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Biomedical subjects

G Hartmann

Publications and source records attributed to G Hartmann.

At least 19 recordsLinked to original sources
PubMed2006

Calculation of stopping power ratios for carbon ion dosimetry.

Water-to-air stopping power ratio calculations for the ionization chamber dosimetry of clinical carbon ion beams with initial energies from 50 to 450 MeV/u have been performed using the Monte Carlo technique. To simulate the transport of a particle in water the computer code SHIELD-HIT v2 was used, which is a newly developed version where substantial modifications were implemented on its predecessor SHIELD-HIT v1 (Gudowska et al 2004 Phys. Med. Biol. 49 1933-58). The code was completely rewritten replacing formerly used single precision variables with double precision variables. The lowest particle transport specific energy was decreased from 1 MeV/u down to 10 keV/u by modifying the Bethe-Bloch formula, thus widening its range for medical dosimetry applications. In addition, the code includes optionally MSTAR and ICRU-73 stopping power data. The fragmentation model was verified and its parameters were also adjusted. The present code version shows excellent agreement with experimental data. It has been used to compute the physical quantities needed for the calculation of stopping power ratios, s(water,air), of carbon beams. Compared with the recommended constant value given in the IAEA Code of Practice, the differences found in the present investigations varied between 0.5% and 1% at the plateau region, respectively for 400 MeV/u and 50 MeV/u beams, and up to 2.3% in the vicinity of the Bragg peak for 50 MeV/u.

Carbon Radioisotopes↗
PubMed2006

Comparative efficiency of the multi-leaf collimator and variable-aperture collimator in intensity-modulated radiotherapy.

The potential of the variable-aperture collimator (VAC) in intensity-modulated radiation therapy (IMRT) has been evaluated by comparing its performance with that of the multi-leaf collimator (MLC). This comparison used a decomposition algorithm to find the series of collimator segments that would treat a given intensity-modulated beam (IMB). Collimator performance was measured using both the number of segments required to complete the IMB and the monitor-unit efficiency of the treatment. The VAC was modelled with aperture sizes from 4 x 4 cm to 20 x 20 cm, and these apertures were allowed to be located anywhere within the IMB. To enable a direct comparison, a similar scanning MLC was modelled at the same range of aperture sizes. Using both collimators, decompositions were run on 10 x 10 and 20 x 20 random IMBs with integer bixel values ranging from 1 to 10. Clinical IMBs from lung, head and neck, and pelvic patients were taken from a Pinnacle treatment-planning system and tested in the same manner. It was found that for all treatment sites, a small, scanning MLC performs as well or better than an equivalent sized VAC in both number of segments and monitor-unit efficiency, and would be an efficient choice for centres looking for a simple collimator for IMRT.

Algorithms↗
PubMed2005

No indication for a defect in toll-like receptor signaling in patients with hyper-IgE syndrome.

Hyper-IgE syndrome is a rare primary immunodeficiency of unknown etiology characterized by recurrent infections of the skin and respiratory system, chronic eczema, elevated total serum IgE, and a variety of associated skeletal symptoms. Recent reports about susceptibility to pyogenic bacterial infections and high IgE levels in patients and animals with defects in toll-like receptor (TLR) signaling pathways prompted us to search for TLR signaling defects as an underlying cause of hyper-IgE syndrome. Blood samples from six patients with hyper-IgE syndrome were analyzed for serum cytokine levels, intracellular cytokine production in T cells after stimulation with PMA/ionomycin, and cytokine production from peripheral blood mononuclear cells stimulated by TLR ligands and bacterial products including LPS (TLR4), peptidoglycan (TLR2), PolyIC (TLR3), R848 (TLR7/8), CpG-A, and CpG-B (TLR9), zymosan and heat killed Listeria monocytogenes. All results were compared to data from healthy controls. A reduction in IFN-gamma, IL-2, and TNF-alpha producing T cells after PMA stimulation suggested a reduced inflammatory T cell response in patients with hyper-IgE syndrome. Increased serum levels of IL-5 indicated a concomitant Th2 shift. However, normal production of cytokines (TNF-alpha, IL-6, IL-10, IFN-alpha, IP-10) and upregulation of CD86 on B cells and monocytes after TLR stimulation made a defect in TLR signaling pathways highly unlikely. In summary, our data confirmed an imbalance in T cell responses of patients with hyper-IgE syndrome as previously described but showed no indication for an underlying defect in toll-like receptor signaling.

Adolescent↗
PubMed2004

Structural studies of oligonucleotides containing G-quadruplex motifs using AFM.

G-quadruplex DNAs are cyclic arrays of four guanine bases binding by Hoogsteen hydrogen bonds, found in the telomeric regions of chromosomes and in transcriptional regulatory regions of several important oncogenes. Here, we used high resolution atomic force microscopy (AFM) to observe a specific guanine (G) tetrad mediated complex formation of oligonucleotides containing a G-quadruplex motifs (G-ODN) combined with a palindromic sequence under physiological extracellular conditions. These oligonucleotides have been investigated in correlation to their immunostimulatory effects. We observed structural dependence on ion concentration and G-ODN concentration, where high concentration self-assembled DNA networks were formed.

Adjuvants, Immunologic↗
PubMed2004

Effects of 5-HT1A receptor agonist and antagonist on anxiety in intact and ovariectomized female rats.

The purpose of this work was to study the role of 5-HT1A receptors on the level of anxiety in adult intact and ovariectomized (OVX) female rats. The influence of chronic administration of 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and 5-HT1A receptor antagonist NAN-190 (0.1 mg/kg, i.p.) given for 14 days alone or in combination with 17beta-estradiol (0.5 microg i.m./rat/day) was studied on behavior in the elevated plus maze. In intact females administration of NAN-190 resulted in significant increase in the number of enterings and the time spent on the open arms in every phase of the estrous cycle, however, 8-OH-DPAT failed to modify these parameters. In OVX females 8-OH-DPAT alone or in combination with 17beta-estradiol significantly increased the number of enterings and time spent on the open arms. On the contrary, NAN-190 alone or in combination with 17beta-estradiol in OVX females failed to evoke behavioral changes in the elevated plus maze. Thus, the 5-HT1A receptor antagonist NAN-190 induced anxiolytic effect in intact female rats, while 5-HT1A receptor agonist 8-OH-DPAT produced an anxiolytic profile on OVX rats. Results of this work specify the involvement of 5-HT1A receptors in behavioral mechanisms of anxiety in OVX female rats.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2004

Involvement of 5-HT1A receptors in passive avoidance learning in intact and ovariectomized female rats.

The influence of chronic administration of 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and 5-HT1A receptor antagonist NAN-190 (0.1 mg/kg, i.p.) injected for 14 days alone or in combination with 17beta-estradiol (0.5 microg i.m./rat/day) was studied on passive avoidance performance (PAR) and on behavior in the open field test in adult intact and ovariectomized (OVX) female rats. Administration of 5-HT1A receptor antagonist NAN-190 alone significantly improved PAR (p<0.05) in intact females with proestrus and estrus and in OVX females. Administration of 5-HT1A receptor agonist 8-OH-DPAT alone or in combination with 17beta-estradiol significantly (p<0.05) improved PAR in OVX rats and failed to normalize PAR in intact rats with proestrus and estrus. Results of the work specify the involvement of 5-HT1A receptors in the mechanisms of passive avoidance learning in OVX female rats.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2003

First tests of a liquid ionization chamber to monitor intensity modulated radiation beams.

First measurements with a prototype ionization chamber are described to be applied in online monitoring of modulated fields in radiation therapy. The liquids isooctane, isononane (TMP) and tetramethylsilane (TMS) are used in a high purity grade in order to realize high current signals for electronic read-out in parallel at frequencies exceeding 10 Hz. Signals of more than a factor 4 with respect to isooctane, analysis grade, are obtained. With an electrode structure of 400 pads, a uniformity in efficiency within 1.2% has been measured. The penumbra of a multileaf collimator could be resolved. Theoretical examination verifies that the free electrons in the liquids cause higher signals when the measured currents are compared with expectation for ion transport only.

Computer Simulation↗
PubMed2003

Intensity-modulated radiation therapy using a variable-aperture collimator.

This paper extends some earlier concepts of using a tertiary mask plus jaws for delivering IMRT without a multileaf collimator. The new concept is to sweep a variable-aperture collimator (VAC) across the space of the intensity-modulated beam (IMB) to be delivered and to strip this IMB down into multiple-static-field components, each deliverable with the VAC. The stripping algorithm is described and it is shown, for several designs of VAC, that the mean number of field components and mean number of monitor units is less using the VAC than would be required for a jaws-only (JO) decomposition. The VAC would be simpler to construct than several previously suggested jaws-plus-mask (J+M) combinations. As well as describing a simple VAC for the use with jaws, we propose a design concept of a hybrid VAC. We also show that adding the potential to rotate the simple or hybrid VAC for some components relative to the field to be modulated is advantageous.

Algorithms↗
PubMed2002

Actinomyces neuii and neonatal sepsis.

Actinomyces neuii belongs to the coryneform bacteria. In the case presented here this gram-positive rod had to be considered the pathogen causing not only the chorioam nionitis but also the neonatal sepsis. Conventional therapeutic regimes are effective due to the high sensitivity of A. neuii to beta-lactam antibiotics.

Actinomyces↗
PubMed2002

[Identification of CD11c+ myeloid dentritic cells in adenoids and in nasal mucosa of patients with and without allergies].

BACKGROUND: Dendritic cells form a link between innate and acquired immunity. They are capable to detect pathogens based on the recognition of pathogen-associated microbial molecules and trigger the appropriate type of immune responses. In humans, three major subsets of dendritic cells can be distinguished, Langerhans cells of the skin, myeloid DC (MDC) and plasmacytoid DC (PDC). It was reported that PDC infiltrate nasal mucosa in allergen-induced rhinitis. Information about the role of MDC in nasal mucosa and the corresponding mucosa-associated lymphoid tissue, the nasopharyngeal adenoids, is limited. PATIENTS AND METHODS: : Here we examined the presence of MDC in adenoids and in nasal mucosa of healthy individuals (n = 9) and in patients with allergic rhinitis. MDC were detected by flow cytometry by positive staining for MHC II and CD11c and the lack of lineage markers. Dead cells were excluded from analysis. RESULTS: In adenoids, 0.4 % of all cells were MDC. Considerable numbers of MDC could also be detected in nasal mucosa. No difference was found between healthy individuals and patients with allergies (0.3 % vs. 0.45 % MDC; p = 0.12). Interestingly, MDC were absent in patients who received treatment with glucocorticoids, while very high numbers of MDC were found in patients who recently had upper respiratory tract infections. CONCLUSION: Our results demonstrate for the first time the presence of MDC in nasal mucosa. MDC numbers were similar in healthy individuals and in patients with allergy. This study forms the basis for examining the role of MDC in the pathogenesis of allergic rhinitis, and for the modulation of MDC functional activity with microbial molecules such as CpG oligonucleotides.

Adenoids↗
PubMed2002

Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN.

Inhibition of bcl-2 expression by antisense oligodeoxynucleotides (ODN) might render bcl-2 overexpressing malignant B cells more susceptible to chemotherapy. ODN containing unmethylated CG dinucleotides (CpG) are known to activate B cells. We studied the effects of two bcl-2 antisense ODN, with (G3139) or without CG dinucleotides (NOV 2009) within the sequence, and the effects of a nonantisense, CpG-containing ODN (ODN 2006) on activation and apoptosis of malignant B cell lines and primary B-CLL cells. Without cationic lipids, no antisense-mediated inhibition of bcl-2 synthesis was achieved with G3139 and NOV 2009. Instead, G3139, but not NOV 2009, induced similar changes as ODN 2006 in proliferation, expression of costimulatory and antigen-presenting molecules, as well as in bcl-2 and bcl-xL levels of primary B-CLL cells. G3139 and ODN 2006 inhibited in vitro, spontaneous apoptosis in B-CLL cells of patients with high serum thymidine kinase activity (s-TK, marker for proliferative activity of malignant B cells), whereas in patients with low s-TK activity, apoptosis was induced. In conclusion, our results suggest that modulation of malignant B cell apoptosis by G3139 depends on its immunostimulatory properties rather than on antisense-mediated reduction of bcl-2 expression. Immunostimulatory CpG ODN may have a therapeutic potential in patients with B-CLL, especially those with low s-TK activity.

Adjuvants, Immunologic↗
PubMed2001

Antisense therapy in oncology: new hope for an old idea?

There is a potential role for antisense oligonucleotides in the treatment of disease. The principle of antisense technology is the sequence-specific binding of an antisense oligonucleotide to target mRNA, resulting in the prevention of gene translation. The specificity of hybridisation makes antisense treatment an attractive strategy to selectively modulate the expression of genes involved in the pathogenesis of diseases. One antisense drug has been approved for local treatment of cytomegalovirus-induced retinitis, and several antisense oligonucleotides are in clinical trials, including oligonucleotides that target the mRNA of BCL2, protein-kinase-C alpha, and RAF kinase. Antisense oligonucleotides are well tolerated and might have therapeutic activity. Here, we summarise treatment ideas in this field, summarise clinical trials that are being done, discuss the potential contribution of CpG motif-mediated effects, and look at promising molecular targets to treat human cancer with antisense oligonucleotides.

Animals↗
PubMed2001

Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12.

Human plasmacytoid dendritic cells (DC) (PDC, CD123+) and myeloid DC (MDC, CD11c+) may be able to discriminate between distinct classes of microbial molecules based on a different pattern of Toll-like receptor (TLR) expression. TLR1-TLR9 were examined in purified PDC and MDC. TLR9, which is critically involved in the recognition of CpG motifs in mice, was present in PDC but not in MDC. TLR4, which is required for the response to LPS, was selectively expressed on MDC. Consistent with TLR expression, PDC were susceptible to stimulation by CpG oligodeoxynucleotide (ODN) but not by LPS, while MDC responded to LPS but not to CpG ODN. In PDC, CpG ODN supported survival, activation (CD80, CD86, CD40, MHC class II), chemokine production (IL-8, IP-10) and maturation (CD83). CD40 ligand (CD40L) and CpG ODN synergized to activate PDC and to stimulate the production of IFN-alpha and IL-12 including bioactive IL-12 p70. Previous incubation of PDC with IL-3 decreased the amount of CpG-induced IFN-alpha and shifted the cytokine response in favor of IL-12. CpG ODN-activated PDC showed an increased ability to stimulate proliferation of naive allogeneic CD4 T cells, butTh1 polarization of developing T cells required simultaneous activation of PDC by CD40 ligation and CpG ODN. CpG ODN-stimulated PDC expressed CCR7, which mediates homing to lymph nodes. In conclusion, our studies reveal that IL-12 p70 production by PDC is under strict control of two signals, an adequate exogenous microbial stimulus such as CpG ODN, and CD40L provided endogenously by activated T cells. Thus, CpG ODN acts as an enhancer of T cell help, while T cell-controlled restriction to foreign antigens is maintained.

Adjuvants, Immunologic↗
PubMed2001

Identification of CpG oligonucleotide sequences with high induction of IFN-alpha/beta in plasmacytoid dendritic cells.

The immature plasmacytoid dendritic cell (PDC) is identical with the principal type I IFN-producing cell upon viral infection. Oligodeoxynucleotides which contain unmethylated CpG motifs (CpG ODN) are recognized by the vertebrate immune system. Previously, we described CpG ODN that strongly activate human B cells and human blood dendritic cells. Here we describe distinct CpG-containing oligonucleotide sequences which, in contrast to previously described CpG ODN, induced high amounts of IFN-alpha and IFN-beta in peripheral blood mononuclear cells (PBMC). Intracellular staining for IFN-alpha revealed that within PBMC CpG ODN-induced IFN-alpha is produced exclusively by PDC. Unlike IFN-alpha, TNF-alpha is up-regulated in PDC by all CpG ODN tested. Purified PDC responded to CpG ODN, demonstrating direct activation of PDC by CpG ODN. The most active sequence induced the production of up to 5 pg IFN-alpha per single PDC, resulting in more than 400 ng/ml IFN-alpha in the supernatant of PBMC enriched for PDC. The potency of CpG ODN to stimulate IFN-alpha correlated with their ability to stimulate NK cell lytic activity, while purified NK cells did not respond to CpG ODN. IFNgamma production in PBMC was dependent on CpG ODN-induced IFN-alpha/beta as demonstrated by IFN-alpha/beta blocking antibodies. IFN-alpha-inducing CpG ODN strongly supported IFN-gamma production of TCR-triggered CD4 T cells but were less active than other CpG ODN in stimulating B cells. In conclusion our results demonstrate that particular CpG ODN sequences exist which, due to high IFN-alpha/beta induction in PDC, induce a set of immune responses typical for viral infection.

Adjuvants, Immunologic↗
PubMed2001

Distinct CpG oligonucleotide sequences activate human gamma delta T cells via interferon-alpha/-beta.

Oligodeoxynucleotides with CpG motifs (CpG ODN) mimic microbial DNA and activate effectors of innate immunity including NK cells. Human gamma delta T cells (Vgamma9/Vdelta2) are antigen specific "natural memory" T cells in a preactivated stage, which respond to common non-protein phosphoantigens. Among several CpG ODN tested, distinct CpG ODN sequences characterized by inducing high amounts of IFN-alpha/-beta in PBMC elicited strong gamma delta T cell and NK cell responses, as determined by CD69 expression, IFN-gamma production, perforin content and lytic activity. These CpG ODN activated gamma delta T cells and NK cells in the absence of an additional stimulus and synergistically increased responsiveness to cell-type-specific antigens like isopentenylpyrophosphate for gamma delta T cells and NK-sensitive tumor cells for NK cells. NK cells and gamma delta T cells were activated via IFN-alpha/-beta released by CpG ODN-stimulated PBMC. Purified gamma delta T cells and NK cells did not respond to CpG ODN but to recombinant IFN-alpha/-beta. In conclusion, CpG ODN sequences were identified which, based on their ability to induce high amounts of IFN-alpha/-beta, represent strong adjuvants for "natural memory" cells including responses of gamma delta T cells to non-protein antigens. Early IFN-alpha/-beta dependent stimulation of IFN-gamma synthesis in NK cells and gamma delta T cells may contribute to the CpG ODN-induced Th1 bias of an evolving immune response.

Adjuvants, Immunologic↗
PubMed2001

Shock waves: a novel method for cytoplasmic delivery of antisense oligonucleotides.

Intracytoplasmic delivery of oligonucleotides (ODN) can improve ODN-based strategies such as the antisense approach and the use of immunostimulatory CpG dinucleotide containing ODN. Shock waves are established for the treatment of nephrolithiasis and other diseases. Here we describe the use of shock waves as a new physical method for the direct transport of antisense ODN into the cytoplasm and the nucleus of cells. Human peripheral blood mononuclear cells together with antisense ODN were exposed to shock waves generated by an electrohydraulic lithotripter. ODN uptake was examined by flow cytometry and fluorescence microscopy. By optimization of physical parameters we achieved the transfer of high amounts of ODN which were detected within less than 5 min after shock wave exposure, with viability of cells higher than 95%. Transfection of human peripheral blood mononuclear cells with an antisense ODN directed against tumor necrosis factor (TNF) alpha resulted in a reduction in lipopolysaccharide-induced TNF production by 62% (n=5, P=0.006). Specificity of TNF suppression was confirmed with a four-mismatch oligonucleotide. Positive atmospheric pressure abolished antisense-mediated inhibition of TNF synthesis by blocking shock wave-induced cavitation and formation of oscillating air bubbles. Electroporation was less effective. The use of shock waves is thus an efficient physical tool for ODN delivery to cells. Shock waves may allow the evaluation of target proteins in cell types difficult to transfect with other methods and thus may improve the antisense technique for the analysis of unknown genes.

Cytoplasm↗
PubMed2001

Regulation of the hepatic multidrug resistance gene expression by endotoxin and inflammatory cytokines in mice.

P-glycoprotein (PGP), an ATP-dependent membrane transporter is found in epithelial tissues of the liver, kidneys, intestine and blood-brain barrier. In tumor cells, PGP is often overexpressed and confers multidrug resistance toward cancer chemotherapeutics. It has been previously shown in rats that induction of an inflammatory response evokes a decrease in hepatic expression of PGP. In order to identify the inflammatory mediators involved in this phenomenon, we examined the influence of experimentally induced inflammation and pro-inflammatory cytokines (interleukin (IL)-6, IL-1beta and tumor necrosis factor (TNF)-alpha) on the hepatic expression of PGP in mice. A significant reduction in the hepatic expression of mdr1a, mdr1b, mdr2 and spgp genes were seen in endotoxin (lipopolysaccharide (LPS)) and turpentine-treated mice. Similarly, IL-6-treated mice displayed a 70% reduction in protein expression and a 40-70% reduction in the mRNA levels of all PGP mdr isoforms. Administration IL-1beta caused an increase in both mdr1b mRNA and protein expression, however, mRNA levels of mdr1a, mdr2 and spgp were significantly reduced. Administration of TNF-alpha also caused increases in mdr1b mRNA. These findings indicate that IL-6 plays a principal role in the downregulation of PGP that is observed in the livers of mice during an inflammatory response.

ATP Binding Cassette Transporter, Subfamily B, Mem↗