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The lack of fetal immune responses to foreign antigens, i.e., fetal immunologic tolerance, is the most compelling rationale for prenatal stem cell and gene therapy. However, the frequency of engraftment following in utero hematopoietic cell transplantation (IUHCT) in the murine model is reduced in allogeneic, compared with congenic, recipients. This observation supports the existence of an immune barrier to fetal transplantation and challenges the classic assumptions of fetal tolerance. Here, we present evidence that supports the presence of an adaptive immune response in murine recipients of IUHCT that failed to maintain engraftment. However, when IUHCT recipients were fostered by surrogate mothers, they all maintained long-term chimerism. Furthermore, we have demonstrated that the cells responsible for rejection of the graft were recipient in origin. Our observations suggest a mechanism by which IUHCT-dependent sensitization of the maternal immune system and the subsequent transmission of maternal alloantibodies to pups through breast milk induces a postnatal adaptive immune response in the recipient, which, in turn, results in the ablation of engraftment after IUHCT. Finally, we showed that non-fostered pups that maintained their chimerism had higher levels of Tregs as well as a more suppressive Treg phenotype than their non-chimeric, non-fostered siblings. This study resolves the apparent contradiction of induction of an adaptive immune response in the pre-immune fetus and confirms the potential of actively acquired tolerance to facilitate prenatal therapeutic applications.

In utero hematopoietic stem cell transplantation (IUHCT) is a potential therapeutic alternative to postnatal hematopoietic stem cell transplantation (HSCT) for congenital hematologic disorders that can be diagnosed early in gestation and can be cured by HSCT. The rationale is to take advantage of normal events during hematopoietic and immunologic ontogeny to facilitate allogeneic hematopoietic engraftment. Although the rationale remains compelling, IUHCT has not yet achieved its clinical potential. Achieving therapeutic levels of engraftment by IUHCT alone remains challenging. However, considerable experimental progress has been made toward the clinical strategy of using IUHCT to induce donor-specific tolerance to facilitate a relatively nontoxic postnatal HSCT. Because donor specific tolerance induction requires relatively minimal engraftment, this strategy may hold the key to broad clinical application of IUHCT in the near future.

S martphones are one of the fastest-growing sectors in the technology industry, and they continue to evolve to combine faster processors, better memory, and more efficient operating systems into a compact handheld device. Smartphones also offer a dynamic tool for use in personal and professional environments. 1 The role of smartphones in medicine continues to expand as additional uses and applications emerge. An estimated 80% of physicians, trainees, and medical students use smartphones, and this percentage is expected to increase.2-4 Smartphones provide a multifaceted platform for mobile health care, allowing users to access a vast amount of information and interact with resources conveniently and quickly.5 Applications range from patient monitoring to use as a tool for diagnosis, to communication and medical education.Recent advances in smartphone technology have led many educators to extend their teaching methods into the mobile learning environment, providing an ''anytime, anywhere'' approach to learning. Mobile learning has been shown to have efficacy within the traditional classroom environment, and brief communications via short message service (SMS) supplement interactive classroom sessions, resulting in enhanced interest in and attention to classroom activity.6 Given the nature of graduate medical education (GME), where trainees are expected to assimilate a vast amount of information that is constantly evolving, and often are away from traditional classroom settings, the benefits of mobile learning with its uninterrupted access to educational resources can be particularly advantageous.In this perspective, we characterize the current and potential uses of smartphone technology in GME and provide recommendations for future studies on incorporating smartphone technology as an educational platform. Smartphones and EducationThe smartphone, in addition to having voice and text communication capabilities, is equipped with Internet access, a high-quality camera, and a recording device. With each new generation, smartphones come with more memory, faster computing capabilities, bigger screens, and sharper resolution. These features allow for instant and reliable access not only to the Internet and its wealth of information, but also for constant social connectivity to personal and professional peer groups. Given these functionalities, the potential for smartphone technology to enhance traditional educational methods is tremendous.Smartphones provide several mechanisms through which educational interventions can be administered (T A B L E). Mobile learning makes use of web-based and mobile-based platforms already in common use among young adults and the public. In fact, up to 35% of Americans use a smartphone, 7 and development of educational material into text messages, applications (apps), or mobile website formats has the potential to target a broad audience. Incorporation of information on social networking sites into curricula also is feasible. The trend toward universal smartphone ownership and trainees' wil...

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Efficient gene transfer to muscle stem cells (satellite cells) has not been achieved despite broad transduction of skeletal muscle by systemically administered adeno-associated virus serotype 2/9 (AAV-9) in mice. We hypothesized that cellular migration during fetal development would make satellite cells accessible for gene transfer following in utero intravascular injection. We injected AAV-9 encoding green fluorescent protein (GFP) marker gene into the vascular space of mice ranging in ages from post-coital day 12 (E12) to postnatal day 1 (P1). Satellite cell transduction was examined using: immunohistochemistry and confocal microscopy, satellite cell migration assay, myofiber isolation and FACS analysis. GFP positive myofibers were detected in all mature skeletal muscle groups and up to 100% of the myofibers were transduced. We saw gestational variation in cardiac and skeletal muscle expression. E16 injection resulted in 27.7 ± 10.0% expression in satellite cells, which coincides with the timing of satellite cell migration, and poor satellite cell expression before and after satellite cell migration (E12 and P1). Our results demonstrate that efficient gene expression is achieved in differentiated myofibers and satellite cells after injection of AAV-9 in utero. These findings support the potential of prenatal gene transfer for muscle based treatment strategies.

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