Bis-isonicotinoyl linkers containing polyaromatic scaffolds: synthesis, structure and spectroscopic properties.

In this study, a new series of extended linkers containing different polyaromatic chromophores (biphenyl, naphthalene, anthracene, fluorene, 9,9-dimethylfluorene and fluorenone) functionalized with isonicotinoyl moieties have been synthesized by Pd-catalyzed cross-coupling reactions involving isonicotinamide and the appropriate aromatic dibromide. The optimized protocol led to the isolation of the target molecules in good yield and with high purity. These were characterized by 1H NMR, FTIR, MS, and elemental analysis and their solid state structures were solved by single-crystal X-ray diffraction analysis. Electronic absorption and emission spectra were collected both in solution (DMF) and in the solid state. TDDFT calculations were carried out to investigate the effect of the isonicotinoyl moieties on the spectral features of the central chromophores. Although in solution only the linker containing a fluorenone scaffold shows a weak fluorescence, all the isolated linkers turned out to be fluorescent in the solid state, thus paving the way for their use for the fabrication of fluorescent MOFs.

Copy number variant scan in more than four thousand Holstein cows bred in Lombardy, Italy.

Copy Number Variants (CNV) are modifications affecting the genome sequence of DNA, for instance, they can be duplications or deletions of a considerable number of base pairs (i.e., greater than 1000 bp and up to millions of bp). Their impact on the variation of the phenotypic traits has been widely demonstrated. In addition, CNVs are a class of markers useful to identify the genetic biodiversity among populations related to adaptation to the environment. The aim of this study was to detect CNVs in more than four thousand Holstein cows, using information derived by a genotyping done with the GGP (GeneSeek Genomic Profiler) bovine 100K SNP chip. To detect CNV the SVS 8.9 software was used, then CNV regions (CNVRs) were detected. A total of 123,814 CNVs (4,150 non redundant) were called and aggregated into 1,397 CNVRs. The PCA results obtained using the CNVs information, showed that there is some variability among animals. For many genes annotated within the CNVRs, the role in immune response is well known, as well as their association with important and economic traits object of selection in Holstein, such as milk production and quality, udder conformation and body morphology. Comparison with reference revealed unique CNVRs of the Holstein breed, and others in common with Jersey and Brown. The information regarding CNVs represents a valuable resource to understand how this class of markers may improve the accuracy in prediction of genomic value, nowadays solely based on SNPs markers.

A sterilizable platform based on crosslinked xanthan gum for controlled-release of polymeric micelles: Ocular application for the delivery of neuroprotective compounds to the posterior eye segment.

TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) polymeric micelles show interesting properties for ocular administration thanks to their solubilization capability, nanometric size and tissue penetration ability. However, micelles formulations are generally characterized by low viscosity, poor adhesion and very short retention time at the administration site. Therefore, the idea behind this work is the preparation and characterization of a crosslinked film based on xanthan gum that contains TPGS micelles and is capable of controlling their release. The system was loaded with melatonin and cyclosporin A, neuroprotective compounds to be delivered to the posterior eye segment. Citric acid and heating at different times and temperatures were exploited as crosslinking approach, giving the possibility to tune swelling, micelles release and drug release. The biocompatibility of the platform was confirmed by HET-CAM assay. Ex vivo studies on isolated porcine ocular tissues, conducted using Franz cells and two-photon microscopy, demonstrated the potential of the xanthan gum-based platform and enlightened micelles penetration mechanism. Finally, the sterilization step was approached, and a process to simultaneously crosslink and sterilize the platform was developed.

Amphiphilic Fluorinated Unimer Micelles as Nanocarriers of Fluorescent Probes for Bioimaging.

The unique self-assembly properties of unimer micelles are exploited for the preparation of fluorescent nanocarriers embedding hydrophobic fluorophores. Unimer micelles are constituted by a (meth)acrylate copolymer with oligoethyleneglycol and perflurohexylethyl side chains (PEGMA90-co-FA10) in which the hydrophilic and hydrophobic comonomers are statistically distributed along the polymeric backbone. Thanks to hydrophobic interactions in water, the amphiphilic copolymer forms small nanoparticles (<10 nm), with tunable properties and functionality. An easy procedure for the encapsulation of a small hydrophobic molecule (C153 fluorophore) within unimer micelles is presented. UV-vis, fluorescence, and fluorescence anisotropy spectroscopic experimental data demonstrate that the fluorophore is effectively embedded in the nanocarriers. Moreover, the nanocarrier positively contributes to preserve the good emissive properties of the fluorophore in water. The efficacy of the dye-loaded nanocarrier as a fluorescent probe is tested in two-photon imaging of thick ex vivo porcine scleral tissue.

Aggregates of Cyanine Dyes: When Molecular Vibrations and Electrostatic Screening Make the Difference.

Aggregates of cyanine dyes are currently investigated as promising materials for advanced electronic and photonic applications. The spectral properties of aggregates of cyanine dyes can be tuned by altering the supramolecular packing, which is affected by the length of the dye, the presence of alkyl chains, or the nature of the counterions. In this work, we present a joint experimental and theoretical study of a family of cyanine dyes forming aggregates of different types according to the length of the polymethinic chain. Linear and nonlinear optical spectra of aggregates are rationalized here in terms of an essential-state model accounting for intermolecular interactions together with the molecular polarizability and vibronic coupling. A strategy is implemented to properly account for screening effects, distinguishing between electrostatic intermolecular interactions relevant to the ground state (mean-field effect) and the interactions relevant to the excited states (excitonic effects). To the best of our knowledge, this is the first attempt to simulate nonlinear spectral properties of aggregates of symmetric dyes accounting for molecular vibrations.

Nanostructured Lipid Carriers for Enhanced Transscleral Delivery of Dexamethasone Acetate: Development, Ex Vivo Characterization and Multiphoton Microscopy Studies.

Corticosteroids, although highly effective for the treatment of both anterior and posterior ocular segment inflammation, still nowadays struggle for effective drug delivery due to their poor solubilization capabilities in water. This research work aims to develop nanostructured lipid carriers (NLC) intended for periocular administration of dexamethasone acetate to the posterior segment of the eye. Pre-formulation studies were initially performed to find solid and liquid lipid mixtures for dexamethasone acetate solubilization. Pseudoternary diagrams at 65 °C were constructed to select the best surfactant based on the macroscopic transparency and microscopic isotropy of the systems. The resulting NLC, obtained following an organic solvent-free methodology, was composed of triacetin, Imwitor® 491 (glycerol monostearate >90%) and tyloxapol with Z-average = 106.9 ± 1.2 nm, PDI = 0.104 ± 0.019 and zeta potential = -6.51 ± 0.575 mV. Ex vivo porcine sclera and choroid permeation studies revealed a considerable metabolism in the sclera of dexamethasone acetate into free dexamethasone, which demonstrated higher permeation capabilities across both tissues. In addition, the NLC behavior once applied onto the sclera was further studied by means of multiphoton microscopy by loading the NLC with the fluorescent probe Nile red.

From symmetry breaking to symmetry swapping: is Kasha's rule violated in multibranched phenyleneethynylenes?

The phenomenon of excited-state symmetry breaking is often observed in multipolar molecular systems, significantly affecting their photophysical and charge separation behavior. As a result of this phenomenon, the electronic excitation is partially localized in one of the molecular branches. However, the intrinsic structural and electronic factors that regulate excited-state symmetry breaking in multibranched systems have hardly been investigated. Herein, we explore these aspects by adopting a joint experimental and theoretical investigation for a class of phenyleneethynylenes, one of the most widely used molecular building blocks for optoelectronic applications. The large Stokes shifts observed for highly symmetric phenyleneethynylenes are explained by the presence of low-lying dark states, as also established by two-photon absorption measurements and TDDFT calculations. In spite of the presence of low-lying dark states, these systems show an intense fluorescence in striking contrast to Kasha's rule. This intriguing behavior is explained in terms of a novel phenomenon, dubbed "symmetry swapping" that describes the inversion of the energy order of excited states, i.e., the swapping of excited states occurring as a consequence of symmetry breaking. Thus, symmetry swapping explains quite naturally the observation of an intense fluorescence emission in molecular systems whose lowest vertical excited state is a dark state. In short, symmetry swapping is observed in highly symmetric molecules having multiple degenerate or quasi-degenerate excited states that are prone to symmetry breaking.

Buccal Permeation of Polysaccharide High Molecular Weight Compounds: Effect of Chemical Permeation Enhancers.

The greatest achievement in the advanced drug delivery field should be the optimization of non-invasive formulations for the delivery of high molecular weight compounds. Peptides, proteins, and other macromolecules can have poor membrane permeation, principally due to their large molecular weight. The aim of this work was to explore the possibility of administering fluorescently labeled dextrans (molecular weight 4-150 kDa) across the buccal mucosa. Permeation experiments across pig esophageal mucosa were carried out using fatty acids and bile salts as penetration enhancers. The data obtained show that it is possible to increase or promote the mucosa permeation of high molecular weight dextrans by using caprylic acid or sodium taurocholate as the chemical enhancers. With these enhancers, dextrans with molecular weight of 70 and 150 kDa, that in passive conditions did not permeate, could cross the mucosa in detectable amounts. FD-70 and FD-150 showed comparable permeability values, despite the molecular weight difference. The results obtained in the present work suggest that the buccal administration of high molecular weight compounds is feasible.

Cyclosporine-loaded micelles for ocular delivery: Investigating the penetration mechanisms.

Cyclosporine is an immunomodulatory drug commonly used for the treatment of mild-to-severe dry eye syndrome as well as intermediate and posterior segment diseases as uveitis. The ocular administration is however hampered by its relatively high molecular weight and poor permeability across biological barriers. The aim of this work was to identify a micellar formulation with the ability to solubilize a considerable amount of cyclosporine and promote its transport across ocular barriers. Non-ionic amphiphilic polymers used for micelles preparation were tocopherol polyethylene glycol 1000 succinate (TPGS) and Solutol® HS15. Furthermore, the addition of alpha-linolenic acid was assessed. A second aim was to evaluate micelles fate in the ocular tissues (cornea and sclera) to shed light on penetration mechanisms. This was possible by extracting and quantifying both drug and polymer in the tissues, by studying TPGS hydrolysis in a bio-relevant environment and by following micelles penetration with two-photon microscopy. Furthermore, TPGS role as permeation enhancer on the cornea, with possible irreversible modifications of tissue permeability, was analyzed. Results showed that TPGS micelles (approx. 13 nm in size), loaded with 5 mg/ml of cyclosporine, promoted drug retention in both the cornea and the sclera. Data demonstrated that micelles behavior strictly depends on the tissue: micelles disruption occurs in contact with the cornea, while intact micelles diffuse in the interfibrillar pores of the sclera and form a reservoir that can sustain over time drug delivery to the deeper tissues. Finally, cornea quickly restore the barrier properties after TPGS removal from the tissue, demonstrating its potential good tolerability for ocular application.

Biomimetic design of bioartificial scaffolds for the in vitro modelling of human cardiac fibrosis.

In vitro models of pathological cardiac tissue have attracted interest as predictive platforms for preclinical validation of therapies. However, models reproducing specific pathological features, such as cardiac fibrosis size (i.e., thickness and width) and stage of development are missing. This research was aimed at engineering 2D and 3D models of early-stage post-infarct fibrotic tissue (i.e., characterized by non-aligned tissue organization) on bioartificial scaffolds with biomimetic composition, design, and surface stiffness. 2D scaffolds with random nanofibrous structure and 3D scaffolds with 150 µm square-meshed architecture were fabricated from polycaprolactone, surface-grafted with gelatin by mussel-inspired approach and coated with cardiac extracellular matrix (ECM) by 3 weeks culture of human cardiac fibroblasts. Scaffold physicochemical properties were thoroughly investigated. AFM analysis of scaffolds in wet state, before cell culture, confirmed their close surface stiffness to human cardiac fibrotic tissue. Following 3 weeks culture, biomimetic biophysical and biochemical scaffold properties triggered the activation of myofibroblast phenotype. Upon decellularization, immunostaining, SEM and two-photon excitation fluorescence microscopy showed homogeneous decoration of both 2D and 3D scaffolds with cardiac ECM. The versatility of the approach was demonstrated by culturing ventricular or atrial cardiac fibroblasts on scaffolds, thus suggesting the possibility to use the same scaffold platforms to model both ventricular and atrial cardiac fibrosis. In the future, herein developed in vitro models of cardiac fibrotic tissue, reproducing specific pathological features, will be exploited for a fine preclinical tuning of therapies.

Improvement of Imiquimod Solubilization and Skin Retention via TPGS Micelles: Exploiting the Co-Solubilizing Effect of Oleic Acid.

Imiquimod (IMQ) is an immunostimulant drug approved for the topical treatment of actinic keratosis, external genital-perianal warts as well as superficial basal cell carcinoma that is used off-label for the treatment of different forms of skin cancers, including some malignant melanocytic proliferations such as lentigo maligna, atypical nevi and other in situ melanoma-related diseases. Imiquimod skin delivery has proven to be a real challenge due to its very low water-solubility and reduced skin penetration capacity. The aim of the work was to improve the drug solubility and skin retention using micelles of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a water-soluble derivative of vitamin E, co-encapsulating various lipophilic compounds with the potential ability to improve imiquimod affinity for the micellar core, and thus its loading into the nanocarrier. The formulations were characterized in terms of particle size, zeta potential and stability over time and micelles performance on the skin was evaluated through the quantification of imiquimod retention in the skin layers and the visualization of a micelle-loaded fluorescent dye by two-photon microscopy. The results showed that imiquimod solubility strictly depends on the nature and concentration of the co-encapsulated compounds. The micellar formulation based on TPGS and oleic acid was identified as the most interesting in terms of both drug solubility (which was increased from few µg/mL to 1154.01 ± 112.78 µg/mL) and micellar stability (which was evaluated up to 6 months from micelles preparation). The delivery efficiency after the application of this formulation alone or incorporated in hydrogels showed to be 42- and 25-folds higher than the one of the commercial creams.

Desnutrición al ingreso hospitalario y estancia prolongada en un hospital público de la Provincia de Buenos Aires / Malnutrition upon hospital admission and prolonged stay in a state hospital in the Province of Buenos Aires

Resumen Introducción: la desnutrición hospitalaria, vinculada principalmente a la enfermedad o injuria, tiene una alta prevalencia a nivel mundial. Está asociada negativamente con resultados clínicos y económicos. Objetivo: Determinar si existe asociación entre el estado nutricional al ingreso hospitalario y el tiempo de internación. Materiales y método: se realizó un estudio observacional, descriptivo y retrospectivo, en pacientes adultos ingresados al Hospital Interzonal General de Agudos "San Roque" durante el año 2019. Para el tamizaje nutricional se utilizó el Malnutrition Screening Tool (MST) y para la evaluación nutricional la Valoración Global Subjetiva. Se calculó la estancia hospitalaria como la diferencia entre la fecha de ingreso y egreso. Resultados: se evaluaron 2296 pacientes. La prevalencia global de desnutrición fue del 25,4%. Se encontraron diferencias estadísticamente significativas entre estancia hospitalaria prolongada y estado nutricional; tanto en pacientes con desnutrición moderada [OR crudo 2,75 (IC 95% 2,1-3,4; p < 0,0001)] como en pacientes con desnutrición severa [OR crudo 5 (IC 95% 3,5 - 7,0; p < 0,0001)]. Conclusión: este estudio refleja la alta prevalencia de desnutrición que padecen los pacientes al ingreso hospitalario, como así también el mayor riesgo de tener estancias más prolongadas cuando existe desnutrición.

Abstract Introduction: hospital malnutrition, mainly linked to illness or injury, has a high prevalence worldwide. It is negatively associated with clinical and economic outcomes. Objective: to determine if there is an association between nutritional status and length of hospital stay. Materials and method: observational, descriptive and retrospective study was carried out in adult patients admitted to the Hospital Interzonal General de Agudos "San Roque" during 2019. For nutritional screening, the Malnutrition Screening Tool was used and for nutritional assessment, the Subjective Global Assessment. Length of hospital stay was calculated as the difference between the date of admission and discharge. Results: 2296 patients were assessed. The global prevalence of malnutrition was 25,4%. Statistically significant differences were found between prolonged hospital stay and nutritional status; both in patients with moderate malnutrition [crude OR 2,75 (95% CI 2,1-3,4; p<0.0001)] and in patients with severe malnutrition [crude OR 5 (95% CI 3,5 - 7,0; p<0,0001)]. Conclusion: this study reflects the high prevalence of malnutrition suffered by patients at hospital admission, as well as the increased risk of having longer stays when malnutrition exists.

Conocimientos, prácticas y valoraciones sobre manipulación de alimentos en hospitales públicos bonaerenses, Argentina, 2020 / Knowledge, practices, and appraisals on food handling in public hospital of Buenos Aires province, Argentina, 2020

INTRODUCCIÓN: La manipulación de alimentos dentro del ámbito hospitalario juega un papel crucial en la cadena causal de enfermedades transmitidas por alimentos. Actualmente no existe información sobre conocimientos, prácticas y valoraciones de los manipuladores de alimentos a nivel local. El objetivo de este estudio fue evaluar a los manipuladores de alimentos de hospitales públicos de la provincia de Buenos Aires y su asociación con características sociodemográficas, laborales y de capacitación. MÉTODOS: Se realizó un estudio transversal analítico. Se envió una encuesta virtual a los hospitales públicos de la provincia para que fuera distribuida a todos los manipuladores de alimentos. Se relevaron datos sociodemográficos, laborales y de capacitación. Se evaluaron conocimientos y prácticas mediante preguntas de opción múltiple y se indagaron valoraciones personales sobre su trabajo. RESULTADOS: La encuesta fue completada por 561 manipuladores de 56 hospitales. Más del 80% había recibido algún tipo de capacitación. El 22,9% presentó conocimientos suficientes y el 15,3%, prácticas adecuadas. La valoración de prácticas adecuadas se asoció a mayor antigüedad, servicios tercerizados y a la realización de 5 o más capacitaciones en servicio. La escasez de elementos de trabajo y la infraestructura inadecuada fueron las principales barreras. DISCUSIÓN: La realización de capacitaciones en servicio y la presencia de personal con mayor antigüedad podrían mejorar la manipulación de alimento.

Valoración del estado nutricional en pacientes pre-quirúrgicos en un hospital de agudos de la provincia de Buenos Aires / Assessment of nutritional status in pre-surgical patients in an acute care hospital in the province of Buenos Aires

Introducción: la desnutrición en pacientes pre-quirúrgicos incrementa el riesgo de padecer complicaciones, aumentando la estancia hospitalaria y los costos para el sistema de salud. Objetivo: Evaluar el estado nutricional de los pacientes admitidos en el servicio de “Clínica Quirúrgica”, antes de someterse a una cirugía programada, durante los meses de marzo a mayo de 2015. Materiales y método: Estudio observacional, descriptivo, de corte transversal. Se evaluaron pacientes ingresados en la institución por el servicio de “Clínica Quirúrgica”, con motivo de cirugía. Las variables estudiadas fueron edad en dos estratos, sexo, grupo de patologías y estado nutricional. Para el diagnóstico de esta última se utilizó la Valoración Global Subjetiva (VGS). El análisis estadístico se realizó a través de la prueba de chi cuadrado (X²) o Fisher. Resultados: Se evaluaron 106 pacientes, de los cuales el 70,7% se categorizaron como bien nutridos, el 25,5% con riesgo de desnutrición o desnutrición moderada y el 3,8% como desnutrición severa. Ser ≥60 años tuvo una diferencia estadísticamente significativa con el riesgo de desnutrición. La prevalencia de desnutrición fue mayor en el grupo de pacientes con patologías de hígado y vía biliar. Dentro de la categoría C de la VGS, el 75% presentaba neoplasias. Conclusión: En la población estudiada se identificó un porcentaje considerable de pacientes con desnutrición, por lo que es necesaria la implementación de una estrategia de tamizaje nutricional al momento de la programación de la cirugía para realizar una intervención oportuna que permita que los pacientes candidatos a cirugía lleguen con el mejor estado nutricional posible.