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Transcription factors adjust the up- and downregulation of inflammatory genes. Within the bounds of the SIC-study (Selenium in Intensive Care) the authors will investigate the role of transcription factors NF-kappa B and AP-1 in S.I.R.S/septic patients. The goal of these investigations is the corroboration of therapy of septic patients with sodium selenite at the molecular biological level.
The authors have investigated the relationship between selenium and transcription factors (NF-kappa B and AP-1) in the field of pathogenesis of polytrauma. Correlations between plasma selenium content and transcription factor binding activity have been found. The measured connecting capacitances of transcription factors have been associated with the severity of disease. To harden the results of this research a randomized double blind study with sodium selenite substitution is necessary next. This study will be to establish the therapy with sodium selenite in the treatment of polytrauma.
BACKGROUND: Many nonthyroidal illnesses, such as major trauma, severe burn injury, sepsis or immune deficiency are associated with a reduced T3 concentration without increased serum TSH secretion. The pathopysiologic meaning of this phenomenon was controversely discussed since its investigation 20 years ago. The identification of the Type I 5-iodthyronine-deiodinase as a selenoenzyme brought many new aspects into this discussion. PATIENTS AND METHODS: To investigate the correlation of T3 blood levels and the selenium concentrations in consideration of the severity of the nonthyroidal illness 20 patients with major trauma where included in this study. In all these patients frequently T3, T4, fT3, fT4, TSH, Se (whole blood), Se (plasma) and Glasgow-Coma-Scale (GCS), APACHE II and MOF-Score where measured until the 28th day of illness. RESULTS: Five patients (20%) died during the study until the 8th day of measurement. Survivors and nonsurvivors initial showed a low T3 and fT3 level in serum. While the T3 serum concentrations of nonsurvivors remained on a low level the thyronine concentrations of survivors distinctly increased. The measured thyroid hormone concentrations were significantly correlated with MOF-score, APACHE II and inversely with GCS. There was no significant correlation between low T3/fT3 blood levels and low selenium concentrations in all observed patients. CONCLUSION: The selenium deficiency in all patients with major trauma seems to be not the single cause of the low T3 syndrome. The distinctly suppression of TSH could be caused by the action of various cytokines such as IL-6 and TNF-alpha. Further investigations should improve the effectivity of substitution of selenium and/or thyroid hormones in the therapy of patients with severe nonthyroidal illness.
From extensive research over the last decade it has been known that selenium is essential as necessary component of selenoaminoacids and of specific enzymes. Among others, the redoxpair GSH/GSSG is closely connected with antioxidative processes. Moreover it inhibits and/or activates molecular key reactions with the involvement of various small reactive O- and N-species. We investigated the direct interaction of selenite with components of the respiratory burst of human blood cells, considering the redoxamphoterie of alkali-selenite. Selenite tend to redox-disproportation depending on the pH-value. Whether selenite leads to oxidation or reductation is dependent not only on the pH-value, but also on the redox-potential of the reaction partners. In in-vivo adapted in-vitro conditions (ph = 7.4; mumolar concentrations of reaction partners) we observed the following results: 1. SeO3(2-) is not oxidized by H2O2/NO or triplet-oxygen, when the oxidatives are applied alone; 2. SeO3(2-) is quantitatively oxidized from SeO4(2-) by the combination H2O2/NO2- or O2-/NO; 3. SeO3(2-) is semiquantitatively oxidized by singlett oxygen to SeO4(2-). The composition of reaction products was measured by 77Se-NMR-spectroscopy. The reactive intermediate product for the 2. reaction should be peroxynitrite (HOONO). One cannot rule out the possibility that HOONO reacts on a large scale with H2O2 to singlett oxygen. Subsequently singlett oxygen oxidizes selenite. The pathophysiological impact of singlett oxygen in processes like arteriosclerosis is now being investigated. It has been supposed, that singlett oxygen is participating in processes of lipidperoxidation invivo. Further investigations have to show, to what extent selenite is effective as direct 1O2-scavanger.
PATIENTS AND METHOD: At the Clinic for Paediatric Surgery of the University of Dresden, in a time period ranging from 5/1994 to 12/1996, all patients aged between 1 and 16 years with severe inflammatory surgical diseases or extended scalded skin, were given an adjuvant selenium substitution. As control group, all patients with the same diagnosis and age treated during the months 1/1997 to 12/1998, did not receive this adjuvant selenium substitution. All these patients fulfilled the criteria of "Systemic Inflammatory Response Syndrome" (SIRS). The selenium-therapy group consisted of 34 patients and the control group without substitution consisted of 31 patients. The following laboratory parameters were measured on the 1st, 2nd, 3rd, 6th and last treatment day: white blood cell count, interleukin 6, C-reactive protein, fibrinogen, malondialdehyde, activity of glutathione peroxidase in plasma and level of selenium in plasma and whole blood. RESULTS: The initially high interleukin 6 rates declined significantly in both groups from the 2nd day on. The acute phase proteins, i.e. the C-reactive protein and fibrinogen, normalized in both groups after the 3rd day of treatment. The initial low rates of selenium in plasma and blood gained more rapidly a normal level in the therapy group than in the control group. On the 1st day of therapy the glutathione peroxidase activity in plasma was in both groups at the inferior limit of norm range and remained at this level in the control group for the whole observation period. In the selenium-substitution group on the contrary, these initial low values raised to the double as an expression of an elevated cell membrane protection. The initial significant elevated malondialdehyde rates in both groups, expressing a raised lipidperoxidation, fell down to a normal level in the selenium-substitution group, whereas they remained at their initial high level in the control group during the whole observation period. CONCLUSION: The substitution of selenium in children with SIRS is a supportive therapy.
Tissue factor (TF), the cellular receptor and cofactor for clotting factor VII/VIIa (FVII/VIIa), is known mainly as the initiator of the coagulation protease cascade. Recently, it was shown that inactivation of the murine TF gene (TF-/-) results in embryonic lethality which is most likely due to some failure of vascular integrity. On the other hand, gene disruption in mice of coagulation proteins like FVII, prothrombin, and fibrinogen results in phenotypes of embryonic development that contrast with that of TF-/-, suggesting a role for TF beyond fibrin formation in embryogenesis. In addition, there is a growing body of evidence that cellular TF may be involved in nonhemostatic functions. To determine the microtopography of membrane TF with regard to the cytoskeleton organization, we examined the expression patterns of TF and cytoskeletal proteins in various cell lines by means of double immunofluorescence and electron microscopy (EM). In spreading cells, a granular membrane TF expression of the cell cortex and a pronounced granular TF staining of microspikes, lamellipodes, and ruffled membrane areas were observed. Especially, actin and alpha-actinin were in close proximity to TF in these regions. Colocalization of TF and nonmuscle filamin (ABP-280) at the leading edge of spreading cells indicated an association of TF with the actin filament system, too. Using scanning EM we found gold-labeled TF at long processes and actin-filament-containing microspikes of neighboring cells in both branching and contact sites. By the means of immunogold EM we observed that TF is localized at the cell surface in a spotty pattern, at the base and at the top of budding processes. The observed staining pattern points to a connection of TF with elements of the cytoskeleton in these highly dynamic membrane regions, a fact which is underlined by the recently described molecular interaction of TF's cytoplasmic domain with ABP-280. In cells undergoing cytokinesis, we detected also strong TF expression in dynamic membrane areas and protrusions of the midbodies, indicating an accumulation of TF in actin-rich membrane areas with high contractile activity. In addition, we were able to demonstrate that immobilized ligands for TF, both catalytically active and inactive FVIIa or anti-TF mAbs, accelerated adhesion and spreading of TF-expressing cancer cells. Thus, our findings support the contention that ligation of cellular TF may be involved in morphogenic processes such as adhesion and spreading by an association to cytoskeletal structures. On the other hand, incubation of these cells with proteolytically active FVIIa but not with covalently inactivated FVIIa (DEGR-FVIIa) or anti-TF mAbs in solution resulted in increased motility of these cells, indicating that not only ligation of TF but also the proteolytic activity of TF-FVIIa complex is involved in cell migration.
Hepatoblastomas (HBs) are embryonal tumors affecting young children and representing the most frequent malignant liver tumors in childhood. The molecular pathogenesis of HB is poorly understood. Although most cases are sporadic, the incidence is highly elevated in patients with familial adenomatous polyposis coli. These patients carry germline mutations of the APC tumor suppressor gene. APC controls the degradation of the oncogene product beta-catenin after its NH2-terminal phosphorylation on serine/threonine residues. APC, as well as beta-catenin, has been found to be a central effector of the growth promoting wingless signaling pathway in development. To find out if this pathway is involved in the pathogenesis of sporadic HBs, we examined 52 biopsies and three cell lines from sporadic HBs for mutations in the APC and beta-catenin genes. Using single-strand conformational polymorphism analysis, deletion screening by PCR, and direct sequencing, we found a high frequency of beta-catenin mutations in sporadic HBs (48%). The mutations affected exon 3 encoding the degradation targeting box of beta-catenin leading to accumulation of intracytoplasmic and nuclear beta-catenin protein. The high frequency of activating mutations in the beta-catenin gene indicates an important role in the pathogenesis of HB.
The influence of IL-3 on the bone marrow cells of 53 patients with acute myeloid leukaemia (AML) was investigated after 72 h suspension in cultures by analysing the proliferation of blasts and the secretion of cytokines. The titres of IL-1beta IL-6, TNF-alpha and IL-3 were measured in the supernatants of these cultures with ELISA tests. Comparing the percentage of cells in S-phases of control cultures and cultures with IL-3, the leukaemias were divided into two growth pattern groups: IL-3-insensitive (n=19) and IL-3-sensitive (n=34) leukaemias. The IL-3-insensitive AML cells show a greater ability for autonomous growth, first by the increase of S-phase in the control culture compared with the S-phase in vivo (P=0.0486) and second, by the higher constitutive secretion (control culture) of IL-1beta P =0.0004), IL-6 ( P =0.0395) and TNF-alpha P=0.0005). The IL-3-induced secondary cytokine secretion is also different in the two growth pattern groups. Whereas in the IL-3-insensitive AML cells a moderate increase of IL-1beta (1.48-fold increase) was present, in the IL-3-sensitive AML cells a 4.72-fold increase of IL-1beta 2.71-fold increase of IL-6 and 11.81-fold increase of the TNF-alpha titre could be detected. Overall, the data show an inverse correlation between the ability of AML cells to respond to IL-3 with increase of an S-phase and the constitutive secretion of IL-1beta, II-6 and TNF-alpha. A further effect of IL-3 is the induction of secondary cytokine secretion in the bone marrow of IL-3-sensitive growing AML cells.
OBJECTIVE: We investigated the pharmacologic properties of midazolam with special regard to age using the electroencephalogram (EEG) as a measure of the hypnotic-sedative effect. METHODS: Nine younger (24 to 28 years) and nine elderly (67 to 81 years) male volunteers received midazolam by a computer-controlled device. Two infusion cycles with linearly increasing target plasma levels (slope, 40 ng/mL/min for the younger subjects; 20 ng/mL/min for the elderly subjects) were administered until defined end points were attained (median EEG frequency <4 Hz and loss of responsiveness to acoustic stimuli). An EEG was recorded to quantitate the hypnotic effect, relating the median frequency of the power spectrum to the plasma level by a sigmoid Emax model, including an effect compartment. Pharmacokinetic data were derived from arterial blood samples with use of a three-compartment model. RESULTS: The total doses needed to reach the defined end points were 71+/-9 mg and 35+/-6 mg for the younger and elderly subjects, respectively (P < .001). Pharmacokinetic parameters were similar in both groups (clearance, 399+/-91 and 388+/-97 mL/min; steady-state volume of distribution, 85+/-22 and 104 +/-11 L in young and elderly subjects, respectively). Pharmacodynamic data showed a large difference in half-maximum concentration (EC50; young subjects, 522+/-236 ng/mL; elderly subjects, 223+/-56 ng/mL; P < .05), a steep concentration-response curve, and distinct hysteresis. We found much interindividual variability in the plasma concentrations necessary to achieve the clinical end points, regardless of age. CONCLUSIONS: These results suggest that the lower doses needed to reach sedation in the elderly subjects were attributable to a 50% decrease in EC50, not to changes in pharmacokinetics.
More than 400,000 deaths a year in the United States are attributed to active and passive tobacco smoke exposure. Healthy People 2000 objectives target a reduction in the tobacco use of high-risk populations such as youth and pregnant women. This article describes guidelines for health professionals to address smoking cessation when working with pregnant adolescents and teen mothers who smoke.
Especially for medical disciplines like anesthesiology, which represent only a small economic market, drug development is a cost intensive and with respect to financial aspects a high risk task. This situation requires methods, which in the early stages of the drug development process of an interesting compound allow the establishment of a reliable and valid data set, in order to make decisions on the continuation or discontinuation of a project. Given a compound out of the group of benzodiazepines as an example this paper represents todays methods of integrated pharmacokinetic-pharmacodynamic modelling as well as the special computer aided strategies of drug dosing as powerful tools in the anaesthetic drug development process. It is shown that one can generate data concerning differences in drug requirement and drug duration in the therapeutic dose range between different groups of possible patients, e.g. young and elderly, as early as the early phase II. It is concluded that these clinical pharmacological tools and the high resolution data generated by them facilitate the Go/No-Go decision to proceed to phase III and enhance the likelihood of passing phase III successfully.
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An in vitro model consisting of endothelium grown on collagen was used to investigate how mononuclear phagocytes traverse endothelium in the basal-to-apical direction (reverse transmigration), a process that mimics their migration across vascular and/or lymphatic endothelium during atherosclerosis and resolution of inflammation, respectively. Monoclonal antibody (MoAb) VIC7 against tissue factor (TF) inhibited reverse transmigration by 77%. Recombinant tissue factor fragments containing at least six amino acids C-terminal to residue 202 also strongly inhibited reverse transmigration. TF was absent on resting monocytes but was induced on these cells after initial apical-to-basal transendothelial migration. Two additional observations suggest that TF is involved in adhesion between mononuclear phagocytes and endothelium: (1) when monocytes were incubated with lipopolysaccharide (LPS) to stimulate expression of TF before they were added to endothelium, VIC7 or soluble TF modestly inhibited their adhesion to the apical endothelial surface, each by about 35%; and (2) endothelial cells specifically bound to surfaces coated with TF fragments containing amino acids 202-219. This binding was blocked by anti-TF MoAb, suggesting that endothelial cells bear a receptor for TF. These data suggest that mononuclear phagocytes use TF, perhaps as an adhesive protein, to exit sites of inflammation.
A physiological gradient in intracellular calcium ([Ca2+]i) has been hypothesized to exist along the colonic crypt base-mouth axis, which may be involved in the regulation of colonocyte proliferation, differentiation and apoptosis. In addition [Ca2+]i may be modulated by dietary vitamin D3 which is thought to be protective against colorectal cancer. CF1 mice were maintained for 6 weeks on a defined diet containing either high or low vitamin D3. A colonic crypt base-mouth [Ca2+]i gradient of 201 +/- 79 nM (mean +/- SEM, P < 0.05) was observed in animals maintained on a high vitamin D3 diet and was abolished in mice maintained on a low vitamin D3 diet. The [Ca2+]i gradient was independent of extracellular calcium and elevated levels of [Ca2+]i observed in the basal regions of the crypt in animals maintained on low levels of vitamin D3 were also associated with an increase in intracellular calcium stores. Therefore, a [Ca2+]i gradient exists in colonic crypts and is dependent on dietary vitamin D3.
UNLABELLED: In Germany a TCI-system for propofol (Disoprifusor-TCI) has been commercially available since spring 1997. We investigated the prediction error and precision of this TCI system as part of a multicentre study. Bias, precision, blood concentrations and dosage of propofol were compared with patients receiving propofol via a manually controlled infusion device. METHODS: After approval by the local Ethics Committee and written informed consent, 21 patients of ASA-classification I to III scheduled for major abdominal surgery received either a target controlled infusion (group T, Disoprifusor-TCI) or a manually controlled infusion (group M) of propofol. The propofol plasma concentrations were measured by HPLC. The prediction error for each measurement, the median prediction error (MDPE) or bias, the median absolute prediction error (MDAPE) or precision and the divergence (change of the prediction error over infusion time) were calculated for both groups. RESULTS: For all patients in group T (n = 12) the bias of the TCI system was 6.7% and the precision 27.5%. For 70% of all measured plasma concentrations the absolute prediction error was < or = 37%. The divergence was -5.4% per hour. For all patients in group M (n = 9) the bias was 44.2% and the precision 50%. The mean amount of propofol infused per kilogram body weight and hour was significant higher in T (9.0 +/- 1.2 mg/kg/h) than in M (6.6 +/- 1.2 mg/kg/h, p < 0.005). CONCLUSIONS: With a precision of 27.5% the investigated TCI system (Diprifusor-TCI) showed an acceptable inaccuracy, as for TCI-systems a median prediction error of +/- 30% has to be expected due to the inherent variability of pharmacokinetic parameters. Further studies will be necessary to find out whether the investigated TCI system for propofol may offer substantial advantages.
Basing on electrophysiological data measured by us we studied the course of the radial nerve or its motoric branches with regard to anatomically conditioned bony contractions and their possible significance for pain experienced at the radial epicondyle of humerus, the pain being known under several synonymous designations. To differentiate between the various pathomechanisms discussed in the literature, we performed longitudinal and transversal dissections on a total of 40 cadaveric arms. We found as constant variations to the topographic anatomy published in the standard literature a regularly extended and (in relation to the other muscles we examined) exposed course of the nerve branch proceeding towards the m. extensor carpi radialis brevis. As the only long wrist extensor muscle this is innervated in most cases from the superficial end branch of the radial nerve. The origin of the muscle projected regularly over the common aponeurosis of the extensor tendon and delimitated in most of the preparations the distal end of the tunnel of the deep radial nerve. Since the deep radial branch and the muscular branches parallel to that branch cross this part of the tendon at an obtuse angle we believe that the repeatedly discussed possibility of a dynamic nerve compression without structural influences is the triggering mechanism for the observed nerve damage.
A number of authors assumed a compression syndrome of the radial nerve or its branches to be responsible for the heterogenous classified picture of radiohumeral epicondylopathy. Various structural and functional stenoses have been discussed as possible causes. We performed electromyographies on the extensor muscles, subdividing from the radial epicondyle and found significant (p < 0.05) changes in 27/51 patients regarding latency, velocity of neural conduction and rate of polyphasic potentials. Especially affected were the extensor carpi radialis brevis and extensor digitorum muscle. These findings were confirmed by torque measurements and histologic observations from both muscular and tendon biopsies. In summary, we believe the model of a neurogenous origin of radio-humeral epicondylopathy to be an appropriate explanation.
This article describes preliminary findings of an experimental, randomized, three-group, controlled design examining the effectiveness of a smoking cessation intervention for pregnant teens. The three groups are: Teen FreshStart with a buddy program (TFSB), a Teen FreshStart program (TFS) without peer support, and the Usual Care (UC) control group. Forty-six subjects completed the post-intervention assessment of smoking status. The TFSB group consistently achieved greater smoking cessation across all measures when compared to the subjects in the other two groups. These results indicate that the use of peer support may be an effective adjunct in smoking cessation programs for pregnant adolescents.