Transferosomas conteniendo ftalocianina de aluminio clorada como alternativa terapeútica en leishmaniasis cutánea: permeabilidad y biodistribución en ratas Wistar

Introducción: Los transferosomas o liposomas ultradeformables (LUD) conteniendo ftalocianina de aluminio clorada (LUD-PcAlCl) podrían constituir un vehículo transdérmico de liberación de compuestos en el tratamiento de la leishmaniasis cutánea.  Objetivo: Evaluar la permeabilidad, retención y biodistribución de los LUD-PcAlCl in vivo. Metodología: Los trasnferosomas fueron obtenidos mediante rehidratación de película lipídica. Ratas Wistar fueron tratadas tópica e intraperitonealmente con los transferosomas por 5 días. La penetración ex vivo fue determinada mediante el ensayo en celdas de Franz y la retención por el método de la cinta adhesiva. Cinco y treinta días post-tratamiento se obtuvo la piel y órganos para determinar la retención del compuesto y realizar estudios histopatológicos. La PcAlCl fue extraída con solventes y cuantificada por fluorometría. Los resultados se expresaron en nM PcAlCl/mg órgano. Resultados: La PcAlCl no penetró la piel en los ensayos ex vivo reteniéndose principalmente en el estrato corneo. Cinco días post-tratamiento tópico la PcAlCl fue retenida en estrato córneo (41,76±0,02) mostrando concentraciones mínimas en bazo (0,09±0,02), epidermis-dermis (0,06±0,17), hígado (0,03±0,02) y pulmón (0,02±0,01 nM). Por vía intraperitoneal se encontró PcAlCl en bazo (0,58±0,4), cerebro (0,07±0,07), corazón (0,07±0,12), pulmón (0,012±0,01) y piel (0,021±0,02 nM). Treinta días post-tratamiento no se encontró PcAlCl en ningún órgano. Los estudios histopatológicos fueron negativos. Conclusión: La PcAlCl contenida en transferosomas fue retenida principalmente en estrato córneo mostrando bajas concentraciones en la dermis sitio donde se aloja el parásito. Se sugiere modificar los componentes vesiculares del sistema para aumentar la permeación del compuesto

Reclutamiento de la merluza argentina, Merluccius hubbsi, del stock patagónico: una revisión de las principales características que afectan el potencial reproductivo y la supervivencia durante las primeras etapas de la vida

Understanding the causes that generate variability of recruitment in marine populations constitutes one of the greatest challenges in fishery science. Our predictive capacity to explain these variations is relatively low, due to the interaction of exogenous and endogenous factors, which vary across time and space within populations. In order to gain information on recruitment fluctuations of the Argentine hake (Merluccius hubbsi) from Patagonian stock, we reviewed the results obtained analyzing the reproductive ecology, trophic and energetic dynamics during different stages of development of this species, and its relationship with environmental variables. We observed that the reproductive potential is strongly influenced by characteristics of the parental stock, particularly females, in terms of their size, age and condition. This feature, called ‘maternal effect’, suggests that the spawning stock biomass, commonly used as an index of productivity in fishery assessment, is a poor predictor of recruitment. We also observed that survival during hake early life is affected by the spatial coincidence with the North Patagonian Frontal System, characterized by a high concentration of nutrients, high productivity, and food availability. Physical conditions and larval density in the nursery area affected the nutritional state and mortality of hake, mainly by competition for food or predation. It was observed that the transition of juveniles from pelagic to demersal habitat occurs over a longer period than previously recognized for this species, stressing the importance of using acoustic information to complement data from bottom trawls. This is one of the main topics to be further developed in order to estimate new recruitment indices for Argentine hake, along with other research items proposed to improve stock assessment.Comprender las causas que generan la variabilidad del reclutamiento en las poblaciones marinas constituye uno de los mayores desafíos de la ciencia pesquera. Nuestra capacidad predictiva para explicar estas variaciones es relativamente baja, debido a la interacción de factores exógenos y endógenos, que varían en el tiempo y el espacio dentro de las poblaciones. Con el fin de obtener información sobre las fluctuaciones en el reclutamiento de la merluza argentina (Merluccius hubbsi) del stock patagónico, revisamos los resultados obtenidos analizando la ecología reproductiva, la dinámica trófica y energética durante las diferentes etapas de desarrollo de esta especie y su relación con variables ambientales. Observamos que el potencial reproductivo está fuertemente influenciado por las características parentales, particularmente de las hembras, en cuanto a su tamaño, edad y condición. Esta característica, denominada “efecto materno”, sugiere que la biomasa de la población reproductora, comúnmente utilizada como índice de productividad en la evaluación de pesquerías, es un predictor deficiente del reclutamiento. También observamos que la supervivencia durante los primeros años de vida de la merluza se ve afectada por la coincidencia espacial con el Sistema Frontal Norpatagónico, caracterizado por una alta concentración de nutrientes, alta productividad y disponibilidad de alimento. Las condiciones físicas y la densidad larvaria en la zona de crianza afectaron el estado nutricional y la mortalidad de la merluza, principalmente por competencia por alimento o depredación. Se observó que la transición del hábitat pelágico al demersal en los juveniles se produce durante un período más extenso que el reconocido anteriormente para esta especie, lo que destaca la importancia de utilizar los registros acústicos para complementar la información de las redes de arrastre de fondo. Este es uno de los principales temas a desarrollar para estimar nuevos índices de reclutamiento de merluza argentina, junto con otras líneas de investigación propuestas para mejorar la evaluación del stock

Offer of primary care services and detection of tuberculosis incidence in Brazil

OBJECTIVE: To evaluate the association between the health services offered by primary care teams and the detection of new tuberculosis cases in Brazil. METHODS: This was an ecological study covering all Brazilian municipalities that registered at least one new tuberculosis case (diagnosed between 2012 to 2014 and notified in the Information System of Notifiable Diseases) and with at least one primary care team evaluated by the second cycle of the National Program for Improving Access and Quality of Primary Care (PMAQ-AB). The variables of the PMAQ-AB were classified as proximal or distal, according to their relation with the tuberculosis diagnosis. Then, they were tested hierarchically in multiple models (adjusted by States) using negative binomial regression. RESULTS: An increase of 10% in the primary health care coverage was associated with a decrease of 2.24% in the tuberculosis detection rate (95%CI -3.35– -1.11). Regarding the proximal variables in relation to diagnosis, in the multiple model, the detection of tuberculosis was associated with the proportion of teams that conduct contact investigation (increase in Incidence Rate Ratio [IRR] = 2.97%, 95%CI 2.41–3.53), carry out tuberculosis active case finding (increase in IRR = 2.17%, 95%CI 1.48–2.87), and request culture for mycobacteria (increase in IRR = 1.87%, 95%CI 0.98–2.76). CONCLUSIONS: The variables related to the search actions were positively associated with the detection of new tuberculosis cases, which suggests a significant contribution to the strengthening of the sensitivity of the surveillance system. On the other hand, primary care coverage was inversely associated with the tuberculosis detection rate, which could represent the overall effect of the primary care on transmission control, probably from the identification and early treatment of cases.OBJETIVO: Avaliar a associação entre os serviços de saúde ofertados por equipes de atenção básica e a detecção de casos novos de tuberculose no Brasil. MÉTODOS: Estudo ecológico, abrangendo todos os municípios brasileiros que registraram pelo menos um caso novo de tuberculose (diagnosticado entre 2012 a 2014 e notificado no Sistema de Informação de Agravos de Notificação) e com pelo menos uma equipe de atenção básica avaliada pelo segundo ciclo do Programa Nacional de Melhoria do Acesso e da Qualidade da Atenção Básica (PMAQ-AB). As variáveis do PMAQ-AB foram classificadas como próximais ou distais, segundo a sua relação com o diagnóstico de tuberculose. Em seguida, foram testadas hierarquicamente em modelos múltiplos (ajustados por Unidade Federada), usando regressão binomial negativa. RESULTADOS: Um incremento de 10% na cobertura da atenção básica esteve associado à redução de 2,24% na taxa de detecção de tuberculose (IC95% -3,35– -1,11). No que se refere às variáveis proximais ao diagnóstico, no modelo múltiplo, a detecção da tuberculose esteve associada à proporção de equipes que: realizam vigilância de contatos (incremento na Razão de Taxas de Incidência [RTI] = 2,97%; IC95% 2,41–3,53); fazem busca ativa de casos de tuberculose (incremento na RTI = 2,17%; IC95% 1,48–2,87); e, ofertam cultura para micobactérias (incremento na RTI = 1,87%; IC95% 0,98–2,76). CONCLUSÕES: As variáveis relacionadas às ações de detecção estiveram positivamente associadas à detecção de casos novos de tuberculose, sugerindo uma contribuição significativa ao fortalecimento da sensibilidade do sistema de vigilância. Por outro lado, a cobertura da atenção básica esteve inversamente associada à taxa de detecção de tuberculose, o que poderia representar o efeito global da atenção básica sobre o controle da transmissão, provavelmente, através da identificação e tratamento precoce de casos

Impact of Bacillus Calmette–Guérin Moreau vaccine on lung remodeling in experimental asthma

AbstractWe analyzed the effects of different administration routes and application times of the BCG-Moreau strain on airway and lung inflammation and remodeling in a murine model of allergic asthma. BALB/c mice (n=168) were divided into two groups. The first group received BCG-Moreau strain while the second group received saline using the same protocol. BCG or saline were intradermally or intranasally injected one or two months before the induction of asthma. Mice were further sensitized and challenged with ovalbumin or received saline. Twenty-four hours after the last challenge, BCG prevented the triggering of pro-inflammatory cytokines, probably by increasing Foxp3 and interleukin (IL)-10, modulating eosinophil infiltration and collagen fiber deposition, thus reducing airway hyperresponsiveness. In conclusion, BCG-Moreau prevented lung remodeling in the present model of allergic asthma, regardless of administration route and time of vaccination. These beneficial effects may be related to the increase in regulatory T cells and to IL-10 production in tandem with decreased Th2 cytokines (IL-4, IL-5, and IL-13)

Stabilization of angiotensin-(1-7) by key substitution with a cyclic non-natural amino acid

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system (RAAS), is a promising candidate as a treatment for cancer that reflects its antiproliferative and anti-angiogenic properties. However, the peptide’s therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA. The analogues containing the ACCA substitution at the site of ACE cleavage exhibit complete resistance to human ACE, while substitution at the DDP3 cleavage site provided stability against DPP 3 hydrolysis. Furthermore, the analogues retain the anti-proliferative properties of Ang-(1-7) against the 4T1 and HT-1080 cancer cell lines. These results suggest that ACCA-substituted Ang-(1-7) analogues which show resistance against proteolytic degradation by peptidases known to hydrolyze the native heptapeptide may be novel therapeutics in the treatment of cancer

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file