GRK2 regulates ADP signaling in platelets via P2Y1 and P2Y12.

The critical role of G protein-coupled receptor kinase 2 (GRK2) in regulating cardiac function has been well documented for >3 decades. Targeting GRK2 has therefore been extensively studied as a novel approach to treating cardiovascular disease. However, little is known about its role in hemostasis and thrombosis. We provide here the first evidence that GRK2 limits platelet activation and regulates the hemostatic response to injury. Deletion of GRK2 in mouse platelets causes increased platelet accumulation after laser-induced injury in the cremaster muscle arterioles, shortens tail bleeding time, and enhances thrombosis in adenosine 5'-diphosphate (ADP)-induced pulmonary thromboembolism and in FeCl3-induced carotid injury. GRK2-/- platelets have increased integrin activation, P-selectin exposure, and platelet aggregation in response to ADP stimulation. Furthermore, GRK2-/- platelets retain the ability to aggregate in response to ADP restimulation, indicating that GRK2 contributes to ADP receptor desensitization. Underlying these changes in GRK2-/- platelets is an increase in Ca2+ mobilization, RAS-related protein 1 activation, and Akt phosphorylation stimulated by ADP, as well as an attenuated rise of cyclic adenosine monophosphate levels in response to ADP in the presence of prostaglandin I2. P2Y12 antagonist treatment eliminates the phenotypic difference in platelet accumulation between wild-type and GRK2-/- mice at the site of injury. Pharmacologic inhibition of GRK2 activity in human platelets increases platelet activation in response to ADP. Finally, we show that GRK2 binds to endogenous Gßγ subunits during platelet activation. Collectively, these results show that GRK2 regulates ADP signaling via P2Y1 and P2Y12, interacts with Gßγ, and functions as a signaling hub in platelets for modulating the hemostatic response to injury.

Malaria outbreak response in urban Santo Domingo, Dominican Republic: lessons learned for community engagement.

Community engagement is crucial for public health initiatives, yet it remains an under-studied process within national disease elimination programs. This report shares key lessons learned for community engagement practices during a malaria outbreak response in the Los Tres Brazos neighborhood of urban Santo Domingo, Dominican Republic from 2015-2016. In this two-year period, 233 cases of malaria were reported-more than seven times the number of cases (31) reported in the previous two years. The initial outbreak response by the national malaria program emphasized "top-down" interventions such as active surveillance, vector control, and educative talks within the community. Despite a transient reduction in reported cases in mid-2015, transmission resurged at the end of 2015. The program responded by introducing active roles for trained community members that included door-to-door fever screening, testing with rapid diagnostic tests and treatment. Malaria cases declined significantly throughout 2016 and community-based active surveillance infrastructure helped to detect and limit a small episode of transmission in 2017. Results from qualitative research among community members revealed two key factors that facilitated their cooperation with community-based surveillance activities: motivation to help one's community; and trust among stakeholders (community health workers, their neighbors and other key figures in the community, and malaria program staff and leadership). This experience suggests that community-led interventions and the program's willingness to learn and adapt under changing circumstances can help control malaria transmission and pave the way for elimination.

La participación de la comunidad es crucial para las iniciativas de salud pública, pero sigue siendo un proceso poco estudiado dentro de los programas nacionales de eliminación de enfermedades. En este informe se presentan las principales lecciones aprendidas respecto de las prácticas de participación comunitaria durante la respuesta al brote de malaria en el barrio Los Tres Brazos de la zona urbana de Santo Domingo, República Dominicana, de 2015 a 2016. En este período de dos años se notificaron 233 casos de malaria, más de siete veces el número de casos (31) notificados en los dos años anteriores. La respuesta inicial al brote por parte del programa nacional de malaria hizo hincapié en intervenciones "de arriba abajo" como la vigilancia activa, el control de vectores y las charlas educativas dentro de la comunidad. A pesar de la reducción transitoria de los casos notificados hacia mediados de 2015, la transmisión resurgió a finales de ese año. El programa respondió introduciendo funciones activas para miembros de la comunidad capacitados que incluían la detección de fiebre de casa en casa, pruebas de diagnóstico rápido y tratamiento. Los casos de malaria disminuyeron significativamente durante 2016 y la infraestructura de vigilancia activa basada en la comunidad ayudó a detectar y contener un episodio pequeño de transmisión en 2017. Los resultados de la investigación cualitativa entre los miembros de la comunidad revelaron dos factores clave que facilitaron su cooperación con las actividades de vigilancia basadas en la comunidad: la motivación para ayudar a la propia comunidad y la confianza entre las partes interesadas (los trabajadores sanitarios de la comunidad, los vecinos y otros actores clave de la comunidad, y el personal y la dirección del programa de lucha contra la malaria). Esta experiencia indica que las intervenciones dirigidas por la comunidad y la voluntad del programa de aprender y adaptarse a las circunstancias cambiantes pueden ayudar a controlar la transmisión de la malaria y facilitar el camino para su eliminación.

Malaria outbreak response in urban Santo Domingo, Dominican Republic: lessons learned for community engagement

[ABSTRACT]. Community engagement is crucial for public health initiatives, yet it remains an under-studied process within national disease elimination programs. This report shares key lessons learned for community engagement practices during a malaria outbreak response in the Los Tres Brazos neighborhood of urban Santo Domingo, Dominican Republic from 2015-2016. In this two-year period, 233 cases of malaria were reported—more than seven times the number of cases (31) reported in the previous two years. The initial outbreak response by the national malaria program emphasized “top-down” interventions such as active surveillance, vector control, and educative talks within the community. Despite a transient reduction in reported cases in mid-2015, transmission resurged at the end of 2015. The program responded by introducing active roles for trained community members that included door-to-door fever screening, testing with rapid diagnostic tests and treatment. Malaria cases declined significantly throughout 2016 and community-based active surveillance infrastructure helped to detect and limit a small episode of transmission in 2017. Results from qualitative research among community members revealed two key factors that facilitated their cooperation with community-based surveillance activities: motivation to help one’s community; and trust among stakeholders (community health workers, their neighbors and other key figures in the community, and malaria program staff and leadership). This experience suggests that community-led interventions and the program’s willingness to learn and adapt under changing circumstances can help control malaria transmission and pave the way for elimination.

[RESUMEN]. La participación de la comunidad es crucial para las iniciativas de salud pública, pero sigue siendo un proceso poco estudiado dentro de los programas nacionales de eliminación de enfermedades. En este informe se presentan las principales lecciones aprendidas respecto de las prácticas de participación comunitaria durante la respuesta al brote de malaria en el barrio Los Tres Brazos de la zona urbana de Santo Domingo, República Dominicana, de 2015 a 2016. En este período de dos años se notificaron 233 casos de malaria, más de siete veces el número de casos (31) notificados en los dos años anteriores. La respuesta inicial al brote por parte del programa nacional de malaria hizo hincapié en intervenciones "de arriba abajo" como la vigilancia activa, el control de vectores y las charlas educativas dentro de la comunidad. A pesar de la reducción transitoria de los casos notificados hacia mediados de 2015, la transmisión resurgió a finales de ese año. El programa respondió introduciendo funciones activas para miembros de la comunidad capacitados que incluían la detección de fiebre de casa en casa, pruebas de diagnóstico rápido y tratamiento. Los casos de malaria disminuyeron significativamente durante 2016 y la infraestructura de vigilancia activa basada en la comunidad ayudó a detectar y contener un episodio pequeño de transmisión en 2017. Los resultados de la investigación cualitativa entre los miembros de la comunidad revelaron dos factores clave que facilitaron su cooperación con las actividades de vigilancia basadas en la comunidad: la motivación para ayudar a la propia comunidad y la confianza entre las partes interesadas (los trabajadores sanitarios de la comunidad, los vecinos y otros actores clave de la comunidad, y el personal y la dirección del programa de lucha contra la malaria). Esta experiencia indica que las intervenciones dirigidas por la comunidad y la voluntad del programa de aprender y adaptarse a las circunstancias cambiantes pueden ayudar a controlar la transmisión de la malaria y facilitar el camino para su eliminación.

The roles of stakeholder experience and organizational learning in declining mass drug administration coverage for lymphatic filariasis in Port-au-Prince, Haiti: A case study.

The World Health Organization (WHO) defines an effective round of mass drug administration (MDA) for lymphatic filariasis (LF) as one that reaches at least 65% of the target population. In its first round of MDA in 2011-2012, the National Program to Eliminate LF in Haiti achieved a 79% epidemiological coverage in urban Port-au-Prince. In 2013, coverage dropped below the WHO threshold and has declined year-over-year to a low of 41% in 2017. We conducted a retrospective qualitative case study to identify key factors behind the decline in coverage in Port-au-Prince and ways to address them. Our findings suggest that the main contributors to the decline in MDA coverage appear to be the absence of effective documentation of practices, reporting, analysis, and program quality improvement-i.e., learning mechanisms-within the program's MDA design and implementation strategy. In addition to their contribution to the program's failure to meet its coverage targets, these deficits have resulted in a high cost for the MDA campaign in both lost momentum and depleted morale. Through a proposed operating logic model, we explore how the pathway from program inputs to outcomes is influenced by a wide array of mediating factors, which shape potential participants' experience of MDA and, in turn, influence their reasoning and decisions to take, or not take, the pills. Our model suggests that the decisions and behavior of individuals are a reflection of their overall experience of the program itself, mediated through a host of contextual factors, and not simply the expression of a fixed choice or preference. This holistic approach offers a novel and potentially valuable framing for the planning and evaluation of MDA strategies for LF and other diseases, and may be applicable in a variety of global health programs.

Citizen science data reveals the cryptic migration of the common potoo Nyctibius griseus in Brazil

The Common Potoo Nyctibius griseus is abundant, charismatic and generally considered to be sedentary across its range. Using citizen science data from eBird and WikiAves, we demonstrate that the Common Potoo may be a partial migrant whose breeding populations depart southeastern Brazil, Uruguay and northern Argentina in May to August during the region’s austral winter. MaxEnt models revealed that spatio‐temporal shifts in Common Potoo distributions were driven by seasonal changes in temperature and precipitation. We examined potential seasonal detection biases by restricting our analysis to daytime observations and testing for seasonally dependent shifts in distribution for two nocturnal non‐migratory species. Our results provide the first evidence of migration for any member of the family Nyctibiidae. Our approach exposes the potential value that WikiAves data offer towards elucidating seasonal movements of South American birds.

Natural variation in expression of genes associated with carotenoid biosynthesis and accumulation in cassava (Manihot esculenta Crantz) storage root.

BACKGROUND: Cassava (Manihot esculenta Crantz) storage root provides a staple food source for millions of people worldwide. Increasing the carotenoid content in storage root of cassava could provide improved nutritional and health benefits. Because carotenoid accumulation has been associated with storage root color, this study characterized carotenoid profiles, and abundance of key transcripts associated with carotenoid biosynthesis, from 23 landraces of cassava storage root ranging in color from white-to-yellow-to-pink. This study provides important information to plant breeding programs aimed at improving cassava storage root nutritional quality. RESULTS: Among the 23 landraces, five carotenoid types were detected in storage root with white color, while carotenoid types ranged from 1 to 21 in storage root with pink and yellow color. The majority of storage root in these landraces ranged in color from pale-to-intense yellow. In this color group, total ß-carotene, containing all-E-, 9-Z-, and 13-Z-ß-carotene isomers, was the major carotenoid type detected, varying from 26.13 to 76.72 %. Although no α-carotene was observed, variable amounts of a α-ring derived xanthophyll, lutein, was detected; with greater accumulation of α-ring xanthophylls than of ß-ring xanthophyll. Lycopene was detected in a landrace (Cas51) with pink color storage root, but it was not detected in storage root with yellow color. Based on microarray and qRT-PCR analyses, abundance of transcripts coding for enzymes involved in carotenoid biosynthesis were consistent with carotenoid composition determined by contrasting HPLC-Diode Array profiles from storage root of landraces IAC12, Cas64, and Cas51. Abundance of transcripts encoding for proteins regulating plastid division were also consistent with the observed differences in total ß-carotene accumulation. CONCLUSIONS: Among the 23 cassava landraces with varying storage root color and diverse carotenoid types and profiles, landrace Cas51 (pink color storage root) had low LYCb transcript abundance, whereas landrace Cas64 (intense yellow storage root) had decreased HYb transcript abundance. These results may explain the increased amounts of lycopene and total ß-carotene observed in landraces Cas51 and Cas64, respectively. Overall, total carotenoid content in cassava storage root of color class representatives were associated with spatial patterns of secondary growth, color, and abundance of transcripts linked to plastid division. Finally, a partial carotenoid biosynthesis pathway is proposed.

Zika virus infections in Military Health System beneficiaries since the introduction of the virus in the Western Hemisphere, 1 January 2016 through 30 November 2016.

The introduction and rapid spread of Zika virus (ZIKV) across the Western Hemisphere have posed a risk of infection to Military Health System (MHS) beneficiaries. The associated consequences of infection and the dynamics of transmission may place a unique burden on military personnel, their dependents, and the MHS. This article summarizes the impact of ZIKV transmission on MHS beneficiaries between 1 January and 30 November 2016. Cases were identified from a variety of sources, including direct reporting from the services, extraction of laboratory data, and data from the Defense Medical Surveillance System (DMSS) Reportable Medical Events database. There have been 156 confirmed cases of Zika in MHS beneficiaries, including five Zika cases in pregnant beneficiaries and 110 cases in service members. A majority of cases reported exposure in Puerto Rico (n=91, 58.3%). Although most ZIKV infections are asymptomatic or have a relatively mild illness, the gravity of pregnancy and neurologic issues linked to infection remains a significant impetus for the continued surveillance of ZIKV in the MHS population.

Chikungunya infection in DoD healthcare beneficiaries following the 2013 introduction of the virus into the Western Hemisphere, 1 January 2014 to 28 February 2015.

The introduction and rapid spread of chikungunya virus (CHIKV) into the Western Hemisphere after December 2013 pose a potentially significant risk to Department of Defense (DoD) personnel, operations, and the military healthcare system. This report describes the DoD experience with CHIKV between January 2014 and February 2015 using case reports in the Defense Medical Surveillance System's (DMSS) Reportable Medical Events database and the Navy and Marine Corps Public Health Center's laboratory test results database. Case finding identified 157 confirmed cases; of these, 118 (75.2%) were either active or reserve component service members and 39 (24.8%) were other beneficiaries. Exposure locations were known for 117 (74.5%) of all cases, and of these, 113 (96.6%) reported likely exposures in the Western Hemisphere; 85 (75.2%) of those cases occurred in Puerto Rico. Although historical data on CHIKV in DoD populations are scant, introduction of CHIKV into the Western Hemisphere with ongoing transmission appears to have resulted in a significant increase in the number of cases among DoD healthcare beneficiary populations.

Mercury concentrations, speciation, and isotopic composition in sediment from a cold seep in the northern Gulf of Mexico.

Total-Hg, monomethylmercury (MMHg), and mercury isotopic composition was determined in sediment from a cold seep and background sites in the northern Gulf of Mexico (nGoM). Total-Hg averaged 50 ng/g (n=28), ranged from 31 to 67 ng/g, and decreased with depth (0-15 cm). MMHg averaged 0.91 ng/g (n=18), and ranged from 0.2 to 1.9 ng/g. There was no significant difference for total-Hg or MMHg between cold seep and background sites. δ(202)Hg ranged from -0.5 to -0.8‰ and becomes more negative with depth (r=0.989). Mass independent fractionation (Δ(199)Hg) was small but consistently positive (0.04-0.12‰); there was no difference between cold seeps (Δ(199)Hg = +0.09±0.03; n=7, 1SD) and background sites (Δ(199)Hg=+0.07±0.02; n=5, 1SD). This suggests that releases of hydrocarbons at the cold seep do not significantly alter Hg levels, and that cold seeps are likely not major sources of MMHg to nGoM waters.

Characterization of Carotenoid-protein Complexes and Gene Expression Analysis Associated with Carotenoid Sequestration in Pigmented Cassava (Manihot Esculenta Crantz) Storage Root.

Carotenoid-protein complex (CPC) was isolated from chromoplast-enriched suspensions of cassava storage root (CSR) using size exclusion chromatography and characterized. Peptide sequences (LC_MS/MS spectrum) obtained from CPC and their corresponding proteins were obtained using publically available databases. Small Heat Shock Proteins (sHSPs) were the most abundant proteins identified in the CPC. Western blot analysis showed that Fribrillin and Or-protein were present in chromoplast-enriched suspensions of yellow root but not in the complex or white root. Results from qRT-PCR helped identify an isoform of HSP21 possessing four single point mutations in the intense yellow CSR that may be responsible for increased sequestration of b-carotene.

Utilidad de los anestésicos locales en anestesia regional / Local anesthetics for regional anesthesia: an update

La anestesia regional en el siglo XXI, específicamente el bloqueos nervioso periférico y el bloqueo continuo de nervios periféricos, siguen gozando de una popularidad sin precedentes. A pesar de este resurgimiento de la popularidad, la investigación de un anestésico local nuevo y de acción más prolongada e inyectable con mejor perfil de seguridad sigue siendo un objetivo distante y difícil de lograr. Se han creado pocos anestésicos locales nuevos para uso clínico desde comienzos de la década de 1970. Los esfuerzos por mejorar la eficacia, la duración y la seguridad de los anestésicos locales inyectables incluyen aditivos y la nueva tecnología de localización de la aguja. Cualquier explicación convincente de los anestésicos locales de uso frecuente utilizados en la anestesia regional debe incluir un resumen detallado de la toxicidad de los anestésicos locales que incluya prevención, detección y tratamiento. Se plantea un enfoque específico sobre la aparición reciente de intralipid como tratamiento de la cardiotoxicidad inducida por anestésicos locales. Esta revisión de los anestésicos locales examinará la farmacología básica, explorará las tendencias actuales en la práctica de la anestesia regional y describirá los adelantos recientes en el uso clínico de los anestésicos locales y sus aditivos.

Regional anesthesia in the 21st century, specifically peripheral nerve blocks (PNBs) and continuous peripheralnerve blocks (CPNBs), continues to enjoy unparalleled popularity. Despite this resurgence in popularity, thesearch for a new, longer-acting local anesthetic (LA) forinjection with an improved safety profile remains anelusive and distant goal. A paucity of new local anestheticshas been developed for clinical use since the early 1970’s.Efforts to improve the efficacy, duration, and safety ofinjected LAs include drug additives to LAs and new need lelocalization technology. Any cogent discussion of the common LAs used with regional anesthesia must includea thorough summary of LA toxicity to include prevention,detection, and treatment. A specific focus on the recentemergence of Intralipid as a treatment for local anestheticinducedcardiac toxicity will ensue. This LA review willexamine basic pharmacology, explore current trends in regional anesthesia practice, and describe recent developments in the clinical use of LA and additives.

Assessing evidence for a pervasive alteration in tropical tree communities.

In Amazonian tropical forests, recent studies have reported increases in aboveground biomass and in primary productivity, as well as shifts in plant species composition favouring fast-growing species over slow-growing ones. This pervasive alteration of mature tropical forests was attributed to global environmental change, such as an increase in atmospheric CO2 concentration, nutrient deposition, temperature, drought frequency, and/or irradiance. We used standardized, repeated measurements of over 2 million trees in ten large (16-52 ha each) forest plots on three continents to evaluate the generality of these findings across tropical forests. Aboveground biomass increased at seven of our ten plots, significantly so at four plots, and showed a large decrease at a single plot. Carbon accumulation pooled across sites was significant (+0.24 MgC ha(-1) y(-1), 95% confidence intervals [0.07, 0.39] MgC ha(-1) y(-1)), but lower than reported previously for Amazonia. At three sites for which we had data for multiple census intervals, we found no concerted increase in biomass gain, in conflict with the increased productivity hypothesis. Over all ten plots, the fastest-growing quartile of species gained biomass (+0.33 [0.09, 0.55] % y(-1)) compared with the tree community as a whole (+0.15 % y(-1)); however, this significant trend was due to a single plot. Biomass of slow-growing species increased significantly when calculated over all plots (+0.21 [0.02, 0.37] % y(-1)), and in half of our plots when calculated individually. Our results do not support the hypothesis that fast-growing species are consistently increasing in dominance in tropical tree communities. Instead, they suggest that our plots may be simultaneously recovering from past disturbances and affected by changes in resource availability. More long-term studies are necessary to clarify the contribution of global change to the functioning of tropical forests.

Infection with group C rotavirus in a suburban community in Brazil.

Group C rotaviruses are associated with sporadic outbreaks of gastroenteritis worldwide. Age-specific seroprevalence of group C rotavirus antibodies was investigated in sera, randomly collected and representative of a suburban community in Brazil which had previously been screened for group A rotavirus antibodies. Antibody prevalence to group C rotavirus was low in children under 5 years and increased slowly with age to 36% seropositivity in adults, reflecting continuous exposure to primary infection in all age groups. This suggests a higher incidence of infection than disease might predict. Adult antibody prevalence was similar to that in other geographical settings. No obvious patterns of infection with group A and group C rotavirus were found within individuals, which suggests independent transmission. However, further epidemiological studies are required to understand group C rotavirus dynamics and possible interactions with group A rotavirus transmission and immunity.

Blood polymorphisms and morphological variability in Brazilian Indians.

A total of 1,025 adults belonging to four Brazilian tribes were simulataneously studied for 12-16 anthropometric characteristics and 7-11 blood polymorphic loci. Several comparisons using both univariate and multivariate statistical techniques failed to show the negative correlation between these two sets of variables found by other workers. © 1994 Wiley-Liss, Inc.

Sindrome de Cushing / Cushing's syndrome

Las entidades clinicas que causan el sindrome de Cushing son muy diversas pero, con contadas excepciones, producen siempre los mismos signos y sintomas. Por ello, alcanzar un diagnostico causal definitivo puede parecerle al medico atareado de atencion primaria una labor demnadante de tiempo. En este ariiculo el autor simplifica el proceso diagnostico con su descripcion tanto de las mas probables causas del exceso de glucocorticoides, como de los procedimientos diagnosticos y metodos terapeuticos especificos