Human mesenchymal stromal cells (hMSCs) are emerging as one of the most important cell types in advanced therapies and regenerative medicine due to their great therapeutic potential. The development ...of hMSC‐based products focuses on the use of hMSCs as biological active substances, and they are considered medicinal products by the primary health agencies worldwide. Due to their regulatory status, the development of hMSC‐based products is regulated by specific criteria that range from the design phase, nonclinical studies, clinical studies, to the final registration and approval. Patients should only be administered hMSC‐based products within the framework of a clinical trial or after the product has obtained marketing authorization; in both cases, authorization by health authorities is usually required. Considering the above, this paper describes the current general regulatory requirements for hMSC‐based products, by jurisdiction, to be implemented throughout their entire development process. These measures may provide support for researchers from both public and private entities and academia to optimize the development of these products and their subsequent marketing, thereby improving access to them by patients.
Targeted delivery of therapeutics is an alternative approach for the selective treatment of infectious diseases. The surface of African trypanosomes, the causative agents of African trypanosomiasis, ...is covered by a surface coat consisting of a single variant surface glycoprotein, termed VSG. This coat is recycled by endocytosis at a very high speed, making the trypanosome surface an excellent target for the delivery of trypanocidal drugs. Here, we report the design of a drug nanocarrier based on poly ethylen glycol (PEG) covalently attached (PEGylated) to poly(D,L-lactide-co-glycolide acid) (PLGA) to generate PEGylated PLGA nanoparticles. This nanocarrier was coupled to a single domain heavy chain antibody fragment (nanobody) that specifically recognizes the surface of the protozoan pathogen Trypanosoma brucei. Nanoparticles were loaded with pentamidine, the first-line drug for T. b. gambiense acute infection. An in vitro effectiveness assay showed a 7-fold decrease in the half-inhibitory concentration (IC50) of the formulation relative to free drug. Furthermore, in vivo therapy using a murine model of African trypanosomiasis demonstrated that the formulation cured all infected mice at a 10-fold lower dose than the minimal full curative dose of free pentamidine and 60% of mice at a 100-fold lower dose. This nanocarrier has been designed with components approved for use in humans and loaded with a drug that is currently in use to treat the disease. Moreover, this flexible nanobody-based system can be adapted to load any compound, opening a range of new potential therapies with application to other diseases.
Burn wounds are highly debilitating injuries, with significant morbidity and mortality rates worldwide. In association with the damage of the skin integrity, the risk of infection is increased, ...posing an obstacle to healing and potentially leading to sepsis. Another limitation against healing is associated with antibiotic resistance mainly due to the use of systemic antibiotics for the treatment of localized infections. Nanotechnology has been successful in finding strategies to incorporate antibiotics in nanoparticles for the treatment of local wounds, thereby avoiding the systemic exposure to the drug. This review focuses on the most recent advances on the use of nanoparticles in wound dressing formulations and in tissue engineering for the treatment of burn wound infections.
Live fuel moisture content (LFMC) is an input factor in fire behavior simulation models highly contributing to fire ignition and propagation. Developing models capable of accurately estimating ...spatio-temporal changes of LFMC in different forest species is needed for wildfire risk assessment. In this paper, an empirical model based on multivariate linear regression was constructed for the forest cover classified as shrublands in the central part of the Valencian region in the Eastern Mediterranean of Spain in the fire season. A sample of 15 non-monospecific shrubland sites was used to obtain a spatial representation of this type of forest cover in that area. A prediction model was created by combining spectral indices and meteorological variables. This study demonstrates that the Normalized Difference Moisture Index (NDMI) extracted from Sentinel-2 images and meteorological variables (mean surface temperature and mean wind speed) are a promising combination to derive cost-effective LFMC estimation models. The relationships between LFMC and spectral indices for all sites improved after using an additive site-specific index based on satellite information, reaching a R2adj = 0.70, RMSE = 8.13%, and MAE = 6.33% when predicting the average of LFMC weighted by the canopy cover fraction of each species of all shrub species present in each sampling plot.
Radiologic accidents or terrorist acts involving radioactive material, as well as radiation exposure in medical or industrial procedures are potential sources of risk for human health. All these ...risks share a common element, exposure to ionizing radiation. The extent of ionizing radiation injury will depend on a number of independent variables such as dose, type of radiation and tissue, etc. As a result of ionizing radiation exposure, biological effects can take place in acute or long-term manner. As in the case of other self-renewing tissues (e.g. hematopoietic system and intestinal epithelium), skin is also extremely sensitive to ionizing radiation. In this way, appropriate management of radiation skin effects might improve the therapeutic benefit of medical radiation therapy, as well as reduce the mortality associated with any radiological incident (e.g. accident or terrorist attack). For this reason, current and potential future treatment approaches for skin radiation injury are reviewed in this work. Unfortunately, there is no sufficient evidence for establishing a standard treatment to prevent or mitigate radiation-induced cutaneous injury. Thus, continued research is necessary to achieve effective therapies to address this important health problem.
The motor system may rely on a modular organization (muscle synergies activated in time) to execute different tasks. We investigated the common control features of walking and cycling in healthy ...humans from the perspective of muscle synergies. Three hypotheses were tested: 1) muscle synergies extracted from walking trials are similar to those extracted during cycling; 2) muscle synergies extracted from one of these motor tasks can be used to mathematically reconstruct the electromyographic (EMG) patterns of the other task; 3) muscle synergies of cycling can result from merging synergies of walking. A secondary objective was to identify the speed (and cadence) at which higher similarities emerged. EMG activity from eight muscles of the dominant leg was recorded in eight healthy subjects during walking and cycling at four matched cadences. A factorization technique nonnegative matrix factorization (NNMF) was applied to extract individual muscle synergy vectors and the respective activation coefficients behind the global muscular activity of each condition. Results corroborated hypotheses 2 and 3, showing that 1) four synergies from walking and cycling can successfully explain most of the EMG variability of cycling and walking, respectively, and 2) two of four synergies from walking appear to merge together to reconstruct one individual synergy of cycling, with best reconstruction values found for higher speeds. Direct comparison of the muscle synergy vectors of walking and the muscle synergy vectors of cycling (hypothesis 1) produced moderated values of similarity. This study provides supporting evidence for the hypothesis that cycling and walking share common neuromuscular mechanisms.
Clinical decompensation of cirrhosis is associated with poor prognosis. Clinically significant portal hypertension (CSPH), defined by a hepatic venous pressure gradient (HVPG) ≥10 mm Hg, is the ...strongest predictor of decompensation. This study aimed at assessing whether lowering HVPG with β blockers could decrease the risk of decompensation or death in compensated cirrhosis with CSPH.
This study on β blockers to prevent decompensation of cirrhosis with portal hypertension (PREDESCI) was an investigator-initiated, double-blind, randomised controlled trial done in eight hospitals in Spain. We enrolled patients with compensated cirrhosis and CSPH without high-risk varices. All participants had HVPG measurements with assessment of acute HVPG-response to intravenous propranolol. Responders (HVPG-decrease ≥10%) were randomly assigned to propranolol (up to 160 mg twice a day) versus placebo and non-responders to carvedilol (≤25 mg/day) versus placebo. Doses were individually determined during an open-label titration period after which randomisation was done with 1:1 allocation by a centralised web-based system. The primary endpoint was incidence of cirrhosis decompensation (defined as development of ascites, bleeding, or overt encephalopathy) or death. Since death in compensated cirrhosis is usually unrelated to the liver, an intention-to-treat analysis considering deaths unrelated to the liver as competing events was done. This study is registered with ClinicalTrials.gov, number NCT01059396. The trial is now completed.
Between Jan 18, 2010, and July 31, 2013, 631 patients were evaluated and 201 were randomly assigned. 101 patients received placebo and 100 received active treatment (67 propranolol and 33 carvedilol). The primary endpoint occurred in 16 (16%) of 100 patients in the β blockers group versus 27 (27%) of 101 in the placebo group (hazard ratio HR 0·51, 95% CI 0·26–0·97, p=0·041). The difference was due to a reduced incidence of ascites (HR 0·42, 95% CI 0·19–0·92, p=0·03). The overall incidence of adverse events was similar in both groups. Six patients (four in the β blockers group) had severe adverse events.
Long-term treatment with β blockers could increase decompensation-free survival in patients with compensated cirrhosis and CSPH, mainly by reducing the incidence of ascites.
Spanish Ministries of Health and Economy.
1. Habitat filtering (HF, trait convergence) and niche differentiation (ND, trait divergence) are known to impact upon plant community structure. Both processes integrate individual responses to the ...abiotic environment and biotic interactions. Thus, it is difficult to clearly identify the underlying abiotic and biotic factors that ultimately impact community structure by looking at community-level patterns of trait divergence or convergence alone. 2. We used a functional trait-based and multiscale approach to assess how biotic interactions and aridity determine the functional structure of semi-arid shrublands sampled along a large aridity gradient in Spain. At the regional scale, we investigated functional differences among species (axes of specialization) to identify important traits for community assembly. At the community scale, we evaluated the relative impact of HF and ND on community structure using a null model approach. Finally, at the plant neighbourhood scale, we evaluated the impact of biotic interactions on community structure by investigating the spatial patterns of trait aggregation. 3. The shrub species surveyed can be separated along four axes of specialization based on their above-ground architecture and leaf morphology. Our community scale analysis suggested that the functional structure of semi-arid communities was clearly non-random, HF and ND acting independently on different traits to determine community structure along the aridity gradient. At the plant neighbourhood scale, the spatial distribution of species was also clearly not random, suggesting that competition and facilitation impacted on the observed changes in the functional diversity of shrubland communities along the aridity gradient. 4. Synthesis: Our results demonstrated that HF and ND acted simultaneously on independent traits to jointly determine community structure. Most importantly, our multiscale approach suggested that competition and facilitation interplayed with aridity to determine this structure. Competition appeared to be constant along the aridity gradient and explained the high functional diversity observed in semi-arid shrublands. Facilitation affected subordinate and rare species and, thus, may act to enhance the biodiversity of these ecosystems. Finally, the framework employed in our study allows moving forward from the examination of patterns to the development of mechanistic traitbased approaches to study plant community assembly.
The main goal of this study was the design, development and characterization of a poloxamer/chitosan/hyaluronic based vehicle including three biological antioxidant molecules such as vitamins A, D ...and E aimed at improving the treatment of skin burns. The physical characterization of hydrogel, its mechanical and rheological properties as well as internal structure were investigated. Furthermore, biological characteristics such as ex vivo antimicrobial properties and in vivo wound healing were also accomplished and compared with a commercial reference. Results showed optimal physicochemical properties with biocompatible pH value of 4.6 ± 0.1 and zeta potential dependent on pH. The swelling rate was around 350% with optimal wettability, adhesion and leakage properties, as well as thermosensitive gelation processes. The microbiological assay demonstrated similar antimicrobial activity to that of commercial reference. In vivo tolerance study revealed no skin reactions. Finally, the wound healing efficacy of hydrogel in skin burn model showed dermal appendages and similar epidermis, dermis and stratum corneum to the commercial reference. These findings indicated that our hydrogel loading vitamins could be considered an outstanding candidate for further clinical studies.
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Clotrimazole (CLT) was formulated in a nanoemulsion (NE) for the topical treatment of candidiasis consisting of 10% labrafac® lipophile, 60% labrasol®:capryol® 90 mixture (ratio 4:1) ...and 30% propylene glycol. Physicochemical properties, stability, rheology, in vitro drug release, ex vivo drug permeation through human skin and porcine buccal, sublingual and vaginal mucosae, antifungal efficacy, as well as in vivo skin tolerance were evaluated. 1% CLT-NE (CLT-NE1) and 2% CLT-NE (CLT-NE2) exhibited 153 ± 17.25 and 186 ± 15.38 nm droplet sizes, low polydispersity indexes, negative zeta potentials and biocompatible pH values. The CLT-NEs exhibited typical Newtonian profiles with viscosities of 42.14 ± 0.037 mPa·s and 41.35 ± 0.041 mPa·s, respectively and higher extensibility properties than commercial counterparts retaining their physicochemical properties for 180 days. NEs provided a sustained release of drug according to the first order model. Similar skin permeation properties were observed between CLT-NE1 and commercial reference. However, significant higher CLT amounts retained in mucosae were provided by CLT-NE2 when compared with references. Antifungal efficacies were also higher than commercial references, and the in vivo tolerance study confirmed the suitability for topical application, making CLT-NEs a great tool for clinical investigation of topical candidiasis treatments.
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