Does gamma-aminobutyric acid (GABA) influence the development of chronic inflammation in rheumatoid arthritis?

<p>Abstract</p> <p>Background</p> <p>Recent studies have demonstrated a role for spinal p38 MAP kinase (MAPK) in the development of chronic inflammation and peripheral arthritis and a role for GABA in the inhibition of p38 MAPK mediated effects. Integrating these data suggests that GABA may play a role in downregulating mechanisms that lead to the production of proinflammatory agents such as interleukin-1, interleukin-6, and matrix metalloproteinase 3 – agents implicated in the pathogenesis of rheumatoid arthritis (RA). Genetic studies have also associated RA with members of the p38 MAPK pathway.</p> <p>Hypothesis</p> <p>We propose a hypothesis for an inefficient GABA signaling system that results in unchecked proinflammatory cytokine production via the p38 MAPK pathway. This model also supports the need for increasing research in the integration of immunology and neuroscience.</p

Is salinity the main ecologic factor that shapes the distribution of two endemic Mediterranean plant species of the genus Gypsophila?

The final publication is available at Springer via http://dx.doi.org/10.1007/s11104-014-2218-2Aims Responses to salt stress of two Gypsophila species that share territory, but with different ecological optima and distribution ranges, were analysed. G. struthium is a regionally dominant Iberian endemic gypsophyte, whereas G. tomentosa is a narrow endemic reported as halophyte. Theworking hypothesis is that salt tolerance shapes the presence of these species in their specific habitats. Methods Taking a multidisciplinary approach, we assessed the soil characteristics and vegetation structure at the sampling site, seed germination and seedling development, growth and flowering, synthesis of proline and cation accumulation under artificial conditions of increasing salt stress and effect of PEG on germination and seedling development. Results Soil salinity was low at the all sampling points where the two species grow, but moisture was higher in the area of G. tomentosa. Differences were found in the species salt and drought tolerance. The different parameters tested did not show a clear pattern indicating the main role of salt tolerance in plant distribution. Conclusions G. tomentosa cannot be considered a true halophyte as previously reported because it is unable to complete its life cycle under salinity. The presence of G. tomentosa in habitats bordering salt marshes is a strategy to avoid plant competition and extreme water stressSoriano, P.; Moruno Manchón, JF.; Boscaiu Neagu, MT.; Vicente Meana, Ó.; Hurtado, A.; Llinares Palacios, JV.; Estrelles, E. (2014). Is salinity the main ecologic factor that shapes the distribution of two endemic Mediterranean plant species of the genus Gypsophila?. Plant and Soil. 384(1-2):363-379. doi:10.1007/s11104-014-2218-2S3633793841-2Alonso MA (1996) Flora y vegetación del Valle de Villena (Alicante). Instituto de Cultura Juan Gil-Albert, AlicanteAlvarado JJ, Ruiz JM, López-Cantarero I, Molero J, Romero L (2000) Nitrogen metabolism in five plant species characteristic of gypsiferous soils. Plant Physiol 156:612–616Ashraf M, Foolad MR (2007) Roles of glycine betaine and proline in improving plant abiotic stress resistance. Environ Exp Bot 59:206–216Ashraf MY (2009) Salt tolerance mechanisms in some halophytes from Saudi Arabia and Egypt. Res J Agric Biol Sci 5:191–206Bates LS, Waldren RP, Tear LD (1973) Rapid determination of free proline for water-stress studies. Plant Soil 39:205–207Ben-Gal A, Neori-Borochov H, Yermiyahu U, Shani U (2009) Is osmotic potential a more appropriate property than electrical conductivity for evaluating whole plant response to salinity? Environ Exp Bot 65:232–237Biondi E (2011) Phytosociology today: Methodological and conceptual evolution. Plant Biosyst 145:19–29Boscaiu M, Bautista I, Lidón A, Llinares J, Lull C, Donat P, Mayoral O, Vicente O (2013a) Environmental-dependent proline accumulation in plants living on gypsum soils. Acta Physiol Plant 35:2193–2204Boscaiu M, Llul C, Llinares J, Vicente O, Boira H (2013b) Proline as a biochemical marker in relation to the ecology of two halophytic Juncus species. J Plant Ecol 6:177–186Bradford KJ (1990) A water relations analysis of seed germination rates. Plant Physiol 94:840–849Breckle SW (1999) Halophytic and gypsophytic vegetation of the Ebro-Basin at Los Monegros. In: Melic A, Blasco-Zumeta J (eds) Manifiesto científico por Los Monegros, vol 24, Bol. SEA., pp 101–104Brenchley JL, Probert RJ (1998) Seed germination responses to some environmental factors in the sea grass Zoostera capricorni from eastern Australia. Aquat Bot 62:177–188Cañadas EM, Ballesteros M, Valle F, Lorite J (2013) Does gypsum influence seed germination? Turk J Bot 38:141–147Chen Z, Cuin TA, Zhou M et al (2007) Compatible solute accumulation and stress-mitigating effects in barley genotypes contrasting in their salt tolerance. J Exp Bot 58:4245–4255Chutipaijit S, Cha-Um S, Sompornailin K (2009) Differential accumulation of proline and flavonoids in Indica rice varieties against salinity. Pak J Bot 41:2497–2506Cushman JC (2001) Osmoregulation in plants: implications for agriculture. Am Zool 41:758–769Debussche M, Thompson JD (2003) Habitat differentiation between two closely related Mediterranean plant species, the endemic Cyclamen balearicum and the widespread C. repandum. Acta Oecol 24:35–45Eskandari H, Kazemi K (2011) Germination and seedling properties of different wheat cultivars under salinity conditions. Not Sci Biol 3:130–134FAO (2006) Guidelines for soil descriptions, 5th edn. Food and Agricultural Organization of United Nation, RomeFerrandis P, Herranz JM, Copete MA (2005) Caracterización florística y edáfica de las estepas yesosas de Castilla-La Mancha. Invest Agrar Sist Recur For 14:195–216Flowers TJ, Hall JL (1978) Salt tolerance in Suaeda maritima (L.) Dum. The effect of sodium chloride on growth and soluble enzymes in a comparative study with Pisum sativum L. J Exp Bot 23:310–321Flowers TJ, Colmer TD (2008) Salinity tolerance in halophytes. New Phytol 179:945–963Flowers TJ, Hajibagheri MA, Clipson NJW (1986) Halophytes. Q Rev Biol 61:313–335García-Fuentes A, Salazar C, Torres JA, Cano E, Valle F (2001) Review of communities of Lygeum spartum L. in the south-eastern Iberian Peninsula (western Mediterranean). J Arid Environ 48:323–339Géhu JM (2006) Dictionnaire de Sociologie et Synécologie Végétales. J. Cramer, Berlin-Stuttgart, p 899Géhu JM (2011) On the opportunity to celebrate the centenary of modern phytosociology in 2010. Plant Biosyst 145(suppl):4–8Ghassemi F, Jakeman AJ, Nix HA (1995) Salinisation of land and water resources: human causes, extent, management and case studies. Canberra, Australia. CAB International, The Australian National University, WallingfordGrigore MN, Boscaiu M, Vicente O (2011) Assessment of the relevance of osmolyte biosynthesis for salt tolerance of halophytes under natural conditions. Eur J Plant Sci Biotech 5:12–19Grigore MN, Villanueva M, Boscaiu M, Vicente O (2012a) Do halophytes really require salts for their growth and development? An experimental approach mitigation of salt stress-induced inhibition of Plantago crassifolia reproductive development by supplemental calcium or magnesium. Not Sci Biol 4:23–29Grigore MN, Boscaiu M, Llinares J, Vicente O (2012b) Mitigation of salt stressed-induced Inhibition of Plantago crassifolia reproductive development by supplemental calcium or magnesium. Not Bot Horti Agrobo 40:58–66Hare PD, Cress WA (1997) Metabolic implications of stress-induced proline accumulation in plants. Plant Growth Regul 21:79–102Ishikawa SI, Kachi N (2000) Differential salt tolerance of two Artemisia species growing in contrasting coastal habitats. Ecol Res 15:241–247Kebreab E, Murdoch AJ (1999) Modelling the effects of water stress and temperature on germination rate of Orobanche aegyptiaca seeds. J Exp Bot 50:655–664Khan MA (2002) Halophyte seed germination: Success and Pitfalls. In: Hegazi AM, El-Shaer HM, El-Demerdashe S et al (eds) International symposium on optimum resource utilization in salt affected ecosystems in arid and semi arid regions. Desert Research Centre, Cairo, pp 346–358Khan MA, Gul B, Weber DJ (2000) Germination responses of Salicornia rubra to temperature and salinity. J Arid Environ 45:207–214Khan A, Rayner GD (2003) Robustness to non-normality of common tests for the many-sample location problem. J Appl Math Decis Sci 7:187–206Lidón A, Boscaiu M, Collado F, Vicente O (2009) Soil requirements of three salt tolerant, endemic species from south-east Spain. Not Bot Horti Agrobo 37:64–70López González G (1990) Gypsohila L. In: Castroviejo S, Laínz M, López G et al (eds) Flora Ibérica 2. Real Jardín Botánico, Madrid, pp 408–415Lutts S, Kinet JM, Bouharmont J (1996) Effects of salt stress on growth, mineral nutrition and proline accumulation in relation to osmotic adjustment in rice (Oryza sativa L.) cultivars differing in salinity resistance. Plant Growth Regul 19:207–218Madidi S, Baroudi B, Ameur FB (2004) Effects of salinity on germination and early growth of barley (Hordeum vulgare L.) cultivars. Int J Agric Biol 6:767–770Marchal FM, Lendínez ML, Salazar C, Torres JA (2008) Aportaciones al conocimiento de la vegetación gispsícola en el occidente de la provincia de Granada (sur de España). Lazaroa 29:95–100Médail F, Verlaque R (1997) Ecological characteristics and rarity of endemic plants from southern France and Corsica: implications for biodiversity conservation. Biol Conserv 80:269–281Meyer SE (1986) The ecology of gypsophile endemism in the Eastern Mojave desert. Ecology 67:1303–1313Moruno F, Soriano P, Oscar V, Boscaiu M, Estrelles E (2011) Opportunistic germination behaviour of Gypsophila (Caryophyllaceae) in two priority habitats from semi-arid Mediterranean steppes. Not Bot Horti Agrobo 9:18–23Mota JF, Sánchez Gómez P, Merlo Calvente ME, Catalán Rodríguez P, Laguna Lumbreras E, de la Cruz RM, Navarro Reyes FB, Marchal Gallardo F, Bartolomé Esteban C, Martínez Labarga JM, Sainz Ollero H, Valle Tendero F, Serra Laliga L, Martínez Hernández F, Garrido Becerra JA, Pérez García FJ (2009) Aproximación a la checklist de los gipsófitos ibéricos. An Biol 31:71–80Mota JF, Sola AJ, Jiménez-Sánchez ML, Pérez-García F, Merlo ME (2004) Gypsicolous flora, conservation and restoration of quarries in the southeast of the Iberian Peninsula. Biodivers Conserv 13:1797–1808Munns R (2002) Comparative physiology of salt and water stress. Plant Cell Environ 25:239–250Palacio S, Escudero A, Montserrat-Martí G, Maestro M, Milla R, Albert M (2007) Plants living on gypsum: beyond the specialist model. Ann Bot 99:333–343Peinado M, Martínez-Parras JM (1982) Sobre la posición fitosociológica de Gypsophila tomentosa L. Lazaroa 4:129–140Pueyo Y, Alados CL, Maestro M, Komac B (2007) Gypsophile vegetation patterns under a range of soil properties induced by topographical position. Plant Ecol 189:301–311Rasband WS (1997–2012) ImageJ. U S National Institutes of Health. http://rsb.info.nih.gov/ij/ , Bethesda, MarylandRivas-Martínez S (2005) Notions on dynamic-catenal phytosociology as a basis of landscape science. Plant Biosyst 139:135–144Rivas-Martínez S, Rivas-Saenz S (1996–2009) Worldwide bioclimatic classification system, Phytosociological Research Center, Spain. http://www.globalbioclimatics.org . Accessed 1 July 2013Rivas-Martínez S, Fernández-González F, Loidi J, Lousã M, Penas A (2001) Syntaxonomical checklist of vascular plant communities of Spain and Portugal to association level. Itinera Geobot 14:5–341Salmerón-Sánchez E, Martínez-Nieto MI, Martínez-Hernández F, Garrido-Becerra JA, Mendoza-Fernández AJ, Gil de Carrasco C, Ramos-Miras JJ, Lozano R, Merlo ME, Mota JF (2014) Ecology, genetic diversity and phylogeography of the Iberian endemic plant Jurinea pinnata (Lag.) DC. (Compositae) on two special edaphic substrates: dolomite and gypsum. Plant Soil 374:233–250Saradhi P, Alia P, Arora S, Prasad KV (1995) Proline accumulates in plants exposed to UV radiation and protects them against UV induced peroxidation. Biochem Biophys Res Commun 209:1–5Sekmen AH, Turkan I, Tanyolac ZO, Ozfidan C, Dinc A (2012) Different antioxidant defense responses to salt stress during germination and vegetative stages of endemic halophyte Gypsophila oblanceolata Bark. Environ Exp Bot 77:63–76Tipirdamaz R, Gagneul D, Duhaze C, Ainouche A, Monnier C, Ozkum D, Larher F (2006) Clustering of halophytes from an inland salt marsh in Turkey according to their ability to accumulate sodium and nitrogenous osmolytes. Environ Exp Bot 57:139–153Ungar IA (1996) Effect of salinity on seed germination, growth, and ion accumulation of Atriplex patula (Chenopodiaceae). Am J Bot 83:604–607USDA-ARS (2008) Research databases. Bibliography on salt tolerance. George E. Brown, Jr. Salinity Lab. US Dep. Agric., Agric. Res. Serv. Riverside, CA. http://www.ars.usda.gov/Services/docs.htm?docid=8908USSL Staff (1954) Diagnosis and improvement of saline and alkali soils. US Department of Agriculture Handbook no. 60, 160 ppVicente O, Boscaiu M, Naranjo M, Estrelles E, Bellés JM, Soriano P (2004) Responses to salt stress in the halophyte Plantago crassifolia (Plantaginaceae). J Arid Environ 58:463–48

A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling

Inflammation, airway hyper-responsiveness and airway remodelling are well-established hallmarks of asthma, but their inter-relationships remain elusive. In order to obtain a better understanding of their inter-dependence, we develop a mechanochemical morphoelastic model of the airway wall accounting for local volume changes in airway smooth muscle (ASM) and extracellular matrix in response to transient inflammatory or contractile agonist challenges. We use constrained mixture theory, together with a multiplicative decomposition of growth from the elastic deformation, to model the airway wall as a nonlinear fibre-reinforced elastic cylinder. Local contractile agonist drives ASM cell contraction, generating mechanical stresses in the tissue that drive further release of mitogenic mediators and contractile agonists via underlying mechanotransductive signalling pathways. Our model predictions are consistent with previously described inflammation-induced remodelling within an axisymmetric airway geometry. Additionally, our simulations reveal novel mechanotransductive feedback by which hyper-responsive airways exhibit increased remodelling, for example, via stress-induced release of pro-mitogenic and procontractile cytokines. Simulation results also reveal emergence of a persistent contractile tone observed in asthmatics, via either a pathological mechanotransductive feedback loop, a failure to clear agonists from the tissue, or a combination of both. Furthermore, we identify various parameter combinations that may contribute to the existence of different asthma phenotypes, and we illustrate a combination of factors which may predispose severe asthmatics to fatal bronchospasms

Five insights from the Global Burden of Disease Study 2019

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3.5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.Peer reviewe

Identification of a biological signature for schizophrenia in serum

Biomarkers are now used in many areas of medicine but are still lacking for psychiatric conditions such as schizophrenia (SCZ). We have used a multiplex molecular profiling approach to measure serum concentrations of 181 proteins and small molecules in 250 first and recent onset SCZ, 35 major depressive disorder (MDD), 32 euthymic bipolar disorder (BPD), 45 Asperger syndrome and 280 control subjects. Preliminary analysis resulted in identification of a signature comprised of 34 analytes in a cohort of closely matched SCZ (n = 71) and control (n = 59) subjects. Partial least squares discriminant analysis using this signature gave a separation of 60-75% of SCZ subjects from controls across five independent cohorts. The same analysis also gave a separation of similar to 50% of MDD patients and 10-20% of BPD and Asperger syndrome subjects from controls. These results demonstrate for the first time that a biological signature for SCZ can be identified in blood serum. This study lays the groundwork for development of a diagnostic test that can be used as an aid for distinguishing SCZ subjects from healthy controls and from those affected by related psychiatric illnesses with overlapping symptoms. Molecular Psychiatry (2012) 17, 494-502; doi:10.1038/mp.2011.42; published online 12 April 201

Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages. Methods Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (≥65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0–100 based on the 2·5th and 97·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—we estimated additional population equivalents with UHC effective coverage from 2018 to 2023. Findings Globally, performance on the UHC effective coverage index improved from 45·8 (95% uncertainty interval 44·2–47·5) in 1990 to 60·3 (58·7–61·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2·6% [1·9–3·3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010–2019 relative to 1990–2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach $1398 pooled health spending per capita (US$ adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388·9 million (358·6–421·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3·1 billion (3·0–3·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968·1 million [903·5–1040·3]) residing in south Asia. Interpretation The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all people—the ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how close—or how far—all populations are in benefiting from UHC. Funding Bill & Melinda Gates Foundation

Flow Cytometric Analysis of Leishmania Reactive CD4+/CD8+ Lymphocyte Proliferation in Cutaneous Leishmaniasis

Background: Determination of the division history of T cells in vitro is helpful in the study of effector mechanisms against infections. Technique described here uses the intracellular fluorescent label carboxyfluorescein diacetate succinimidyl ester (CFSE) to monitor the proliferation. Methods: In a cross sectional study, blood samples were collected from 7 volunteers with history of cutaneous leishmania­sis (CL) and one healthy control from endemic areas in Isfahan province who referred to the Center for Research and Training in Skin Diseases and Leprosy (CRTSDL), then CD4+/CD8+ lymphocytes and CD14+ monocytes were isolated from peri­pheral blood mononuclear cells (PBMC) using mAbs and magnetic nanoparticles. CFSE labeled CD4+ or CD8+ lympho­cytes cultured with autologous monocytes in the presence of PHA, SLA, live Leishmania major or as control with­out sti­mulation. Cells were harvested after 7 days and were analyzed using flow cytometry. Results: Five consecutive divisions were monitored separately. Stimulation of CD4+ or CD8+ lymphocytes from CL sub­jects with SLA showed a significant difference in proliferation comparing with unstimulated cells (P< 0.05). The signifi­cant difference in the percentages of CD4+ cells stimulated with SLA was revealed at different divisions for each subject. In CD8+ lymphocyte, significant stronger stimulation of SLA was evident later in the proliferation process. The mean number of divisions in both CD4+/CD8+ lymphocytes stimulated with SLA was significantly greater than when stimulated with live L. major (P=0.007 / P=0.012, respectively) Conclusion: The percentage of divided cells might be calculated separately in each division. The cells remained active following CFSE staining and there is possibility of functional analysis simultaneously