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

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Albumin nanoparticles carrying cyclodextrins for nasal delivery of the anti-Alzheimer drug tacrine

Peroral administration of tacrine, the first acetylcholinestearse inhibitor licensed for the treatment of Alzheimer's disease, is associated with low bioavailability, due to an extended first-pass methabolism, short elimination half-life and hepatotoxicity. Nasal drug delivery may reduce the degree of these problems. Tacrine hydrochloride nasal delivery is here investigated by means of albumin nanoparticles carrying beta cyclodextrin and two different beta cyclodextrin derivatives (hydroxypropyl beta cyclodextrin and sulphobutylether beta cyclodextrin). Bovine serum albumin nanoparticles were obtained using a coacervation method, followed by thermal cross-linking, starting from protein solution at alkaline pH. After preparation, nanoparticles were loaded by soaking from solutions of tacrine hydrochloride and lyophilized. Thermal analysis (Differential Scanning Calorimetry and Thermogravimetric analysis) supported by Fourier Transform Infrared Spectroscopy were performed in order to confirm protein cross-linking in nanosphere structure and possible drug/carrier interaction occurred after the loading process. Moreover, size, polydispersity, zeta potential and morphology of the nanoparticles were investigated as well as drug loading, mucoadhesion properties and ex-vivo drug permeation ability. Results indicate that all the nanoparticles presented a mean size and a polydispersity lower than 300 nm and 0.33 respectively, were spherical shaped and negatively charged even after drug loading. Moreover, the presence of the different beta cyclodextrins in the polymeric network affected drug loading and could differently modulate nanoparticle mucoadhesiveness and drug permeation behaviour

Correlative Measurement of Four Biological Contaminants on Cotton Lint, and Their Implications for Occupational Health

Four biological contaminants of cotton fibers (gramnegative bacterial cells, endotoxin, fungal cells, and (1-3)-(3-D-glucan)were measured in 13 cotton lint samples from international origins, using traditional microbio-logical spread plating and adaptation of the Limulus amoebocyte lysate (LAL) assay. Correlations were evaluated using Spearman's rank correlation analyses. Contamination levels ranged from 713 ± 212 to 216,830 ± 30,413 CFU/g gram-negative bacteria; 281 ± 29 to 9,250 ± 820 CFU/g fungal cells; 8.30 ± 0.89 to 137.89 ± 21.55 ng/g endotoxin; and 15.96 ± 5.18 to 2,964.42 ± 313.90 LAL-reactive units/g glucan. Positive correlations existed between all contaminants; however, they were significant only between fungal cells and glucan (P < 0.05) and between endotoxin and glucan (P < 0.01). The highly significant positive correlation between endotoxin and glucan has implications for the health risk posed by the cotton-production environment, as simultaneous inhalation of these agents may cause or exacerbate lung inflammation