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The current gold standard grafting material is autologous bone due to its osteoinductive and osteoconductive properties. Autograft harvesting results in donors site morbidity. Coral scaffolds offer a natural autograft alternative, sharing the density and porosity of human bone. This study investigated the biocompatibility and osteogenic potential of a novel, sustainably grown Pocillopora scaffold with human bone marrow-derived mesenchymal stromal cells (MSCs). The coral-derived scaffold displays a highly textured topography, with concavities of uniform size and a high calcium carbonate content. Large scaffold samples exhibit compressive and diametral tensile strengths in the range of trabecular bone, with strengths likely increasing for smaller particulate samples. Following the in vitro seeding of MSCs adjacent to the scaffold, the MSCs remained viable, continued proliferating and metabolising, demonstrating biocompatibility. The seeded MSCs densely covered the coral scaffold with organized, aligned cultures with a fibroblastic morphology. In vivo coral scaffolds with MSCs supported earlier bone and blood vessel formation as compared to control constructs containing TCP-HA and MSCs. This work characterized a novel, sustainably grown coral scaffold that was biocompatible with MSCs and supports their in vivo osteogenic differentiation, advancing the current repertoire of biomaterials for bone grafting.

IntroductionDespite advances in the treatment of bipolar disorder (BD), most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience neurocognitive dysfunction, reduced daytime activity levels, and sleep disturbances. This 8-week, randomized, placebo-controlled pilot study evaluated the feasibility, safety and preliminary efficacy of the wake-promoting drug, modafinil (Provigil®), on neurocognitive functioning, daytime sleepiness, and sleep quality in affectively-stable BD patients.MethodsTwelve individuals with affectively-stable BD were recruited and randomized to a flexible dose of modafinil (100 to 200 mg/day) or placebo, adjunctive to a therapeutic dose of a mood stabilizer. Weekly in-person visits tracked sleep quality and daytime sleepiness as well as side effects and mood symptoms. Neurocognitive functioning was assessed at baseline, week 4, and week 8.ResultsNo serious adverse events were reported. Newly emergent side effects in the modafinil group included heart palpitations, itching, fatigue, and decreased energy. Two patients discontinued modafinil owing to side effects and one of these patients withdrew from the study. One patient discontinued placebo and was withdrawn from the study. Preliminary evaluations of clinical efficacy showed a marginally significant interaction between treatment group and time in two cognitive domains (speed of processing and verbal learning), indicating greater improvement in the modafinil group versus placebo. Additionally, there was a marginally significant effect of treatment group on daytime sleepiness, suggesting lower daytime sleepiness in the modafinil group versus placebo. Counterintuitively, we found a significant treatment group by time interaction effect on sleep quality, suggesting greater improvement in sleep quality in the placebo group versus the modafinil group.DiscussionResults suggest that modafinil is a relatively safe medication for affectively-stable BD patients when given with adjunctive mood stabilizers. Results are suggestive of cognitive benefit and improved daytime sleepiness, but worse sleep quality in those patients prescribed modafinil. A fully powered clinical trial is warranted with specific attention to the characteristics of patients who are most likely to benefit from treatment with modafinil and other methodological lessons learned from this pilot.Clinical trial registrationClinicalTrials.gov, identifier NCT01965925.

Cognitive impairment is a prominent and difficult to treat symptom in schizophrenia (SZ), which is directly related to functional disability. A variant in the gene coding for the alpha 1C subunit of L-type voltage gated calcium channel (CACNA1C) has been shown to negatively affect several neurocognitive domains. We conducted a 4-week, open label, pilot study of isradipine, a calcium channel blocker, to determine its feasibility, safety, and efficacy in improving cognition in SZ patients.Ten adults with stable SZ were started on a flexible dose of isradipine 5 mg/day (up to 10 mg/day) for 4 weeks. Weekly in-person visits tracked side effects and symptoms while neurocognition and functional capacity were assessed at baseline and week 4.There were no serious adverse events reported. Newly emergent side effects were dizziness (1 new incidence at week 4); difficulty sleeping (2 new incidences at week 4); and decreased energy (3 new incidences at week 4). 1 patient discontinued medication and was withdrawn. Treatment did not exacerbate clinical symptoms. Although power is limited, results indicate no clear benefit on neurocognition but a positive effect (baseline mean = 6.8 ± 1.3 to week 4 mean = 7.9 ± 1.1; t = 2.91, p = 0.017) on functional capacity was noted.This open label, pilot study provides preliminary evidence that isradipine is a relatively safe medication when used adjunctively in SZ patients. This study suggests that isradipine offers no clear cognitive and only minimal functional benefit; however, additional studies may be warranted in symptomatic patients, or those with specific CACNA1C genotypes.

Historical pre-settlement conditions in ponderosa pine ecosystems ranged from savannas (<30% canopy cover) with contiguous grasslands and scattered tree groups, to forests with isolated mosaic-meadows surrounded by trees. We use the term mosaic-meadows for non-treed areas that weave around individual trees and tree groups, supporting diverse understory plant communities in ponderosa pine ecosystems. The long-term sustainability of ponderosa pine ecosystems may depend on mosaic-meadows that provide fine fuels and support frequent, low-severity fires. Increasing tree densities over the past century have eliminated mosaic-meadows and contiguous grasslands from many ponderosa pine landscapes. The link between restored ecosystem structure and function is often assumed but not empirically demonstrated, so we assessed the impact of mosaic-meadows (areas > 6 m from overstory trees) on understory vegetation in five recently thinned ponderosa pine stands and one long-undisturbed stand in Colorado. We also compared historical spatial patterns in mosaic-meadows to current conditions in ponderosa pine stands and determined whether thinning treatments are recreating historical conditions. Mosaic-meadows in ponderosa pine ecosystems declined substantially from a mean of 55% of stand area in 1860–1875 to 7% in 2010–2013 prior to tree thinning. The loss of mosaic-meadows has ecological consequences for the function of ponderosa pine ecosystems because spatial patterns of mosaic-meadows strongly influenced understory vegetation. At our sites, understory cover increased by 3%/m with distance from overstory trees, and understory richness increased from 6 species/m 2 within 1 m of overstory trees to 9 species/m 2 at 10 m away from overstory trees. Cover and richness of understory vegetation (especially native forbs) responded rapidly to creation of mosaic-meadows within 1 to 4 years after treatment. Thinning treatments at two stands brought the coverage of mosaic-meadows within the historical range of variation, but there was a noticeable lack of mosaic-meadows >12 m from overstory trees at all treated stands. Restoration of the fundamental ecological characteristics of ponderosa pine ecosystems should intentionally include variably sized mosaic-meadows. [ABSTRACT FROM AUTHOR]