Lester Kwock

Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD)

Phosphatidylethanolamine N‐methyltransferase (PEMT) catalyzes phosphatidylcholine synthesis. PEMT knockout mice have fatty livers, and it is possible that, in humans, nonalcoholic fatty liver disease (NAFLD) might be associated with PEMT gene polymorphisms. DNA samples from 59 humans without fatty liver and from 28 humans with NAFLD were genotyped for a single nucleotide polymorphism in exon 8 of PEMT, which leads to a V175M substitution. V175M is a loss of function mutation, as determined by transiently transfecting McArdle‐RH7777 cells with constructs of wild‐type PEMT open reading frame or the V175M mutant. Met/Met at residue 175 (loss of function SNP) occurred in 67.9% of the NAFLD subjects and in only 40.7% of control subjects (P<0.03). For the first time we report that a polymorphism of the human PEMT gene (V175M) is associated with diminished activity and may confer susceptibility to NAFLD. Song, J., da Costa, K. A., Fischer, L. M., Kohlmeier, M., Kwock, L., Wang, S., Zeisel, S. H. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J. 19, 1266–1271 (2005)

Cerebral blood volume measurements and proton MR spectroscopy in grading of oligodendroglial tumors.

OBJECTIVE The purpose of this study was to determine whether perfusion-weighted imaging (PWI) and proton MR spectroscopy (MRS) are useful in differentiating high- and low-grade oligodendroglial tumors. MATERIALS AND METHODS PWI and MRS studies of 22 patients with histologically proven oligodendroglioma or oligoastrocytoma (13 low-grade and nine anaplastic tumors) were retrospectively reviewed. PWI of 14 subjects was performed with a dynamic contrast-enhanced susceptibility-weighted echo-planar technique. Intratumoral relative cerebral blood volume ratio was calculated and normalized to the same value in contralateral normal-appearing white matter. Multivoxel MRS was performed with a point-resolved spectroscopy sequence at a TE of 135 milliseconds in 20 patients and with the addition of a TE of 30 seconds in 17 patients. MRS data were expressed as intratumoral metabolite ratios (choline to creatine [Cho/Cr], choline to N-acetyl aspartate, N-acetyl aspartate to creatine, and myoinositol to creatine). RESULTS Relative cerebral blood volume ratios were significantly different (p = 0.004) between low-grade (1.61 +/- 1.20) and high-grade tumors (5.45 +/- 1.96). The optimal relative cerebral blood volume ratio cutoff value in identification of anaplastic oligodendroglial tumors was 2.14. Analysis of MRS data showed significantly higher Cho/Cr ratios (p = 0.002) in high-grade than in low-grade tumors. A Cho/Cr ratio cutoff value of 2.33 had the highest accuracy in identification of high-grade tumors. CONCLUSION Relative cerebral blood volume measurement and MRS are helpful in differentiating low-grade from anaplastic oligodendroglial tumors.

Clinical applications of proton MR spectroscopy in oncology.

Proton magnetic resonance spectroscopy (H1-MRS) has been increasingly receiving more attention from radiologists, neurosurgeons, radiation and medical oncologists in the “in situ” clinical evaluation of human tumors. The utilization of H1-MRS, especially in human brain tumors, coupled to both routine magnetic resonance imaging (MRI) and functional MRI techniques provides greater information concerning tumor grading and extension and characterization of the normal surrounding tissue than what is possible with any other imaging technique alone. In this paper, we will review the current status of proton MR spectroscopy with emphasis on its clinical utility to diagnose tumors, its utility in planning surgical and radiation therapy interventions, and in its use in monitoring tumor treatment.

Dietary choline requirements of women: effects of estrogen and genetic variation

BACKGROUND Choline is obtained from the diet and from the biosynthesis of phosphatidylcholine. Phosphatidylcholine is catalyzed by the enzyme phosphatidylethanolamine-N-methyltransferase (PEMT), which is induced by estrogen. Because they have lower estrogen concentrations, postmenopausal women are more susceptible to the risk of organ dysfunction in response to a low-choline diet. A common genetic polymorphism (rs12325817) in the PEMT gene can also increase this risk. OBJECTIVE The objective was to determine whether the risk of low choline-related organ dysfunction increases with the number of alleles of rs12325817 in premenopausal women and whether postmenopausal women (with or without rs12325817) treated with estrogen are more resistant to developing such symptoms. DESIGN Premenopausal women (n = 27) consumed a choline-sufficient diet followed by a very-low-choline diet until they developed organ dysfunction (or for 42 d), which was followed by a high-choline diet. Postmenopausal women (n = 22) were placed on the same diets but were first randomly assigned to receive estrogen or a placebo. The women were monitored for organ dysfunction and plasma choline metabolites and were genotyped for rs12325817. RESULTS A dose-response effect of rs12325817 on the risk of choline-related organ dysfunction was observed in premenopausal women: 80%, 43%, and 13% of women with 2, 1, or 0 alleles, respectively, developed organ dysfunction. Among postmenopausal women, 73% who received placebo but only 18% who received estrogen developed organ dysfunction during the low-choline diet. CONCLUSIONS Because of their lower estrogen concentrations, postmenopausal women have a higher dietary requirement for choline than do premenopausal women. Choline requirements for both groups of women are further increased by rs12325817. This trial was registered at clinicaltrials.gov as NCT00065546.

Matching Visual Saliency to Confidence in Plots of Uncertain Data

Conveying data uncertainty in visualizations is crucial for preventing viewers from drawing conclusions based on untrustworthy data points. This paper proposes a methodology for efficiently generating density plots of uncertain multivariate data sets that draws viewers to preattentively identify values of high certainty while not calling attention to uncertain values. We demonstrate how to augment scatter plots and parallel coordinates plots to incorporate statistically modeled uncertainty and show how to integrate them with existing multivariate analysis techniques, including outlier detection and interactive brushing. Computing high quality density plots can be expensive for large data sets, so we also describe a probabilistic plotting technique that summarizes the data without requiring explicit density plot computation. These techniques have been useful for identifying brain tumors in multivariate magnetic resonance spectroscopy data and we describe how to extend them to visualize ensemble data sets.

MR spectroscopy of brain tumors.

MR spectroscopy is a non-invasive technique for measuring tissue metabolites. Changes in tissue metabolites may be useful for diagnosing or characterizing primary and other brain neoplasms, planning treatment, and assessing the results of treatment. Ongoing improvements in equipment and pulse sequence design may make full brain spectroscopy clinically practical in the near future. The authors review the basic concepts of MR spectroscopy and its use in clinical management of brain neoplasms.

Sydenham's chorea: MRI and proton spectroscopy.

Abstract We present the MRI and proton spectroscopy findings in a child with clinical diagnosis of Sydenhams chorea. MRI showed high signal in the caudate nuclei and putamina on T2-weighted images. We believe that the spectra showed an abnormality in the number and/or function of neurons, lipids from cellular breakdown (cytolytic effect of antibodies), aminoacids (related to the presence of antibodies in the neostriatum), and sugars (also related to the presence of antibodies). The spectroscopy features correlate well with the histopathology and biochemistry of this rare disorder.

Tumor retention of 5-fluorouracil following irradiation observed using 19F nuclear magnetic resonance spectroscopy

PURPOSE The combination of 5-fluorouracil (5FU) and radiation results in improved tumor control in a variety of gastrointestinal cancers. We propose the enhancement is related to radiation potentiating the antitumor effects of 5FU. To better understand the mechanism of the 5FU-radiation interaction, 19F nuclear magnetic resonance (NMR) spectroscopy experiments were performed to observed the tumor clearance and metabolism of 5FU. METHODS AND MATERIALS Experiments were performed on 10 3-6-week-old female (Nu/Nu) athymic nude mice. Flank tumors measuring approximately 1.0 cm in diameter 3 weeks following a subcutaneous injection of 1 x 10(6) human colon adenocarcinoma (HT-29) cells were studied. In our first group, all animals received an intravenous bolus injection of 5FU (100 mg/kg) immediately before spectroscopic analysis. Animals in the second group were first treated with a single tumor radiation dose of 10 Gy just before the 5FU injection and subsequent spectroscopy. Spectroscopic analysis was performed with a 2.0-T NMR spectroscopy system. RESULTS The tumor retention of 5FU was prolonged in animals receiving radiation before the drug infusion. The tumor clearance rate of the 5FU for nonirradiated animals was 0.0178 +/- 0.0082/min vs. 0.0055 +/- 0.0027/min for irradiated animals, reflecting a threefold reduction in drug clearance in the irradiated tumors. The difference was significant at p < 0.005. CONCLUSION Our preliminary experiments suggest the enhanced cytotoxicity seen with concurrent 5FU and radiation is related to prolonged tumor retention of 5FU induced by radiation. This is consistent with the hypothesis that radiation is potentiating the cytotoxic effects of 5FU.

Evaluation of a fluorinated 2-nitroimidazole binding to hypoxic cells in tumor-bearing rats by 19F magnetic resonance spectroscopy and immunohistochemistry

We have examined a hexafluorinated 2-nitroimidazole, CCI-103F, as a probe for hypoxic tumor cells by in vivo 19F magnetic resonance spectroscopy (MRS). Following initial intraperitoneal injections of the drug in tumor-bearing (Dunning R3327-AT1-Matlylu) rats, 19F spectra were obtained on an Otsuka 2.0T Vivospec spectrometer using a 1.5-cm surface coil. Signal at 1- and 2-h time points indicated initial biodistribution of drug in the tumor. At 4 and 8 h, a progressive increase in signal intensity was observed, indicating retention of drug within the tumor. Tumor signal remained detectable in 4 of 10 rats at 24 h, indicating possible nitroreductive bioactivation by hypoxic cells. Immunohistochemistry of these tumors revealed a staining pattern consistent with labeling of hypoxic cells. No detectable 19F signal was found at 24 h for the other rats, indicating complete washout of unbound drug. Immunohistochemical assessment of these tumors revealed some staining for bound drug at the periphery of necrotic zones. 31P-MRS of the tumors showed good correlation with the presence or absence of hypoxia as evaluated by 19F-MRS, T1- and T2-weighted images, and immunohistochemistry. These results provide the groundwork for further studies using this misonidazole analog for noninvasive identification of hypoxic tumor cells in vivo by MRS.

Magnetic resonance imaging and spectroscopy of pilomyxoid astrocytomas: case reports and comparison with pilocytic astrocytomas.

Background and Purpose: Pilomyxoid astrocytomas (PMAs) have been described only recently. They appear as low-grade tumors sharing imaging features similar to pilocytic astrocytomas (PAs). However, pilomyxoid astrocytomas have different histological features and behave more aggressively than PAs. We present the imaging and proton spectroscopic (magnetic resonance spectroscopy; MRS) findings in 3 patients with PMA and compare them with those of PA arising in other sites. Methods: Three patients who later proved to harbor PMA were studied with MR imaging and multivolume MRS. We analyzed the imaging findings, with attention to location, size, signal intensities, pattern of enhancement, and edema. In addition, we analyzed the MRS, with attention to the peaks of choline (Cho), creatine (Cr), N-acetyl aspartate, lipids, lactate, and myoinositol, and ratios between these metabolites. We compared the MRS studies of PMA with those of PA located in the hypothalamus and brain stem. Results: In 2 patients, the PMAs were located in the chiasmatic-hypothalamic and third-ventricular-hypothalamic regions, showing solid enhancement, high T2 signal intensity, and hydrocephalus. One PMA was found in the right parietal lobe showing a well-defined mass without enhancement and high T2 signal intensity. The 2 PMAs showed high Cho/Cr ratios in peritumoral regions at long echo time in comparison with PA. A third PMA showed slight elevation of Cho/Cr ratio in peritumoral regions and no elevation of Cho/Cr ratios within the mass when compared with a PA. Short echo time MRS obtained in 2 PMAs showed low myoinositol/Cr ratios in tumoral regions in comparison with PA. Conclusions: Our 2 PMAs showed imaging features similar to those described in the literature. Magnetic resonance spectroscopy showed elevated Cho/Cr outside their enhancing margins, which may be related to their more aggressive behavior when compared with PA. The third PMA was different to those previously reported in the literature because it was hemispheric rather than hypothalamic in location in addition to having low intratumoral ratios of Cho/Cr.