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Although a number of studies have investigated the relationship of sleep duration to overweight and obesity, studies conducted among population-based elementary schoolchildren have been limited in Japan. The aim of the present study was to investigate the relationship between sleep duration and overweight among elementary schoolchildren in Japan. The study subjects were all fourth-grade schoolchildren (9 or 10 years of age) in Ina-town, Saitama Prefecture, Japan from 1999 to 2008. Information concerning each subject's sex, age, and lifestyle was obtained using a self-administered questionnaire, while measurements of his or her height and weight were carried out. Childhood overweight was determined according to the definition established by the International Obesity Task Force. Data from 3,433 children were analyzed. In logistic regression analysis, a statistically significant dose-response relationship was observed between sleep duration and overweight among boys (p for trend = 0.014) but not among girls (p for trend = 0.149). Short sleep duration was associated with childhood overweight, and the sex difference in the association was observed. These findings suggested that it is important to consider sleep duration as part of any program to prevent overweight among elementary schoolchildren, especially among boys.

Background: Monitoring secular trends in blood pressure (BP) among children is important in predicting subsequent hypertension and cardiovascular disease. We investigated secular trends in BP using data from population-based annual screenings of Japanese schoolchildren., Methods: The participants were 10 894 children (all fourth graders between 1994 and 2010 and all seventh graders between 1997 and 2010) living in the town of Ina in Saitama Prefecture, Japan. Body height, weight, and BP were measured, after which children were classified as non-overweight, overweight, or obese. Trends in variables relative to calendar year were analyzed using regression models., Results: Systolic BP was significantly associated with calendar year among fourth- and seventh-grade boys (-0.350 and -0.434 mm Hg/year, respectively) and fourth- and seventh-grade girls (-0.513 and -0.473 mm Hg/year, respectively) (all P < 0.001), respectively, over time. Systolic BP and calendar year were significantly negatively correlated regardless of physique or sex among all fourth graders, but not among obese seventh-grade girls. In addition, diastolic BP and calendar year did not significantly correlate among seventh-grade overweight or obese boys or obese seventh-grade girls., Conclusions: BP decreased among fourth-grade schoolchildren in Ina during the past 17 years, regardless of sex or physique. However, BP and calendar year did not significantly correlate among obese seventh graders.

Little research has been done on the association between relaxation and health. In the present study, by conducting a nationwide cross-sectional survey, we aimed to obtain scientific data on the preferable forms of relaxation for health promotion, and to clarify the associations between specific recreational activities and self-perceived mental and physical health. We selected 4,000 households by stratified random sampling from across Japan in November 2009 and used the interview method to collect data (number of subjects: 2,206). The questionnaire contained items on sleep, recreation status, recreational activities, and self-perceived mental and physical health status. We obtained responses from 1,224 adults (response rate: 55.5%). Insufficient rest from sleep, short sleep duration (<6 h/day), ineffective use of free time, and less free time used for activities other than rest showed independent positive associations with poor mental and physical health. The results of the logistic regression analyses showed significantly low adjusted odds ratios with regard to the status of poor mental and physical health for outings/walking among men (0.33 [95% confidence interval; 0.16-0.68] and 0.49 [0.26-0.90], respectively), and for community activities among women (0.19 [0.04-0.79] and 0.27 [0.09-0.77], respectively). Relaxation for the promotion of health should include both passive relaxation (rest) and active relaxation (recreation). In addition, ensuring sufficient sleep duration is important for passive relaxation, and engaging in outings/walking for men and community activities for women are important for active relaxation.

Empirical data indicative of the health conditions and medical needs of homeless persons are scarce in Japan. In this study, with the aim of contributing to the formulation of future healthcare strategies for the homeless, we conducted a self-administered questionnaire survey and interviews at a park in Shinjuku Ward, Tokyo, to clarify the living conditions of homeless persons and their health conditions and awareness about the availability of medical treatment. Responses from 55 homeless men were recorded (response rate: 36.7%). With the exception of one person, none of them possessed a health insurance certificate. Half of the respondents reported having a current income source, although their modal monthly income was 30,000 yen($1 was approximately 90 yen). The number of individuals who responded "yes" to the questions regarding "Consulting a doctor on the basis of someone's recommendation" and "Being aware of the location of the nearest hospital or clinic" was significantly higher among those who had someone to consult when they were ill than among those who did not (the odds ratios [95% confidence intervals] were 15.00 [3.05-93.57] and 11.45 [1.42-510.68], respectively). This showed that whether or not a homeless person had a person to consult might influence his healthcare-seeking behavior. When queried about the entity they consulted (multiple responses acceptable), respondents mentioned "life support organizations" (61.1%) and "public offices" (33.3%). Overall, 94.5% of the respondents were aware of swine flu (novel influenza A (H1N1)). Their main sources of information were newspapers and magazines. On the basis of these findings, with regard to the aim of formulating healthcare strategies for homeless persons, while life support organizations and public offices play significant roles as conduits to medical institutions, print media should be considered useful for communicating messages to homeless persons.

Background: Combined effects between mitochondrial DNA 5178 (Mt5178) C/A polymorphism and alcohol consumption on the risk of hypertension or hyperuricemia have been reported. The objective of this study was to investigate whether Mt5178 C/A polymorphism modulates the effects of alcohol consumption on the risk of dyslipidemia., Methods: A total of 394 male subjects were selected from among individuals visiting the hospital for regular medical check-ups. After Mt5178 C/A genotyping, a cross-sectional study assessing the combined effect of Mt5178 polymorphism and alcohol consumption on the risk of dyslipidemia was conducted., Results: For men with Mt5178C, alcohol consumption was significantly and negatively associated with the risk of hyper-low-density lipoprotein (LDL) cholesterolemia (serum LDL cholesterol ≥ 140 mg/dl) (P for trend = 0.015). After adjustment for age, body mass index (BMI), habitual smoking, coffee consumption and use of antihypertensive medicine, the odds ratio (OR) for hyper-LDL cholesterolemia was significantly lower in daily drinkers with Mt5178C than non-drinkers with Mt5178C (OR = 0.360, 95% confidence intervals: 0.153-0.847). A significant and negative association between alcohol consumption and serum LDL cholesterol levels was also observed in Mt5178C genotypic men (P for trend < 0.01). On the other hand, the association between Mt5178A genotype and risk of hyper-LDL cholesterolemia does not appear to depend on alcohol consumption., Conclusions: For Mt5178C genotypic men, alcohol consumption may reduce the risk of hyper-LDL cholesterolemia.

In order to elucidate the transcriptional response of kidney epithelial cells to cadmium, the gene expression pattern was examined in normal rat kidney epithelial cells (NRK-52E cells) exposed to 50 µM cadmium for 4 hr using DNA microarray. Cadmium was found to increase the expression of 73 genes and decrease the expression of 42 genes in NRK-52E cells before the development of cytotoxicity.

Objective: The objective of this study was to clarify the prevalence of nightmares and sleep paralysis and associated factors among Japanese adolescents., Methods: This study was designed as a cross-sectional sampling survey. The targets were junior and senior high schools throughout Japan. Self-reported anonymous questionnaires were sent to schools for all students to complete., Results: A total of 90,081 questionnaires were analyzed. The overall response rate was 62.6%, and the prevalence of nightmares and sleep paralysis was 35.2% and 8.3%, respectively. Multiple logistic analyses revealed that female sex, drinking alcohol, poor mental health, difficulty initiating sleep, low subjective sleep assessment, presence of excessive daytime sleepiness, and presence of sleep paralysis had higher odds ratios than others for nightmares. Male sex, poor mental health, drinking alcohol, taking a long daytime nap, early or late bedtime, difficulty initiating sleep, low subjective sleep assessment, presence of excessive daytime sleepiness, and presence of nightmares had higher odds ratios than other factors for sleep paralysis., Conclusions: This study has revealed the prevalence of nightmares and sleep paralysis among Japanese adolescents. Furthermore, the results of this study suggest that it is important to maintain regular sleep habits for preventing these symptoms. We propose that health education about regular sleep habits should be promoted among Japanese adolescents., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Although ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) therapy has been regarded as a standard of care for advanced-stage Hodgkin lymphoma (HL) since 1992, there has been no prospective data of ABVD therapy in Japan. To investigate the efficacy and safety of ABVd therapy with the lower dose of dacarbazine (250 mg/m(2)) in patients with newly diagnosed stage II-IV HL, Lymphoma Study Group of Japan Clinical Oncology Group conducted a phase II study. The primary endpoints were complete response rate (%CR) and progression-free survival (PFS). A total of 128 patients with age less than 70 years were enrolled and received 6-8 cycles of ABVd followed by radiation to initial bulky mass. The %CR in 118 eligible patients was 81.4% [95% confidence interval (CI) 73.1-87.9%]. Major toxicity was grade 4 neutropenia (45.3%). Grade 3 nausea/vomiting was the most frequent non-hematological toxicity (10.9%). Transient grade 4 constipation, infection (abscess), hypoxemia and hyperbilirubinemia were observed in 4 patients. No treatment-related death was observed. PFS and overall survival at 5 years were 78.4% (95% CI 70.9-85.9%) and 91.3% (95% CI 86.1-96.5%), respectively. In conclusion, ABVd is effective in Japanese patients with stage II-IV HL with acceptable toxicities (UMIN-CTR Number: C000000092).

The objective of this study was to investigate whether the mitochondrial DNA 5178 cytosine/adenine (Mt5178 C/A) polymorphism modifies the effects of coffee consumption on serum lipid levels and the risk of dyslipidemia in middle-aged Japanese men. A total of 397 male subjects (age, 53.9±7.8 years; mean±s.d.) were selected from among individuals visiting the hospital for regular medical check-ups. After adjustment for age, body mass index, habitual alcohol consumption, habitual smoking and use of antihypertensive medication, among subjects who consumed <1 cup of coffee per day, the odds ratio (OR) for hyper-low-density lipoprotein (LDL) cholesterolemia (serum LDL cholesterol > or =140 mg per 100 ml) was significantly lower in those with Mt5178A than in those with Mt5178C (OR=0.378, 95% confidence interval: 0.153-0.919). After adjustment, the association between the Mt5178A genotype and hyper-LDL cholesterolemia depended on coffee consumption (P for trend=0.018). Coffee consumption was positively associated with serum LDL cholesterol levels only in subjects with Mt5178A. However, in subjects with Mt5178C, serum LDL cholesterol level or risk of hyper-LDL cholesterolemia did not seem to depend on coffee consumption. These results suggest that for men with Mt5178A, coffee consumption negates the genetic benefit of lower risk for hyper-LDL cholesterolemia.

Over the past two decades, the liquor industry in Japan has strived to address alcohol-related problems through initiatives such as warnings in the various media. In this study, we conducted an Internet-based questionnaire survey to examine general consumer awareness of such warnings, and the media by which they are conveyed, on the consumption of alcoholic beverages. A total of 985 subjects (males: 487, females: 498) in age groups ranging from 20s to 70s responded (response rate: 22.4%). The awareness rates for warnings regarding underage drinking, drunk driving, and drinking during pregnancy, and those for messages encouraging moderation in drinking, were 96.4%, 83.7%, 59.6%, and 45.5%, respectively. Logistic regression analysis adjusted for habitual alcohol consumption demonstrated significant gender- and/or age-based differences in the rates of awareness of warnings and the media publicizing them. For example, the odds ratio of awareness among women of warnings against underage drinking was significantly higher than that of awareness among men. Issues that must be addressed in the future include:(1) increasing public awareness about messages regarding drinking during pregnancy and drinking in moderation;(2) reviewing the wording of warnings to make them more effective;and (3) devising and employing, on a regular basis, more effective means of transmitting messages in consideration of gender and age.

Background: Although the prevalences of obesity and hypertension (HT) are increasing in children, there have been few epidemiological studies of HT in Japanese children. We evaluated the prevalences of HT and high-normal blood pressure (HNBP), and examined the relationship between blood pressure (BP) and body mass index (BMI), in Japanese children., Methods: The subjects of this study were 2420 children living in the town of Ina, Saitama Prefecture, Japan during the period from 2006 through 2008. Body height, weight, and BP were measured. HT and HNBP were defined according to the HT criteria for Japanese children. Children with HNBP or HT were defined as having high blood pressure (HBP)., Results: The prevalences of HBP were 15.9% and 15.8% in fourth-grade boys and girls, respectively, and 11.1% and 10.8% in seventh-grade boys and girls, respectively. Irrespective of sex or grade level, a higher BMI was associated with a higher prevalence of HBP (P < 0.001). When compared with the <50th percentile BMI category, the crude odds ratios (ORs) were statistically significant for the 75th to 84th percentile category in fourth-grade boys (OR: 4.54, 95% CI: 2.36-8.76), the ≥95th percentile in fourth-grade girls (13.29, 5.93-29.77), the 85th to 94th percentile (3.16, 1.46-6.84) in seventh-grade boys, and the ≥95th percentile (7.96, 3.18-19.93) in seventh-grade girls., Conclusions: BMI was associated with HBP in Japanese school children. In addition, some children in the lower BMI categories also had HBP.

Reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism, is reportedly associated with longevity in the Japanese population. The ND2-237Met genotype may exert resistance to atherogenic diseases, such as myocardial infarction or cerebrovascular disorders. To investigate whether ND2-237 Leu/Met polymorphism is associated with yearly changes in serum lipid levels, we conducted a longitudinal study of 107 healthy Japanese male subjects. Analysis of covariance revealed that the interaction between the ND2-237 Leu/Met genotypes and habitual drinking was significantly associated with yearly changes in serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) levels (p=0.036 and p=0.006, respectively). In multiple regression analysis, daily drinking was significantly and positively associated with yearly changes in serum LDLC levels in men with ND2-237Met (p=0.026). After adjusting for covariates, yearly changes in serum LDLC levels were significantly lower in non-daily drinkers with ND2-237Met than in those with ND2-237Leu (p=0.047). These results suggest that ND2-237Met has a beneficial impact on yearly changes in serum LDLC in non-daily drinkers but not in daily drinkers.

The structural deficits and problems associated with application of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) were investigated. For this purpose, mortality statistics in Japan were examined for bias in the proportions of death causes classified using the ICD-10 four-character subcategory system, particularly the large distribution of cases classified under the .9 (unspecified) codes. The results showed that most deaths due to the 3 major causes were coded into the .9 subcategories. For example, 97.6% of the 607,065 deaths between 1995 and 2007 classified as I21 (acute myocardial infarction) were coded as I21.9 (acute myocardial infarction, unspecified). This suggests that the quality of the data recorded on many death certificates is poor. Thus, to ensure that the fourth-digit-level subcategories of the ICD-10 code system are effectively used to represent mortality data and actual causes of death in Japan, future studies should address the following objectives:(1) to minimize the discrepancy between the ICD classification terms and the names of diseases actually used in clinical practice, and (2) to actively raise awareness among physicians about the need to accurately record death causes on death certificates, since these records form the basis for determining mortality statistics in Japan.

The number of suicide deaths in Japan has continued to be high, and is a pressing social problem. Although the weekly distribution of suicide deaths has been documented, no nationwide analysis has yet been conducted. In the present study, the ratios of the number of suicide deaths per day, by day of the week, and on weekdays relative to holidays were calculated using the data for all suicide deaths recorded in 2003. The suicide deaths recorded on holidays were treated as the reference, and a confidence interval of 95% (95% CI) was used. We calculated the suicide death ratios among men and women of all ages (men:23,396, women:8,713, total:32,109) and also among those of productive age (age:15-64 years, men:18,552, women:5,481, total:24,033). Among men of all ages, the suicide death ratio on Mondays was found to be significantly high at 1.49 (95% CI:1.04-2.14), and the ratios were found to decrease over the course of the week from Monday to Friday. On each weekday, the suicide death ratios among men of productive age were found to be higher than those among men of all ages. Among women, the suicide death ratios on any weekday were found to be higher than 1, but there was no significant difference between the days. Among both men and women, the number of suicide deaths on holidays was lower than that on weekdays. This study revealed that the number of suicide deaths recorded per day on Mondays is 1.5 times higher than that on holidays among men. This suggests that the structure of the work week may possibly influence suicide deaths among men. Future discussions regarding the arrangement and distribution of weekly holidays should be conducted in order to reduce the number of suicide deaths.

This phase II, multicenter, open-label, sequential-cohort, dose-escalation study was designed to evaluate the safety and efficacy of romiplostim, a novel peptibody that increases platelet production, in Japanese patients with chronic immune thrombocytopenic purpura (ITP). Sequential cohorts of four patients each received romiplostim (1, 3, or 6 microg/kg) subcutaneously on days 1 and 8 of the dose-escalation phase. Patients who achieved platelet responses (doubling of baseline platelet counts to > or =50 x 10(9)/L) continued romiplostim weekly during the treatment-continuation phase. Romiplostim produced dose-dependent increases in mean and peak platelet counts. Five patients received romiplostim during the treatment-continuation phase, with platelet counts > or =50 x 10(9)/L maintained in approximately half of the weekly assessments. Romiplostim was well tolerated. No severe, serious, or life-threatening adverse events were reported. No binding antibodies to romiplostim or thrombopoietin were detected. Romiplostim is safe and well tolerated in Japanese patients with chronic ITP and is effective in producing platelet count increases, consistent with the results from studies in non-Japanese patients. On the basis of these findings, a starting dose of 3 microg/kg was recommended for phase III evaluation of romiplostim in Japanese patients with chronic ITP.

Polyhistidine-tag (His-tag) is a powerful tool for purification of recombinant protein. His-tagged protein can be affinity-purified by using resins immobilizing Ni2+ or anti-His-tag antibodies. However, Ni2+-affinity-purification is prevented by the presence of divalent cations. The purification with antibodies has contamination of antibody peptides, which interferes with following analysis. In the present study, we isolated RNA aptamers binding to His-tag. The best clone, named shot47, bound to the target with low picomolar dissociation constant. In the presence of divalent cations, shot47 was substitutable for antibodies against His-tag on ELISA, immunoprecipitation, and Western blotting. Shot47 can be synthesized easily by in vitro transcription. Thus, shot47 would be applicable as a useful and cost-effective tool for biochemical analyses.

An aptamer is a short RNA or DNA molecule that binds to a specific target. The main strategy for obtaining aptamers is systematic evolution of ligands by exponential enrichment (SELEX). Although various SELEX techniques have been devised and refined on the basis of the selection technique used, in most cases, the isolation of an aptamer still requires several trials or the use of special equipment. In the present study, we attempted SELEX in which PCR bias was suppressed by using RNA transcription to amplify nucleic acids. This procedure, which can be accomplished easily and inexpensively without special equipment, effectively simplifies the SELEX process. Using this SELEX, we obtained large numbers of RNA aptamers against the target that could not be isolated by standard SELEX. The results of our study suggest that exclusion of PCR bias may be far more important than previously assumed for isolating RNA aptamers via SELEX.

Background: Panitumumab is a fully human, monoclonal antibody against the epidermal growth factor receptor. Previous studies in non-Japanese patients with solid tumors showed that panitumumab exhibited nonlinear pharmacokinetics, was well tolerated (skin toxicities were the most common treatment-related adverse events), and had antitumor activity in some patients. This open-label, phase 1 study investigated panitumumab safety and pharmacokinetics in Japanese patients., Methods: Japanese patients with advanced solid tumors were enrolled into one of three sequential panitumumab dose cohorts (cohort 1, 2.5 mg/kg weekly; cohort 2, 6.0 mg/kg every 2 weeks; and cohort 3, 9.0 mg/kg every 3 weeks) and received panitumumab until disease progression or drug intolerability. Safety endpoints included the incidence of adverse events, changes in laboratory values, and the appearance of anti-panitumumab antibodies. Serial pharmacokinetic samples were collected after the first and third doses of panitumumab. Tumors were assessed at week 8 and every 8 weeks thereafter., Results: Eighteen patients (6 per cohort) were enrolled. No dose-limiting toxicities, investigator-reported infusion reactions, or deaths occurred. Seven patients had grade-3/4 adverse events; fatigue and anorexia were most common. The most common skin toxicities were rash and acneiform dermatitis. No neutralizing anti-panitumumab antibodies were detected. Panitumumab exhibited nonlinear pharmacokinetics, and antitumor activity was observed in 31% (4/13) of the patients with colorectal cancer., Conclusion: In Japanese patients with solid tumors, panitumumab was well tolerated, demonstrated pharmacokinetic and safety profiles similar to those observed previously in non-Japanese patients, and exhibited encouraging antitumor activity in patients with colorectal cancer.

Aptamers are short single-stranded DNA or RNA sequences that are selected in vitro based on their high affinity to a target molecule. Here we demonstrate that an RNA aptamer selected against eukaryotic initiation factor 4A (eIF4A) serves as an efficient biosensor. The aptamer, when immobilized to resin, purifies eIF4A from crude cell extracts by affinity pull-down, and 32P-labeled aptamer can detect some 300 ng of eIF4A by dot-blot analysis. Moreover, by use of an aptamer-immobilized sensor chip, we developed a surface plasmon resonance assay to detect eIF4A at the nanogram level within whole cell lysates after optimizing sample preparation, thereby showing a real-time sensor for eIF4A in cell extract solution.

In this study we investigated the attitudes of Japanese medical students toward being informed of a diagnosis of life-threatening illness. Fourth-year medical students from 20 randomly sampled universities were administered questionnaires that examined their opinion about whether they would welcome disclosure of medical information if they were diagnosed as having an ultimately fatal disease. Data from 1,619 students (male 1,074, female 545, effective collection rate 90.6%) were analyzed. With regard to attitudes about disclosure of a diagnosis of life-threatening illness, 87.7% of the students stated that they would wish to be informed even if there was little chance of recovery, and 11.6% expressed a wish to be informed of their condition only if there was a chance of recovery. Students who did not wish to be informed even if there was a chance of recovery accounted for 0.7% of those surveyed. Our study reveals that medical students are more positive than are members of the general population with regard to being informed of the truth. The proportion of those who wished to be informed even if there was little chance of recovery was higher among students from national and public universities than among those from private universities, and the inter-group difference was statistically significant. Among male students, answers to the survey were significantly correlated with 12-item General Health Questionnaire scores and mental health status, suggesting that mental health status may have affected how this study population viewed being informed of their diagnosis.

Background: Habitual coffee consumption has been reported to lower blood pressure in the Japanese population. The NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism is associated with longevity and modifies the effects of alcohol consumption on blood pressure in the Japanese population. The objective of this study was to determine whether this polymorphism also modifies the effects of coffee consumption on blood pressure or the risk of hypertension in middle-aged Japanese men., Methods: A total of 398 men (mean age +/- standard deviation, 53.8 +/- 7.8 years) were selected from among individuals visiting the hospital for regular medical check-ups. Hypertension was defined as a systolic blood pressure > or =140 mm Hg, diastolic blood pressure > or =90 mm Hg, or antihypertensive drug treatment. Polymerase chain reaction-restriction fragment length polymorphism using the restriction enzyme AluI was performed to determine ND2-237 Leu/Met genotype., Results: In subjects with ND2-237Leu, coffee consumption was significantly and negatively associated with diastolic blood pressure (P = 0.007). The odds ratio (OR) for hypertension was significantly lower in subjects with ND2-237Leu who consumed 2 or 3 cups of coffee per day than in those who consumed less than 1 cup of coffee per day (OR, 0.517; 95% confidence interval [CI], 0.276 to 0.968; P = 0.039). After adjustment, the OR remained significant (OR = 0.399; 95% CI, 0.184 to 0.869; P = 0.020). Moreover, after adjustment, the OR was significantly lower in subjects with ND2-237Leu who consumed more than 4 cups of coffee per day than in those who consumed less than 1 cup of coffee per day (OR, 0.246; 95% CI, 0.062 to 0.975; P = 0.046). However, the association between ND2-237Met genotype and hypertension did not depend on coffee consumption., Conclusions: The present results suggest that the ND2-237 Leu/Met polymorphism modulates the effects of coffee consumption on hypertension risk in middle-aged Japanese men.

Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappa B ligand (RANKL), suppresses bone resorption. This open-label, multicenter, phase 1 study evaluated the safety, pharmacodynamics, and pharmacokinetics of denosumab in Japanese women with breast cancer-related bone metastases. Patients (n = 18; median age, 57 years) received a single subcutaneous injection of denosumab 60 mg or 180 mg or three doses of denosumab 180 mg on days 1, 29, and 57 (every 4 weeks) and were followed for > or = 141 days. No major safety concerns related to denosumab were noted in any cohort. All patients experienced at least 1 adverse event (AE); most were mild (grade < or = 2). One patient reported grade 4 myositis and grade 3 anemia, malaise, and dysphagia that the investigator deemed treatment-related; other treatment-related AE were grade < or = 2. No antidenosumab antibodies or clinically significant changes in laboratory findings, vital signs, or electrocardiograms were observed. Pharmacokinetics were approximately dose-linear. Denosumab caused rapid, substantial, and sustained suppression of urinary N-telopeptide corrected for creatinine (uNTx/Cr) across all doses; at day 85, the median change from baseline uNTx/Cr ranged from -61.9% to -90.8%. No dose-limiting toxicity was observed at any dosage. Coupled with pharmacokinetic and pharmacodynamic data, these results were consistent with those observed in non-Japanese populations.

Eukaryotic translation initiation factor 4G (eIF4G) plays a crucial multimodulatory role in mRNA translation and decay by interacting with other translation factors and mRNA-associated proteins. In this study, we isolated eight different RNA aptamers with high affinity to mammalian eIF4G by in vitro RNA selection amplification. Of these, three aptamers (apt3, apt4, and apt5) inhibited the cap-dependent translation of two independent mRNAs in a rabbit reticulocyte lysate system. The cap-independent translation directed by an HCV internal ribosome entry site was not affected. Addition of exogenous eIF4G reversed the aptamer-mediated inhibition of translation. Even though apt3 and apt4 were selected independently, they differ only by two nucleotides. The use of truncated eIF4G variants in binding experiments indicated that apt4 (and probably apt3) bind to both the middle and C-terminal domains of eIF4G, while apt5 binds only to the middle domain of eIF4G. Corresponding to the difference in the binding sites in eIF4G, apt4, but not apt5, hindered eIF4G from binding to eIF4A and eIF3, in a purified protein solution system as well as in a crude lysate system. Therefore, the inhibition of translation by apt4 (and apt3) is due to the inhibition of formation of initiation factor complexes involving eIF4A and eIF3. On the other hand, apt5 had a much weaker affinity to eIF4G than apt4, but inhibited translation much more efficiently by an unknown mechanism. The five additional aptamers have sequences and predicted secondary structures that are largely different from each other and from apt3 through apt5. Therefore, we speculate that these seven sets of aptamers may bind to different regions in eIF4G in different fashions.

In most cases, anti-protein aptamers are selected by systematic evolution of ligands by exponential enrichment (SELEX) using purified recombinant protein targets. Cell surface proteins, however, are not easy targets for SELEX due to the difficulties associated with their purification. Here, we developed a novel SELEX procedure (referred to as TECS-SELEX) in which cell-surface displayed recombinant protein is directly used as the selection target. Using this method, we isolated RNA aptamers against transforming growth factor-beta type III receptor expressed on Chinese hamster ovary (CHO) cells. One of the RNA aptamers has a dissociation constant in the 1 nM range and competed with transforming growth factor-beta to bind to the cell surface receptor in vitro.

Seasonal hibernation in mammals is under a unique adaptation system that protects organisms from various harmful events, such as lowering of body temperature (Tb), during hibernation. However, the precise factors controlling hibernation remain unknown. We have previously demonstrated a decrease in hibernation-specific protein (HP) complex in the blood of chipmunks during hibernation. Here, HP is identified as a candidate hormone for hibernation. In chipmunks kept in constant cold and darkness, HP is regulated by an individual free-running circannual rhythm that correlates with hibernation. The level of HP complex in the brain increases coincident with the onset of hibernation. Such HP regulation proceeds independently of Tb changes in constant warmth, and Tb decreases only when brain HP is increased in the cold. Blocking brain HP activity using an antibody decreases the duration of hibernation. We suggest that HP, a target of endogenously generated circannual rhythm, carries hormonal signals essential for hibernation to the brain.

Sorption of ionizable compounds of pyridines and aromatic carboxylic acids into low-density polyethylene (LDPE) film was investigated as a function of pH ranging from 4 to 7. The sorptions for pyridines were increased with increasing pH. Within the range examined, pH 7 was observed to promote the highest degree of sorption. When the pH increased by one unit from 6 to 7, the sorptions for 2-propylpyridine and 2,4,6-trimethylpyridine were both increased approximately 3.8 and 10.5 times, respectively. At pH 4, the sorption for the pyridines entirely disappeared. In contrast, the sorptions for aromatic carboxylic acids increased with decreasing pH. Within the range examined, pH 4 was observed to promote the highest degree of sorption. The magnitude of sorption for pyridines and carboxylic acids apparently depended on the affinity (delta(c)) of these compounds for LDPE film. Another factor affecting the sorption at various pHs was the pK(a) of these compounds; the sorption greatly decreased with the ionization degree of these compounds. To elucidate the phenomena, the following thermodynamic sorption equation was applied: S = S(0)gamma exp[V(v){(delta(w) - delta(v))(2) - delta(c)(2))/RT}. The plots of ln S for pyridines vs the term of the equation gave an insufficient relationship (r = 0.519). In contrast, taking into account the ratio (chi(i)()) of concentration of un-ionized compound to total concentration, the improvement for the equation was made: S' = S/chi(i)() = S(0)gamma exp[V(v){(delta(w) - delta(v))(2) - delta(c)(2))/RT}. The plots of ln S' vs the term of the equation gave a better relationship (r = 0.884). Furthermore, the equation was also applicable for the sorption behavior of carboxylic acids into LDPE (r = 0.769).

A high affinity RNA aptamer (APT58, 58 nt long) against mammalian initiation factor 4A (eIF4A) requires nearly its entire nucleotide sequence for efficient binding. Since splitting either APT58 or eIF4A into two domains diminishes the affinity for each other, it is suggested that multiple interactions or a global interaction between the two molecules accounts for the high affinity. To understand the structural basis of APT58's global recognition of eIF4A, we determined the solution structure of two essential nucleotide loops (AUCGCA and ACAUAGA) within the aptamer using NMR spectroscopy. The AUCGCA loop is stabilized by a U-turn motif and contains a non-canonical A:A base pair (the single hydrogen bond mismatch: Hoogsteen/Sugar-edge). On the other hand, the ACAUAGA loop is stabilized by an AUA tri-nucleotide loop motif and contains the other type of A:A base pair (single hydrogen bond mismatch: Watson-Crick/Watson-Crick). Considering the known structural and functional properties of APT58, we propose that the AUCGCA loop is directly involved in the interaction with eIF4A, while the flexibility of the ACAUAGA loop is important to support this interaction. The Watson-Crick edges of C7 and C9 in the AUCGCA loop may directly interact with eIF4A.

On February 13, 2002, a public health center in Hiroshima Prefecture, Japan, was notified that many individuals living at the Japan Maritime Self-Defence Force base had symptoms resembling those of food poisoning. Self-administered questionnaires requesting information regarding meal consumption and symptoms were distributed to all 281 members at the base. A case of the illness was defined as a member who had had watery or mucousy stool, or loose stool with abdominal cramps, more than twice a day after consuming dinner on February 12. Control of the illness was defined as a member with no symptoms. The dinner on February 12 was significantly associated with the illness (Mantel-Haenszel odds ratio: 3.59, 95% confidence interval: 1.06-12.20). A case-control study showed that, among the food supplied at dinner on February 12, the braised chop suey was significantly associated with the illness (odds ratio: 12.30, 95% confidence interval: 1.90-521.00). The braised chop suey had been stored in a chafing dish. An environmental investigation indicated that Clostridium perfringens (C. perfringens) in the chafing dish proliferated under an inappropriate heat-retention temperature, and the contaminated braised chop suey could have caused the food poisoning. This study demonstrated that the recommended heat-retention temperature (over 65 degrees C) should be confirmed thoroughly.

Isolation of anti-protein aptamers is typically carried out against purified recombinant protein. Thus, certain cell surface proteins including pharmacologically important receptors do not become targets of aptamers due to the difficulties encountered in their purification. In order to overcome this limitation, we developed a new SELEX procedure in which cells displaying the target protein on the cell surface are used, thereby precluding the need for target purification. As a model experiment, CHO cells expressing human transforming growth factor-beta type III receptor (TbRIII) were used as the target for SELEX, resulting in the successful isolation of a specific, high-affinity aptamer.

The eukaryotic translation initiation factor 4F (eIF4F) consists of three polypeptides (eIF4A, eIF4G, and eIF4E) and is responsible for recruiting ribosomes to mRNA. eIF4E recognizes the mRNA 5'-cap structure (m7GpppN) and plays a pivotal role in control of translation initiation, which is the rate-limiting step in translation. Overexpression of eIF4E has a dramatic effect on cell growth and leads to oncogenic transformation. Therefore, an inhibitory agent to eIF4E, if any, might serve as a novel therapeutic against malignancies that are caused by aberrant translational control. Along these lines, we developed two RNA aptamers, aptamer 1 and aptamer 2, with high affinity for mammalian eIF4E by in vitro RNA selection-amplification. Aptamer 1 inhibits the cap binding to eIF4E more efficiently than the cap analog m7GpppN or aptamer 2. Consistently, aptamer 1 inhibits specifically cap-dependent in vitro translation while it does not inhibit cap-independent HCV IRES-directed translation initiation. The interaction between eIF4E and eIF4E-binding protein 1 (4E-BP1), however, was not inhibited by aptamer 1. Aptamer 1 is composed of 86 nucleotides, and the high affinity to eIF4E is affected by deletions at both termini. Moreover, relatively large areas in the aptamer 1 fold are protected by eIF4E as determined by ribonuclease footprinting. These findings indicate that aptamers can achieve high affinity to a specific target protein via global conformational recognition. The genetic mutation and affinity study of variant eIF4E proteins suggests that aptamer 1 binds to eIF4E adjacent to the entrance of the cap-binding slot and blocks the cap-binding pocket, thereby inhibiting translation initiation.

The receptor activator of NF-kappaB (RANK) is a member of the tumor necrosis factor (TNF) receptor family and acts to cause osteoclastgenesis through the interaction with its ligand, RANKL. We isolated RNA aptamers with high affinity to human RANK by SELEX. Sequence and mutational analysis revealed that the selected RNAs form a G-quartet conformation that is crucial for binding to RANK. When the aptamer binding to RANK was challenged by RANKL, there was no competition between the aptamer and RANKL. Instead, the formation of a ternary complex, aptamer-RANK-RANKL, was detected by a spin down assay and by BIAcore surface plasmon resonance analysis. Moreover, the selected aptamer efficiently bound to other TNF receptor family proteins, such as TRAIL-R2, CD30, NGFR as well as osteoprotegerin, a decoy receptor for RANK. These results suggest that the selected aptamer recognizes not the ligand-binding site, but rather a common structure conserved in the TNF receptor family proteins.

The effect of enhancing the dose intensity (DI) of the key drugs in multidrug combination chemotherapy for malignant lymphoma is uncertain. We investigated the survival benefit of dose-intensified multidrug combination chemotherapy for intermediate- or high-grade non-Hodgkin's lymphoma (NHL). Patients without any prior chemotherapy were randomly assigned either to dose-intensified multidrug combination chemotherapy, LSG9 (VEPA-B/FEPP-AB/M-FEPA, treated 3 times every 10 weeks for 28 weeks total), or to control-arm combination chemotherapy, mLSG4 (VEPA-B/FEPP-B/M-FEPA, treated 4 times every 14 weeks for 54 weeks total). The planned DI of doxorubicin and cyclophosphamide were 1.96 and 1.47 times higher, respectively, in LSG9 than in mLSG4. Overall survival, complete response (CR) rate, and toxicities were evaluated. The 447 patients (230 for LSG9 and 217 for mLSG4) were enrolled between February 1991 and March 1995. The 5-year overall survival rates were 56.8% for LSG9 patients and 55.1% for mLSG4 patients (log-rank P = .42). The rates for CR plus uncertain CR were 70.0% for LSG9 and 64.5% for mLSG4. The toxicities of both regimens were similar and tolerable. The median actual DI of doxorubicin and cyclophosphamide were 1.56 and 1.17 times higher, respectively, in LSG9 than in mLSG4. Compared with the control regimen mLSG4, the dose-intensified regimen LSG9 did not show significant survival benefit. An increase in the DI of doxorubicin in multidrug combination chemotherapy did not improve the survival of patients with intermediate- or high-grade NHL.

We examined the distribution of physical activity among different occupations in Japan. A questionnaire was sent to full-time employees at nine companies in Japan between 1996 and 1998, with an average response rate of 85.2%. Data from 20,654 respondents (17,637 male and 3017 female) were analyzed. We classified the occupations into eight groups according to the International Standard Classification of Occupations (1988). Daily energy expenditure, weekly physical activity, and monthly leisure-time physical activity (LTPA) were measured using a physical activity questionnaire and some additional questions. In males, LTPA was significantly different among occupations, with clerks having greater physical activity than managers and blue-collar workers (P<0.001). The pattern was similar even after adjusting for education, age, and working hours. In females, the difference among occupations was not clear. The distribution of LTPA among occupations exhibits a "barrel-shape" in Japan. It was higher for intermediate class occupations such as clerks, which was in agreement with a lower coronary heart disease mortality observed in intermediate class occupations among Japanese male employees.

The mammalian translation initiation factor 4A (eIF4A) is a prototype member of the DEAD-box RNA helicase family that couples ATPase activity to RNA binding and unwinding. In the crystal form, eIF4A has a distended "dumbbell" structure consisting of two domains, which probably undergo a conformational change, on binding ATP, to form a compact, functional structure via the juxtaposition of the two domains. Moreover, additional conformational changes between two domains may be involved in the ATPase and helicase activity of eIF4A. The molecular basis of these conformational changes, however, is not understood. Here, we generated RNA aptamers with high affinity for eIF4A by in vitro RNA selection-amplification. On binding, the RNAs inhibit ATP hydrolysis. One class of RNAs contains members that exhibit dissociation constant of 27 nM for eIF4A and severely inhibit cap-dependent in vitro translation. The binding affinity was increased on Arg substitution in the conserved motif Ia of eIF4A, which probably improves a predicted arginine network to bind RNA substrates. Selected RNAs, however, failed to bind either domain of eIF4A that had been split at the linker site. These findings suggest that the selected RNAs interact cooperatively with both domains of eIF4A, either in the dumbbell or the compact form, and entrap it into a dead-end conformation, probably by blocking the conformational change of eIF4A. The selected RNAs, therefore, represent a new class of specific inhibitors that are suitable for the analysis of eukaryotic initiation, and which pose a potential therapeutic against malignancies that are caused by aberrant translational control.

PSC-833 reverses multidrug resistance by P-glycoprotein at concentrations < or = 1000 ng / ml. A phase I study of PSC-833 and doxorubicin was conducted to determine the maximum tolerated dose and to investigate pharmacokinetics. PSC-833 was intravenously infused as a 2-h loading dose (LD) and a subsequent 24-h continuous dose (CD). Doxorubicin was infused over 5 min, 1 h after the LD. The starting dose was 1 mg / kg for both LD and CD with 30 mg / m(2) doxorubicin; these dosages were increased to 2 and 10 mg / kg and 50 mg / m(2), respectively. Thirty-one patients were treated. Nausea / vomiting was controllable with granisetron and dexamethasone. Neutropenia and ataxia were dose limiting. Steady-state concentrations of PSC-833 > 1000 ng / ml were achieved at a 2 mg / kg LD and a 10 mg / kg CD. Ex-vivo bioassay revealed that activity in serum for reversing multidrug resistance was achieved in all patients; IC(50) of P-glycoprotein expressing 8226 / Dox(6) in patients' serum was decreased from 5.9 to 1.3 microg / ml (P < 0.0001) by PSC-833 administration. Doxorubicin clearance was 24.3 +/- 13.7 (mean +/- SD) liter / h/m(2), which was lower than the 49.0 +/- 16.9 liter / h/m(2) without PSC-833 (P < 0.0001). The relationship between doxorubicin exposure and neutropenia did not differ between patients treated and not treated with PSC-833. The recommended phase II dose of PSC-833 was 2 and 10 mg / kg for LD and CD, respectively, which achieved a sufficient concentration in serum to reverse drug resistance, as confirmed by bioassay. The dose of doxorubicin should be reduced to 40 mg / m(2), not because of the pharmacodynamic interaction between PSC-833 and doxorubicin affecting hematopoiesis, but because of pharmacokinetic interaction.

The purpose of this study was to investigate the toxicity and the efficacy of re-treatment with rituximab, a chimeric mouse human anti-CD20 monoclonal antibody, in relapsed patients with indolent B-cell non-Hodgkin's lymphoma (NHL) who responded to rituximab in the previous phase I or phase II study. Thirteen patients with relapsed B-cell NHL, each of whom was confirmed to have Revised European-American Lymphoma Classification type II, 1-6 histology (indolent B-NHL), enrolled in this re-treatment study. All were re-treated with rituximab at 375 mg/m2 weekly for 4 consecutive weeks. Rituximab re-treatment was well tolerated with no grade 3/4 nonhematological toxicities, similar to that of the initial treatment. No patients developed detectable human anti-chimeric antibody. Partial responses were observed in 5 of 13 patients (38%; 95% confidence interval [CI], 14% to 68%); 6 patients showed stable disease and 2 showed progressive disease. Overall survival rate was 93% at 19 months of median follow-up after rituximab re-treatment. Median progression-free survival (PFS) after the re-treatment was 5.1 months (95% CI, 4.1 to 5.6 months), and the median PFS after the initial treatment was 8.2 months (95%CI, 5.9 to 11.3 months). Although rituximab re-treatment induced prolonged depletion of normal peripheral blood B cells in all patients, no significant decrease in serum immunoglobulin or complement level was observed. In conclusion, rituximab re-treatment was well tolerated, and it may produce a prolonged PFS in some patients with indolent B-cell NHL who showed initial response to rituximab.

This study was conducted to describe the relationship between pharmacokinetics of CPT-11 and its active metabolite SN-38, and clinical values with special emphasis on the influence of relative weight referring to the appropriateness of a conventional dose adjustment method by body surface area (BSA). Thirty-six patients received 100 mg/m2 of CPT-11 intravenously over 90 min. Body Mass Index (BMI) was used as a measure of relative weight which is calculated from the equation: BMI=weight(kg)/[height(m)]2. The area under the concentration-time curve (AUC) of CPT-11 was significantly correlated with sex, age, poorer creatinine clearance and indocyanine green retention test (ICG). The peak plasma concentration (Cmax) of CPT-11 was significantly correlated with sex a larger BMI, BSA and age. The AUC of SN-38 was significantly correlated with ICG. The volume of distribution at steady state of CPT-11 inversely correlated with BMI. Multiple regression analysis revealed that the best fitting model with significant independent predictors for AUC of CPT-11 included age and sex (F=6.93, R2=0.29). That of Cmax of CPT-11 included sex and BMI (F=8.96, R2=0.35). The only independent predictor of AUC of SN-38 was ICG (F=7.75, R2=0.19). These results indicated that several factors affect pharmacological behaviors of CPT-11 even in patients with normal organ functions. The dose modification method based solely on BSA is not sufficient to reduce interpatient variability of cancer chemotherapy. The influence of relative weight, sex and age on pharmacokinetics/pharmacodynamics should be taken into consideration in every pharmacological approach to establish the ideal dose modification method.

A powerful artificial anti-apoptotic factor will be useful for medical applications of the future therapies for many diseases by prolonging survival of sick cells. For constructing it, we designed the super anti-apoptotic factor by disturbing three intramolecular polar interactions among alpha-helix structures of Bcl-x(L). The resultant mutant Bcl-x(L), named Bcl-xFNK, was expected to make the pore-forming domain more mobile and flexible than the wild-type. When overexpressed in Jurkat cells, Bcl-xFNK was markedly more potent in prolonging survival following apoptosis-inducing treatment with a kind of cell death cytokines (anti-Fas), a protein kinase inhibitor (staurosporine), cell cycle inhibitors (TN-16, camptothecin, hydroxyurea, and trichostatin A), or oxidative stress (hydrogen peroxide and paraquat) than wild-type Bcl-x(L). Furthermore, the transfectants of bcl-xFNK became more resistant against a calcium ionophore and even a heat treatment than wild-type Bcl-x(L). In addition, Bcl-xFNK showed marked anti-apoptotic activity in Chinese hamster ovary and Jurkat cells deprived of serum. Thus, Bcl-xFNK may be the first mutant generated by site-directed mutagenesis of Bcl-x(L) with a gain-of-function phenotype. Interestingly, Bcl-xFNK was found to allow interleukin-3-dependent FDC-P1 to grow without interleukin-3, but not BaF/3. In Bcl-xFNK transfectants of FDC-P1 and Jurkat, the p42/p44 mitogen-activated protein kinase was activated by 2 to 5 times, but not in those of BaF/3 and Chinese hamster ovary. Bcl-xFNK might gain a new function to activate the mitogen-activated protein kinase in a cell-type specific manner. The findings of this study suggest that the central alpha5-alpha6 pore-forming region of anti-apoptotic factor Bcl-x(L) has a pivotal role in suppressing apoptosis.

Background: CHOP is accepted as the gold standard for first line chemotherapy of aggressive non-Hodgkin's lymphoma (NHL). A dose-escalation study of CHOP was conducted to determine the maximal tolerated dose (MTD) and toxicity profile of CHOP at three-week intervals with or without prophylactic recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in patients with aggressive NHL., Patients and Methods: The doses of drugs were escalated from 50 mg/m2 to 70 mg/m2 for doxorubicin and from 750 mg/m2 to 2250 mg/m2 for cyclophosphamide, with conventional doses of vincristine and oral prednisolone. After the MTD was determined without rHuG-CSF, dose escalation was conducted with prophylactic rHuG-CSF., Results: Thirty-three patients with NHL were enrolled into the study. The MTD without prophylactic rHuG-CSF was 70 mg/m2 of doxorubicin and 1250 mg/m2 of cyclophosphamide, with neutropenia as a dose-limiting toxicity. The MTD with prophylactic rHuG-CSF was 70 mg/m2 of doxorubicin and 2250 mg/m2 of cyclophosphamide. The overall response rate was 100% (76% complete response and 24% partial response). Progression-free survival and overall survival at five years were 45% and 66%, respectively., Conclusions: Significant dose escalation of doxorubicin and cyclophosphamide was feasible with prophylactic rHuG-CSF. The efficacy of dose-escalated CHOP should be compared with that of standard CHOP.

The imaging of ultrafine Au, Pd, CdS, and ZnS particles prepared in reverse micelles has been studied by atomic force microscopy (AFM). Mica substrates, derivatized with a monolayer of amine or thiol-terminated silanes, were used to immobilize the particles. The substrates were exposed to reverse micellar solutions containing the particles and were then immersed in appropriate solvent media to remove surfactants. This resulted in a partial coating of the surfaces by the particles. The particle size was estimated as the height of protrusion, shown on the AFM images. The size values for the Pd and CdS particles, thus obtained, were found to be almost identical to those obtained by transmission electron microscopy (TEM), whereas those for the Au and ZnS particles were larger than those obtained by TEM. Scanning electron microscopy showed that the Au particles tended to aggregate on the surfaces, while Pd particles were isolated from one another. Copyright 2000 Academic Press.

The objectives of the present study were to evaluate whether a schedule-dependent pharmacokinetic and/or pharmacodynamic interaction exists between two sequences of docetaxel and doxorubicin administration and to determine the maximal tolerated dose (MTD) of this combination. Patients with chemotherapy-naïve metastatic or recurrent advanced breast cancer were enrolled. In the crossover design, tandem dose escalation of docetaxel and doxorubicin was performed. Docetaxel, in doses ranging from 50-70 mg/m2, was administered for 1 h by drip infusion either just before or after a 5-min bolus i.v. injection of doxorubicin at dosages from 40-50 mg/ m2. The sequence of drug administration was switched after the first course in each patient, and the sequence of drug administration thereafter depended on the patient's choice. Twenty-five patients were initially assessable for toxicity. The MTD in the sequence of doxorubicin after docetaxel was 40 and 50 mg/m2, respectively, with the dose-limiting toxicity of neutropenia. On the other hand, the MTD of the sequence of docetaxel after doxorubicin was 70 and 50 mg/m2, respectively. The dose-limiting toxicities in this sequence were neutropenia and diarrhea. Duration of grade 4 neutropenia in the sequence of docetaxel followed by doxorubicin was significantly longer than that in the alternate sequence (P = 0.0062). However, there was no difference in pharmacokinetic parameters of docetaxel, doxorubicin, and doxorubicinol between the two sequences. The sequence of 50 mg/m2 doxorubicin followed by 60 mg/m2 docetaxel is recommended for subsequent clinical trials for practical reasons.

High-dose chemotherapy with autologous hematopoietic stem cell transplantation has been expected to result in a promising outcome in high risk aggressive non-Hodgkin's lymphoma (NHL). However, it remains unknown what type of initial chemotherapy is optimal, especially regarding progenitor cell mobilization. Sixty-three untreated patients with aggressive NHL in a high risk group were randomized to either a biweekly arm with 8 cycles of standard CHOP or 6 cycles of the dose-escalated CHOP arm with cyclophosphamide 1.5 g/m2 and doxorubicin 70 mg/m2. Lenograstim (glycosylated rHuG-CSF 2.0 microg/kg/day) was administered daily from day 3 to patients in both arms. The mobilization effect of the two regimens on circulating CD34+ cells was evaluated. Twenty-seven of 29 patients in the biweekly CHOP arm and 33 of 34 patients in the dose-escalated CHOP were assessable. Dose-escalated CHOP yielded a significantly higher number of circulating CD34+ cells in the first cycle compared with biweekly CHOP (p=0.05). The peak number of circulating CD34+ cells with biweekly CHOP did not significantly change from cycle to cycle; however, in dose-escalated CHOP, the peak number of circulating CD34+ cells mobilized after the fifth and sixth cycle was lower than after the first cycle (p=0.07 and 0.009, respectively). Routine conventional-dose chemotherapy and low-dose G-CSF can mobilize sufficient CD34+ cells in patients with aggressive NHL. The mobilization kinetics of circulating progenitor cells in patients with aggressive NHL is dependent on the dosage and schedule of CHOP.

We report an 80-year-old man with the lamina lucida type of linear IgA disease, with IgA autoantibodies reactive with 200-kDa and 280-kDa epidermal proteins. The patient presented with widespread bullous lesions on his trunk and extremities without mucosal involvement. Histopathology of lesional skin showed a subepidermal blister with papillary microabscesses of neutrophils and a few eosinophils. Direct immunofluorescence microscopy of perilesional skin showed linear deposits of IgA and C3 at the basement membrane zone. The patient's serum contained IgA autoantibodies that bound exclusively to the epidermal side of 1 mol L-1 NaCl split skin as determined by indirect immunofluorescence microscopy. Circulating IgA autoantibodies to 200- and 280-kDa antigens were detected in the patient's serum by immunoblot analysis using extracts from normal human epidermis and human epidermal keratinocytes. These two antibodies, eluted from individual nitrocellulose membranes, reacted with the epidermal side of 1 mol L-1 NaCl split skin on indirect immunofluorescence microscopy, and bound to hemidesmosomes as determined by immunoperoxidase electron microscopy. This observation suggests the presence of hitherto uncharacterized 200- and 280-kDa hemidesmosomal proteins distinct from BPAG1, BPAG2 and beta4 integrin as target antigens in linear IgA disease.

We conducted a cohort study for 2 years to examine the causal relationship between perceived job stress and mental health. Questionnaire surveys, including a 30-item General Health Questionnaire (GHQ) and a questionnaire on perceived job stress were carried out every 6 months for 2 years. To clarify the causal relationship between job stress and mental health, we followed a group of workers who initially had a GHQ score < or = 7. Out of 462 workers who were thought to be in a healthy mental state, 282 were successfully followed for 2 years. We considered subjects who developed unhealthy mental health states (GHQ score > or = 8) as hazardous cases. To control potential confounding factors, proportional hazard analysis was done. The overall proportion hazardous cases detected in the development of an unhealthy mental health state over two years was 55.7%. Using Cox's proportional hazard model, workers who complained of perceived job stress had a greater hazard than those without job stress. In particular, the item 'poor relationship with superior' showed the largest adjusted hazard ratio [95% confidence interval (CI)] of 1.51 (1.06-2.15). The item 'too much trouble at work' also had a significant hazardous effect on mental health with an adjusted hazard ratio (95% CI) of 1.43 (1.00-2.04). Some specific items of perceived job stress could cause mental ill health in workers.

We describe a 29-year-old woman with rheumatoid arthritis who suffered an acute myocardial infarction 70 days after an initial presentation with toxic epidermal necrolysis (TEN). The trigger for the TEN was probably an over-the-counter anti-influenza treatment containing tipepidine hibenzate. Although the patient had familial hypercholesterolemia, we believe that thrombocytosis, induced by the inflammatory response and metabolic stress resulting from the TEN, may also have played a significant role in the pathogenesis of the myocardial infarction. Although TEN manifests itself principally as a skin disease, the potential for systemic morbidity, including cardiovascular abnormalities, should also be remembered.

The combination of ifosfamide, carboplatin and etoposide (modified ICE), was evaluated for its toxicity and activity in relapsed or refractory aggressive non-Hodgkin's lymphoma. Twenty patients, 14-69 years of age, with relapsed (19 cases) or refractory (one case) aggressive non-Hodgkin's lymphoma were treated with modified ICE therapy, consisting of ifosfamide 6 g/m2 (1.2 g/m2 day 1-5), carboplatin 400 mg/m2 (day 1) and etoposide 500 mg/m2 (100 mg/m2 day 1-5). The regimen was repeated at approximately 28-day intervals. All patients had undergone a doxorubicin-containing regimen before modified ICE therapy. Median total dose of previously received doxorubicin was 406 mg/m2 (range: 200-825 mg/m2). The median interval from diagnosis to modified ICE therapy was 9.4 months (range: 3.6-121 months). Two patients achieved CR and five achieved PR out of 16 patients with measurable lesions (response rate 43.8%; 95% confidence interval 19.0-68.6%). Median overall survival was 227 days (range: 41-552 days) from the start of modified ICE therapy. Myelosuppression was the most serious toxicity, namely 16 patients (80%) and 11 patients (55%) showed grade 4 neutropenia and grade 4 thrombocytopenia after the first course, respectively. Modified ICE therapy might be an active regimen with acceptable toxicity as a salvage chemotherapy in aggressive non-Hodgkin's lymphoma.

Background: Because both the nadir count and the duration of leukopenia after chemotherapy with anticancer drugs are important, a pharmacodynamic model describing the entire time course of leukopenia is valuable. In this study, a pharmacodynamic model was developed to simulate leukopenia., Methods: The model was developed with the 3-hour infusion data of paclitaxel. A concentration-time curve of paclitaxel for each patient estimated by a 3-compartment pharmacokinetic model was used as input to the model, which had 2 compartments corresponding to leukocytes in bone marrow and peripheral blood, respectively. Differentiation stages of myeloid cells sensitive to anticancer drugs were assumed, and exposure to a drug during their sensitive period as a function of time was used to inhibit the production of leukocytes in bone marrow. The model was validated by fitting the data of 24-hour infusion of paclitaxel or 14-day infusion of etoposide., Results: Successful fitting of the leukopenia after a 3-hour infusion of paclitaxel was achieved. The following parameters were estimated: lag-time, 58 +/- 38 (mean +/- SD) hours before the leukocyte count started to decline; exposure giving 50% inhibition of leukocyte production (IC), 12.1 +/- 6.1 microg x h/mL; and sensitive period, 288 +/- 64 hours. These estimations were within physiologic ranges. In validation, leukopenia after 24-hour infusion of paclitaxel or 14-day infusion of etoposide was also explained by the model. Age was significantly negatively correlated with IC of paclitaxel (P = .039)., Conclusions: This mechanistic model describes the time course of leukopenia and may provide a platform for pharmacodynamic analysis of anticancer drugs.