Combined local delivery of tacrolimus and stem cells in hydrogel for enhancing peripheral nerve regeneration

The application of scaffold-based stem cell transplantation to enhance peripheral nerve regeneration has great potential. Recently, the neuroregenerative potential of tacrolimus (a U.S. Food and Drug Administration-approved immunosuppressant) has been explored. In this study, a fibrin gel-based drug delivery system for sustained and localized tacrolimus release was combined with rat adipose-derived mesenchymal stem cells (MSC) to investigate cell viability in vitro. Tacrolimus was encapsulated in poly(lactic-co-glycolic) acid (PLGA) microspheres and suspended in fibrin hydrogel, using concentrations of 0.01 and 100 ng/ml. Drug release over time was measured. MSCs were cultured in drug-released media collected at various days to mimic systemic exposure. MSCs were combined with (i) hydrogel only, (ii) empty PLGA microspheres in the hydrogel, (iii) 0.01, and (iv) 100 ng/ml of tacrolimus PLGA microspheres in the hydrogel. Stem cell presence and viability were evaluated. A sustained release of 100 ng/ml tacrolimus microspheres was observed for up to 35 days. Stem cell presence was confirmed and cell viability was observed up to 7 days, with no significant differences between groups. This study suggests that combined delivery of 100 ng/ml tacrolimus and MSCs in fibrin hydrogel does not result in cytotoxic effects and could be used to enhance peripheral nerve regeneration

Gravity Recovery and Interior Laboratory (GRAIL): Extended Mission and End-Game Status

The Gravity Recovery and Interior Laboratory (GRAIL) [1], NASA s eleventh Discovery mission, successfully executed its Primary Mission (PM) in lunar orbit between March 1, 2012 and May 29, 2012. GRAIL s Extended Mission (XM) initiated on August 30, 2012 and was successfully completed on December 14, 2012. The XM provided an additional three months of gravity mapping at half the altitude (23 km) of the PM (55 km), and is providing higherresolution gravity models that are being used to map the upper crust of the Moon in unprecedented detail

Preliminary Results on Lunar Interior Properties from the GRAIL Mission

The Gravity Recovery and Interior Laboratory (GRAIL) mission has provided lunar gravity with unprecedented accuracy and resolution. GRAIL has produced a high-resolution map of the lunar gravity field while also determining tidal response. We present the latest gravity field solution and its preliminary implications for the Moon's interior structure, exploring properties such as the mean density, moment of inertia of the solid Moon, and tidal potential Love number k2. Lunar structure includes a thin crust, a deep mantle, a fluid core, and a suspected solid inner core. An accurate Love number mainly improves knowledge of the fluid core and deep mantle. In the future GRAIL will search for evidence of tidal dissipation and a solid inner core

Integrative Review of Programs to Improve Outcomes for Children With Comorbid Asthma and Anxiety/Depressive Symptoms

Asthma is one of the most common pediatric chronic physical conditions. Youth with comorbid asthma and anxiety/depressive symptoms tend to have less controlled asthma and an increased use of health services in schools. The purpose of this integrative review was to examine the literature on educational and behavioral/ cognitive behavioral skills interventions for children with asthma and anxiety/depressive symptoms. Five electronic databases and forward/backward citations were searched. Eleven peer reviewed articles were retained for review. Main findings of the limited evidence suggest that educational and behavioral/cognitive behavioral skills programs may increase asthma knowledge and asthma-related self-efficacy while reducing anxiety/depressive symptoms. One study showed a decrease in use of quick relief inhalers and another had increased adherence to asthma controller medication. The literature indicates that educational and cognitive behavioral skills programs can have a positive impact on children with asthma and symptoms of anxiety/depression. School-based skills programs had better retention than outpatient programs

Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: a report from the Children's Oncology Group

To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma

Lunar interior properties from the GRAIL mission

International audienceThe Gravity Recovery and Interior Laboratory (GRAIL) mission has sampled lunar gravity with unprecedented accuracy and resolution. The lunar GM, the product of the gravitational constant G and the mass M, is very well determined. However, uncertainties in the mass and mean density, 3345.56 ± 0.40 kg/m 3 , are limited by the accuracy of G. Values of the spherical harmonic degree-2 gravity coefficients J 2 and C 22 , as well as the Love number k 2 describing lunar degree-2 elastic response to tidal forces, come from two independent analyses of the 3 month GRAIL Primary Mission data at the Jet Propulsion Laboratory and the Goddard Space Flight Center. The two k 2 determinations, with uncertainties of~1%, differ by 1%; the average value is 0.02416 ± 0.00022 at a 1 month period with reference radius R = 1738 km. Lunar laser ranging (LLR) data analysis determines (C À A)/B and (B À A)/C, where A < B < C are the principal moments of inertia; the flattening of the fluid outer core; the dissipation at its solid boundaries; and the monthly tidal dissipation Q = 37.5 ± 4. The moment of inertia computation combines the GRAIL-determined J 2 and C 22 with LLR-derived (C À A)/B and (B À A)/C. The normalized mean moment of inertia of the solid Moon is I s /MR 2 = 0.392728 ± 0.000012. Matching the density, moment, and Love number, calculated models have a fluid outer core with radius of 200-380 km, a solid inner core with radius of 0-280 km and mass fraction of 0-1%, and a deep mantle zone of low seismic shear velocity. The mass fraction of the combined inner and outer core is ≤1.5%

Sorbitol is a severity biomarker for PMM2-CDG with therapeutic implications

OBJECTIVE: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG. METHODS: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. RESULTS: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein N-glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts’ glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months. INTERPRETATION: Epalrestat improved PMM enzyme activity, N-glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems-level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well-tolerated and led to significant clinical improvements in the first pediatric patient with PMM2-CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG