Design of experiment (DoE) as a quality by design (QbD) tool to optimise formulations of lipid nanoparticles for nose-to-brain drug delivery.

INTRODUCTION: The nose-to-brain route has been widely investigated to improve drug targeting to the central nervous system (CNS), where lipid nanoparticles (solid lipid nanoparticles - SLN and nanostructured lipid carriers - NLC) seem promising, although they should meet specific criteria of particle size (PS) <200 nm, polydispersity index (PDI) <0.3, zeta potential (ZP) ~|20| mV and encapsulation efficiency (EE) >80%. To optimize SLN and NLC formulations, design of experiment (DoE) has been recommended as a quality by design (QbD) tool. AREAS COVERED: This review presents recently published work on the optimization of SLN and NLC formulations for nose-to-brain drug delivery. The impact of different factors (or independent variables) on responses (or dependent variables) is critically analyzed. EXPERT OPINION: Different DoEs have been used to optimize SLN and NLC formulations for nose-brain drug delivery, and the independent variables lipid and surfactant concentration and sonication time had the greatest impact on the dependent variables PS, EE, and PDI. Exploring different DoE approaches is important to gain a deeper understanding of the factors that affect successful optimization of SLN and NLC and to facilitate future work improving machine learning techniques.

Research-based flow cytometry assays for pathogenic assessment in the human B-cell biology of gene variants revealed in the diagnosis of inborn errors of immunity: a Bruton's tyrosine kinase case-study.

Introduction: Inborn errors of immunity (IEI) are an expanding group of rare diseases whose field has been boosted by next-generation sequencing (NGS), revealing several new entities, accelerating routine diagnoses, expanding the number of atypical presentations and generating uncertainties regarding the pathogenic relevance of several novel variants. Methods: Research laboratories that diagnose and provide support for IEI require accurate, reproducible and sustainable phenotypic, cellular and molecular functional assays to explore the pathogenic consequences of human leukocyte gene variants and contribute to their assessment. We have implemented a set of advanced flow cytometry-based assays to better dissect human B-cell biology in a translational research laboratory. We illustrate the utility of these techniques for the in-depth characterization of a novel (c.1685G>A, p.R562Q) de novo gene variant predicted as probably pathogenic but with no previous insights into the protein and cellular effects, located in the tyrosine kinase domain of the Bruton's tyrosine kinase (BTK) gene, in an apparently healthy 14-year-old male patient referred to our clinic for an incidental finding of low immunoglobulin (Ig) M levels with no history of recurrent infections. Results and discussion: A phenotypic analysis of bone marrow (BM) revealed a slightly high percentage of pre-B-I subset in BM, with no blockage at this stage, as typically observed in classical X-linked agammaglobulinemia (XLA) patients. The phenotypic analysis in peripheral blood also revealed reduced absolute numbers of B cells, all pre-germinal center maturation stages, together with reduced but detectable numbers of different memory and plasma cell isotypes. The R562Q variant allows Btk expression and normal activation of anti-IgM-induced phosphorylation of Y551 but diminished autophosphorylation at Y223 after anti IgM and CXCL12 stimulation. Lastly, we explored the potential impact of the variant protein for downstream Btk signaling in B cells. Within the canonical nuclear factor kappa B (NF-κB) activation pathway, normal IκBα degradation occurs after CD40L stimulation in patient and control cells. In contrast, disturbed IκBα degradation and reduced calcium ion (Ca2+) influx occurs on anti-IgM stimulation in the patient's B cells, suggesting an enzymatic impairment of the mutated tyrosine kinase domain.

Anterolateral ligament of the knee-Cadaver study in a Caucasian population / Ligamento anterolateral de la rodilla. Estudio en cadáver en una población caucásica

Introduction: Despite the recognized importance of the anterolateral ligament (ALL) in rotational stability of the knee, some studies still deny its role and even its existence. We studied the prevalence of the ALL in a Caucasian population, as well as its characteristics and anatomical relationships. Materials and methods: The study was performed on 20 knees from 10 embalmed cadavers. A lateral approach, as described by Steven Claes, was used and the relations of the ALL with the lateral epicondyle, lateral inferior genicular artery, lateral meniscus, Gerdy's tubercle and fibular head were recorded. Its length and its width were also measured. Results: The ALL was identified in 16 knees. Its origin was at a distance inferior to 1mm posterior and proximal to the lateral femoral epicondyle and insertion within a mean distance of 2.1±0.6mm from de tibial articular surface, 20.6±1.3mm from the Gerdy's tubercle and 20.3±1.2mm from the fibular head. In all cases ALL presented mutual fibers with the lateral meniscus. The length was 35.8±4.6mm and the width was 4.2±1.3/4.9±1.0/6.5±1.5mm at its proximal, middle and distal third, respectively. No difference was found between gender and the dimensions of the ligament. Conclusions: The ALL was found in 80% of the knees. Its origin is closely related to the lateral collateral ligament and its insertion is halfway between the fibular head and the Gerdy's tubercle. In all cases, we verified the connection between ALL and the lateral meniscus.(AU)

Introducción: Aunque ha sido reconocida la importancia del ligamento anterolateral (ALL) en la estabilidad rotacional de la rodilla, algunos estudios siguen negando su existencia. Estudiamos la prevalencia del ALL en una población caucásica, así como sus características y relaciones anatómicas. Métodos: El estudio se realizó en 20 rodillas de 10 cadáveres embalsamados. Se utilizó un abordaje lateral, como lo describe Steven Claes, y se registraron las relaciones del ALL con el epicóndilo lateral, la arteria genicular inferior lateral, el menisco lateral, el tubérculo de Gerdy y la cabeza del peroné. También se midió el ancho y el largo. Resultados: El ALL fue identificado en 16 rodillas. Su origen estaba a una distancia inferior a 1mm posterior y proximal al epicóndilo femoral lateral y su inserción a una distancia media de 2,1±0,6mm de la superficie articular tibial, 20,6±1,3mm de la tuberosidad de Gerdy y 20,3±1,2mm de la cabeza del peroné. En todos los casos se presentaban fibras mutuas con el menisco lateral. El largo fue de 35,8±4,6mm y el ancho fue de 4,2±1,3/4,9±1,0/6,5±1,5mm en su tercio proximal, medio y distal. Conclusiones: El ALL se encontró en el 80% de las rodillas. Su origen está íntimamente relacionado con el ligamento colateral lateral y su inserción se encuentra a media distancia entre la cabeza del peroné y el tubérculo de Gerdy. En todos los casos comprobamos la conexión entre el ALL y el menisco lateral.(AU)

[Artículo traducido] Ligamento anterolateral de la rodilla. Estudio en cadáver en una población caucásica / Anterolateral ligament of the knee-Cadaver study in a Caucasian population

Introduction: Despite the recognized importance of the anterolateral ligament (ALL) in rotational stability of the knee, some studies still deny its role and even its existence. We studied the prevalence of the ALL in a Caucasian population, as well as its characteristics and anatomical relationships. Materials and methods: The study was performed on 20 knees from 10 embalmed cadavers. A lateral approach, as described by Steven Claes, was used and the relations of the ALL with the lateral epicondyle, lateral inferior genicular artery, lateral meniscus, Gerdy's tubercle and fibular head were recorded. Its length and its width were also measured. Results: The ALL was identified in 16 knees. Its origin was at a distance inferior to 1mm posterior and proximal to the lateral femoral epicondyle and insertion within a mean distance of 2.1±0.6mm from de tibial articular surface, 20.6±1.3mm from the Gerdy's tubercle and 20.3±1.2mm from the fibular head. In all cases ALL presented mutual fibers with the lateral meniscus. The length was 35.8±4.6mm and the width was 4.2±1.3/4.9±1.0/6.5±1.5mm at its proximal, middle and distal third, respectively. No difference was found between gender and the dimensions of the ligament. Conclusions: The ALL was found in 80% of the knees. Its origin is closely related to the lateral collateral ligament and its insertion is halfway between the fibular head and the Gerdy's tubercle. In all cases, we verified the connection between ALL and the lateral meniscus.(AU)

Introducción: Aunque ha sido reconocida la importancia del ligamento anterolateral (ALL) en la estabilidad rotacional de la rodilla, algunos estudios siguen negando su existencia. Estudiamos la prevalencia del ALL en una población caucásica, así como sus características y relaciones anatómicas. Métodos: El estudio se realizó en 20 rodillas de 10 cadáveres embalsamados. Se utilizó un abordaje lateral, como lo describe Steven Claes, y se registraron las relaciones del ALL con el epicóndilo lateral, la arteria genicular inferior lateral, el menisco lateral, el tubérculo de Gerdy y la cabeza del peroné. También se midió el ancho y el largo. Resultados: El ALL fue identificado en 16 rodillas. Su origen estaba a una distancia inferior a 1mm posterior y proximal al epicóndilo femoral lateral y su inserción a una distancia media de 2,1±0,6mm de la superficie articular tibial, 20,6±1,3mm de la tuberosidad de Gerdy y 20,3±1,2mm de la cabeza del peroné. En todos los casos se presentaban fibras mutuas con el menisco lateral. El largo fue de 35,8±4,6mm y el ancho fue de 4,2±1,3/4,9±1,0/6,5±1,5mm en su tercio proximal, medio y distal. Conclusiones: El ALL se encontró en el 80% de las rodillas. Su origen está íntimamente relacionado con el ligamento colateral lateral y su inserción se encuentra a media distancia entre la cabeza del peroné y el tubérculo de Gerdy. En todos los casos comprobamos la conexión entre el ALL y el menisco lateral.(AU)

Anterolateral ligament of the knee-Cadaver study in a Caucasian population. / [Artículo traducido] Ligamento anterolateral de la rodilla. Estudio en cadáver en una población caucásica.

INTRODUCTION: Despite the recognized importance of the anterolateral ligament (ALL) in rotational stability of the knee, some studies still deny its role and even its existence. We studied the prevalence of the ALL in a Caucasian population, as well as its characteristics and anatomical relationships. MATERIALS AND METHODS: The study was performed on 20 knees from 10 embalmed cadavers. A lateral approach, as described by Steven Claes, was used and the relations of the ALL with the lateral epicondyle, lateral inferior genicular artery, lateral meniscus, Gerdy's tubercle and fibular head were recorded. Its length and its width were also measured. RESULTS: The ALL was identified in 16 knees. Its origin was at a distance inferior to 1mm posterior and proximal to the lateral femoral epicondyle and insertion within a mean distance of 2.1±0.6mm from the tibial articular surface, 20.6±1.3mm from the Gerdy's tubercle and 20.3±1.2mm from the fibular head. In all cases ALL presented mutual fibers with the lateral meniscus. The length was 35.8±4.6mm and the width was 4.2±1.3/4.9±1.0/6.5±1.5mm at its proximal, middle and distal third, respectively. No difference was found between gender and the dimensions of the ligament. CONCLUSIONS: The ALL was found in 80% of the knees. Its origin is closely related to the lateral collateral ligament and its insertion is halfway between the fibular head and the Gerdy's tubercle. In all cases, we verified the connection between ALL and the lateral meniscus.

Anterolateral ligament of the knee-Cadaver study in a Caucasian population.

INTRODUCTION: Despite the recognized importance of the anterolateral ligament (ALL) in rotational stability of the knee, some studies still deny its role and even its existence. We studied the prevalence of the ALL in a Caucasian population, as well as its characteristics and anatomical relationships. MATERIALS AND METHODS: The study was performed on 20 knees from 10 embalmed cadavers. A lateral approach, as described by Steven Claes, was used and the relations of the ALL with the lateral epicondyle, lateral inferior genicular artery, lateral meniscus, Gerdy's tubercle and fibular head were recorded. Its length and its width were also measured. RESULTS: The ALL was identified in 16 knees. Its origin was at a distance inferior to 1mm posterior and proximal to the lateral femoral epicondyle and insertion within a mean distance of 2.1±0.6mm from de tibial articular surface, 20.6±1.3mm from the Gerdy's tubercle and 20.3±1.2mm from the fibular head. In all cases ALL presented mutual fibers with the lateral meniscus. The length was 35.8±4.6mm and the width was 4.2±1.3/4.9±1.0/6.5±1.5mm at its proximal, middle and distal third, respectively. No difference was found between gender and the dimensions of the ligament. CONCLUSIONS: The ALL was found in 80% of the knees. Its origin is closely related to the lateral collateral ligament and its insertion is halfway between the fibular head and the Gerdy's tubercle. In all cases, we verified the connection between ALL and the lateral meniscus.

Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: Crossing or circumventing the blood-brain barrier (BBB) to manage neurological disorders.

The main limitation to the success of central nervous system (CNS) therapies lies in the difficulty for drugs to cross the blood-brain barrier (BBB) and reach the brain. Regarding its structure and enzymatic complexity, crossing the BBB is a challenge, although several alternatives have been identified. For instance, the use of drugs encapsulated in lipid nanoparticles has been described as one of the most efficient approaches to bypass the BBB, as they allow the passage of drugs through this barrier, improving brain bioavailability. In particular, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) have been a focus of research related to drug delivery to the brain. These systems provide protection of lipophilic drugs, improved delivery and bioavailability, having a major impact on treatments outcomes. In addition, the use of lipid nanoparticles administered via routes that transport drugs directly into the brain seems a promising solution to avoid the difficulties in crossing the BBB. For instance, the nose-to-brain route has gained considerable interest, as it has shown efficacy in 3D human nasal models and in animal models. This review addresses the state of the art on the use of lipid nanoparticles to modify the pharmacokinetics of drugs employed in the management of neurological disorders. A description of the structural components of the BBB, the role of the neurovascular unit and limitations for drugs to entry into the CNS is first addressed, along with the developments to increase drug delivery to the brain, with a special focus on lipid nanoparticles. In addition, the obstacle of BBB complexity in the creation of new effective drugs for the treatment of the most prevalent neurological disorders is also addressed. Finally, the proposed strategies for lipid nanoparticles to reach the CNS, crossing or circumventing the BBB, are described. Although promising results have been reported, especially with the nose-to-brain route, they are still ongoing to assess its real efficacy in vivo in the management of neurological disorders.

Thermosensitive in situ hydrogels of rivastigmine-loaded lipid-based nanosystems for nose-to-brain delivery: characterisation, biocompatibility, and drug deposition studies.

Acetylcholinesterase inhibitors are the most used drugs to manage Alzheimer's disease, although they show low bioavailability in the brain. In this sense, nasal administration has been considered as a promising route for the direct delivery of these drugs to the brain (nose-to-brain delivery). In this work, in situ thermosensitive nasal gels with nanostructured lipid carriers (NLC) and nanoemulsion loaded with an acetylcholinesterase inhibitor (rivastigmine- RVG) were tested. In situ gels containing optimised rivastigmine -loaded NLC and rivastigmine -loaded nanoemulsion were first characterised (size, polydispersity index - PDI, zeta potential - ZP, encapsulation efficiency - EE, loading capacity - LC, pH, osmolarity, organoleptic and morphological analysis and accelerated stability). Afterwards, rheology and texture tests and in vitro studies were conducted to evaluate mucoadhesion, drug release, biocompatibility (with nasal and pulmonary cells, respectively RPMI-2650 and Calu-3) and drug deposition in a nasal cast model. The in situ gels of rivastigmine-loaded NLC and rivastigmine-loaded nanoemulsion had a respective particle/droplet size, PDI, ZP, EE, LC, pH and osmolarity of: 114.00 ± 1.91 nm and 135.80 ± 0.50 nm; 0.45 ± 0.00 and 0.43 ± 0.02; -3.58 ± 1.62 mV and -4.06 ± 1.03 mV; 95.13 ± 0.34% and 89.86 ± 0.19%; 9.30 ± 0.03% and 8.70 ± 0.01%; 6.47 ± 0.01 and 6.451 ± 0.00; 275 ± 0.02 and 280 ± 0.00 mOsm/kg. Organoleptic analysis showed homogeneous appearance, while morphological studies demonstrated that rivastigmine -loaded NLC and rivastigmine -loaded nanoemulsion had a spherical shape. Accelerated stability studies predicted good long-term stability. Rheological and texture analysis revealed that both in situ gels showed desirable characteristics for nasal administration. In addition, suitable nasal mucoadhesion and prolonged drug release were observed. Biocompatibility studies showed low and concentration-dependent cytotoxicity in RPMI 2650 and Calu-3 cells. Nasal deposition studies revealed that 4.0% of the drug was deposited in the olfactory region for both rivastigmine -loaded NLC and rivastigmine -loaded nanoemulsion alone, while in situ gels with these lipid-based nanosystems showed 8.0% of drug deposition. The results of this study highlight the potential of using thermosensitive in situ hydrogels containing lipid-based nanosystems to improve the nose-to-brain delivery of rivastigmine, providing a promising alternative therapeutic option to advance the management of Alzheimer's disease.

Validation of an algorithm to identify incident interstitial lung disease in patients with rheumatoid arthritis.

BACKGROUND/PURPOSE: Interstitial lung disease (ILD) is an important problem for patients with rheumatoid arthritis (RA). However, current approaches to ILD case finding in real-world data have been evaluated only in limited settings and identify only prevalent ILD and not new-onset disease. Our objective was to develop, refine, and validate a claims-based algorithm to identify both prevalent and incident ILD in RA patients compared to the gold standard of medical record review. METHODS: We used administrative claims data 2006-2015 from Medicare to derive a cohort of RA patients. We then identified suspected ILD using variations of ILD algorithms to classify both prevalent and incident ILD based on features of the data that included hospitalization vs. outpatient setting, physician specialty, pulmonary-related diagnosis codes, and exclusions for potentially mimicking pulmonary conditions. Positive predictive values (PPV) of several ILD algorithm variants for both prevalent and incident ILD were evaluated. RESULTS: We identified 234 linkable RA patients with sufficient data to evaluate for ILD. Overall, 108 (46.2%) of suspected cases were confirmed as ILD. Most cases (64%) were diagnosed in the outpatient setting. The best performing algorithm for prevalent ILD had a PPV of 77% (95% CI 67-84%) and for incident ILD was 96% (95% CI 85-100%). CONCLUSION: Case finding in administrative data for both prevalent and incident interstitial lung disease in RA patients is feasible and has reasonable accuracy to support population-based research and real-world evidence generation.

A new DOSXYZnrc method for Monte Carlo simulations of 4D dose distributions.

The purpose of this study is to present a novel method for generating Monte Carlo 4D dose distributions in a single DOSXYZnrc simulation. During a standard simulation, individual energy deposition events are summed up to generate a 3D dose distribution and their associated temporal information is discarded. This means that in order to determine dose distributions as a function of time, separate simulations would have to be run for each interval of interest. Consequently, it has not been clinically feasible until now to routinely perform Monte Carlo simulations of dose rate, time-resolved dose accumulation, or electronic portal imaging devices (EPID) cine-mode images for volumetric modulated arc therapy (VMAT) plans. To overcome this limitation, we modified DOSXYZnrc and defined new input and output variables that allow a time-like parameter associated with each particle history to be binned in a user-defined manner. Under the new code version, computation times are the same as for a standard simulation, and the time-integrated 4D dose is identical to the standard 3D dose. We present a comparison of scintillator measurements and Monte Carlo simulations for dose rate during a VMAT beam delivery, a study of dose rate in a VMAT total body irradiation plan, and simulations of transit (through-patient) EPID cine-mode images.

Quality by design (QbD) optimization of diazepam-loaded nanostructured lipid carriers (NLC) for nose-to-brain delivery: Toxicological effect of surface charge on human neuronal cells.

Diazepam is commonly used in the management of epileptic seizures, although it has limitations that can be overcome by using formulations that are easier to administer and capable of directing the drug to the brain. In this field, it has been reported that the use of nanostructured lipid carriers (NLC) via intranasal (or via nose-to-brain) promotes the targeting of drugs to the brain, improving the effectiveness of therapy. The aim of this work was to optimize two diazepam-loaded NLC formulations for nose-to-brain delivery, one with positive surface charge and one with negative surface charge. The quality by design (QbD) approach was used to design the experiments, where the quality target product profile (QTPP), the risk assessment and the critical quality attributes (CQAs) were defined to ensure safety, efficacy and quality of the final formulations. The experiments started with the optimization of critical material attributes (CMAs), related to the ratios of lipids and emulsifiers, followed by the selection of critical process parameters (CPPs), related to the production methods of the diazepam-loaded NLC formulation (ultrasound technique and high-pressure homogenization - HPH). Afterwards, the positive surface charge of the diazepam-loaded NLC was optimized. Finally, the biocompatibility with human neuronal cells of the formulation with a negative surface charge and of the formulation with a positive surface charge was evaluated. The results of the optimization of the CMAs showed that the ratios of lipids and emulsifiers more adequate were 6.7:2.9 and 4.2:0.3 (% w,w), respectively. Regarding the CPPs, HPH was considered the most suitable production method, resulting in an optimized diazepam-loaded NLC formulation (F1C15) with negative surface charge, showing particle size of 69.59 ± 0.22 nm, polydispersity index (PDI) of 0.19 ± 0.00, zeta potential (ZP) of -23.50 ± 0.24 mV and encapsulation efficiency (EE) of 96.60 ± 0.03 %. The optimized diazepam-loaded NLC formulation (F2A8) with positive surface charge had particle size of 124.40 ± 0.84 nm, PDI of 0.17 ± 0.01, ZP of 32.60 ± 1.13 mV and EE of 95.76 ± 0.24 %. In addition, the incorporation of diazepam in NLC resulted in a sustained release of the drug. No significant changes in particle size, PDI, ZP and EE were observed for the formulation F1C15, after 3 months of storage, whereas for formulation F2A8, particle size increased significantly. Biocompatibility studies showed that the formulation F2A8 was more cytotoxic than the formulation F1C15. Thereby, we conclude that the formulation F1C15 is more suitable for targeting the brain, when compared with the formulation F2A8. From the results of these studies, it can be confirmed that the QbD approach is an adequate and central tool to optimize NLC formulations.

Sensor Noise in LISA Pathfinder: In-Flight Performance of the Optical Test Mass Readout.

We report on the first subpicometer interferometer flown in space. It was part of ESA's Laser Interferometer Space Antenna (LISA) Pathfinder mission and performed the fundamental measurement of the positional and angular motion of two free-falling test masses. The interferometer worked immediately, stably, and reliably from switch on until the end of the mission with exceptionally low residual noise of 32.0_{-1.7}^{+2.4} fm/sqrt[Hz], significantly better than required. We present an upper limit for the sensor performance at millihertz frequencies and a model for the measured sensitivity above 200 mHz.

Pessaries containing nanostructured lipid carriers (NLC) for prolonged vaginal delivery of progesterone.

Progesterone (PRG) plays a crucial role in the female reproductive system, being the vaginal route the most adequate for its administration, as this drug has an extensive hepatic first pass effect. Nonetheless, vaginal PRG dosage forms originate immediate drug release and requires repeated administrations, which is unpleasant. Thereby, it is necessary to develop alternative delivery systems for prolonged vaginal release of PRG. The objective of this work was the development of pessaries for the prolonged vaginal delivery of PRG. Studies began with the preparation of an aqueous dispersion of PRG-loaded NLC (NLC_PRG), followed by the evaluation of its biocompatibility in human immortalized keratinocytes (HaCat cells), using three different methods (neutral red uptake, resazurin reduction and sulforhodamine B assays). Finally, the NLC_PRG was incorporated into pessaries, which were further characterized according to the European Pharmacopoeia to assess their suitability to prolong PRG release through the vaginal route. The results showed that, after preparation, 90% of the NLC_PRG had sizes equal or lower than 315.60 ± 0.01 nm, and an EE of 96.42 ± 0.00%. All the assays used to assess the biocompatibility of NLC_PRG showed the absence of cytotoxicity towards HaCaT cells for concentrations up to 10 µg/mL. In all cytotoxicity assays, a cytotoxic effect was only observed for concentrations equal or higher than 25 µg/mL, which provides high confidence in the obtained results. The outcomes of this study suggest the suitability of using pessaries containing PRG-loaded NLC for sustained drug release, which is an innovative therapeutic strategy and constitutes a promising alternative for the vaginal use of PRG. However, further ex vivo and in vivo studies are needed to fully clarify the pharmacokinetic and toxicological profile before reaching the clinical use.

Lipid nanocarriers containing Passiflora edulis seeds oil intended for skin application.

Nanostructured lipid carriers (NLC) have been studied for over 20 years, constituting the second generation of lipid nanoparticles. These nanosystems were introduced to overcome the drawbacks of solid lipid nanoparticles (SLN). Passion fruit seeds oil have a high antioxidant potential and also skin whitening properties. The objectives of this work were to prepare NLC by two methods (ultrasonication and High pressure homogenization) using different solid lipids (Glyceryl Distearate, Glyceryl Dibehenate and Cetyl Palmitate) and passion fruit seeds oil as liquid lipid. The nanoparticles prepared with glyceryl distearate, using the ultrasonication method showed better characteristics, since these nanosystems presented smaller particle sizes and polydispersity index, and higher zeta potential. Besides that, these nanoparticles showed a high occlusion factor and non-irritant potential in HET-CAM assay. Based on the results obtained, it may be suggested that the prepared NLCs can be applied to the face, since they did not cause any irritation, and represent a potential strategy for further use in topical formulations with antioxidant activity.

Occurrence, prevalence, and explanatory environmental variables of Spirocerca vulpis infestation in the foxes of western Spain.

The main aim of this study was to not only establish the prevalence of the recently described Spirocerca vulpis parasite in the wild-life cycle of carnivores in western Spain but to also elaborate a model to explain the risk of infestation based on 16 topo-climatic and habitat variables. During the period from June 2016 to November 2017, 1644 carcasses of red foxes (Vulpes vulpes) and another 105 wild mammals, legally hunted or killed in car accidents, were analyzed. Parasitic nodules of Spirocerca were found in 6% of the foxes, and the molecular analyses established a homology of our samples with the species S. vulpis. There were no differences in the occurrence of the infestation between sexes, but there were differences in terms of age, such that infestation was proportionally more frequent among young individuals. In terms of temporality, a higher percentage of positive cases was observed during the late-autumn and winter months, especially between December and February. This study provides new data on the factors that predispose S. vulpis infection in the red fox. Model results indicate that a spatial pattern exists in the occurrence and prevalence of this species in the studied area (higher probabilities to the west), and that this pattern seems to mainly be associated with topo-climatic variables.

Cytokines and Growth Factors.

Several cytokines have been used to treat autoimmune diseases, viral infections, and cancer and to regenerate the skin. In particular, interferons (INFs) have been used to treat cancer, hepatitis B and C, and multiple sclerosis, while interleukins (ILs) and tumor necrosis factors (TNFs) have been used in the management of different types of cancer. Concerning the hematopoietic growth factors (HGFs), epoetin has been used for anemia, whereas the colony-stimulating factors (CSFs) have been used for neutropenia. Other growth factors have been extensively explored, although most still need to demonstrate in vivo clinical relevance before reaching the market.This chapter provides an overview on the therapeutic applications of biological medicines containing recombinant cytokines and growth factors (HGFs and others). From this review, we concluded that the clinical relevance of recombinant cytokines has been increasing. Since the 1980s, the European Medicines Agency (EMA) and/or Food and Drug Administration (FDA) have approved 89 biological medicines containing recombinant cytokines. Among these, 18 were withdrawn, 24 are biosimilars, and 18 are orphans.So far, considerable progress has been made in discovering new cytokines, additional cytokine functions, and how they interfere with human diseases. Future prospects include the approval of more biological and biosimilar medicines for different therapeutic applications.

LISA Pathfinder Performance Confirmed in an Open-Loop Configuration: Results from the Free-Fall Actuation Mode.

We report on the results of the LISA Pathfinder (LPF) free-fall mode experiment, in which the control force needed to compensate the quasistatic differential force acting on two test masses is applied intermittently as a series of "impulse" forces lasting a few seconds and separated by roughly 350 s periods of true free fall. This represents an alternative to the normal LPF mode of operation in which this balancing force is applied continuously, with the advantage that the acceleration noise during free fall is measured in the absence of the actuation force, thus eliminating associated noise and force calibration errors. The differential acceleration noise measurement presented here with the free-fall mode agrees with noise measured with the continuous actuation scheme, representing an important and independent confirmation of the LPF result. An additional measurement with larger actuation forces also shows that the technique can be used to eliminate actuation noise when this is a dominant factor.