Mucopolysaccharidosis type VII (MPS7) is a lysosomal storage disorder (LSD) resulting from mutations in the β-glucuronidase gene, leading to multiorgan dysfunction and fetal demise. While postnatal enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation have resulted in some phenotypic improvements, prenatal treatment might take advantage of a unique developmental window to penetrate the blood-brain barrier or induce tolerance to the missing protein, addressing two important shortcomings of postnatal therapy for multiple LSDs. We performed in utero ERT (IUERT) at E14.5 in MPS7 mice and improved survival of affected mice to birth. IUERT penetrated brain microglia, whereas postnatal administration did not, and neurological testing (after IUERT plus postnatal administration) showed decreased microglial inflammation and improved grip strength in treated mice. IUERT prevented antienzyme antibody development even after multiple repeated postnatal challenges. To test a more durable treatment strategy, we performed in utero hematopoietic stem cell transplantation (IUHCT) using congenic CX3C chemokine receptor 1–green fluorescent protein (CX3CR1-GFP) mice as donors, such that donor-derived microglia are identified by GFP expression. In wild-type recipients, hematopoietic chimerism resulted in microglial engraftment throughout the brain without irradiation or conditioning; the transcriptomes of donor and host microglia were similar. IUHCT in MPS7 mice enabled cross-correction of liver Kupffer cells and improved phenotype in multiple tissues. Engrafted microglia were seen in chimeric mice, with decreased inflammation near donor microglia. These results suggest that fetal therapy with IUERT and/or IUHCT could overcome the shortcomings of current treatment strategies to improve phenotype in MPS7 and other LSDs.

Fetal injection of antibodies against the c-Kit receptor and CD47 effectively depletes host HSCs in immunocompetent mice.• In utero depletion of host HSCs increases long-term engraftment after neonatal hematopoietic cell transplantation.Recently, simultaneous treatment with an anti-CD47 antibody was shown to potentiate the effect of ACK2 and result in much higher chimerism levels than seen in mice that received ACK2 alone. 20 CD47 is expressed on HSCs and acts as a "don't eat me" signal, preventing phagocytosis by macrophages and neutrophils via interaction with SIRPa. 21,22 Blockade of the CD47-SIRPa interaction enhances antibody-dependent depletion, allowing the combination strategy to achieve depletion, even in wild-type mice. Here, we explore the safety and efficacy of this combination strategy in fetal mice. Methods MiceWild-type C57BL/6J (C57; CD45.2) and B6.SJL-PtrcaPep3b/BoyJ (BoyJ; CD45.1) mice were obtained from the National Cancer Institute. All mice were bred and maintained at the University of California, San Francisco. All procedures were performed according to the protocol approved by the University of California, San Francisco Institutional Animal Care and Use Committee. In utero ACK2/MIAP410 injectionsPregnant dams were anesthetized at embryonic day 14.5 (E14.5) using isoflurane. A midline laparotomy was made, and the uterus was exteriorized. Fetal mice were injected with 2.5 mg of ACK2 or 2.5-mg concentrations of ACK2 and varying doses of MIAP410 (2.5 and 5 mg), or Dulbecco's phosphate buffered saline (PBS) as controls, in a volume of 5 mL per fetus at E14.5. ACK2 antibody was purchased from BioLegend (San Diego, CA). MIAP410 was purchased from Bio X Cell (West Lebanon, NH). Neonatal transplantationNeonates were transplanted with congenic (B6.CD45.1/CD45.2) fetal liver mononuclear cells (FLMCs) on postnatal day 0 (P0) or P1. FLMCs were isolated from E13.5 or E14.5 donor fetuses by density

No abstract

Background Vancouver B2 periprosthetic femur fractures have traditionally been treated with revision arthroplasty. However, there is increasing evidence that open reduction and internal fixation (ORIF) may be a valid alternative treatment strategy. The purpose of this study was to compare the outcomes of ORIF versus revision arthroplasty for the treatment of Vancouver B2 fractures and evaluate the influence of the treating surgeon’s fellowship training on treatment selection. Methodology This was a retrospective cohort study of 31 patients treated for Vancouver B2 periprosthetic fractures (16 ORIF and 15 revision arthroplasty) at a single academic Level 1 trauma center. Outcome measures included one-year mortality, revision, reoperation, infection, and blood loss. Results There were no statistically significant differences in revision, reoperation, or infection at an average follow-up of 65 weeks. Median estimated blood loss was higher in the arthroplasty group (700 cc versus 400 cc; P = 0.04). There were five deaths in the ORIF group versus one in the revision group ( P = 0.18). Cases treated by surgeons with fellowship training in arthroplasty were more likely to be treated with revision arthroplasty (10/11, 90.9%) than those treated by surgeons with fellowship training in trauma (5/15, 33.3%; P < 0.01). Conclusions There was no difference in outcomes between the two treatment strategies, but revision was associated with higher blood loss. The appropriate treatment method should be based on surgeon familiarity and patients' characteristics.