Restoring Carboxylates on Highly Modified Alginates Improves Gelation, Tissue Retention and Systemic Capture.

Alginate hydrogels are gaining traction for use in drug delivery, regenerative medicine, and as tissue engineered scaffolds due to their physiological gelation conditions, high tissue biocompatibility, and wide chemical versatility. Traditionally, alginate is decorated at the carboxyl group to carry drug payloads, peptides, or proteins. While low degrees of substitution do not cause noticeable mechanical changes, high degrees of substitution can cause significant losses to alginate properties including complete loss of calcium cross-linking. While most modifications used to decorate alginate deplete the carboxyl groups, we propose that alginate modifications that replenish the carboxyl groups could overcome the loss in gel integrity and mechanics. In this report, we demonstrate that restoring carboxyl groups during functionalization maintains calcium cross-links as well as hydrogel shear-thinning and self-healing properties. In addition, we demonstrate that alginate hydrogels modified to a high degree with azide modifications that restore the carboxyl groups have improved tissue retention at intramuscular injection sites and capture blood-circulating cyclooctynes better than alginate hydrogels modified with azide modifications that deplete the carboxyl groups. Taken together, alginate modifications that restore carboxyl groups could significantly improve alginate hydrogel mechanics for clinical applications. STATEMENT OF SIGNIFICANCE: Chemical modification of hydrogels provides a powerful tool to regulate cellular adhesion, immune response, and biocompatibility with local tissues. Alginate, due to its biocompatibility and easy chemical modification, is being explored for tissue engineering and drug delivery. Unfortunately, modifying alginate to a high degree of substitution consumes carboxyl group, which are necessary for ionic gelation, leading to poor hydrogel crosslinking. We introduce alginate modifications that restore the alginate's carboxyl groups. We demonstrate that modifications that reintroduce carboxyl groups restore gelation and improve gel mechanics and tissue retention. In addition to contributing to a basic science understanding of hydrogel properties, we anticipate our approach will be useful to create tissue engineered scaffolds and drug delivery platforms.

Relationship between neuroleptic extrapyramidal syndromes and patients' all-cause mortality.

INTRODUCTION: It is important to understand factors contributing to a neuroleptic-related increased mortality risk. The objective of this study was to test whether the occurrence of neuroleptic-induced extrapyramidal syndromes (EPS) including tardive dyskinesia (TD) is associated with an increased patients' all-cause mortality. METHODS: In 1995, a sample of 200 patients on neuroleptics was assessed with regard to the presence of Parkinson syndrome, akathisia, and TD. By 2003-2004, i.e., during the following 8-9 year period, 63 patients had died. Patients who had died were compared with 120 patients known to be still alive with regard to several socio-demographic variables and the presence of EPS at the first examination. RESULTS: At the basic assessment, there were no significant differences between patients later still alive and deceased patients with regard to TD. The deceased patients were more frequently women, older, suffered more frequently from an organic disorder, had higher average scores for Parkinson syndrome and less frequently akathisia. Multivariate analysis confirmed age as the only factor contributing to the group difference. Repeating the meta-analysis by Ballesteros et al. (2000) after inclusion of our data, TD remains a weak but a significant predictor of death (OR=1.4). DISCUSSION: Neuroleptic-induced EPS of parkinsonism, akathisia, and TD did not contribute to the patients' all-cause mortality in this study. The association between TD and mortality merits further attention.

Pediatric reference ranges for creatine kinase, CKMB, Troponin I, iron, and cortisol.

OBJECTIVES: To determine the pediatric reference ranges for iron, cortisol, CK, CKMB, and troponin I. METHODS: Iron and CK were measured on the Vitros analyzer (Johnson and Johnson) while CKMB, troponin I, and cortisol were measured on the Immuno I (Bayer Corp.). Pediatric reference ranges were determined on hospitalized patients using the Hoffmann approach. RESULTS: Pediatric reference ranges were obtained for iron (AM and PM) and cortisol (AM and PM). Ranges were also obtained for CKMB, troponin I, and total CK. CONCLUSION: This work represents an expansion in our knowledge base on pediatric reference ranges. For iron, the 97.5th percentiles were significantly higher in the PM than in the AM. The diurnal fluctuation in 97.5th percentiles for cortisol was only 10-20%. Pediatric reference ranges for CKMB were not previously available and are important especially in the first year of life. The elevated Troponin I is found in the first year of life also represents new data.