Tomoyuki Kawada

Ankle-Brachial Blood Pressure Index Predicts All-Cause and Cardiovascular Mortality in Hemodialysis Patients

A reduction in ankle-brachial BP index (ABPI) is associated with generalized atherosclerotic diseases and predicts cardiovascular mortality and morbidity in several patient populations. However, a large-scale analysis of ABPI is lacking for hemodialysis (HD) patients, and its use in this population is not fully validated. A cohort of 1010 Japanese patients undergoing chronic hemodialysis was studied between November 1999 and May 2002. Mean age at entry was 60.6 +/- 12.5 yr, and duration of follow-up was 22.3 +/- 5.6 mo. Patients were stratified into five groups (< 0.9, > or = 0.9 to < 1.0, > or = 1.0 to < 1.1, > or = 1.1 to < 1.3, and > or = 1.3) by ABPI measured at entry by an oscillometric method. The frequency distribution of ABPI was 16.5% of patients < 0.9, 8.6% of patients > or = 0.9 to < 1.0, 16.9% of patients 1.0 > or = to < 1.1, and 47.0% of patients > or 1.1 to < 1.3, whereas 10.9% of patients had an abnormally high ABPI (> or = 1.3). The relative risk of a history of diabetes mellitus (DM), cardiovascular, and cerebrovascular disease was significantly higher in patients with lower ABPI than those with ABPI > or = 1.1 to <1.3. During the study period, 77 cardiovascular and 41 noncardiovascular fatal events occurred. On the basis of Cox proportional hazards regression analysis, ABPI emerged as a strong independent predictor of all-cause and cardiovascular mortality. After adjustment for confounding variables, the hazard ratio (HR) for ABPI < 0.9 was 4.04 (95% confidence interval, 2.38 to 6.95) for all-cause mortality and 5.90 (2.83 to 12.29) for cardiovascular mortality. Even those with modest reductions in the ABPI (> or = 0.9 to <1.1) appeared to be at increased risk. Patients having abnormally high ABPI (> or = 1.3) also had poor prognosis (HR, 2.33 [1.11 to 4.89] and 3.04 [1.14 to 8.12] for all-cause and cardiovascular mortality, respectively). Thus, the present findings validate ABPI as a powerful and independent predictor for all-cause and cardiovascular mortality among hemodialysis patients.

Predictors of dementia in Parkinson disease: A prospective cohort study

Objective: We investigated an array of possible markers of early dementia in Parkinson disease. Methods: We performed a comprehensive assessment of autonomic, sleep, psychiatric, visual, olfactory, and motor manifestations in 80 patients with Parkinson disease who were dementia-free at baseline. After 4.4 years’ follow-up, patients were evaluated for dementia. Predictive variables were assessed using logistic regression adjusting for disease duration, follow-up duration, age, and sex. Results: Of 80 patients, 27 (34%) developed dementia. Patients destined to develop dementia were older and more often male (odds ratio [OR] = 3.64, p = 0.023). Those with baseline mild cognitive impairment had increased dementia risk (OR = 22.5, p < 0.001). REM sleep behavior disorder at baseline dramatically increased dementia risk (OR = 49.7, p = 0.001); however, neither daytime sleepiness nor insomnia predicted dementia. Higher baseline blood pressure increased dementia risk (OR = 1.37 per 10 mm Hg, p = 0.032). Orthostatic blood pressure drop was strongly associated with dementia risk (OR = 1.84 per 10 mm Hg, p < 0.001); having a systolic drop of >10 mm Hg increased dementia odds 7-fold (OR = 7.3, p = 0.002). Abnormal color vision increased dementia risk (OR = 3.3, p = 0.014), but olfactory dysfunction did not. Among baseline motor variables, proportion of gait involvement (OR = 1.12, p = 0.023), falls (OR = 3.02, p = 0.042), and freezing (OR = 2.63, p = 0.013), as well as the Purdue Pegboard Test (OR = 0.67, p = 0.049) and alternate tap test (OR = 0.97, p = 0.033) predicted dementia. Conclusion: Cardiovascular autonomic dysfunction, REM sleep behavior disorder, color discrimination ability, and gait dysfunction strongly predict development of dementia in Parkinson disease.

Forest bathing enhances human natural killer activity and expression of anti-cancer proteins.

In order to explore the effect of forest bathing on human immune function, we investigated natural killer (NK) activity; the number of NK cells, and perforin, granzymes and granulysin-expression in peripheral blood lymphocytes (PBL) during a visit to forest fields. Twelve healthy male subjects, age 37–55 years, were selected with informed consent from three large companies in Tokyo, Japan. The subjects experienced a three-day/two-night trip in three different forest fields. On the first day, subjects walked for two hours in the afternoon in a forest field; and on the second day, they walked for two hours in the morning and afternoon, respectively, in two different forest fields. Blood was sampled on the second and third days, and NK activity; proportions of NK, T cells, granulysin, perforin, and granzymes A/B-expressing cells in PBL were measured. Similar measurements were made before the trip on a normal working day as the control. Almost all of the subjects (11/12) showed higher NK activity after the trip (about 50% increased) compared with before. There are significant differences both before and after the trip and between days 1 and 2 in NK activity. The forest bathing trip also significantly increased the numbers of NK, perforin, granulysin, and granzymes A/B-expressing cells. Taken together, these findings indicate that a forest bathing trip can increase NK activity, and that this effect at least partially mediated by increasing the number of NK cells and by the induction of intracellular anti-cancer proteins.

Association between high-sensitivity cardiac troponin T levels and the predicted cardiovascular risk in middle-aged men without overt cardiovascular disease

BACKGROUND A slight elevation of cardiac troponin T (TnT) levels in the circulating blood can be detected by the recently developed, high-sensitivity TnT (hsTnT) assay. However, it remains unclear whether a slight elevation of hsTnT is associated with an increased cardiovascular risk in subjects without overt cardiovascular disease (CVD). METHODS The serum hsTnT levels were measured in a work site-based population of 1,072 middle-aged males (mean age 44 years) without any history or presence of CVD. The lower detection limit of the hsTnT assay used in the present study was 0.002 ng/mL. The association of the hsTnT levels with cardiovascular risk factors and the predicted CVD risk, as determined by the Framingham CVD risk prediction score, were examined. RESULTS Detectable hsTnT levels were seen in 867 subjects (80.9%). The highest value of the hsTnT was 0.020 ng/mL. Among various cardiovascular risk factors, age, blood pressure, estimated glomerular filtration rate, current smoking, and left ventricular hypertrophy were independent determinants of hsTnT levels. The odds ratio for a high predicted CVD risk (10-year risk > or =20%) in the highest tertile of hsTnT (> or =0.005 ng/mL) in comparison to the lowest tertile (< or =0.002 ng/mL) was 3.98 (95% CI 1.72-9.24, P = .001) after adjusting for multiple potential confounders. CONCLUSIONS The present study showed the hsTnT levels to be significantly associated with several cardiovascular risk factors and the predicted CVD risk in middle-aged men without overt CVD, thus suggesting the usefulness of measuring hsTnT to identify high-risk subjects in the primary prevention of CVD.

Phytoncides (Wood Essential Oils) Induce Human Natural Killer Cell Activity

To explore the effect of forest bathing on the human immune system, we investigated the effect of phytoncides (wood essential oils) on natural killer (NK) activity and the expression of perforin, granzyme A and granulysin in human NK cells. We used NK-92MI cell, an interleukin-2 independent human NK cell line derived from the NK-92 cell, in the present study. NK-92MI cells express the CD56 surface marker, perforin, granzyme A, and granulysin by flow cytometry and are highly cytotoxic to K562 cells in chromium release assay. Phytoncides significantly increase cytolytic activity of NK-92MI cells in a dose-dependent manner and significantly increase the expression of perforin, granzyme A, and granulysin in the NK-92MI cells. Phytoncides also partially, but significantly, restore the decreased human NK activity and the decreased perforin, granzyme A, and granulysin expression in NK-92MI cells induced by dimethyl 2,2-dichlorovinyl phosphate (DDVP), an organophosphorus pesticide. Pretreatment with phytoncides partially prevents DDVP-induced inhibition of NK activity. Taken together, these data indicate that phytoncides significantly enhance human NK activity and this effect is at least partially mediated by induction of intracellular perforin, granzyme A, and granulysin.

Self-rated health and life prognosis

BACKGROUND Effects of self-rated health on survival using prospective surveys were evaluated during the past 20 years mainly in Europe and the US. An overview on this field of research was necessary to know the range of risk ratio (RR) of poor self-rated health. METHODS The MEDLINE database from 1982 until the end of 2001 was assessed. Self-rated health, mortality, and associated terms were used as key words and information retrieval was executed. After reference papers were broadly collected, 30 papers that included relative risk or odds ratio (OR) to express risk of poor self-rated health on survival were precisely reviewed. RR or OR of poor self-rated health against excellent self-rated health-controlling factors also recognized as relating to survival was calculated in these papers using multiple logistic regression or Cox regression analysis. RESULTS Multiple logistic regression analysis was frequently used in the first 10 years and Cox regression analysis was subsequently adopted in the following 10 years. Nearly one half of the study subjects were followed up for 5 years or less, and two thirds of the studies had a target population <5,000 persons. Mortality was largely dependent on age and ranged from 4.6 to 33%. When 54 data with 95% confidence interval (95% CI) were checked, statistical significance was observed in 41 data (75.9%). CONCLUSIONS Self-rated health is an independent predictor of survival that controls for other related health indicators or covariates. These types of research should be conducted not only in Western countries, but also in other areas including Japan.

EM703 improves bleomycin-induced pulmonary fibrosis in mice by the inhibition of TGF-β signaling in lung fibroblasts

BackgroundFourteen-membered ring macrolides have been effective in reducing chronic airway inflammation and also preventing lung injury and fibrosis in bleomycin-challenged mice via anti-inflammatory effects. EM703 is a new derivative of erythromycin (EM) without the bactericidal effects. We investigated the anti-inflammatory and antifibrotic effects of EM703 in an experimental model of bleomycin-induced lung injury and subsequent fibrosis in mice.MethodsSeven-week-old male ICR mice were used. All experiments used eight mice/group, unless otherwise noted in the figure legends. Bleomycin was administered intravenously to the mice on day 0. EM703 was orally administered daily to mice. All groups were examined for cell populations in the bronchoalveolar lavage (BAL) fluid and for induction of messenger RNA (mRNA) of Smad3 and Smad4 in the lung tissues by reverse transcriptase (RT)-polymerase chainreaction (PCR) on day 7. Fibroblastic foci were assessed histologically, and the hydroxyproline content was chemically determined in the lung tissues on day 28. We performed assay of proliferation and soluble collagen production, and examined the induction of mRNA of Smad3 and Smad4 by RT-PCR in murine lung fibroblast cell line MLg2908. We also examined Smad3, Smad4 and phosphorylated Smad2/3 (p-Smad2/3) protein assay by western blotting in MLg2908.ResultsBleomycin-induced lung fibrosis, and the infiltration of macrophages and neutrophils into the airspace were inhibited by EM703. The expression of Smad3 and Smad4 mRNA was clearly attenuated by bleomycin, but was recovered by EM703. EM703 also inhibited fibroblast proliferation and the collagen production in lung fibroblasts induced by Transforming growth factor-beta (TGF-β). The expression of Smad3 and Smad4 mRNA in murine lung fibroblasts disappeared due to TGF-β, but was recovered by EM703. EM703 inhibited the expression of p-Smad2/3 and Smad4 protein in murine lung fibroblasts induced by TGF-β.ConclusionThese findings suggest that EM703 improves bleomycin-induced pulmonary fibrosis in mice by actions of anti-inflammation and regulation of TGF-β signaling in lung fibroblasts.

Chlorpyrifos induces apoptosis in human T cells.

It was found previously that organophosphorus pesticides (OPs) significantly inhibited cytotoxic T lymphocyte (CTL) activity. To explore the mechanism of OP-induced inhibition of CTL activity, the present study investigated whether OPs can induce cell death/apoptosis in T cells. Jurkat human T cells were treated with chlorpyrifos at 0-100 ppm for 2, 4, and 6h at 37 degrees C in vitro. It was found that chlorpyrifos induced cell death of Jurkat human T cells in a dose- and time-dependent manner, as shown by MTT and LDH assays. Then, it was investigated if chlorpyrifos-induced cell death consisted of apoptosis, as determined by analysis of Annexin-V staining and the intracellular level of active caspase-3 by flow cytometry, and DNA fragmentation analysis. It was found that chlorpyrifos induces apoptosis in Jurkat T cells in a dose- and time-dependent manner, as determined by analysis of Annexin-V staining. DNA fragmentation was detected when cells were treated with 50 or 100 ppm chlorpyrifos for 4 and 6h. Chlorpyrifos also induced an increase in intracellular active caspase-3 in Jurkat T cells in a dose- and time-dependent manner, and a caspase-3 inhibitor, Z-DEVD-FMK, significantly inhibited chlorpyrifos-induced apoptosis. These findings indicate that chlorpyrifos can induce apoptosis in human Jurkat T cell cells, and this effect is partially mediated by the activation of intracellular caspase-3.

Effect of phytoncide from trees on human natural killer cell function.

We previously reported that the forest environment enhanced human natural killer (NK) cell activity, the number of NK cells, and intracellular anti-cancer proteins in lymphocytes, and that the increased NK activity lasted for more than 7 days after trips to forests both in male and female subjects. To explore the factors in the forest environment that activated human NK cells, in the present study we investigate the effect of essential oils from trees on human immune function in twelve healthy male subjects, age 37–60 years, who stayed at an urban hotel for 3 nights from 7.00p.m. to 8.00a.m. Aromatic volatile substances (phytoncides) were produced by vaporizing Chamaecyparis obtusa (hinoki cypress) stem oil with a humidifier in the hotel room during the night stay. Blood samples were taken on the last day and urine samples were analysed every day during the stay. NK activity, the percentages of NK and T cells, and granulysin, perforin, granzyme A/B-expressing lymphocytes in blood, and the concentrations of adrenaline and noradrenaline in urine were measured. Similar control measurements were made before the stay on a normal working day. The concentrations of phytoncides in the hotel room air were measured. Phytoncide exposure significantly increased NK activity and the percentages of NK, perforin, granulysin, and granzyme A/B-expressing cells, and significantly decreased the percentage of T cells, and the concentrations of adrenaline and noradrenaline in urine. Phytoncides, such as α-pinene and β-pinene, were detected in the hotel room air. These findings indicate that phytoncide exposure and decreased stress hormone levels may partially contribute to increased NK activity.

Cadmium, NAG activity, and beta 2-microglobulin in the urine of cadmium pigment workers.

Cadmium (Cd), N-acetyl-beta-D-glucosaminidase (NAG) activity, beta 2-microglobulin (BMG), and creatinine (cr) in urine were measured during April and September 1986 in workers exposed to cadmium pigment dust (maximum exposure 3.0 micrograms/m3/8 h for respirable dust). In April and September urinary Cd ranged from 0.2 to 9.5 and from 0.5 to 7.0 micrograms/g cr with a geometric mean of 0.7 and 1.2 micrograms/g cr, respectively. The correlation coefficient between Cd and NAG was 0.261 (n = 61) in April and 0.389 (n = 50) in September. The correlation coefficient between Cd and BMG was 0.241 (n = 63) in April and 0.115 (n = 50) in September. It appears that urinary Cd concentrations have a closer relation with urinary NAG than urinary BMG, even when urinary Cd concentrations are less than 10 micrograms/g cr. It is concluded that NAG is a more sensitive indicator of Cd absorption than BMG even at urinary Cd concentrations of less than 10 micrograms/g cr.