In Vivo Biodistribution of Respirable Solid Lipid Nanoparticles Surface-Decorated with a Mannose-Based Surfactant: A Promising Tool for Pulmonary Tuberculosis Treatment?

The active targeting to alveolar macrophages (AM) is an attractive strategy to improve the therapeutic efficacy of ‘old’ drugs currently used in clinical practice for the treatment of pulmonary tuberculosis. Previous studies highlighted the ability of respirable solid lipid nanoparticle assemblies (SLNas), loaded with rifampicin (RIF) and functionalized with a novel synthesized mannose-based surfactant (MS), both alone and in a blend with sodium taurocholate, to efficiently target the AM via mannose receptor-mediated mechanism. Here, we present the in vivo biodistribution of these mannosylated SLNas, in comparison with the behavior of both non-functionalized SLNas and bare RIF. SLNas biodistribution was assessed, after intratracheal instillation in mice, by whole-body real-time fluorescence imaging in living animals and RIF quantification in excised organs and plasma. Additionally, SLNas cell uptake was determined by using fluorescence microscopy on AM from bronchoalveolar lavage fluid and alveolar epithelium from lung dissections. Finally, histopathological evaluation was performed on lungs 24 h after administration. SLNas functionalized with MS alone generated the highest retention in lungs associated with a poor spreading in extra-pulmonary regions. This effect could be probably due to a greater AM phagocytosis with respect to SLNas devoid of mannose on their surface. The results obtained pointed out the unique ability of the nanoparticle surface decoration to provide a potential more efficient treatment restricted to the lungs where the primary tuberculosis infection is located

Dynamics of bubbles under stochastic pressure forcing

Several studies have investigated the dynamics of a single spherical bubble at rest under a nonstationary pressure forcing. However, attention has almost always been focused on periodic pressure oscillations, neglecting the case of stochastic forcing. This fact is quite surprising, as random pressure fluctuations are widespread in many applications involving bubbles (e.g., hydrodynamic cavitation in turbulent flows or bubble dynamics in acoustic cavitation), and noise, in general, is known to induce a variety of counterintuitive phenomena in nonlinear dynamical systems such as bubble oscillators. To shed light on this unexplored topic, here we study bubble dynamics as described by the Keller-Miksis equation, under a pressure forcing described by a Gaussian colored noise modeled as an Ornstein-Uhlenbeck process. Results indicate that, depending on noise intensity, bubbles display two peculiar behaviors: when intensity is low, the fluctuating pressure forcing mainly excites the free oscillations of the bubble, and the bubble's radius undergoes small amplitude oscillations with a rather regular periodicity. Differently, high noise intensity induces chaotic bubble dynamics, whereby nonlinear effects are exacerbated and the bubble behaves as an amplifier of the external random forcin

Correlation between US-PSV and 64-Row MDCTA with Advanced Vessel Analysis in the Quantification of 50–70% Carotid Artery Stenosis

Purpose. To correlate ultrasonographic peak systolic velocity (US-PSV) and 64-row multidetector computed tomography angiography (MDCTA) with advanced vessel analysis (AVA) software in the quantification of 50–70% carotid artery stenosis. Materials and methods. 199 consecutive patients (247 arteries) with internal carotid artery (ICA) or third proximal bifurcation stenosis. Each patient was studied by duplex US (DUS) and 64-row MDCTA with AVA software. Results. DUS showed PSV measurements less than 125 cm/s in 51 carotid stenosis and a value greater than this in 196 arteries. 64-row MDCTA AVA software showed a grade of stenosis less than 50% in 42 carotid arteries while a greater 70% was found in 4 carotid arteries; then, carotid arteries with stenosis percentage between 50% and 70% were 201. Linear regression analysis showed a good linear correlation (r = 0.88) between MDCTA-AVA software percentage stenosis and PSV: between 50% grade of stenosis and PSV value corresponding to 133,6 cm/sec and between 70% stenosis and PSV value corresponding to 268 cm/sec. The sensitivity, specificity, positive predictive value(PPV), negative predictive value(NPV) of this analysis were 93%, 82%, 97%, 75%, respectively. Conclusion. Linear correlation between PSV data and grade of stenosis from 50% to 70% obtained with 64-row MDCTA AVA software. Main PSV value corresponding to 50% and 70% grade of stenosis at AVA analysis

The Impact of Lipid Corona on Rifampicin Intramacrophagic Transport Using Inhaled Solid Lipid Nanoparticles Surface-Decorated with a Mannosylated Surfactant

The mimicking of physiological conditions is crucial for the success of accurate in vitro studies. For inhaled nanoparticles, which are designed for being deposited on alveolar epithelium and taken up by macrophages, it is relevant to investigate the interactions with pulmonary surfactant lining alveoli. As a matter of fact, the formation of a lipid corona layer around the nanoparticles could modulate the cell internalization and the fate of the transported drugs. Based on this concept, the present research focused on the interactions between pulmonary surfactant and Solid Lipid Nanoparticle assemblies (SLNas), loaded with rifampicin, an anti-tuberculosis drug. SLNas were functionalized with a synthesized mannosylated surfactant, both alone and in a blend with sodium taurocholate, to achieve an active targeting to mannose receptors present on alveolar macrophages (AM). Physico-chemical properties of the mannosylated SLNas satisfied the requirements relative to suitable respirability, drug payload, and AM active targeting. Our studies have shown that a lipid corona is formed around SLNas in the presence of Curosurf, a commercial substitute of the natural pulmonary surfactant. The lipid corona promoted an additional resistance to the drug diffusion for SLNas functionalized with the mannosylated surfactant and this improved drug retention within SLNas before AM phagocytosis takes place. Moreover, lipid corona formation did not modify the role of nanoparticle mannosylation towards the specific receptors on MH-S cell membrane

Appropriateness in allergic respiratory diseases health care in Italy: definitions and organizational aspects

In a historical period in which sustainability of the National Health Service is mandatory because of the international economical situation, the limited available resources at national level and the tendency of passing from a "population medicine" model towards the concept of "individualized medicine", the debate on appropriateness of medical and surgical procedures is of central importance. The choosing wisely campaign, started in United States in 2012 and then spread all over the world, tries to summarize which are the most inappropriate procedures for each medical and surgical speciality; as far as allergic respiratory diseases, the most relevant Italian societies and the American Academy defined the allergological procedures with the highest probability of inappropriateness. In Italy, a recent decree of the Ministry of Health defined a list of more than 200 procedures that will be considered as inappropriate in certain conditions; many of these procedures concern allergology, including allergic respiratory diseases. In this commentary we discuss the above mentioned decree and the concept of appropriateness in the field of allergic respiratory diseases, trying to figure out some practical considerations based on the current health resources available in the field of allergology in Italy

Nasal delivery devices: A comparative study on cadaver model

Nasal nebulization is a more effective method of delivering topical medication than nasal spray. The purpose of this study was to assess the deposition patterns of nebulization in delivering topical agents to the nasal cavities in the human cadaveric model using a color-based method. We have compared these following nasal devices: single-dose vial irrigation, syringe-irrigation, common nasal spray, Spray-sol, MAD nasal, and Rinowash nasal douche. Endoscopic images were recorded at six anatomical regions prior to and following each nasal device application and four reviewers evaluated the amount of surface area staining. At the nasal vestibule, the blue dye distribution achieved with Spray-sol was more extensive than nasal sprays. At inferior turbinate and nasal cavity floor, single dose vial, syringe, MAD nasal, Spray-sol, and Rinowash demonstrated a greater extent of dye distribution than nasal spray. At the middle turbinate, the average score of both Spray-sol and MAD nasal was significantly higher than other nasal investigated devices. At the nasopharynx, Spray-sol nebulization covers a surface significantly greater than other devices. Compared to traditional sprays, Spray-sol and MAD nasal provided a more effective method of delivering topical agents to the deeper and higher portions of the nasal cavities

Digital twin reference model development to prevent operators' risk in process plants

In the literature, many applications of Digital Twin methodologies in the manufacturing, construction and oil and gas sectors have been proposed, but there is still no reference model specifically developed for risk control and prevention. In this context, this work develops a Digital Twin reference model in order to define conceptual guidelines to support the implementation of Digital Twin for risk prediction and prevention. The reference model proposed in this paper is made up of four main layers (Process industry physical space, Communication system, Digital Twin and User space), while the implementation steps of the reference model have been divided into five phases (Development of the risk assessment plan, Development of the communication and control system, Development of Digital Twin tools, Tools integration in a Digital Twin perspective and models and Platform validation). During the design and implementation phases of a Digital Twin, different criticalities must be taken into consideration concerning the need for deterministic transactions, a large number of pervasive devices, and standardization issues. Practical implications of the proposed reference model regard the possibility to detect, identify and develop corrective actions that can affect the safety of operators, the reduction of maintenance and operating costs, and more general improvements of the company business by intervening both in strictly technological and organizational terms

Structural characterization of the of inorganic and organic hydrotalcites

Layered double hydroxides are versatile materials used for intercalating bioactive molecules, both in pharmaceutical and cosmetic fields, with the purpose of protecting them from degradation, enhancing their water solubility to increase bioavailability, and/or obtaining modified release properties. Hydrotalcite is commercially available in its carbonate form, which is usually transformed into the nitrate form and finally exchanged by organic anions to obtain or regulate bioactivity or photo-activity effects (1). In this study all the steps of these transformations were characterized from the structural viewpoints by X-ray powder diffraction (XRPD) and automated electron diffraction tomography (ADT). ADT allowed shedding light on the nitrate position and conformation inside LDH. XRPD demonstrated at first that the presence of carbonate impurities is able to drive the intercalation of organic molecules into LDH, since CO32- contaminated samples tend to assume d-spacings roughly multiple of LDH-CO3 d-spacing. Finally XRPD was employed at in situ conditions to unravel the structural transformation occurring during the substitution of carbonate by nitrate ion and of the nitrate ion by organic anions. The carbonate-nitrate substitutions resulted to be very rapid (only few seconds) and only the use of a fast area detector, coupled to synchrotron radiation, allowed obtaining reliable patterns to perform XRPD refinement of the disordered structure at the sub-second time resolution. The nitrate-organic substitution resulted slower and depending on the chemical properties of the organic molecules

Different fetal-neonatal outcomes in siblings born to a mother with Graves-Basedow disease after total thyroidectomy: a case series

ABSTRACT:INTRODUCTION: We describe three different fetal or neonatal outcomes in the offspring of a mother who had persistent circulating thyrotropin receptor antibodies despite having undergone a total thyroidectomy several years before. CASE PRESENTATION: The three different outcomes were an intrauterine death, a mild and transient fetal and neonatal hyperthyroidism and a severe fetal and neonatal hyperthyroidism that required specific therapy. CONCLUSIONS: The three cases are interesting because of the different outcomes, the absence of a direct correlation between thyrotropin receptor antibody levels and clinical signs, and the persistence of thyrotropin receptor antibodies several years after a total thyroidectomy

Allergic sensitization to common pets (cats/dogs) according to different possible modalities of exposure: an Italian Multicenter Study

Background: The query "are there animals at home?" is usually administered for collecting information on anamnesis. This modality to consider exposure to pet allergens constitutes a potential bias in epidemiological studies and in clinical practice. The aim of our study was to evaluate/quantify different modalities of exposure to cat/dog in inducing allergic sensitization. Methods: Thirty Italian Allergy units participated in this study. Each centre was required to collect the data of at least 20 consecutive outpatients sensitized to cat/dog allergens. A standardized form reported all demographic data and a particular attention was paid in relieving possible modalities of exposure to cat/dog. Results: A total 723 patients sensitized to cat/dog were recorded, 359 (49.65%) reported direct pet contact, 213 patients (29.46%) were pet owners, and 146 subjects (20.19%) were exposed to pets in other settings. Other patients were sensitized by previous pet ownership (150-20.75%) or indirect contact (103-14.25%), in 111 subjects (15.35%) any contact was reported. Conclusions: Only 213 patients (29.46%) would be classified as "exposed to animals" and 510 (70.54%) as "not exposed" according to usual query. Our classification has shown that many "not-exposed" subjects (399-55.19%) were "really exposed". The magnitude of exposure to pet allergens at home is not related exclusively to pet ownership. These considerations should be taken into account during the planning of epidemiological studies and in clinical practice for the management of pet allergic individuals