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

Thermo-Mixed Hydrodynamics of Piston Compression Ring Conjunction

The final publication is available at http://link.springer.com.A new method, comprising Navier-Stokes equations, Rayleigh-Plesset volume fraction equation, an analytical control-volume thermal mixed approach and asperity interactions is reported. The method is employed for prediction of lubricant flow and assessment of friction in the compression ring-cylinder liner conjunction. The results are compared with Reynolds-based laminar flow with Elrod cavitation algorithm. Good conformance is observed for medium load intensity part of the engine cycle. At lighter loads and higher sliding velocity, the new method shows more complex fluid flow, possessing layered flow characteristics on account of pressure and temperature gradient into the depth of the lubricant film, which leads to a cavitation region with vapour content at varied volume fractions. Predictions also conform well to experimental measurements reported by other authors

A decade of right liver adult-to-adult living donor liver transplantation: The recipient mid-term outcomes

Objective: We analyzed a single centers experience over a decade of right liver living donor liver transplantation (RLDLT). Summary Background Data: To define the donor risk and recipient benefit ratio, midterm outcome of this life-saving treatment modality ought to be known. Methods: Consecutive patients from 9 May 1996 were included. Era I comprised the first 50 patients and Era II comprised the remaining 184 patients. Their midterm outcomes were compared with patients receiving deceased donor liver transplantation (DDLT) of the same period in the same center. Results: With a median follow-up of 48 months, the 1-, 3-, and 5-year overall survival rates were 93.2%, 85.7%, and 82.4%, respectively and were comparable with those of DDLT (n = 131) (90.1%, 87.7%, and 85.2%) (P = 0.876). Hospital mortality decreased from 16% in Era I to 2.2% in Era II (P = 0.000). Reduced hospital mortality improved the overall survival rates from Era I to Era II (78%, 74%, and 72% vs. 97.3%, 88.7%, and 85.1%, respectively) (P = 0.003). The 5-year survival rate of recipients with hepatocellular carcinoma (HCC) (n = 65) was 65.7%. Starting from Era II, excellent 5-year survival of recipients without HCC was achieved as compared with DDLT in the same period (93.4% vs. 88.2%) (P = 0.493). The 5-year survival rates of recipients with HCC within the Milan criteria of Era II and DDLT in the same period were 72.0% and 100%, respectively (P = 0.091). Multivariate analysis indicated that only Era I (relative risk = 2.606; P = 0.005) and pretransplant HCC (relative risk = 2.729; P = 0.002) adversely affected overall survival. Conclusions: High midterm survivals were achieved by reduction of hospital mortality through accumulation of experience and transplanting recipients with low chance of recurrence of HCC. RLDLT could be considered as a legitimate alternative to DDLT. © 2008 Lippincott Williams & Wilkins.link_to_subscribed_fulltex

Discovery of a novel site regulating glucokinase activity following characterization of a new mutation causing hyperinsulinemic hypoglycemia in humans.

Type 2 diabetes is a global problem, and current ineffective therapeutic strategies pave the way for novel treatments like small molecular activators targeting glucokinase (GCK). GCK activity is fundamental to beta cell and hepatocyte glucose metabolism, and heterozygous activating and inactivating GCK mutations cause hyperinsulinemic hypoglycemia (HH) and maturity onset diabetes of the young (MODY) respectively. Over 600 naturally occurring inactivating mutations have been reported, whereas only 13 activating mutations are documented to date. We report two novel GCK HH mutations (V389L and T103S) at residues where MODY mutations also occur (V389D and T103I). Using recombinant proteins with in vitro assays, we demonstrated that both HH mutants had a greater relative activity index than wild type (6.0 for V389L, 8.4 for T103S, and 1.0 for wild type). This was driven by an increased affinity for glucose (S(0.5), 3.3 ± 0.1 and 3.5 ± 0.1 mm, respectively) versus wild type (7.5 ± 0.1 mm). Correspondingly, the V389D and T103I MODY mutants had markedly reduced relative activity indexes (<0.1). T103I had an altered affinity for glucose (S(0.5), 24.9 ± 0.6 mm), whereas V389D also exhibited a reduced affinity for ATP and decreased catalysis rate (S(0.5), 78.6 ± 4.5 mm; ATP(K(m)), 1.5 ± 0.1 mm; K(cat), 10.3 ± 1.1s(-1)) compared with wild type (ATP(K(m)), 0.4 ± <0.1; K(cat), 62.9 ± 1.2). Both Thr-103 mutants showed reduced inhibition by the endogenous hepatic inhibitor glucokinase regulatory protein. Molecular modeling demonstrated that Thr-103 maps to the allosteric activator site, whereas Val-389 is located remotely to this position and all other previously reported activating mutations, highlighting α-helix 11 as a novel region regulating GCK activity. Our data suggest that pharmacological manipulation of GCK activity at locations distal from the allosteric activator site is possible

Pineal function: Impact of microarray analysis

Microarray analysis has provided a new understanding of pineal function by identifying genes that are highly expressed in this tissue relative to other tissues and also by identifying over 600 genes that are expressed on a 24-h schedule. This effort has highlighted surprising similarity to the retina and has provided reason to explore new avenues of study including intracellular signaling, signal transduction, transcriptional cascades, thyroid/retinoic acid hormone signaling, metal biology, RNA splicing, and the role the pineal gland plays in the immune/inflammation response. The new foundation that microarray analysis has provided will broadly support future research on pineal function. Published by Elsevier Ireland Ltd