Effect of Asymptomatic Severe Aortic Stenosis on Outcomes of Individuals Aged 80 and Older.

OBJECTIVES: To examine the effect of asymptomatic severe aortic stenosis (AS) on mortality late in life. DESIGN: Retrospective cohort study. SETTING: Large medical center. PARTICIPANTS: Asymptomatic adults aged 80 and older (mean age 86 ± 4; N=1,060, n=569 women) with preserved left ventricular ejection fraction (LVEF; > 50%); 927 (87.5%) with no AS, 70 (6.6%) with nonsevere AS, and 63 (5.9%) with severe AS. MEASUREMENTS: Information was collected on demographic characteristics, comorbidities, and laboratory and echocardiographic data. Survival was assessed according to longest follow-up available. RESULTS: During a mean follow-up of 2.2 ± 2.3 years, there were 203 (19%) deaths, 51 of which were from cardiovascular causes. Four-year estimates of survival were 72% for no AS, 58% for nonsevere AS, and 23% for severe AS (p<.001). Univariable analysis showed that asymptomatic severe AS was significantly associated with greater risk of all-cause mortality (hazard ratio (HR)=3.06, 95% confidence interval (CI)=1.96-4.58, p<.001). After adjustment for age, sex, LVEF, hypertension, dyslipidemia, diabetes, atrial fibrillation, chronic kidney disease, and coronary artery disease, asymptomatic severe AS was an independent predictor of all-cause mortality (HR=3.16, 95% CI=1.97-4.88, p<.001). CONCLUSION: Asymptomatic severe AS has a major effect on prognosis even in very old adults.

High-density lipoprotein and apolipoprotein A-I inhibit palmitate-induced translocation of toll-like receptor 4 into lipid rafts and inflammatory cytokines in 3T3-L1 adipocytes.

Saturated fatty acids (SFAs) activate toll-like receptor 4 (TLR4) signal transduction in macrophages and are involved in the chronic inflammation accompanying obesity. High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) produce anti-inflammatory effects via reverse cholesterol transport. However, the underlying mechanisms by which HDL and apoA-I inhibit inflammatory responses in adipocytes remain to be determined. Here we examined whether palmitate increases the translocation of TLR4 into lipid rafts and whether HDL and apoA-I inhibit inflammation in adipocytes. Palmitate exposure (250 µM, 24 h) increased interleukin-6 and tumor necrosis factor-α gene expressions and translocation of TLR4 into lipid rafts in 3T3-L1 adipocytes. Pretreatment with HDL and apoA-I (50 µg/mL, 6 h) suppressed palmitate-induced inflammatory cytokine expression and TLR4 translocation into lipid rafts. Moreover, HDL and apoA-I inhibited palmitate-induced phosphorylation of nuclear factor-kappa B. HDL showed an anti-inflammatory effect via ATP-binding cassette transporter G1 and scavenger receptor class B, member 1, whereas apoA-I showed an effect via ATP-binding cassette transporter A1. These results demonstrated that HDL and apoA-I reduced palmitate-potentiated TLR4 trafficking into lipid rafts and its related inflammation in adipocytes via these specific transporters.

Coexistence of papillary thyroid cancer and Hashimoto thyroiditis in children: report of 3 cases.

This report documents 3 pediatric papillary thyroid carcinoma cases with associated Hashimoto thyroiditis. In all 3 cases, hypoechoic nodules accompanied by multiple echogenic spots were noted on sonography of the thyroid. Hashimoto thyroiditis was suspected on the basis of positive thyroid autoantibody test results and pathologic examinations of thyroidectomy specimens, which revealed chronic thyroiditis with lymphocytic infiltration as the background of papillary thyroid carcinoma development. The potential for papillary carcinoma development warrants close follow-up, and meticulous sonographic examinations must be performed in children with Hashimoto thyroiditis.

Effect of eicosapentaenoic acid agent on aggravated hypertriglyceridemia during pregnancy.

Aggravated hypertriglyceridemia with a serum triglyceride of more than 1000 mg/dL is a risk of acute pancreatitis during pregnancy. However, there have been few reports on the administration of an eicosapentaenoic acid (EPA) agent for aggravated hypertriglyceridemia during pregnancy. A 29-year-old multiparous Japanese woman was transferred to our hospital at 29 + 0 weeks of gestation due to hypertriglyceridemia of 898 mg/dL. Because diet control was not enough, we decided to use an EPA agent, resulting in a reduction in triglyceride levels to 550 mg/dL. A male infant, weighing 2667 g, was born at 37 + 2 weeks transabdominally, and was complicated with respiratory distress syndrome. The final diagnosis was type III hyperlipoproteinemia with the apolipoprotein E3/2 phenotype and a broad ß-migrating lipoprotein on polyacrylamide gel electrophoresis of serum lipoproteins. In conclusion, an EPA agent may be a possible therapeutic approach for aggravated hypertriglyceridemia during pregnancy, although it may increase a risk of respiratory distress syndrome.

Educational courses for physiological function examination at Jichi Medical University: practical trainings in ultrasonography.

To foster work-ready general physicians, Jichi Medical University has developed various clinical teaching practices since its foundation. The educational courses for clinical laboratory medicine, being one of them, adopt practical trainings in ultrasonography, which is essential in practical medicine today. The aims and the specifics of the trainings adopted in the seminar of ultrasound and the required or the optional subjects of Bedside Learning (BSL) at Jichi Medical University are reported.

Plasma NOx concentrations in glucose intolerance and type 2 diabetes. A case-control study in a Vietnamese population.

AIM: The Vietnamese develop type 2 diabetes (T2D) and metabolic syndrome (MS) at a lower BMI than other ethnicities. Thus, biomarkers that identify subjects at an increased risk of T2D independently of obesity are being sought. Recent studies show that circulating NO metabolites (NOx) are increased in T2D. We investigated whether plasma NOx levels predict insulin resistance and glucose intolerance before the development of T2D, independently of obesity. METHODS: The current study was derived from a population-based study in HCMC, Vietnam, which was designed to investigate the prevalence of MS and T2D in a population aged 30-69 years. Four hundred and twenty-two subjects were recruited from the study and were stratified into 4 age- and gender-matched groups according to a glucose tolerance test {normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and T2D}. RESULTS: Plasma NOx concentrations were significantly increased in T2D but not in IFG or IGT compared with NGT. Multiregression analysis showed that plasma NOx levels were inversely correlated with BMI in T2D whereas no association was found between plasma NOx levels and BMI in non-diabetic subjects. Moreover, there was no correlation between plasma NOx levels and homeostasis model assessment-insulin resistance (HOMA-IR) in both diabetic and non-diabetic subjects. CONCLUSION: Plasma NOx levels did not predict glucose intolerance or insulin resistance before the development of T2D and the increase in plasma NOx levels in T2D was not caused by adiposity. Thus, plasma NOx is not a useful marker for the prediction of high-risk subjects for T2D among Vietnamese.

Comparative study of atherosclerotic parameters in Mongolian and Japanese patients with hypertension and diabetes mellitus.

AIM: Cardiovascular disease is becoming increasingly more problematic in Mongolia. The cardioankle vascular index (CAVI) and circulating C-reactive protein (CRP) are new atherosclerosis-related parameters, but no comparative studies of atherosclerotic parameters including CAVI and CRP are available between Mongolian and Japanese populations, such as disease populations of hypertension (HT) and diabetes mellitus (DM). Our study objective was to examine atherosclerotic profiles in HT and DM patients in both countries. METHODS: From a hospital-based population, 156 Mongolian outpatients with HT and DM (men: 46%, mean age: 57.1 years) and 156 age- and sex-matched Japanese outpatients with HT and DM (men: 46%, age: 57.7) were recruited. Body mass index (BMI), heart rate (HR), blood pressure (BP), pulse pressure (PP), ankle-brachial index (ABI), ultrasonographic carotid intima-media thickness (IMT), blood total cholesterol (T-Cho), glucose, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were measured, in addition to CAVI and CRP. RESULTS: The levels of BMI, HR, BP, PP, insulin and IMT were significantly higher and T-Cho and glucose were significantly lower in the Mongolian patients in comparison to the Japanese patients. Particularly, the levels of CAVI (mean+/-SD) (8.1+/-1.1 vs. 8.8+/-1.2) and CRP(median[interquartile range])(0.05[0.03-0.12]vs. 0.19[0.09-0.42]mg/dL)were significantly higher in Mongolian than Japanese patients. These significant differences remained unchanged, even after taking into account multiple variables, including BP and HOMA-IR. In addition, except for CAVI in the subgroup of DM, generally similar trends regarding atherosclerotic parameters were seen in the subgroup by sex and disease (HT, DM and HT plus DM). CONCLUSION: These findings suggest that Mongolian patients with HT and DM may be at higher risk for cardiovascular disease than Japanese patients.

Sentinel node detection method using contrast-enhanced ultrasonography with sonazoid in breast cancer: preliminary clinical study.

This study aimed to evaluate the usefulness of sentinel lymph node (SLN) detection in breast cancer using contrast-enhanced ultrasonography (CEUS) with subareolar Sonazoid injection. The subjects were 20 breast cancer patients. General anesthesia was induced and 2 mL of Sonazoid was injected subareolarly. After massage of the injection site, the axillary area was observed transdermally using coded phase inversion harmonic ultrasonography with mechanical indices of 0.15 to 0.19. When contrast-enhanced lymph nodes (LNs) were seen, they were defined as CE-SLN. Two other SLN detection methods, the gamma-probe-guided and dye-guided methods, were performed together. We evaluated the SLNs detected by each method to determine if they corresponded with each other and calculated the SLN detection rate. After the SLNs were resected, pathologic examinations were done. The SLN detection rate of the CEUS-guided method, the dye-guided method and the gamma-probe-guided method were 70%, 75% and 100%, respectively. There was no statistically significant difference in these rates between the CEUS-guided and dye-guided methods (p = 0.99) but the CEUS-guided method showed a significantly lower rate than the gamma-probe-guided method (p = 0.020), and dye-guided method also showed a significantly lower rate than the gamma-probe-guided method (p = 0.047). The number of CE-SLNs was 1 or 2 (average 1.1) and each took 2 to 20 (average 5.3) min to detect. The CE-SLNs corresponded grossly with SLNs detected by the gamma-probe-guided and dye-guided methods. The pathologic results indicated no metastasis from the resected SLNs in 15 of 20 cases. However, the CEUS-guided method detected 12 cases of these 15 and CE-SLNs were detected in two of the remaining five metastasis cases. In summary, in breast cancer patients, after subareolar injection of Sonazoid, contrast-enhanced LNs were observed in real time with ultrasonography. In an initial clinical study of 20 cases, the detection rate of the CEUS-guided method was less than that of the gamma-probe-guided method. It is suggested that the CEUS-guided method using Sonazoid may, with some improvements, be a useful new modality for sentinel node identification.

A novel missense mutation of ABCA1 in transmembrane alpha-helix in a Japanese patient with Tangier disease.

Tangier disease (TD) is a hereditary disorder characterized by the severe deficiency or absence of high-density lipoprotein cholesterol (HDL-C). TD is caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene, most of which are located in the extracellular loops and nucleotide-binding domains. Here we describe the first case of TD carrying a missense mutation in a transmembrane alpha-helix of ABCA1. A 31-year-old Japanese woman had an extremely low level of HDL-C (1mg/dl) and yellowish tonsillar swelling, leading to the diagnosis of TD. The proband was homozygous for a point mutation of T4978C in exon 37, which results in the substitution of cysteine-1660 to arginine (C1660R) in the 8th transmembrane segment of ABCA1. Her parents, grandmother, and brother were found to be heterozygous for the same mutation. Both peripheral blood leukocytes from the patient and HEK293 cells transfected with T4978C-mutated ABCA1 normally expressed ABCA1 on the plasma membrane and had normal apolipoprotein A-I-binding ability. However, apolipoprotein A-I-mediated efflux of cholesterol and phospholipids was markedly diminished in HEK293 cells transfected with T4978C-mutated ABCA1. These results suggest that this mutant is normally translated and exists as a stable product with normal localization, yet is functionally defective. Cysteine-1660 appears to be a critical residue for cholesterol transport of ABCA1.

Comparative study of the cardio-ankle vascular index and ankle-brachial index between young Japanese and Mongolian subjects.

Mongolian people have higher mortality and morbidity rates due to cardiovascular disease (CVD) than Japanese people. The cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI) are both atherosclerosis-related indexes. Presently, there is no comparative information on CAVI and ABI among young subjects between Mongolian and Japanese people. A total of one hundred Mongolian (men: 39%, mean age: 20.9+/-2.2 years) and 115 Japanese volunteers (men: 39%, mean age: 22.0+/-1.8 years) were recruited from among university students. The body mass index (BMI), heart rate (HR), blood pressure (BP), CAVI, ABI, carotid intima-media thickness, blood total cholesterol (TC), glucose and C reactive protein levels were measured. The levels of BMI, HR and diastolic BP were significantly higher, and TC and glucose were significantly lower in the Mongolian subjects than in the Japanese subjects. The CAVI values (median (interquartile range): 6.5 (5.8-7.0) vs. 5.6 (5.2-6.0)) and ABI (1.11 (1.05-1.17) vs. 1.09 (1.05-1.15)) were significantly higher in the Mongolian subjects than in the Japanese subjects. The patterns of correlation between CAVI, ABI and other atherosclerotic parameters were different: in age-, gender- and BMI-adjustment correlation tests for CAVI and ABI, HR (r=-0.25 for CAVI and ABI) showed a correlation in the Mongolian subjects, and for ABI systolic BP (r=-0.28) showed a correlation in the Japanese subjects. These results suggest that Mongolian subjects may be at higher risk of CVD, even among younger individuals, than Japanese subjects.

Novel automated pulse immunoassay for human alpha-fetoprotein.

BACKGROUND: To improve current alpha-fetoprotein (AFP) assays, which are expensive and time-consuming, a specific AFP reagent has been developed for practical use in our newly developed high-speed, highly sensitive pulse immunoassay (PIA) system, in which a latex immunoagglutination reaction is carried out under a high-frequency pulse voltage, leading to an enhanced immunological reaction. METHODS: We evaluated the assay performance (reproducibility, sensitivity, dilution linearity, interference) of the newly developed automated AFP PIA compared with the current AFP assay. RESULTS: Using pooled serum samples, the within-run reproducibility resulted in a correlation variation of 3.6-4.7%. The AFP assay detection limit was determined to be 2.5 microg/L. Linear sequential dilution was found up to nearly 700 microg/L. Even up to an AFP concentration of 1.0 g/L, the prozone phenomenon was not observed. Free and conjugated bilirubin, haemolytic haemoglobin, chyle and rheumatoid factor did not show any test interference. Using AFP-positive serum samples from 114 patients, the correlation between our PIA and a chemiluminescence immunoassay resulted in an excellent correlation coefficient of 0.994. CONCLUSIONS: The performance of AFP reagents in the PIA device shows that the system has excellent speed and equal sensitivity and specificity compared with the most highly sensitive conventional method. Our PIA system thus appears ready for use in the clinical diagnosis setting.

[Evoked potential monitoring in an operation of neurosurgery].

In the neurosurgical field, the evoked potential is employed for the monitoring of intraoperative nerve function. During evoked potential monitoring, surgical manipulation-related nerve dysfunction is detected, and functional localization/nerves in the cerebral cortex are identified to prevent postoperative neurological complications. It is important to reduce the contact resistance to 2 kOmega or less on the application of plate electrodes used for recording and prevent noise by bundling electrode leads, to ensure a stable evoked potential during surgery. In our laboratory, intraoperative monitoring, such as ABR to prevent auditory disturbance, SEP to detect cerebral ischemia, cortical SEP and MEP to prevent motor paralysis, and evoked electromyography to identify/maintain the cranial nerves including the facial, trigeminal, oculomotor, and abducens nerves, is performed based on requests from the Department of Neurosurgery.

Pitavastatin decreases plasma prebeta1-HDL concentration and might promote its disappearance rate in hypercholesterolemic patients.

AIM: Prebeta1-HDL is involved in the initial step of cholesterol efflux from peripheral cells and plays an important role in reverse cholesterol transport. We studied the effect of pitavastatin on the HDL subfraction profile, prebeta1-HDL concentration and its disappearance rate. METHODS: Twenty-nine hypercholesterolemic patients were treated with pitavastatin at 2 mg/day for 4 weeks, and plasma levels of total cholesterol (TC), triglyceride, HDL-cholesterol (C), HDL(2)-C, HDL(3)-C, prebeta1-HDL, LCAT activity, and CETP mass were assayed. The prebeta1-HDL disappearance rate was determined as the difference in prebeta1-HDL concentration before and after incubation at 37 degrees C for 90 min divided by the pre-incubation prebeta1-HDL concentration. RESULTS: Pitavastatin led to significant decreases in TC by 26.9% and LDL-C by 39.8%. HDL-C and HDL(2)-C increased significantly by 6.0% and 9.0%, respectively, but there was no significant change in HDL(3)-C. Prebeta1-HDL concentration significantly decreased (-8.7%; p<0.05); however, its disappearance rate significantly increased (13.0%; p<0.05). There were significant decreases in both LCAT activity and CETP mass. CONCLUSION: Although pitavastatin decreased plasma prebeta1-HDL concentration, it increased the prebeta1-HDL disappearance rate. These data suggest that pitavastatin might promote the early step of reverse cholesterol transport.

Serum ghrelin and carotid atherosclerosis in older Japanese people with metabolic syndrome.

Ghrelin may play a role in the development of atherosclerosis. However, the effect of serum ghrelin on carotid intima-media thickness (cIMT) (well-established as a surrogate marker to atherosclerosis) in metabolic syndrome (MS), particularly among relatively older subjects, has still not been thoroughly investigated. A total of 101 subjects >60 years of age (mean age, 72.3 years) with MS were enrolled in the study to investigate the relationship between serum total ghrelin and B-mode ultrasonographic cIMT levels. There were significantly positive correlations between cIMT and both age and systolic BP, but cIMT was significantly inversely correlated to ghrelin levels. In the multiple regression analysis for cIMT adjusted by other measured parameters, ghrelin was a significant and independent factor along with age and systolic BP. These findings suggest that decreased ghrelin levels may be related to carotid atherosclerosis among older subjects with MS.

[Evaluation of samples that indicated the difference of immunoglobulin values between different assays].

Since the immunoglobulin levels of survey samples for the survey of Japanese Association of Medical Tech7ologists in 2003, especially the IgA and IgM, became different by the immunological methods (LAIA [latex agglutination immunoassay] and TIA [turbidimetric immunoassay]), the cause of difference was investigated. From the results of gel filtration and immunoblotting analysis, it was suggested that profiles of the reaction of purified IgA and IgM polymers in survey samples were different on each method. In the case of M protein, also, there were higher levels of IgM and IgA type M protein by TIA and SRID methods than other methods even though the precipitation curve was obscure. Similarly, several samples from patients with M protein demonstrated higher values by SRID method than that of other methods. When these samples were analyzed by gel filtration and immunoblotting, they did not indicate the presence of the polymeric IgM. It will be suggested that non-specific reactions on TIA (weak reaction) and SRID (unusual precipitin line) methods were present. Furthermore, in a case of IgM type M protein, IgM level was twice higher by LAIA than that by TIA. However, it did not indicate any polymer or fragment of IgM by gel filtration and immunoblotting. Accordingly, it was assumed that the difference in measured values between the methods was attributable to the difference of the reaction to the samples.

Involvement of the tumor necrosis factor (TNF)/TNF receptor system in leukemic cell apoptosis induced by histone deacetylase inhibitor depsipeptide (FK228).

Inhibition of histone deacetylase (HDAC) is a novel strategy for the treatment of leukemias via restoration of aberrantly silenced genes. In this study, we conducted a detailed analysis of anti-leukemic effects of an HDAC inhibitor (HDI), depsipeptide (FK228), using myeloid leukemia cell lines HL-60 and K562. DNA chip analysis revealed upregulation of TNF-alpha mRNA and a number of molecules involved in TNF-signaling such as TRAF-6, caspases-10, and -7 in depsipeptide-treated HL-60 cells, which prompted us to examine the involvement of the TNF/TNF receptor system in the anti-leukemic effects of the drug. Upregulation of TNF-alpha was induced by depsipeptide in HL-60 and K562 cells, which expressed type I TNF receptors (TNF-RI). Depsipeptide activated caspases-8 and -10, which in turn cleave caspases-3 and -7, leading to apoptotic cell death in both cell lines. Anti-TNF-alpha neutralizing antibody and short interfering RNA (siRNA) against TNF-RI alleviated the activation of the caspase cascade and the induction of apoptosis, indicating the presence of an autocrine loop. Finally, we demonstrated that the enhanced production of TNF-alpha by depsipeptide was due to transcriptional activation of the TNF-alpha gene through hyperacetylation of histones H3 and H4 in its promoter region (-208 to +35). These results suggest that autocrine production of TNF-alpha plays a role in the cytotoxicity of depsipeptide against a subset of leukemias.