The Caenorhabditis elegans JNK signaling pathway activates expression of stress response genes by derepressing the Fos/HDAC repressor complex.

MAP kinases are integral to the mechanisms by which cells respond to a wide variety of environmental stresses. In Caenorhabditis elegans, the KGB-1 JNK signaling pathway regulates the response to heavy metal stress. In this study, we identified FOS-1, a bZIP transcription factor, as a target of KGB-1-mediated phosphorylation. We further identified two transcriptional targets of the KGB-1 pathway, kreg-1 and kreg-2/lys-3, which are required for the defense against heavy metal stress. FOS-1 plays a critical role in the transcriptional repression of the kreg-1 gene by recruiting histone deacetylase (HDAC) to its promoter. KGB-1 phosphorylation prevents FOS-1 dimerization and promoter binding, resulting in promoter derepression. Thus, HDAC behaves as a co-repressor modulating FOS-1-mediated transcriptional regulation. This study describes the direct link from JNK signaling, Fos phosphorylation, and regulation of kreg gene transcription, which modulates the stress response in C. elegans.

Estimation of BVAS in patients with microscopic polyangiitis in Japan.

The validity of the Birmingham Vasculitis Activity Score (BVAS) as an index of disease activity and a predictor of the prognosis and outcome in patients with MPA has not yet been established in Japan. We conducted a retrospective study of the data of 73 patients with MPA who were followed up for at least 2 years. We divided the patients into two groups according to the BVAS, namely, the high-BVAS group (≥16) and the low-BVAS group (<16), and compared the clinical characteristics. In addition, the distribution of the BVAS items in the patients and the items contributing to the total score in MPA patients were analyzed. Remission was achieved in 85% of patients at 1 month. There were no significant differences in the serum CRP, creatinine (Cre), or MPO-ANCA between the high- and low-BVAS group; however, the survival time was significantly shorter (p = 0.048) and the mortality rate significantly higher in the high-BVAS group (p = 0.04). The items of the BVAS contributing to the total score were motor neuropathy, sensory neuropathy, pulmonary infiltrate, hematuria, proteinuria, Cre ≥5.6 mg/dL, hypertension, scleritis, rise in Cre by ≥30%, and myalgia. BVAS was found to be a useful tool for determining the disease activity and outcome in patients with MPA in Japan. The initial BVAS was also predictive of the mortality and survival time and can also be used as a prognostic tool; therefore, use of the tool may facilitate the selection of appropriate treatment.

Receptor for activated C kinase 1 stimulates nascent polypeptide-dependent translation arrest.

Nascent peptide-dependent translation arrest is crucial for the quality control of eukaryotic gene expression. Here we show that the receptor for activated C kinase 1 (RACK1) participates in nascent peptide-dependent translation arrest, and that its binding to the 40S subunit is crucial for this. Translation arrest by a nascent peptide results in Dom34/Hbs1-independent endonucleolytic cleavage of mRNA, and this is stimulated by RACK1. We propose that RACK1 stimulates the translation arrest that is induced by basic amino-acid sequences that leads to endonucleolytic cleavage of the mRNA, as well as to co-translational protein degradation.

Clinical outcome and prognosis of anti-neutrophil cytoplasmic antibody-associated vasculitis in Japan.

BACKGROUND/AIMS: We conducted a broad survey of 99 patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and investigated both prognosis and outcomes. METHODS: Clinical data evaluated were age, sex, patient survival, renal survival, serum albumin, serum creatinine, urinary protein, hematuria, C-reactive protein (CRP), ANCA titer, IgG and the Birmingham Vasculitis Activity Score (BVAS). RESULTS: The patient survival rate at 6 months after onset was 84.8%, and that at 2 years after onset was 82.0%. Most deaths were within 6 months of onset. Infection accounted for 9 deaths (60.0%). Infection together with pulmonary involvement of active vasculitis accounted for 2 deaths (13.3%). Organ-specific involvement of active vasculitis alone caused 3 deaths (20.0%). Others died of cardiac events. At 1 and 3 months after onset, BVAS (p < 0.0001, p = 0.002), albumin (p = 0.006, p = 0.0004) and CRP (p = 0.04, p = 0.0002) were also associated with patient death. CONCLUSION: To improve the prognosis of those with ANCA-associated vasculitis, the intensity of initial treatment should be aimed at disease severity. Employing BVAS improved the ability to evaluate therapeutic responses. Finally, prescription with sulfamethoxazole-trimethoprim during the induction therapy with immunosuppressive agents may be advised.

Relation of oral 1alpha-hydroxy vitamin D3 to the progression of aortic arch calcification in hemodialysis patients.

The role of decreased active vitamin D levels on vascular calcification has not been elucidated in hemodialysis (HD) patients. The aim of the present study was to evaluate the relationship between progression of aortic arch calcification (AoAC) and prescribed dose of 1alpha-hydroxy vitamin D. The enrolled study subjects were 65 (40 men and 25 women) HD patients. Calcification of the aortic arch was semiquantitatively estimated with a score (AoACS) on plain chest radiology. Change in AoACS (DeltaAoACS) was obtained by subtracting the baseline AoACS value from the follow-up AoACS value. The second assessment was performed from 2 years after the first determination. The nonprogressors (63.2 +/- 14.5 years) were significantly younger than the progressors (68.2 +/- 10.8 years) (P = 0.0419). In addition, prescribed dose of 1alpha-hydroxy vitamin D3 was significantly higher in the nonprogressors (125.5 +/- 109.1 microg) than progressors (84.8 +/- 81.1 microg) (P = 0.0371). Multiple regression analysis revealed prescribed dose of 1alpha-hydroxy vitamin D(3) (beta value = -0.324, P = 0.0051) as well as DBP (beta value = -0.418, P = 0.007), serum levels of P (beta value = 0.333, P = 0.006) and C-reactive protein (beta value = 0.237, P = 0.0048) to be significant independent determinants of DeltaAoACS. In conclusion, the evaluation of AoACS on chest radiography is a very simple tool in HD patients. Active vitamin D therapy seems to protect patients from developing vascular calcification.

Progression of aortic arch calcification and all-cause and cardiovascular mortality in chronic hemodialysis patients.

OBJECTIVE: Although aortic arch calcification (AoAC) is reported as a predictor for cardiovascular mortality in the general population, it is unknown whether this is also true in hemodialysis (HD) patients in whom vascular calcification and cardiovascular diseases are highly prevalent. METHODS: The enrolled study subjects were 401 patients (270 men and 131 women) on chronic HD therapy. Calcification of the aortic arch was semiquantitatively estimated with a score (AoACS) on plain chest radiography. Survival curves were estimated by means of the Kaplan-Meier method and evaluated using the log-rank test. RESULTS: AoAC was present in 203 patients (50.6%). During a follow-up period of 4.0 years, there were 72 all-cause deaths, of which 41 were from cardiovascular diseases. Of patients with and without AoAC, 15.2 and 20.7% died, respectively (11.3 and 6.6% of cardiovascular diseases, respectively). Kaplan-Meier analysis showed that cardiovascular mortality was significantly greater in patients with AoAC compared to those without (P = 0.0396, log-rank test). Multivariate Cox proportional hazards analysis found that the presence of AoAC was significantly associated with increased cardiovascular mortality (hazard ratio, 2.556; 95% confidence interval, 1.006-6.490; P < 0.05) after adjustment for age, presence of diabetes, body mass index, diastolic blood pressure, and serum albumin level. CONCLUSION: The presence of AoAC is significantly associated with cardiovascular mortality in HD patients, suggesting that careful attention should be given to the presence of AoAC in a plain chest radiograph as a prognostic indicator.

Clinical assessment of atherosclerotic parameters and cardiac function in chronic hemodialysis patients.

BACKGROUND/AIM: Atherosclerosis is evaluated by carotid mean intima-media thickness (mean IMT), pulse wave velocity (PWV), and the aortic calcification index (ACI). We have attempted to examine if these atherosclerotic parameters are associated with each other and which parameters are closely related to cardiac function in chronic HD patients. METHODS: The mean IMT, PWV and ACI were examined in 69 maintenance HD patients using carotid ultrasonography, a blood volume plethysmographic apparatus and abdominal CT, respectively. Echocardiographic studies were also performed for measuring left ventricular (LV) geometry. Serum total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride, albumin, C-reactive protein (CRP), calcium and phosphate were measured. RESULTS: The mean IMT correlated positively with ACI (r = 0.461, P < 0.0001) and tended to be correlated with PWV, but did not reach statistical significance. The PWV value correlated positively with ACI (r = 0.494, P