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Background: The concept of organ transplantation as treatment for complex genetic conditions, including Wolcott-Rallison syndrome (WRS), continues to show promise. Liver transplantation is essential for survival of patients with WRS, and pancreas transplantation cures their type I diabetes mellitus., Methods: The recipient, a 3-year-old girl weighing 14 kg at the time of transplantation, suffered from major complications of WRS, including repetitive liver failure episodes and poorly controlled diabetes. The patient underwent a nonacute, combined, simultaneous liver and pancreas transplantation from a pediatric donor without using the en bloc technique., Results: Well-preserved graft functions at 2-year follow-up with normal liver and pancreas function., Conclusions: This is the first case report of simultaneous liver and pancreas transplantation as treatment of WRS in a small child in Europe. Two-year follow-up demonstrates that organ transplantation can halt life-threating recurrent liver failure episodes and cure type 1 diabetes.

Rationale: Long living individuals show delay of aging, which is characterized by the progressive loss of cardiovascular homeostasis, along with reduced endothelial nitric oxide synthase activity, endothelial dysfunction, and impairment of tissue repair after ischemic injury., Objective: Exploit genetic analysis of long living individuals to reveal master molecular regulators of physiological aging and new targets for treatment of cardiovascular disease., Methods and Results: We show that the polymorphic variant rs2070325 (Ile229Val) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) associates with exceptional longevity, under a recessive genetic model, in 3 independent populations. Moreover, the expression of BPIFB4 is instrumental to maintenance of cellular and vascular homeostasis through regulation of protein synthesis. BPIFB4 phosphorylation/activation by protein-kinase-R-like endoplasmic reticulum kinase induces its complexing with 14-3-3 and heat shock protein 90, which is facilitated by the longevity-associated variant. In isolated vessels, BPIFB4 is upregulated by mechanical stress, and its knock-down inhibits endothelium-dependent vasorelaxation. In hypertensive rats and old mice, gene transfer of longevity-associated variant-BPIFB4 restores endothelial nitric oxide synthase signaling, rescues endothelial dysfunction, and reduces blood pressure levels. Furthermore, BPIFB4 is implicated in vascular repair. BPIFB4 is abundantly expressed in circulating CD34(+) cells of long living individuals, and its knock-down in endothelial progenitor cells precludes their capacity to migrate toward the chemoattractant SDF-1. In a murine model of peripheral ischemia, systemic gene therapy with longevity-associated variant-BPIFB4 promotes the recruitment of hematopoietic stem cells, reparative vascularization, and reperfusion of the ischemic muscle., Conclusions: Longevity-associated variant-BPIFB4 may represent a novel therapeutic tool to fight endothelial dysfunction and promote vascular reparative processes., (© 2015 American Heart Association, Inc.)