The efficacy of thiopurines, including azathioprine (AZA) and 6-mercaptopurine (6MP), has been demonstrated for the treatment of inflammatory bowel disease (IBD). The most common and serious adverse ...event of treatment with thiopurines altered by doctors is leukopenia. Hair loss is also a serious event that could be a critical reason for patients to decline thiopurine treatment. Thiopurine-induced severe hair loss causes cosmetic problems, and it takes a long time to recover. In a recent study, NUDT15 R139C was strongly associated with thiopurine-induced leukopenia in Korean and Caucasian populations. In this study, we performed an association study to investigate and replicate the association of R139C with adverse events of thiopurines in Japanese patients. A total of 142 Japanese patients with IBD, with histories of thiopurine treatment, were examined. NUDT15 R139C was genotyped using a custom TaqMan genotyping assay. Adverse events including leukopenia were reviewed from medical records. The 6MP dose was adjusted to AZA equivalents by multiplying with 2 as a thiopurine dose. Five patients developed severe hair loss and all of them were risk homozygous (T/T) for R139C. No early severe hair loss was observed in patients with the C/T or C/C genotype (P=3.82 × 10(-16), odds ratio=212). The association of R139C with early (<8 weeks) leukopenia (white blood cells<3000 mm(-3)), which was previously reported in Korean patients, was replicated in our Japanese IBD cohort (P=1.92 × 10(-16), odds ratio=28.4). However, we could not confirm the association with late leukopenia in the Japanese subjects. Patients with the C/T genotype discontinued treatment or required thiopurine dose reduction significantly earlier than patients with the C/C genotype (P=1.45 × 10(-4)); however, on manipulating the doses, there was no significant difference in the thiopurine continuation rates between the groups. In the maintenance period, the frequencies of 6MP usage were higher, and the doses of thiopurines were significantly lower in patients with the C/T genotype than in those with the C/C genotype (0.574±0.316 mg kg(-1) per day vs 1.03±0.425 mg kg(-1) per day, P=6.21 × 10(-4)). NUDT R139C was significantly associated with early severe hair loss in Japanese patients with IBD. We also verified the previously reported association of R139C with early leukopenia in a different East Asian population. It is recommended that treatment with thiopurines should be avoided for patients with the T/T genotype. Low-dose 6MP (0.2-0.3 mg kg(-1) per day) could be used rather than AZA for the patients with C/T genotype to continue thiopurine treatments. However, late leukopenia and other several adverse events could not be completely predicted by R139C genotypes.
AIMTo clarify the usefulness and accuracy of segmental adrenal venous sampling (sAVS) on localisation and functional diagnosis of various adrenal lesions in primary aldosteronism. MATERIALS AND ...METHODSConsecutive patients (n=162) who underwent adrenalectomy and 138 patients indicated for medication following sAVS were analysed retrospectively. Based on immunohistopathological diagnosis, the positive predictive value (PPV) of computed tomography (CT)-detectable aldosterone-producing adenoma (APA) was calculated. Moreover, endocrinological and sAVS characteristics were analysed quantitatively and qualitatively among APA, CT-undetectable aldosterone-producing nodules (APNs), multiple aldosterone-producing micronodules (MAPM), and medication groups. RESULTSThe PPV of APA by sAVS was 137/141 (97.1%; 95% confidence interval, 92.9-99.2%). Compared to the medication cases, the APA group showed stronger disease activity clinically and significant differences in adrenal hormones, such as a higher aldosterone level and aldosterone-to-cortisol ratio, and lower cortisol levels in the adrenal central vein and aldosterone maximum tributaries on the dominant side after cosyntropin stimulation. The APA group shows focal aldosterone hypersecretion, such as mean number of aldosterone elevated segments (1.7 ± 0.7 versus 2 ± 0.9, p=0.003) and presence of aldosterone-not-elevated segments (93% versus 41%, p<0.001). Clinically and in terms of sAVS, APN and MAPM showed similar characteristics to APA and to the medication cases, respectively. CONCLUSIONsAVS can localise functionally active tissues of CT-detectable and CT-undetectable lesions enabling decisions on surgical or medical treatment.
Abstract Background Post-transplant anemia (PTA) is a risk factor for mortality and graft loss in kidney transplant patients. Methods In all, 172 patients were included in this study. PTA was defined ...as hemoglobin <13.0 g/dL in men and 12.0 g/dL in women. The primary outcome of interest was the renal outcome, defined as a 50% increase in serum levels of creatinine, a return to chronic dialysis, and subsequent kidney transplantation (KTx). The secondary outcome was a composite of the primary outcome and death. Results At baseline, 75 patients (43.6%) had PTA. During follow-up of a median of 7.3 years, 52 patients (30.2%) had 2-fold higher creatinine levels than at baseline, 24 patients (14.0%) had to return to chronic dialysis or subsequent KTx, and 11 patients (6.4%) died; 8 (4.7%) of the deceased patients had functioning allografts. Univariate regression analyses showed that a lower hemoglobin level and positive proteinuria were significantly associated with both outcomes. After adjusting for important clinical variables, a lower hemoglobin level remained a strong predictor for both outcomes. Restricted cubic splines showed an almost linear inverse association with a hemoglobin level ≥12 g/dL. The risk of the outcomes increased with decreasing tertiles of the baseline hemoglobin level for both men and women, but the associations in women were much weaker than those in men, suggesting a different prognostic value of the hemoglobin level between men and women. Conclusions PTA strongly influenced the renal and patient outcomes in living kidney transplant patients.
...to identify the pathogenic SNP, a functional study is clearly needed. ...overexpressed TNFSF15 promotes a Th1 mediated immunological state and initiates or exacerbates the severity of CD.
Abstract Background It was reported that the glomerula filtration rate (GFR) equation based on serum creatinine underestimated the GFR in potential kidney donors. Recently, the Japanese GFR equation ...based on standardized serum cystatin C was reported. Therefore, we assessed the performance of the equation in potential kidney donors. Methods Forty-five potential kidney donors from 2 hospitals were included. GFR was measured (mGFR) using inulin renal clearance. Serum creatinine was measured using the enzymatic method. Serum cystatin C was measured using a nephelometric immunoassay (Siemens) and calibrated to the standardized value traceable to ERM-DA471/IFCC using an equation reported previously. The estimated GFR (eGFR) was calculated using the Japanese GFR equation based on serum creatinine (eGFRcreat) and the Japanese GFR equation based on serum cystatin C (eGFRcys). Bias (mGFR - eGFR) and accuracy (P30) of the equations were evaluated. Results Inulin clearance, eGFRcreat, and eGFRcys were 91.0 ± 18.2, 78.5 ± 18.8, and 93.3 ± 16.3 mL/min/1.73 m2 , respectively. Bias of eGFRcreat was 12.4 ± 15.8 mL/min/1.73 m2 and significantly different from zero, indicating underestimation of GFR. Bias of eGFRcys was −2.3 ± 16.3 mL/min/1.73 m2 and was not significantly different from zero, suggesting better performance. But, the precision (standard deviation SD of bias) and accuracy (P30: Percentage of participants with eGFR within 30% of mGFR) of eGFRcys were not better compared with eGFRcreat. Accuracies (P30) of eGFRcreat and eGFRcys were 87% (95% confidence interval CI, 74–94) and 82% (95% CI, 69–91), respectively. Conclusion Bias of eGFRcys was better compared with eGFRcreat. But, the precision (SD of bias) and accuracy of eGFRcys were not superior compared with eGFRcreat in potential kidney donors.
AIM: To obtain more information about the toxin/antitoxin (TA) systems in the Vibrio genus and also to examine their involvement in the induction of a viable but nonculturable (VBNC) state, we ...searched homologues of the Escherichia coli TA systems in the Vibrio parahaemolyticus genome. METHODS AND RESULTS: We found that a gene cluster, vp1842/vp1843, in the V. parahaemolyticus genome database has homology to that encoding the E. coli TA proteins, DinJ/YafQ. Expression of the putative toxin gene vp1843 in E. coli cells strongly inhibited the cell growth, while coexpression with the putative antitoxin gene vp1842 neutralized this effect. Mutational analysis identified Lys37 and Pro45 in the gene product VP1843 of vp1843 as crucial residues for the growth retardation of E. coli cells. VP1843, unlike the E. coli toxin YafQ, has no protein synthesis inhibitory activity, and that instead the expression of vp1843 in E. coli caused morphological change of the cells. CONCLUSIONS: The gene cluster vp1842/vp1843 encodes the V. parahaemolyticus TA system; VP1843 inhibits cell growth, whereas VP1842 serves as an antitoxin by forming a stable complex with VP1843. SIGNIFICANCE AND IMPACT OF THE STUDY: The putative toxin, VP1843, may be involved in the induction of the VBNC state in V. parahaemolyticus by inhibiting cell division.
Ribonuclease P (RNase P) is a ubiquitous trans-acting ribozyme that processes the 5' leader sequence of precursor tRNA (pre-tRNA). The secondary structure of RNase P RNA (PhopRNA) in the ...hyperthermophilic archaeon Pyrococcus horikoshii OT3 has several peripheral stem-loops. In order to investigate their functional role, we prepared six mutants, ΔP1, ΔP3, ΔP8, ΔP9, ΔP12 and ΔP15, in which the stem-loops including helices P1, P3, P8, P9, P12/12.1/12.2 and P15/16 in PhopRNA were individually deleted, respectively, and characterized them with respect to pre-tRNA cleavage activity in the presence of five proteins and also to the ability to form a complex with the proteins. The reconstituted particles containing ΔP3, ΔP8 or ΔP9 retained considerable levels of activity (35-65%), while those containing ΔP1, ΔP12 or ΔP15 had markedly reduced activity (13%). It was further found that the reconstituted particles comprising ΔP3 or ΔP15 lacked PhoPop5 and PhoRpp30, whereas those containing ΔP1, ΔP8, ΔP9 or ΔP12 bound to all five proteins. Since it is known that PhoPop5 functions in a complex with PhoRpp30, the present result suggests that the peripheral stem-loops containing P3 or P15/16 are involved in the structural formation of a catalytic site by interacting with the protein complex PhoPop5-PhoRpp30.
Abstract Objectives Current adherence to dietary recommendations for chronic kidney disease was evaluated in kidney transplant patients in the maintenance phase. Methods A total of 268 maintenance ...phase kidney transplant patients were included in the study. Estimated daily intakes of oral protein and salt were calculated from 24-h urinary excretion of nitrogen and sodium, respectively. Dietary recommendations for chronic kidney disease, as issued in 2014 by the Japanese Society of Nephrology, were used as the basis for assessing diet. Results The study included 114 female patients and 154 male patients. The mean age, posttransplantation years, body mass index, estimated glomerular filtration rate, and 24-h urinary excretion of protein were 56.3 years, 11.2 years, 22.0 kg/m2 , 42.6 mL/min/1.73 m2 , and 321 mg/d, respectively. Estimated daily protein and salt intakes were 0.98 ± 0.26 g/kg/d and 9.3 ± 3.9 g/d. Only 47 patients (17.5%) in the case of salt intake and 105 patients (39.2%) in the case of protein intake were within reference values. The 24-h urinary protein excretion of the daily salt intake–adherent group (<6 g) was significantly less than that of the nonadherent group (≥6 g) ( P = .021). Conclusions The adherence rate to dietary recommendations for chronic kidney disease in kidney transplant patients was low. The 24-h urinary protein excretion of the daily salt intake–adherent group was significantly less than that of the nonadherent group. Dietary therapy for these patients may have the potential to improve kidney graft function and survival.
Using 19 samples of fly ash collected from various MSW incineration facilities, residual carbon was characterized by gasifiable fraction at 450
°C (C
450), and the correlations with de novo synthesis ...of PCDD/Fs were experimentally examined. Fly ashes were classified into three groups by the ratio of C
450 to total residual carbon. By comparison of CO and CO
2 generation patterns with those of reference materials, unburnt carbon of solid waste and activated carbon powder injected into flue gas were identified as a carbon source in fly ash. In the experiment of de novo synthesis of PCDD/Fs, the content of PCDD/F synthesis depended on C
450 regardless of the origin of carbon. In addition, the model to predict the content of PCDD/F synthesis, ΔPCDD/F
=
0.989
·
Cu
·
C
450, fitted well with experimental values.
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