Thrombopoietin induces production of nucleated thrombocytes from liver cells in Xenopus laevis.

The development of mammalian megakaryocytes (MKs) and platelets, which are thought to be absent in non-mammals, is primarily regulated by the thrombopoietin (TPO)/Mpl system. Although non-mammals possess nucleated thrombocytes instead of platelets, the features of nucleated thrombocyte progenitors remain to be clarified. Here, we provide the general features of TPO using Xenopus laevis TPO (xlTPO). Hepatic and splenic cells were cultured in liquid suspension with recombinant xlTPO. These cells differentiated into large, round, polyploid CD41-expressing cells and were classified as X. laevis MKs, comparable to mammalian MKs. The subsequent culture of MKs after removal of xlTPO produced mature, spindle-shaped thrombocytes that were activated by thrombin, thereby altering their morphology. XlTPO induced MKs in cultured hepatic cells for at least three weeks; however, this was not observed in splenic cells; this result demonstrates the origin of early haematopoietic progenitors in the liver rather than the spleen. Additionally, xlTPO enhanced viability of peripheral thrombocytes, indicating the xlTPO-Mpl pathway stimulates anti-apoptotic in peripheral thrombocytes. The development of thrombocytes from MKs via the TPO-Mpl system in X. laevis plays a crucial role in their development from MKs, comparable to mammalian thrombopoiesis. Thus, our results offer insight into the cellular evolution of platelets/MKs in vertebrates. (200/200).

Efficacy of mizoribine pulse therapy in patients with rheumatoid arthritis who show a reduced or insufficient response to infliximab.

The efficacy of infliximab, a chimeric antibody against tumor necrosis factor-alpha used to treat patients with rheumatoid arthritis (RA), tends to decrease as patients develop human antichimeric antibody against infliximab (HACA). The clinical study reported here was designed to evaluate the efficacy of mizoribine (MZR) pulse therapy in patients who show a reduced or insufficient response to infliximab. Ten RA patients who had active arthritis despite infliximab therapy were treated with MZR pulse therapy at a dose of 100 mg MZR and methotrexate (MTX) and the disease activity assessed at baseline and at weeks 4-8, 12-16, and 20-24. The dose was increased to 150 mg in those patients who showed an insufficient response to MZR. The mean 28-joint disease activity score (DAS28) at weeks 12-16 and 20-24 of therapy was significantly lower than that at baseline. A moderate or good European League against Rheumatism (EULAR) response was achieved in seven patients (70%) at weeks 12-16 and in five patients (50%) at weeks 20-24. The dose of 150 mg MZR was effective in one of the three patients who showed an insufficient response to pulse therapy with 100 mg MZR. Based on these results, we propose that MZR pulse therapy should be attempted before the patient is switched to other biologics.

Relationship between antinuclear antibody and microalbuminuria in the general population: the Takahata study.

BACKGROUND: Microalbuminuria, a marker of vascular damage, is associated with increased risk of progressive renal deterioration, cardiovascular disease and mortality. However, the relationship between antinuclear antibody (ANA) and microalbuminuria in the general population is unknown. Thus, we conducted a cross-sectional study to examine the relationship between ANA and microalbuminuria. METHODS: The subjects of this community-based study were individuals over 40 years old in Takahata, Japan. The urine albumin-creatinine ratio (UACR) was calculated from a single-spot urine specimen collected in the morning. ANA was examined by enzyme immunoassay (EIA). RESULTS: Among the 2,875 subjects (mean age 63 years; men 1,276; women 1,599), positive ANA (ANA index >or=20.0) was detected in 16.9% of the total population (men 12.9%, women 20.3%) and the prevalence of positive ANA increased with age. The prevalence of microalbuminuria (UACR 30-300 mg/g), but not macroalbuminuria (UACR > 300 mg/g), was significantly higher in the positive ANA group than the negative ANA group (24.1% vs. 16.0%, respectively, P < 0.001). Along with the increase of the ANA index, the prevalence of microalbuminuria and UACR levels were increased. Multivariate logistic regression analyses showed that ANA was significantly associated with microalbuminuria (odds ratio [OR] 1.63 and 95% confidence interval [95%CI] 1.27-2.10). These associations were significant in women, but not men, when examined separately. CONCLUSIONS: These results indicate that the presence of ANA is associated with microalbuminuria in the general population, especially women.

The association between microalbuminuria and metabolic syndrome in the general population in Japan: the Takahata study.

OBJECTIVE: The metabolic syndrome is associated with an increased risk of chronic kidney disease, cardiovascular disease and mortality. However, the association between microalbuminuria and the metabolic syndrome has not yet been reported in the general population in Japan. Therefore, we undertook a population-based study to examine the association between microalbuminuria and the metabolic syndrome in Takahata, Japan. METHODS: Subjects of this cross-sectional study were individuals aged from 40 to 87 years old. The metabolic syndrome was defined according to the criteria of the Adult Treatment Panel III. Microalbuminuria was defined as a urine albumin-creatinine ratio of 30 to 300 mg/g. RESULTS: A total of 2,321 subjects (mean age 64 years old) were entered into the final analysis. Among them, the prevalence of the metabolic syndrome and microalbuminuria was 16.5% and 13.7%, respectively. There was a significantly positive correlation between the number of components of the metabolic syndrome and the corresponding prevalence of microalbuminuria (p<0.001). In the subjects with metabolic syndrome compared with those without metabolic syndrome, the age- and gender-adjusted odds ratio of microalbuminuria was 1.99 (95% CI, 1.49-2.66). Multiple logistic regression analysis revealed that high glucose, high blood pressure and obesity were independently associated with microalbuminuria. CONCLUSIONS: Our study revealed a strong relationship between microalbuminuria and the metabolic syndrome in the general population in Japan. More comprehensive and intensive management of the metabolic syndrome at its early stage is important to prevent the progression of renal injury and cardiovascular complications.

Clinical utility of trace proteinuria for microalbuminuria screening in the general population.

BACKGROUND: The urine dipstick test that regards > 1+ proteinuria as positive is unsuitable for microalbuminuria screening owing to its low sensitivity in the general population. We conducted a cross-sectional survey to examine whether trace proteinuria could be an indicator of microalbuminuria. METHODS: The subjects were 2321 participants in a community-based health check-up in Takahata, Japan. Dipstick tests for proteinuria and the urine albumin-creatinine ratio (UACR) measurement were performed with single-spot urine specimens collected early in the morning. The results of the dipstick tests were recorded as (-), trace, (1+), (2+), and (3+). Micro- and macroalbuminuria were defined as UACR 30-300 mg/g and > 300 mg/g, respectively. RESULTS: Overall, the prevalence and median UACR levels of urine protein (-), trace, (1+), (2+), and (3+) were 92.0% (8.8 mg/g), 3.5% (43 mg/g), 2.6% (81 mg/g), 1.4% (315 mg/g), and 0.5% (1073 mg/g), respectively. Within the trace proteinuria category, the prevalence of microalbuminuria in all subjects, men, subjects >or=60 years, diabetic subjects, and hypertensive subjects was 59.3%, 73.8%, 71.2%, 88.9%, and 68.0%, respectively. By regarding trace proteinuria as positive, the sensitivity of the urine protein dipstick test for micro- and macroalbuminuria was improved (from 23.3% to 37.1%), while its specificity was not significantly changed (from 98.9% to 97.3%). CONCLUSION: Trace proteinuria could be a useful indicator of microalbuminuria in the general population, and especially in subjects at high risk of cardiovascular disease.