Analysis of Agonist and Antagonist Effects on Thyroid Hormone Receptor Conformation by Hydrogen/Deuterium Exchange

Thyroid hormone receptors (TRs) are ligand-gated transcription factors with critical roles in development and metabolism. Although x-ray structures of TR ligand-binding domains (LBDs) with agonists are available, comparable structures without ligand (apo-TR) or with antagonists are not. It remains important to understand apo-LBD conformation and the way that it rearranges with ligands to develop better TR pharmaceuticals. In this study, we conducted hydrogen/deuterium exchange on TR LBDs with or without agonist (T(3)) or antagonist (NH(3)). Both ligands reduce deuterium incorporation into LBD amide hydrogens, implying tighter overall folding of the domain. As predicted, mass spectroscopic analysis of individual proteolytic peptides after hydrogen/deuterium exchange reveals that ligand increases the degree of solvent protection of regions close to the buried ligand-binding pocket. However, there is also extensive ligand protection of other regions, including the dimer surface at H10-H11, providing evidence for allosteric communication between the ligand-binding pocket and distant interaction surfaces. Surprisingly, C-terminal activation helix H12, which is known to alter position with ligand, remains relatively protected from solvent in all conditions suggesting that it is packed against the LBD irrespective of the presence or type of ligand. T(3), but not NH(3), increases accessibility of the upper part of H3-H5 to solvent, and we propose that TR H12 interacts with this region in apo-TR and that this interaction is blocked by T(3) but not NH(3.) We present data from site-directed mutagenesis experiments and molecular dynamics simulations that lend support to this structural model of apo-TR and its ligand-dependent conformational changes. (Molecular Endocrinology 25: 15-31, 2011)

Gaining ligand selectivity in thyroid hormone receptors via entropy

Nuclear receptors are important targets for pharmaceuticals, but similarities between family members cause difficulties in obtaining highly selective compounds. Synthetic ligands that are selective for thyroid hormone (TH) receptor beta (TR beta) vs. TR alpha reduce cholesterol and fat without effects on heart rate; thus, it is important to understand TR beta-selective binding. Binding of 3 selective ligands (GC-1, KB141, and GC-24) is characterized at the atomic level; preferential binding depends on a nonconserved residue (Asn-331 beta) in the TR beta ligand-binding cavity (LBC), and GC-24 gains extra selectivity from insertion of a bulky side group into an extension of the LBC that only opens up with this ligand. Here we report that the natural TH 3,5,3`-triodothyroacetic acid (Triac) exhibits a previously unrecognized mechanism of TR beta selectivity. TR x-ray structures reveal better fit of ligand with the TR alpha LBC. The TR beta LBC, however, expands relative to TR alpha in the presence of Triac (549 angstrom(3) vs. 461 angstrom(3)), and molecular dynamics simulations reveal that water occupies the extra space. Increased solvation compensates for weaker interactions of ligand with TR beta and permits greater flexibility of the Triac carboxylate group in TR beta than in TR alpha. We propose that this effect results in lower entropic restraint and decreases free energy of interactions between Triac and TR beta, explaining subtype-selective binding. Similar effects could potentially be exploited in nuclear receptor drug design.

Functional and Structural Connectivity Between the Perigenual Anterior Cingulate and Amygdala in Bipolar Disorder

Objective: Abnormalities in the morphology and function of two gray matter structures central to emotional processing, the perigenual anterior cingulate cortex (pACC) and amygdala, have consistently been reported in bipolar disorder (BD). Evidence implicates abnormalities in their connectivity in BD. This study investigates the potential disruptions in pACC-amygdala functional connectivity and associated abnormalities in white matter that provides structural connections between the two brain regions in BD. Methods: Thirty-three individuals with BD and 31 healthy comparison subjects (HC) participated in a scanning session during which functional magnetic resonance imaging (fMRI) during processing of face stimuli and diffusion tensor imaging (DTI) were performed. The strength of pACC-amygdala functional connections was compared between BD and HC groups, and associations between these functional connectivity measures from the fMRI scans and regional fractional anisotropy (FA) from the DTI scans were assessed. Results: Functional connectivity was decreased between the pACC and amygdala in the BD group compared with HC group, during the processing of fearful and happy faces (p < .005). Moreover, a significant positive association between pACC-amygdala functional coupling and FA in ventrofrontal white matter, including the region of the uncinate fasciculus, was identified (p < .005). Conclusion: This study provides evidence for abnormalities in pACC-amygdala functional connectivity during emotional processing in BD. The significant association between pACC-amygdala functional connectivity and the structural integrity of white matter that contains pACC-amygdala connections suggest that disruptions in white matter connectivity may contribute to disturbances in the coordinated responses of the pACC and amygdala during emotional processing in BD.

Abnormal Corpus Callosum Integrity in Bipolar Disorder: A Diffusion Tensor Imaging Study

Objective: Abnormalities in the anterior interhemispheric connections provided by the corpus callosum (CC) have long been implicated in bipolar disorder (BID). In this study, we used complementary diffusion tensor imaging methods to study the structural integrity of the CC and localization of potential abnormalities in BD. Methods: Subjects included 33 participants with BID and 40 healthy comparison participants. Fractional anisotropy (FA) measures were compared between groups with region of interest (ROD methods to investigate the anterior, middle, and posterior CC and voxel-based methods to further localize abnormalities. Results: In ROI-based analyses, FA was significantly decreased in the anterior and middle CC in the BID group (p <.05). Voxel-based analyses similarly localized group differences to the genu, rostral body, and anterior midbody of CC (p <.05, corrected). Conclusion: The findings demonstrate abnormalities in the structural integrity of the anterior CC in BID that might contribute to altered interhemispheric connectivity in this disorder.

Redox regulation of the mitochondrial K(ATP) channel in cardioprotection

The mitochondrial ATP-sensitive potassium channel (mK(ATP)) is important in the protective mechanism of ischemic preconditioning (IPC). The channel is reportedly sensitive to reactive oxygen and nitrogen species, and the aim of this study was to compare such species in parallel, to build a more comprehensive picture of mK(ATP) regulation. mK(ATP) activity was measured by both osmotic swelling and Tl(+) flux assays, in isolated rat heart mitochondria. An isolated adult rat cardiomyocyte model of ischemia-reperfusion (IR) injury was also used to determine the role of mK(ATP) in cardioprotection by nitroxyl. Key findings were as follows: (i) mK(ATP) was activated by O(2)(center dot-) and H(2)O(2) but not other peroxides. (ii) mK(ATP) was inhibited by NADPH. (iii) mK(ATP) was activated by S-nitrosothiols, nitroxyl, and nitrolinoleate. The latter two species also inhibited mitochondrial complex II. (iv) Nitroxyl protected cardiomyocytes against IR injury in an mK(ATP)-dependent manner. Overall, these results suggest that the mK(ATP) channel is activated by specific reactive oxygen and nitrogen species, and inhibited by NADPH. The redox modulation of mK(ATP) may be an underlying mechanism for its regulation in the context of IPC. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. (C) 2010 Elsevier B.V. All rights reserved.

Diagnostics for the Developing World: Microfluidic Paper-Based Analytical Devices

Microfluidic paper-based analytical devices (mu PADs) are a new class of point-of-care diagnostic devices that are inexpensive, easy to use, and designed specifically for use in developing countries. (To listen to a podcast about this feature, please go to the Analytical Chemistry multimedia page at pubs.acs.org/page/ancham/audio/index.html.)

Atenção à saúde da pessoa idosa na estratégia saúde da família no município de Santo Antônio/RN: um estudo de caso

According to demographic estimates, by the year 2025 Brazil will be the sixth country in the world in number of elderly. For this reason, it is a purpose of public policies to help people to reach that age being healthier. The current health care model of health surveillance through the Family Health Strategy (EFS, in portuguese) is configured as a gateway into the care of the elderly in the Unified Health System (SUS, in portuguese). It is also an area of development of practices to promote health, prevention and control of chronic nondegenerative diseases. The aim of this study was to analyze the health care of the elderly provided by ESF professionals for the achievement of a full care. The study is descriptive case study with a quantitative approach, performed in the city of Santo Antônio/RN. The population included all health professionals, who are FHS members of the city that agreed to participate of the survey, a total of 80 professionals. Data were collected using a structured questionnaire, having mostly closed questions and divided into two parts: one containing sociodemographic information of health professionals and vocational training and the other, the activities carried on by the professionals in senior care, being analyzed from a database tabulated in a spreadsheet and discussed according to the descriptive statistics in tables, graphs and charts using frequencies, medians and values of central tendency. It was verified a predominance of professionals who finished highschool, mostly female, aged from 30 to 34 years old, with training completed in the last 10 years, without being graduated in the field of geriatrics or gerontology and mostly without training in gerontology. Family members and caregivers were the components of the social support network most identified by the professionals (66.3%).The elderly access to the Family Health Basic Unit was considered by83.8% of professionals as the most important factor that interferes in the activities of health care of the elderly. Considering the inclusion of the family in care: 98.8% of professionals consider the family as one of the goals of care, but 82.5% assist the family to know their role and participate in the care of the elderly, emphasizing that no professional makes use of tools for evaluating the functionality of the family. Regarding the actions taken to assist the elderly, 91.25% have home visits program to the elderly, 88.75% use the host program; 77.5% know the habits of life, cultural, ethical and religious values of the elderly, their families and their community ;51.25% complement the activities through intersectoral actions, 50%participate in groups of living with the elderly; 33.75% keeps track and maintain updated the health information of the elderly; 11.25% of the professionals perform the Single Therapy Planning (PTS, in portuguese) and few implement the actions to promote health according to PTS; there is a deficit in the number of professional categories in the identification and monitoring of the frail older people in their households. It is concluded that the health care of the elderly developed by ESF professionals differs among the professional categories. It was identified weaknesses in the promotion of an active and healthy aging and also in the establishment of an integrated and full care of the elderly. It is recommended the adoption of permanent educational activities by the City Management, initially for ESF professionals in the the perspective of the guidelines of the National Policy of Health Care for the Elderly and later to the other professionals that are part of the health care network of the elderly, at all levels of care in the city for the development of strategies and practices that promote the improvement of the quality of healthcare for the elderly, expecting concrete and effective results in terms of promoting health within Brazilian reality

A educação permanente em saúde na ótica dos cirurgiões dentistas

This study aimed to examine the perception of dentist-surgeon about the Permanent Education in Health (PEH). It is characterized as a qualitative research with focus in the field of public health policies. It refers specifically to the development of Permanent Education policy in Health in the state of Rio Grande do Norte. They were participants of this research 42 dentist surgeons and 83.3% females and 16.7% males, participants in Specialization courses approved and agreed by the Permanent Education Center in Health (PEC-RN) in the period 2005 to 2007. These professionals are part of the Family Health Strategy (FHS), and 11.9% work in management at the central level and 88.1% are directly related to oral health care in the Basic Health Units of the Family, 30 cities in the state. Data collection was through a questionnaire, with questions that guided the research development and achieve the objectives proposed. The socio-demographic data were analyzed using the descriptive statistics and subjective content was subjected to content analysis by Bardin. The emerging categories from the textual material generated by respondents were: program content, methodological approach and concepts of Permanent Education in Health. The subjects surveyed reported that the program content is more comprehensive and directs to the reflection of everyday practices, with regard to the methodological approach, concern that occurs through discussion and reflection with dynamic, participative, varied and constructive activities, questioning and putting as the main focus. As for understanding of the concepts of the PEH, there was a consensus that define as education stable strategies which contributing to transform and improve the health workers to have the upgrade, improvement of practices, being based on everyday experience and taking into account the accumulation and renewal of these experiences. Therefore, results presented showed that there is a clear understanding of the subjects on the proposals and guidelines of the PEH. It was concluded that lack continuous access to the policies proposed by Ministry of Health involving health workers, managers, communities, through social control and the teaching-service integration and that they are worked within the health system and can classify all these segments of society favor the existence of a more participatory, effective, fair and better quality health service

Fatores relacionados à adesão das drogarias e farmácias de Tatuí-SP no projeto Farmácias Notificadoras

Pharmacovigilance is accomplished by voluntary notification of suspected adverse reactions, medication errors, and deviations from quality, by users and health professionals, through the filling in of forms that are sent to a data bank. To broaden the sources of notifications, the National Health Surveillance Agency (ANVISA), in partnership with the Regional Pharmacy Council (CRF) and Center for Health Surveillance (CVS) of each state, introduced the scheme of Notifying Pharmacies. The present study was aimed at determining the factors influencing the decision of drugstores and private pharmacies in Tatuí/SP in 2007, to join this project A descriptive, observational survey of knowledge, attitude and practice (KAP) was applied to volunteer pharmacists in the town. The results showed that the professionals are awave of pharmacovigilance, (95.24%) and have attitude (95.24%). However, practice is limited (6.0%). Based on this information we concluded that the low support of the project was due to lack of time, interest and no information about the benefits to society of such activity and a lack of support from the pharmacists' organizations. This situation is expected to change with the current introduction of a professional profile, the fusion of professional bodies and the promotion of social awareness on pharmacovigilance.

Distribuição de fisioterapeutas entre estabelecimentos públicos e privados nos diferentes níveis de complexidade de atenção à saúde

Background: The Brazilian Health System is organized on a regional and hierarchical form with three levels of complexity of health care. The Primary Care represents the first element of a continuing health care process, complemented by specialized actions. However, the centrality of the specialized care is still a problem in Brazil, especially in the private sector. Studies on the distribution of professionals in the health system allowing the formulation of appropriate policies are needed. Objectives: To investigate the distribution of physical therapists in the levels of complexity of health care and between public and private establishments, according to data from the National Register of Health Service Providers (NRHSP). Method: A descriptive cross-sectional study was performed considering NRHSP-national bank data collected in March 2010 and demographic census 2010 data. Data were analyzed through descriptive statistics techniques. Results: We identified 53,181 registries of physical therapists, 60% linked to the private sector. Only 13% of all entries were linked to primary care. The predominance in specialized care occurred in the public sector (65%) and private sector (100%). The specialized establishments of private sector linked to the southeast region (16,043) were the main sites of physical therapists. Only the public sector in the south had a majority in the Primary Care. When considering the sizes of the cities, there is focus on specialist care in bigger cities. Conclusions: This study identified the concentration of physical therapists in the specialized care, mostly in metropolis and big cities and in the private sector, with restricted to participation in the primary care.

Ações de Educação Física na saúde coletiva brasileira: expectativas versus evidências

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Review of This Land: A Guide to Central National Forests by Robert H. Mohlenbrock

Robert Mohlenbrock's guide to the national forests of the central U.S. provides the traveling naturalist with a wealth of information on the wide array of national forest lands in the heart of the country. Part of a three-volume series of field guides, this volume covers the states of Louisiana, Minnesota, Missouri, Montana, Nebraska, New Mexico, South Dakota, Texas, and Wyoming. While most of the forests are along the western and eastern borders of the Great Plains, readers will find a detailed travelog for a National Forest within a day's drive of most areas within the region. While not the focus of this volume, a brief mention of the National Grasslands of the Great Plains would have made it more comprehensive for the traveling naturalist.

Macrofaunal succession in sediments around kelp and wood falls in the deep NE Pacific and community overlap with other reducing habitats

Sunken parcels of macroalgae and wood provide important oases of organic enrichment at the deep-sea floor, yet sediment community structure and succession around these habitat islands are poorly evaluated. We experimentally implanted 100-kg kelp falls and 200 kg wood falls at 1670 m depth in the Santa Cruz Basin to investigate (1) macrofaunal succession and (2) species overlap with nearby whale-fall and cold-seep communities over time scales of 0.25-5.5 yr. The abundance of infaunal macrobenthos was highly elevated after 0.25 and 0.5 yr near kelp parcels with decreased macrofaunal diversity and evenness within 0.5 m of the falls. Apparently opportunistic species (e.g., two new species of cumaceans) and sulfide tolerant microbial grazers (dorvilleid polychaetes) abounded after 0.25-0.5 yr. At wood falls, opportunistic cumaceans become abundant after 0.5 yr, but sulfide tolerant species only became abundant after 1.8-5.5 yr, in accordance with the much slower buildup of porewater sulfides at wood parcels compared with kelp falls. Species diversity decreased significantly over time in sediments adjacent to the wood parcels, most likely due to stress resulting from intense organic loading of nearby sediments (up to 20-30% organic carbon). Dorvilleid and ampharetid polychaetes were among the top-ranked fauna at wood parcels after 3.0-5.5 yr. Sediments around kelp and wood parcels provided low-intensity reducing conditions that sustain a limited chemoautrotrophically-based fauna. As a result, macrobenthic species overlap among kelp, wood, and other chemosynthetic habitats in the deep NE Pacific are primarily restricted to apparently sulfide tolerant species such as dorvilleid polychaetes, opportunistic cumaceans, and juvenile stages of chemosymbiont containing vesicomyid bivalves. We conclude that organically enriched sediments around wood falls may provide important habitat islands for the persistence and evolution of species dependent on organic- and sulfide-rich conditions at the deep-sea floor and contribute to beta and gamma diversity in deep-sea ecosystems. (C) 2010 Elsevier Ltd. All rights reserved.

Role of common mental and physical disorders in partial disability around the world

Background Mental and physical disorders are associated with total disability, but their effects on days with partial disability (i.e. the ability to perform some, but not full-role, functioning in daily life) are not well understood. Aims To estimate individual (i.e. the consequences for an individual with a disorder) and societal effects (i.e. the avoidable partial disability in the society due to disorders) of mental and physical disorders on days with partial disability around the world. Method Respondents from 26 nationally representative samples (n=61 259, age 18+) were interviewed regarding mental and physical disorders, and day-to-day functioning. The Composite International Diagnostic Interview, version 3.0 (CIDI 3.0) was used to assess mental disorders; partial disability (expressed in full day equivalents) was assessed with the World Health Organization Disability Assessment Schedule in the CIDI 3.0. Results Respondents with disorders reported about 1.58 additional disability days per month compared with respondents without disorders. At the individual level, mental disorders (especially post-traumatic stress disorder, depression and bipolar disorder) yielded a higher number of days with disability than physical disorders. At the societal level, the population attributable risk proportion due to physical and mental disorders was 49% and 15% respectively. Conclusions Mental and physical disorders have a considerable impact on partial disability, at both the individual and at the societal level. Physical disorders yielded higher effects on partial disability than mental disorders.

Somatic Mosaic Activating Mutations in PIK3CA Cause CLOVES Syndrome

Congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. We hypothesized that CLOVES syndrome would be caused by a somatic mutation arising during early embryonic development. Therefore, we employed massively parallel sequencing to search for somatic mosaic mutations in fresh, frozen, or fixed archival tissue from six affected individuals. We identified mutations in PIK3CA in all six individuals, and mutant allele frequencies ranged from 3% to 30% in affected tissue from multiple embryonic lineages. Interestingly, these same mutations have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity. We conclude that CLOVES is caused by postzygotic activating mutations in PIK3CA. The application of similar sequencing strategies will probably identify additional genetic causes for sporadically occurring, nonheritable malformations.