Tarsal osteotomies in the childs foot

Ohne Zusammenfassung     

Interaction of a plasminogen activator proteinase, LV-PA with human alpha2-macroglobulin.

Lachesis venom plasminogen activator (LV-PA) is a 33-kDa serine proteinase isolated from bushmaster (Lachesis muta muta) snake venom, which activates the fibrinolytic system in vitro. This study has examined the effect of the plasma proteinase inhibitor alpha2-macroglobulin (alpha2-M) towards LV-PA and compares it with the effect on tissue type plasminogen activator (t-PA). The proteolytic activity of LV-PA alone or previously incubated with human plasminogen (Plg) on the large molecular mass protein substrates, dimethylcasein (DMC) and fibrinogen (Fg) was completely inhibited by human alpha2-M. However, the synthetic peptides Tos-Gly-Pro-Lys-pNA and H-D-Pro-Phe-Arg-pNA (S-2302) were hydrolyzed with almost no reduction in rate. At pH 7.4 and 37 degrees C the proteinase (0.15 microM over 15 min) interacted with alpha2-M, and each mole of alpha2-M bound 2 mol of enzyme. Sodium dodecyl sulfate gel electrophoresis of reduced samples showed that the interaction of alpha2-M with either LV-PA or t-PA preincubated with Plg resulted in the formation of approximately 90 kDa fragments and high molecular mass complexes (Mr 180 kDa), generated by the incubation mixture (LV-PA or t-PA) and Plg. The data suggest that LV-PA is a direct-type PA and its fibrinolytic effect can be reduced by alpha2-M in vivo.     

Dolastatin 10, a powerful cytostatic peptide derived from a marine animal. Inhibition of tubulin polymerization mediated through the vinca alkaloid binding domain

Dolastatin 10, a cytostatic peptide containing several unique amino acid subunits, was isolated from the marine shell-less mollusk Dolabella auricularia (Pettit GR, Kamano Y, Herald CL, Tuinman AA, Boettner FE, Kizu H, Schmidt JM, Baczynskyj L, Tomer KB and Bontems RJ, J Am Chem Soc 109: 6883-6885, 1987). Since our preliminary studies demonstrated that dolastatin 10 inhibited tubulin polymerization and the binding of radiolabeled vinblastine to tubulin, an initial characterization of the properties of dolastatin 10 included a comparison to other antimitotic drugs interfering with vinca alkaloid binding to tubulin (vinblastine, maytansine, rhizoxin, and phomopsin A). Dolastatin 10 inhibited the growth of L1210 murine leukemia cells in culture, with a concordant rise in the mitotic index, and its IC50 value for cell growth was 0.5 nM. Comparable values for the other drugs were 0.5 nM for maytansine, 1 nM for rhizoxin, 20 nM for vinblastine, and 7 microM for phomopsin A. IC50 values were also obtained for the polymerization of purified tubulin in glutamate: 1.2 microM for dolastatin 10, 1.4 microM for phomopsin A, 1.5 microM for vinblastine, 3.5 microM for maytansine, and 6.8 microM for rhizoxin. Dolastatin 10 and vinblastine were comparable in their effects on microtubule assembly dependent on microtubule-associated proteins. Preliminary studies indicated that dolastatin 10, like vinblastine, causes formation of a cold-stable tubulin aggregate at higher drug concentrations. We confirmed that rhizoxin, phomopsin A, and maytansine also inhibit the binding of radiolabeled vinblastine and vincristine to tubulin. Dolastatin 10 and phomopsin A were the strongest inhibitors of these reactions, and rhizoxin the weakest. Dolastatin 10, phomopsin A, maytansine, vinblastine, and rhizoxin all inhibited tubulin-dependent GTP hydrolysis. The greatest inhibition of hydrolysis was observed with dolastatin 10 and phomopsin A, and the least inhibition with rhizoxin.     

Suicidal attempts and ideations among adolescents and young adults: the contribution of the father's and mother's care and of parental separation

Summary Parental care was analyzed separately with the PBI for both father and mother or their surrogate to assess its association with suicidal behavior (attempt or serious ideation). The study was conducted on two French-speaking samples from Montreal: the first included 2,327 high school students and the second 701 young adults (18 to 24) reached by phone. Results showed poor care of father to be highly associated with suicidal behavior in the highschool group. Poor care of the mother and parental divorce obtained a lower association. In the second sample, only poor care of the father was significantly associated with suicidal behavior. The conclusion is that more attention should be focused on the father and that parental divorce may have a short-term effect but not a lasting influence when poor care is absent.     

Increase in brain cerebrospinal fluid volume is greater in older than in younger alcoholic patients: A replication study and CT/MRI comparison

This cross-sectional study used a semi-automated analysis technique to quantify regional brain cerebrospinal fluid (CSF) volumes derived from computed tomography (CT) in 84 healthy men ranging from 21 to 82 years of age and 28 patients meeting Research Diagnostic Criteria for alcohol dependence. The goals were to replicate an earlier CT study of an independent sample of alcoholic and control subjects (Pfefferbaum et al., 1988a; Zipursky et al., 1988) and to compare CT assessments of brain changes with magnetic resonance imaging (MRI) assessments made in the same alcoholic patients (Pfefferbaum et al., 1992). Regional brain changes associated with normal aging were derived by regression analysis, using CT data collected from the healthy control subjects. As in the earlier CT study and in the concurrent MRI study, ventricular and sulcal CSF volumes in alcoholic patients were greater than would be expected for their age. Furthermore, the present CT study replicated the previous CT and MRI findings of a positive relationship between age and CSF volume enlargement in alcoholic patients over and above the normal age-related increase in CSF volume, suggesting greater vulnerability of the aging brain to alcohol. Comparison of CT-and MRI-derived estimates of ventricular and cortical sulcal volume revealed high correlations (>0.80). MRI and CT produced similar absolute ventricular volumes, while MRI produced larger sulcal volume estimates than did CT. The difference in sulcal volume estimate may be due to differences between CT and MRI in slice thickness and sensitivity to partial volume effects.     

A simple mechanical model using a piston to produce localized cerebral contusions in pigs

Summary A simple mechanical model using a piston to produce localized cerebral contusions in pigs, is presented.The precision and reproducibility of the method are described by the biomechanical and pathological results.There are only pathological changes with haemorrhage and laceration close to the place of entry of the piston. The changes in the physiological parameters also indicate that the damage is focal.In this model, when kept intact, the dura mater offers considerable protection as no pathological changes in the brain are observed even when the energy at the time of the contusion is increased to twice the values which, when the dura is open, cause considerable damage.     

Structure-activity studies with chiral isomers and with segments of the antimitotic marine peptide dolastatin 10

Eighteen configurational isomers of the antimitotic peptide dolastatin 10 (Bai et al., Biochem Pharmacol 39: 1941-1949, 1990) derived from Dolabella auricularia, together with segments obtained as precursors in its synthesis (Pettit et al., J Am Chem Soc 111: 5463-5465, 1989), were examined as inhibitors of tubulin polymerization and as inhibitors of growth of L1210 murine leukemia cells in culture. Dolastatin 10 consists of four amino acids (in order from the amino terminus: dolavaline, valine, dolaisoleucine, and dolaproine), three unique to D. auricularia, linked to an unusual primary amine (dolaphenine, probably derived from phenylalanine) at what would otherwise be its carboxyl terminus. Dolastatin 10 has nine asymmetric carbon atoms, and available isomers included alternate configurations at five positions (positions 9 and 10 in the dolaproine moiety and positions 18, 19 and 19a in the dolaisoleucine moiety). For tubulin polymerization, only alterations at positions 18 and 19 resulted in loss of inhibitory activity of the isomer. In addition, a tripeptide containing dolavaline, valine and dolaisoleucine with all asymmetric carbons identical configurationally to those in dolastatin 10 was found to be about 30% as effective as dolastatin 10 in inhibiting tubulin polymerization. Cytotoxic effects were much more sensitive to alterations in the dolastatin 10 structure. The only modification which did not lead to reduced cytotoxicity was reversal of configuration at position 19a in the dolaisoleucine moiety. Both this isomer and dolastatin 10 had IC50 values of less than 1 nM. Several other isomers had IC50 values with the L1210 cells in the range of 30-90 nM, but these did not correlate well with their inhibitory effects on tubulin polymerization. The tripeptide effective as an inhibitor of tubulin polymerization had no activity against the L1210 cells.