Associations Between hOGG1 Ser326Cys Polymorphism and Increased Body Mass Index and Fasting Glucose Level in the Japanese General Population

Background

Evidence suggests that Ser326Cys, a genetic polymorphism of human 8-oxoguanine glycosylase 1 (hOGG1), is associated with insulin resistance and type 2 diabetes; however, the underlying mechanism is unclear. Recently, an animal study showed a significant association between the hOGG1 genotype and obesity, although evidence for such an association in humans is limited. The purpose of this study was to examine the association between the hOGG1 genotype and body mass index (BMI) and fasting blood glucose (FBG) levels.

Methods

Cross-sectional analysis was conducted using the baseline survey data from a Japan Multi-Institutional Collaborative Cohort Study, which included 1793 participants aged 40–69 years. The hOGG1 polymorphism was detected using a multiplex polymerase chain reaction-based invader assay. Multiple linear regression, analysis of covariance, and logistic regression were used to control for confounding variables.

Results

The Cys allele was significantly associated with increased BMI, FBG level, and total cholesterol (TC) level, even after adjustment for gender, age, energy intake, alcohol, smoking, physical activity, and family history of diabetes. An association with BMI was still observed after further adjustment for FBG and TC, but not for the study area (Amami or the mainland). The Cys/Cys genotype was significantly more prevalent in the participants with higher BMI (>27.5 kg/m²). However, the impact of genotype decreased and significance disappeared after adjusting for the study area.

Conclusions

The present results suggest that the study area being inside Japan confounds the association between hOGG1 genotype and obesity.Key words: human 8-oxoguanine glycosylase 1 (hOGG1), obesity, body mass index (BMI), fasting blood glucose (FBG), polymorphism, study area     

Highly sensitive detection of GATA1 mutations in patients with myeloid leukemia associated with Down syndrome by combining Sanger and targeted next generation sequencing

Myeloid leukemia associated with Down syndrome (ML‐DS) is characterized by a predominance of acute megakaryoblastic leukemia, the presence of GATA1 mutations and a favorable outcome. Because DS children can also develop conventional acute myeloid leukemia with unfavorable outcome, detection of GATA1 mutations is important for diagnosis of ML‐DS. However, myelofibrosis and the significant frequency of dry taps have hampered practical screening of GATA1 mutations using bone marrow (BM) samples. In response to those problems, 82 patients were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML‐D11 study. GATA1 mutations were analyzed by Sanger sequencing (SS) using genomic DNA (gDNA) from BM and cDNA from peripheral blood (PB) followed by targeted next‐generation sequencing (NGS) using pooled diagnostic samples. BM and PB samples were obtained from 71 (87%) and 82 (100%) patients, respectively. GATA1 mutations were detected in 46 (56%) and 58 (71%) patients by SS using BM gDNA and PB cDNA, respectively. Collectively, GATA1 mutations were identified in 73/82 (89%) patients by SS. Targeted NGS detected GATA1 mutations in 74/82 (90%) patients. Finally, combining the results of SS with those of targeted NGS, GATA1 mutations were identified in 80/82 (98%) patients. These results indicate that SS using BM gDNA and PB cDNA is a rapid and useful method for screening for GATA1 mutations in ML‐DS patients. Thus, a combination of SS and targeted NGS is a sensitive and useful method to evaluate the actual incidence and clinical significance of GATA1 mutations in ML‐DS patients.     

Aerobic Exercise Attenuates the Loss of Skeletal Muscle during Energy Restriction in Adults with Visceral Adiposity

ObjectiveTo evaluate the effects of energy restriction with or without aerobic exercise on thigh muscle mass and quality in adults with visceral adiposity.Methods75 males and females were randomly assigned to the groups ‘diet only’ (DO; n = 42) or ‘diet plus aerobic exercise’ (D/Ex; n = 33) for 12 weeks. The target energy intake in both groups was 25 kcal/kg of ideal body weight. Subjects in the D/Ex group were instructed to exercise for ≥300 min/week at lactate threshold. Computed tomography was used to measure thigh muscle cross-sectional area (CSA), normal-density muscle area (NDMA), and visceral fat area.ResultsTotal body weight (DO: −6.6 ± 3.6%; D/Ex: −7.3 ± 4.6%) and visceral fat (DO: −16.0 ± 13.8%; D/Ex: −23.1 ± 14.7%) decreased significantly in both groups; however, the changes were not significantly different between the two groups. The decrease in muscle CSA was significantly greater in the DO group (-5.1 ± 4.5%) compared with the D/Ex group (-2.5 ± 5.0%). NDMA decreased significantly in the DO (-4.9 ± 4.9%) but not in the D/Ex group (-1.4 ± 5.0%).ConclusionAerobic exercise attenuated the loss of skeletal muscle during energy restriction in adults with visceral adiposity.Key Words: Aerobic exercise, Skeletal muscle, Normal density muscle, Visceral adiposity, Energy restriction     

Th1, Th2, and activated T-cell marker and clinical prognosis in peripheral T-cell lymphoma,unspecified: comparison with AILD,ALCL, lymphoblastic lymphoma,and ATLL

A new World Health Organization classification was recently proposed. However, classification of peripheral T-cell lymphomas remains to be clarified. Particularly, unspecified type was considered as a heterogeneous category. Here we studied the expressions of chemokine receptors, Th1-associated CXCR3 and CCR5 and Th2-associated marker ST2(L), and activated T-cell receptor OX40/CD134 in 185 patients with nodal T-cell lymphoma, and evaluated the relationship to prognosis. Their expression patterns correlated with the specific subtype of nodal T-cell lymphoma, such as angioimmunoblastic T-cell lymphoma (AILD), anaplastic large cell lymphoma (ALCL), and in peripheral T-cell lymphoma (PTCL), unspecified. In AILD, almost all cases were immunoreactive for OX40/CD134 (96%) and for CXCR3 (89%). In ALCL, all cases were immunonegative for OX40/CD134, and only a few cases (24%) were immunoreactive for CXCR3, whereas almost all cases (94%) were positive for ST2(L). Cases of PTCL, unspecified, were divided into 2 groups; group 1 (cases positive for either ST2(L), CCR5, or CXCR3) tended to show favorable prognosis compared with group 2 (cases negative for ST2(L), CCR5, and CXCR3). Our results indicate that further subtyping of PTCL, unspecified, into groups 1 and 2 could be significant for evaluating prognosis and understanding the functional role of these tumors.     

Flow cytometric analysis of de novo acute lymphoblastic leukemia in childhood: report from the Japanese Pediatric Leukemia/Lymphoma Study Group

Although the antigen expression patterns of childhood acute lymphoblastic leukemia (ALL) are well known, little attention has been given to standardizing the diagnostic and classification criteria. We retrospectively analyzed the flow cytometric data from a large study of antigen expression in 1,774 children with newly diagnosed ALL in JPLSG. T- and B-lineage ALL accounted for 13 and 87% of childhood ALL cases, respectively. Cytoplasmic CD3 and CD7 antigens were positive in all T-ALL cases. More than 80% of T-ALL cases expressed CD2, CD5 and TdT. In B-lineage ALL, the frequencies of early pre-B, pre-B, transitional pre-B and B-ALL were 81, 15.5, 0.6 and 2.9%, respectively. More than 90% of early pre-B ALL cases expressed CD19, CD79a, CD22, CD10 and TdT. CD34 was expressed in three-fourths of early pre-B ALL cases. The frequencies of TdT and CD34 expression were lower in pre-B ALL than in early pre-B ALL. B-ALL showed less frequent expression of CD22, CD10, CD34 and TdT than other B-lineage ALL cases. Expression of CD13 and CD33, aberrant myeloid antigens, was significantly more frequently associated with B-lineage ALL than with T-ALL. Based on this retrospective study of antigen expression in 1,774 de novo childhood ALL cases in JPLSG, we propose standardized clinical guidelines for the immunophenotypic criteria for diagnosis and classification of pediatric ALL.     

In vitro and in vivo evaluation of DU6859a,a new fluoroquinolone,among injectable antibacterials tested against clinical isolates

DU6859a was evaluated for its in vitro and in vivo antibacterial activities in comparison with those of imipenem, meropenem, cefpirome, vancomycin, gentamicin, ciprofloxacin and levofloxacin. DU6859a had activity comparable to that of imipenem against methicillin-susceptible staphylococci and penicillin-susceptible and-resistantStreptococcus pneumoniae, with MICs at which 90% of strains tested are inhibited (MIC₉₀)≤0.063μg/mL. Against methicillin-resistant staphylococci and enterococci, DU6859a was as active as vancomycin and more active than other drugs tested, with MIC₉₀s ranging from 1 to 4 μg/mL. DU6859a was as active as ciprofloxacin and more active than other drugs tested against imipenem-resistantPseudomonas aeruginosa. Differences in activity between DU6859a and reference drugs against ciprofloxacin-resistant and gentamicin-resistantP. aeruginosa were particularly striking. The in vivo efficacy of subcutaneous injections of DU6859a against experimental septicemia, respiratory and pyelonephritic infections caused by gram-positive and-negative bacteria, including methicillin-resistantStaphylococcus aureus and imipenem-resistantP. aeruginosa, reflected its potent in vitro activity.     

Multiple system atrophy variant with severe hippocampal pathology

The striatonigral and olivopontocerebellar systems are known to be vulnerable in multiple system atrophy (MSA), showing neuronal loss, astrogliosis, and alpha-synuclein-immunoreactive inclusions. MSA patients who displayed abundant neuronal cytoplasmic inclusions (NCIs) in the regions other than the striatonigral or olivopontocerebellar system have occasionally been diagnosed with variants of MSA. In this study, we report clinical and pathologic findings of MSA patients characterized by prominent pathologic involvement of the hippocampus. We assessed 146 consecutively autopsied MSA patients. Semi-quantitative analysis of anti-alpha-synuclein immunohistochemistry revealed that 12 of 146 patients (8.2%) had severe NCIs in two or more of the following areas: the hippocampal granule cells, cornu ammonis areas, parahippocampal gyrus, and amygdala. In contrast, the remaining 134 patients did not show severe NCIs in any of these regions. Patients with severe hippocampal involvement showed a higher representation of women (nine women/three men; Fisher's exact test, p = 0.0324), longer disease duration (13.1 ± 5.9 years; Mann–Whitney U-test, p = 0.000157), higher prevalence of cognitive impairment (four patients; Fisher's exact test, p = 0.0222), and lower brain weight (1070.3 ± 168.6 g; Mann–Whitney U-test, p = 0.00911) than other patients. The hippocampal granule cells and cornu ammonis area 1/subiculum almost always showed severe NCIs. The NCIs appeared to be ring-shaped or neurofibrillary tangle-like, fibrous configurations. Three of 12 patients also had dense, round-shaped NCIs that were morphologically similar to pick bodies. The patients with Pick body-like inclusions showed more severe atrophy of the medial temporal lobes and broader spreading of NCIs than those without. Immunohistochemistry for hyperphosphorylated tau and phosphorylated TDP-43 revealed minimal aggregations in the hippocampus of the hippocampal MSA patients. Our observations suggest a pathological variant of MSA that is characterized by severe involvement of hippocampal neurons. This phenotype may reinforce the importance of neuronal alpha-synucleinopathy in the pathogenesis of MSA.     

Released washed platelet concentrates are effective and safe in patients with a history of transfusion reactions

Background

Plasma removal by washing is an effective approach to prevent transfusion reactions by platelet concentrates (PCs). Recently, washed PCs were released by the Japanese Red Cross Society (JRCS).

Abnormalities in perineuronal nets and behavior in mice lacking CSGalNAcT1, a key enzyme in chondroitin sulfate synthesis

Chondroitin sulfate (CS) is an important glycosaminoglycan and is mainly found in the extracellular matrix as CS proteoglycans. In the brain, CS proteoglycans are highly concentrated in perineuronal nets (PNNs), which surround synapses and modulate their functions. To investigate the importance of CS, we produced and precisely examined mice that were deficient in the CS synthesizing enzyme, CSGalNAcT1 (T1KO). Biochemical analysis of T1KO revealed that loss of this enzyme reduced the amount of CS by approximately 50% in various brain regions. The amount of CS in PNNs was also diminished in T1KO compared to wild-type mice, although the amount of a major CS proteoglycan core protein, aggrecan, was not changed. In T1KO, we observed abnormalities in several behavioral tests, including the open-field test, acoustic startle response, and social preference. These results suggest that T1 is important for plasticity, probably due to regulation of CS-dependent PNNs, and that T1KO is a good model for investigation of PNNs.