Molecular determinants for the action of general anesthetics at recombinant α2β3γ2γ-aminobutyric acidA receptors

General anesthetics modulate the activity of ligand-gated ion channels including the GABA(A) receptor. Mutational studies mainly on the benzodiazepine-insensitive alpha(2)beta(1(M286W)) and alpha(6)beta(3(N289M))gamma(2) GABA(A) receptors revealed that a serine in transmembrane domain 2 and a methionine in transmembrane domain 3 are essential for the action of most general anesthetics. We investigated whether these residues would similarly be relevant for their action at the benzodiazepine-sensitive GABA receptor subtype, alpha(2)beta(3)gamma(2). We found that not only the N265M but also the M286W mutation nearly abolished the modulatory effect of etomidate. However, the anti-convulsant loreclezole, a structural homologue of etomidate, was inactive on the N265M mutant, but displayed normal modulatory activity on the M286W mutant. Both mutations did not affect the modulatory action of the neurosteroid alphaxalone. The direct action of alphaxalone, however, was dramatically increased in the M286W mutant to about twice the maximal GABA current but not significantly affected in the N265M mutant. These data demonstrate that the structural requirements for modulatory and direct actions of various general anesthetics are distinct. The molecular switches induced by these mutations can be exploited to identify the molecular determinants for the action of general anesthetics.     

The development of subunit and synthetic vaccines using recombinant DNA technology

Vaccination of humans and animals against invasion by pathogenic organisms is an effective and integral component of preventive medicine. Traditionally, vaccines have been prepared from various forms of killed or attenuated whole organisms. Such killed or attenuated vaccines presumably retain some of the important antigenic determinants of the organism which can elicite an effective immune response in the vaccinated host. Major drawbacks encountered with these types of vaccines include the introduction of undesirable side-effects after vaccination, as well as induction of only partial protection in some cases. In addition to killed or attenuated vaccines, partially purified antigenic determinants from the whole organism have been used as vaccines. However, the cost and difficulties involved in preparation of the purified antigen often make this an uneconomical approach. Within the last decade, the advent of recombinant DNA technology has brought about a new approach in the preparation of vaccines. In this review, some of the recent developments in several research areas leading to the production of effective vaccines will be presented to demonstrate the promising future of this new approach to vaccine development.     

GLOBALIZATION, HUMAN RIGHTS, AND THE SOCIAL DETERMINANTS OF HEALTH

Globalization, a process characterized by the growing interdependence of the world's people, impacts health systems and the social determinants of health in ways that are detrimental to health equity. In a world in which there are few countervailing normative and policy approaches to the dominant neoliberal regime underpinning globalization, the human rights paradigm constitutes a widely shared foundation for challenging globalization's effects. The substantive rights enumerated in human rights instruments include the right to the highest attainable level of physical and mental health and others that are relevant to the determinants of health. The rights stipulated in these documents impose extensive legal obligations on states that have ratified these documents and confer health entitlements on their residents. Human rights norms have also inspired civil society efforts to improve access to essential medicines and medical services, particularly for HIV/AIDS. Nevertheless, many factors reduce the potential counterweight human rights might exert, including and specifically the nature of the human rights approach, weak political commitments to promoting and protecting health rights on the part of some states and their lack of institutional and economic resources to do so. Global economic markets and the relative power of global economic institutions are also shrinking national policy space. This article reviews the potential contributions and limitations of human rights to achieving greater equity in shaping the social determinants of health.     

Trends in undernutrition mortality among children under five years of age and adults over 60

Introduction: Children under five years of age living in poor areas and with low availability of healthy food have a higher risk of undernutrition-related mortality. However, this relationship has not been well established among older adults.Objective: To analyse socioeconomic inequality trends related to undernutrition mortality in children under five years of age and adults over 60 in Colombian municipalities during 2003-2009 and 2010-2016.Materials and methods: We conducted an ecological study of trends between 2003 and 2016. The study population consisted of children under five years of age and adults over 60 residing in the Colombian municipalities during the study period. We estimated smoothed and standardized mortality rates by fitting a hierarchical Bayesian model and explored their relationship with five socioeconomic area-level variables.Results: In most of the municipalities, undernutrition-related mortality was three times higher in older adults compared to children. Moreover, the difference in the risk of undernutrition-related mortality between municipalities showed a marked reduction. Finally, the poor and less developed municipalities had higher rates of undernutrition-related mortality in children; conversely, wealthier territories had higher rates in older adults.Conclusions: Although in most of the municipalities the mortality rates due to undernutrition in children under five and older adults have decreased, their socioeconomic conditions influence in different ways the risk of mortality for these two populations so there is the need to develop age-specific strategies to close social gaps considering the structural conditions of the areas.     

Exploring the Determinants of the Perceived Risk of Food Allergies in Canada

Food allergies are emerging health risks in much of the Western world, and some evidence suggests prevalence is increasing. Despite lacking scientific consensus around prevalence and management, policies and regulations are being implemented in public spaces (e.g., schools). These policies have been criticized as extreme in the literature, in the media, and by the non-allergic population. Backlash appears to be resulting from different perceptions of risk between different groups. This article uses a recently assembled national dataset (n = 3,666) to explore how Canadians perceive the risks of food allergy. Analyses revealed that almost 20% self-report having an allergic person in the household, while the average respondent estimated the prevalence of food allergies in Canada to be 30%. Both of these measures overestimate the true clinically defined prevalence (7.5%), indicating an inflated public understanding of the risks of food allergies. Seventy percent reported food allergies to be substantial risks to the Canadian population. Multivariate logistic regression models revealed important determinants of risk perception including demographic, experience-based, attitudinal, and regional predictors. Results are discussed in terms of understanding emerging health risks in the post-industrial era, and implications for both policy and risk communication.     

Female genital cutting and reproductive experience in Minya, Egypt

In African populations practicing female genital cutting (FGC), beliefs exist that these procedures enhance reproduction and that their medicalization may diminish adverse effects, yet available findings are mixed in part for methodological reasons. We use data from a representative sample of ever-married women aged 17-55 years in Minya, Egypt, to examine the effects of type of FGC and type of circumciser on a woman's risks of primary infertility and pregnancy loss. Contrary to previous studies in Egypt, neither type of circumcision nor type of circumciser is associated with adverse fertility outcomes among circumcised women in Minya.     

Distance dependence and salt sensitivity of pairwise, coulombic interactions in a protein

Histidine pK(a) values were measured in charge-reversal (K78E, K97E, K127E, and K97E/K127E) and charge-neutralization (E10A, E101A, and R35A) mutants of staphylococcal nuclease (SNase) by (1)H-NMR spectroscopy. Energies of interaction between pairs of charges (DeltaG(ij)) were obtained from the shifts in pK(a) values relative to wild-type values. The data describe the distance dependence and salt sensitivity of pairwise coulombic interactions. Calculations with a continuum electrostatics method captured the experimental DeltaG(ij) when static structures were used and when the protein interior was treated empirically with a dielectric constant of 20. The DeltaG(ij) when r(ij) < or = 10 A were exaggerated slightly in the calculations. Coulomb's law with a dielectric constant near 80 and a Debye-Hückel term to account for screening by the ionic strength reproduced the salt sensitivity and distance dependence of DeltaG(ij) as well as the structure-based method. In their interactions with each other, surface charges behave as if immersed in water; the Debye length describes realistically the distance where interactions become negligible at a given ionic strength. On average, charges separated by distances (r(ij)) approximately 5 A interacted with DeltaG(ij) approximately 0.6 kcal/mole in 0.01 M KCl, but DeltaG(ij) decayed to < or =0.10 kcal/mole when r(ij) = 20 A. In 0.10 M KCl, DeltaG(ij) approximately 0.10 kcal/mole when r(ij) = 10 A. In 1.5 M KCl, only short-range interactions with r(ij) < or = 5 A persisted. Although at physiological ionic strengths the interactions between charges separated by more than 10 A are extremely weak, in situations where charge imbalance exists many weak interactions can cumulatively produce substantial effects.     

Double abdomen induction with low UV-doses inSmittia spec. (Chironomidae,diptera): Sensitive period and complete photoreversibility

Summary In embryos of the chironomid midgeSmittia spec., UV-irradiation of anterior pole regions results in double abdomen formation. In this abnormal body pattern, head and thorax are replaced by a mirror image of the abdomen. Irradiation at a particular stage between nuclear migration and blastoderm formation, and with the anterior pole facing the UV-beam, yields 100% double abdomens after a minimum UV-dose (140 J·m^–2 at 285 nm wavelength). By subsequent exposure to light of longer wavelength, embryos can be reprogrammed so that they develop normally again. The irradiation procedure described is suitable for programming large numbers of embryos for double abdomen formation, with a minimum of side effects and virtually complete photoreversibility.     

Transformation-mediated exchange of virulence determinants by co-cultivation of pathogenic Neisseriae

The horizontal flow of genetic material between microbes utilizes three principal routes: conjugation, transduction and transformation. While the significance in nature of the first two pathways is generally accepted, the in vivo role of transformation remains uncertain, despite the early observations by Griffith in 1928 on the transformation of streptococci from an avirulent to a virulent state [1]. Recently, circumstantial evidence was collected suggesting a role for transformation-mediated horizontal exchange in the modulation of virulence determinants of pathogenic Neisseriae and the variation of surface structures. In order to further assess the significance of transformation-mediated exchange we performed simple co-cultivation experiments of different Neisseria strains. We observed an efficient intra- and interspecies transfer of essential virulence determinants; the process was sensitive to the presence of DNaseI in the culture and was blocked in transformation-deficient recipients.     

Specific macromolecular interactions between tau and the microtubule system

The microtubule-associated protein Tau, a major component of brain microtubules, shares common repeated C-terminal sequences with the high molecular-weight protein MAP-2. It has been shown that tau peptides V¹⁸⁷-G²⁰⁴ and V²¹⁸-G²³⁵ representing two main repeats, induced brain tubulin assembly in a concentration-dependent fashion. The specific roles of these repeats in the interaction of tau with microtubules, and its antigenic nature were investigated using synthetic tau peptides and site-directed monoclonal antibodies. Tau peptides appeared to compete with MAP-2 incorporation into assembled microtubules. The interactions of the tau fragments with -tubulin peptides bearing the tau binding domain on tubulin were analyzed by fluorescence spectroscopy. The specificity of the binding was further demonstrated by the reactivity of tau and the tau peptides with a monoclonal anti-idiotypic antibody produced after immunization with the -11(422–434) tubulin peptide, as assessed by enzyme-linked immunoassay. Western blots confirmed the interaction of tau with the monoclonal antibody. In addition, immunoassays revealed a competition between the MAP-reacting monoclonal antibody and the tubulin peptide -11(422–434) for their interaction with the tau molecule.