Within the field of bone tissue engineering, the endochondral approach to forming bone substitutes represents a novel concept, where cartilage will undergo hypertrophic differentiation before its conversion into bone. For this purpose, clinically relevant multipotent stromal cells (MSCs), MSCs, can be differentiated into the chondrogenic lineage before stimulating hypertrophy. Controversy exists in literature on the oxygen tensions naturally present during this transition in, for example, the growth plate. Therefore, the present study focused on the effects of different oxygen tensions on the progression of the hypertrophic differentiation of MSCs. Bone marrow-derived MSCs of four human donors were expanded, and differentiation was induced in aggregate cultures. Normoxic (20% oxygen) and hypoxic (5%) conditions were imposed on the cultures in chondrogenic or hypertrophic differentiation media. After 4 weeks, the cultures were histologically examined and by real-time polymerase chain reaction. Morphological assessment showed the chondrogenic differentiation of cultures from all donors under normoxic chondrogenic conditions. In addition, hypertrophic differentiation was observed in cultures derived from all but one donor. The deposition of collagen type X was evidenced in both chondrogenically and hypertrophically stimulated cultures. However, mineralization was exclusively observed in hypertrophically stimulated, normoxic cultures. Overall, the progression of hypertrophy was delayed in hypoxic compared with normoxic groups. The observed delay was supported by the gene expression patterns, especially showing the up-regulation of the late hypertrophic markers osteopontin and osteocalcin under normoxic hypertrophic conditions. Concluding, normoxic conditions are more beneficial for hypertrophic differentiation of MSCs than are hypoxic conditions, as long as the MSCs possess hypertrophic potential. This finding has implications for cartilage tissue engineering as well as for endochondral bone tissue engineering, as these approaches deal with, respectively, the inhibition or enhancement of hypertrophic chondrogenesis.

prophylactic low-dose oral haloperidol did not reduce delirium incidence in acutely hospitalised older patients. Therefore, prophylactic use of haloperidol in this population is not recommended.

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IntroductionNoninvasive hemodynamic (HD) assessments in the emergency department (ED) might assist in the diagnosis, therapeutic plan development and risk stratification of acutely ill patients. This multinational observational study was designed to initiate noninvasive HD measurements prior to any ED patient therapeutic interventions and broadly evaluate them for potential diagnostic, therapeutic and predictive value.MethodsWe enrolled patients with suspected acute heart failure (AHF), sepsis or stroke. Continuous noninvasive HD monitoring was begun using the Nexfin finger cuff device (Edwards LifeSciences, BMEYE, Amsterdam, Netherlands). Beat-to-beat HD measurements were averaged for the initial 15 minutes, prior to therapeutic intervention. We performed suspected disease group comparisons and evaluated HD predictors of 30-day mortality.ResultsOf 510 patients enrolled: 185 (36%) AHF, 194 (38%) sepsis and 131 (26%) stroke. HD variables were significantly different (p<0.05) amongst the groups. Cardiac output and index and stroke volume index (SVI) were highest in sepsis (6.5, 3.5, 36), followed by stroke (5.5, 2.7, 35.8), and lowest in AHF (5.4, 2.7, 33.6). The in-group HD standard deviations and ranges measurements were large, indicating heterogeneous underlying HD profiles. Presenting SVI predicted 30-day mortality for all groups.ConclusionPresenting ED noninvasive HD data has not been previously reported in any large patient population. Our data suggest a potential role for early noninvasive HD assessments aiding in diagnosing of patients, individualizing therapy based on each person’s unique HD values and predicting 30-day mortality. Further studies and analyses are needed to determine how HD assessments should be best used in the ED.