Cytocompatibility assessment of Ti-Zr-Pd-Si-(Nb) alloys with low Young's modulus, increased hardness and enhanced osteoblast differentiation for biomedical applications

Ti-based alloys have increased importance for biomedical applications due to their excellent properties. In particular, the two recently developed TiZrPdSi(Nb) alloys, with a predominant β-Ti phase microstructure, have good mechanical properties, such as a relatively low Young's modulus and high hardness. In the present work, the cytocompatibility of these alloys was assessed using human osteoblast-like Saos-2 cells. Cells grown on the alloys showed larger spreading areas (more than twice) and higher vinculin content (nearly 40% increment) when compared with cells grown on glass control surfaces, indicating a better cell adhesion. Moreover, cell proliferation was 18% higher for cells growing on both alloys than for cells growing on glass and polystyrene control surfaces. Osteogenic differentiation was evaluated by quantifying the expression of four osteogenic genes (osteonectin, osteocalcin, osteopontin, and bone sialoprotein), the presence of three osteogenic proteins (alkaline phosphatase, collagen I, and osteocalcin) and the activity of alkaline phosphatase at different time-points. The results demonstrated that TiZrPdSi and TiZrPdSiNb alloys enhance osteoblast differentiation, and that cells grown on TiZrPdSiNb alloy present higher levels of some late osteogenic markers during the first week in culture. These results suggest that the TiZrPdSi(Nb) alloys can be considered as excellent candidates for orthopaedical uses

High-resolution tSZ cartography of clusters of galaxies with NIKA at the IRAM 30-m telescope

The thermal Sunyaev-Zeldovich effect (tSZ) is a powerful probe to study clusters of galaxies and is complementary with respect to X-ray, lensing or optical observations. Previous arcmin resolution tSZ observations ({\it e.g.} SPT, ACT and Planck) only enabled detailed studies of the intra-cluster medium morphology for low redshift clusters ($z < 0.2$). Thus, the development of precision cosmology with clusters requires high angular resolution observations to extend the understanding of galaxy cluster towards high redshift. NIKA2 is a wide-field (6.5 arcmin field of view) dual-band camera, operated at $100 \ {\rm mK}$ and containing $\sim 3300$ KID (Kinetic Inductance Detectors), designed to observe the millimeter sky at 150 and 260 GHz, with an angular resolution of 18 and 12 arcsec respectively. The NIKA2 camera has been installed on the IRAM 30-m telescope (Pico Veleta, Spain) in September 2015. The NIKA2 tSZ observation program will allow us to observe a large sample of clusters (50) at redshift ranging between 0.5 and 1. As a pathfinder for NIKA2, several clusters of galaxies have been observed at the IRAM 30-m telescope with the NIKA prototype to cover the various configurations and observation conditions expected for NIKA2.Comment: Proceedings of the 28th Texas Symposium on Relativistic Astrophysics, Geneva, Switzerland, December 13-18, 201

Challenges and strategies in the repair of ruptured annulus fibrosus

Lumbar discectomy is the surgical procedure most frequently performed for patients suffering from low back pain and sciatica. Disc herniation as a consequence of degenerative or traumatic processes is commonly encountered as the underlying cause for the painful condition. While discectomy provides favourable outcome in a majority of cases, there are conditions where unmet requirements exist in terms of treatment, such as large disc protrusions with minimal disc degeneration; in these cases, the high rate of recurrent disc herniation after discectomy is a prevalent problem. An effective biological annular repair could improve the surgical outcome in patients with contained disc herniations but otherwise minor degenerative changes. An attractive approach is a tissue-engineered implant that will enable/stimulate the repair of the ruptured annulus. The strategy is to develop three-dimensional scaffolds and activate them by seeding cells or by incorporating molecular signals that enable new matrix synthesis at the defect site, while the biomaterial provides immediate closure of the defect and maintains the mechanical properties of the disc. This review is structured into (1) introduction, (2) clinical problems, current treatment options and needs, (3) biomechanical demands, (4) cellular and extracellular components, (5) biomaterials for delivery, scaffolding and support, (6) pre-clinical models for evaluation of newly developed cell- and material-based therapies, and (7) conclusions. This article highlights that an interdisciplinary approach is necessary for successful development of new clinical methods for annulus fibrosus repair. This will benefit from a close collaboration between research groups with expertise in all areas addressed in this review

Association between serum soluble CD40 ligand levels and mortality in patients with severe sepsis

INTRODUCTION: CD40 Ligand (CD40L) and its soluble counterpart (sCD40L) are proteins that exhibit prothrombotic and proinflammatory properties on binding to their cell surface receptor CD40. The results of small clinical studies suggest that sCD40L levels could play a role in sepsis; however, there are no data on the association between sCD40L levels and mortality of septic patients. Thus, the aim of this study was to determine whether circulating sCD40L levels could be a marker of adverse outcome in a large cohort of patients with severe sepsis. METHODS: This was a multicenter, observational and prospective study carried out in six Spanish intensive care units. Serum levels of sCD40L, tumour necrosis factor-alpha and interleukin-10, and plasma levels of tissue factor were measured in 186 patients with severe sepsis at the time of diagnosis. Serum sCD40L was also measured in 50 age- and sex-matched controls. Survival at 30 days was used as the endpoint. RESULTS: Circulating sCD40L levels were significantly higher in septic patients than in controls (P = 0.01), and in non-survivors (n = 62) compared to survivors (n = 124) (P = 0.04). However, the levels of CD40L were not different regarding sepsis severity. Logistic regression analysis showed that sCD40L levels >3.5 ng/mL were associated with higher mortality at 30 days (odds ratio = 2.89; 95% confidence interval = 1.37 to 6.07; P = 0.005). The area under the curve of sCD40L levels >3.5 ng/mL as predictor of mortality at 30 days was 0.58 (95% CI = 0.51 to 0.65; P = 0.03). CONCLUSIONS: In conclusion, circulating sCD40L levels are increased in septic patients and are independently associated with mortality in these patients; thus, its modulation could represent an attractive therapeutic target

Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis

INTRODUCTION: Matrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation. Although higher levels of MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) have been found in small series of patients with sepsis, MMP-10 levels have not been studied in this setting. The objective of this study was to determine the predictive value of MMP-9, MMP-10, and TIMP-1 on clinical severity and mortality in a large series of patients with severe sepsis. METHODS: This was a multicenter, observational, and prospective study carried out in six Spanish Intensive Care Units. We included 192 (125 surviving and 67 nonsurviving) patients with severe sepsis and 50 age- and sex-matched healthy controls in the study. Serum levels of MMP-9, MMP-10, TIMP-1, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10 were measured in patients with severe sepsis at the time of diagnosis and in healthy controls. RESULTS: Sepsis patients had higher levels of MMP-10 and TIMP-1, higher MMP-10/TIMP-1 ratios, and lower MMP-9/TIMP-1 ratios than did healthy controls (P < 0.001). An association was found between MMP-9, MMP-10, TIMP-1, and MMP-9/TIMP-1 ratios and parameters of sepsis severity, assessed by the SOFA score, the APACHE-II score, lactic acid, platelet count, and markers of coagulopathy. Nonsurviving sepsis patients had lower levels of MMP-9 (P = 0.037), higher levels of TIMP-1 (P < 0.001), lower MMP-9/TIMP-1 ratio (P = 0.003), higher levels of IL-10 (P < 0.001), and lower TNF-alpha/IL-10 ratio than did surviving patients. An association was found between MMP-9, MMP-10, and TIMP-1 levels, and TNF-alpha and IL-10 levels. The risk of death in sepsis patients with TIMP-1 values greater than 531 ng/ml was 80% higher than that in patients with lower values (RR = 1.80; 95% CI = 1.13 to 2.87;P = 0.01; sensitivity = 0.73; specificity = 0.45). CONCLUSIONS: The novel findings of our study on patients with severe sepsis (to our knowledge, the largest series reporting data about MMP levels in sepsis) are that reduced MMP-9/TIMP-1 ratios and increased MMP-10 levels may be of great pathophysiologic significance in terms of severity and mortality, and that TIMP-1 levels may represent a biomarker to predict the clinical outcome of patients with sepsis

Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3–5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective. In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1G93A mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi-differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed

Seasonal dynamics of active SAR11 ecotypes in the oligotrophic Northwest Mediterranean Sea

A seven-year oceanographic time series in NW Mediterranean surface waters was combined with pyrosequencing of ribosomal RNA (16S rRNA) and ribosomal RNA gene copies (16S rDNA) to examine the environmental controls on SAR11 ecotype dynamics and potential activity. SAR11 diversity exhibited pronounced seasonal cycles remarkably similar to total bacterial diversity. The timing of diversity maxima was similar across narrow and broad phylogenetic clades and strongly associated with deep winter mixing. Diversity minima were associated with periods of stratification that were low in nutrients and phytoplankton biomass and characterised by intense phosphate limitation (turnover time80%) by SAR11 Ia. A partial least squares (PLS) regression model was developed that could reliably predict sequence abundances of SAR11 ecotypes (Q2=0.70) from measured environmental variables, of which mixed layer depth was quantitatively the most important. Comparison of clade-level SAR11 rRNA:rDNA signals with leucine incorporation enabled us to partially validate the use of these ratios as an in-situ activity measure. However, temporal trends in the activity of SAR11 ecotypes and their relationship to environmental variables were unclear. The strong and predictable temporal patterns observed in SAR11 sequence abundance was not linked to metabolic activity of different ecotypes at the phylogenetic and temporal resolution of our study

Current strategies for treatment of intervertebral disc degeneration: substitution and regeneration possibilities

Background: Intervertebral disc degeneration has an annual worldwide socioeconomic impact masked as low back pain of over 70 billion euros. This disease has a high prevalence over the working age class, which raises the socioeconomic impact over the years. Acute physical trauma or prolonged intervertebral disc mistreatment triggers a biochemical negative tendency of catabolic-anabolic balance that progress to a chronic degeneration disease. Current biomedical treatments are not only ineffective in the long-run, but can also cause degeneration to spread to adjacent intervertebral discs. Regenerative strategies are desperately needed in the clinics, such as: minimal invasive nucleus pulposus or annulus fibrosus treatments, total disc replacement, and cartilaginous endplates decalcification. Main Body: Herein, it is reviewed the state-of-the-art of intervertebral disc regeneration strategies from the perspective of cells, scaffolds, or constructs, including both popular and unique tissue engineering approaches. The premises for cell type and origin selection or even absence of cells is being explored. Choice of several raw materials and scaffold fabrication methods are evaluated. Extensive studies have been developed for fully regeneration of the annulus fibrosus and nucleus pulposus, together or separately, with a long set of different rationales already reported. Recent works show promising biomaterials and processing methods applied to intervertebral disc substitutive or regenerative strategies. Facing the abundance of studies presented in the literature aiming intervertebral disc regeneration it is interesting to observe how cartilaginous endplates have been extensively neglected, being this a major source of nutrients and water supply for the whole disc. Conclusion: Severalinnovative avenues for tackling intervertebral disc degeneration are being reported â from acellular to cellular approaches, but the cartilaginous endplates regeneration strategies remain unaddressed. Interestingly, patient-specific approaches show great promise in respecting patient anatomy and thus allow quicker translation to the clinics in the near future.The authors would like to acknowledge the support provided by the Portuguese Foundation for Science and Technology (FCT) through the project EPIDisc (UTAP-EXPL/BBBECT/0050/2014), funded in the Framework of the “International Collaboratory for Emerging Technologies, CoLab”, UT Austin|Portugal Program. The FCT distinctions attributed to J. Miguel Oliveira (IF/00423/2012 and IF/01285/ 2015) and J. Silva-Correia (IF/00115/2015) under the Investigator FCT program are also greatly acknowledged.info:eu-repo/semantics/publishedVersio