Biomedical subjects
Publications and source records attributed to G Hartmann.
Recent studies have demonstrated the essential role of tumor necrosis factor alpha (TNF-alpha) in rheumatoid arthritis and Crohn's disease. This article discusses agents known to suppress the formation or activity of TNF-alpha, and summarizes clinical studies using anti-TNF-alpha antibodies.
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The in vitro extract-viscosity and the content of non-starch-polysaccharides were investigated in 34 defined wheat varieties grown at 5 locations each. Both, wheat genotype as well as growing location clearly influenced the viscosity of soluble extract from wheat. Furthermore, the content of non-starch-polysaccharides (soluble/total) and pentosans (soluble/total) were determined in 13 wheat varieties each grown at two locations. Soluble pentosan contents were highly positively correlated with extract viscosity of wheat at the locations Hayn (r = 0.86) and Biendorf (r = 0.90). The classical apparent metabolisable energy of 5 wheat samples having different extract viscosities was assessed. The AMEN values ranged from 14.0 to 14.6 MJ/kg DM and were significant negatively correlated to content of soluble arabinoxylans (r = 0.67) and to the extract viscosity (r = 0.83). Furthermore, the viscosity of jejunal (4.0 to 22.8 mPas) and ileal (13.1 to 78.0 mPas) digesta exhibited a clear relationship with soluble pentosan contents and extract viscosity. Under the conditions applied in this study the technique of extract viscosity measurement can predict the AME.
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Therapeutic oligonucleotides - short strands of synthetic nucleic acids - encompass antisense and aptamer oligonucleotides. Antisense oligonucleotides are designed to bind to target RNA by complementary base pairing and to inhibit translation of the target protein. Antisense oligonucleotides enable specific inhibition of cytokine synthesis. In contrast, aptamer oligonucleotides are able to bind directly to specific proteins. This binding depends on the sequence of the oligonucleotide. Aptamer oligonucleotides with CpG motifs can exert strong immunostimulatory effects. Both kinds of therapeutic oligonucleotides - antisense and aptamer oligonucleotides - provide promising tools to modulate immunological functions. Recently, therapeutic oligonucleotides have moved towards clinical application. An antisense oligonucleotide directed against the proinflammatory intercellular adhesion molecule 1 (ICAM-1) is currently being tested in clinical trials for therapy of inflammatory disease. Immunostimulatory aptamer oligonucleotides are in preclinical development for immunotherapy. In the present review we summarize the application of therapeutic oligonucleotides to modulate immunological functions. We include technological aspects as well as current therapeutic concepts and clinical studies.
UNLABELLED: The aim of the present study was to evaluate the association between 24 h urinary excretion of sodium and blood pressure, fasting plasma insulin, renin, aldosterone and serum norepinephrine concentrations in 45 obese and 15 control children. Urinary sodium excretion was significantly lower in obese subjects (1.3 +/- 0.6 mmol/kg/24 h, P < 0.01) than in controls (2.8 +/- 1.3 mmol/kg/24 h). Hyperinsulinaemia did not affect sodium excretion of obese children. Plasma renin and aldosterone levels did not correlate with sodium excretion and were significantly higher in overweight children. Serum norepinephrine levels were also significantly higher in the obese group (0.66 +/- 0.89 microgram/100 ml) as compared to the controls (0.11 +/- 0.03 microgram/100 ml, P < 0.01) and showed significant negative correlation with urinary sodium excretion (r = 0.43, P < 0.05). CONCLUSION: Hyperinsulinaemia and the consequently increased sympathetic nervous system activity might be involved in the development of high blood pressure in obese children by decreasing urinary sodium excretion.
BACKGROUND AND PURPOSE: Methods for determining absorbed dose in clinical proton beams are based on dosimetry protocols provided by the AAPM and the ECHED. Both groups recommend the use of air-filled ionization chambers calibrated in terms of exposure or air kerma in a 60Co beam when a calorimeter or Faraday cup dosimeter is not available. The set of input data used in the AAPM and the ECHED protocols, especially proton stopping powers and w-value is different. In order to verify inter-institutional uniformity of proton beam calibration, the AAPM and the ECHED recommend periodic dosimetry intercomparisons. In this paper we report the results of an international proton dosimetry intercomparison which was held at Loma Linda University Medical Center. The goal of the intercomparison was two-fold: first, to estimate the consistency of absorbed dose delivered to patients among the participating facilities, and second, to evaluate the differences in absorbed dose determination due to differences in 60Co-based ionization chamber calibration protocols. MATERIALS AND METHODS: Thirteen institutions participated in an international proton dosimetry intercomparison. The measurements were performed in a 15-cm square field at a depth of 10 cm in both an unmodulated beam (nominal accelerator energy of 250 MeV) and a 6-cm modulated beam (nominal accelerator energy of 155 MeV), and also in a circular field of diameter 2.6 cm at a depth of 1.14 cm in a beam with 2.4 cm modulation (nominal accelerator energy of 100 MeV). RESULTS: The results of the intercomparison have shown that using ionization chambers with 60Co calibration factors traceable to standard laboratories, and institution-specific conversion factors and dose protocols, the absorbed dose specified to the patient would fall within 3% of the mean value. A single measurement using an ionization chamber with a proton chamber factor determined with a Faraday cup calibration differed from the mean by 8%. CONCLUSION: The adoption of a single ionization chamber dosimetry protocol and uniform conversion factors will establish agreement on proton absorbed dose to approximately 1.5%, consistent with that which has been observed in high-energy photon and electron dosimetry.
Recent clinical studies using neutralizing antibodies point to a key role for tumor necrosis factor-alpha (TNF-alpha) in chronic inflammatory diseases. Antisense technique is a recent approach aiming at inhibition of single proteins. Previously, we described nonspecific induction of TNF by phosphorothioate oligonucleotides. In this study, we established an in vitro model that allows specific inhibition of TNF synthesis, bypassing TNF induction. Freshly isolated human monocytes were incubated with oligonucleotides and the cationic lipid lipofectin in different ratios. TNF synthesis was stimulated with lipopolysaccharide and quantified by a specific radioimmunoassay (RIA). Among all sequences tested, one of the antisense oligonucleotides complementary to the translation initiation region of TNF mRNA (5'-CAT GCT TTC AGT CAT-3') revealed highest efficacy. At 2 microM, the antisense oligonucleotide inhibited TNF synthesis by up to 79%. A concentration as low as 250 nM of the antisense oligonucleotide was effective. Scrambled controls and controls with different, defined degrees of mismatches confirmed a sequence-specific action. Examination with confocal fluorescence microscopy showed a marked difference comparing lipofectin-mediated vs. spontaneous uptake. This study defines criteria that from the prerequisite necessary for design and application of antisense oligonucleotides against TNF in vivo.
BACKGROUND: Specific inhibition of target proteins by antisense oligodeoxynucleotides is an extensively studied experimental approach. This technique is currently being tested in clinical trials applying phosphorothioate-modified oligonucleotides as therapeutic agents. These polyanionic molecules, however, may also exert non-antisense-mediated effects. MATERIALS AND METHODS: We examined the influence of oligonucleotides on lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF alpha) synthesis in freshly isolated human peripheral blood mononuclear cells. Oligonucleotides (18 mer) with different degrees of phosphorothioate modification were studied. RESULTS: The addition of phosphorothioate oligonucleotides (5 microM) caused amplification of TNF synthesis of up to 410% compared with the control with LPS alone. Without LPS stimulation, phosphorothioate oligonucleotides did not induce TNF production. We demonstrate that the enhancement of LPS-stimulated TNF production by phosphorothioate oligonucleotides does not rely on the intracellular presence of oligonucleotides and is not mediated by LPS contamination. Partially phosphorothioate-modified oligonucleotides and unmodified oligonucleotides did not increase TNF synthesis. High concentrations of the polyanion heparin reversed the oligonucleotide-induced enhancement of TNF synthesis. CONCLUSIONS: The data suggest that amplification of TNF synthesis may be caused by binding of the polyanionic phosphorothioate oligonucleotide to cationic sites on the cell surface. Such binding sites have been proposed for polyanionic glycoaminoglycans of the extracellular matrix, which have also been described to augment LPS-stimulated TNF synthesis. The present results are relevant to all in vitro studies attempting to influence protein synthesis in monocytes by using phosphorothioate oligonucleotides. The significance of our findings for in vivo applications of phosphorothioates in situations where there is a stimulus for TNF synthesis, such as in sepsis, should be elucidated.
We have examined the role of two mesenchymal ligands of epithelial tyrosine kinase receptors in mouse mammary gland morphogenesis. In organ cultures of mammary glands, hepatocyte growth factor (HGF, scatter factor) promoted branching of the ductal trees but inhibited the production of secretory proteins. Neuregulin (NRG, neu differentiation factor) stimulated lobulo-alveolar budding and the production of milk proteins. These functional effects are paralleled by the expression of the two factors in vivo: HGF is produced in mesenchymal cells during ductal branching in the virgin animal; NRG is expressed in the mesenchyme during lobulo-alveolar development at pregnancy. The receptors of HGF and NRG (c-met, c-erbB3, and c-erbB4), which are expressed in the epithelial cells, are not regulated. In organ culture, branching morphogenesis and lobulo-alveolar differentiation of the mammary gland could be abolished by blocking expression of endogenous HGF and NRG by the respective antisense oligonucleotides; in antisense oligonucleotide-treated glands, morphogenesis could again be induced by the addition of recombinant HGF and NRG. We thus show that two major postnatal morphogenic periods of mammary gland development are dependent on sequential mesenchymal-epithelial interactions mediated by HGF and NRG.
While it is well established that acute allergic urticaria is caused by degranulation of skin mast cells occurring after allergen/IgE-dependent cross-linking of high affinity IgE receptors (FcepsilonRI), the pathophysiologic mechanisms operative in chronic urticaria (CU) are less well understood. Some evidence points to the existence of histamine-releasing activity in the serum of CU patients which possibly acts via triggering of FcepsilonRI. In this study, we aimed to better characterize this anti-FcepsilonRIalpha reactivity of CU patients using affinity-purified, IgE-depleted IgG fractions of such individuals (CU-IgG). Using immobilized, recombinant soluble FcepsilonRIalpha as a a reaction target for Western blot studies, we found that 12/32 (37%) CU-IgG serum samples exhibited IgG autoreactivity against FcepsilonRI- alpha. These findings were confirmed by experiments demonstrating that immunoblot-reactive, but not immunoblot-nonreactive, CU-IgG preparations precipitated the FcepsilonRIalpha from FcepsilonRI- alphagamma-transfected cells. No anti-FcepsilonRIalpha reactivity was observed in IgG fractions from atopic dermatitis (AD) patients (0/15) or healthy control individuals (CO:0/15). As opposed to the selective occurrence of IgG anti-Fc epsilon RI alpha autoantibodies in CU patients, IgG anti-IgE antibodies were detected in all groups investigated (CU: 69%; AD: 73%; CO: 26%). While both types of autoantibodies can exhibit histamine-releasing properties, not all of the autoantibodies proved to be functional in vitro. Our results indicate that the occurrence of IgG anti-FcepsilonRIalpha reactivity defines an autoimmune-mediated subentity of CU and provide a basis for the development of new diagnostic procedures and, perhaps, therapeutic strategies for this disease.
Scatter factor/hepatocyte growth factor (SF/HGF) has various biological effects upon different cells, i.e. induces increased motility and proliferation as well as invasiveness and morphogenesis. The signals given to epithelial cells by SF/HGF are all mediated through the Met receptor tyrosine kinase (Weidner, K. M., Sachs, M., and Birchmeier, W. (1993) J. Cell Biol. 111, 145-154) suggesting that signal diversity is due to the interplay of different downstream pathways. It has also been shown that SF/HGF activates the protooncogene product Ras, i.e. stimulates guanine nucleotide exchange. In order to examine whether Ras is involved in mediating the dissociation and motility signal of SF/HGF to epithelial cells, we have expressed in Madin-Darby canine kidney cells the dominant-negative N17Ras under the control of a modified metallothionein promoter. Induced expression of N17Ras by the addition of Zn2+ clearly prevented dissociation of the cells by SF/HGF. These data indicate that the Ras pathway is indeed essential to mediate the motility signal of SF/HGF-Met to the cell-cell adhesion system and the cytoskeleton of epithelial cells.
Magnetic resonance imaging (MRI) requires the patients to stay for 30-45 min in a magnetic closed noisy space. Therefore most children and agitated adults require general anaesthesia or sedation in order to high quality images. Anaesthesia may be given by several routes (TIVA, inhalational or intrarectal administration) using common drugs. However, the magnetic field limits the selection of patients undergoing MRI and the spectrum of anaesthetic and monitoring equipment. The magnetic field may have deleterious effects on implanted ferromagnetic devices. It may attract objects towards the magnet centre at a dangerous speed. Moreover it may disturb the function of monitors and anaesthesia machines which should be tested for a specific magnetic field strength before introducing their use in a given MRI unit.
The relationship between the hypothalamic catecholamine and serotonin level as well as the activation of the pituitary-adrenal axis was investigated after administration or morphine (MO) in the rat. Five mg/kg b. wt. of MO induced a significant increase in norepinephrine and a 78%, but insignificant, increase in dopamine level of the hypothalamus within 60 min without changing corticosterone secretion. Electric footshock, in addition to elevating hypothalamic norepinephrine and dopamine levels, significantly increased the pituitary-adrenocortical response in the MO pretreated rats. Five mg/kg b. wt. of MO, or electric footshock alone did not influence the hypothalamic serotonin level within 60 min, but the hypothalamic serotonin level decreased significantly in the MO pretreated, electrically shocked animals. We conclude, that 1) low dose of MO may induce changes of the hypothalamic catecholamine levels without influencing pituitary-adrenocortical activation. 2) enhanced hypothalamic catecholamines by MO did not prevent increasing pituitary-adrenocortical response elicited by stress. It appears, that the hypothalamic catecholaminergic mechanism which may inhibit ACTH release during stimulation does not function in the MO treated rats.
Closed loop control of ventilation is traditionally based on end-tidal or mean expired CO2. The controlled variables are the respiratory rate RR and the tidal volume VT. Neither patient size or lung mechanics were considered in previous approaches. Also the modes were not suitable for spontaneously breathing subjects. This report presents a new approach to closed loop controlled ventilation, called Adaptive Lung Ventilation (ALV). ALV is based on a pressure controlled ventilation mode suitable for paralyzed, as well as spontaneously breathing, subjects. The clinician enters a desired gross alveolar ventilation (V'gA in l/min), and the ALV controller tries to achieve this goal by automatic adjustment of mechanical rate and inspiratory pressure level. The adjustments are based on measurements of the patient's lung mechanics and series dead space. The ALV controller was tested on a physical lung model with adjustable mechanical properties. Three different lung pathologies were simulated on the lung model to test the controller for rise time (T90), overshoot (Ym), and steady state performance (delta max). The pathologies corresponded to restrictive lung disease (similar to ARDS), a "normal" lung, and obstructive lung disease (such as asthma). Furthermore, feasibility tests were done in 6 patients undergoing surgical procedures in total intravenous anesthesia. In the model studies, the controller responded to step changes between 48 seconds and 81 seconds. It did exhibit an overshoot between 5.5% and 7.9% of the setpoint after the step change.(ABSTRACT TRUNCATED AT 250 WORDS)
Authors measured the dopamine (DA), noradrenaline (NA) and serotonin (5-HT) contents of amniotic fluid between 19 and 21 weeks with fluorimetric method. The amniotic fluid samples were obtained by transabdominal amniocenteses performed due to elevated maternal serum-alphafetoprotein levels and suspect ultrasound findings. They considered as normal values the average of 30 amniotic fluid samples obtained from pregnant women who gave birth to healthy babies at term. The mean values (mean+SE) of normal cases were 136.6 + 20.2 nmol/l for DA, 29.5 + 9.4 nmol/l for NA and 72.6 + 4.9 nmol/l for 5-HT. Against these values, in cases of open spina bifida the level of NA showed no significant difference, the DA level was higher (p < 0.05) and the 5-HT level was also higher (p < 0.001). The DA level was found higher (p < 0.05) in cases of intrauterine retardation as well, however there was no difference in the NA and 5-HT levels in these cases. In cases of preterm deliveries, none of the above parameters showed differences. Authors suggest that in cases of spina bifida the measurement of 5-HT in the amniotic fluid can be a complementary diagnostic method. They also state that no prognosis about the outcome of pregnancies can be expected from such examinations.
Noradrenaline (NA), serotonin (5HT), dopamine (DA), FSH, LH and prolactin (PRL) content was determined in 104 preovulatory follicular fluids obtained from 44 patients undergoing in vitro fertilization. The patients were given human menopausal gonadotropin (HMG) for ovarium stimulation, ovulation was induced with 10000 IU human chorionic gonadotropin (HCG) 34-36 hours prior to the follicular aspiration by vaginal ultrasound. Classification of the oocytes was performed by direct microscopic evaluation differentiating three groups of oocytes: Group I.: prophase I; Group II.: metaphase I; Group III.: metaphase II. There was no significant difference in monoamine and FSH content of follicular fluid at different stage of the oocyte maturation. LH and PRL significantly increased parallel with oocyte maturation (38.9; 48.8; 56.7 IU/l and 1324; 2382; 3134 IU/l). significant negative correlation was observed in Group I. between 5HT-LH (r = -0.64); in Group II. between NA-LH (r = -0.62) and NA-PRL (r = -0.51). Significant positive correlation were found in Group I. between FSH-LH (r = 0.63), in Group II. between LH-PRL (r = 0.56), in Group III. between NA-5HT (r = 0.66), NA-DA (r = 0.80) and 5HT-DA (r = 0.66). These observations suggest that action of LH and PRL may be negatively modulated by 5HT and NA in the final stage of oocyte maturation.
Tumorous, virus-induced skin lesions in two golden hamsters (Mesocricetus auratus) were characterized macroscopically and by means of light- and electron-microscopy. Evidence of a virus was demonstrated in the ultra-thin sections and by the negative staining method. The morphological findings confirm the assumption that infections with papoviruses--probably of the polyomavirus genus--were involved.