Publications

The lipid mediator sphingosine 1-phosphate (S1P) confers survival benefits in cardiomyocytes and isolated hearts subjected to oxidative stress. High-density lipoprotein (HDL) is a major carrier of S1P in the serum, but whether HDL-associated S1P directly mediates survival in a preparation composed exclusively of cardiomyocytes has not been demonstrated. Accordingly, we tested the hypothesis that signal activation and survival during simulated ischemia-reperfusion injury in response to HDL require lipoprotein-associated S1P. As a model, we used adult mouse cardiomyocytes subjected to hypoxia-reoxygenation. Cells were treated or not with autologous mouse HDL, which significantly increased myocyte viability as measured by trypan blue exclusion. This survival effect was abrogated by the S1P(1) and SIP(3) receptor antagonist VPC 23019. The selective S1P(3) antagonist CAY10444, the G(i) antagonist pertussis toxin, the MEK (MAPK/ERK) kinase inhibitor PD-98059, and the phosphoinositide-3 kinase inhibitor wortmannin also inhibited the prosurvival effect of HDL. We observed that HDL activated both Akt (protein kinase B) and the MEK1/2-ERK1/2 pathway and also stimulated phosphorylation of glycogen synthase kinase-3beta. ERK1/2 activation was through an S1P(1) subtype receptor-G(i) protein-dependent pathway, whereas the activation of Akt was inhibited by CAY10444, indicating mediation by S1P(3) subtype receptors. We conclude that HDL, via its cargo of S1P, can directly protect cardiomyocytes against simulated oxidative injury in the absence of vascular effects and that prosurvival signal activation is dependent on both S1P(1) and S1P(3) subtype receptors.

Alkaline incubation of NADH results in the formation of a very potent inhibitor of lactate dehydrogenase. High resolution mass spectroscopy along with NMR characterization clearly showed that the inhibitor is derived from attachment of a glycolic acid moiety to the 4-position of the dihydronicotinamide ring of NADH. The very potent inhibitor is competitive with respect to NADH. The inhibitor added in submicromolar concentrations to cardiomyocytes protects them from damage caused by hypoxia/reoxygenation stress. In isolated mouse hearts, addition of the inhibitor results in a substantial reduction of myocardial infarct size caused by global ischemia/reperfusion injury.

The mucopolysaccharidoses (MPS) are a common cause of carpal tunnel syndrome (CTS) in children and adolescents. As the MPS diseases are progressive in nature, it is essential that CTS in these children is readily diagnosed and treated, before damage to the median nerve becomes irreversible. Currently, no standards for diagnosing and treating CTS associated with MPS exist. Proper diagnosis of CTS generally involves the assessment of clinical signs and symptoms, in combination with nerve conduction studies. As the clinical signs and symptoms of CTS described for adults are often absent in children with MPS, early diagnosis of CTS in these children requires recognition of subtle findings such as decreased sweating, nocturnal waking, gnawing of hands, and manual clumsiness. Sensory tests could also be useful for detecting early CTS when the integrity of the nerve is still relatively intact. Nerve conduction velocities, which are the gold standard for diagnosing CTS, can be difficult to perform in patients with MPS and should be adapted to the patients' clinical characteristics such as their abnormally small hands and young age. Ongoing monitoring for CTS is indicated for all MPS patients, including those treated with hematopoietic stem cell transplantation or enzyme replacement therapy.

Enzyme replacement therapy has been successful in alleviating morbidity and improving endurance in Mucopolysaccharidosis (MPS) type I, II, and VI, however little attention has been paid to the effects on bone mineralization. Brief case reports in MPS type III and IV suggest that bone mineral density (BMD) is diminished, but did not account for patient size. In this report, BMD was evaluated by quantitative computed tomography and by dual-energy x-ray absorptiometry (DXA) in separate studies involving 10 patients with MPS type VI (7 Female; 7.0 to 21.0 y) and 4 male patients with MPS II (8.1 to 35.5 y). Vitamin D intake met the current RDA (200 IU) for most, though 25-OH vitamin D was insufficient (< 30 ng/mL) in 87.5% of patients tested. Ht Z-score was low -5.8 +/- 3.6, with height deficits greatest in MPS VI. Spine and whole body BMD Z-scores by DXA were considered normal for chronological age in all MPS II, and after correction for Ht Z-score, in all but one subject with MPS VI. These results suggest that vitamin D insufficiency is quite common in MPS. BMD by DXA is within normal range for most, particularly after correction for short stature. A review of bone health assessment is provided as well as a discussion of these results.