Efecto de la Inmunización Intranasal con Toxina de Cólera y Extracto Total de Naegleria fowleri en la Activación de Células Dendríticas y Macrófagos en el Modelo de la Meningitis en Ratones BALB/c.

El tejido linfoide asociado a la naríz (NALT) y los nódulos linfáticos cervicales (CN) constituyen el tejido linfoide organizado, mientras que los pasajes nasales (NP) (pared, paredes laterales, cornetes, y el techo de la naríz) son el tejido linfoide difuso y ambos tipos de tejido proporcionan protección a la mucosa nasal contra las infecciones por patógenos. Se ha observado que la toxina de cólera empleada como adyuvante mejora la respuesta inmune protectora cuando se administra con un antígeno. En este trabajo determinamos si la inmunización con lisados de N. fowleri más CT y un reto posterior es capaz de activar células dendríticas y macrófagos del epitelio nasal de ratones en el modelo de la meningoencefalitis amebiana primaria. Mediante FACS observamos en ratones control e inmunizados la expresión de moléculas coestimudoras CD80 y CD86; estas moléculas incrementan significativamente su expresión en macrófagos y células dendríticas de ratones inmunizados con respecto a los controles en NALT, CN y NP. Indirectamente estos resultados reflejan un incremento en la captura y presentación de antígenos de N. fowleri y CT a los linfocitos T, ya que en otros trabajos hemos encontrado linfocitos TCD4 activados mediante la detección de la activación de moléculas CD69 y CD25. Esto está relacionado directamente con los altos niveles de anticuerpos IgG e IgA en los sitios local o sistémico, lo que se ha reportado para el mismo protocolo de inmunización en otros trabajos. Los macrófagos son APC, sin embargo su participación en la eliminación del antígeno es muy importante, por esta razón nosotros analizamos por inmunohistoquímica algunos factores que indican la activación de estas células tales como MPO, MIF, TLR2 y TLR4. Cuando se incubaron los cortes de tejido de la cavidad nasal con anti-MPO observamos que un gran número de trofozoítos y células inflamatorias fueron positivas para este anticuerpo, principalmente en el lumen del cornete superior. N. fowleri expresa un proteína de tipo MPO. Las células inflamatorias se observaron fuertemente activadas 10 rodeando a los trofozoítos. Para MIF observamos algunas células positivas en la lámina propia del cornete medio. Con respecto a TLR2 y TLR4 solo pocas células se localizaron en la lámina propia de los cornetes para TLR2 y en la lámina propia del septum para TLR4. La enzima MPO es expresada cuando los macrófagos y PMN son activados y como se muestra en el control no se observan células inflamatorias ni en la lámina propia o el lumen de la cavidad nasal. MIF es un factor quimiotáctico para macrófagos y la marca positiva para esta citocina puede estar indicando la migración de macrófagos hacia el lumen de los cornetes para llevar a cabo la posible eliminación de los trofozoítos. Con respecto a TLR2 y TLR4 y se sabe que su función en macrófagos es la de reconocer diacilpilopéptidos y el LPS respectivamente y cuando estos receptores se unen a su ligando inducen un estado de inflamación en el macrófago y aunque la marca de estas moléculas es baja probablemente estas células están participando en la eliminación de N. fowleri una vez que han llegado al sitio de inflamación. Por otra parte, el macrófago cuando se ha activado por la inmunización puede participar tanto en la presentación del antígeno así como en la eliminación de este. Es necesario complementar los estudios para explicar los efectos inmunomoduladores de la inmunización con CT y lisados de N. fowleri en la cavidad nasal del ratón

Development, Characterization, Optimization, and In Vivo Evaluation of Methacrylic Acid–Ethyl Acrylate Copolymer Nanoparticles Loaded with Glibenclamide in Diabetic Rats for Oral Administration

The methacrylic acid–ethyl acrylate copolymer nanoparticles were prepared using the solvent displacement method. The independent variables were the drug/polymer ratio, surfactant concentration, Polioxyl 40 hydrogenated castor oil, the added water volume, time, and stirring speed, while size, PDI, zeta potential, and encapsulation efficiency were the response variables analyzed. A design of screening experiments was carried out to subsequently perform the optimization of the nanoparticle preparation process. The optimal formulation was characterized through the dependent variables size, PDI, zeta potential, encapsulation efficiency and drug release profiles. In vivo tests were performed in Wistar rats previously induced with diabetes by administration of streptozotocin. Once hyperglycemia was determined in rats, a suspension of nanoparticles loaded with glibenclamide was administered to them while the other group was administered with tablets of glibenclamide. The optimal nanoparticle formulation obtained a size of 18.98 +/− 9.14 nm with a PDI of 0.37085 +/− 0.014 and a zeta potential of −13.7125 +/− 1.82 mV; the encapsulation efficiency was of 44.5%. The in vivo model demonstrated a significant effect (p < 0.05) between the group administered with nanoparticles loaded with glibenclamide and the group administered with tablets compared to the group of untreated individuals

Ceftriaxone-Loaded Polymeric Microneedles, Dressings, and Microfibers for Wound Treatment

The objective of this study was to create polymeric dressings, microfibers, and microneedles (MN) loaded with ceftriaxone, using PMVA (Poly (Methyl vinyl ether-alt-maleic acid), Kollicoat® 100P, and Kollicoat® Protect as polymers to treat diabetic wounds and accelerate their recovery. These formulations were optimized through a series of experiments and were subsequently subjected to physicochemical tests. The results of the characterization of the dressings, microfibers, and microneedles (PMVA and 100P) were, respectively, a bioadhesion of 281.34, 720, 720, 2487, and 510.5 gf; a post-humectation bioadhesion of 186.34, 831.5, 2380, and 630.5 gf, tear strength of 2200, 1233, 1562, and 385 gf, erythema of 358, 8.4, 227, and 188; transepidermal water loss (TEWL) of 2.6, 4.7, 1.9, and 5.2 g/h·m2; hydration of 76.1, 89.9, 73.5, and 83.5%; pH of 4.85, 5.40, 5.85, and 4.85; and drug release (Peppas kinetics release) of n: 0.53, n: 0.62, n: 0.62, and n: 0.66). In vitro studies were performed on Franz-type diffusion cells and indicated flux of 57.1, 145.4, 718.7, and 2.7 µg/cm2; permeation coefficient (Kp) of 13.2, 19.56, 42, and 0.00015 cm2/h; and time lag (tL) of 6.29, 17.61, 27. 49, and 22.3 h, respectively, in wounded skin. There was no passage of ceftriaxone from dressings and microfibers to healthy skin, but that was not the case for PMVA/100P and Kollicoat® 100P microneedles, which exhibited flux of 194 and 0.4 µg/cm2, Kp of 11.3 and 0.00002 cm2/h, and tL of 5.2 and 9.7 h, respectively. The healing time of the formulations in vivo (tests carried out using diabetic Wistar rats) was under 14 days. In summary, polymeric dressings, microfibers, and microneedles loaded with ceftriaxone were developed. These formulations have the potential to address the challenges associated with chronic wounds, such as diabetic foot, improving the outcomes

Design and Characterization of Ocular Inserts Loaded with Dexamethasone for the Treatment of Inflammatory Ophthalmic Disease

The short precorneal residence time of ophthalmic drops is associated with their low absorption; therefore, the development of ocular inserts capable of prolonging and controlling the ophthalmic release of drugs is an interesting option in the design and development of these drugs. A surface response design was developed, specifically the Central Composite Design (CCD), to produce ophthalmic films loaded with Dexamethasone (DEX) by the solvent evaporation method having experimental levels of different concentrations of previously selected polymers (PVP K-30 and Eudragit RS100.). Once optimization of the formulation was obtained, the in vivo test was continued. The optimal formulation obtained a thickness of 0.265 ± 0.095 mm, pH of 7.11 ± 0.04, tensile strength of 15.50 ± 3.94 gF, humidity (%) of 22.54 ± 1.7, mucoadhesion strength of 16.89 ± 3.46 gF, chemical content (%) of 98.19 ± 1.124, release of (%) 13,510.71, and swelling of 0.0403 ± 0.023 g; furthermore, in the in vivo testing the number and residence time of PMN cells were lower compared to the Ophthalmic Drops. The present study confirms the potential use of polymeric systems using PVPK30 and ERS100 as a new strategy of controlled release of ophthalmic drugs by controlling and prolonging the release of DEX at the affected site by decreasing the systemic effects of the drug

Discovering HIV related information by means of association rules and machine learning

Acquired immunodeficiency syndrome (AIDS) is still one of the main health problems worldwide. It is therefore essential to keep making progress in improving the prognosis and quality of life of affected patients. One way to advance along this pathway is to uncover connections between other disorders associated with HIV/AIDS-so that they can be anticipated and possibly mitigated. We propose to achieve this by using Association Rules (ARs). They allow us to represent the dependencies between a number of diseases and other specific diseases. However, classical techniques systematically generate every AR meeting some minimal conditions on data frequency, hence generating a vast amount of uninteresting ARs, which need to be filtered out. The lack of manually annotated ARs has favored unsupervised filtering, even though they produce limited results. In this paper, we propose a semi-supervised system, able to identify relevant ARs among HIV-related diseases with a minimal amount of annotated training data. Our system has been able to extract a good number of relationships between HIV-related diseases that have been previously detected in the literature but are scattered and are often little known. Furthermore, a number of plausible new relationships have shown up which deserve further investigation by qualified medical experts

Chronic coronary syndromes without standard modifiable cardiovascular risk factors and outcomes: the CLARIFY registry

Background and Aims: It has been reported that patients without standard modifiable cardiovascular (CV) risk factors (SMuRFs—diabetes, dyslipidaemia, hypertension, and smoking) presenting with first myocardial infarction (MI), especially women, have a higher in-hospital mortality than patients with risk factors, and possibly a lower long-term risk provided they survive the post-infarct period. This study aims to explore the long-term outcomes of SMuRF-less patients with stable coronary artery disease (CAD). Methods: CLARIFY is an observational cohort of 32 703 outpatients with stable CAD enrolled between 2009 and 2010 in 45 countries. The baseline characteristics and clinical outcomes of patients with and without SMuRFs were compared. The primary outcome was a composite of 5-year CV death or non-fatal MI. Secondary outcomes were 5-year all-cause mortality and major adverse cardiovascular events (MACE—CV death, non-fatal MI, or non-fatal stroke). Results: Among 22 132 patients with complete risk factor and outcome information, 977 (4.4%) were SMuRF-less. Age, sex, and time since CAD diagnosis were similar across groups. SMuRF-less patients had a lower 5-year rate of CV death or non-fatal MI (5.43% [95% CI 4.08–7.19] vs. 7.68% [95% CI 7.30–8.08], P = 0.012), all-cause mortality, and MACE. Similar results were found after adjustments. Clinical event rates increased steadily with the number of SMuRFs. The benefit of SMuRF-less status was particularly pronounced in women. Conclusions: SMuRF-less patients with stable CAD have a substantial but significantly lower 5-year rate of CV death or non-fatal MI than patients with risk factors. The risk of CV outcomes increases steadily with the number of risk factors