Molecular determinants of drug access to the receptor site for antiarrhythmic drugs in the cardiac Na+ channel.

The clinical efficacy of local anesthetic and antiarrhythmic drugs is due to their voltage- and frequency-dependent block of Na+ channels. Quaternary local anesthetic analogs such as QX-314, which are permanently charged and membrane-impermeant, effectively block cardiac Na+ channels when applied from either side of the membrane but block neuronal Na+ channels only from the intracellular side. This difference in extracellular access to QX-314 is retained when rat brain rIIA Na+ channel alpha subunits and rat heart rH1 Na+ channel alpha subunits are expressed transiently in tsA-201 cells. Amino acid residues in transmembrane segment S6 of homologous domain IV (IVS6) of Na+ channel alpha subunits have important effects on block by local anesthetic drugs. Although five amino acid residues in IVS6 differ between brain rIIA and cardiac rH1, exchange of these amino acid residues by site-directed mutagenesis showed that only conversion of Thr-1755 in rH1 to Val as in rIIA was sufficient to reduce the rate and extent of block by extracellular QX-314 and slow the escape of drug from closed channels after use-dependent block. Tetrodotoxin also reduced the rate of block by extracellular QX-314 and slowed escape of bound QX-314 via the extracellular pathway in rH1, indicating that QX-314 must move through the pore to escape. QX-314 binding was inhibited by mutation of Phe-1762 in the local anesthetic receptor site of rH1 to Ala whether the drug was applied extracellularly or intracellularly. Thus, QX-314 binds to a single site in the rH1 Na+ channel alpha subunit that contains Phe-1762, whether it is applied from the extracellular or intracellular side of the membrane. Access to that site from the extracellular side of the pore is determined by the amino acid at position 1755 in the rH1 cardiac Na+ channel.

A metasynthesis of qualitative studies regarding opinions and perceptions about barriers and determinants of health services’ accessibility in economic migrants

Background: Access to health services is an important health determinant. New research in health equity is required, especially amongst economic migrants from developing countries. Studies conducted on the use of health services by migrant populations highlight existing gaps in understanding which factors affect access to these services from a qualitative perspective. We aim to describe the views of the migrants regarding barriers and determinants of access to health services in the international literature (1997–2011). Methods: A systematic review was conducted for Qualitative research papers (English/Spanish) published in 13 electronic databases. A selection of articles that accomplished the inclusion criteria and a quality evaluation of the studies were carried out. The findings of the selected studies were synthesised by means of metasynthesis using different analysis categories according to Andersen’s conceptual framework of access and use of health services and by incorporating other emergent categories. Results: We located 3,025 titles, 36 studies achieved the inclusion criteria. After quality evaluation, 28 articles were definitively synthesised. 12 studies (46.2%) were carried out in the U.S and 11 studies (42.3%) dealt with primary care services. The participating population varied depending mainly on type of host country. Barriers were described, such as the lack of communication between health services providers and migrants, due to idiomatic difficulties and cultural differences. Other barriers were linked to the economic system, the health service characteristics and the legislation in each country. This situation has consequences for the lack of health control by migrants and their social vulnerability. Conclusions: Economic migrants faced individual and structural barriers to the health services in host countries, especially those with undocumented situation and those experimented idiomatic difficulties. Strategies to improve the structures of health systems and social policies are needed.

Domino 1,3-Dipolar Cycloadditions of N-Alkyl-α-Amino Esters with Paraformaldehyde: A Direct Access to α-Hydroxymethyl α-Amino Acids

N-Alkyl-α-amino esters undergo a domino reaction, based on the iminium cation generation, with paraformaldehyde, followed by a 1,3-dipolar cycloaddition of the stabilized azometh­ine ylide with another equivalent of formaldehyde. The resulting products are oxazolidines, which can be transformed after hydrolysis into α-hydroxymethyl α-amino acid or its derivatives. The diastereoselective 1,3-dipolar cycloaddition was performed using sarcosine (–)-menthyl or (–)-8-phenylmenthyl esters affording the cyclic product with moderate enantiomeric ratio.

Gender and health inequalities: intersections with other relevant axes of oppression

The risk of disease, disability, and mortality as well as access to health services are unfairly distributed among the population, with certain groups bearing an unequally larger burden of ill health and poorer access to care due to gender, sexual identity/orientation, ethnic background, or class. According to the WHO Commission on Social Determinants of Health (CSDH), these health inequalities emanate from socioeconomic and political factors (governance, cultural values, macroeconomic policies), which generate a set of socioeconomic positions in society according to which populations are stratified based on gender, ethnicity, education, income, or other factors. These societal inequalities influence people’s material and psychosocial circumstances as well as behavioral and biological factors, which in turn impact on health inequalities. Tackling gender, race/ethnic, and socioeconomic inequalities in society is thus recognized as the most powerful action to cope with unequal health risks distribution, and social innovations focusing on these ‘root causes’ are needed in order to prevent and stop endemic social inequalities and social exclusion in health within low-income as well as high-income countries. Increasing existing knowledge and making visible the health status of the most vulnerable and invisible groups are critical in order to contribute to this imperative challenge.

Talking with the “pouvoir constituant” in times of constitutional reform: The European Court of Justice on Private Applicants’ Access to Justice. Research Paper in Law 3/2003

[From the Introduction]. European lawyers, at least those dealing predominantly with institutional matters, are living particularly interesting times since the setting-up of the “European Convention on the Future of Europe” in December 2001.1 As the Convention’s mandate, spelled out in rather broad terms in the European Council’s declaration of Laeken,2 is potentially unlimited, and as the future constitution of the European Union (EU) will be ultimately adopted by the subsequent Intergovernmental Conference (IGC), there appears to be a great possibility to clarify, to simplify and also to reform many of the more controversial elements in the European legal construction. The present debate on the future of the European constitution also highlights the relationship between the pouvoir constituant3 and the European Courts, the Court of Justice (ECJ) and its Court of First Instance (CFI), who have to interpret the basic rules and principles of the EU.4 In that light, the present article will focus on a classic theme of the Court’s case law: the relationship between judges and pouvoir constituant. In the EU, this relationship has traditionally been marked by the ECJ’s role as driving force in the “constitutionalisation” of the EC Treaties – which has, to a large extent, been accepted and even codified by the Member States in subsequent treaty revisions. However, since 1994, the ECJ appears to be more reluctant to act as a “law-maker.”5 The recent judgment in Unión de Pequeños Agricultores (UPA)6 – an important decision by which the ECJ refused to liberalize individuals’ access to the Community Courts – is also interesting in this context. UPA may be seen as another proof of judicial restraint - or even as indicator of the beginning of a new phase in the “constitutional dialogue” between the ECJ and the “Masters of the Treaties.”

Access to environmental information in an Open European Society - Directive 2003/4. Research Paper in Law 5/2003

[From the Introduction]. Information gives knowledge and knowledge gives power. Though in all EC Member States, the task to protect the environment is given to the administration, it is obvious that the administration is not the owner of the environment. The environment is everybody's. It is for this reason that administrative decisions which affect the environment must be transparent, open and must strike a balance between the general interest to preserve, protect and improve the quality of the environment on the one hand, the satisfying of specific private or public interests on the other hand. In order to allow at least a certain control of whether the administration strikes the right balance between the need to protect the environment and other legitimate or less legitimate needs, it appears normal and self-evident that information on the environment which is in the hands of public authorities, be also made available to the public and to citizens.