Position-dependent effects on stability in tricyclo-DNA modified oligonucleotide duplexes

A series of oligodeoxyribonucleotides and oligoribonucleotides containing single and multiple tricyclo(tc)-nucleosides in various arrangements were prepared and the thermal and thermodynamic transition profiles of duplexes with complementary DNA and RNA evaluated. Tc-residues aligned in a non-continuous fashion in an RNA strand significantly decrease affinity to complementary RNA and DNA, mostly as a consequence of a loss of pairing enthalpy DeltaH. Arranging the tc-residues in a continuous fashion rescues T(m) and leads to higher DNA and RNA affinity. Substitution of oligodeoxyribonucleotides in the same way causes much less differences in T(m) when paired to complementary DNA and leads to substantial increases in T(m) when paired to complementary RNA. CD-spectroscopic investigations in combination with molecular dynamics simulations of duplexes with single modifications show that tc-residues in the RNA backbone distinctly influence the conformation of the neighboring nucleotides forcing them into higher energy conformations, while tc-residues in the DNA backbone seem to have negligible influence on the nearest neighbor conformations. These results rationalize the observed affinity differences and are of relevance for the design of tc-DNA containing oligonucleotides for applications in antisense or RNAi therapy.

Position paper on the management of patients with obstructive sleep apnea and hypertension: joint recommendations by the European Society of Hypertension, by the European Respiratory Society and by the members of European COST (COoperation in Scientific and Technological research) ACTION B26 on obstructive sleep apnea

This article is aimed at addressing the current state of the art in epidemiology, pathophysiology, diagnostic procedures and treatment options for appropriate management of obstructive sleep apnea (OSA) in cardiovascular (particularly hypertensive) patients, as well as for the management of cardiovascular diseases (particularly arterial hypertension) in OSA patients. The present document is the result of the work done by a panel of experts participating in the European Union COST (COoperation in Scientific and Technological research) ACTION B26 on OSA, with the endorsement of the European Respiratory Society (ERS) and the European Society of Hypertension (ESH). These recommendations are particularly aimed at reminding cardiovascular experts to consider the occurrence of sleep-related breathing disorders in patients with high blood pressure. They are at the same time aimed at reminding respiration experts to consider the occurrence of hypertension in patients with respiratory problems at night.

Future trials of endovascular mechanical recanalisation therapy in acute ischemic stroke patients - A position paper endorsed by ESMINT and ESNR : Part II: methodology of future trials

Based on current data and experience, the joint working group of the European Society of Minimally Invasive Neurological Therapy (ESMINT) and the European Society of Neuroradiology (ESNR) make suggestions on trial design and conduct aimed to investigate therapeutic effects of mechanical thrombectomy (MT). We anticipate that this roadmap will facilitate the setting up and conduct of successful trials in close collaboration with our neighbouring disciplines.

Future trials of endovascular mechanical recanalisation therapy in acute ischemic stroke patients: a position paper endorsed by ESMINT and ESNR : Part I: Current situation and major research questions

A new era of stroke treatment may have begun with mechanical thrombectomy (MT) by fully deployed closed-cell self-expanding stents (stent-triever). Multiple case series and the first randomised controlled trials (RCTs) have now been published. More studies are under way involving large numbers of patients, which in turn has resulted in less strict "pragmatic" study protocols. Problems with current trials include a lack of standardisation in the conduct of the recanalisation procedure, the definition of primary endpoints such as the grade of arterial recanalisation and tissue reperfusion, and the post-surgical care provided. In Part 1 of this two part series, we outline the current situation and the major research questions.

A Swiss neighbourhood index of socioeconomic position: development and association with mortality

Area-based measures of socioeconomic position (SEP) suitable for epidemiological research are lacking in Switzerland. The authors developed the Swiss neighbourhood index of SEP (Swiss-SEP).

The Position of Russian Provinical Officialdom in the Middle of the 19th Century: Law and Life

The study considered the discrepancy between the official status and real position of Russian provincial officialdom in the middle of the 19th century. The law was not entirely coherent in all aspects of the officials' life and activity, with ordinary deviations from the law being adopted in practice and accepted, albeit not openly, by the public and sometimes even by the authorities. The main law determining the rights and duties of governors was never followed to the letter and in reality governors' activities were determined by the common (unwritten) law existing in the governmental sphere. The volume and nature of the governors' rights depended on a range of factors, with specific regional features and the governor's personal qualities having a particular significance. The standard of living of government clerks was much higher than their official salary would permit and Matkhanova studied the most widespread cases of abuse, identifying those positions in the administration which offered the most opportunities for such abuses. At the start of the period and on the eve of the reforms public opinion towards the bribery of officials underwent a change. From the late 1850s onwards, there appeared among provincial officials a group of young well-educated clerks with liberal ideas and a new system of moral values which did not allow them to accept bribes or infringe the law in any way. There was also a non-official hierarchy side by side with the legally existing one. A significant role in governing the region, and one which has been underestimated by historians, was played by the head of the governor's office, but the reforms of the 1860s contributed to changing this state of affairs.