The Role of Cardio-Ankle Vascular Index as a Predictor of Mortality in Patients on Maintenance Hemodialysis.

AIM: Mortality rate of maintenance hemodialysis patients is known to be high. Cardio-ankle vascular index (CAVI) is an index reflecting the proper stiffness of the arterial tree from the origin of the aorta to the ankle. We aimed to clarify the utility of CAVI as a predictor of mortality in hemodialysis patients. The roles of age and nutritional conditions on survival were also examined. METHODS: We followed 242 patients undergoing hemodialysis for 6 consecutive years. Data from 209 patients (mean age was 60 ± 11 years) excluding those with ankle-brachial index <0.90 were then analyzed. CAVI and heart to ankle pulse wave velocity (haPWV) were measured using Vasera 1500. RESULTS: Thirty-eight hemodialysis patients who died during the 6-year period had higher age, cardiothoracic ratio (CTR), CAVI, and haPWV, and lower diastolic blood pressure, albumin, phosphate, and calcium phosphate product. The Kaplan-Meier curves for cumulative survival among the tertile groups showed that the mortality rate was higher in the highest tertile (T3) compared to T1/T2 for both CAVI and haPWV. Receiver operating characteristic (ROC) analysis revealed that CAVI had better discriminatory power for all-cause mortality compared to haPWV. In the Cox-proportional hazards analyses, 1 SD increase in both parameters contributed independently to all-cause mortality [CAVI: HR 1.595 (95% CI 1.108-2.297), haPWV: HR 1.695 (95% CI 1.185-2.425)], as well as age and CTR. Both parameters above the cut-offs estimated in the ROC analysis (CAVI ≥ 9.2, haPWV ≥ 8.9) also had independent contributions to mortality. CONCLUSION: Through the 6 consecutive years of follow-up in 209 HD patients, increased CAVI might represent a major modifiable risk factor for all-cause mortality. Further research is needed to examine whether CAVI-lowering interventions contribute to improved prognosis.

A concrete example with three limit cycles in Zeeman's class 29 for three dimensional Lotka-Volterra competitive systems.

The number of limit cycles for three dimensional Lotka-Volterra competitive systems is an open problem. Recently, we have presented a concrete example with three limit cycles in Zeeman's class 27 [6]. In this paper, we present a concrete example with three limit cycles which belongs to Zeeman's class 29. We explicitly give the critical parameter values such that the interior equilibrium is an exact unstable weak focus of order two. Also we verify that the system is permanent. This implies that there can exist three limit cycles around the interior equilibrium under suitable perturbations. We actually generate multiple limit cycles, and confirm them by numerical simulation. In addition, we present some other examples with three limit cycles in Zeeman's class 27.

Thymine DNA glycosylase modulates DNA damage response and gene expression by base excision repair-dependent and independent mechanisms.

Thymine DNA glycosylase (TDG) is a base excision repair (BER) enzyme, which is implicated in correction of deamination-induced DNA mismatches, the DNA demethylation process and regulation of gene expression. Because of these pivotal roles associated, it is crucial to elucidate how the TDG functions are appropriately regulated in vivo. Here, we present evidence that the TDG protein undergoes degradation upon various types of DNA damage, including ultraviolet light (UV). The UV-induced degradation of TDG was dependent on proficiency in nucleotide excision repair and on CRL4CDT2 -mediated ubiquitination that requires a physical interaction between TDG and DNA polymerase clamp PCNA. Using the Tdg-deficient mouse embryonic fibroblasts, we found that ectopic expression of TDG compromised cellular survival after UV irradiation and repair of UV-induced DNA lesions. These negative effects on cellular UV responses were alleviated by introducing mutations in TDG that impaired its BER function. The expression of TDG induced a large-scale alteration in the gene expression profile independently of its DNA glycosylase activity, whereas a subset of genes was affected by the catalytic activity of TDG. Our results indicate the presence of BER-dependent and BER-independent functions of TDG, which are involved in regulation of cellular DNA damage responses and gene expression patterns.

Targeting FSTL1 prevents tumor bone metastasis and consequent immune dysfunction.

Bone metastasis greatly deteriorates the quality of life in patients with cancer. Although mechanisms have been widely investigated, the relationship between cancer bone metastasis and antitumor immunity in the host has been much less studied. Here, we report a novel mechanism of bone metastasis mediated by FSTL1, a follistatin-like glycoprotein secreted by Snail(+) tumor cells, which metastasize frequently to bone. We found that FSTL1 plays a dual role in bone metastasis-in one way by mediating tumor cell invasion and bone tropism but also in a second way by expanding a population of pluripotent mesenchymal stem-like CD45(-)ALCAM(+) cells derived from bone marrow. CD45(-)ALCAM(+) cells induced bone metastasis de novo, but they also generated CD8(low) T cells with weak CTL activity in the periphery, which also promoted bone metastasis in an indirect manner. RNA interference-mediated attenuation of FSTL1 in tumor cells prevented bone metastasis along with the parallel increase in ALCAM(+) cells and CD8(low) T cells. These effects were accompanied by heightened antitumor immune responses in vitro and in vivo. In clinical specimens of advanced breast cancer, ALCAM(+) cells increased with FSTL1 positivity in tumor tissues, but not in adjacent normal tissues, consistent with a causal connection between these molecules. Our findings define FSTL1 as an attractive candidate therapeutic target to prevent or treat bone metastasis, which remains a major challenge in patients with cancer.

Occult hepatitis B virus infection in Japanese chronic hemodialysis patients.

We investigated the prevalence of occult hepatitis B virus (HBV) infection in Japanese chronic hemodialysis patients. Hemodialysis patients (n = 1041) were screened for occult HBV. The presence of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody, and hepatitis B core antibody (anti-HBc) was determined by various chemiluminescent immunoassays. HBV-DNA was quantified in patients positive for anti-HBc using quantitative real-time polymerase chain reaction. Among the 1041 patients, six (0.6%) were HBsAg-positive and 218 (20.9%) were anti-HBc-positive. All HBsAg-positive patients also tested positive for the presence of HBV DNA. Of 212 HBsAg-negative and anti-HBc-positive patients, three were positive for HBV DNA. Our study showed that the prevalence of occult HBV infection in chronic hemodialysis patients from eastern Japan was 0.3%.

Recrystallization and reactivation of dopant atoms in ion-implanted silicon nanowires.

Recrystallization of silicon nanowires (SiNWs) after ion implantation strongly depends on the ion doses and species. Full amorphization by high-dose implantation induces polycrystal structures in SiNWs even after high-temperature annealing, with this tendency more pronounced for heavy ions. Hot-implantation techniques dramatically suppress polycrystallization in SiNWs, resulting in reversion to the original single-crystal structures and consequently high reactivation rate of dopant atoms. In this study, the chemical bonding states and electrical activities of implanted boron and phosphorus atoms were evaluated by Raman scattering and electron spin resonance, demonstrating the formation of p- and n-type SiNWs.

Segregation behaviors and radial distribution of dopant atoms in silicon nanowires.

Gaining an understanding the dynamic behaviors of dopant atoms in silicon nanowires (SiNWs) is the key to achieving low-power and high-speed transistor devices using SiNWs. The segregation behavior of boron (B) and phosphorus (P) atoms in B- and P-doped SiNWs during thermal oxidation was closely observed using B local vibrational peaks and Fano broadening in optical phonon peaks of B-doped SiNWs by micro-Raman scattering. Electron spin resonance (ESR) signals from conduction electrons were used for P-doped SiNWs. Our results showed that B atoms preferentially segregate in the surface oxide layer, whereas P atoms tend to accumulate in the Si region around the interface of SiNWs. The radial distribution of P atoms in SiNWs was also investigated to prove the difference segregation behaviors between of P and B atoms.

Thoracoscopy-assisted magnetic resonance guided microwave coagulation therapy for hepatic tumors.

BACKGROUND: Microwave coagulation therapy (MCT) has become a safe and effective modality with which to treat hepatic tumors; MCT can be applied percutaneously, laparoscopically, thoracoscopically, and during laparotomy. When combined with magnetic resonance (MR) imaging, MCT can be used to treat hepatic tumors located in the subdiaphragmatic area that are difficult to approach by ultrasound, because of the overlaying lower lung field. METHODS: To determine the usefulness of thoracoscopy-assisted interventional MR-MCT (T-IVMR-MCT, n = 73), we compared patients with hepatic tumors that were treated with percutaneous IVMR-MCT (P-IVMR-MCT, n = 69) and with T-IVMR-MCT. RESULTS: None of patient background, complication and recurrence rate, or length of hospital stay significantly differed between the 2 groups. CONCLUSIONS: IVMR-MCT is a useful modality for treating hepatic tumors. Especially when tumors are located at the hepatic dome, T-IVMR-MCT was minimally invasive, while it appears to improve targeting of peridiagmatic hepatic lesions and has a complication profile similar to P-IVMR-MCT.

Colestilan, a new bile acid-sequestering resin, reduces bodyweight in postmenopausal women who have dieted unsuccessfully.

OBJECTIVE: Bile acid-sequestering resins are known to be potent hypocholesterolaemic drugs, and a feeling of abdominal fullness has been reported as the most frequent adverse effect associated with their use. However, this unique adverse effect of colestilan, abdominal fullness, may have the potential to reduce total food intake. The aim of this study was to investigate the effect of colestilan, a new bile acid-sequestering resin, on the bodyweight of postmenopausal women who had previously dieted unsuccessfully. METHODS: Forty postmenopausal women who failed to diet successfully over a 4-week period were enrolled in this randomised, open-label, controlled study. Subjects were randomised to two groups: the colestilan group received four colestilan tablets administered in divided doses with three glasses of water before dinner and bedtime for 12 weeks; the control group received three glasses of water before dinner and bedtime for 12 weeks. All patients were monitored and were given the same diet instructions. RESULTS: Twelve weeks' administration of colestilan in addition to diet instruction significantly reduced bodyweight and body mass index from 62.9 +/- 5.7kg to 58.0 +/- 5.4kg (mean +/- SD) and from 26.1 +/- 2.0 kg/m2 to 23.9 +/- 2.0 kg/m2, respectively. There were no significant differences in bodyweight before and after 12 weeks of treatment in the control group. CONCLUSION: Colestilan may be useful for appetite control and exerts anti-obesity effects when used in conjunction with a weight-management programme.

Laparoscopic ureterolysis for idiopathic retroperitoneal fibrosis.

Three patients with idiopathic retroperitoneal fibrosis underwent laparoscopic ureterolysis. Two patients were bilateral cases which were performed successfully as a one stage procedure. Another patient, who was unsuccessfully treated, had a long ureteral stricture. Laparoscopic ureterolysis may be a useful alternative to open surgical management especially in bilateral cases, except for patients with a long ureteral stricture.

Increased expression of type I 17beta-hydroxysteroid dehydrogenase enhances in situ production of estradiol in uterine leiomyoma.

Expression of 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) was compared between leiomyoma and myometrium. Cytosolic fractions from leiomyoma homogenate displayed 5-fold higher activity (estrone to estradiol), compared with surrounding myometrium (n = 6, P < 0.05), whereas microsomal fractions showed no difference. Oxidative activity (estradiol to estrone) did not differ between leiomyoma and myometrium. Levels of mRNA for 17beta-HSDs were then measured using real-time PCR techniques. Among the eight different types of 17beta-HSDs (types 1-5, 7, 8, and 10), type 1 was the only enzyme displaying differential expression between leiomyoma and myometrium. Mean concentration of type 1 17beta-HSD mRNA was 4-fold higher in leiomyoma than in surrounding myometrium (n = 20, P < 0.05). Type 1 transcript levels correlated significantly with reductive activity in individual samples (n = 6, P < 0.05). Northern blot analysis of leiomyoma and myometrium tissues detected 2.3- and 1.0-kb transcripts of type 1 enzyme, whereas the major 1.3-kb transcript for 17beta-HSD in placenta-derived JEG-3 cells was not detected. None of the factors increasing mRNA levels for type 1 enzyme in placenta increased mRNA levels in leiomyoma. These results indicate that leiomyoma tissues overexpress type 1 17beta-HSD, resulting in high conversion of estrone to estradiol. In situ expression of type 1 17beta-HSD may play a role in self-supported growth of leiomyoma cells.

Expression of estrogen receptor-beta in the postischemic monkey hippocampus.

The molecular basis of estrogen-mediated neuroprotection against brain ischemia remains obscure. Here, we studied by immunohistochemistry the expression of estrogen receptor (ER) alpha and beta in the hippocampal CA1 sector of postischemic adult macaque monkeys. ERbeta was present in control CA1 pyramidal neurons, decreasing on day 4 after ischemia. In contrast, ERbeta immunoreactivity increased remarkably in the radiate and molecular layers of CA1, where it was present in astrocytes and microglia. ERalpha was negligible in both control and postischemic monkeys. These results indicate that ERbeta is the major receptor responsible for the direct estrogen actions on the monkey hippocampus, regulating glial response after ischemia.

Effects of the traditional Japanese medicine Unkei-to on the corticotropin-releasing factor-induced increase in locomotor activity.

The effect of Unkei-to, a traditional Japanese herbal medicine and strong in vitro releaser of cytokine-induced neutrophil chemoattractant (CINC), on the increase in locomotor activity induced by intracerebroventricular (icv) injection of corticotropin-releasing factor (CRF) in male rats in a familiar environment was investigated. Oral administration of Unkei-to (100 mg/kg) for 1 week significantly attenuated the CRF-induced increase in locomotor activity. Unkei-to also reduced the CRF-induced accumulation of hypothalamic CINC, which has a functional antagonistic action on the response to CRF; the reduction may reflect an increased release of CINC. These results suggest that Unkei-to has an alleviative effect on the action induced by brain CRF and the mechanism of this effect may partly involve CINC.

Efficacy of the herbal medicine Unkei-to as an adjunctive treatment to hormone replacement therapy for postmenopausal women with depressive symptoms.

OBJECTIVE: Although hormone replacement therapy (HRT) improves menopausal depressive symptoms, women unresponsive to HRT need an antidepressant drug as an effective adjunctive therapy. The aim of this study was to assess whether the herbal medicine Unkei-to has an impact on HRT-resistant menopausal depressive symptoms as an effective adjunctive therapy combined with HRT. METHODS: Twenty-four HRT-resistant menopausal depressive women were randomly assigned to group 1 (n = 12) or group 2 (n = 12). Subjects in group 1 were accessioned into 6 months of open treatment with Unkei-to as an adjunctive therapy and changed to Toki-shakuyaku-san for 6 months following a 1-month washout period. Group 2 started with Toki-shakuyaku-san for 6 months and then changed to Unkei-to for 6 months following a 1-month washout period. RESULTS: Three months' treatment with Unkei-to as an adjunctive therapy significantly improved Zung's Self-Rating Depression Scale (ZSDS) scores, State-Anxiety (STAI-1) scores, and Trait-Anxiety (STAI-2) scores noted before treatment, and this effect continued at 6 months. Treatment with Unkei-to was also significantly effective in reduction of ZSDS scores, STAI-1 scores, and STAI-2 scores at 3 months compared with Toki-shakuyaku-san treatment, and this effect continued at 6 months. CONCLUSIONS: Unkei-to is another option as an adjunctive herbal therapy in HRT-resistant menopausal depressive women.

Decreased expression of early growth response-1 and its role in uterine leiomyoma growth.

Expression of early growth response (Egr)-1, a transcriptional factor implicated in growth regulation, is suppressed in several malignant tumors. The present study investigated the expression of Egr-1 and related genes in uterine leiomyoma and normal myometrium to determine possible contributions of Egr-1 to neoplastic growth in leiomyoma cells. Levels of Egr-1 transcripts were decreased in all leiomyomas (n = 20) to approximately 10% of levels in corresponding myometrium, where basal expression was high. Preoperative leuprorelin acetate therapy increased levels of Egr-1 mRNA in normal myometrium only. Northern blot analysis using additional sample sets (n = 5) revealed the full-length Egr-1 transcript. Western blot analysis (n = 5) confirmed decreased expression of Egr-1 protein. Southern blot analysis of the Egr-1 gene and microsatellite analysis of the chromosomal location at 5q31 (D5S414, D5S500, and D5S476) revealed neither DNA recombination nor loss of heterozygosity in leiomyomas. Moreover, Egr-1 retained identical responsiveness to phorbol 12-myristate 13-acetate in primary cultures derived from both leiomyoma and normal tissues. Electrophoretic mobility shift analysis revealed that phorbol 12-myristate 13-acetate-induced Egr-1 in leiomyoma cells retained DNA binding ability. Egr-1 thus appears functionally intact in leiomyoma cells. Finally, consistent with the role of Egr-1 in growth inhibition, transfection of Egr-1 expression vector into a myometrial cell line (KW) that expresses low levels of Egr-1 and displays rapid growth inhibited thymidine uptake in these cells. Egr-1 may display tumor-suppressing activity and offers a potential target for leiomyoma management.

Sex-determining region Y levels in maternal plasma: Evaluation in abnormal pregnancy.

AIM: A number of studies for the measurement of cell-free fetal DNA in maternal blood have been reported; however, their clinical significance has remained unclear. We proposed to clarify the relationship between fetal DNA levels and obstetrical disorders. METHODS: One hundred and eighty-five cases of normal pregnancy, ranging from 8 to 40 weeks' gestation, and 70 cases of abnormal pregnancy were included. SRY levels in maternal plasma were quantified with a real-time quantitative polymerase chain reaction. RESULTS: Sex-determining region Y (SRY) levels and the number of patients with positive levels peaked at 33-36 weeks in normal pregnancy. The SRY levels in threatened abortion (11.6 +/- 4.8 copies/mL to 0 +/- 0, P < 0.05) and threatened preterm labor (44.6 +/- 16.1 copies/mL to 15.9 +/- 6.2, P < 0.01) were significantly higher than those of the normal group. In pre-eclamptic patients, SRY levels were markedly higher than those of the normal group (173.2 +/- 94.8 copies/mL to 22.4 +/- 8.9, P < 0.05). Patients with premature separation of the placenta (266.8 +/- 137.1 copies/mL to 4.9 +/- 3.7, P < 0.05) and placenta previa (167.7 +/- 32.4 copies/mL to 37.0 +/- 17.3, p <0.01) also showed elevated SRY levels. CONCLUSION: Sex-determining region Y levels in maternal plasma were elevated in patients with an abnormal pregnancy, particularly those with placental injury of damage. These results suggested that increased SRY levels are consistently caused by the leak of fetal components, and thus the measurement of SRY levels in maternal plasma is useful for the evaluation of placental injuries.

Fetal DNA levels in maternal blood correlated with fetal prognosis in a case of intervillous hematoma.

Several methods for detection of fetal components in maternal blood have been reported. However, few have proven clinically useful for determining the treatment in cases of placental injuries. Here, we report a case of extensive intervillous hematoma diagnosed at 25 weeks of gestation with severe intrauterine growth restriction and oligohydramnios. Marked elevation of fetal DNA levels was observed in maternal blood. Fetal DNA levels decreased after 27 weeks of gestation, concurrent with recovery of fetal growth. We conservatively managed this case until 30 weeks of gestation, when a male infant was delivered. He weighed 508 g and displayed Apgar scores of 7 at 1 minute and 9 at 5 minutes. Histological examination of the placenta revealed intervillous thrombosis without infarction or inflammatory changes. In this case, decreasing fetal DNA levels in maternal plasma correlated with recovery of fetal growth and provided useful information for fetal management as well as insight into the pathogenesis of placental injuries.

Successful treatment of a symptomatic uterine leiomyoma in a perimenopausal woman with a nonsteroidal aromatase inhibitor.

OBJECTIVE: To assess the management of symptomatic leiomyomas using a nonsteroidal aromatase inhibitor in perimenopausal women. DESIGN: Case report. SETTING: Academic clinical practice. PATIENT(S): A 53-year-old woman suffering from recurrent urinary retention secondary to a uterine leiomyoma. INTERVENTION(S): Fadrozole, orally, 2 mg daily for 8 weeks and then 1 mg daily for 4 weeks. MAIN OUTCOME MEASURE(S): Measurements of leiomyoma volume, and levels of serum E(2), LH, and FSH. RESULT(S): Urinary retention resolved after 2 weeks of treatment and did not recur. Leiomyoma volume estimated by ultrasonography revealed a 71% reduction after 8 weeks of treatment. CONCLUSION(S): Fadrozole was useful for the management of a symptomatic leiomyoma without transient deterioration of symptoms. Clinical trials are warranted.