Stoff und Applikationsart beim Drogenkonsum Jugendlicher

Zusammenfassung In einer Stichprobe von 382 schweren Drogenkonsumenten wurden Art und Ausmass des Drogenkonsums unter Berücksichtigung der Applikationsart der Stoffe erfragt und die Angaben einer Faktorenanalyse unterworfen. Es bildeten sich drei Faktoren mit den Kurzbezeichnungen «intravenös applizierte illegale Drogen», «oral applizierte illegale Drogen» und «oral applizierte Medikamente». Dies weist darauf hin, dass sich «intravenös spritzen» von den übrigen Applikationsarten eindeutig unterscheidet und dass die Definitionen des Betäubungsmittelgesetzes ein starkes Kriterium für die Einstellung der Drogenkonsumenten den Stoffen gegenüber ist. Pharmakologische Gesichtspunkte und solche der subjektiven Wirkung der Stoffe erlangen daneben kaum sichtbare Bedeutung.

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Drugs and their modes of application — a factor analytic inquiry of drug abuse

Summary In a sample of 382 heavy users mode and extent of drug abuse were inquired. Factor analysis of the data gave three factors named i.v. applicated illegal drugs, oral applicated illegal drugs and oral applicated medicaments for short. Results show that attitudes of the drug users towards their drugs are strongly influenced by the mode of application and the definitions of the drug laws, whereas pharmacological aspects and subjective effects have hardly any demonstrable importance.

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Drogues et leurs modes d'application — une enquête concernant la consommation abusive de drogues utilisant l'analyse factorielle

Résumé Une enquête sur mode et quantité de l'abus de drogues a été faite dans un échantillon de 382 graves consommateurs de drogues. L'analyse factorielle des données mène à trois facteurs abbréviés: «drogues illégales appliquées i.v.», «drogues illégales appliquées per os» et «médicaments appliqués per os». En regardant ces résultats on peut dire que les attitudes des consommateurs envers les drogues sont tout d'abord influencées par la mode d'application et les définitions des lois concernant les narcotiques, pendant que des points de vue pharmacologiques et les effects subjectifs n'ont peu d'importance.

     

Electron microscopic localization of nitric oxide I synthase in the organ of Corti of the guinea pig

Nitric oxide synthase (NOS) activity has been detected previously in the mammalian cochlea at a light microscopic level. Here we present results of electron microscopic analysis for post-embedding immunoreactivity of neural-type NOS I in the cochlea of the guinea pig. Strong enzyme immunoreactivity was identified in the cytoplasm of inner and outer hair cells. Gold-labeled NOS I antibodies were mainly located in electron-dense areas of the cytoplasm, whereas electron-lucent regions of the receptor cells were nearly free from any immunoreactivity. In both types of hair cells anti-NOS I antibodies were also visible in the cuticular plates, hair bundles and nuclei. Further ultrastructural analysis revealed that the submembranous cisternae of the outer hair cells were nearly free from any reaction product, demonstrating that the whole cytoplasm of this hair cell was not immunoreactive. Other NOS I immunoreactivity was identified in the cuticular plates of the inner and outer pillar cells and in the cytoskeletal elements located in the apical parts of Deiter cells, forming the lamina reticularis or in cytoskeletal-containing regions in basal Deiter cells. Anti-NOS antibodies were visible in the nuclei of various cell types. Our findings suggest that nitric oxide produced by NO I synthase in the organ of Corti may act as a modulator of hair cell physiology during the processes of signal transduction with frequence selectivity.     

Alteration of loosely bound calcium in the guinea pig organ of Corti after treatment with diltiazem as calcium channel blocker

After oral administration of the organic calcium channel blocker diltiazem to guinea pigs for 7 days, calcium ions were precipitated with potassium antimonate in the cochleae. The spatial distribution of the precipitates was studied by energy-filtering transmission electron microscopy and the amount of the ultrastructural reaction products formed was determined semiquantitatively by an image processing system. Compared with untreated control ears, the number of the formed precipitates was reduced drastically in the inner hair cells after diltiazem treatment. In addition, electron microscopic analysis revealed that the number of calcium precipitates attached at the basolateral membrane of the outer hair cells was clearly reduced when compared with untreated control specimens. A large number of histochemical reaction products could be identified in the basilar membrane and were also observed in the untreated control specimens. The spatial distribution of the calcium precipitates in the lamina reticularis was not affected by diltiazem treatment and calcium precipitates could be identified within different cell membranes. The technique used was considered to be helpful for identifying calcium channels ultrastructurally in intact undissected tissues and to support light microscopic analyses and patch-clamp electrophysiological measurements.     

Use of electron spectroscopic imaging to determine element composition of the melanin granules in the stria vascularis of the guinea pig

Electron spectroscopic imaging (ESI) was used to analyze the element content of melanin granules in the stria vascularis seen in ultrathin sections of Spurr-embedded cochleae of the guinea pig. To determine element composition, ESI images were taken at different ionization edges, and non-specific background signals were subtracted digitally by an image processing system. The presence of calcium and nitrogen in the melanin granules could be demonstrated clearly. The calcium identified in the melanin granules was then compared with the spatial distributions of calcium binding sites after the application of an antimonate precipitation method, which was used to localize loosely bound calcium. Despite a high calcium concentration within the granules, only very small single scattered calcium precipitates could be detected between these structures as compared with the amount of calcium precipitates attached to the plasma membrane or located within the cell nuclei. The nearly complete absence of precipitates within the melanin granules after the application of antimonate suggests differences in calcium binding and mobility involved in various physiological processes of ion balance regulation within the stria vascularis. Received: 14 October 1997 / Accepted: 11 February 1998     

Evidence that Tamoxifen Preserves Bone Density in Late Postmenopausal Women with Breast Cancer

Tamoxifen, which is used for treating breast cancer, exhibits estrogenic and antiestrogenic characteristics, depending on the tissue. In the human breast it acts as an antiestrogen, whereas estrogenic effects have been reported on endometrium and bone. The purpose of this study was to determine whether tamoxifen (TAM) prevents bone loss in elderly, postmenopausal women. Bone mineral density of the lumbar spine (SBD) was measured in elderly women (at least 10 years after menopause) 5 years after stage I or II breast cancer (n=111). The results showed that SBD in untreated patients (n=74) was significantly lower (p0.05) than SBD in patients (n=37) treated with TAM over 5 years. In a subgroup of patients (n=24) with positive estrogen receptor status, changes in SBD 12 months after discontinuation of 5-year TAM therapy were measured and compared with the changes of extended TAM treatment over a sixth year. Twelve months after withdrawal of 5-year TAM medication (n     

Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium Study B2225.

PURPOSE: The cutaneous malignant tumor dermatofibrosarcoma protuberans (DFSP) is typically associated with a translocation between chromosomes 17 and 22 that places the platelet-derived growth factor-B (PDGFB) under the control of the collagen 1A1 promoter. The purpose of this study was to evaluate molecular, cytogenetic, and kinase activation profiles in a series of DFSPs and to determine whether these biologic parameters are correlated with the clinical responses of DFSP to imatinib. PATIENTS AND METHODS: We analyzed the objective radiologic and clinical response to imatinib at 400 mg twice daily in eight patients with locally advanced DFSP and two patients with metastatic disease. RESULTS: Each of eight patients with locally advanced DFSP had evidence of t(17;22) and showed a clinical response to imatinib. Four of these patients had complete clinical responses. The two patients with metastatic disease had fibrosarcomatous histology and karyotypes that were substantially more complex than those typically associated with localized DFSP. One patient with metastatic DFSP and an associated t(17;22) had a partial response to imatinib but experienced disease progression after 7 months of therapy. In contrast, the other patient with metastatic disease had a tumor lacking t(17;22), and there was no clinical response to imatinib. Unexpectedly, there was minimal platelet-derived growth factor receptor-beta phosphorylation in the untreated DFSP, despite the documented presence of a PDGFB autocrine mechanism. CONCLUSION: Imatinib has clinical activity against both localized and metastatic DFSP with t(17;22). However, fibrosarcomatous variants of DFSP lacking t(17;22) may not respond to imatinib.     

Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred.

PURPOSE: Members of a family with hereditary gastrointestinal stromal tumors (GISTs) and a germline KIT oncogene mutation were evaluated for other potential syndrome manifestations. A tumor from the proband was analyzed to compare features with sporadic GISTs. PATIENTS AND METHODS: Members of a kindred in which six relatives in four consecutive generations comprised an autosomal dominant pattern of documented GISTs and cutaneous lesions underwent physical examination, imaging studies, and germline KIT analysis. A recurrent GIST from the proband was studied using microarray, karyotypic, immunohistochemical, and immunoblotting techniques. RESULTS: In addition to evidence of multiple GISTs, lentigines, malignant melanoma, and an angioleiomyoma were identified in relatives. A previously reported gain-of-function missense mutation in KIT exon 11 (T --> C) that results in a V559A substitution within the juxtamembrane domain was identified in three family members. The proband's recurrent gastric GIST had a 44,XY-14,-22 karyotype and immunohistochemical evidence of strong diffuse cytoplasmic KIT expression without expression of actin, desmin, or S-100. Immunoblotting showed strong expression of phosphorylated KIT and downstream signaling intermediates (AKT and MAPK) at levels comparable with those reported in sporadic GISTs. cDNA array profiling demonstrated clustering with sporadic GISTs, and expression of GIST markers comparable to sporadic GISTs. CONCLUSION: These studies provide the first evidence that gene expression and mechanisms of cytogenetic progression and cell signaling are indistinguishable in familial and sporadic GISTs. Current investigations of molecularly targeted therapies in GIST patients provide opportunities to increase the understanding of features of the hereditary syndrome, and risk factors and molecular pathways of the neoplastic phenotypes.     

PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.

PURPOSE: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs. MATERIALS AND METHODS: We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing. RESULTS: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings. CONCLUSION: Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.     

Discovery and characterization of the short kappaA-conotoxins: a novel subfamily of excitatory conotoxins.

We have characterized the defining members of a novel subfamily of excitatory conotoxins, the short kappaA-conotoxins (kappaA(S)-conotoxins). kappaA-conotoxins PIVE and PIVF (kappaA-PIVE and kappaA-PIVF) were purified from Conus purpurascens venom. Both peptides elicited excitatory activity upon injection into fish. kappaA-PIVE was synthesized for further characterization. The excitatory effects of kappaA-PIVE in vivo were dose dependent, causing hyperactivity at low doses and rapid immobilization at high doses, symptomatic of a type of excitotoxic shock. Consistent with these observations, kappaA-PIVE caused repetitive action potentials in frog motor axons in vitro. Similar results have been reported for other structurally distinct conotoxin families; such peptides appear to be required by most fish-hunting cone snails for the rapid immobilization of prey. Unexpected structure-function relationships were revealed between these peptides and two families of homologous conotoxins: the alphaA-conotoxins (muscle nAChR antagonists) and kappaA-conotoxins (excitotoxins), which all share a common arrangement of cysteine residues (CC-C-C-C-C). Biochemically, the kappaA(S)-conotoxins more closely resemble the alphaA(S)-conotoxins than the other kappaA-conotoxin subfamily, the long kappaA-conotoxins (kappaA(L)-conotoxins); however, kappaA(S)- and alphaA(S)-conotoxins produce different physiological effects. In contrast, the kappaA(S)-and kappaA(L)-conotoxins that diverge in several biochemical characteristics are clearly more similar in their physiological effects.     

Leflunomide therapy following penetrating keratoplasty in the rat

Background: The isoxal derivative, leflunomide (LF), is a new potent immunosuppressive which has been shown to be effective in preventing autoimmune disorders and reactions leading to organ transplantation rejection. LF is thought to antagonise cytokine activity and thereby to interfere with T-helper-cell-dependent B- and T-lymphocyte proliferation. Methods: We used LF to treat corneal allograft rejection in the rat, comparing its effect with that of cyclosporin A (CSA). Corneal buttons were grafted from Lewis/Brown Norway rats to Lewis recipients. Animals were randomly assigned to the following treatment groups: I, untreated; II, CSA (10 mg/kg i.m.); III, LF (2.5 mg/kg p.o.); IV, LF (5 mg/kg p.o.); V, LF (10 mg/kg p.o.); VI, combined therapy (LF 10 mg/kg p.o. and CSA 10 mg/kg i.m). Treatment began on the first postoperative day and was continued until rejection occurred. Results: The mean graft rejection time in the untreated allogeneic group was 12 days. A significant delay in graft rejection was observed in all treatment groups compared with group I (P<0.001). Further, the delay in graft rejection resulting from combined therapy (group VI) was statistically significant compared with all other groups (P<0.001). Conclusion: These results suggest that (a) LF when used alone is as effective as CSA in treating corneal allograft rejection in the rat, and (b) when LF and CSA are combined they are more effective than either drug alone in the prolongation of allograft survival.Presented in abstract form at the Berlin-Brandenburg Eye Congress, 4–5 December 1993. None of the authors has any proprietary or financial interests in the compound leflunomide