Solution structure of acidic fibroblast growth factor bound to 1,3, 6-naphthalenetrisulfonate: a minimal model for the anti-tumoral action of suramins and suradistas

Recent data show that anti-angiogenesis may provide a promising route to treat cancer. Fibroblast growth factors (FGFs) are powerful angiogenic polypeptides, whose mitogenic activity requires the presence of heparin-like compounds. It has been shown that angiogenesis promoted by FGFs on inhibition by monoclonal antibodies and antisense targeting can also inhibit tumour growth. Derivatives of suramin, a polysulfonated binaphthyl urea and binaphthylsulfonated derivatives of distamycin, suradistas, constitute an important group of potential anti-cancer agents. These compounds compete with heparin in forming tight complexes with FGFs. This inhibits the recognition of these growth factors by their tyrosine kinase membrane receptors thereby suppressing their angiogenic activity. Here we show that 1,3,6-naphthalenetrisulfonate, a common chemical function of the suramins and suradistas with the highest anti-angiogenic activity inhibits the mitogenic activity of acidic fibroblast growth factor, and that this inhibition is relieved by increasing concentrations of heparin in the assay. We have also solved the three-dimensional structure in solution of the protein complexed to this compound. The structural data provide clues that may help in understanding the inhibitory effect of suramins and suradistas, and could contribute to the development of new anti-tumoral drugs.     

Mitochondrial creatine kinase is a prime target of peroxynitrite-induced modification and inactivation

The reaction of peroxynitrite (PN) with sarcomeric mitochondrial creatine kinase (Mib-CK; EC 2.7.3.2) was observed at different stages of complexity (i) with purified Mi-CK, (ii) with enzyme bound on isolated mitoplasts, and (iii) within intact respiring mitochondria. Creatine-stimulated respiration was abolished by PN concentrations likely to be physiological and far before the respiratory chain itself was affected, thus demonstrating that Mi-CK is a prime target for inactivation by PN in intact mitochondria. The inactivation by PN of Mi-CK was reversed by 22% with 2-mercaptoethanol. More remarkable protective effects were noticed with the full set of CK substrates, e.g. 30 and 50% protection with MgATP plus creatine and MgADP plus phosphocreatine, respectively, but not with each substrate alone. These data indicate an involvement of the active-site Cys-278 residue of Mi-CK in this process. Furthermore, changes in endogenous tryptophan fluorescence intensity and spectral changes after reaction of Mi-CK with PN suggest additional modifications of Trp and Tyr residues. PN-inactivated Mi-CK can no longer be efficiently converted into dimers by incubation with reagents inducing a transition state analog complex at the active site. Thus, obviously, upon reaction of octameric Mi-CK with PN, the octamer-dimer equilibrium of Mi-CK is also affected. The consequences for cellular energy homeostasis and calcium handling are discussed.     

Augmentation techniques: are they out?

Basics of ligament augmentation are reviewed from the literature. As biomechanical in-vitro studies, animal experiments, and clinical studies show different designs and data, the results may be interpreted variably. Theoretically there is a positive effect of augmentation, but no significant improvement of clinical results is evident. The goal of our own prospective study was to check the healing capacity of a repaired and augmented ACL with respect to stability compared to a primary or secondary BTB ligament replacement with and without augmentation. 200 patients were allocated to 4 groups. In group I (G1) acute proximal ruptures were repaired arthroscopically and augmented with PDS II-cord. Patients in G2 received an acute and in G3 a late BTB ligament replacement. Additionally in G4 a late ligament replacement was augmented with a PDS II-cord. The clinical results reveal a comparative stability between G1 and G2, and gradually less stability in G3 and G4. Subjectively, knee function was felt best in G1 and G2 while being worst in G3 and G4. There is no significant difference in the mobility of knees between primary and secondary ligament replacement. An additional augmentation doesn't improve the knee stability. CLINICAL RELEVANCE: There is no positive effect of an augmentation technique of a biologic ligament replacement concerning stability, morbidity, complication rate, and costs. Very marginal freshly ruptured cruciate ligaments may be reinserted successfully by a biodegradable augmentation. Subjective feeling and functional stability may be at least equal to a primary ligament replacement. There are no advantages in knee mobility, when a secondary ligament replacement is performed.     

Effects of the 5-HT2 receptor antagonist ritanserin on halothane-induced increase of inositol phosphates in porcine malignant hyperthermia

Recent studies have shown a significant increase of inositol phosphates (IPs) in skeletal muscle during episodes of halothane-induced malignant hyperthermia (MH) in pigs. After treatment with dantrolene and disappearance of MH crisis the IP concentrations returned to basal levels. In order to examine if the increase of IPs during halothane-induced MH may be related to an enhanced IP synthesis in response to activation of 5-HT2 (5-hydroxytryptamine) receptors, the effects of ritanserin, a selective 5-HT2 receptor antagonist, on IP levels were investigated. Biopsies of skeletal muscle of the hindlimbs were obtained in random order and IPs were determined in homozygous MH-susceptible (MHS) and MH-non-susceptible (MHN) swine in the following order: (1) basal, (2) after treatment with ritanserin (2.0 mg/kg), (3) after halothane challenge (3 vol% for 20 min). Basal concentrations of all IPs were higher in MHS than in MHN swine. Ritanserin did not cause any significant changes of IP levels compared to the basal concentrations in MHS and MHN pigs. In MHS pigs, ritanserin did not prevent a halothane-induced MH-crisis. After halothane challenge, 1,3,4-IP3, 1,3,4,6-IP4 and 1,3,4,5-IP4 levels were increased in MHS (during MH crisis) vs. basal concentrations, whereas no changes were found in MHN pigs. Since the increases of IP levels in MHS pigs during MH crisis found in the present study were comparable to those without pretreatment with ritanserin, shown by recent studies, it may be concluded that ritanserin does not prevent the increase of IPs during a halothane-induced MH. Thus, the present data indicate that increases of IP levels during halothane-induced MH in swine are due to other mechanisms than 5-HT mediated enhancement of IP synthesis.     

Support for school-based sexuality education among South Carolina voters

A random-digit dialed telephone survey was conducted in a traditionally conservative southern state to determine the level of support for sexuality education in the public schools including support for specific sexuality education topics, the earliest grade level at which each topic should be taught, and the amount of instruction time required for sexuality education in the high schools. Survey data were obtained from 534 South Carolina registered voters in late January/early February 1997. Results demonstrated that most South Carolina registered voters: 1) supported sexuality education in the public schools; 2) supported instruction on a variety of sexuality education topics; 3) supported instruction at all grade levels, especially beginning in middle school; and 4) believed instruction time for sexuality education in the high schools should either remain the same or be increased. In addition, a significant increase in support for sexuality education occurred from the beginning of the survey to the end, suggesting that the instrument itself may have served as an educational tool for respondents. The characteristics of registered voters who supported sexuality education at the beginning of the survey and at the end were examined and compared. These results may assist in the development of educational and marketing strategies designed to build support for school-based sexuality education programs in South Carolina and elsewhere.     

Ein neuer Weg zur quantitativen Erfassung der Vorgänge beim kontrollierten Walzen

Qualitative Ableitung der Größe ?addierte Endverformung“ und ihre quantitative Beschreibung über temperaturabhängige Additionskoeffizienten. Vorausberechnung von Streckgrenze und Festigkeit aus dem Stichplan. Berechnung eines Übergangspunktes der Kristallinität und hieraus Konstruktion der Kerbschlagzähigkeitskurve.