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ObjectivesSelf-stigma is associated with lower patient activation levels for self-care in persons with type 2 diabetes mellitus (T2DM). However, the causal pathway linking self-stigma with patient activation for self-care has not been shown. In order to determine how self-stigma affects patient activation for self-care, we tested a two-path hypothetical model both directly and as mediated by self-esteem and self-efficacy.DesignA cross-sectional study.SettingTwo university hospitals, one general hospital and one clinic in Japan.ParticipantsT2DM outpatients receiving treatment (n=209) completed a self-administered questionnaire comprising the Self-Stigma Scale, Patient Activation Measure, Rosenberg Self-Esteem Scale, General Self-Efficacy Scale, Patient Health Questionnaire, haemoglobin A1c test, age, sex and body mass index.Primary and secondary outcome measuresSelf-stigma levels were measured by using the Self-Stigma Scale. Patient activation levels were measured by the Patient Activation Measure.ResultsPath analysis showed a strong relationship between self-stigma and patient activation (χ2=27.55, p=0.120; goodness-of-fit index=0.97; adjusted goodness-of-fit index=0.94; comparative fit index=0.98; root mean square error of approximation=0.04). Self-stigma had a direct effect on patient activation (β=−0.20; p=0.002). Indirectly, self-stigma affected patient activation along two paths (β=0.31; pConclusionsDue to the cross-sectional design of the study, longitudinal changes between all the variables cannot be established. However, the findings indicate that self-stigma affected patient activation for self-care, both directly and as mediated by self-esteem and self-efficacy. Interventions that increase self-esteem and self-efficacy may decrease self-stigma in patients with T2DM, thus increasing patient activation for self-care.

Chronic kidney disease (CKD) patients accumulate uremic toxins in the body, potentially require dialysis, and can eventually develop cardiovascular disease. CKD incidence has increased worldwide, and preventing CKD progression is one of the most important goals in clinical treatment. In this study, we conducted a series of in vitro and in vivo experiments and employed a metabolomics approach to investigate CKD. Our results demonstrated that ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a major transporter of the uremic toxin indoxyl sulfate. ABCG2 regulates the pathophysiological excretion of indoxyl sulfate and strongly affects CKD survival rates. Our study is the first to report ABCG2 as a physiological exporter of indoxyl sulfate and identify ABCG2 as a crucial factor influencing CKD progression, consistent with the observed association between ABCG2 function and age of dialysis onset in humans. The above findings provided valuable knowledge on the complex regulatory mechanisms that regulate the transport of uremic toxins in our body and serve as a basis for preventive and individualized treatment of CKD.

ObjectivesTo determine whether febuxostat with stepwise dose increase is as useful as colchicine prophylaxis in reducing gout flares during the initial introduction of urate-lowering therapy in patients with gout in comparison with febuxostat with no dose titration.MethodsIn this prospective, multicentre, randomised open-label comparative study, patients were randomised to group A (stepwise dose increase of febuxostat from 10 to 40 mg/day), group B (fixed-dose febuxostat 40 mg/day plus colchicine 0.5 mg/day) or group C (fixed-dose febuxostat 40 mg/day) and observed for 12 weeks. Gout flare was defined as non-steroidal anti-inflammatory drug use for gout symptoms.ResultsA total of 255 patients were randomised, and 241 patients were treated. Among the treated patients, gout flares were experienced by 20/96 (20.8%) in group A, 18/95 (18.9%) in group B and 18/50 (36.0%) in group C. The incidence of flare was significantly lower in groups A and B than that in group C (P=0.047 and P=0.024, respectively), although the differences were not significant after correction for multiple comparisons. No significant difference was noted between the incidence of gout flare in groups A and B.ConclusionsOur data suggested that stepwise dose increase of febuxostat and low-dose colchicine prophylaxis effectively reduced gout flares in comparison with fixed-dose febuxostat alone. Stepwise dose increase of febuxostat may be an effective alternative to low-dose colchicine prophylaxis during the introduction of urate-lowering therapy.Trial registration numberUMIN 000008414.

Objective To explore how patients with type 2 diabetes (T2DM) psychologically and behaviorally respond to internalized stigma through social stigma. Methods A qualitative study with semi-structured interviews was recorded on audiotapes, transcribed verbatim, and analyzed using a grounded theory approach. Participants were adults aged 30–64 years and diagnosed with T2DM. A total of 26 patients participated. Results The qualitative data revealed that participants' responses to social stigma, although varied, could be organized into a four-step process: Encountering Negative Experiences , Reevaluating the Self with Type 2 Diabetes , Reconstructing a Sense of Identity , and Maintaining Balance between Patient and Social Roles. When participants form a negative image of and relationship to their illness, they tend to internalize stigma, which can affect their sense of self-worth, attitude toward social participation, and compliance. Conclusion Participants who internalize stigma tend to have a lower sense of self-worth and their social participation falls somewhere between severely limited ( Social Avoidance ) and highly active ( Role Conflict ). This can hinder devotion to their treatment regimen and affect their degree of compliance with physicians. Practice implications Internalized stigma can be assessed by observing a patient's illness-related negative self-image.

ObjectivePersons with type 2 diabetes are often stigmatised for having what is considered a lifestyle-related disease. Accordingly, some blame themselves for their condition, resulting in feelings of low self-worth that ultimately impact their self-management behaviours. However, there are no studies examining why some do not blame themselves for their condition and manage to maintain their self-worth in relation to their illness. This study aimed to explore an understanding of how such persons experience the maintenance of self-worth in relation to their illness over the lifelong course of treatment.DesignA cross-sectional qualitative study. Face-to-face semistructured interviews were conducted with a purposive sampling strategy. The data was analysed using a qualitative descriptive method that involved concurrent data collection and constant comparative analysis.SettingTwo tertiary-level hospitals in Japan.ParticipantsThirty-three outpatients with type 2 diabetes who currently had good glycaemic control but had previously had poor glycaemic control.ResultsThree themes explaining the maintenance of self-worth were identified: (1) Participants gained ‘control’ over their illness by living a ‘normal life.’ They found a way to eat preferred foods, dine out with family and friends, travel and work as usual; (2) Participants discovered the positive aspects of type 2 diabetes, as they felt ‘healthier’ from the treatment and felt a sense of security and gratitude for the care they received from healthcare professionals; (3) Participants discovered a new sense of self-worth by moving towards goals for type 2 diabetes treatment and experienced inner growth through positive lifestyle choices.ConclusionsThe process of restoring and maintaining self-worth should be brought to the attention of healthcare professionals in diabetes care. These professionals could help patients discover positive self-representations through diabetes treatment (eg, a realisation that one does not lack self-control) and could aid in increasing patient engagement in diabetes self-management.

Mutation of hypoxanthine guanine phosphoribosyltransferase (HPRT) gives rise to Lesch–Nyhan syndrome, which is characterized by hyperuricemia, severe motor disability, and self-injurious behavior, or HPRT-related gout with hyperuricemia. Four mutations were detected in two Lesch–Nyhan families and two families with partial deficiency since our last report. A new mutation of G to TT (c.456delGinsTT) resulting in a frameshift (p.Q152Hfs*3) in exon 3 has been identified in one Lesch–Nyhan family. In the other Lesch–Nyhan family, a new point mutation in intron 7 (c.532 + 5G > T) causing splicing error (exon 7 excluded, p.L163Cfs*4) was detected. In the two partial deficiency cases with hyperuricemia, two missense mutations of p.D20V (c.59A > T) and p.H60R (c.179A >G) were found. An increase of erythrocyte PRPP concentration was observed in the respective phenotypes and seems to be correlated with disease severity.

To examine the role of matrix proteins in the formation of gouty tophus, we analyzed the crystalline components and matrix proteins in a gouty tophus from a patient with recurrent gout. Micro-area X-ray diffraction analysis and infrared spectroscopy indicated that the tophus was composed of monosodium urate monohydrate. Proteomic analysis identified 134 proteins from the tophus as matrix proteins. Many proteins relevant to inflammation and host defense were identified, and immunoglobulin was detected in all four extracted fractions (KCl, formic acid, guanidine-HCl, and ethylenediaminetetraacetic acid) and from many spots throughout a broad molecular weight range after electrophoresis. It is thought that the process of biological defense including the immunity has occurred in the gouty tophus.

Summary Aims Dipeptidyl-peptidase 4 inhibitors have become one of the most popular antidiabetic drugs. However, what kind of combinations with other drugs were advantageous was not known. Here, we tried to elucidate it in a real-life clinical setting. Methods We retrospectively studied efficacies of sitagliptin in 87 Japanese patients with type 2 diabetes mellitus for 52 weeks. We divided subjects into excellent, effective and unresponsive subgroups according to glycemic responses to sitagliptin. Results In the excellent and effective groups the minimum HbA1c values were attained at 16 weeks while HbA1c levels in the unresponsive group kept increasing during the study period. There was a significant difference in the baseline HbA1c values between the excellent and unresponsive groups ( p = 0.02). Interestingly, the mean doses of pioglitazone were highest in the excellent group and lowest in the unresponsive group ( p = 0.02). When we compared the effective and unresponsive groups, the mean doses of sulfonylureas were constantly higher in the effective group than in the unresponsive group ( p = 0.05). Conclusions These data suggest that the baseline HbA1c value can be a factor that predicts the extent of HbA1c reduction and reveal a possibility that the concomitant use of pioglitazone augments glycemic responsiveness to sitagliptin.

To clarify the physiological and pathophysiological roles of intestinal urate excretion via ABCG2 in humans, we genotyped ABCG2 dysfunctional common variants, Q126X (rs72552713) and Q141K (rs2231142), in end-stage renal disease (hemodialysis) and acute gastroenteritis patients, respectively. ABCG2 dysfunction markedly increased serum uric acid (SUA) levels in 106 hemodialysis patients (P = 1.1 × 10−4), which demonstrated the physiological role of ABCG2 for intestinal urate excretion because their urate excretion almost depends on intestinal excretion via ABCG2. Also, ABCG2 dysfunction significantly elevated SUA in 67 acute gastroenteritis patients (P = 6.3 × 10−3) regardless of the degree of dehydration, which demonstrated the pathophysiological role of ABCG2 in acute gastroenteritis. These findings for the first time show ABCG2-mediated intestinal urate excretion in humans, and indicates the physiological and pathophysiological importance of intestinal epithelium as an excretion pathway besides an absorption pathway. Furthermore, increased SUA could be a useful marker not only for dehydration but also epithelial impairment of intestine.

In order to determine the mechanism of urinary stone formation in patients with hyperuricemia, we analyzed the crystal components and matrix proteins in a urinary stone from such a patient. Micro-area X-ray spectrometry and infrared (IR) spectroscopy suggested that the outside of the stone was composed of calcium oxalate monohydrate (COM) and the inside of uric acid (UA). Proteomic analysis identified 37 and 14 proteins from the inside and outside of the stone, respectively, as matrix proteins. The proteins that were identified in an ethylenediaminetetraacetic acid (EDTA) fraction were able to bind calcium ions. Thus, calcium-binding proteins may play a significant role in the formation of urinary stones in patients with hyperuricemia.

We have retrospectively evaluated the uric acid control status and renal function changes over a period of up to 7 years in 35 patients with renal impairment who had stage 3 or higher chronic kidney disease (CKD; stage 3 in 32 patients, stage 4 in 2 patients, and stage 5 in 1 patient) associated with hyperuricemia and were receiving monotherapy with benzbromarone as an antihyperuricemic drug. Serum uric acid levels significantly decreased from 8.5 ± 0.9 to 6.1 ± 0.8 mg/dL at 6 months and were subsequently controlled at less than 7.0 mg/dL in most patients. Most patients received benzbromarone at a dose of 25-50 mg/day, whereas 150-200 mg/day was used in some patients with stage 4 or 5 CKD. No significant changes in estimated glomerular filtration rate (eGFR) from the baseline value of 46.2 ± 11.5 mL/minute/1.73 m(2) were found after benzbromarone therapy. Although the renal function impairment did not improve by reducing the serum uric acid levels with benzbromarone, the renal function did not deteriorate further on the therapy. These results suggest that benzbromarone is applicable to the management of hyperuricemia associated with renal impairment.

Aryl hydrocarbon receptor (AhR) is a transcription factor activated by xenobiotics, including dioxins and polycyclic aromatic hydrocarbons (PAHs). Although AhR is also activated by some dietary constituents, it has not been completely clarified in what circumstances AhR ligands are ingested in our daily life. Because PAHs are formed by the incomplete combustion of organic materials, we hypothesized that scorched foods might contain and leach out AhR ligands sufficient to stimulate AhR in vitro. To test this hypothesis, scorched foods (bread, cheese, etc.) were mixed vigorously with water, and the supernatants were retrieved as samples. The samples were added to HepG2 cells stably expressing an AhR-responsive reporter gene. Also, expression of CYP1A1, an endogenous AhR-responsive gene, was analyzed by RT-PCR in different cell lines treated with the samples. We further tested whether pretreatment of the samples with activated charcoal would alter their AhR-stimulating activity. All the supernatant samples tested induced AhR-dependent reporter gene activity and CYP1A1 mRNA expression. In some samples, these inductions were inhibited by pretreatment with activated charcoal. Our findings indicate that scorched food leachates stimulate AhR in cultured cells and that activated charcoal adsorbs the AhR-stimulating substances in some leachates. Thus, people who habitually eat scorched foods are exposed to AhR ligands on a regular basis. Further studies are needed to elucidate whether burnt foods actually exert biological effects on our health.

Background The role of uric acid (UA) in the progression of chronic kidney disease (CKD) remains controversial due to the unavoidable cause and result relationship. This study was aimed to clarify the independent impact of UA on the subsequent risk of end-stage renal disease (ESRD) by a propensity score analysis. Methods A retrospective CKD cohort was used (n = 803). Baseline 23 covariates were subjected to a multivariate binary logistic regression with the targeted time-averaged UA of 6.0, 6.5 or 7.0 mg/dL. The participants trimmed 2.5 percentile from the extreme ends of the cohort underwent propensity score analyses consisting of matching, stratification on quintile and covariate adjustment. Covariate balances after 1:1 matching without replacement were tested for by paired analysis and standardized differences. A stratified Cox regression and a Cox regression adjusted for logit of propensity scores were examined. Results After propensity score matching, the higher UA showed elevated hazard ratios (HRs) by Kaplan-Meier analysis (≥6.0 mg/dL, HR 4.53, 95%CI 1.79–11.43; ≥6.5 mg/dL, HR 3.39, 95%CI 1.55–7.42; ≥7.0 mg/dL, HR 2.19, 95%CI 1.28–3.75). The number needed to treat was 8 to 9 over 5 years. A stratified Cox regression likewise showed significant crude HRs (≥6.0 mg/dL, HR 3.63, 95%CI 1.25–10.58; ≥6.5 mg/dL, HR 3.46, 95%CI 1.56–7.68; ≥7.0 mg/dL, HR 2.05, 95%CI 1.21–3.48). Adjusted HR lost its significance at 6.0 mg/dL. The adjustment for the logit of the propensity scores showed the similar results but with worse model fittings than the stratification method. Upon further adjustment for other covariates the significance was attained at 6.5 mg/dL. Conclusions Three different methods of the propensity score analysis showed consistent results that the higher UA accelerates the progression to the subsequent ESRD. A stratified Cox regression outperforms other methods in generalizability and adjusting for residual bias. Serum UA should be targeted less than 6.5 mg/dL.

We assessed the efficacy and adverse effects of febuxostat in male hyperuricemia patients.This was a 12-week, multicenter, open-label, uncontrolled study. The enrolled subjects were 89 hyperuricemic male patients (12 overexcretors, 56 normal excretors, and 21 underexcretors). The endpoint was percent change in serum urate level.The concentration of urate in serum before and 12 weeks after beginning administration of febuxostat in the overexcretors was 9.34 ± 1.48 and 5.59 ± 1.17 mg/dl, respectively, while those were 8.59 ± 1.24 and 5.41 ± 1.35 mg/dl, respectively, in the normal excretors, and 8.29 ± 1.01and 5.11 ± 1.71 mg/dl, respectively, in the underexcretors. After 12 weeks, the rate of change in serum urate after beginning administration of febuxostat was - 0.384 ± 0.186 in the overexcretors, - 0.368 ± 0.128 in the normal excretors, and - 0.365 ± 0.217 in the underexcretors, with no significant differences among them. A common adverse event related to febuxostat was gout flare.Febuxostat effectively reduced the concentration of urate in serum in hyperuricemic patients regardless of the level of uric acid excreted in urine without severe adverse effects.

Urolithiasis is a common complication in patients with hypouricemia. Using a microarea x-ray diffractometer and nanoflow liquid chromatography-mass spectrometry (LC-MS) following SDS-polyacrylamide gel electrophoresis (PAGE), recurrent urinary calculi complicating a hypouricemic patient were analyzed. Analysis with the microarea x-ray diffractometer showed that one of the calculi was composed of calcium oxalate monohydrate and hydroxyapatite. The other was found to be formed from calcium oxalate dihydrate. After determination with LC-MS, both were found to contain uromodulin, albumin, osteopontin, protein Z, and defensins. Lysozyme and calgranulin A were also identified in these calculi. Defensins, which were antimicrobial peptides, and lysozyme, a mucopeptide glycohydrolase, were identified as new organic components of urinary stones. The role of these proteins in the process of urolithiasis is of particular interest.

Protein Z, a vitamin K-dependent plasma protein, has been detected for the first time in a renal calculus along with osteopontin and prothrombin. The renal calculus was obtained from a hyperuricemic patient. Following two-dimensional polyacrylamide gel electrophoresis, the calculus was analyzed with the use of liquid chromatography mass spectrometry (LC-MS). The spectrometer was equipped with a nanoelectrospray interface and an ion trap. Four peptides were determined from a protein in the calculus through LC-MS/MS analysis. Tandem mass spectrum database matching tools were used to identify the protein as protein Z. Authentic protein Z was also analyzed using the same method, and all four peptides determined in the calculus were similarly identified. Whereas protein Z has been reported to be one of the vitamin K-dependent calcium-binding proteins, its role has not been well established. The fact that protein Z exists in a renal calculus composed of calcium oxalate will be beneficial in any future investigations into its role in the body.

Objectives The aim of this study was to test the psychological and behavioural patterns of stigma (self-esteem and social participation) and their relationship to self-stigma, patient activation for engaging in self-care and glycaemic control among patients with type 2 diabetes mellitus (T2DM). Design A cross-sectional study. Setting 2 tertiary-level hospitals and 2 secondary-level hospitals in Japan. Participants A consecutive sample of 209 outpatients with T2DM. Inclusion criteria were as follows: presence of T2DM, age 20–74 years, no diagnosis of dementia and/or psychosis, and no need for urgent medical procedures. Outcome measures Study measures included a self-administered questionnaire to assess the Rosenberg Self-Esteem Scale (SES), the 3 subscales of 36-question Short Form Health Survey (SF-36; Social Function, Role Physical, Role Emotional), Self-Stigma Scale and Patient Activation Measure (PAM-13). Glycated haemoglobin was obtained from same day blood work. In our previous qualitative study, we found that psychological and behavioural patterns of stigma varied according to patients' levels of illness-related self-esteem as well as attitudes towards social participation. For quantitative consistency, we used the SES scale to measure self-esteem and the SF-36 subscales to measure social participation. We then divided participants into 4 groups by exhibited psychological and behavioural patterns: group A (high SES/high SF-36), group B (high SES/low SF-36), group C (low SES/high SF-36) and group D (low SES/low SF-36). Results Using analysis of covariance after controlling for age and sex, there was a significant difference in self-stigma levels between the four groups (F[3203]=15.70, p

In order to elucidate the mechanism of hyperuricemia in hematologic malignancies, we have retrospectively investigated the uric acid metabolism in 418 chemotherapy-naive patients with hematologic malignancies. Hyperuricemia was present in 116 (27.8%) of these patients on initial hospitalization. Among 65 hyperuricemic patients analyzed uric acid metabolism, six (9.2%) had overproduction type, 52 (80.0%) had underexcretion type, and seven (10.8%) had a mixed type. Fourteen patients (3.3%) developed tumor lysis syndrome in 418 patients.

The liquid chromatography-mass spectrometry (LC-MS) following on from the two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) technique was applied for the analysis of proteins in a renal stone found in a hyperuricemic patient. This technique was sensitive enough to detect small quantities of proteins even in a renal stone.

Genetic mutations in the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HPRT), are known to cause Lesch-Nyhan syndrome and Kelley-Seegmiller syndrome. In patients, purine metabolism is different from that of normal persons. We have previously developed a method for simultaneously determining the concentration of purine and pyrimidine nucleosides and nucleotides. This system was applied to determine the concentrations of nucleosides and nucleotides in HPRT-deficient cell lines. The amount of inosine 5'-monophosphate (IMP) was different in Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, and control cell lines. The difference in the amount of IMP confirmed the mutation of the enzyme.

Mutation of hypoxanthine guanine phosphoribosyltransferase (HPRT) gives rise to Lesch-Nyhan syndrome, which is characterized by hyperuricemia, severe motor disability, and self-injurious behavior, or HPRT-related gout (Kelley-Seegmiller syndrome). The marked heterogeneity of HPRT deficiency is well known, with more than 300 mutations at the HPRT gene locus having been reported (deletions, insertions, duplications, abnormal splicing, and point mutations at different sites of the coding region from exons 1 to 9). We have identified mutations in Asian families with patients manifesting different clinical phenotypes, including rare cases of female subjects, by analyzing all nine exons of the HPRT gene (HPRT1) from genomic DNA and reverse-transcribed mRNA using the polymerase chain reaction technique coupled with direct sequencing. We developed suitable methods to detect the mutations identified from respective families with HPRT deficiency. Then, prenatal genetic diagnoses in HPRT-deficient families were carried out using both mRNA and genomic DNA from chorionic villi or amniotic fluid cells. As shown here in the heterogeneity of HPRT mutations, the spectrum of 70 mutations identified in the Asian population fits the four main conclusions that emerged previously from worldwide analysis.

Mutations of two enzyme genes, HPRT1 encoding hypoxanthine guanine phosphoribosyltransferase (HPRT) and PRPS1 encoding a catalytic subunit (PRS-I) of phosphoribosylpyrophosphate synthetase, cause X-linked inborn errors of purine metabolism. Analyzing these two genes, we have identified three HPRT1 mutations in Lesch–Nyhan families following our last report. One of them, a new mutation involving the deletion of 4224 bp from intron 4 to intron 5 and the insertion of an unknown 28 bp, has been identified. This mutation resulted in an enzyme polypeptide with six amino acids deleted due to abnormal mRNA skipping exon 5. The other HPRT1 mutations, a single base deletion (548delT, 183fs189X), and a point mutation causing a splicing error (532+1G>A, 163fs165X) were detected first in Japanese patients but have been reported in European families. On the other hand, in the analysis of PRPS1, no mutation was identified in any patient.

Allopurinol has been widely used for treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat is potentially a safe and efficacious alternative.Febuxostat or allopurinol was administered to patients with hyperuricemia including gout for 8 weeks to compare the efficacy and safety of these drugs.Doses of febuxostat and allopurinol were 10 and 100 mg/d, respectively, during a 12-day introduction period and were increased to 40 and 200 mg/d for the subsequent treatment period of 44 days.: The percent changes in serum uric acid levels after 8 weeks were -40.75% for the febuxostat group and -34.41% for the allopurinol group (P0.001, analysis of variance, closing testing procedure). The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less after 8 weeks was 82.0% for the febuxostat group and 70.0% for the allopurinol group (P = 0.019, logistic regression analysis). Regarding safety, 213 adverse events were observed in the febuxostat group and 220 events in the allopurinol group. For 10 patients (8.2%) in the febuxostat group and 14 patients (11.6%) in the allopurinol group, association with the study drugs could not be ruled out. There were no severe adverse drug reactions in the febuxostat group other than a high frequency of gout attacks induced by the sudden reduction in blood uric acid levels during the early treatment period.Febuxostat at 40 mg/d demonstrated more potent hypouricemic effects than allopurinol at 200 mg/d, was efficacious regardless of medical history of gout, and is considered safe for treatment of hyperuricemia.

Background Allopurinol has been widely used for the treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative. Objectives Febuxostat was administered to patients with hyperuricemia including gout in Japan to compare its efficacy and safety with those of allopurinol. Methods The starting dose of febuxostat and allopurinol was 10 and 100 mg/d, respectively, and was increased to the fixed maintenance dose of 40 or 60 mg/d for febuxostat and 300 mg/d for allopurinol for 16 weeks. Results : The percent change in the serum uric acid level at 16 weeks compared with the baseline serum uric acid level was -42.96% ± 13.33% and -52.47% ± 9.79% for the febuxostat 40- and 60-mg/d groups, respectively, and -36.55% ± 18.59% for the allopurinol group, indicating that the hypouricemic effects of febuxostat increased in a dose-dependent manner and equaled to or surpassed those of allopurinol (P = 0.0239, 2-sample t test). The percentage of patients with serum uric acid levels of 6.0 mg/dL or less at 16 weeks was 88.9% and 100% for the febuxostat 40- and 60-mg/d groups, respectively, and 68.8% for the allopurinol group, showing higher achievements for the febuxostat groups compared with the allopurinol group. All adverse drug reactions were mild to moderate in severity, and there were no severe symptoms or reactions leading to drug discontinuation. Conclusions These results suggest that febuxostat is safe at doses of 40 and 60 mg/d and has equal or greater efficacy than 300 mg/d allopurinol.

In previous clinical studies of hyperuricemia including gout, although serum uric acid (sUA) levels reduced to 6.0 mg/dL or less in about 80% of patients treated with 40 mg/d febuxostat, a nonpurine selective xanthine oxidase inhibitor, a few patients did not show this result.The objective of the study was to evaluate the efficacy and safety of long-term febuxostat administration at up to 60 mg/d in patients with hyperuricemia and gout.In a 52-week, multicenter, open-label trial, febuxostat was initially administered at 10 mg/d; then, the dosage was increased in a stepwise fashion to 40 mg/d. For sUA levels greater than 6.0 mg/dL at week 10, the dosage was increased to 60 mg/d from week 14 onward (60-mg group), but it was maintained at 40 mg/d until the end of the study for patients with sUA levels 6.0 mg/dL or less at week 10 (40-mg group).The sUA levels in both groups decreased dose dependently. At 52 weeks, 84.5% and 85.0% of the 40- and 60-mg groups, respectively, achieved mean sUA levels 6.0 mg/dL or less. There was no marked difference between the 2 dosage groups in terms of the incidence of adverse events. Furthermore, there were no noteworthy adverse events or adverse drug reactions in the patients with renal dysfunction, and no differences in drug efficacy up to 60 mg/d were noted between the patients with moderate or mild renal dysfunction and those with normal renal function.Febuxostat seems to be a promising therapeutic drug for gout or hyperuricemia, even in patients with renal dysfunction.

Allopurinol has been widely used for the treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative.A multicenter study with randomized, placebo-controlled, double-blind, parallel, intergroup comparison was carried out to evaluate the dose-response relationship, efficacy, and safety of febuxostat in 202 patients with hyperuricemia (including patients with gout) in Japan.The subjects were treated with febuxostat at fixed maintenance doses (20-80 mg/d) or a placebo for 16 weeks. The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less and the percent change in serum uric acid levels after 16 weeks of treatment were evaluated.The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less at 16 weeks was 87.8% in the 80-mg/d dose group, 83.3% in the 60-mg/d group, 82.9% in the 40-mg/d group, 46.5% in the 20-mg/d group, and 2.6% in the placebo group (P0.001, Mantel-Haenszel test). A statistically significant dose-response relationship was found. The percent change in serum uric acid levels after 16 weeks of treatment differed significantly between each febuxostat dose group and the placebo group and increased in a dose-dependent manner above 40 mg/d. No deaths, events posing a clinical problem, or serious adverse reactions attributable to febuxostat were noted. Similar results were obtained regardless of gout history.Febuxostat can safely reduce serum uric acid levels to 6.0 mg/dL or less in 80% or more of patients with hyperuricemia (including gout) at doses of 40 mg/d or higher.

Background : Allopurinol has been widely used for treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative. Objectives : A multicenter study with randomized, placebo-controlled, double-blind, parallel-group comparison was carried out to evaluate the efficacy and safety of febuxostat in 103 patients with hyperuricemia (including patients with gout) in Japan. Methods : Subjects were treated with febuxostat (20 or 40 mg/d) or a placebo for 8 weeks. The variables evaluated were the percentage of patients achieving serum uric acid levels 6.0 mg/dL or less and the percent change in serum uric acid levels after 8 weeks. Results : The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less after 8 weeks was 91.2% in the febuxostat 40-mg/d group, 45.7% in the 20-mg/d group, and 0.0% in the placebo group. The percent changes in serum uric acid levels after 8 weeks were -44.9% in the febuxostat 40-mg/d group, -28.9% in the 20-mg/d group, and -0.6% to -0.5% in the placebo group. No severe or medically significant adverse reaction attributable to febuxostat was noted, and there was no event that could pose a clinical problem. The efficacy did not differ depending on the presence/absence of gout history. Conclusions : These results suggest that febuxostat (20 or 40 mg/d) is useful as a new means of treating hyperuricemia and is capable of reducing serum uric acid levels to 6.0 mg/dL or less (goal of treatment) with high safety regardless of the presence/absence of gout history.

We have retrospectively investigated the effects of three strong statins, atorvastatin, pitavastatin, and rosuvastatin, on serum uric acid (SUA) levels. SUA levels after a few months of statin treatment were compared with those before treatment in 150 outpatients with dyslipidemia. In the atorvastatin (n = 62) and rosuvastatin (n = 45) groups, the SUA levels were reduced by 6.5% (p < 0.0001) and 3.6% (p = 0.03) respectively, but in the pitavastatin group (n = 43), the SUA level increased by 3.7% (p = 0.38). Because uric acid is considered a risk factor for cardiovascular disorders, atorvastatin or rosuvastatin treatment may be recommended when statins are used in patients at high risk for cardiovascular disorders complicated with hyperuricemia.

Health literacy (HL), the capacity of individuals to access, understand and use health information to make informed and appropriate health-related decisions, is recognized as an important concept in patient education and disease management.To examine the relation of three levels of HL (i.e. functional, communicative and critical HL) to patient-physician information exchange during a visit.Participants were 134 outpatients with type 2 diabetes who were under continuous care by four attending physicians at a university-affiliated hospital. The visit communication was recorded and analysed using the Roter Interaction Analysis System. Patient HL was measured through a self-reported questionnaire using newly developed self-rated scales of functional, communicative and critical HL. Sociodemographic and clinical characteristics and patient's perception of the information exchange were assessed for each patient through self-reported questionnaires and review of electronic medical records.Patient HL levels were related to the information exchange process during the visit. Among the three HL scales, communicative HL (the capacity to extract information, derive meaning from different forms of communication and apply new information to changing circumstances) was related to patient's perceptions of the information exchange. Further, patient communicative HL had a modifying effect on the relationship between physician's information giving and patient's perception of it, suggesting that physician's communication may be perceived differently depending on the patient's HL.The exploration of patient HL may provide a better understanding of potential barriers to patient-physician communication and patient's self-management of disease.

The availability of highly active anti-retroviral therapy (HAART) has greatly improved the outcome of human immunodeficiency virus type-1 (HIV-1) infection and disease. We report here on a case of an HIV-1-seropositive patient with acute myelogenous leukemia who underwent a successful allogeneic unrelated bone marrow transplantation following HAART. A 40-year-old Japanese HIV-seropositive man underwent allogeneic unrelated bone marrow transplantation using a myeloablative pretransplant-conditioning regimen. Neutrophil engraftment occurred on day +18, and donor chimerism was achieved on day +27. During pre- and post- transplantation, the HAART was not interrupted. Over 1 year after transplantation, the patient is alive and in continuous complete remission with undetectable levels of HIV-1 RNA. HAART can lead to a successful hematopoietic stem cell transplantation without severe opportunistic infections.

The purine contents of alcoholic beverages were determined in order to utilize them in the dietary care of gout and hyperuricemia. In the management of these diseases, restriction of both alcohol and purine intake are important. The method employed in this study is a quantitative determination of purine contents by HPLC. Alcoholic beverages were hydrolyzed to corresponding purine bases, which were then separated by HPLC, and base peaks were identified using an enzymatic peak-shift technique. This method is sufficiently accurate and reproducible to examine the purine contents of various alcoholic beverages that patients consume. Purine contents were as follows: spirits, 0.7-26.4 micromol/L; regular beer, 225.0-580.2 micromol/L; low-malt beer, 193.4-267.9 micromol/L; low-malt and low-purine beer, 13.3 micromol/L; other liquors, 13.1-818.3 micromol/L. Some local and low-alcohol beers were found to contain about 2.5 times more purines than regular beer. As some alcoholic beverages contain considerable amounts of purines, we recommend that excess consumption of these beverages be avoided. These data should be useful in the management of hyperuricemia and gout, not only for patients but also for physicians.

5'-Methylthioadenosine (MTA) produced during the synthesis of polyamines is degraded to adenine by MTA phosphorylase. This pathway is considered to be the main source of endogenous adenine. We determined the concentrations of MTA and adenine in control subjects and in those with a pathological disorder. In patients with active leukemias, as well as with other types of malignancies, the concentrations of MTA and adenine in the urine were elevated. These changes seemed to be the result of an accelerated production of MTA due to an accelerated biosynthesis of polyamine. In patients with adenine phosphoribosyltransferase (APRT) deficiency, the concentrations of adenine in the urine were elevated, presumably due to a disturbance in the catabolism of adenine. Although adenine is a potent inhibitor of MTA phosphorylase, APRT-deficient patients did not excrete MTA into urine in concentrations significantly larger than noted for control subjects. However, the amount of MTA excreted positively correlated with that of adenine in these patients, hence that accumulated adenine probably had a slight, but positive, inhibitory effect on the degradation of MTA.

Inherited mutation of hypoxanthine guanine phosphoribosyltransferase, (HPRT) gives rise to Lesch-Nyhan syndrome or HPRT-related gout. We have identified a number of HPRT mutations in patients manifesting different clinical phenotypes, by analyzing all nine exons of the HPRT gene (HPRT1) from genomic DNA and reverse transcribed mRNA using the PCR technique coupled with direct sequencing. Recently, we detected two novel mutations: a single nucleotide substitution (430C > T) resulting in a nonsense mutation Q144X, and a deletion of HPRT1 exon 1 expressing no mRNA of HPRT. Furthermore, we summarized the spectrum of 56 Japanese HPRT mutations.

Gout is a crystal deposition disease. European and Japanese guidelines of management for gout recommend that serum urate concentration should be maintained below 6.0 mg/dL to promote crystal dissolution leading to prevention of recurrent gouty attack. Although allopurinol is recommended to be an adequate drug for urate lowering therapy in all gouty patients by European guideline, it is desirable that allopurinol is indicated in patients with overproduction type and benzbromarone in patients with underexcretion type, recommended by Japanese guideline. Asymptomatic hyperuricemia dose not equate to gout. As there is no evidence to support treatment of isolated hyperuricemia with urate lowering therapy currently, it is difficult to establish lowering goal of serum urate level in patients with asymptomatic hyperuricemia. Advice regarding lifestyle and treatment of associated comorbidity should be preferred to urate lowering therapy. However, urate lowering therapy may be indicated in high risk patients with hyperuricemia who are suffered from hypertension, diabetes mellitus, ischemic heart disease and renal insufficiency.

OBJECTIVES Non-verbal communication (NVC) in medical encounters is an important method of exchanging information on emotional status and contextualising the meaning of verbal communication. This study aimed to assess the impact of medical students' NVC on interview evaluations by standardised patients (SPs). METHODS A total of 89 medical interviews in an objective structured clinical examination (OSCE) for post-clerkship medical students were analysed. All interviews were videotaped and evaluated on 10 non-verbal behaviour items. In addition, the quality of the interview content was rated by medical faculty on 5 items and the interview was rated by SPs on 5 items. The relationships between student NVC and SP evaluation were examined by multivariate regression analyses controlling for the quality of the interview content. RESULTS Standardised patients were likely to give higher ratings when students faced them directly, used facilitative nodding when listening to their talk, looked at them equally when talking and listening, and spoke at a similar speed and voice volume to them. These effects of NVC remained significant after controlling for the quality of the interview content. CONCLUSIONS This study provided evidence of specific non-verbal behaviours of doctors that may have additional impacts on the patient's perception of his or her visit, independently of the interview content. Education in basic NVC should be incorporated into medical education alongside verbal communication.

A 40-year-old normouricemic (5.5 mg/dl) male showed 46% hemolysate and 37% lymphoblast hypoxanthine phosphoribosyltransferase (HPRT) activities but was otherwise completely free of symptoms. His genomic DNA and cDNA had a missense base substitution (CAT-to-CGT in codon 60) leading to the amino-acid substitution His-to-Arg. Western blot analysis revealed that the amount of HPRT protein in lymphoblasts from this individual was 25%-50% of normal cells, suggesting that the decrease in the amount of enzyme protein was responsible for the partial deficiency. This provides the first clear evidence that a genomic missense mutation at the HPRT locus leads to a decrease in the amount of the enzyme protein but that otherwise it has no evident adverse effects in the hemizygote (asymptomatic mutation).

In this study, we have identified a novel mechanism of mutation involving translocation between the HPRT1 loci and other loci on the X chromosome. In HRT‐25's cDNA obtained from a patient with Lesch‐Nyhan syndrome, the upstream region of exon 3 was amplified, but the full‐length region was not amplified. The use of 3′ rapid amplification of cDNA ends polymerase chain reaction (3′RACE‐PCR) for HRT‐25 revealed part of intron 3 and an unknown sequence which have not identified the HPRT1 gene starting at the 3′ end of exon 3. We analyzed HPRT1 genomic DNA in order to confirm the mutation with the unknown sequence in the genomic DNA. Unknown sequence compared through BLAST analysis of human genome (NCBI; http://www.ncbi.nlm.nih.gov/BLAST/) showed that at least 0.5 to 0.6‐Mb telomeric to HPRT1 on chromosome Xq where located near LOC340581. This study provides the molecular basis for the involvement of genomic instability in germ cells.

Metabolic syndrome, synonymous with multiple risk factor syndrome, which has been suggested to be based on insulin resistance and/or visceral fat accumulation, contributes to be the development of atherosclelotic cardiovascular disease. Hyperuricemia is associated with multiple risk factor syndrome. Hyperinsulinemia induced by insulin resistance reduces uric acid clearance, leading to hyperuricemia. On the other hand, visceral fat accumulation increases uric acid synthesis through the activation of triglyceride synthesis. Although a lot of epidemiological and experimental studies concerned with an effect of uric acid on the vascular injury have been performed, any distinct evidence that uric acid per se damage blood vessels, has not been reported. It is most important for managing hyperuricemia in the patients with the so-called lifestyle related disorders to improve the unhealthy lifestyle leading to the obesity which causes insulin resistance and visceral fat accumulation.

We identified the identical large genomic deletion in the hypoxanthine phosphoribosyltransferase (HPRT1) gene in two Japanese patients with Lesch-Nyhan (LN) syndrome. This deletion spanned from an Alu sequence in the promoter region to another Alu-sequence in intron 1, a length of 2,969 base pairs including exon 1. In order to ask whether this deletion was a recurrent mutation, we developed a simple alternative method to determine the separate origin of the HPRT1 mutation of the patients as assessed with an apparent mtDNA polymorphism. Considering that an LN syndrome-causing mutation is not transmitted from patient to offspring as LN syndrome is a fatal disease in childhood and that mtDNA is maternally inherited, HPRT1 mutations and mtDNA would be co-transmitted from carrier mother to offspring since both appeared in females. Two bases were different in the hypervariable region I of the mtDNA between the two patients, indicating the separate origin of their mtDNA over at least several thousand years as calculated based on the molecular evolution rate in this region. We thus conclude that the identical deletion found in HPRT1 of the two patients was derived from recurrent events of genomic recombination. Given that the same Alu-mediated deletion of HPRT1 has not been reported among somatic mutations at the same locus, this region of the HPRT1 gene flanked by Alu-sequences is likely a mutational hot spot in the germline but not in somatic cells. In addition, we also report novel LN-syndrome-conferring mutations in intron 6 (IVS6+1G C) and intron 8 (IVS7-9T G) that resulted in exclusions of exon 6 and exon 8, respectively. Hum Mutat 18:435–443, 2001. © 2001 Wiley-Liss, Inc.

A 32-year-old man who had had frequent gouty arthritis over the past 17 years, was admitted for acute renal failure. Acute renal failure was improved rapidly after medication was resumed and the patient was sufficiently hydrated. The hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity in the patient had been reduced to about 30% of the normal control. Therefore we considered that this patient suffered from a partial deficiency of HPRT. A point mutation of HPRT gene 68G (guanine) to T (thymine) was detected. This is a mutation that has not been previously reported. Familial analysis indicated that his mother and sister were heterozygotes.

Lesch-Nyhan syndrome caused by a complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT) is the result of a heterogeneous group of germ line mutations. Identification of each mutant gene provides valuable information as to the type of mutation that occurs spontaneously. We report here a newly identified HPRT mutation in a Japanese patient with Lesch-Nyhan syndrome. This gene, designated HPRT Tokyo, had a single nucleotide change from G to A, as identified by sequencing cDNA amplified by the polymerase chain reaction. Allele specific oligonucleotide hybridization analysis using amplified genomic DNA showed that the mutant gene was transmitted from the maternal germ line. This mutation would lead to an amino acid substitution of Asp for Gly at the amino acid position 140 located within the putative 5-phosphoribosyl-1-pyrophosphate (PRPP) binding region. Missense mutations in human HPRT deficient patients thus far reported tend to accumulate in this functionally active region. However, a comparison of the data suggested that both missense and synonymous mutations can occur at any coding sequence of the human germ line HPRT gene, but that a limited percentage of all the missense mutations cause disease. The probability that a mutation will cause disease tends to be higher when the missense mutation is within a functionally important sequence.

A previously undescribed nucleotide substitution at codon 51 (CGA to TGA) has been identified using the polymerase chain reaction technique in hypoxanthine guanine phosphoribosyltransferase (HPRT) cDNA; this is the first molecular evidence for a point mutation in a Japanese patient with Lesch-Nyhan syndrome. The present mutation is the 19th nucleotide substitution identified as a germ-line mutation at this locus and the second mutation generating a stop codon. The position of the nucelotide substitution is exactly the same as a previously described mutation HPRTToronto, indicating for the first time that nucleotide substitutions at the same position in the sequence of HPRT can generate different mutant alleles, one causing a partial deficiency and the other a complete deficiency. Although the type of nucleotide substitution is different between the two cases, a single base position has twice become the target of a mutation. However, the calculation of the probability of finding substitution mutations at the same base position in the coding region of hprt indicates that there is no evidence for the presence of a hot spot for substitution mutations in the human hprt germ line.

The amount of polyamines in urine from patients with various neoplasms is larger than in normal subjects. We have determined the concentration of 5'-methylthioadenosine (MTA), a by-product of the polyamine biosynthesis, in patients with malignancies as well as normal subjects. Our studies indicate that the amount of MTA in urine from patients with leukemias and malignant lymphomas was higher than in normal subjects (p less than 0.005). Urine samples from patients with other malignancies contained normal amounts of MTA. The levels of blood MTA in patients with leukemias before treatment or in relapse was higher than in control subjects (p less than 0.005), while in patients with other malignancies and leukemia in remission, the levels were not different from control subjects. Peripheral blood MTA levels clearly decreased after effective chemotherapy. The measurement of MTA levels in urine and blood may not be as useful as polyamine assays for the detection of malignancies, but blood levels of MTA may be useful as an indicator of the efficacy of chemotherapy in leukemic patients.