[DNA tandem lesion: 5',8-cyclo-2'-deoxyadenosine. The influence on human health].

Nucleic acids are the targets for various endogenous and exogenous genotoxic agents, including reactive oxygen species. The appearance of a hydroxyl racial (^(.)OH), the most harmful molecule, next to an oligonucleotide can lead to two types of DNA damage: strand breaks or nucleobase modifications. Since clustered DNA damage is defined as the presence of two or more lesions in one helix turn, purine 5',8-cyclo-2'-deoxynucleosides are recognized as tandem lesions: both sugar moieties and base have been modified within one nucleoside/nucleotide. The hydrogen abstraction from the C5' group of nucleosides/nucleotides by ^(.)OH, with subsequent C8 C5' cyclisation results in purine 5',8-cyclonucleoside formation. Due to its unusual 3D structure and the fact that only one radical hit is needed for purine 5',8-cyclonucleoside formation their influence on genome stability/integrity and DNA repair processes are subjects of medical interest. In the present work the influence of 5',8-cyclo-2'-deoxyadenosine on DNA spatial geometry and DNA repair hinder in connection with human health, such as neurological disorders is discussed.

Structural effect of complete [Rp]-phosphorothioate and phosphorodithioate substitutions in the DNA strand of a model antisense inhibitor-target RNA complex.

Chemically modified DNA oligonucleotides have been crucial to the success of antisense therapeutics. Although such modifications are ubiquitous in the clinic, high-resolution structural studies of pharmaceutically relevant derivatives have been limited to only a few molecules. We have completed a high-resolution NMR structural study of three DNA.RNA hybrids with the sequence d(CCTATAATCC). r(GGAUUAUAGG). All hybrids contain an unmodified RNA strand, whereas the DNA strand of each hybrid contains one of three different sugar-phosphate backbone linkages at each nucleotide: (1) phosphate, (2) [Rp]-phosphorothioate, or (3) phosphorodithioate. The UV and NMR melting profiles revealed that the normal hybrid is more stable than the [Rp]-phosphorothioate, which in turn is more stable than the phosphorodithioate. Homonuclear two-dimensional nuclear Overhauser effect spectroscopy and double quantum-filtered correlation spectroscopy afforded nearly complete non-labile proton assignments. The three molecules show nearly equivalent chemical shifts, with the exception of H3' protons, which are shifted downfield in a manner that appears correlated with the degree of sulfur substitution at phosphate. All three hybrids exhibit unusually broad linewidths for deoxyribose protons H2' and H2".Distance restraints were calculated from NOE cross-peak intensities via a complete relaxation matrix approach using the program RANDMARDI. Detailed comparison of interproton distances from each hybrid indicates that the three molecules share a common structure, with neither strand in canonical A or B form. Correlation of R factors, calculated using the program CORMA with DNA H2'-base and H3'-base distances, revealed a relative increase in the population of B-type sugar conformations for deoxyriboses in the A+T-rich center of the hybrid sequence. It is widely known that the activity of enzymes which act upon DNA.RNA hybrid substrates (e.g. ribonuclease H) is impacted when the hybrids contain phosphorothioate or phosphorodithioate substitutions. The structural similarity of the three hybrids examined here suggests that factors other than global structure may mediate the activity of these enzymes.

[Delayed results of the surgical treatment of stenosis and occlusion of extracranial cerebral arteries]. / Odlegle wyniki leczenia chirurgicznego zwezen i niedroznosci pozaczaszkowych tetnic mózgowych.

Late (up to 15 years) results of surgical and conservative treatment were compared in patients with stenosis or occlusion of the extracranial brain-supplying arteries. The results of surgical treatment were better in patients with transient brain ischaemia as well as in those with completed stroke. In the surgically treated group the per cent of patients improved was greater (especially in cases with transient ischaemia), the survival time was longer, and the number of deaths caused by cerebral diseases was lower.

[Speech rehabilitation in the early stage of stroke]. / Reedukacja mowy we wczesnym okresie udaru mózgowego.

Re-education of disturbed speech was conducted in 224 patients from 1 to 8 weeks after strike. The diagnostic neuropsychological examination was carried out in each case on the 3rd day of the disease, after 2 weeks and after 8 weeks. It was found that the speech was much better after re-educaton than in patients in a later stage of this disease who had no speech rehabilitation in the early stage of the disease. For demonstrating these differences two groups of patients (30 subjects in each) matched for age, stroke aetiology and type of speech disorders were compared.

[Angiographic assessment of collateral circulation pathways in the stenosis and occlusion of the extracranial cerebral arteries]. / Angiograficzna ocena dróg krazenia obocznego w zwezeniu i niedroznosci mózgowych tetnic pozaczaszkowych.

Visualization in angiographic investigations of the common carotid artery of certain collateral circulation routes can sometimes facilitate evaluation of the site of occlusion and its extent. Collateral circulation via the arterial network of the nape of the neck indicates stenosis or occlusion of the subclavian artery. Collateral circulation through the muscular branches of the occipital artery to the vertebral and basal arteries suggests lesions in the vertebral artery. Collateral circulation via the anterior communicating artery suggests stenosis or occlusion of the contralateral internal carotid artery. Visualization in the angiograms of the common carotid artery of numerous channels of collateral circulation indicates presence of disseminated changes in the extracranial brain-supplying arteries.

[Evaluation of sulocton action in patients with atherosclerotic brain ischemia]. / Ocena dzialania suloctonu u chorych z niedokrwieniem mózgu w przebiegu miazdzycy.

Sulocton effect was evaluated in 33 patients with symptoms of brain ischaemia during atherosclerosis. Thirty patients received the drug orally for 2 months in doses of 100 mg thrice daily. Three patients discontinued the treatment earlier (two of them discontinued it because of side effects). After two months of treatment a significant improvement was observed in such disturbances important for wellbeing and social contacts as: anxiety and fear, mood depression, disequilibrium of emotion, motivation and initiative. In many patients headaches, dizziness and gait disturbances disappeared or diminished. Sulocton was useful in the treatment of patients with cerebral atherosclerosis.

[Angio-ultrasonography--a method of examining the extracranial arteries]. / Angioultrasonografia--metoda badania tetnic pozaczaszkowych.

The authors describe a method of investigations of the extracranial cerebral arteries--angioultrasonography based on the Doppler effect. The study was done with a Polish apparatus designed and produced by the Experimental Laboratory of the Institute of Basic Technical Problems, Polish Academy of Sciences. The study confirmed the usefulness of this method in the diagnosis of arterial diseases involving the extracranial arteries supplying the brain. A high agreement was demonstrated between the results of angioultrasonography and classical angiography. Owing to the use of a grey scale it was possible to localize accurately the site of stenosis or occlusion of the studied artery.

[The clinical picture of stenosis and occlusion of the extracranial cerebral arteries]. / Obraz kliniczny zwezen i niedroznosci tetnic mózgowych pozaczaszkowych.

The authors report a clinical analysis of 200 cases of various forms of stenosis and occlusion of the extracranial arteries supplying the brain. The cases were collected in a period of 15 years. Follow-up investigations were conducted in 100 conservatively treated patients and 100 surgically treated ones. Syndromes of cerebral, ophthalmic, trophic and vascular signs are described, their incidence is discussed and the most salient features are emphasized.

[Radiological image of aneurysm of the internal carotid artery as a complication of angiography]. / Obraz radiologiczny tetniaka tetnicy szyjnej wewnetrznej jako powiklania angiografii.

A case of posttraumatic false aneurysm of the internal carotid artery development after intraparietal injection of contrast during angiography is reported.

Stereocontrolled synthesis of LNA dinucleoside phosphorothioate by the oxathiaphospholane approach.

The application of the oxathiaphospholane approach for the stereocontrolled synthesis of LNA dinucleoside phosphorothioate is described. The reaction of ring opening condensation proceeds in CH3CN solution in high yield and with over 96% stereoselectivity. One of diastereomers of LNA dinucleoside phosphorothioate (presumably R(P)) was found to be readily digested by svPDE.

Effect of P-chirality of internucleotide bonds on B-Z conversion of stereodefined self-complementary phosphorothioate oligonucleotides of the [PS]-d(CG)4 and [PS]-d(GC)4 series.

Diastereomerically pure, partially modified (in selected positions) or fully modified phosphorothioate oligomers of the [PS]-d(CG)(4) and [PS]-d(GC)(4) series were investigated with respect to their ability to adopt the left-handed conformation at high sodium chloride concentration. NaCl induces the B-Z transition of [All-S(P)R(P)-PS]-d(CG)(4) with a midpoint of transition at ca. 2 M, which is approximately 1 M less than for unmodified d(CG)(4). Also, [All-R(P)S(P)-PS]-d(GC)(4) at 5 M NaCl converts to the Z form to the extent of ca. 55%, while the unmodified d(GC)(4) counterpart does not convert at all. This enhanced ability of stereodefined phosphorothioate oligomers to adopt the Z conformation is discussed in terms of already known structural factors (hydrogen bonding and water bridges) facilitating the B-Z transition, identified for unmodified d(CG)(n) oligonucleotides. By CD spectroscopy, the [All-S(P)-PS]-d(CG)(4) oligomer at a NaCl concentration higher than 0.01 M adopts a unique conformation as assessed from the presence of an additional negative band centered at 282 nm.

Binding of phosphorothioate oligodeoxynucleotides to basic fibroblast growth factor, recombinant soluble CD4, laminin and fibronectin is P-chirality independent.

Antisense oligodeoxynucleotides can selectively inhibit the expression of individual genes and thus have potential applications in anticancer and antiviral therapy. A critical prerequisite to their use as therapeutic agents is the understanding of their non-specific interactions with biological structures, e.g. proteins. In this study we examined the interactions of P-chiral phosphorothioate oligodeoxynucleotides with several proteins. The Rp- and Sp- diastereomers, and racemic machine-made mixtures, or M-oligodeoxynucleotides were used independently as competitors of the binding of a probe, phosphodiester oligodeoxynucleotide bearing a 5' alkylating moiety, to rsCD4, bFGF and laminin. These oligodeoxynucleotides were also used as competitors of the binding of a non-alkylating probe M-phosphorothioate oligodeoxynucleotide, 5'-32P-SdT18 to fibronectin. The average values of and quantitative estimates for the IC50 of competition and the constant of competition (Kc) of Rp-, Sp- and M-stereoisomers of several homo- and heteropolymer oligodeoxynucleotides were determined and compared. Surprisingly, in the proteins we studied, the values of IC50 and Kc for the Rp-, Sp- and M-oligodeoxynucleotides were essentially identical. Thus, the ability of the phosphorothioate oligodeoxynucleotides we employed, to bind to the proteins studied in this work, is virtually independent of P-chirality. Our results also imply that the role of the purine and pyrimidine bases in oligodeoxynucleotide-protein interactions, as well as the nature of the contact points (sulfur versus oxygen) between the oligomer and the protein, may be relatively unimportant.

Stability of stereoregular oligo(nucleoside phosphorothioate)s in human plasma: diastereoselectivity of plasma 3'-exonuclease.

The stability of stereoregular oligo(nucleoside phosphorothioate)s (PS-oligos) in human plasma has been studied. 3'-Exonuclease present in human plasma appeared to be RP specific, that is, it cleaves internucleotide phosphorothioate linkages of [RP]-configuration and not those of [SP]-configuration. Therefore, PS-oligos containing all phosphorothioate internucleotide linkages of [RP]-configuration [RP-PS-oligos]) are more effectively degraded by the enzyme than PS-oligos prepared via nonstereo-controlled methods (so-called random mixture of diastereomers [Mix-PS-oligos]), whereas oligo(nucleoside phosphorothioate)s of [S(P)]-configuration remain intact. The enzyme activity depends on the sequence of nucleobases. The presence of deoxycytidine units (three or more residues) at the 3'-end of PS-oligo substrate significantly inhibits the enzyme activity.