Katsutoshi Terasawa

Suicide attempt and n-3 fatty acid levels in red blood cells: A case control study in china

BACKGROUND Epidemiologic studies show that low fish intake is a risk factor of suicidality; however, there are no case-control studies investigating suicide attempt risk and tissue n-3 fatty acid levels. METHODS We recruited 100 suicide-attempt cases and another 100 control patients injured by accidents who were admitted to three hospitals affiliated with Dalian Medical University in Dalian, China. Case and control subjects were matched for age, gender, and smoking status. Those who were inebriated at the time of hospitalization were excluded. Blood was sampled immediately after admission to a hospital. Washed red blood cells (RBCs) were obtained, and the fatty acid composition of the total RBC phospholipid fraction was analyzed by gas chromatography. RESULTS Eicosapentaenoic acid (EPA) levels in RBC in the case subjects were significantly lower than those of the control subjects (.74 +/-.52% vs. 1.06 +/-.62%, p <.0001). When the highest and lowest quartiles of EPA in RBC were compared, the odds ratios of suicide attempt was.12 in the highest quartile (95% confidence interval:.04-.36, p for trend =.0001) after adjustment for possible confounding factors CONCLUSIONS Our findings suggest that low n-3 fatty acid levels in tissues were a risk factor of suicide attempt. Further studies including intervention with fish oil are warranted.

Evidence-based Reconstruction of Kampo Medicine: Part II—The Concept of Sho

In this lecture, I would like to focus on and discuss what I think is the central concept of Kampo: the concept of Sho. It can be roughly translated into English as, for example, symptoms, signs or evidence, and I shall try to explain (though not define) it in more detail in the second section of this article. There are several reasons why I try to represent Kampo practice as based centrally on Sho, besides the fact that I believe it is really part of the essence of Kampo. First, many Western scientists and physicians are put off from the start if they are told that it is impossible for them to understand traditional Chinese medicine (TCM) or Kampo without grasping the full complexities of its basic concepts such as Ying-Yang, five elements, five organs, Qi, etc. If Western scientists and physicians are told that the TCM paradigm is so different from modern Western medicine that they should first switch the paradigm itself, they will be hopeless when they try to come to terms with any specific Kampo or TCM remedies. In some sense this is true and it is very risky for Western physicians to pick up any Kampo or TCM formulae outside the context of Kampos cognitive paradigm. However, since saying that the paradigm should come first may only result in shutting the door against those who genuinely wish to enter the rich field of TCM or Kampo, I would think that it is more productive to first focus on what I think is the central medical concept of Kampo without going any deeper into its paradigm, philosophical foundations or the system itself. Secondly, I have to emphasize that TCM and Kampo are not monolithic ideological systems. They are broad systems of medical practice and thinking evolved over thousands of years. Therefore, the systems themselves have a rather wide variation. There have been many schools in TCM and Kampo and disputes among them are the rule, rather than the exception. Basic concepts like Yin-You (Ying-Yang in Chinese) or Ki (Qi in Chinese) have been held invariantly among different schools, but slightly different interpretations are common, even for such central concepts as Ying-Yang, and no less common are different emphases on more peripheral concepts. In the first article of this lecture series (1), I pointed out that Kampo could be seen as a simplified or practical version of TCM. Stated differently, Kampo is a sort of school or an important variant of TCM. In that article I stated that modern Kampo in Japan can be traced back to the 18th century Renaissance (or restoration) movement of the Koho (old formula) school of, for example, Yamawaki and Yoshimasu. Western readers may be astonished to know that Yoshimasu went so far as to suggest the irrelevance of the very concept of Ying-Yang, emphasizing, in effect, that anything should go as long as it is effective, regardless of philosophy. Though I should hastily add that such attitudes did not become orthodox in Japan, it cannot be denied that Kampo is less rigorous about its philosophical or ideological basis than the orthodox TCM. Thus, if I were asked by outsiders what the central concept held as consensus among Kampo practitioners in Japan is, I would say that it is Sho. Thirdly, it is very interesting to highlight the concept of Sho in this journal, Evidence-based CAM, because the Chinese character representing Sho can be translated in English to mean evidence. Also of interest is that the same word may have been differently represented in ancient Chinese character, the meaning of which in turn could be translated in English to mean symptom. Thus, the term Sho bears very interesting medical implications, unlike Ying-Yang or Qi, which would be of interest to any Western scientist or physician who wished to acquire medical knowledge about Kampo or TCM. Finally, there is a very practical reason peculiar to the Japanese situation surrounding Kampo. This is related to the governments policy on prescriptive drugs. In Japan, it is not possible for a physician to use TCMs three elements/eight categories interpretations in order for his/her Kampo formulae to be covered by the National Health Insurance System (NHIS). Thus, a Kampo formula, if it is to be covered by the NHIS, must be prescribed for disease entities expressed in terms of modern Western medicine, such as gastritis or atopic eczema. For rigorous practitioners of TCM this would be a great insult, as their diagnostic interpretations are not recognized as official or scientific categories of diseases. Thus, nowadays it has become more common for Japanese medical doctors to prescribe Kampo formula just by saying that the patient now has a condition which requires such formula. Though it has long been legitimate in Kampo to prescribe a formula as the patient is simply in its Sho, this tendency has become more prominent these days. For example, a patient can just be said to be Rikkunshi-To-Sho, regardless of his/her diagnosis in terms of modern western medicine. As I shall explain later, this situation arises in the Kampo system itself, where any symptoms (Sho) can be taken as evidence (Sho, again) for some formulae, and very often symptoms are called Sho-for-some Kampo formulae. As drugs covered by NHIS can only be prescribed by medical doctors trained in Western medicine in Japan, there is a tendency for them to use Kampo formula without paying much attention to the TCM interpretations of the symptoms of the patient. Therefore, I think the mainstream of Kampo is Sho-oriented, meaning that it does not rely so much on the rigorous interpretation of the disease state in terms of the basic TCM concepts as on the direct practical effects of a formula itself.

Evidence-based Reconstruction of Kampo Medicine: Part I—Is Kampo CAM?

I would like to express my hearty congratulations at the launching of the new journal Evidence-based Complementary and Alternative Medicine (eCAM). I would also like to thank the Editors, Drs Tomio Tada, Edwin Cooper and Nobuo Yamaguchi, for inviting me to contribute a lecture series on the evidential basis of Kampo (Chinese herbal) medicine. This series will run for several issues with the following main topics (in this issue the first three topics are mainly covered): Is Kampo CAM? The historical background of Kampo What characterizes Kampo? Herbal compositions of Kampo medicines Composition and analysis of Kampo medicines Sho (symptoms) Construction of evidence for Kampo, based on Sho Various designs for clinical trials to construct an evidential basis for Kampo Outline of the existing evidence of using Kampo for the treatment of various diseases Preliminary notes for those who are not acquainted with Kampo: the term ‘Kampo’ is a Japanese name for Chinese herbal medicine. The difference between ‘Chinese’ Chinese herbal medicine and Kampo will be discussed in the historical overview section. Sho is broadly defined as Kampo diagnosis in the epistemic framework of Kampos view of illness. The response to Kampo medicine is predicted by Sho.

Effects of Keishi-bukuryo-gan on vascular function and hemorheological factors in spontaneously diabetic (WBN/kob) rats

Keishi-bukuryo-gan (Gui-zhi-fu-ling-wan) is a formula used for the improvement of blood circulation. Recently it has often also been used for arteriosclerosis. One of the mechanisms involved is thought to be the improvement of endothelial dysfunction, but the details are still unclear. In this study, the effect of Keishi-bukuryo-gan on vascular function and hemorheological factors in spontaneously diabetic (WBN/kob) rats was studied. Rats were given Keishi-bukuryo-gan in chow for 30 weeks. Body weight, blood glucose, endothelium-dependent/-independent relaxation, vasocontraction by free radical-induced and contractive prostanoids, triglyceride, advanced glycation endproduct, lipid peroxides, serum NO2-/NO3- and blood viscosity were measured. The results indicated that Keishi-bukuryo-gan caused a decrease in endothelium-dependent relaxation by acetylcholine to become significantly increased, and vasocontraction induced by free radicals and contractive prostanoids was significantly decreased. Furthermore, serum NO2-/NO3- and blood viscosity were significantly decreased. From these results, it was supposed that Keishi-bukuryo-gan exerted a protective effect on the endothelium. The WBN/kob rat is a useful study model for the complications of human diabetes, and Keishi-bukuryo-gan showed a protective effect against vascular injury in the susceptible rat.

n−3 long-chain FA decrease serum levels of TG and remnant-like particle-cholesterol in humans

A large number of papers have reported that administration of n−3 FA reduced serum TG concentrations in hypertriglyceridemic patients. However, few studies have examined the effect of n−3 FA on serum concentrations of remnant-like particle (RLP) cholesterol. Volunteers (n=41) whose serum TG concentrations were 100–300 mg/dL were recruited and randomly assigned to either an n−3 FA group or a control group with stratification by sex, age, and serum TG level in a double-blind manner. The subjects in the n−3 FA group were administered 125 ml of fermented soybean milk with fish oil containing 600 mg of EPA and 260 mg of DHA/d for 12 wk. The controls consumed control soybean milk with olive oil. Fasting blood samples were obtained before the start of administration and at 4, 8 and 12 wk. EPA concentrations in red blood cells increased significantly in all but one subject in the n−3 FA group, with no significant changes in the control group. TG levels decreased more in the n−3 FA group than in the control group at weeks 4 (P<0.05), 8 (P<0.01), and 12 (P<0.05) with their baseline as covariate. RLP cholesterol levels decreased more in the n−3 FA group than in the control at weeks 8 (P<0.01) and 12 (P<0.05) with their baseline as covariate. The groups did not differ in the other lipid levels. It is likely that n−3 long-chain FA may exert anti-atherosclerotic effects by lowering serum TG and RLP-cholesterol levels even at the dose of 860 mg/d.

Enteric Excretion of Baicalein, a Flavone of Scutellariae Radix, via Glucuronidation in Rat: Involvement of Multidrug Resistance-Associated Protein 2

AbstractPurpose. Baicalin (BG) and its aglycone, baicalein (B), are strong antioxidants and have various pharmacological actions. The purpose of this study was to evaluate efflux of BG from rat intestinal mucosal cell following glucuronidation of B absorbed after oral administration of B. Methods. The absorption and excretion of BG and B were evaluated in rats using the in situ jejunal loop technique and in vitro jejunal everted sac experiments. BG and B levels were determined by high-performance liquid chromatography with electro-chemical detection to ensure selectivity and high sensitivity. Results. A large amount (30.4% recovery) of BG, but no B, was detected in the intestinal lumens of germ-free rats 4 h after oral administration of B (12.1 mg/kg), in comparison with a substantial recovery (55.1%) of unabsorbed BG 4 h after its administration. During the in situ rat jejunal loop absorption experiment, B disappeared rapidly, and 8% of the lost B was excreted into the loop as BG 20 min after infusing 0.1 mM B. In an in vitro absorption experiment using everted rat jejunal sac, BG also appeared outside the sac, accompanied by the disappearance of B from the outer (mucosal) side. However, very little of B was transferred to the inner (serosal) side of the sac, and only a trace of BG was detected inside the sac. Thus, in both the loop and the everted sac systems, the efflux of BG from the mucosal surface was saturated with the concentration of B added. Moreover, the efflux rate of BG in the everted jejunal sac from Eisai hyperbilirubinemic rat (EHBR) was significantly lower by 56.4% than that from Sprague-Dawley rat. Conclusions. These results indicate that, in rat, a large proportion of any B absorbed is retained, transformed into BG within the intestinal mucosal cells, and coordinately excreted through multidrug resis- tance-associated protein 2 (MRP2) into the intestinal lumen.

Evidence-based Reconstruction of Kampo Medicine: Part-III-How Should Kampo be Evaluated?

In the previous two lectures, I tried to explain in detail that the paradigm of Kampo is basically different from that of modern Western medicine, focusing especially on the concept of Sho. Kampo has been developed to cope with Sho, not with the disease entities understood in terms of modern Western medicine. Thus, there is little point asking, for example, ‘Are there any Kampo remedies effective for lung cancer (or type C hepatitis, or essential hypertension)?’ This question, asked wrongly, however, highlights two important issues, one intriguing and long term, and the other important and short term. The former is that the effects of Kampo herbs have so far not been tested properly against any of the specific disease entities defined in the framework of modern Western medicine. The latter is that we urgently need some methods to accommodate evaluation of the clinical effects of Kampo remedies in the framework of evidence-based medicine of the West.

The efficacy of a herbal medicine (Mao-to) in combination with intravenous natural interferon-β for patients with chronic hepatitis C, genotype 1b and high viral load: a pilot study

Patients with chronic hepatitis C, with a high serum viral load (> or = 1 Meq/ml) and genotype 1b seem to be resistant to interferon (IFN) therapy. To evaluate the efficacy of a herbal medicine (Mao-to) in combination with natural IFN-beta for the treatment of these patients, eighteen Japanese patients were enrolled in this study. Every patient received 6 million units (MU) of IFN-beta intravenously daily for 8 weeks. Mao-to was given orally 3-4 times a day during the IFN-beta administration, Sixteen of the 18 patients (89%) became negative for serum HCV RNA at the end of treatment, but only 2 of them (11%) remained negative for the virus RNA at 6 months of follow-up. Serum ALT levels normalized in 17 patients (94%) at 2 weeks of follow-up after the cessation of therapy, and 11 patients (61%) retained normal ALT levels for more than 6 months of follow-up. This rate of biochemical response was high as compared with that of therapy with IFN-beta alone (19%) in the largest IFN-beta trial in Japan. Serum hyaluronic acid levels were decreased significantly from 147.0 +/- 110.5 ng/ml to 77.4 +/- 67.4 ng/ml in the sustained biochemical response group (P = 0.003). None of the patients needed to interrupt therapy because of side effects of IFN-beta. Thus, Mao-to administration together with IFN-beta treatment could increase the sustained biochemical response rate, and reduce liver fibrosis.

The Efficacy of Herbal Medicine (Kampo) in Reducing the Adverse Effects of IFN-β in Chronic Hepatitis C

The purpose of this study was to determine if the adverse effects of interferon (IFN) in hepatitis C patients could be reduced by treatment with Japanese Oriental (Kampo) medicine. Twelve patients with chronic hepatitis C were treated with a combination of IFN-beta and either Mao-to or Dai-seiryu-to (groups A and B), and 16 patients were treated with IFN-beta alone (group C). Mao-to was administered to eight patients and Dai-seiryu-to was administered to four in groups A and B, respectively. Adverse effects were evaluated by clinical and laboratory examinations. The severity of symptoms was daily self-classified into four categories (1: none, 2: very slight, 3: moderate, and 4: serious), using a questionnaire consisting of 29 items. Scores of symptom such as discomfort and fever in group A, and discomfort, general malaise, paresthesia and arthralgia in group B were significantly lower than those in group C (p < 0.05). In all patients, HCV-RNA was negative at the end of the treatment, and serum alanine aminotransferase (ALT) levels had normalized transiently in all group A and B patients with genotype 1b by 2 weeks after cessation of IFN treatment. This study indicates that Kampo medicines are useful for reducing the adverse effects accompanying IFN treatment in patients with chronic hepatitis C without reducing the antiviral effects.

Natural killer cytolytic activity is associated with the expression of killer cell immunoglobulin-like receptors on peripheral lymphocytes in human

Although it has been shown that killer cell immunoglobulin-like receptors (KIRs) on peripheral lymphocytes are upregulated by interleukin-2 (IL-2), which activates natural killer (NK) activity, it has not been demonstrated whether the expression of KIRs is related to NK activity. Therefore, we investigated the association between the KIR expression on lymphocytes and NK activity. CD158a/b expression on lymphocytes obtained from 37 subjects was analyzed using flow cytometry. Simultaneously, NK activity was measured each sample using a 51Cr-release assay. Additionally, lymphocytes were cultured in RPMI 1640 medium with or without IL-2 for 48 h, and then their CD158a/b expression and NK activity was analyzed. CD158a/b expression was significantly correlated with NK activity. Especially, the percentage of CD16+CD158a+ and CD8+CD158a/b+ cells in lymphocytes showed a highly significant correlation with NK activity. However, analysis of CD8+ and CD16+ cells revealed that there was only a significant correlation between the percentage of CD8+CD158a+ cells among only CD8+ cells and NK activity. The upregulation of CD16+CD158a+/b+ cells in response to IL-2 tended to be related to the increase of NK activity, but the relationship was not significant. In conclusion, the level of KIR expression was correlated with NK activity, and IL-2 treatment resulted in an increase of NK activity as well as KIR expression, suggesting that upregulation of KIRs enhances the ability to sort target cells, such as virus-infected cells from uninfected cells, according to major histocompatibility complex class I expression.