[Functional and aesthetic therapy concepts of keloids in the head- and neck area]. / Funktionelle und ästhetische Therapiekonzepte von Keloiden im Kopf-Hals Bereich.

Keloids are fibroproliferative extreme variants of an impaired wound healing, developing a tumour-like growth. In the ENT area keloids arise mainly at auricle. Often caused by piercings or trauma. They grow bulging excessively over the original scar edges and adopt sometimes bizarre morphologies. The patients complain often of dysesthesias such as burning pain, severe itching and are suffering often from stigmatization. The huge number of therapy methods, for the treatment of keloids described in the literature (silicon therapy, compression, intralesional corticoids, intra- or extralesional surgical excision, kryosurgery, radiatio, Interferon- or Bleomycin-therapy) emphasize the enormous challenge for the treating doctor, particularly in facial plastic surgery.

[Epithesial craniofacial reconstructions after mutilating surgery in head and neck cancer patients]. / Epithetische Wiederherstellungsmöglich-keiten nach mutilierenden onkologi-schen Eingriffen in der Kopf-Hals-Region.

The construction of facial prostheses is frequently used as a remedial treatment method in otorhinolaryngology. Modern prostheses are often attached to the face via bone anchored titanium implants and magnetic attachments. The use of specialised silicones and colouring techniques produces prostheses which realistically mimic lost facial tissues and significantly enhance patient quality of life. The article provides an overview of the possibilities of modern epithetics in the treatment of facial defects resulting from head and neck tumors.

Anticoagulative effects of the inhaled low molecular weight heparin certoparin in healthy subjects.

Inhalation of heparin results in local antiinflammatory and antifibrotic effects and an inhibition of blood coagulation. A number of experimental and clinical studies demonstrated that inhalant administration of heparin or low molecular weight heparin (LMWH) is a feasible and save tool for anticoagulative treatment. However, heparin and LMWH differ in respect to their molecular weight, pulmonary absorption, and principle of their anticoagulative pattern. In our study we investigated the anticoagulative effect of different doses of the LMWH certoparin after inhalation (3000 IU-9000 IU) and subcutaneous injection (3000 IU) in healthy individuals in a cross-over design. Inhalations were performed using a new device allowing inhalations with optimized and standardized breathing patterns. The anticoagulative effect was determined by measurement of the anti-factor-Xa (anti-FXa) activity. Lung function parameters were measured before and after drug inhalation. Analysis of the anti-FXa activity as a function of the time after administration revealed values of the area under the curve (AUC) of 5.70+/-1.58 U.hour/ml and 8.43+/-1.31 U.hour/ml (mean+/-SD) with interindividual coefficients of variation of 28% and 13% after injection of 3000 IU and inhalation of 9000 IU, respectively. The AUC after inhalation of 9000 IU was significantly higher (P=0.0007) compared with subcutaneous injection of 3000 IU. In consequence, in order to obtain plasma anti-FXa activities of above 0.2 U/ml, which is considered sufficient for prophylaxis of venous thrombosis, 9000 IU LMWH have to be inhaled. Compared with the subcutaneous administration, the action of certoparin is longer after inhalation than after injection. Apparently, the drug is released rapidly according to a two-compartment kinetics, and its anticoagulant activity lasts over a long time without a marked plasma peak after administration. In detail, an elevation of plasma anti-FXa activity is achieved for 12 hours to 24 hours without a distinct peak shortly after inhalation. Inhalation of LMWH does not result in any changes in lung function or other side effects. The administration of LMWH by inhalation bears the following: the non-invasive route of drug application, the low interindividual variability of the anticoagulative effect, and a long-time pharmacological effect. These properties suggest that controlled inhalation of heparin is an attractive alternative to subcutaneous administration.

Functional characteristics of leukotriene C4- and D4-metabolizing enzymes (gamma-glutamyl transpeptidase, dipeptidase) within human plasma.

Several properties of the leukotriene C4- and leukotriene D4-metabolizing enzymes within human plasma were studied after fractionation of the plasma proteins using ammonium sulfate precipitation. Leukotriene D4-metabolizing enzymes were widely distributed among the fractions obtained. They showed different pH optima (pH 6.5, pH 7.0 and pH greater than or equal to 8.5) and revealed a different degree of thermal stability. The results indicate the presence of more than one enzyme in plasma which interacts with leukotriene D4. EDTA and L-cysteine inhibited the metabolism of leukotriene D4. Two leukotriene C4-metabolizing activities (gamma-glutamyl transpeptidases) differing in their molecular weights were detected after gel filtration. Their molecular weights were estimated to be Mr greater than or equal to 150 000 and Mr between 55 000 and 100 000.

GTP-binding proteins in polymorphonuclear granulocytes of severely burned patients.

In order to study the biochemical mechanism underlying the cellular dysfunctions of polymorphonuclear granulocytes (PMNs) from severely burned patients, we analyzed the role of GTP-binding proteins (G-proteins) in PMNs from 11 burned patients. Our data demonstrate a significant enhancement of the basal GTPase activity within unstimulated neutrophils of severely burned patients compared to cells from healthy donors. This enhancement was significant within 4 weeks after the trauma, followed by a return to control levels. The increase in GTPase activity correlated with enhanced expression of the small G-protein Ras and the regulatory Ras-GTPase activating protein (Ras-GAP) compared to that in healthy donor cells. However, expression of the Ras-related protein Rap1, which is involved in initiation of the respiratory burst, was reduced. The observed changes in G-protein activity and expression impair the signal transduction cascade as well as bacterial killing and may lead to high susceptibility toward infections and finally to septic conditions.

Drug permeation through human skin: I. Effect of storage conditions of skin.

The purpose of this study was to establish conditions for the preparation and storage of excised human skin such that it most closely retained the permeation characteristics seen with skin samples studied immediately after having been removed from cadavers. Using skin taken from the inner thighs of cadavers within 48 hr post mortem, we have compared drug permeation through samples that were used immediately following removal with samples that had been stored in either the frozen or dried state. With the chromone acid under investigation, it was found that samples of stratum corneum attached to the underlying epidermis used without prior storage consistently showed less permeation than samples taken from the same individual that had been frozen at -17 degrees C upon removal and then thawed before permeation studies were started. However, drug permeation through samples of stratum corneum plus epidermis that had been allowed to dry under controlled humidity conditions at room temperature were found to be similar to those obtained with fresh skin. These results indicate that dried skin, when appropriately rehydrated before use, exhibits rates of drug permeation similar to those found with fresh skin. With the chromone acids under investigation, the use of frozen samples of excised skin should be avoided since the extent of permeation exceeds that obtained with fresh skin samples.

Treatment of acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the TOPAS trial. Therapy of Patients With Acute Stroke (TOPAS) Investigators.

BACKGROUND AND PURPOSE: To study the safety and efficacy of the low-molecular-weight heparin certoparin, we performed a randomized, double-blind, dose-finding multicenter trial in patients with acute ischemic stroke (Therapy of Patients With Acute Stroke [TOPAS]). METHODS: We randomized 404 patients to 4 treatment groups within 12 hours of stroke onset: 3000 U anti-factor Xa (aXa) certoparin once daily (treatment group 1); 3000 U aXa twice daily (group 2); 5000 U aXa twice daily (group 3); and 8000 U aXa twice daily (group 4). The primary efficacy variable was the proportion of patients reaching a favorable functional outcome (Barthel Index >/=90 points) at 3 months. CT was performed at trial entry, after 7 days, and on clinical deterioration. RESULTS: The proportion of patients with Barthel Index >/=90 was not different between treatment arms (61.5%, 60.8%, 63.3%, and 56.3% in the 4 groups, respectively; intent-to-treat population). European Stroke Scale scores improved in all treatment groups within the first 14 days to a similar extent. During the follow-up of 6 months, percentages of patients with recurrent stroke/transient ischemic attack were 11.0%, 5.9%, 9.7%, and 13.0% in the 4 groups, respectively. Overall mortality was only 7.4%. Two parenchymal cerebral hematomas and 1 extracranial bleeding episode occurred in treatment group 1 versus 1 and 0 in group 2, 2 and 0 in group 3, and 4 and 5 in group 4, respectively. During certoparin treatment, 1 deep vein thrombosis but no pulmonary embolism was observed. CONCLUSIONS: Dose increase of certoparin up to 8000 U aXa twice daily did not improve the functional outcome of patients with ischemic stroke. Severe bleeding tended to be more frequent in the highest dose group only.

Signal Transduction and Priming of Human Neutrophils.

Preincubation of human polymorphonuclear neutrophils (PMN) with diverse cytokines for 15 s enhanced the subsequent formyl-Met-Leu-Phe (FMLP)- induced leukotriene (LT) generation. These results correlated with a significant enhanced GTPase activity and an additive actin polymerization. Preincubation with genistein, an inhibitor of tyrosine kinases, inhibited LT formation as well as GTPase activities. Incubation with IL-3 or 11-3 and FMLP led to a shift in [35S]-γ-GTP binding to microsomal proteins as compared to unstimulated or FMLP-stimulated PMN. These results suggest a fundamental role of low molecular weight GTP-binding proteins and tyrosine kinases for cellular activation.

GTPases and Low Molecular Weight G Proteins during Cell-Cell Interaction between Neutrophils and Platelets.

The involvement of low molecular weight G proteins (LMWG) was determined during cell-cell interaction between human neutrophils and platelets. α-[32P]-GTP binding revealed an enhanced expression of an 18-kD band and a diminished band at 21 kD derived from platelets after coincubation of both cell types. Coincubation of the cells did not show any effect on the expression of rap2, whereas rapl was enhanced. The subadditive GTPase activity after coincubation of PMN and platelets could be due to some extent to the diminished expression of the ras protein. The presented data suggest an important role of the LMWG during cell-cell interaction between PMN and platelets.

Multiple effects of ethylmercurithiosalicylate on the metabolization of arachidonic acid by human neutrophils.

The effects of ethylmercurithiosalicylate (thimerosal) on the transformation of arachidonic acid via the 5-lipoxygenase pathway in human leukocytes stimulated with the Ca-ionophore A23187 were studied. Thimerosal inhibited acyltransferase, 5-lipoxygenase and the omega-oxidation system of LTB4 in a concentration-dependent fashion which was characteristic for the individual metabolites. LTA4 hydrolase activity was not affected. The inhibitory effects of thimerosal occurred instantaneously. The effects of the drug were not influenced by the concentration of the stimulus Ca-ionophore A23187.

Heat shock induces alterations of the lipoxygenase pathway in human polymorphonuclear granulocytes.

We have investigated the effect of the heat shock response on the leukotriene generation, chemotaxis, and generation of oxygen radicals of human polymorphonuclear granulocytes (PMNs) by preincubating the PMNs at 42 degrees C. Subsequently, the different test systems were performed at 37 degrees C. As we confirmed by the release of lactate dehydrogenase and beta-glucuronidase the elevated temperatures did not result in cytotoxic or degranulating processes. After heat shock treatment the generation of leukotrienes induced by the Ca(++)-ionophore A23187, fMLP or opsonized zymosan was inhibited in a time and temperature dependent manner (preincubation phase) as was measured by HPLC-analysis. In contrast, the conversion of 14C-arachidonic acid revealed the generation of LTB4, 5-HPETE and 5-HETE solely as a result of the preincubation at 42 degrees C without any further stimulation. In addition, the chemiluminescence response induced by opsonized zymosan and the chemotaxis against C5a and LTB4 was clearly inhibited after heat shock treatment. With regard to enzyme activities of the heat treated PMNs the protein kinase C activities were enhanced whereas the LTD4-dipeptidase and the LTB4-omega-hydroxylase were not affected.

Decreased expression of leukotriene B4 receptor sites on polymorphonuclear granulocytes of severely burned patients.

Polymorphonuclear granulocytes were isolated from patients with burn injury and the specific binding of (3H)leukotriene B4 was assessed. We observed a decreased receptor expression as compared to healthy donor cells, which may be the result of receptor downregulation as a consequence of cellular preactivation. In addition, leukotriene B4-synthesis was also reduced and differential cell counts demonstrated a shift from segmented neutrophils to immature cells. In survivors the values returned to normal parameters whereas nonsurvivors who succumbed in the course of generalized sepsis showed depressed cellular functions up to their death.

Prior cytomegalovirus, Chlamydia pneumoniae or Helicobacter pylori infection and the risk of restenosis after percutaneous transluminal coronary angioplasty.

We investigated a possible correlation between the serologic status concerning Cytomegalovirus (CMV), Chlamydia pneumoniae (CP) and Helicobacter pylori (HP) and the occurrence of restenosis in patients undergoing percutaneous transluminal coronary angioplasty for symptomatic coronary artery disease. Tests for anti-CMV IgG, anti-Chlamydia pneumoniae IgG and IgA and HP IgG and IgA were performed with an enzyme-linked immunosorbent assay (ELISA). Restenosis was defined as >/=50% stenosis at follow-up angiography in a vessel with less than 50% stenosis immediately after PTCA. Of 148 patients, 112 (75.7%) were seropositive for CMV, 75 (50.7%) were seropositive for CP and 78 (52.7%) were seropositive for HP. Restenosis occured in 31.8% of patients. CMV seropositivity was established in 74.5% of patients with restenosis versus 76.2% without restenosis (P=0.82), CP seropositivity was established in 44. 7% of patients with restenosis versus 53.5% without restenosis (P=0. 32), HP seropositivity was established in 53.2% of patients with restenosis versus 52.5% without restenosis (P=0.94). In contrast to some earlier studies CMV or HP seropositivity could not be found to be associated with the risk of restenosis after coronary intervention. An association between the serological status of CP and restenosis could also not be established.

Drug permeation through human skin II: Permeability of ionizable compounds.

The aim of this study was to establish whether ionized as well as un-ionized forms of certain 4-oxo-4H-1-benzopyran-2-carboxylic acids (chromone-2-carboxylic acids) with pKa values less than 2 permeated through excised human skin and, if so, to determine the permeability coefficients of the permeating species. The permeation properties of four carboxylic acids were studied as a function of concentration over the pH range 5-7 at 37 degrees C with plexiglass diffusion cells. Plots of J/CA- (the total flux due to un-ionized and ionized species obtained under steady-state conditions per unit concentration of ionized drug in the donor compartment) against CH3O+ resulted in straight-line relationships. The intercepts of these plots were shown to equal PA-, whereas the slopes multiplied by the Ka values of the compounds equalled PHA, the permeability coefficients of the ionized and un-ionized species, respectively. With all four compounds, both species were found to permeate skin, although the permeability coefficients of the un-ionized species were approximately 10(4) greater than those for the ionized species. It was demonstrated that the relative contributions of the ionized and un-ionized species to the total flux, as well as the total flux, vary significantly, depending on the pH of the drug solution in the donor cell. This may provide a means of controlling the flux of these and similar compounds through human skin.

Influence of low molecular weight heparin (certoparin) and unfractionated heparin on the release of cytokines from human leukocytes.

We analyzed the influence of heparins (unfractionated heparin, UFH and low molecular weight heparin certoparin) on the generation of IL-1ra, IL-6, IL-10, and IL-12p40 and from leukocyte fractions in vitro. Polymorphonuclear neutrophil leukocytes (PMN) and peripheral blood mononuclear cells (PBMC) from 16 different healthy donors were isolated and adjusted to 1 x 10(6) cells/ml supplemented RPMI 1640. Leukocyte fractions were differentially stimulated (PMN with 1 microg and 5 microg LPS, PBMC with 10 ng TSST- 1 or 2 microg ConA) in the presence or absence of heparins (1 U/ml, 2 U/ml, and 4 U/ml) for 24 h at 37 degrees C. Cytokine release was analyzed by ELISA. Certoparin but not UFH led to a dose-dependent increase in IL-6 from non-stimulated PBMC. In contrast, the release of IL-1ra, IL-10, and IL-12p40 was not modulated by heparins in a dose-dependent fashion. Increases in these cytokines occurred only as single incidents at intermediate heparin levels. An influence of the heparins on the apoptosis of PMN (measured as DNA-fragmentation in non-stimulated or LPS-stimulated cell-fractions) was not observed.

Expression of the adhesion molecule CD11b and polymerization of actin by polymorphonuclear granulocytes of patients endangered by sepsis.

The integrin CD11b is an important adhesion molecule mediating the transendothelial migration of circulating polymorphonuclear granulocytes into an inflammatory region. The expression of CD11b is closely related to the ability to polymerize actin, a major component of the cytoskeleton within the phagocyte. In this study we compared the CD11b expression as well as the polymerization of actin of isolated neutrophils from patients endangered by sepsis with cells from healthy donors. The patient population was subdivided into a group of patients with severe thermal injuries and a group of patients who were admitted to an intensive care unit on suspicion of sepsis. The following results were obtained: (1) cells from burn patients, but not from non-burn patients, showed a reduced basal expression of CD11b during the first week after the burn trauma; (2) stimulation with the chemotactic peptide formyl-Met-Leu-Phe (FMLP) led to a strong overexpression of CD11b on the cells from the burn patients, this effect was not observed using cells of the second subgroup; (3) the content of polymerized actin was reduced within resting and stimulated cells from burn patients during the first 2 weeks postinjury, non-burn patient cells showed an enhanced F-actin content within the first week; (4) the ability of burn and non-burn patient cells to polymerize actin after stimulation with FMLP was slightly impaired during the first week post injury/admission. The results demonstrate that cells from patients endangered by sepsis show dysfunctions on the level of adhesion molecule expression and the strongly related actin polymerization.(ABSTRACT TRUNCATED AT 250 WORDS)