Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes. This study provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and gene therapies.
Treatment of respiratory distress syndrome in premature infants with continuous positive airway pressure (CPAP) preserves surfactant and keeps the lung open but is insufficient in severe surfactant deficiency. Traditional surfactant administration is related to short periods of positive pressure ventilation and implies the risk of lung injury. CPAP with surfactant but without any positive pressure ventilation may work synergistically. This randomized trial investigated a less invasive surfactant application protocol (LISA).OBJECTIVE To test the hypothesis that LISA increases survival without bronchopulmonary dysplasia (BPD) at 36 weeks' gestational age in extremely preterm infants.
DESIGN, SETTING, AND PARTICIPANTSThe Nonintubated Surfactant Application trial was a multicenter, randomized, clinical, parallel-group study conducted between April 15, 2009, and March 25, 2012, in 13 level III neonatal intensive care units in Germany. The final follow-up date was June 21, 2012. Participants included 211 of 558 eligible (37.8%) spontaneously breathing preterm infants born between 23.0 and 26.8 weeks' gestational age with signs of respiratory distress syndrome. In an intention-to-treat design, infants were randomly assigned to receive surfactant either via a thin endotracheal catheter during CPAP-assisted spontaneous breathing (intervention group) or after conventional endotracheal intubation during mechanical ventilation (control group). Analysis was conducted from September 6, 2012, to June 20, 2013.INTERVENTION LISA via a thin catheter.
MAIN OUTCOMES AND MEASURESSurvival without BPD at 36 weeks' gestational age.
RESULTSOf 211 infants who were randomized, 104 were randomized to the control group and 107 to the LISA group. Of the infants who received LISA, 72 (67.3%) survived without BPD compared with 61 (58.7%) of those in the control group. The reduction in absolute risk was 8.6% (95% CI, −5.0% to 21.9%; P = .20). Intervention group infants were less frequently intubated (80 infants [74.8%] vs 103 [99.0%]; P < .001) and required fewer days of mechanical ventilation. Significant reductions were seen in pneumothorax (5 of 105 intervention group infants [4.8%] vs 13 of 103 12.6%]; P = .04) and severe intraventricular hemorrhage (11 infants [10.3%] vs 23 [22.1%]; P = .02), and the combined survival without severe adverse events was increased in the intervention group (54 infants [50.5%] vs 37 [35.6%]; P = .02; absolute risk reduction, 14.9; 95% CI, 1.4 to 28.2).CONCLUSIONS AND RELEVANCE LISA did not increase survival without BPD but was associated with increased survival without major complications. Because major complications are related to lifelong disabilities, LISA may be a promising therapy for extremely preterm infants.
Surfactant treatment of spontaneously breathing infants was associated with lower rates of mechanical ventilation and BPD. Additional large-scale randomised controlled trials are needed to assess the possible long-term benefits of LISA.
Highlights d YAP sustains epidermal stem cells d LAMB3-dependent JEB leads to YAP inactivation and epidermal stem cell depletion d JEB cell and gene therapy rescue adhesion, YAP, and stem cells in vitro and in vivo d Enforced YAP rescues stem cells in the absence of cell adhesion
It is well known that the human immune system is functionally less mature at birth and, within the first years of life, undergoes a process of sequential development. Two subsets of dendritic cells (DCs) were identified in the blood: plasmacytoid and myeloid DCs. DCs stain negative for CD3, CD14, CD16, CD19, CD20 and CD56, and positive for human leucocyte antigen (HLA)-DR. In addition, plasmacytoid DCs strongly express CD123 while myeloid DCs express CD11. The number of the two different subsets was measured by flow cytometry in the peripheral blood from 44 healthy infants and children, aged 8 months to 18 years. While the number of CD11c myeloid cells (mean 11 cells/ml) did not change with age, the proportion of CD123 plasmacytoid DCs decreased significantly (P < 0.001) from about 20 cells/ml to 8 cells/ml with age. In addition, we found a direct correlation between the number of plasmacytoid DC and interferon (IFN)-a production. As the two subsets of DC preferentially recognize different pathogens, age-related changes may have an impact on the maturation of the immune response.
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