Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice

De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood mortality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models, we found that Asxl1 global loss as well as conditional deletion in osteoblasts and their progenitors led to significant bone loss and a markedly decreased number of bone marrow stromal cells (BMSCs) compared with wild-type littermates. Asxl1(-/-) BMSCs displayed impaired self-renewal and skewed differentiation, away from osteoblasts and favoring adipocytes. RNA-sequencing analysis revealed altered expression of genes involved in cell proliferation, skeletal development, and morphogenesis. Furthermore, gene set enrichment analysis showed decreased expression of stem cell self-renewal gene signature, suggesting a role of Asxl1 in regulating the stemness of BMSCs. Importantly, re-introduction of Asxl1 normalized NANOG and OCT4 expression and restored the self-renewal capacity of Asxl1(-/-) BMSCs. Our study unveils a pivotal role of ASXL1 in the maintenance of BMSC functions and skeletal development

Elevation of cardiac troponin I is a marker of developing myocardial hypoxia in sepsis

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Treatment of intraparenchymal hypertension with hyperosmotic therapy: Hypertonic saline 7.45% vs. mannitol 20%

BACKGROUND: There is controversy about the superiority of hypertonic saline (HS) over mannitol (M) to treat intracranial hypertension (ICHT). We aim to compare the effects of HS 7.45% vs. M 20% on systemic hemodynamics, intracranial pressure (ICP) and brain regional metabolism or oxygenation during experimental ICHT. METHODS: In 16 sedated and mechanically-ventilated pigs, ICHT was obtained by inflation of a balloon catheter inserted in the right frontal lobe. Ventilation was set to maintain normoxia and normocapnia. Mean arterial pressure was maintained above 80 mmHg by IV isotonic fluids. Animals were randomized to receive a 30-minute IV load of 255 mOsm/ dose of either HS 7.45% (N.=7) or M 20% (N.=7). Brain oxygen tension (PbO2) was measured hourly by a parenchymal Clark electrode and cerebral lactate/pyruvate ratio (LPR) was assessed using brain microdialysis. A linear mixed model was used to analyze the time course of considered variables from baseline to 180 minutes after infusion. RESULTS: There was no significant difference in systemic hemodynamics between the two groups over the study period. HS 7.45% administration maintained a lower ICP and a higher cerebral perfusion pressure at 180 minutes, but with no significant difference in PbO2 or LPR. CONCLUSIONS: In this model of ICHT, only small differences were found in maintaining a better cerebral perfusion using HS 7.45% compared to M 20% in the early phase of therapy. These differences were not dependent on changes in systemic hemodynamics and did not result in significant differences in brain regional oxygenation or metabolism.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Treatment of intraparenchymal hypertension with hyperosmotic therapy: hypertonic saline 7.45% vs. mannitol 20%

BACKGROUND: There is controversy about the superiority of hypertonic saline (HS) over mannitol (M) to treat intracranial hypertension (ICHT). We aim to compare the effects of HS 7.45% vs. M 20% on systemic hemodynamics, intracranial pressure (ICP) and brain regional metabolism or oxygenation during experimental ICHT. METHODS: In 16 sedated and mechanically-ventilated pigs, ICHT was obtained by inflation of a balloon catheter inserted in the right frontal lobe. Ventilation was set to maintain normoxia and normocapnia. Mean arterial pressure was maintained above 80 mmHg by IV isotonic fluids. Animals were randomized to receive a 30-minute IV load of 255 mOsm/ dose of either HS 7.45% (N.=7) or M 20% (N.=7). Brain oxygen tension (PbO2) was measured hourly by a parenchymal Clark electrode and cerebral lactate/pyruvate ratio (LPR) was assessed using brain microdialysis. A linear mixed model was used to analyze the time course of considered variables from baseline to 180 minutes after infusion. RESULTS: There was no significant difference in systemic hemodynamics between the two groups over the study period. HS 7.45% administration maintained a lower ICP and a higher cerebral perfusion pressure at 180 minutes, but with no significant difference in PbO2 or LPR. CONCLUSIONS: In this model of ICHT, only small differences were found in maintaining a better cerebral perfusion using HS 7.45% compared to M 20% in the early phase of therapy. These differences were not dependent on changes in systemic hemodynamics and did not result in significant differences in brain regional oxygenation or metabolism