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Aims/Introduction: We have previously reported that the Pro198Leu missense polymorphism in the glutathione peroxidase 1 (GPx-1) gene was associated with frequent macrovascular disease (MVD). Our goal was to examine whether the GPx-1 genotype is associated with diabetic neuropathy. Materials and Methods: We determined the GPx-1 genotype in 173 Japanese type 2 diabetic patients who received medical interviews, physical examinations, nerve conduction studies, quantitative vibratory perception (QVP), head-up tilt and heart rate variability tests by polymerase chain reaction-restriction fragment-length polymorphism. Diabetic sensorimotor distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathy (DAN) were evaluated separately. DSPN and DAN were defined by two or more abnormalities of neuropathic leg symptoms, diminished Achilles tendon reflexes or impaired QVP in toes, and two autonomic dysfunctions, respectively. The association of the GPx-1 genotype with DSPN, DAN, MVD and other clinical manifestations was analyzed. Results: The prevalence of DSPN, impaired QVP and painful leg cramps in patients having a genotype with Pro/Leu at the codon 198 (Pro/Leu type) was significantly higher than those with Pro/Pro type. As a result of multivariate analyses that contained the GPx-1 genotype as an independent variable, the Pro/Leu type was extracted as a significant risk factor of DSPN, QVP impairment and MVD. The statistical significance did not disappear, even after proteinuria, retinopathy and a history of MVD were introduced as independent variables. In contrast, the GPx-1 genotype was not associated with DAN. Conclusions: The Pro198Leu missense polymorphism of the GPx-1 gene might have a common genetic predisposition to DSPN and MVD. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00127.x, 2011)

Aims/Introduction: In order to diagnose diabetic symmetric polyneuropathy (DSPN) more simply and accurately, we identified symptoms that correlated with neurological functions and existed more frequently in diabetic than non-diabetic subjects. Materials and Methods: The relationships between 10 symptoms (numbness or paresthesia in toe and sole, numbness in hand, pain in foot or hand, coldness in legs, painful leg cramp, dizziness on standing, sweating restricted to face/trunk and frequent constipation/diarrhea) and clinical background, defined as DSPN and cardiovascular autonomic neuropathy (CAN) by the criteria proposed in the statement of the American Diabetes Association, and seven quantitative nerve function data were evaluated in 593 diabetic patients in Wakayama Medical University Hospital (WMUH). Furthermore, the prevalence of various symptoms was examined by three questionnaires: a WMUH survey (999 diabetic outpatients), a Nationwide survey (1524 male diabetic outpatients under a primary-care physician) and a Control survey (501 non-diabetic subjects). Results: Bilateral ‘numbness in toe and sole’, ‘paresthesia in toe and sole’, ‘pain in foot’ and ‘sweating restricted to face/trunk’ were significantly associated with diabetes duration, retinopathy, probable and confirmed DSPN, possible and advanced CAN, and all or six nerve functions. Questionnaire surveys clarified that symptoms that are not rare (>15%) and more frequent in diabetic than non-diabetic subjects were bilateral ‘numbness in toe and sole’, ‘paresthesia in toe and sole’, ‘coldness in legs’, ‘dizziness on standing’ and ‘sweating restricted to face/trunk’. Conclusions: Therefore, bilateral ‘numbness in toe and sole’, ‘paresthesia in toe and sole’ and ‘sweating restricted to face/trunk’ are suitable symptoms useful for the diagnosis of DSPN. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00124.x, 2011)

In a single-nucleotide polymorphism array-based analysis of 56 hepatoblastoma (HB) tumors, allelic imbalances were detected in 37 tumors (66%). Chromosome gains were found in 1q (28 tumors), 2q (24), 6p (8), 8q (8), 17q (6), and 20pq (10), and losses in 1p (6), 4q (9), and 16q (4). Fine mapping delineated the shortest overlapping region (SOR) of gains at 1q32.1 (1.3 Mb) and 2q24.2-q24.3 (4.8 Mb), and losses at 4q34.3-q35.2 (8.7 Mb) and 4q32.3 (1.6 Mb). Uniparental disomy of 11pter-11p15.4 (IGF2) and loss of 11pter-p14.1 were found in 11 and 2 tumors, respectively. Expression of HTATIP2 (11p15.1) was absent in 9 of 20 tumors. Amplification was identified in four tumors at 1q32.1, where the candidate oncogene MDM4 is located. In the 4q32.3-SRO, ANXA10S, a variant of the candidate tumor suppressor ANXA10, showed no expression in 19 of 24 tumors. Sequence analysis of ANXA10S identified a missense mutation (E36K, c.106G>A) in a HB cell line. Multivariate analysis revealed that both 4q deletion and RASSF1A methylation (relative risks: 4.21 and 7.55, respectively) are independent prognostic factors. Our results indicate that allelic imbalances and gene expression patterns provide possible diagnostic and prognostic markers, as well as therapeutic targets in a subset of HB.