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1.  Estimating Lymphodynamic Conditions and Lymphovenous Anastomosis Efficacy Using 99mTc-phytate Lymphoscintigraphy with SPECT-CT in Patients with Lower-limb Lymphedema 
Diagnostic and therapeutic strategies for lower-limb lymphedema have not yet been established. The purpose of this study was to estimate the lymphodynamic condition and therapeutic efficacy of lymphovenous anastomosis (LVA) in lower-limb lymphedema patients using 2-phase 99mTc-phytate lymphoscintigraphy with single-photon emission computed tomography-computed tomography (SPECT-CT).
In this study, consecutive patients with lower-limb lymphedema who underwent 2-phase lymphoscintigraphy using 99mTc-phytate were enrolled between June 2013 and June 2014. SPECT-CT was also performed to clarify the relationships between functional and morphological information. In both the early and delayed images, inguinal lymph node accumulation, dermal backflow, and their sequential alternations were evaluated, and liver-to-blood ratio and inguinal lymph node-to-blood ratio were calculated. All participants were classified into 6 types of lymphodynamic conditions based on the image findings. Patients with both dermal backflow and associated normal lymphatic vessel accumulation proceeded to LVA and underwent a second lymphoscintigraphy after the operation.
Of all 30 participants, the largest population was categorized as type 4, which had consistent inguinal lymph node accumulation defect with dermal backflow. In 12 operated cases, dermal backflow was degraded in 10 cases by LVA. Liver-to-blood ratio in both early and delayed images and inguinal lymph node-to-blood ratio in delayed image significantly increased after LVA.
Lymphoscintigraphy with SPECT-CT can provide both functional and morphological information simultaneously in patients with lower-limb lymphedema. Using these procedures, a type categorization for the patients was devised, which reflects their lymphodynamic conditions. The therapeutic efficacy of LVA could also be estimated quantitatively by the derived findings.
PMCID: PMC4457267  PMID: 26090294
2.  Patients with reduced heart rate response to adenosine infusion have low myocardial flow reserve in 13N-ammonia PET studies 
To assess the effect of adenosine infusion by evaluating the relationship between heart rate (HR) response to adenosine and myocardial flow reserve (MFR) of remote regions supplied by normal coronary arteries in 13N-ammonia PET. Thirty-one consecutive subjects (20 known coronary artery disease patients, 4 chronic heart failure patients, and 7 normal volunteers) except cases having 3-vessel disease underwent rest and adenosine stress 13N-ammonia myocardial perfusion PET. Semi-quantitative, quantitative, and gated analyses were performed. Subjects were divided into two groups with regard to HR response to adenosine. Twenty-two subjects had normal HR response (peak/rest HR > 1.20), while reduced HR response (≤1.20) was observed in nine subjects. There were no differences in rest myocardial blood flow (MBF) of remote regions between the groups. Subjects with reduced HR response had significantly lower stress MBF and MFR of remote regions than those with normal HR response (stress MBF: 1.559 ± 0.517 vs. 2.279 ± 0.530, p = 0.004, MFR: 1.59 ± 0.36 vs. 2.35 ± 0.53, p = 0.001). There were no significant differences between the groups by means of semi-quantitative scoring. Rest and stress ejection fraction (EF) in the reduced HR response group was lower than that in the normal HR response group. In a multiple stepwise regression analysis, HR ratio, dyslipidemia, and Brinkman index were identified as predictors of the change in MFR of remote regions. Subjects with reduced HR response to adenosine had lower stress MBF and MFR of remote regions and lower EF. Moreover, HR response was one of the predictors of the change in MFR of remote regions.
PMCID: PMC4446519  PMID: 25846547
Heart rate response; Adenosine; Myocardial blood flow (MBF); Myocardial flow reserve (MFR); 13N-ammonia; Positron emission tomography (PET)
3.  Breakpoint analysis of the recurrent constitutional t(8;22)(q24.13;q11.21) translocation 
The t(8;22)(q24.13;q11.2) has been identified as one of several recurrent constitutional translocations mediated by palindromic AT-rich repeats (PATRRs). Although the breakage on 22q11 utilizes the same PATRR as that of the more prevalent constitutional t(11;22)(q23;q11.2), the breakpoint region on 8q24 has not been elucidated in detail since the analysis of palindromic sequence is technically challenging.
In this study, the entire 8q24 breakpoint region has been resolved by next generation sequencing. Eight polymorphic alleles were identified and compared with the junction sequences of previous and two recently identified t(8;22) cases . All of the breakpoints were found to be within the PATRRs on chromosomes 8 and 22 (PATRR8 and PATRR22), but the locations were different among cases at the level of nucleotide resolution. The translocations were always found to arise on symmetric PATRR8 alleles with breakpoints at the center of symmetry. The translocation junction is often accompanied by symmetric deletions at the center of both PATRRs. Rejoining occurs with minimal homology between the translocation partners. Remarkably, comparison of der (8) to der(22) sequences shows identical breakpoint junctions between them, which likely represent products of two independent events on the basis of a classical model.
Our data suggest the hypothesis that interactions between the two PATRRs prior to the translocation event might trigger illegitimate recombination resulting in the recurrent palindrome-mediated translocation.
PMCID: PMC4255720  PMID: 25478009
PATRR; t(8;22); Palindrome-mediated translocation; Supernumerary der(8)t(8;22)
4.  Voxel-based analysis of 201Tl SPECT for grading and diagnostic accuracy of gliomas: comparison with ROI analysis 
Annals of Nuclear Medicine  2013;27(6):493-501.
The aim of this retrospective study was to assess the utility of a voxel-based analysis (VBA) method for 201Tl SPECT in glioma, compared to conventional ROI analysis.
We recruited 24 patients with glioma (high-grade 15; low-grade 9), for whom pre-operative 201Tl SPECT and MRI were performed. SPECT images were coregistered with MRI. The uptake ratio (UR) images of tumor to contralateral normal tissue were measured on early and delayed images, and the 201Tl retention index (RI) map was calculated from the early and delayed uptake ratio maps. In the ROI analysis, tumors were traced on a UR map, and the mean and maximal uptake ratio values on the early images were, respectively, defined as the mean and maximal UR. The mean and maximal RI values (mean and maximal RI) were calculated by division of the mean and maximal UR, respectively, on the delayed image by the mean and maximal UR on the early image. For the RI map calculated voxel by voxel, the maximal RI value was defined as VBA-RI. We evaluated sensitivity and accuracy of differential analysis with the mean and maximal UR, RI, and VBA-RI.
The high- and low-grade groups showed no significant difference in mean and maximal RI (0.98 ± 0.12 vs. 1.05 ± 0.09 and 0.98 ± 0.18 vs. 1.05 ± 0.14, respectively). The AUC and accuracy of the mean and maximal RI were 0.681 and 66.7 %, and 0.622 and 62.5 %, respectively. In contrast, VBA-RI was higher in high-grade than in low-grade glioma (1.69 ± 0.27 vs. 0.68 ± 0.66, p < 0.001). The AUC and accuracy of VBA-RI were 0.963 and 95.8 %, which are higher than those obtained for mean (p < 0.05) and maximal RI (p < 0.01). There was no significant difference in ROC between the VBA-RI and the mean UR (0.911, p = 0.456) and maximal UR (0.933, p = 0.639); however, the AUC, sensitivity, and diagnostic accuracy of VBA-RI were all higher than those of the mean and maximal UR.
The voxel-based analysis method of 201Tl SPECT may improve diagnostic performance for gliomas, compared with ROI analysis.
PMCID: PMC3713261  PMID: 23592309
201Tl SPECT; Glioma; Voxel-based analysis
5.  Visualization of the spatial positioning of the SNRPN, UBE3A, and GABRB3 genes in the normal human nucleus by three-color 3D fluorescence in situ hybridization 
Chromosome Research  2012;20(6):659-672.
The three-dimensional (3D) structure of the genome is organized non-randomly and plays a role in genomic function via epigenetic mechanisms in the eukaryotic nucleus. Here, we analyzed the spatial positioning of three target regions; the SNRPN, UBE3A, and GABRB3 genes on human chromosome 15q11.2–q12, a representative cluster of imprinted regions, in the interphase nuclei of B lymphoblastoid cell lines, peripheral blood cells, and skin fibroblasts derived from normal individuals to look for evidence of genomic organization and function. The positions of these genes were simultaneously visualized, and all inter-gene distances were calculated for each homologous chromosome in each nucleus after three-color 3D fluorescence in situ hybridization. None of the target genes were arranged linearly in most cells analyzed, and GABRB3 was positioned closer to SNRPN than UBE3A in a high proportion of cells in all cell types. This was in contrast to the genomic map in which GABRB3 was positioned closer to UBE3A than SNRPN. We compared the distances from SNRPN to UBE3A (SU) and from UBE3A to GABRB3 (UG) between alleles in each nucleus, 50 cells per subject. The results revealed that the gene-to-gene distance of one allele was longer than that of the other and that the SU ratio (longer/shorter SU distance between alleles) was larger than the UG ratio (longer/shorter UG distance between alleles). The UG distance was relatively stable between alleles; in contrast, the SU distance of one allele was obviously longer than the distance indicated by the genome size. The results therefore indicate that SNRPN, UBE3A, and GABRB3 have non-linear and non-random curved spatial positioning in the normal nucleus, with differences in the SU distance between alleles possibly representing epigenetic evidence of nuclear organization and gene expression.
Electronic supplementary material
The online version of this article (doi:10.1007/s10577-012-9300-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3481056  PMID: 22801776
Genome organization; Spatial positioning; 3D-FISH; SNRPN; Chromatin; Epigenetic
6.  Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spectrum Disorder 
Autism Research and Treatment  2012;2012:724072.
Mutations in the X-linked genes neuroligin 3 (NLGN3) and neuroligin 4X (NLGN4X) were first implicated in the pathogenesis of X-linked autism in Swedish families. However, reports of mutations in these genes in autism spectrum disorder (ASD) patients from various ethnic backgrounds present conflicting results regarding the etiology of ASD, possibly because of genetic heterogeneity and/or differences in their ethnic background. Additional mutation screening study on another ethnic background could help to clarify the relevance of the genes to ASD. We scanned the entire coding regions of NLGN3 and NLGN4X in 62 Japanese patients with ASD by polymerase chain reaction-high-resolution melting curve and direct sequencing analyses. Four synonymous substitutions, one in NLGN3 and three in NLGN4X, were identified in four of the 62 patients. These substitutions were not present in 278 control X-chromosomes from unrelated Japanese individuals and were not registered in the database of Single Nucleotide Polymorphisms build 132 or in the Japanese Single Nucleotide Polymorphisms database, indicating that they were novel and specific to ASD. Though further analysis is necessary to determine the physiological and clinical importance of such substitutions, the possibility of the relevance of both synonymous and nonsynonymous substitutions with the etiology of ASD should be considered.
PMCID: PMC3420546  PMID: 22934180
7.  A novel balanced chromosomal translocation found in subjects with schizophrenia and schizotypal personality disorder: altered L-serine level associated with disruption of PSAT1 gene expression 
Neuroscience research  2010;69(2):154-160.
L-Serine is required for the synthesis of glycine and D-serine, both of which are NMDA receptor co-agonists. Although roles for D-serine and glycine have been suggested in schizophrenia, little is known about the role of the L-serine synthesizing cascade in schizophrenia or related psychiatric conditions. Here we report a patient with schizophrenia carrying a balanced chromosomal translocation with the breakpoints localized to 3q13.12 and 9q21.2. We examined this proband and her son with schizotypal personality disorder for chromosomal abnormalities, molecular expression profiles, and serum amino acids. Marked decrease of L-serine and glutamate was observed in the sera of the patient and her son, compared with those in normal controls. Interestingly, expression of PSAT1 gene, which is located next to the breakpoint and encodes one of the enzymes in the L-serine synthesizing cascade, was reduced in both patient and her son. Direct effect of impaired PSAT1 gene expression on decreased serum L-serine level was strongly implicated by rat astrocyte experiments. In summary, we propose an idea that PSAT1 may be implicated in altered serine metabolism and schizophrenia spectrum conditions.
PMCID: PMC3049551  PMID: 20955740
schizophrenia; balanced chromosomal translocation; PSAT1; L-serine; D-serine; glycine; glutamate; expression
8.  Common variants in CASP3 confer susceptibility to Kawasaki disease 
Human Molecular Genetics  2010;19(14):2898-2906.
Kawasaki disease (KD; OMIM 611775) is an acute vasculitis syndrome which predominantly affects small- and medium-sized arteries of infants and children. Epidemiological data suggest that host genetics underlie the disease pathogenesis. Here we report that multiple variants in the caspase-3 gene (CASP3) that are in linkage disequilibrium confer susceptibility to KD in both Japanese and US subjects of European ancestry. We found that a G to A substitution of one commonly associated SNP located in the 5′ untranslated region of CASP3 (rs72689236; P = 4.2 × 10−8 in the Japanese and P = 3.7 × 10−3 in the European Americans) abolished binding of nuclear factor of activated T cells to the DNA sequence surrounding the SNP. Our findings suggest that altered CASP3 expression in immune effecter cells influences susceptibility to KD.
PMCID: PMC2893807  PMID: 20423928
9.  Prediction of Limb Salvage after Therapeutic Angiogenesis by Autologous Bone Marrow Cell Implantation in Patients with Critical Limb Ischemia 
Annals of Vascular Diseases  2011;4(1):24-31.
Purpose: Despite advances in therapeutic angiogenesis by bone marrow cell implantation (BMCI), limb amputation remains a major unfavorable outcome in patients with critical limb ischemia (CLI). We sought to identify predictor(s) of limb salvage in CLI patients who received BMCI.
Materials and Methods: Nineteen patients with CLI who treated by BMCI were divided into two groups; four patients with above-the-ankle amputation by 12 weeks after BMCI (amputation group) and the remaining 15 patients without (salvage group). We performed several blood-flow examinations before BMCI. Ankle-brachial index (ABI) was measured with the standard method. Transcutaneous oxygen tension (TcPO2) was measured at the dorsum of the foot, in the absence (baseline) and presence (maximum TcPO2) of oxygen inhalation. 99mtechnetium-tetrofosmin (99mTc-TF) perfusion index was determined at the foot and lower leg as the ratio of brain.
Results: Maximum TcPO2 (p = 0.031) and 99mTc-TF perfusion index in the foot (p = 0.0068) was significantly higher in the salvage group than in the amputation group. Receiver operating characteristic (ROC) curve analysis identified maximum TcPO2 and 99mTc-TF perfusion index in the foot as having high predictive accuracy for limb salvage.
Conclusion: Maximum TcPO2 and 99mTc-TF perfusion index in the foot are promising predictors of limb salvage after BMCI in CLI.
PMCID: PMC3595769  PMID: 23555423
critical limb ischemia; bone marrow cell implantation; limb salvage; 99mtechnetium-tetrofosmin perfusion scintigraphy; transcutaneous oxygen tension
10.  ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms 
Nature genetics  2007;40(1):35-42.
Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.
PMCID: PMC2876982  PMID: 18084290
11.  Identification of a high incidence region for retroviral vector integration near exon 1 of the LMO2 locus 
Retrovirology  2009;6:79.
Therapeutic retroviral vector integration near the oncogene LMO2 is thought to be a cause of leukemia in X-SCID gene therapy trials. However, no published studies have evaluated the frequency of vector integrations near exon 1 of the LMO2 locus. We identified a high incidence region (HIR) of vector integration using PCR techniques in the upstream region close to the LMO2 transcription start site in the TPA-Mat T cell line. The integration frequency of the HIR was one per 4.46 × 104 cells. This HIR was also found in Jurkat T cells but was absent from HeLa cells. Furthermore, using human cord blood-derived CD34+ cells we identified a HIR in a similar region as the TPA-Mat T cell line. One of the X-linked severe combined immunodeficiency (X-SCID) patients that developed leukemia after gene therapy had a vector integration site in this HIR. Therefore, the descriptions of the location and the integration frequency of the HIR presented here may help us to better understand vector-induced leukemogenesis.
PMCID: PMC2742512  PMID: 19725963
12.  Short stature in a girl with partial monosomy of the pseudoautosomal region distal to DXYS15: further evidence for the assignment of the critical region for a pseudoautosomal growth gene(s) 
Journal of Medical Genetics  1995;32(10):831-834.
This report describes a 12 year 10 month old girl with short stature and a non-mosaic 46,X,Xp+ karyotype. Her height remained below −2 SD of the mean, and her predicted adult height (143 cm) was below her target height (155·5 cm) and target range (147·5 cm−163·5 cm). Cytogenetic and molecular studies showed that the Xp+ chromosome was formed by an inverted duplication of the Xp21.3−Xp22.33 segment and was missing about 700 kb of DNA from the pseudoautosomal region distal to DXYS15. The results provide further support for the previously proposed hypothesis that the region between DXYS20 and DXYS15 is the critical region for a pseudoautosomal growth gene(s).
PMCID: PMC1051714  PMID: 8558568

Results 1-12 (12)