Comparison of Baseline Covariate Adjustment Methods for Restricted Mean Survival Time

The restricted mean survival time is a clinically easy-to-interpret measure that does not require any assumption of proportional hazards. We focus on two ways to directly model the survival time and adjust the covariates. One is to calculate the pseudo-survival time for each subject using leave-one-out, and then perform a model analysis using all pseudo-values to adjust for covariates. The pseudo-survival time is used to reflect information of censored subjects in the model analysis. The other method adjusts for covariates using subjects for whom the time-to-event was observed while adjusting for the censored subjects using the inverse probability of censoring weighting (IPCW). This paper evaluates the performance of these two methods in terms of the power to detect group differences through a simple example dataset and computer simulations. The simple example illustrates the intuitive behavior of the two methods. With the method using pseudo-survival times, it is difficult to interpret the pseudo-values. We confirm that the pseudo-survival times are different from the actual data obtained in a primary biliary cholangitis clinical trial because of the many censored data. In the simulations, the method using IPCW is found to be more powerful. Even in the case of group differences with respect to the censor incidence rates and covariates, the method using IPCW maintains a nominal significance level for the type-1 error rate. We conclude that the IPCW method should be used to estimate the restricted mean survival time when adjusting the covariates

Traditional Chinese Medicine for Chronic Fatigue Syndrome

More and more patients have been diagnosed as having chronic fatigue syndrome (CFS) in recent years. Western drug use for this syndrome is often associated with many side-effects and little clinical benefit. As an alternative medicine, traditional Chinese medicine (TCM) has provided some evidences based upon ancient texts and recent studies, not only to offer clinical benefit but also offer insights into their mechanisms of action. It has perceived advantages such as being natural, effective and safe to ameliorate symptoms of CFS such as fatigue, disordered sleep, cognitive handicaps and other complex complaints, although there are some limitations regarding the diagnostic standards and methodology in related clinical or experimental studies. Modern mechanisms of TCM on CFS mainly focus on adjusting immune dysfunction, regulating abnormal activity in the hypothalamic-pituitary-adrenal (HPA) axis and serving as an antioxidant. It is vitally important for the further development to establish standards for ‘zheng’ of CFS, i.e. the different types of CFS pathogenesis in TCM, to perform randomized and controlled trials of TCM on CFS and to make full use of the latest biological, biochemical, molecular and immunological approaches in the experimental design

Selection for linear structure models with different variances

This paper is concerned with selection of some linear structure models with different variances. The models are based on the study of relationships between two fracture toughness testing methods of dental luting cemments. The measurements are made by using several kinds of materials. They are assumed to have different variances depending on the materials, but they have the same variance between two testing methods. For such data, we consider three types of structures between two methods: (1) proportionality, (2) linearity, and (3) no structure. We give Akaike information criterion, AIC, to evaluate these models. Then, we derive corrected AIC (CAIC) which is useful for small samples. By simulation experiments, we find that CAIC is more effective than AIC in the case of small samples. Our results are applied to a real data of dental luting cements.【査読有

A Kampo Medicine, Boi-ogi-to, Inhibits Obesity in Ovariectomized Rats

In women facing menopause, end of menstrual activity is accompanied by lower levels of estrogen and gradual weight gain. Postmenopausal weight gain sounds an alarm for women's health and may lead to hyperlipidemia, a lipid increase and glucose intolerance. These phenomena are connected to lifestyle-related diseases such as hypertension, type II diabetes mellitus, arteriosclerosis and metabolic syndrome, making it essential to prevent weight gain in women. A Kampo medicine, Boi-ogi-to, is traditionally used to treat obese conditions, but the mechanism has not yet been investigated. In this experiment, we tested the antiobesity properties of Boi-ogi-to in ovariectomized rats by measuring changes of serum cytokine levels and adipocytokines in fat cells. After treatment with this extract for 6 weeks (20-week-old rats), we found that there was a significant weight decrease in rats treated with Boi-ogi-to as compared with that in the control group. Serum tumor necrosis factor (TNF)-α levels increased significantly in a dose-dependent manner. Gene expression of adipose tissue in uterus also dose dependently showed a significant increase of TNF-α levels, suggesting that secretion of TNF-α by fat cells might play a role in the ability of Boi-ogi-to to inhibit weight gain. While peroxisome proliferators-activated receptor-γ and adiponectin levels did not show a significant difference as compared with those in the control, levels of mRNA expression showed a tendency to increase dose dependently. Resistin did not show any significant change. These results suggest that Boi-ogi-to might be useful for the prevention of obesity that occurs in women with reduction of estrogen

Beneficial Effect of Brewers' Yeast Extract on Daily Activity in a Murine Model of Chronic Fatigue Syndrome

The aim of this study was to assess the effect of Brewers' yeast extract (BYE) on daily activity in a mouse model of chronic fatigue syndrome (CFS). CFS was induced by repeated injection of Brucella abortus (BA) antigen every 2 weeks. BYE was orally administered to mice in a dose of 2 g per kg per day for 2 weeks before injecting BA and for 4 weeks thereafter. We evaluated daily running activity in mice receiving BYE as compared with that in untreated mice. Weekly variation of body weight (BW) and survival in both groups was monitored during the observation period. Spleen weight (SW), SW/BW ratio, percent splenic follicular area and expression levels of interferon-γ (IFN-γ) and interleukin-10 (IL-10) mRNA in spleen were determined in both groups at the time of sacrifice. The daily activity during 2 weeks after the second BA injection was significantly higher in the treated group than in the control. There was no difference in BW between both groups through the experimental course. Two mice in the control died 2 and 7 days after the second injection, whereas no mice in the treated group died. Significantly decreased SW and SW/BW ratio were observed in the treated mice together with elevation of splenic follicular area. There were suppressed IFN-γ and IL-10 mRNA levels in spleens from the treated mice. Our results suggest that BYE might have a protective effect on the marked reduction in activity following repeated BA injection via normalization of host immune responses

Significance of Kampo, Traditional Japanese Medicine, in Supportive Care of Cancer Patients

The current standard treatment for cancer is a multidisciplinary therapy whereby various types of treatment are properly combined. Chemotherapy with multiple anticancer drugs is now common, and traditional, complementary, and alternative therapies are adopted as supportive measures. Medical care in Japan is distinguished by the ability for patients to access both Western and Kampo medical cares at the same time. There is a high degree of trust in the safety of Kampo therapies because they are practiced by medical doctors who are educated with fundamental diagnosis of Western medicine. Highly reliable clinical studies are being published, demonstrating that palliative or supportive care for cancer patients using Kampo preparations alleviates adverse effects of chemotherapy or radiotherapy. This paper reports the circumstances around cancer care in Japan where traditional therapeutic Kampo formulas are used for patients undergoing cancer treatment with cutting-edge chemotherapy, specifically to alleviate adverse effects of anticancer drugs

Effect of Hochu-ekki-to (TJ-41), a Japanese Herbal Medicine, on Daily Activity in a Murine Model of Chronic Fatigue Syndrome

We aimed to evaluate the effect of a Japanese herbal medicine, Hochu-ekki-to (TJ-41), on daily activity in a murine model of chronic fatigue syndrome (CFS). CFS was induced by repeated injection of Brucella abortus (BA) antigen every 2 weeks. TJ-41 was orally administered to mice in a dose of 500 mg/kg/day for 1 week before injecting BA and for 4 weeks thereafter. We evaluated daily running activity in mice receiving TJ-41 as compared with that in untreated mice. Survival of both mouse groups was also monitored during the observation period. Body weight (BW), spleen weight (SW), SW/ BW ratio and expression levels of interleukin-10 (IL-10) mRNA in spleen were determined in both groups at the time of sacrifice. The daily activity was significantly higher in the treated group than in the control. Two mice in the untreated group died 2 days after the second injection of BA, whereas no mice in the group treated with TJ-41 died. The SW and SW/BW ratio were significantly lower in the treated mice than in the control. Suppressed IL-10 mRNA levels were observed in the spleens of the mice treated with TJ-41. Our data suggest that Hochu-ekki-to might possess an inhibitory effect on the marked decrease in running activity following BA injection

Effects of Preoperative Use of an Immune-Enhancing Diet on Postoperative Complications and Long-Term Outcome: A Randomized Clinical Trial in Colorectal Cancer Surgery in Japanese Patients

Background: Despite recent advances in surgical techniques and perioperative management, postoperative infectious complications remain a problem in surgical patients. We performed a prospective randomized clinical trial to examine the effects of preoperative Immune Enhancing Diets (IEDs) on postoperative complications in Japanese patients who underwent curative colorectal cancer surgery. This study was also designed to evaluate the optimal dose of preoperative IEDs for the patients without malnutrition. Finally, we analyzed recurrence free survival (RFS) and disease-specific survival (DSS) after surgery in patients who did and did not receive IEDspreoperatively.Material and Methods: This was a prospective, randomized clinical trial conducted at the Department of Surgery, National Defense Medical College, from October 2002 to October 2005. The 88 patients undergoing colorectal surgery were enrolled and were randomly divided into 3 groups. The high- (High, N=26) and low- (Low, N=31) dose groups received normal food and, respectively, 750ml/day or 250ml/ day of IEDs for 5 days before the operation. The primary endpoint was the rates of surgical site infection (SSI) and non- infectious complications. We also evaluated the RFS and DSS rate, respectively. Results: The patients were followed for 77±10 months (9-133 months) after surgery. Incisional SSI rates in the IEDs (High and Low) groups were significantly lower than in the Control group. (0%*, 0%* and 17%) (*P<0.01 vs. Control) The incidences of the infections not involving the surgical site (non-SSI) and the lengths of hospital stay were similar among the three groups. No significant differences were observed in RFS or DSS.Conclusion: In Japanese patients undergoing colorectal cancer surgery, preoperative IEDs significantly reduced the rate of incisional SSI as compared with the control group. Very interestingly, in Japanese patients, preoperative 250ml/day IED intake may be adequate for colorectal cancer patients without malnutrition. However, with regard to the long term outcome, beneficial effects of preoperative IEDs are not evident

COMT Val158Met, but not BDNF Val66Met, is associated with white matter abnormalities of the temporal lobe in patients with first-episode, treatment-naïve major depressive disorder: a diffusion tensor imaging study

We investigated the association between the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene, and white matter changes in patients with major depressive disorder (MDD) and healthy subjects using diffusion tensor imaging (DTI). We studied 30 patients with MDD (17 males and 13 females, with mean age ± standard deviation [SD] =44±12 years) and 30 sex- and age-matched healthy controls (17 males and 13 females, aged 44±13 years). Using DTI analysis with a tract-based spatial statistics (TBSS) approach, we investigated the differences in fractional anisotropy, radial diffusivity, and axial diffusivity distribution among the three groups (patients with the COMT gene Val158Met, those with the BDNF gene Val66Met, and the healthy subjects). In a voxel-wise-based group comparison, we found significant decreases in fractional anisotropy and axial diffusivity within the temporal lobe white matter in the Met-carriers with MDD compared with the controls (P<0.05). No correlations in fractional anisotropy, axial diffusivity, or radial diffusivity were observed between the MDD patients and the controls, either among those with the BDNF Val/Val genotype or among the BDNF Met-carriers. These results suggest an association between the COMT gene Val158Met and the white matter abnormalities found in the temporal lobe of patients with MDD

Brain structural connectivity and neuroticism in healthy adults

Understanding the neural correlates of the neurotic brain is important because neuroticism is a risk factor for the development of psychopathology. We examined the correlation between brain structural networks and neuroticism based on NEO Five-Factor Inventory (NEO-FFI) scores. Fifty-one healthy participants (female, n = 18; male, n = 33; mean age, 38.5 ± 11.7 years) underwent the NEO-FFI test and magnetic resonance imaging (MRI), including diffusion tensor imaging and 3D T1WI. Using MRI data, for each participant, we constructed whole-brain interregional connectivity matrices by deterministic tractography and calculated the graph theoretical network measures, including the characteristic path length, global clustering coefficient, small-worldness, and betweenness centrality (BET) in 83 brain regions from the Desikan-Killiany atlas with subcortical segmentation using FreeSurfer. In relation to the BET, neuroticism score had a negative correlation in the left isthmus cingulate cortex, left superior parietal, left superior temporal, right caudal middle frontal, and right entorhinal cortices, and a positive correlation in the bilateral frontal pole, left caudal anterior cingulate cortex, and left fusiform gyrus. No other measurements showed significant correlations. Our results imply that the brain regions related to neuroticism exist in various regions, and that the neuroticism trait is likely formed as a result of interactions among these regions. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Science, Sports and Culture of Japan