Compatibility of superparamagnetic iron oxide nanoparticle labeling for 1H MRI cell tracking with 31P MRS for bioenergetic measurements

Labeling of cells with superparamagnetic iron oxide nanoparticles permits cell tracking by ¹H MRI while ³¹P MRS allows non‐invasive evaluation of cellular bioenergetics. We evaluated the compatibility of these two techniques by obtaining ³¹P NMR spectra of iron‐labeled and unlabeled immobilized C2C12 myoblast cells in vitro. Broadened but usable ³¹P spectra were obtained and peak area ratios of resonances corresponding to intracellular metabolites showed no significant differences between labeled and unlabeled cell populations. We conclude that ³¹P NMR spectra can be obtained from cells labeled with sufficient iron to permit visualization by ¹H imaging protocols and that these spectra have sufficient quality to be used to assess metabolic status. This result introduces the possibility of using localized ³¹P MRS to evaluate the viability of iron‐labeled therapeutic cells as well as surrounding host tissue in vivo. Published in 2010 by John Wiley & Sons, Ltd.     

Regulation of bone mass through pineal‐derived melatonin‐MT2 receptor pathway

Tryptophan, an essential amino acid through a series of enzymatic reactions gives rise to various metabolites, viz. serotonin and melatonin, that regulate distinct biological functions. We show here that tryptophan metabolism in the pineal gland favors bone mass accrual through production of melatonin, a pineal‐derived neurohormone. Pineal gland‐specific deletion of Tph1, the enzyme that catalyzes the first step in the melatonin biosynthesis lead to a decrease in melatonin levels and a low bone mass due to an isolated decrease in bone formation while bone resorption parameters remained unaffected. Skeletal analysis of the mice deficient in MT1 or MT2 melatonin receptors showed a low bone mass in MT2?/? mice while MT1?/? mice had a normal bone mass compared to the WT mice. This low bone mass in the MT2?/? mice was due to an isolated decrease in osteoblast numbers and bone formation. In vitro assays of the osteoblast cultures derived from the MT1?/? and MT2?/? mice showed a cell intrinsic defect in the proliferation, differentiation and mineralization abilities of MT2?/? osteoblasts compared to WT counterparts, and the mutant cells did not respond to melatonin addition. Finally, we demonstrate that daily oral administration of melatonin can increase bone accrual during growth and can cure ovariectomy‐induced structural and functional degeneration of bone by specifically increasing bone formation. By identifying pineal‐derived melatonin as a regulator of bone mass through MT2 receptors, this study expands the role played by tryptophan derivatives in the regulation of bone mass and underscores its therapeutic relevance in postmenopausal osteoporosis.     

Long-Term Measurement of Impedance in Chronically Implanted Depth and Subdural Electrodes During Responsive Neurostimulation in Humans

Long-term stability of the electrode–tissue interface may be required to maintain optimal neural recording with subdural and deep brain implants and to permit appropriate delivery of neuromodulation therapy. Although short-term changes in impedance at the electrode–tissue interface are known to occur, long-term changes in impedance have not previously been examined in detail in humans. To provide further information about short- and long-term impedance changes in chronically implanted electrodes, a dataset from 191 persons with medically intractable epilepsy participating in a trial of an investigational responsive neurostimulation device (the RNS^® System, NeuroPace, Inc.) was reviewed. Monopolar impedance measurements were available for 391 depth and subdural leads containing a total of 1564 electrodes; measurements were available for median 802 days post-implant (range 28–1634). Although there were statistically significant short-term impedance changes, long-term impedance was stable after one year. Impedances for depth electrodes transiently increased during the third week after lead implantation and impedances for subdural electrodes increased over 12 weeks post-implant, then were stable over the subsequent long-term follow-up. Both depth and subdural electrode impedances demonstrated long-term stability, suggesting that the quality of long-term electrographic recordings (the data used to control responsive brain stimulation) can be maintained over time.     

Genetically engineered mouse models for hereditary cancer syndromes

Advances in molecular diagnostics have led to improved diagnosis and molecular understanding of hereditary cancers in the clinic. Improving the management, treatment, and potential prevention of cancers in carriers of predisposing mutations requires preclinical experimental models that reflect the key pathogenic features of the specific syndrome associated with the mutations. Numerous genetically engineered mouse (GEM) models of hereditary cancer have been developed. In this review, we describe the models of Lynch syndrome and hereditary breast and ovarian cancer syndrome, the two most common hereditary cancer predisposition syndromes. We focus on Lynch syndrome models as illustrative of the potential for using mouse models to devise improved approaches to prevention of cancer in a high-risk population. GEM models are an invaluable tool for hereditary cancer models. Here, we review GEM models for some hereditary cancers and their potential use in cancer prevention studies.     

Diagnostic dilemma in diagnosing rare cause of protein losing enteropathy: Waldmann's disease

Waldmann''s disease, or primary intestinal lymphangiectasia, is an unusual cause of protein‐losing enteropathy primarily characterized by lymphopenia, hypoalbuminemia, and hypogammaglobulinemia. However, variable clinical presentations result dilemmas in diagnosis and effective management. We present a toddler diagnosed with Waldmann''s disease managed with a high‐protein diet and medium‐chain triglyceride supplementation.