Application of the lithium and magnesium initiators for the synthesis of glycolide, lactide, and epsilon-caprolactone copolymers biocompatible with brain tissue.

The subject of this work is new method of the synthesis of biodegradable copolymers compatible with brain tissue. Copolymerization of glycolide with lactide was conducted in solution or in bulk in the presence of LiBu, LiAcac, MgBu(2), Mg(acac)(2) as initiators. In all cases, copolymers with molecular weight of 20000-40000 were obtained, which enables to use them as drug carriers. During the reactions of copolymer chain growth, the intermolecular transesterification occurs, changing the distribution of comonomeric units in copolymer chain. Magnesium initiators showed a lower contribution to transesterification in comparison with lithium and calcium compounds. The copolymerization of glycolide with epsilon-caprolactone using magnesium compounds as initiators was also described. The random glycolide/epsilon-caprolactone copolymer (10/90) obtained with MgBu(2) was used in in vivo study in the forms of microspheres and foils. Complete degradation of microspheres during 6 weeks was observed after the implantation to brain tissue. All implanted copolymers are compatible with brain tissue.

Preclinical development of biodegradable polymer foils for intracerebral delivery of cytotoxic nucleosides.

Intracerebral implantation of biodegradable polymers loaded with cytotoxic or radiosensitising nucleoside analogues is a promising treatment strategy for malignant gliomas, which are currently intractable. The aim of the study was to develop biodegradable polymers containing nucleosides which could be implanted intracerebrally. Methods of synthesis were developed for the copolymers composed of D,L-lactide, glycolide and caprolactone in different proportions, as well as a novel method of introducing nucleosides to these copolymers at the polymerisation step. Upon degradation in an aqueous medium some of these copolymers emit nucleosides in micromolar concentration over several months. Their in situ degradation and biocompatibility with brain tissues was assessed by means of scanning and transmission electron microscopy. At the ultrastructural level tissue responses to the copolymer implantation closely resembled the responses to mechanical trauma.

2-deoxyglucose induces beta-APP overexpression, tau hyperphosphorylation and expansion of the trans-part of the Golgi complex in rat cerebral cortex.

The effects of a single intraperitoneal injection of a non-metabolizable glucose analog 2-deoxyglucose (2-DG, 500 mg/kg) on the levels of beta-APP expression, and phosphorylated and unphosphorylated tau protein in the rat cerebral cortex were investigated. The effects of 2-DG on the ultrastructure of cortical neurons with particular emphasis on the morphology of the Golgi apparatus, and on brain bioenergetics assessed by in vivo 31P-MRS technique were also evaluated. Seven and a half hours after injection of 2-deoxyglucose a significant increase in brain cortex beta-APP expression, increased tau phosphorylation, and a marked relative expansion of the trans- part of the Golgi intracellular secretory pathway in cortical neurons has been found. The changes of beta-APP expression and tau phosphorylation appeared within 1 h after 2-DG application and continued for at least 24 h. However, brain 31P resonance spectra remained unchanged for up to 7.5 h after 2-DG. It is suggested that the increase of beta-APP expression represents a response of brain tissues to 2-DG-evoked biochemical stress, while tau hyperphosphorylation and the change in Golgi morphology may be secondary phenomena.

Can genetic material retrotransposition be a cause of pathology accompanying cerebral aneurysm rupture?

Our considerations were prompted by observation of patients who underwent surgery due to cerebral aneurysm rupture. Elevated anti-HIV antibody titers were detected in such patients. The above condition was not observed either in subjects with intracranial hemorrhages from cerebral angiomas. The observed titers remained certainly below the cut off level indicating contact with HIV. We analyzed the subpopulations of peripheral blood lymphocytes both in the surgery patients and in the control group represented by blood collected from blood donors. On the other hand, the proliferation potential of circulating lymphocytes in the blood of patients with subarachnoid hemorrhages due to cranial aneurysm ruptures was found to be decreased. Dislocation of transposons, so-called 'unauthorized recombination' is known to occur within the framework of genetic code pathology. Endogenous human viruses have been described, and they may be involved in the development of autoimmune disorders. Additionally, viruses involved in autoimmune processes, which may be 'identical' with retrotransposons, have been described. Moreover, there are studies demonstrating that AIDS is caused by retrotransposition of genetic code material fragments. Our considerations are substantiated by ultrastructural analyses of material coming from the gyrus rectus cortex fragments, resected in patients who underwent clipping of a ruptured aneurysm of the anterior communicating artery. We demonstrated in neuronal chromatin the presence of a molecule ca. 80 nm in diameter, corresponding with its size to retroviruses or genetic material molecules with altered substructure. The authors suggest a new mechanism of development of neurological deficits in patients with ruptured cerebral aneurysms.

Electron microscope investigation of the role of Chlamydia sp. in the process of rebuilding the arterial wall. Neoangiogenesis in atherosclerotic plaques in human cervical artery walls.

BACKGROUND: The inflammatory process has an essential impact on the development of atherosclerosis. Three mechanisms are mentioned: 1) possibility of direct development of Chlamydia infection in the vicinity of the blood vessel wall; 2) impact of persistent or recurrrent Chlamydia infection on the increased blood concentration of risk factors for atherosclerosis; 3) an autoimmunological reaction. MATERIAL/METHODS: Electron microscope examinations were performed on specimens from atherosclerotic lesions of the interior cervical arteries, collected from patients who had undergone endarterectomy. The material came from 8 patients (age from 58 to 72). The specimens were fixed for electron microscopy, and after dehydration were immersed in Spurr resin. Ultrathin slices were examined under a transmission electron microscope. RESULTS: In the successive tested layers nearest the lumen of the vessel we found erythrocytic elements, fibrin, and lipid membranes. In deeper layers there were lymphocytic cells, monocytes, and macrophages loaded with phagocyted lipid material. Under this layer we found in some specimens a coating which had undergone mineralization: calcium structures and cholesterol were overlaid on a proteoglycanate base. Smooth muscles cells had undergone the heaviest proliferation among the cells on artery wall. In the tested material we detected diversified morphological forms of Chlamydia sp. Particular attention should be drawn to the appearance of very young vessel forms, which suggests a process of angiogenesis in the atherosclerotic plaques. CONCLUSIONS: We found that one of the pathogens that may lead to atherosclerotic lesions is Chlamydia sp. The process of atherogenesis in cervical arteries is accompanied by angiogenetic processes.