Mesenchymal stromal cells (MSCs) are a promising option to treat knee osteoarthritis (OA). Their safety and usefulness have been reported in several short-term clinical trials but less information is ...available on the long-term effects of MSC in patients with osteoarthritis. We have evaluated patients included in our previous randomized clinical trial (CMM-ART, NCT02123368) to determine their long-term clinical effect.
A phase I/II multicenter randomized clinical trial with active control was conducted between 2012 and 2014. Thirty patients diagnosed with knee OA were randomly assigned to Control group, intraarticularly administered hyaluronic acid alone, or to two treatment groups, hyaluronic acid together with 10 × 10
or 100 × 10
cultured autologous bone marrow-derived MSCs (BM-MSCs), and followed up for 12 months. After a follow up of 4 years adverse effects and clinical evolution, assessed using VAS and WOMAC scorings are reported.
No adverse effects were reported after BM-MSCs administration or during the follow-up. BM-MSCs-administered patients improved according to VAS, median value (IQR) for Control, Low-dose and High-dose groups changed from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 7 (6, 7), 2 (2, 5) and 3 (3, 4), respectively at the end of follow up (Low-dose vs Control group, p = 0.01; High-dose vs Control group, p = 0.004). Patients receiving BM-MSCs also improved clinically according to WOMAC. Control group showed an increase median value of 4 points (- 11;10) while Low-dose and High-dose groups exhibited values of - 18 (- 28;- 9) and - 10 (- 21;- 3) points, respectively (Low-dose vs Control group p = 0.043). No clinical differences between the BM-MSCs receiving groups were found.
Single intraarticular injection of in vitro expanded autologous BM-MSCs is a safe and feasible procedure that results in long-term clinical and functional improvement of knee OA.
Fused filament fabrication (FFF) is a promising additive manufacturing (AM) technology due to its ability to build thermoplastics parts with advantages in the design and optimization of models with ...complex geometries, great design flexibility, recyclability and low material waste. This technique has been extensively used for the manufacturing of conceptual prototypes rather than functional components due to the limited mechanical properties of pure thermoplastics parts. In order to improve the mechanical performance of 3D printed parts based on polymeric materials, reinforcements including nanoparticles, short or continuous fibers and other additives have been adopted. The addition of graphene nanoplatelets (GNPs) to plastic and polymers is currently under investigation as a promising method to improve their working conditions due to the good mechanical, electrical and thermal performance exhibited by graphene. Although research shows particularly promising improvement in thermal and electrical conductivities of graphene-based nanocomposites, the aim of this study is to evaluate the effect of graphene nanoplatelet reinforcement on the mechanical properties, dimensional accuracy and surface texture of 3D printed polylactic acid (PLA) structures manufactured by a desktop 3D printer. The effect of build orientation was also analyzed. Scanning Electron Microscope (SEM) images of failure samples were evaluated to determine the effects of process parameters on failure modes. It was observed that PLA-Graphene composite samples showed, in general terms, the best performance in terms of tensile and flexural stress, particularly in the case of upright orientation (about 1.5 and 1.7 times higher than PLA and PLA 3D850 samples, respectively). In addition, PLA-Graphene composite samples showed the highest interlaminar shear strength (about 1.2 times higher than PLA and PLA 3D850 samples). However, the addition of GNPs tended to reduce the impact strength of the PLA-Graphene composite samples (PLA and PLA 3D850 samples exhibited an impact strength about 1.2-1.3 times higher than PLA-Graphene composites). Furthermore, the addition of graphene nanoplatelets did not affect, in general terms, the dimensional accuracy of the PLA-Graphene composite specimens. In addition, PLA-Graphene composite samples showed, in overall terms, the best performance in terms of surface texture, particularly when parts were printed in flat and on-edge orientations. The promising results in the present study prove the feasibility of 3D printed PLA-graphene composites for potential use in different applications such as biomedical engineering.
This paper studies whether unilateral divorce affects women’s welfare. Unilateral divorce refers to a divorce regime where each of the spouses can dissolve the marriage unilaterally (i.e. without ...mutual consent). First, it builds a simple theoretical model that finds that women are better off under unilateral divorce than under mutual consent. Second, it makes use of data from the U.S. between 2003 and 2014 to explore empirically whether unilateral divorce affects the amount of time women devote to three different activities that might be seen as proxies of their level of welfare, such as, housework, leisure and relaxing activities, and personal care. We find causal evidence suggesting that unilateral divorce improves women’s welfare. Namely, it reduces housework carried out by women, while it increases their amount of time devoted to leisure and relaxing activities, and personal care. Further results suggest these changes are not due to improvements in gender equality per se. Moreover, we find that the decrease in housework and the surges in leisure and relaxing activities are permanent, whereas the increase in personal care is temporary. These findings are important from a policy perspective to motivate the introduction of unilateral divorce laws.
Society challenges higher education institutions and their members to generate inclusive communities to enable the full development of all members. This study aims to analyze who is responsible for ...generating inclusion according to community members from a traditional Chilean University. We carried out qualitative research based on the Grounded Theory. We collected data through focus group and semi-structured Interviews, involving 14 undergraduate students, two post-graduate students, 17 faculty members, five non-teaching staff members, and nine executives officers. All of thembelonging to the three campuses of the University. We analyzed data using ATLAS.ti 7.5.7, using the constant comparison method and reaching an axial codification level. From the data analysis, 25 subcategories emerged, grouped into six categories. Later we organized them under the codification paradigm. Results highlighted the perception of the interaction and influence of the social, institutional, and personal fields in the inclusion phenomenon. Also, that inclusive practices must be a responsibility shared among different educational community members.
The optimal diuretic treatment strategy for patients with acute heart failure and renal dysfunction remains unclear. Plasma carbohydrate antigen 125 (CA125) is a surrogate of fluid overload and a ...potentially valuable tool for guiding decongestion therapy. The aim of this study was to determine if a CA125-guided diuretic strategy is superior to usual care in terms of short-term renal function in patients with acute heart failure and renal dysfunction at presentation.
This multicenter, open-label study randomized 160 patients with acute heart failure and renal dysfunction into 2 groups (1:1). Loop diuretics doses were established according to CA125 levels in the CA125-guided group (n = 79) and in clinical evaluation in the usual-care group (n = 81). Changes in estimated glomerular filtration rate (eGFR) at 72 and 24 hours were the co-primary endpoints, respectively.
The mean age was 78 ± 8 years, the median amino-terminal pro-brain natriuretic peptide was 7765 pg/mL, and the mean eGFR was 33.7 ± 11.3 mL/min/1.73m2. Over 72 hours, the CA125-guided group received higher furosemide equivalent dose compared to usual care (P = 0.011), which translated into higher urine volume (P = 0.042). Moreover, patients in the active arm with CA125 >35 U/mL received the highest furosemide equivalent dose (P <0.001) and had higher diuresis (P = 0.013). At 72 hours, eGFR (mL/min/1.73m2) significantly improved in the CA125-guided group (37.5 vs 34.8, P = 0.036), with no significant changes at 24 hours (35.8 vs 39.5, P = 0.391).
A CA125-guided diuretic strategy significantly improved eGFR and other renal function parameters at 72 hours in patients with acute heart failure and renal dysfunction.
The generation of induced pluripotent stem (iPS) cells has enabled the derivation of patient-specific pluripotent cells and provided valuable experimental platforms to model human disease. ...Patient-specific iPS cells are also thought to hold great therapeutic potential, although direct evidence for this is still lacking. Here we show that, on correction of the genetic defect, somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency to generate patient-specific iPS cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals. Most importantly, we show that corrected Fanconi-anaemia-specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, that is, disease-free. These data offer proof-of-concept that iPS cell technology can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications.
Abstract
Objectives
Xerostomia in SS patients has been associated with low quality and quantity of salivary mucins, which are fundamental for the hydration and protection of the oral mucosa. The aim ...of this study was to evaluate if cytokines induce aberrant mucin expression and whether tauroursodeoxycholic acid (TUDCA) is able to counteract such an anomaly.
Methods
Labial salivary glands from 16 SS patients and 15 control subjects, as well as 3D acini or human submandibular gland cells stimulated with TNF-α or IFN-γ and co-incubated with TUDCA, were analysed. mRNA and protein levels of Mucin 1 (MUC1) and MUC7 were determined by RT-qPCR and western blot, respectively. Co-immunoprecipitation and immunofluorescence assays for mucins and GRP78 an endoplasmic reticulum (ER)-resident protein were also performed. mRNA levels of RelA/p65 (nuclear factor-κB subunit), TNF-α, IL-1β, IL-6, SEL1L and EDEM1 were determined by RT-qPCR, and RelA/p65 localization was evaluated by immunofluorescence.
Results
MUC1 is overexpressed and accumulated in the ER of labial salivary gland from SS patients, while MUC7 accumulates throughout the cytoplasm of acinar cells; however, MUC1, but not MUC7, co-precipitated with GRP78. TUDCA diminished the overexpression and aberrant accumulation of MUC1 induced by TNF-α and IFN-γ, as well as the nuclear translocation of RelA/p65, together with the expression of inflammatory and ER stress markers in 3D acini.
Conclusion
Chronic inflammation alters the secretory process of MUC1, inducing ER stress and affecting the quality of saliva in SS patients. TUDCA showed anti-inflammatory properties decreasing aberrant MUC1 accumulation. Further studies are necessary to evaluate the potential therapeutic effect of TUDCA in restoring glandular homeostasis in SS patients.
Imaging of subclinical atherosclerosis improves cardiovascular risk prediction on top of traditional risk factors. However, cardiovascular imaging is not universally available. This work aims to ...identify circulating proteins that could predict subclinical atherosclerosis.
Hypothesis-free proteomics was used to analyze plasma from 444 subjects from PESA cohort study (222 with extensive atherosclerosis on imaging, and 222 matched controls) at two timepoints (three years apart) for discovery, and from 350 subjects from AWHS cohort study (175 subjects with extensive atherosclerosis on imaging and 175 matched controls) for external validation. A selected three-protein panel was further validated by immunoturbidimetry in the AWHS population and in 2999 subjects from ILERVAS cohort study.
PIGR, IGHA2, APOA, HPT and HEP2 were associated with subclinical atherosclerosis independently from traditional risk factors at both timepoints in the discovery and validation cohorts. Multivariate analysis rendered a potential three-protein biomarker panel, including IGHA2, APOA and HPT. Immunoturbidimetry confirmed the independent associations of these three proteins with subclinical atherosclerosis in AWHS and ILERVAS. A machine-learning model with these three proteins was able to predict subclinical atherosclerosis in ILERVAS (AUC 95%CI:0.73 0.70–0.74, p < 1 × 10−99), and also in the subpopulation of individuals with low cardiovascular risk according to FHS 10-year score (0.71 0.69–0.73, p < 1 × 10−69).
Plasma levels of IGHA2, APOA and HPT are associated with subclinical atherosclerosis independently of traditional risk factors and offers potential to predict this disease. The panel could improve primary prevention strategies in areas where imaging is not available.
This study was supported by competitive grants from the Spanish Ministry of Science, Innovation and Universities (BIO2015-67580-P, PGC2018-097019-B-I00, PID2019-106814RB-I00 and SAF2016-80843-R), through the Carlos III Institute of Health-Fondo de Investigacion Sanitaria grant PRB3 (IPT17/0019 - ISCIII-SGEFI / ERDF, ProteoRed), CIBERCV and CIBERDEM, the Fundacio MaratoTV3 (grant 122/C/2015) and “la Caixa” Banking Foundation (project HR17-00247). The PESA study is co-funded equally by the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain, and Banco Santander, Madrid, Spain. The ILERVAS study was funded by the Diputacio de Lleida. The study also receives funding from the Instituto de Salud Carlos III (PI15/02019; PI18/00610; RD16/0009) and the FEDER funds. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovacion y Universidades (MCNU) and the Pro CNIC Foundation.
Mesenchymal stromal cells are a safe and promising option to treat knee osteoarthritis as previously demonstrated in different clinical trials. However, their efficacy, optimal dose and addition of ...adjuvants must be determined. Here, we evaluated the clinical effects of a dose of 100 × 10
bone marrow mesenchymal stromal cells (BM-MSCs) in combination with Platelet Rich Plasma (PRGF®) as adjuvant in a randomized clinical trial.
A phase II, multicenter, randomized clinical trial with active control was conducted. Sixty patients diagnosed with knee OA were randomly assigned to 3 weekly doses of PRGF® or intraarticular administration of 100 × 10
cultured autologous BM-MSCs plus PRGF®. Patients were followed up for 12 months, and pain and function were assessed using VAS and WOMAC and by measuring the knee range of motion range. X-ray and magnetic resonance imaging analyses were performed to analyze joint damage.
No adverse effects were reported after BM-MSC administration or during follow-up. According to VAS, the mean value (SD) for PRGF® and BM-MSC with PRGF® went from 5 (1.8) to 4.5 (2.2) (p = 0.389) and from 5.3 (1.9) to 3.5 (2.5) (p = 0.01), respectively at 12 months. In WOMAC, the mean (SD) baseline and 12-month overall WOMAC scores in patients treated with PRGF® was 31.9 (16.2) and 22.3 (15.8) respectively (p = 0.002) while that for patients treated with BM-MSC plus PRGF® was 33.4 (18.7) and 23.0 (16.6) (p = 0.053). Although statistical significances between groups have been not detected, only patients being treated with BM-MSC plus PRGF® could be considered as a OA treatment responders following OARSI criteria. X-ray and MRI (WORMS protocol) revealed no changes in knee joint space width or joint damage.
Treatment with BM-MSC associated with PRGF® was shown to be a viable therapeutic option for osteoarthritis of the knee, with clinical improvement at the end of follow-up. Further phase III clinical trials would be necessary to confirm the efficacy. Trial registration Clinical Trials.gov identifier NCT02365142. Nº EudraCT: 2011-006036-23.
Fluctuating asymmetry (FA) is an indicator of developmental instability referred to random deviations from mean asymmetry. That average asymmetry is the directional asymmetry (DA), which, in the ...particular case of adolescent idiopathic scoliosis (AIS), corresponds to a right thoracic and left lumbar curves. Investigating the presence of FA and DA in AIS has never been done, and it is a key element of the pathophysiology of the scoliotic condition. Thirty‐six X‐rays of patients with AIS were digitized and analysed using Geometric Morphometric analyses to test for both statistical effects. The individual FA score for each patient was calculated using Procrustes ANOVA and a methodology based on the components of shape was used to estimate the individual DA score. DA is a stronger effect than FA (2.12 to 1), as it has been found in other clinical conditions. The individual DA score, with an effect size of 0.58, is a better predictor of the Cobb angle than FA score. The methodology presented in this paper to estimate DA score is a valid approach in the study of asymmetries in AIS. FA should be correlated in future studies with environmental covariates to serve as a variable in the medical prognosis, while DA will serve as a good predictor of the Cobb angle during the course of the condition, avoiding the abuse of X‐rays. This potential use of DA should be tested on 3D shape due to the three‐dimensional clinical presentation of AIS.
A new methodology has been developed that measures directional and fluctuating asymmetry, and these individual scores make it possible to predict the Cobb angle (from the DA score) and measure developmental instability (from the FA score) in patients with adolescent idiopathic scoliosis.
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