Topical co-delivery of indomethacin and nigella sativa L. essential oil in poly-cappa-caprolactone nanoparticles: in vitro study of anti-inflammatory activity

Indomethacin is a potent, nonselective Non-steroidal Antiinflammatory Drug (NSAID) but its low water-solubility precludes its use as topical dosage form. As with other NSAIDs, the systemic delivery is associated with high risk of serious gastrointestinal adverse events including bleeding, ulceration and perforation of stomach and intestines. Here we demonstrate a safer way of administration i.e via topical demonstrating synergistic effects when co-delivered with Nigella sativa L. seeds essential oil (NSSEO) in the form of coencapsulated particles (~200 nm) of poly--caprolactone. The particles showed penetrability across stratum corneum to dermis layer in ex-vivo human skin. Further study in the xyline-induced ear edema in mice was performed, and co-encapsulated particles demonstrated highest antiinflammatory effect compared to indomethacin particles and indomethacin gels. Despite slower onset compared to indomethacin gels, the inflamed ear continued to show reduction in thickness over 8 hours of observation demonstrating synergistic and pro-longed effect contributed by NSSEO. In immunohistochemistry study of CD45+, the mice ears treated with co-encapsulated particles showed considerable reduction in lesions, epidermal-dermal separation and inflammatory cells (lymphocytes and neutrophils) infiltration as compared to other formulation. Based on microscopic evaluation, the anti-inflammatory inhibition effect of co-encapsulated particles is the highest (90%) followed by indomethacin particles (79%) and indomethacin gel (49%). The findings suggest not only skin permeability of indomethacin significantly improved but also the therapeutic effects, all provided by the presence of NSSEO in the particles. This study paves the way to more co-encapsulation of any other contemporary medicines in combination with this wholesome natural oil, NSSEO

Preparation of Microcrystals of Piroxicam Monohydrate by Antisolvent Precipitation via Microfabricated Metallic Membranes with Ordered Pore Arrays

Microcrystals of piroxicam (PRX) monohydrate with a narrow size distribution were prepared from acetone/PRX solutions by antisolvent crystallization via metallic membranes with ordered pore arrays. Crystallization was achieved by controlled addition of the feed solution through the membrane pores into a well-stirred antisolvent. A complete transformation of an anhydrous form I into a monohydrate form of PRX was confirmed by Raman spectroscopy and differential scanning calorimetry. The size of the crystals was 7–34 μm and was controlled by the PRX concentration in the feed solution (15–25 g L¯¹), antisolvent/solvent volume ratio (5–30), and type of antisolvent (Milli-Q water or 0.1–0.5 wt % aqueous solutions of hydroxypropyl methyl cellulose (HPMC), poly(vinyl alcohol) or Pluronic P-123). The smallest crystals were obtained by injecting 25 g L¯¹ PRX solution through a stainless-steel membrane with a pore size of 10 μm into a 0.06 wt % HPMC solution stirred at 1500 rpm using an antisolvent/solvent ratio of 20. HPMC provided better steric stabilization of microcrystals against agglomeration than poly(vinyl alcohol) and Pluronic P-123, due to hydrogen bonding interactions with PRX and water. A continuous production of large PRX monohydrate microcrystals with a volume-weighted mean diameter above 75 μm was achieved in a continuous stirred membrane crystallizer. Rapid pouring of Milli-Q water into the feed solution resulted in a mixture of highly polydispersed prism-shaped and needle-shaped crystals

Variations of training load, monotony, and strain and dose-response relationships with maximal aerobic speed, maximal oxygen uptake, and isokinetic strength in professional soccer players

This study aimed to identify variations in weekly training load, training monotony, and training strain across a 10-week period (during both, pre- and in-season phases); and to analyze the dose-response relationships between training markers and maximal aerobic speed (MAS), maximal oxygen uptake, and isokinetic strength. Twenty-seven professional soccer players (24.9±3.5 years old) were monitored across the 10-week period using global positioning system units. Players were also tested for maximal aerobic speed, maximal oxygen uptake, and isokinetic strength before and after 10 weeks of training. Large positive correlations were found between sum of training load and extension peak torque in the right lower limb (r = 0.57, 90%CI[0.15;0.82]) and the ratio agonist/antagonist in the right lower limb (r = 0.51, [0.06;0.78]). It was observed that loading measures fluctuated across the period of the study and that the load was meaningfully associated with changes in the fitness status of players. However, those magnitudes of correlations were small-to-large, suggesting that variations in fitness level cannot be exclusively explained by the accumulated load and loading profile

A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available

Monitoring of post-match fatigue in professional soccer: Welcome to the real world

Participation in soccer match-play leads to acute and transient subjective, biochemical, metabolic and physical disturbances in players over subsequent hours and days. Inadequate time for rest and regeneration between matches can expose players to the risk of training and competing whilst not entirely recovered. In professional soccer, contemporary competitive schedules can require teams to compete in-excess of 60 matches over the course of the season while periods of fixture congestion occur prompting much attention from researchers and practitioners to the monitoring of fatigue and readiness to play. A comprehensive body of research has investigated post-match acute and residual fatigue responses. Yet the relevance of the research for professional soccer contexts is debatable notably in relation to the study populations and designs employed. Monitoring can indeed be invasive, expensive, time-inefficient and difficult to perform routinely and simultaneously in a large squad of regularly competing players. Uncertainty also exists regarding the meaningfulness and interpretation of changes in fatigue response values and their functional relevance, and practical applicability in the field. The real-world need and cost-benefit of monitoring must be carefully weighed up. In relation to professional soccer contexts, this opinion paper intends to: 1) debate the need for PMF monitoring, 2) critique the real-world relevance of the current research literature, 3) discuss the practical burden relating to measurement tools and protocols and the collection, interpretation and application of data in the field, and, 4) propose future research perspectives