment planning with respect to the biologically effective dose distribution must be applied. A typical patient irradiation comprises two singly optimized opposing fields. This paper discusses the superposition of biologically effective dose distributions for radiotherapy with 12C ions, which is non-trivial due to the nonlinear nature of the dose response of biological systems. Sum rules for the nonlinear addition of singly optimized fields are derived. This method is being used clinically, and has been successfully applied to more than 50 patients.

Animals↗
PubMed2001

Cellular and humoral immune response in progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a fatal, demyelinating disease caused by JC virus (JCV) in patients with severe immunosuppression. We studied the JCV-specific cellular and humoral immune response in 7 healthy donors (HD), 6 human immunodeficiency virus-1 (HIV-1)-infected patients without PML (HIV), 4 HIV-1-negative patients with PML (PML), and 8 HIV-1-positive patients with PML (HIV/PML). As antigens, recombinant virus-like particles of the major structural protein VP1 (VP1-VLP) of JCV, tetanus toxoid (TT), or the mitogen phytohemagglutinin (PHA) were used. Proliferation of peripheral blood mononuclear cells (PBMC) after stimulation with the VP1-VLP was significantly suppressed in PML and HIV/PML patients compared to HD. After antigen stimulation the production of interferon-gamma (IFN-gamma) was reduced in PML, in HIV/PML, and in HIV patients. The production of interleukin-10 (IL-10), however, was elevated in HIV/PML patients. Neither proliferation nor cytokine production correlated with the presence of JCV DNA in PBMC. The immunoglobulin G serum antibody titer to the VP1-VLP was slightly elevated in HIV, elevated in PML, and highly elevated in HIV/PML patients compared to HD. The development of PML appears to coincide with a general impairment of the Th1-type T-helper cell function of cell-mediated immunity.

Cytokines↗