Mucopolysaccharidosis type I (MPS IH;Hurler syndrome) is a congenital deficiency of ␣-L-iduronidase, leading to lysosomal storage of glycosaminoglycans that is ultimately fatal following an insidious onset after birth. Hematopoietic cell transplantation (HCT) is a life-saving measure in MPS IH. However, because a suitable hematopoietic donor is not found for everyone, because HCT is associated with significant morbidity and mortality, and because there is no known benefit of immune reaction between the host and the donor cells in MPS IH, gene-corrected autologous stem cells may be the ideal graft for HCT. Thus, we generated induced pluripotent stem cells from 2 patients with MPS IH (MPS-iPS cells). We found that ␣-L-iduronidase was not required for stem cell renewal, and that MPS-iPS cells showed lysosomal storage characteristic of MPS IH and could be differentiated to both hematopoietic and nonhematopoietic cells. The specific epigenetic profile associated with dedifferentiation of MPS IH fibroblasts into MPS-iPS cells was maintained when MPS-iPS cells IntroductionThe seminal insight that cells with 2 different enzyme deficiencies can functionally complement each other 1 made possible the use of allogeneic hematopoietic cell transplantation (HCT) to correct the biochemical and clinical phenotype of several fatal nonmalignant enzymatic deficiency disorders, including Hurler syndrome (mucopolysaccharidosis type I-Hurler, MPS IH). 2 In MPS IH the deficiency of ␣-L-iduronidase (IDUA) results in the toxic accumulation of glycosaminoglycans (GAG) heparan sulfate and dermatan sulfate. This in turn leads to progressive cellular and multiorgan dysfunction in viscera, bone, connective tissue, and brain. Untreated, early death is observed usually between 5 and 10 years of age. 3 The sole agent needed for MPS IH correction is the missing IDUA, which after secretion and intercellular transfer is taken up by IDUA-deficient cells through receptor-mediated endocytosis. Weekly doses of intravenous IDUA have been used for mild forms of MPS I. However, because IDUA does not cross the blood-brain barrier efficiently, enzyme replacement therapy alone is not indicated for the severe form of IDUA deficiency, MPS IH. 4 Allogeneic HCT, in contrast, leads not only to donor hematopoietic engraftment and systemic expression of IDUA but also to donor myeloid cells crossing the blood-brain barrier and correcting IDUA deficiency in the brain. [5][6][7][8] Although HCT is a life-saving measure in MPS IH, a suitable HCT donor is not found for everyone. To achieve a cure, children with MPS IH must survive both the disease and its therapy because allogeneic HCT is associated with significant morbidity and mortality from physical and immune injury by both the myeloablative conditioning regimen and the transplantation of an immunologically matched allogeneic cellular graft. [9][10][11] In contrast to some malignancies, 12 in patients with congenital enzymopathies there is no known benefit of immune reaction between the host and the donor cells.Pa...

Mucopolysaccharidosis type I (Hurler syndrome) is caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA), and is characterized by widespread lysosomal glycosaminoglycan (GAG) accumulation. Successful treatment of central nervous system (CNS) diseases is limited by the presence of the blood-brain barrier, which prevents penetration of the therapeutic enzyme. Given that the brain capillary endothelial cells that form this barrier express high levels of the transferrin receptor (TfR), we hypothesized that the coupling of IDUA to transferrin (Tf) would facilitate IDUA delivery to the CNS. A plasmid bearing a fusion gene consisting of Tf and IDUA was constructed which, when delivered in vivo, resulted in the production of high levels of an enzymatically active protein that was transported into the CNS by TfR-mediated endocytosis. Short-term treatment resulted in a decrease in GAGs in the cerebellum of mucopolysaccharidosis type I (MPS I) mice. This approach, therefore, represents a potential strategy for the delivery of therapeutic enzyme to the CNS.

This study serves to further elucidate the role of biomolecules in the regulation of affective disorders, such as depression. Resulting in providing a network of clinically relevant biomarkers to objectively assess and monitor general depression.

Lyme borreliosis is transmitted through the bite of a tick that is infected by the bacterial spirochete Borrelia burgdorferi. Clinical manifestation of the disease can lead to heart conditions, neurological disorders, and inflammatory disorders. Oxidative stress has been implicated in the pathogenesis of many human diseases. The aim of this study was to investigate the mechanisms of oxidative stress and intracellular communication in Lyme borreliosis patients. Mitochondrial superoxide and cytosolic ionized calcium was measured in peripheral blood mononuclear cells (PBMCs) of Lyme borreliosis patients and healthy controls. Mitochondrial superoxide levels were significantly higher (p<0.0001) in Lyme borreliosis patients (n=32) as compared to healthy controls (n=30). Significantly low (p<0.0001) levels of cytosolic ionized calcium were also observed in Lyme borreliosis patients (n=11) when compared to healthy controls (n=11). These results indicate that there is an imbalance of reactive oxygen species and cytosolic calcium in Lyme borreliosis patients. The results further suggest that oxidative stress and interrupted intracellular communication may ultimately contribute to a condition of mitochondrial dysfunction in the immune cells of Lyme borreliosis patients.

Minority female youth are significantly affected by the HIV epidemic. The purpose of this pilot study was to explore sexual behavior practices, disclosure of HIV status, attitudes about disclosure, and knowledge of HIV disclosure laws among female youth with HIV (YWH). Findings suggest that the majority of YWH studied have been sexually active since their HIV diagnosis, although the nature and extent of sexual activity varied. Rates of nondisclosure to sexual partners varied based on the type of question asked, but at least some of the YWH in this sample reported sexual activity with a partner who was unaware of the participant's HIV status. YWH appear to be more likely to disclose before, as opposed to after, sexual activity. Although most YWH believe disclosure to sexual partners is important for a variety of reasons, many reasons exist for nondisclosure, including fear of rejection and limited communication skills. The majority of YWH in this sample were aware of the potential legal ramifications of nondisclosure although fear of legal repercussions was not the most important factor related to disclosure. These findings favor the implementation of HIV disclosure interventions over the enactment of HIV criminalization laws as a strategy for reducing HIV transmission.