Nanoparticle Synthesis and Their Integration into Polymer-Based Fibers for Biomedical Applications.

The potential of nanoparticles as effective drug delivery systems combined with the versatility of fibers has led to the development of new and improved strategies to help in the diagnosis and treatment of diseases. Nanoparticles have extraordinary characteristics that are helpful in several applications, including wound dressings, microbial balance approaches, tissue regeneration, and cancer treatment. Owing to their large surface area, tailor-ability, and persistent diameter, fibers are also used for wound dressings, tissue engineering, controlled drug delivery, and protective clothing. The combination of nanoparticles with fibers has the power to generate delivery systems that have enhanced performance over the individual architectures. This review aims at illustrating the main possibilities and trends of fibers functionalized with nanoparticles, focusing on inorganic and organic nanoparticles and polymer-based fibers. Emphasis on the recent progress in the fabrication procedures of several types of nanoparticles and in the description of the most used polymers to produce fibers has been undertaken, along with the bioactivity of such alliances in several biomedical applications. To finish, future perspectives of nanoparticles incorporated within polymer-based fibers for clinical use are presented and discussed, thus showcasing relevant paths to follow for enhanced success in the field.

Sodium alginate/polycaprolactone co-axial wet-spun microfibers modified with N-carboxymethyl chitosan and the peptide AAPV for Staphylococcus aureus and human neutrophil elastase inhibition in potential chronic wound scenarios.

In chronic wound (CW) scenarios, Staphylococcus aureus-induced infections are very prevalent. This leads to abnormal inflammatory processes, in which proteolytic enzymes, such as human neutrophil elastase (HNE), become highly expressed. Alanine-Alanine-Proline-Valine (AAPV) is an antimicrobial tetrapeptide capable of suppressing the HNE activity, restoring its expression to standard rates. Here, we proposed the incorporation of the peptide AAPV within an innovative co-axial drug delivery system, in which the peptide liberation was controlled by N-carboxymethyl chitosan (NCMC) solubilization, a pH-sensitive antimicrobial polymer effective against Staphylococcus aureus. The microfibers' core was composed of polycaprolactone (PCL), a mechanically resilient polymer, and AAPV, while the shell was made of the highly hydrated and absorbent sodium alginate (SA) and NCMC, responsive to neutral-basic pH (characteristic of CW). NCMC was loaded at twice its minimum bactericidal concentration (6.144 mg/mL) against S. aureus, while AAPV was loaded at its maximum inhibitory concentration against HNE (50 µg/mL), and the production of fibers with a core-shell structure, in which all components could be detected (directly or indirectly), was confirmed. Core-shell fibers were characterized as flexible and mechanically resilient, and structurally stable after 28-days of immersion in physiological-like environments. Time-kill kinetics evaluations revealed the effective action of NCMC against S. aureus, while elastase inhibitory activity examinations proved the ability of AAPV to reduce HNE levels. Cell biology testing confirmed the safety of the engineered fiber system for human tissue contact, with fibroblast-like cells and human keratinocytes maintaining their morphology while in contact with the produced fibers. Data confirmed the engineered drug delivery platform as potentially effective for applications in CW care.

In Vitro Evaluation of Biphasic Calcium Phosphate Scaffolds Derived from Cuttlefish Bone Coated with Poly(ester urea) for Bone Tissue Regeneration.

This study investigates the osteogenic differentiation of umbilical-cord-derived human mesenchymal stromal cells (hUC-MSCs) on biphasic calcium phosphate (BCP) scaffolds derived from cuttlefish bone doped with metal ions and coated with polymers. First, the in vitro cytocompatibility of the undoped and ion-doped (Sr2+, Mg2+ and/or Zn2+) BCP scaffolds was evaluated for 72 h using Live/Dead staining and viability assays. From these tests, the most promising composition was found to be the BCP scaffold doped with strontium (Sr2+), magnesium (Mg2+) and zinc (Zn2+) (BCP-6Sr2Mg2Zn). Then, samples from the BCP-6Sr2Mg2Zn were coated with poly(ԑ-caprolactone) (PCL) or poly(ester urea) (PEU). The results showed that hUC-MSCs can differentiate into osteoblasts, and hUC-MSCs seeded on the PEU-coated scaffolds proliferated well, adhered to the scaffold surfaces, and enhanced their differentiation capabilities without negative effects on cell proliferation under in vitro conditions. Overall, these results suggest that PEU-coated scaffolds are an alternative to PCL for use in bone regeneration, providing a suitable environment to maximally induce osteogenesis.

Osteosarcoma-Derived Exosomes as Potential PET Imaging Nanocarriers for Lung Metastasis.

Lung metastases represent the most adverse clinical factor and rank as the leading cause of osteosarcoma-related death. Nearly 80% of patients present lung micrometastasis at diagnosis not detected with current clinical tools. Herein, an exosome (EX)-based imaging tool is developed for lung micrometastasis by positron emission tomography (PET) using osteosarcoma-derived EXs as natural nanocarriers of the positron-emitter copper-64 (64 Cu). Exosomes are isolated from metastatic osteosarcoma cells and functionalized with the macrocyclic chelator NODAGA for complexation with 64 Cu. Surface functionalization has no effect on the physicochemical properties of EXs, or affinity for donor cells and endows them with favorable pharmacokinetics for in vivo studies. Whole-body PET/magnetic resonance imaging (MRI) images in xenografted models show a specific accumulation of 64 Cu-NODAGA-EXs in metastatic lesions as small as 2-3 mm or in a primary tumor, demonstrating the exquisite tropism of EXs for homotypic donor cells. The targetability for lung metastasis is also observed by optical imaging using indocyanine green (ICG)-labeled EXs and D-luciferin-loaded EXs. These findings show that tumor-derived EXs hold great potential as targeted imaging agents for the noninvasive detection of small lung metastasis by PET. This represents a step forward in the biomedical application of EXs in imaging diagnosis with increased translational potential.

Cerebellar morphometric and spectroscopic biomarkers for Machado-Joseph Disease.

Machado-Joseph disease (MJD) or Spinocerebellar ataxia type 3 (SCA3) is the most common form of dominant SCA worldwide. Magnetic Resonance Imaging (MRI) and Proton Magnetic Resonance Spectroscopy (1H-MRS) provide promising non-invasive diagnostic and follow-up tools, also serving to evaluate therapies efficacy. However, pre-clinical studies showing relationship between MRI-MRS based biomarkers and functional performance are missing, which hampers an efficient clinical translation of therapeutics. This study assessed motor behaviour, neurochemical profiles, and morphometry of the cerebellum of MJD transgenic mice and patients aiming at establishing magnetic-resonance-based biomarkers. 1H-MRS and structural MRI measurements of MJD transgenic mice were performed with a 9.4 Tesla scanner, correlated with motor performance on rotarod and compared with data collected from human patients. We found decreased cerebellar white and grey matter and enlargement of the fourth ventricle in both MJD mice and human patients as compared to controls. N-acetylaspartate (NAA), NAA + N-acetylaspartylglutamate (NAA + NAAG), Glutamate, and Taurine, were significantly decreased in MJD mouse cerebellum regardless of age, whereas myo-Inositol (Ins) was increased at early time-points. Lower neurochemical ratios levels (NAA/Ins and NAA/total Choline), previously correlated with worse clinical status in SCAs, were also observed in MJD mice cerebella. NAA, NAA + NAAG, Glutamate, and Taurine were also positively correlated with MJD mice motor performance. Importantly, these 1H-MRS results were largely analogous to those found for MJD in human studies and in our pilot data in human patients. We have established a magnetic resonance-based biomarker approach to monitor novel therapies in preclinical studies and human clinical trials.

Tunable Spun Fiber Constructs in Biomedicine: Influence of Processing Parameters in the Fibers' Architecture.

Electrospinning and wet-spinning have been recognized as two of the most efficient and promising techniques for producing polymeric fibrous constructs for a wide range of applications, including optics, electronics, food industry and biomedical applications. They have gained considerable attention in the past few decades because of their unique features and tunable architectures that can mimic desirable biological features, responding more effectively to local demands. In this review, various fiber architectures and configurations, varying from monolayer and core-shell fibers to tri-axial, porous, multilayer, side-by-side and helical fibers, are discussed, highlighting the influence of processing parameters in the final constructs. Additionally, the envisaged biomedical purposes for the examined fiber architectures, mainly focused on drug delivery and tissue engineering applications, are explored at great length.

Mesenchymal stem cells for lysosomal storage and polyglutamine disorders: Possible shared mechanisms.

BACKGROUND: Mesenchymal stem cells' (MSC) therapeutic potential has been investigated for the treatment of several neurodegenerative diseases. The fact these cells can mediate a beneficial effect in different neurodegenerative contexts strengthens their competence to target diverse mechanisms. On the other hand, distinct disorders may share similar mechanisms despite having singular neuropathological characteristics. METHODS: We have previously shown that MSC can be beneficial for two disorders, one belonging to the groups of Lysosomal Storage Disorders (LSDs) - the Krabbe Disease or Globoid Cell Leukodystrophy, and the other to the family of Polyglutamine diseases (PolyQs) - the Machado-Joseph Disease or Spinocerebellar ataxia type 3. We gave also input into disease characterization since neuropathology and MSC's effects are intrinsically associated. This review aims at describing MSC's multimode of action in these disorders while emphasizing to possible mechanistic alterations they must share due to the accumulation of cellular toxic products. RESULTS: Lysosomal storage disorders and PolyQs have different aetiology and associated symptoms, but both result from the accumulation of undegradable products inside neuronal cells due to inefficient clearance by the endosomal/lysosomal pathway. Moreover, numerous cellular mechanisms that become compromised latter are also shared by these two disease groups. CONCLUSIONS: Here, we emphasize MSC's effect in improving proteostasis and autophagy cycling turnover, neuronal survival, synaptic activity and axonal transport. LSDs and PolyQs, though rare in their predominance, collectively affect many people and require our utmost dedication and efforts to get successful therapies due to their tremendous impact on patient s' lives and society.

Highly Porous Composite Scaffolds Endowed with Antibacterial Activity for Multifunctional Grafts in Bone Repair.

The present study deals with the development of multifunctional biphasic calcium phosphate (BCP) scaffolds coated with biopolymers-poly(ε-caprolactone) (PCL) or poly(ester urea) (PEU)-loaded with an antibiotic drug, Rifampicin (RFP). The amounts of RFP incorporated into the PCL and PEU-coated scaffolds were 0.55 ± 0.04 and 0.45 ± 0.02 wt%, respectively. The in vitro drug release profiles in phosphate buffered saline over 6 days were characterized by a burst release within the first 8h, followed by a sustained release. The Korsmeyer-Peppas model showed that RFP release was controlled by polymer-specific non-Fickian diffusion. A faster burst release (67.33 ± 1.48%) was observed for the PCL-coated samples, in comparison to that measured (47.23 ± 0.31%) for the PEU-coated samples. The growth inhibitory activity against Escherichia coli and Staphylococcus aureus was evaluated. Although the RFP-loaded scaffolds were effective in reducing bacterial growth for both strains, their effectiveness depends on the particular bacterial strain, as well as on the type of polymer coating, since it rules the drug release behavior. The low antibacterial activity demonstrated by the BCP-PEU-RFP scaffold against E. coli could be a consequence of the lower amount of RFP that is released from this scaffold, when compared with BCP-PCL-RFP. In vitro studies showed excellent cytocompatibility, adherence, and proliferation of human mesenchymal stem cells on the BCP-PEU-RFP scaffold surface. The fabricated highly porous scaffolds that could act as an antibiotic delivery system have great potential for applications in bone regeneration and tissue engineering, while preventing bacterial infections.

Bioactivity of Chitosan-Based Particles Loaded with Plant-Derived Extracts for Biomedical Applications: Emphasis on Antimicrobial Fiber-Based Systems.

Marine-derived chitosan (CS) is a cationic polysaccharide widely studied for its bioactivity, which is mostly attached to its primary amine groups. CS is able to neutralize reactive oxygen species (ROS) from the microenvironments in which it is integrated, consequently reducing cell-induced oxidative stress. It also acts as a bacterial peripheral layer hindering nutrient intake and interacting with negatively charged outer cellular components, which lead to an increase in the cell permeability or to its lysis. Its biocompatibility, biodegradability, ease of processability (particularly in mild conditions), and chemical versatility has fueled CS study as a valuable matrix component of bioactive small-scaled organic drug-delivery systems, with current research also showcasing CS's potential within tridimensional sponges, hydrogels and sutures, blended films, nanofiber sheets and fabric coatings. On the other hand, renewable plant-derived extracts are here emphasized, given their potential as eco-friendly radical scavengers, microbicidal agents, or alternatives to antibiotics, considering that most of the latter have induced bacterial resistance because of excessive and/or inappropriate use. Loading them into small-scaled particles potentiates a strong and sustained bioactivity, and a controlled release, using lower doses of bioactive compounds. A pH-triggered release, dependent on CS's protonation/deprotonation of its amine groups, has been the most explored stimulus for that control. However, the use of CS derivatives, crosslinking agents, and/or additional stabilization processes is enabling slower release rates, following extract diffusion from the particle matrix, which can find major applicability in fiber-based systems within ROS-enriched microenvironments and/or spiked with microbes. Research on this is still in its infancy. Yet, the few published studies have already revealed that the composition, along with an adequate drug release rate, has an important role in controlling an existing infection, forming new tissue, and successfully closing a wound. A bioactive finishing of textiles has also been promoting high particle infiltration, superior washing durability, and biological response.

Functionalization of Crosslinked Sodium Alginate/Gelatin Wet-Spun Porous Fibers with Nisin Z for the Inhibition of Staphylococcus aureus-Induced Infections.

Nisin Z, an amphipathic peptide, with a significant antibacterial activity against Gram-positive bacteria and low toxicity in humans, has been studied for food preservation applications. Thus far, very little research has been done to explore its potential in biomedicine. Here, we report the modification of sodium alginate (SA) and gelatin (GN) blended microfibers, produced via the wet-spinning technique, with Nisin Z, with the purpose of eradicating Staphylococcus aureus-induced infections. Wet-spun SAGN microfibers were successfully produced at a 70/30% v/v of SA (2 wt%)/GN (1 wt%) polymer ratio by extrusion within a calcium chloride (CaCl2) coagulation bath. Modifications to the biodegradable fibers' chemical stability and structure were then introduced via crosslinking with CaCl2 and glutaraldehyde (SAGNCL). Regardless of the chemical modification employed, all microfibers were labelled as homogeneous both in size (≈246.79 µm) and shape (cylindrical and defect-free). SA-free microfibers, with an increased surface area for peptide immobilization, originated from the action of phosphate buffer saline solution on SAGN fibers, were also produced (GNCL). Their durability in physiological conditions (simulated body fluid) was, however, compromised very early in the experiment (day 1 and 3, with and without Nisin Z, respectively). Only the crosslinked SAGNCL fibers remained intact for the 28 day-testing period. Their thermal resilience in comparison with the unmodified and SA-free fibers was also demonstrated. Nisin Z was functionalized onto the unmodified and chemically altered fibers at an average concentration of 178 µg/mL. Nisin Z did not impact on the fiber's morphology nor on their chemical/thermal stability. However, the peptide improved the SA fibers (control) structural integrity, guaranteeing its stability for longer, in physiological conditions. Its main effect was detected on the time-kill kinetics of the bacteria S. aureus. SAGNCL and GNCL loaded with Nisin Z were capable of progressively eliminating the bacteria, reaching an inhibition superior to 99% after 24 h of culture. The peptide-modified SA and SAGN were not as effective, losing their antimicrobial action after 6 h of incubation. Bacteria elimination was consistent with the release kinetics of Nisin Z from the fibers. In general, data revealed the increased potential and durable effect of Nisin Z (significantly superior to its free, unloaded form) against S. aureus-induced infections, while loaded onto prospective biomedical wet-spun scaffolds.

Mesenchymal stromal cells to fight SARS-CoV-2: Taking advantage of a pleiotropic therapy.

The devastating global impact of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has prompted scientists to develop novel strategies to fight Coronavirus Disease of 2019 (COVID-19), including the examination of pre-existing treatments for other viral infections in COVID-19 patients. This review provides a reasoned discussion of the possible use of Mesenchymal Stromal Cells (MSC) or their products as a treatment in SARS-CoV-2-infected patients. The main benefits and concerns of using this cellular therapy, guided by preclinical and clinical data obtained from similar pathologies will be reviewed. MSC represent a highly immunomodulatory cell population and their use may be safe according to clinical studies developed in other pathologies. Notably, four clinical trials and four case reports that have already been performed in COVID-19 patients obtained promising results. The clinical application of MSC in COVID-19 is very preliminary and further investigational studies are required to determine the efficacy of the MSC therapy. Nevertheless, these preliminary studies were important to understand the therapeutic potential of MSC in COVID-19. Based on these encouraging results, the United States Food and Drug Administration (FDA) authorized the compassionate use of MSC, but only in patients with Acute Respiratory Distress Syndrome (ARDS) and a poor prognosis. In fact, patients with severe SARS-CoV-2 can present infection and tissue damage in different organs, such as lung, heart, liver, kidney, gut and brain, affecting their function. MSC may have pleiotropic activities in COVID-19, with the capacity to fight inflammation and repair lesions in several organs.

Mesenchymal Stromal Cells' Therapy for Polyglutamine Disorders: Where Do We Stand and Where Should We Go?

Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by the expansion of the cytosine-adenine-guanine (CAG) repeat. This mutation encodes extended glutamine (Q) tract in the disease protein, resulting in the alteration of its conformation/physiological role and in the formation of toxic fragments/aggregates of the protein. This group of heterogeneous disorders shares common molecular mechanisms, which opens the possibility to develop a pan therapeutic approach. Vast efforts have been made to develop strategies to alleviate disease symptoms. Nonetheless, there is still no therapy that can cure or effectively delay disease progression of any of these disorders. Mesenchymal stromal cells (MSC) are promising tools for the treatment of polyQ disorders, promoting protection, tissue regeneration, and/or modulation of the immune system in animal models. Accordingly, data collected from clinical trials have so far demonstrated that transplantation of MSC is safe and delays the progression of some polyQ disorders for some time. However, to achieve sustained phenotypic amelioration in clinics, several treatments may be necessary. Therefore, efforts to develop new strategies to improve MSC's therapeutic outcomes have been emerging. In this review article, we discuss the current treatments and strategies used to reduce polyQ symptoms and major pre-clinical and clinical achievements obtained with MSC transplantation as well as remaining flaws that need to be overcome. The requirement to cross the blood-brain-barrier (BBB), together with a short rate of cell engraftment in the lesioned area and low survival of MSC in a pathophysiological context upon transplantation may contribute to the transient therapeutic effects. We also review methods like pre-conditioning or genetic engineering of MSC that can be used to increase MSC survival in vivo, cellular-free approaches-i.e., MSC-conditioned medium (CM) or MSC-derived extracellular vesicles (EVs) as a way of possibly replacing the use of MSC and methods required to standardize the potential of MSC/MSC-derived products. These are fundamental questions that need to be addressed to obtain maximum MSC performance in polyQ diseases and therefore increase clinical benefits.

Single Cell Oil Production by Oleaginous Yeasts Grown in Synthetic and Waste-Derived Volatile Fatty Acids.

Four yeast isolates from the species-Apiotrichum brassicae, Candida tropicalis, Metschnikowia pulcherrima, and Pichia kudriavzevii-previously selected by their oleaginous character and growth flexibility in different carbon sources, were tested for their capacity to convert volatile fatty acids into lipids, in the form of single cell oils. Growth, lipid yields, volatile fatty acids consumption, and long-chain fatty acid profiles were evaluated in media supplemented with seven different volatile fatty acids (acetic, butyric, propionic, isobutyric, valeric, isovaleric, and caproic), and also in a dark fermentation effluent filtrate. Yeasts A. brassicae and P. kudriavzevii attained lipid productivities of more than 40% (w/w), mainly composed of oleic (>40%), palmitic (20%), and stearic (20%) acids, both in synthetic media and in the waste-derived effluent filtrate. These isolates may be potential candidates for single cell oil production in larger scale applications by using alternative carbon sources, combining economic and environmental benefits.

The blood-brain barrier is disrupted in Machado-Joseph disease/spinocerebellar ataxia type 3: evidence from transgenic mice and human post-mortem samples.

Blood-brain barrier (BBB) disruption is a common feature in neurodegenerative diseases. However, BBB integrity has not been assessed in spinocerebellar ataxias (SCAs) such as Machado-Joseph disease/SCA type 3 (MJD/SCA3), a genetic disorder, triggered by polyglutamine-expanded ataxin-3. To investigate that, BBB integrity was evaluated in a transgenic mouse model of MJD and in human post-mortem brain tissues.Firstly, we investigated the BBB permeability in MJD mice by: i) assessing the extravasation of the Evans blue (EB) dye and blood-borne proteins (e.g fibrinogen) in the cerebellum by immunofluorescence, and ii) in vivo Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI). The presence of ataxin-3 aggregates in brain blood vessels and the levels of tight junction (TJ)-associated proteins were also explored by immunofluorescence and western blotting. Human brain samples were used to confirm BBB permeability by evaluating fibrinogen extravasation, co-localization of ataxin-3 aggregates with brain blood vessels and neuroinflammation.In the cerebellum of the mouse model of MJD, there was a 5-fold increase in EB accumulation when compared to age-matched controls. Moreover, vascular permeability displayed a 13-fold increase demonstrated by DCE-MRI. These results were validated by the 2-fold increase in fibrinogen extravasation in transgenic animals comparing to controls. Interestingly, mutant ataxin-3 aggregates were detected in cerebellar blood vessels of transgenic mice, accompanied by alterations of TJ-associated proteins in cerebellar endothelial cells, namely a 29% decrease in claudin-5 oligomers and a 10-fold increase in an occludin cleavage fragment. These results were validated in post-mortem brain samples from MJD patients as we detected fibrinogen extravasation across BBB, the presence of ataxin-3 aggregates in blood vessels and associated microgliosis.Altogether, our results prove BBB impairment in MJD/SCA3. These findings contribute for a better understanding of the disease mechanisms and opens the opportunity to treat MJD with medicinal products that in normal conditions would not cross the BBB.

Spun Biotextiles in Tissue Engineering and Biomolecules Delivery Systems.

Nowadays, tissue engineering is described as an interdisciplinary field that combines engineering principles and life sciences to generate implantable devices to repair, restore and/or improve functions of injured tissues. Such devices are designed to induce the interaction and integration of tissue and cells within the implantable matrices and are manufactured to meet the appropriate physical, mechanical and physiological local demands. Biodegradable constructs based on polymeric fibers are desirable for tissue engineering due to their large surface area, interconnectivity, open pore structure, and controlled mechanical strength. Additionally, biodegradable constructs are also very sought-out for biomolecule delivery systems with a target-directed action. In the present review, we explore the properties of some of the most common biodegradable polymers used in tissue engineering applications and biomolecule delivery systems and highlight their most important uses.

Modified high-throughput Nile red fluorescence assay for the rapid screening of oleaginous yeasts using acetic acid as carbon source.

BACKGROUND: Over the last years oleaginous yeasts have been studied for several energetic, oleochemical, medical and pharmaceutical purposes. However, only a small number of yeasts are known and have been deeply exploited. The search for new isolates with high oleaginous capacity becomes imperative, as well as the use of alternative and ecological carbon sources for yeast growth. RESULTS: In the present study a high-throughput screening comprising 366 distinct yeast isolates was performed by applying an optimised protocol based on two approaches: (I) yeast cultivation on solid medium using acetic acid as carbon source, (II) neutral lipid estimation by fluorimetry using the lipophilic dye Nile red. CONCLUSIONS: Results showed that, with the proposed methodology, the oleaginous potential of yeasts with broad taxonomic diversity and variety of growth characteristics was discriminated. Furthermore, this work clearly demonstrated the association of the oleaginous yeast character to the strain level, contrarily to the species-level linkage, as usually stated.

Repeated Mesenchymal Stromal Cell Treatment Sustainably Alleviates Machado-Joseph Disease.

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3, the most common dominant spinocerebellar ataxia (SCA) worldwide, is caused by over-repetition of a CAG repeat in the ATXN3/MJD1 gene, which translates into a polyglutamine tract within the ataxin-3 protein. There is no treatment for this fatal disorder. Despite evidence of the safety and efficacy of mesenchymal stromal cells (MSCs) in delaying SCA disease progression in exploratory clinical trials, unanticipated regression of patients to the status prior to treatment makes the investigation of causes and solutions urgent and imperative. In the present study, we compared the efficacy of a single intracranial injection with repeated systemic MSC administration in alleviating the MJD phenotype of two strongly severe genetic rodent models. We found that a single MSC transplantation only produces transient effects, whereas periodic administration promotes sustained motor behavior and neuropathology alleviation, suggesting that MSC therapies should be re-designed to get sustained beneficial results in clinical practice. Furthermore, MSC promoted neuroprotection, increased the levels of GABA and glutamate, and decreased the levels of Myo-inositol, which correlated with motor improvements, indicating that these metabolites may serve as valid neurospectroscopic biomarkers of disease and treatment. This study makes important contributions to the design of new clinical approaches for MJD and other SCAs/polyglutamine disorders.

Stem Cell-Based Therapies for Polyglutamine Diseases.

Polyglutamine (polyQ) diseases are a family of neurodegenerative disorders with very heterogeneous clinical presentations, although with common features such as progressive neuronal death. Thus, at the time of diagnosis patients might present an extensive and irreversible neuronal death demanding cell replacement or support provided by cell-based therapies. For this purpose stem cells, which include diverse populations ranging from embryonic stem cells (ESCs), to fetal stem cells, mesenchymal stromal cells (MSCs) or induced pluripotent stem cells (iPSCs) have remarkable potential to promote extensive brain regeneration and recovery in neurodegenerative disorders. This regenerative potential has been demonstrated in exciting pre and clinical assays. However, despite these promising results, several drawbacks are hampering their successful clinical implementation. Problems related to ethical issues, quality control of the cells used and the lack of reliable models for the efficacy assessment of human stem cells. In this chapter the main advantages and disadvantages of the available sources of stem cells as well as their efficacy and potential to improve disease outcomes are discussed.

Biomarkers in Chronic Kidney Disease / Biomarcadores en enfermedad renal crónica

Chronic kidney disease (CKD) is an important public health problem. The classification of CKD by KDOQI and KDIGO and routine reports of the estimation of the glomerular filtration rate (eGFR), have resulted in a higher frequency in the diagnosis of CKD. Identification of CKD subjects and high risk of disease progression and cardiovascular disease (CVD) development is important. In clinical practice, proteinuria is the most sensitive marker of the progression of CKD, especially when combined with eGFR, but these have limitations. Therefore, the use of other early and sensitive biomarkers is required. Promising biomarkers are now being identified for the detection of CKD progression and its associated CVD morbidity and mortality. These are sensitive biomarkers of renal function, underlying pathophysiological processes and/or cardiovascular risk.

La enfermedad renal crónica (ERC) es un importante problema de salud pública. La clasificación de la ERC por KDOQI y KDIGO, y los informes rutinarios de la estimación de la tasa de filtración glomerular (eTFG), han dado lugar a una mayor frecuencia en el diagnóstico de ERC. Es importante la identificación de los pacientes con ERC y alto riesgo de progresión de la enfermedad y del desarrollo de enfermedad cardiovascular (ECV). En la práctica clínica, la proteinuria es el marcador más sensible de la progresión de la ERC, especialmente cuando se combina con eTFG, pero, aun con ello, tienen limitaciones. Por lo tanto, se requiere del uso de otros biomarcadores tempranos y sensibles. Actualmente se tienen identificados biomarcadores prometedores para la detección de la progresión de la ERC y de su morbilidad y mortalidad por ECV asociada. Estos son biomarcadores sensibles de la función renal, de los procesos fisiopatológicos subyacentes y/o del riesgo cardiovascular.

[Factors related to residual renal function loss in patients in peritoneal dialysis]. / Factores relacionados con pérdida de la función renal residual en pacientes en diálisis peritoneal.

BACKGROUND: Residual renal function (RRF) contributes to the quality of life of patients on dialysis. The preservation of RRF is associated with higher patient survival in peritoneal dialysis (PD), and is now accepted that RRF and peritoneal clearance are not of equal value in patient survival. The aim of this study is to know the factors related to RRF loss in prevalent patients in continuous ambulatory peritoneal dialysis (CAPD). METHODS: This is an analysis of secondary outcomes. Forty-three adult patients with type 2 diabetes were included. They had RRF preserved. Clinical and laboratory assessments were done in each visit during a year. RESULTS: The male gender (p = 0.042), systolic (p = 0.009) and diastolic (p = 0.006) blood pressure (BP), hemoglobin (p = 0.008), peritoneal creatinine clearance (p = 0.014), peritoneal ultrafiltration (p = 0.017) and levels of tumor necrosis factor-alpha (TNF-alpha) in plasma (p = 0.022) and dialysate (p = 0.008) were related with RRF loss. CONCLUSIONS: It is important to understand the factors associated with RRF loss in our patients to prevent the gradual loss and its implications on the mortality and quality of life.

Introducción: la conservación de la función renal residual (FRR) en los pacientes en diálisis peritoneal (DP) tiene una clara influencia sobre la calidad de vida, independientemente de que su preservación ha demostrado influir en la mayor supervivencia de los pacientes. El objetivo del presente estudio fue conocer los factores relacionados con pérdida de la FRR en un grupo de pacientes prevalentes en diálisis peritoneal continua ambulatoria (DPCA). Métodos: se trata de un estudio de análisis de resultados secundarios. Se incluyeron 43 adultos con diabetes tipo 2 (DT2), con FRR conservada, a quienes se les dio seguimiento durante un año. Resultados: los factores relacionados con la pérdida de la FRR fueron: género masculino (p = 0.042), presión arterial sistólica (p = 0.009) y diastólica (p = 0.006), hemoglobina (p = 0.008), aclaramiento peritoneal de creatinina (p = 0.014), ultrafiltración (p = 0.017), niveles de factor de necrosis tumoral alfa (FNT­alfa) en plasma (p = 0.022) y dializado (p = 0.008). Conclusiones: es importante conocer los factores relacionados con pérdida de la FRR en nuestros pacientes para evitar la pérdida gradual de la misma y sus implicaciones sobre la mortalidad y calidad de vida.