A at Single Nucleotide Polymorphism-358 Is Required for G at -420 to Confer the Highest Plasma Resistin in the General Japanese Population

Insulin resistance is a feature of type 2 diabetes. Resistin, secreted from adipocytes, causes insulin resistance in mice. We previously reported that the G/G genotype of single nucleotide polymorphism (SNP) at −420 (rs1862513) in the human resistin gene (RETN) increased susceptibility to type 2 diabetes by enhancing its promoter activity. Plasma resistin was highest in Japanese subjects with G/G genotype, followed by C/G, and C/C. In this study, we cross-sectionally analyzed plasma resistin and SNPs in the RETN region in 2,019 community-dwelling Japanese subjects. Plasma resistin was associated with SNP-638 (rs34861192), SNP-537 (rs34124816), SNP-420, SNP-358 (rs3219175), SNP+299 (rs3745367), and SNP+1263 (rs3745369) (P<10−13 in all cases). SNP-638, SNP -420, SNP-358, and SNP+157 were in the same linkage disequilibrium (LD) block. SNP-358 and SNP-638 were nearly in complete LD (r2 = 0.98), and were tightly correlated with SNP-420 (r2 = 0.50, and 0.51, respectively). The correlation between either SNP-358 (or SNP-638) or SNP-420 and plasma resistin appeared to be strong (risk alleles for high plasma resistin; A at SNP-358, r2 = 0.5224, P = 4.94×10−324; G at SNP-420, r2 = 0.2616, P = 1.71×10−133). In haplotypes determined by SNP-420 and SNP-358, the estimated frequencies for C-G, G-A, and G-G were 0.6700, 0.2005, and 0.1284, respectively, and C-A was rare (0.0011), suggesting that subjects with A at −358, generally had G at −420. This G-A haplotype conferred the highest plasma resistin (8.24 ng/ml difference/allele compared to C-G, P<0.0001). In THP-1 cells, the RETN promoter with the G-A haplotype showed the highest activity. Nuclear proteins specifically recognized one base difference at SNP-358, but not at SNP-638. Therefore, A at -358 is required for G at −420 to confer the highest plasma resistin in the general Japanese population. In Caucasians, the association between SNP-420 and plasma resistin is not strong, and A at −358 may not exist, suggesting that SNP-358 could explain this ethnic difference

Cellular HIV-1 DNA levels in patients receiving antiretroviral therapy strongly correlate with therapy initiation timing but not with therapy duration

<p>Abstract</p> <p>Background</p> <p>Viral reservoir size refers to cellular human immunodeficiency virus-1 (HIV-1) DNA levels in CD4⁺T lymphocytes of peripheral blood obtained from patients with plasma HIV-1-RNA levels (viral load, VL) maintained below the detection limit by antiretroviral therapy (ART). We measured HIV-1 DNA levels in CD4⁺lymphocytes in such patients to investigate their clinical significance.</p> <p>Methods</p> <p>CD4⁺T lymphocytes were isolated from the peripheral blood of 61 patients with a VL maintained at less than 50 copies/ml for at least 4 months by ART and total DNA was purified. HIV-1 DNA was quantified by nested PCR to calculate the copy number per 1 million CD4⁺lymphocytes (relative amount) and the copy number in 1 ml of blood (absolute amount). For statistical analysis, the Spearman rank or Wilcoxon signed-rank test was used, with a significance level of 5%.</p> <p>Results</p> <p>CD4 cell counts at the time of sampling negatively correlated with the relative amount of HIV-1 DNA (median = 33 copies/million CD4⁺lymphocytes; interquartile range [IQR] = 7-123 copies/million CD4⁺lymphocytes), but were not correlated with the absolute amounts (median = 17 copies/ml; IQR = 5-67 copies/ml). Both absolute and relative amounts of HIV-1 DNA were significantly lower in six patients in whom ART was initiated before positive seroconversion than in 55 patients in whom ART was initiated in the chronic phase, as shown by Western blotting. CD4 cell counts before ART introduction were also negatively correlated with both the relative and absolute amounts of HIV-1 DNA. Only the relative amounts of HIV-1 DNA negatively correlated with the duration of VL maintenance below the detection limit, while the absolute amounts were not significantly correlated with this period.</p> <p>Conclusions</p> <p>The amounts of cellular HIV-1 DNA in patients with VLs maintained below the detection limit by the introduction of ART correlated with the timing of ART initiation but not with the duration of ART. In addition, CD4⁺T lymphocytes, which were newly generated by ART, diluted latently infected cells, indicating that measurements of the relative amounts of cellular HIV-1 DNA might be underestimated.</p

Perceived motion in structure from motion: Pointing responses to the axis of rotation

We investigated the ability to match finger orientation to the direction of the axis of rotation in structure-from-motion displays. Preliminary experiments verified that subjects could accurately use the index finger to report direction. The remainder of the experiments studied the perception of the axis of rotation from full rotations of a group of discrete points, the profiles of a rotating ellipsoid, and two views of a group of discrete points. Subjects' responses were analyzed by decomposing the pointing responses into their slant and tilt components. Overall, the results indicated that subjects were sensitive to both slant and tilt. However, when the axis of rotation was near the viewing direction, subjects had difficulty reporting tilt with profiles and two views and showed a large bias in their slant judgments with two views and full rotations. These results are not entirely consistent with theoretical predictions. The results, particularly for two views, suggest that additional constraints are used by humans in the recovery of structure from motion

An update of the Japanese Oslo Sports Trauma Research Center questionnaires on overuse injuries and health problems.

Monitoring the health of athletes is important for their protection, and questionnaires such as those produced by the Oslo Sports Trauma Research Center (OSTRC) are a valuable tool in this process. In 2020, several changes were made to the OSTRC questionnaires (OSTRC-O, OSTRC-H), including changes to the wording, structure, and logic of the original questionnaires. In the present study, the Japanese versions of the OSTRC questionnaires (OSTRC-O.JP, OSTRC-H.JP) were revised to meet the requirements of the updated versions and to analyse new and previously collected data to illustrate the impact of the changes on Japanese athletes. Proposed changes were categorized as minor or more substantial; minor changes were effected to the questionnaire instructions and to the wording of all four questions, and more substantial changes were made to the wording of question 2. The updated questionnaires also included changes to questionnaire logic and answer categories. To assess the consequences of the changes to the wording of question 2, 101 athletes were asked to complete the OSTRC-H.JP, which included both the original and updated versions of question 2, over 10 consecutive weeks. We calculated the number of health problems identified when new gatekeeper logic was and was not applied, using 1585 OSTRC-H.JP responses to assess the consequences of the changes to the questionnaire logic. The kappa coefficient, which measures the level of agreement between the responses to question 2 of the original and updated versions, was high. By applying gatekeeper logic, there was a remarkable reduction in the number of injuries and illnesses among all health problems but less reduction in substantial health problems and time loss health problems. These changes will make it easier for Japanese athletes to complete the questionnaires and improve the quality of collected data

Mast Cells Exhibiting Strong Cytoplasmic Staining for IgE and High Affinity IgE Receptor are Increased in IgG4-Related Disease

Abstract Immunoglobulin G4 (IgG4)-related disease is characterized by elevated serum IgG4 levels and increased numbers of IgG4-positive cells. However, its pathogenesis is not fully understood. We previously suggested that mast cells may play an important role in IgG4-related disease. In this study, we confirmed the characteristics of mast cells in IgG4-related lymphadenopathy by using immunohistochemistry and dual immunofluorescence. We analyzed 23 cases of IgG4-related lymphadenopathy and compared them with 23 cases of non-specific lymphoid hyperplasia. The majority of patients with IgG4-related lymphadenopathy had cervical lesions with involvement of other organs. Immunohistologically, mast cells with strong cytoplasmic staining for immunoglobulin E and high affinity immunoglobulin E receptor were significantly increased in IgG4-related lymphadenopathy as compared to those in non-specific lymphoid hyperplasia (mean: 3.83 ± 3.99 cells per high power field and 7.14 ± 8.21 cells per high power field, respectively; P = 0.007 and P = 0.011). In addition, dual immunofluorescence assay showed that immunoglobulin E and high affinity immunoglobulin E receptor staining exhibited a cytoplasmic granular pattern in IgG4-related lymphadenopathy, suggesting internalization of the antibodies and receptors. Our findings showed that mast cell activation might be involved in the pathogenesis of IgG4-related disease

Association of hematological parameters with insulin resistance, insulin sensitivity, and asymptomatic cerebrovascular damage: The J-SHIP and Toon Health Study.

BACKGROUND: Elevated hematocrit levels have been suggested to be an independent determinant of insulin resistance and type 2 diabetes. To clarify the diagnostic significance of hematocrit level, we investigated the association with hemodynamic profiles, insulin resistance and insulin sensitivity, arterial properties, and asymptomatic cerebrovascular damage in a general Japanese population. METHODS: This study included 1, 978 participants from two independent cohorts. Insulin sensitivity was assessed by the oral 75 g glucose tolerance test. Carotid ultrasonography was performed to evaluate atherosclerosis and wall shear stress. Periventricular hyperintensity and lacunar infarction were assessed by brain magnetic resonance imaging. RESULTS: Hematocrit quartile showed a stepwise association with insulin sensitivity (Q1: 2.2 ± 0.7, Q2: 2.0 ± 0.7, Q3: 1.9 ± 0.7, Q4: 1.8 ± 0.6, p < 0.001) and insulin resistance (1.0 ± 0.6, 1.2 ± 0.7, 1.3 ± 0.8, 1.5 ± 1.0, p < 0.001). Multiple linear regression analysis adjusted for possible covariates identified hematocrit as an independent determinant of insulin sensitivity (β = −0.074, p = 0.019) and insulin resistance (β = 0.115, p < 0.001). However, this association was lost after further adjustment for visceral fat area and plasma alanine aminotransferase level. Further, no significant association was observed between hematocrit and carotid intima-media thickness (p = 0.306) where as wall shear stress was inversely associated with the carotid atherosclerosis (r = −0.250, p < 0.001). In contrast, a low hematocrit level was independently associated with periventricular hyperintensity (odds ratio 0.87 (95% CI 0.80–0.95), p = 0.001). CONCLUSION: Hematocrit was positively associated with insulin resistance and insulin sensitivity. This association was epiphenomenon of visceral and hepatic adiposity. Conversely, low hematocrit was a significant risk factor for periventricular hyperintensity independent of insulin resistance

Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1

Abstract Background Dolutegravir (DTG) is metabolized mainly by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1), and partly by cytochrome P450 3A (CYP3A). Therefore, we focused on UGT1A1 gene polymorphisms (*6 and *28) in Japanese individuals infected with human immunodeficiency virus (HIV)-1 to examine the relationship between their plasma trough concentration of DTG and gene polymorphisms. Recently, neuropsychiatric adverse events (NP-AEs) after the use of DTG have become a concern, so the association between UGT1A1 gene polymorphisms and selected NP-AEs was also investigated. Methods The study subjects were 107 Japanese patients with HIV-1 infections who were receiving DTG. Five symptoms (dizziness, headache, insomnia, restlessness, and anxiety) were selected as NP-AEs. The subjects were classified by their UGT1A1 gene polymorphisms for the group comparison of DTG trough concentration and the presence or absence of NP-AEs. Results The subjects consisted of eight (7%) *6 homozygotes, three (3%) *28 homozygotes, four (4%) for *6/*28 compound heterozygotes, 23 (21%) *6 heterozygotes, 18 (17%) *28 heterozygotes, and 51 (48%) patients carrying the normal allele. The plasma DTG trough concentration of the *6 homozygous patients was significantly higher than that of the patients carrying the normal allele (median, 1.43 and 0.82 μg/mL, respectively, p = 0.0054). The *6 and *28 heterozygous patients also showed significantly higher values than those shown by patients with the normal allele. Multivariate analysis revealed that carrying one or two UGT1A1*6 gene polymorphisms, one UGT1A1*28 polymorphism, and age of < 40 years were independent factors associated with high DTG trough concentrations. The median DTG trough concentration was significantly higher in the patients with NP-AEs (1.31 μg/mL) than in those without NP-AEs (1.01 μg/mL). Consistent with these results, subjects carrying UGT1A1*6, UGT1A1*28, or both alleles showed a higher cumulative incidence of having selected NP-AEs than those carrying the normal alleles (p = 0.0454). Conclusion In addition to younger age, carrying UGT1A1*6 and/or UGT1A1*28 was demonstrated to be a factor associated with high DTG trough concentrations. Our results also suggest a relationship between plasma DTG trough concentrations and NP-AEs, and that carrying UGT1A1*6 and/or UGT1A1*28 alleles might be a risk factor for NP-AEs