Kazuki Ide

Green tea consumption affects cognitive dysfunction in the elderly: a pilot study.

Green tea is known to have various health benefits for humans. However, the effect of green tea consumption on cognitive dysfunction remains to be clinically verified. We conducted a clinical study to investigate the effects of green tea consumption on cognitive dysfunction. Twelve elderly nursing home residents with cognitive dysfunction (Mini-Mental State Examination Japanese version (MMSE-J) score: <28) participated in the study (2 men, 10 women; mean age, 88 years). The participants consumed green tea powder 2 g/day for 3 months. After three months of green tea consumption, the participants’ MMSE-J scores were significantly improved (before, 15.3 ± 7.7; after, 17.0 ± 8.2; p = 0.03). This result suggests that green tea consumption may be effective in improving cognitive function or reducing the progression of cognitive dysfunction; however, long-term large-scale controlled studies are needed to further clarify the effect.

Involvement of glucocorticoid-mediated Zn2+ signaling in attenuation of hippocampal CA1 LTP by acute stress.

Glucocorticoid-glutamatergic interactions have been proposed as a potential model to explain stress-mediated impairment of cognition. However, it is unknown whether glucocorticoid-zincergic interactions are involved in this impairment. Histochemically reactive zinc (Zn(2+)) is co-released with glutamate from zincergic neurons. In the present study, involvement of synaptic Zn(2+) in stress-induced attenuation of CA1 LTP was examined in hippocampal slices from young rats after exposure to tail suspension stress for 30s, which significantly increased serum corticosterone. Stress-induced attenuation of CA1 LTP was ameliorated by administration of clioquinol, a membrane permeable zinc chelator, to rats prior to exposure to stress, implying that the reduction of synaptic Zn(2+) by clioquinol participates in this amelioration. To pursue the involvement of corticosterone-mediated Zn(2+) signal in the attenuated CA1 LTP by stress, dynamics of synaptic Zn(2+) was checked in hippocampal slices exposed to corticosterone. Corticosterone increased extracellular Zn(2+) levels measured with ZnAF-2 dose-dependently, as well as the intracellular Ca(2+) levels measured with calcium orange AM, suggesting that corticosterone excites zincergic neurons in the hippocampus and increases Zn(2+) release from the neuron terminals. Intracellular Zn(2+) levels measured with ZnAF-2DA were also increased dose-dependently, but not in the coexistence of CaEDTA, a membrane-impermeable zinc chelator, suggesting that intracellular Zn(2+) levels is increased by the influx of extracellular Zn(2+). Furthermore, corticosterone-induced attenuation of CA1 LTP was abolished in the coexistence of CaEDTA. The present study suggests that corticosterone-mediated increase in postsynaptic Zn(2+) signal in the cytosolic compartment is involved in the attenuation of CA1 LTP after exposure to acute stress.

Therapeutic effect of Yokukansan on social isolation-induced aggressive behavior of zinc-deficient and pair-fed mice

In patients with dementia including Alzheimers disease, hallucinations, agitation/aggression and irritability are known to frequently occur and as distressing behavioral and psychological symptoms of dementia (BPSD). On the basis of the evidence on clinical efficacy and safety of Yokukansan, a traditional Japanese herbal medicine, on BPSD, in the present study, Yokukansan was examined in the therapeutic effects on social isolation-induced aggressive behavior of zinc-deficient and pair-fed mice. Yokukansan was p.o. administered for 7 days as a drinking water to isolated mice fed a zinc-deficient diet for 10 days, which exhibited aggressive behavior, and isolated pair-fed mice fed a control diet of the amount consumed by zinc-deficient mice for 10 days, which exhibited aggressive behavior. Aggressive behavior was evaluated by the resident-intruder test. Yokukansan (312 mg/kg/day) attenuated both aggressive behaviors of zinc-deficient and pair-fed mice. Because Yokukansan can suppress abnormal glutamatergic neuron activity, MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, and aminooxyacetic acid (AOAA), a γ-amino butyric acid (GABA) transaminase blocker, were also examined in the effects on social isolation-induced aggressive behavior. MK-801 (0.1 mg/kg) or AOAA (23 mg/kg) was i.p. injected into isolated aggressive mice. Thirty minutes later, the resident-intruder test was performed to evaluate the effect of the drugs. Both drugs attenuated aggressive behavior of zinc deficient mice, but not that of pair-fed mice. These results suggest that Yokukansan ameliorates social isolation-induced aggressive behavior of zinc-deficient and pair-fed mice through the action against glutamatergic neurotransmitter system and other neurotransmitter systems.

Distribution of Total Depressive Symptoms Scores and Each Depressive Symptom Item in a Sample of Japanese Employees

Background In a previous study, we reported that the distribution of total depressive symptoms scores according to the Center for Epidemiologic Studies Depression Scale (CES-D) in a general population is stable throughout middle adulthood and follows an exponential pattern except for at the lowest end of the symptom score. Furthermore, the individual distributions of 16 negative symptom items of the CES-D exhibit a common mathematical pattern. To confirm the reproducibility of these findings, we investigated the distribution of total depressive symptoms scores and 16 negative symptom items in a sample of Japanese employees. Methods We analyzed 7624 employees aged 20–59 years who had participated in the Northern Japan Occupational Health Promotion Centers Collaboration Study for Mental Health. Depressive symptoms were assessed using the CES-D. The CES-D contains 20 items, each of which is scored in four grades: “rarely,” “some,” “much,” and “most of the time.” The descriptive statistics and frequency curves of the distributions were then compared according to age group. Results The distribution of total depressive symptoms scores appeared to be stable from 30–59 years. The right tail of the distribution for ages 30–59 years exhibited a linear pattern with a log-normal scale. The distributions of the 16 individual negative symptom items of the CES-D exhibited a common mathematical pattern which displayed different distributions with a boundary at “some.” The distributions of the 16 negative symptom items from “some” to “most” followed a linear pattern with a log-normal scale. Conclusions The distributions of the total depressive symptoms scores and individual negative symptom items in a Japanese occupational setting show the same patterns as those observed in a general population. These results show that the specific mathematical patterns of the distributions of total depressive symptoms scores and individual negative symptom items can be reproduced in an occupational population.

Methods for estimating causal relationships of adverse events with dietary supplements

Objective Dietary supplement use has increased over past decades, resulting in reports of potentially serious adverse events. The aim of this study was to develop optimised methods to evaluate the causal relationships between adverse events and dietary supplements, and to test these methods using case reports. Design Causal relationship assessment using prospectively collected data. Setting and participants 4 dietary supplement experts, 4 pharmacists and 11 registered dietitians (5 men and 14 women) examined 200 case reports of suspected adverse events using the modified Naranjo scale and the modified Food and Drug Administration (FDA) algorithm. Primary outcome measures The distribution of evaluation results was analysed and inter-rater reliability was evaluated for the two modified methods employed using intraclass correlation coefficients (ICC) and Fleiss’ κ. Results Using these two methods, most of the 200 case reports were categorised as ‘lack of information’ or ‘possible’ adverse events. Inter-rater reliability among entire assessors ratings for the two modified methods, based on ICC and Fleiss’ κ, were classified as more than substantial (modified Naranjo scale: ICC (95% CI) 0.873 (0.850 to 0.895); Fleiss’ κ (95% CI) 0.615 (0.615 to 0.615). Modified FDA algorithm: Fleiss’ κ (95% CI) 0.622 (0.622 to 0.622). Conclusions These methods may help to assess the causal relationships between adverse events and dietary supplements. By conducting additional studies of these methods in different populations, researchers can expand the possibilities for the application of our methods.

Relationship between Item Responses of Negative Affect Items and the Distribution of the Sum of the Item Scores in the General Population

Background Several studies have shown that total depressive symptom scores in the general population approximate an exponential pattern, except for the lower end of the distribution. The Center for Epidemiologic Studies Depression Scale (CES-D) consists of 20 items, each of which may take on four scores: “rarely,” “some,” “occasionally,” and “most of the time.” Recently, we reported that the item responses for 16 negative affect items commonly exhibit exponential patterns, except for the level of “rarely,” leading us to hypothesize that the item responses at the level of “rarely” may be related to the non-exponential pattern typical of the lower end of the distribution. To verify this hypothesis, we investigated how the item responses contribute to the distribution of the sum of the item scores. Methods Data collected from 21,040 subjects who had completed the CES-D questionnaire as part of a Japanese national survey were analyzed. To assess the item responses of negative affect items, we used a parameter r, which denotes the ratio of “rarely” to “some” in each item response. The distributions of the sum of negative affect items in various combinations were analyzed using log-normal scales and curve fitting. Results The sum of the item scores approximated an exponential pattern regardless of the combination of items, whereas, at the lower end of the distributions, there was a clear divergence between the actual data and the predicted exponential pattern. At the lower end of the distributions, the sum of the item scores with high values of r exhibited higher scores compared to those predicted from the exponential pattern, whereas the sum of the item scores with low values of r exhibited lower scores compared to those predicted. Conclusions The distributional pattern of the sum of the item scores could be predicted from the item responses of such items.

Effects of Green Tea Gargling on the Prevention of Influenza Infection in High School Students: A Randomized Controlled Study

Background The anti-influenza virus activity of green tea catechins has been demonstrated in experimental studies, but clinical evidence has been inconclusive. School-aged children play an important role in the infection and spread of influenza in the form of school-based outbreaks. Preventing influenza infection among students is essential for reducing the frequency of epidemics and pandemics. As a non-pharmaceutical intervention against infection, gargling is also commonly performed in Asian countries but has not yet been extensively studied. Methods and Findings A randomized, open label, 2-group parallel study of 757 high school students (15 to 17 years of age) was conducted for 90 days during the influenza epidemic season from December 1st, 2011 to February 28th, 2012, in 6 high schools in Shizuoka Prefecture, Japan. The green tea gargling group gargled 3 times a day with bottled green tea, and the water gargling group did the same with tap water. The water group was restricted from gargling with green tea. The primary outcome measure was the incidence of laboratory-confirmed influenza using immunochromatographic assay for antigen detection. 757 participants were enrolled and 747 participants completed the study (384 in the green tea group and 363 in the water group). Multivariate logistic regression indicated no significant difference in the incidence of laboratory-confirmed influenza between the green tea group (19 participants; 4.9%) and the water group (25 participants; 6.9%) (adjusted OR, 0.69; 95%CI, 0.37 to 1.28; P = 0.24). The main limitation of the study is the adherence rate among high school students was lower than expected. Conclusions Among high school students, gargling with green tea three times a day was not significantly more efficacious than gargling with water for the prevention of influenza infection. In order to adequately assess the effectiveness of such gargling, additional large-scale randomized studies are needed. Trial Registration ClinicalTrials.gov NCT01225770

The Effect of Green Tea With Exceptionally High Catechin Content on Nadolol Plasma Concentration

To the Editor: We read with great interest the article “Green Tea Ingestion Greatly Reduces Plasma Concentrations of Nadolol in Healthy Subjects,” by Misaka et al.1 The authors claim that repeated ingestion of green tea reduces nadolol plasma concentrations, and suggest that green tea catechins may have an inhibitory effect on the organic anion– transporting polypeptide 1A2. There is no doubt that food–drug interaction studies on common beverages are important for developing safe pharmaceutical treatments2,3; however, this study was conducted with an atypical type of green tea and under unusual conditions. The green tea–type beverage used in this study is classed as a “Food for Specified Health Use” by the Ministry of Health, Labour, and Welfare of Japan. It contains exceptionally high total catechin content: ~540 mg/ bottle (350 ml; data obtained from Kao Corporation, Tokyo, Japan), constituting a total catechin concentration of 154 mg/dl. This concentration is two to five times higher than that of typical bottled green tea sold in Japan.4 This concentration is closer to that of a dietary supplement than to that of a beverage consumed for refreshment. In fact, in their article the authors do not report the total catechin concentration of the beverage. Instead, they report separate concentrations for only four types of catechins present in the beverage, despite the fact that several additional types of catechins must also have been present. This may give the impression that the beverage has a lower total catechin concentration than it actually does. The unusual design of the study also raises some concern. The study subjects took nadolol with 700 ml of the green tea beverage or water. However, it is uncommon in Japan to take medication with green tea—especially with green tea beverages that have large quantities of catechins. To ingest the same quantity of catechins consumed by subjects in this study, 2–3 liters of typical bottled green tea would have to be consumed with a single dose of nadolol. Even if the inhibitory effect observed in the authors’ in vitro study accurately reflects an effect in humans, this effect does not realistically reflect the way in which patients ordinarily take medication. We strongly recommend further investigation into the concentrationdependent effects of green tea; however, studies that more realistically reflect actual green tea consumption patterns should provide more useful information for assessing the potential risks associated with consuming green tea.

Behaviors of consumers, physicians and pharmacists in response to adverse events associated with dietary supplement use

BackgroundThe prevalence of dietary supplements has increased in Japan, and, as a consequence, the adverse events associated with dietary supplement use have become more prominent. Severe adverse events must be reported to the Japanese government via public health centers. However, the number of cases reported to the Japanese government is limited. To clarify this discrepancy, we conducted an internet questionnaire, and surveyed how consumers, physicians and pharmacists acted when they or their patients developed adverse events due to dietary supplement use.MethodsThis study was completed by 2732 consumers, 515 physicians, and 515 pharmacist via internet surveillance on November 2015.ResultsAlthough 8.8% of consumers developed adverse events including diarrhea, constipation, stomachache, headache, and nausea and vomiting, most of them did not report their adverse events to public health centers. However, some consumers went to hospitals because of adverse events. We also surveyed how physicians and pharmacists acted when their patients developed adverse events due to dietary supplement use. Most physicians and pharmacists did not report these cases to public health centers because they were unable to definitively prove the cause-and-effect relationship of these adverse events. Furthermore, some physicians and pharmacists did not know how or where to report these adverse events.ConclusionsWe clarified the reasons for the limited number of reports of adverse events to the Japanese government in this survey. It is important to encourage not only consumers, but also physicians and pharmacists to report adverse events to public health centers. In addition, an analyzing tool of cause-and-effect relationships might be helpful for physicians and pharmacists.

Age-related changes in the distributions of depressive symptom items in the general population: a cross-sectional study using the exponential distribution model

Background. Previous research has reported inconsistent evidence of the trajectory of depressive symptoms across the adult lifespan. We investigated how the distributions of each item score change with age and determined whether the trajectory of depressive symptoms varied with the scoring methods of the questionnaire. Methods. We analyzed data collected from 21,040 subjects who participated in the national survey in Japan. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The CES-D has 20 items, each of which is scored in four grades of “rarely,” “some,” “much,” and “most of the time.” We used the exponential distribution model which fits the distributions of 16 negative symptom items of CES-D, with the probabilities of “some,” “much,” “most,” and “rarely” expressed as P, Pr, Pr2, and 1 − P × (r2 + r + 1). Results. The distributions of the responses to 16 negative symptom items followed the common exponential model across all age groups. The mean of the estimated parameter r of 16 negative items showed a U-shape pattern, being high during 12–29 years, remaining low during 30–50 years, and then increasing again over 60 years. The trajectory of depressive symptom scores simulating the binary method was different from that of the empirical scores using the Likert method. Conclusions. Our findings show that the increase in the depressive symptoms score during older age is based on the increase of the parameter r. The differences in the scoring method may contribute to the different age-related patterns across the adult lifespan.