Identification of circulating tumour DNA (ctDNA) from the liquid biopsy results: Findings from an observational cohort study.

Liquid biopsies can be a rapid, cost-effective and non-invasive alternative to tumour biopsies for detecting genetic mutations in somatic tumours. Genetic profiling of liquid biopsies can also be used to identify novel antigens for targeted therapy, provide updated information on disease prognosis and evaluate treatment efficacy. In this study, we aimed to examine mutations that could be identified in liquid biopsy and their distribution in a small study cohort. We studied the genomic profiles of 99 blood samples from 85 patients with 21 different types of cancer using two commercially available liquid biopsy tests. The mean circulating free DNA (cfDNA) concentration was 162.7 ± 352.3 nanograms per 20 millilitres. Amongst cfDNA, the circulating tumour DNA (ctDNA) percentage ranged from 0.006% to 90.6%. With the exception of samples with gene amplification and high microsatellite instability, the number of mutations in each sample varied from zero to 21, with an average of 5.6 mutations in each patient. Amongst these mutations, nonsynonymous mutations were the most frequently observed type of mutation (90% of the sample, with an average frequency of 3.6 mutations per patient). Mutations were observed in 76 different genes. TP53 mutations constituted more than 16% of the detectable mutations, especially in non-small cell lung cancer. All the tumour types, except the ovary, kidney and apocrine gland tumours, harboured at least one type of TP53 mutation. KRAS (mainly in pancreatic cancer) and PIK3CA (mostly in breast cancer) mutations, were responsible for an additional 10% of the mutations in the studied samples. The tumour mutations were specific to each patient, as approximately 94.7% of the mutations were so unique that there was almost no duplication amongst the patients. These findings indicate that liquid biopsy can detect specific molecular changes of tumour, which is useful for precision oncology and personalized cancer treatment.

Clinical utility of paced finger tapping assessment in idiopathic normal pressure hydrocephalus.

Background: The Finger Tapping (F-T) test is useful for assessing motor function of the upper limbs in patients with idiopathic normal pressure hydrocephalus (iNPH). However, quantitative evaluation of F-T for iNPH has not yet been established. The purpose of this study was to investigate the usefulness of the quantitative F-T test and optimal measurement conditions as a motor evaluation and screening test for iNPH. Methods: Sixteen age-matched healthy controls (mean age 73 ± 5 years; 7/16 male) and fifteen participants with a diagnosis of definitive iNPH (mean age 76 ± 5 years; 8/15 male) completed the study (mean ± standard deviation). F-T performance of the index finger and thumb was quantified using a magnetic sensing device. The performance of repetitive F-T by participants was recorded in both not timing-regulated and timing-regulated conditions. The mean value of the maximum amplitude of F-T was defined as M-Amplitude, and the mean value of the maximum velocity of closure of F-T was defined as cl-Velocity. Results: Finger Tapping in the iNPH group, with or without timing control, showed a decrease in M-Amplitude and cl-Velocity compared to the control group. We found the only paced F-T with 2.0 Hz auditory stimuli was found to improve both M-Amplitude and cl-Velocity after shunt surgery. Conclusion: The quantitative assessment of F-T with auditory stimuli at the rate of 2.0 Hz may be a useful and potentially supplemental screening method for motor assessment in patients with iNPH.

Alcohol consumption from midlife and risk of disabling dementia in a large population-based cohort study in Japan.

OBJECTIVES: The association between alcohol consumption and dementia in Japanese is poorly understood, and use of single-point alcohol assessment may cause measurement error. We explored this association in Japanese using repeated alcohol assessments. METHODS: Participants in the Japan Public Health Center-based Prospective Study (JPHC Study) since 1990 and who were alive in 2006 were followed from 2006 until 2016 for dementia ascertainment. Disabling dementia was identified through long-term care insurance records. Alcohol consumption was assessed at the 5-year questionnaire survey (1995-1999) and drinking patterns were assessed on repeated follow-up (2000-2003). We performed Cox proportional hazards models with age as the time-scale with adjustment for various lifestyle factors and medical history using light consumption (<75 g ethanol/week, hereinafter "g") as reference. Analysis considering death as a competing risk was also conducted. RESULTS: Among 42,870 participants aged 54-84 years, 4802 cases of disabling dementia were newly diagnosed. Average years from alcohol assessment until dementia incidence was 14.9 years. Non-drinkers and regular drinkers with ≥450 g at 5 years had adjusted HRs (95% CI) of 1.29 (1.12-1.47) and 1.34 (1.12-1.60). Patterns of long-term abstinence, former drinking, and regular heavy weekly consumption of ≥450 g showed increased adjusted HRs of 1.61 (1.28-2.03), 2.54 (1.93-3.35), and 1.96 (1.49-2.59), respectively. Competing risk analysis yielded similar results. CONCLUSIONS: In Japanese, non-drinking and regular weekly consumption of ≥450 g from midlife were associated with high risk of disabling dementia compared with light drinking.

Coping in Mid- to Late Life and Risk of Mild Cognitive Impairment Subtypes and Dementia: A JPHC Saku Mental Health Study.

BACKGROUND: The relationship between coping in mid- to late life and cognitive functions remains unclear. OBJECTIVE: To investigate the relationship between habitual coping behaviors of a large Japanese population in their mid- to late-lives and their risk of cognitive decline 15 years later. METHODS: Overall 1,299 participants were assessed for coping behaviors (in 2000) and cognition (2014-2015). We used the Stress and Coping Inventory to assess the frequency of six coping behaviors (i.e., consulting, planning, positive reappraisal, avoidance, fantasizing, and self-blame). Logistic regression analyses were conducted to examine odds ratios (ORs) for the diagnosis of mild cognitive impairment (MCI), MCI subtypes (single- and multiple-domain MCI), and dementia for coping behaviors. RESULTS: Among the eligible 1,015 participants (72.6 [SD = 5.5] years old in 2014-2015), the numbers for cognitively normal, single-domain MCI, multiple-domain MCI, and dementia were 650 (64.0%), 116 (11.4%), 213 (21.0%), and 36 (3.5%), respectively. Among the six coping behaviors, avoidant coping was significantly associated with noticeable cognitive decline (multiple-domain MCI and dementia). This association remained significant after adjusting for sex, age, education, diagnosis of current major depressive disorder, past history of ischemic heart disease, diabetes, regular alcohol consumption, and smoking (OR = 2.52, 95% CI = 1.23 to 5.15). No significant association with other coping behaviors was found. CONCLUSION: Avoidant coping in mid- and late life is associated with cognitive decline among older people.

CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury.

Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis, and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153/CD30 signaling in TLT formation and propose targeting the CD153/CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

Glucolipids and lipoteichoic acids affect the activity of SigI, an alternative sigma factor, and WalKR, an essential two-component system, in Bacillus subtilis.

In a Bacillus subtilis ugtP mutant lacking glucolipids, SigI was activated in the log phase, and the activation of SigI in the mutant was suppressed by the expression of native ugtP. By contrast, SigI was inhibited in a yfnI mutant lacking one of the lipoteichoic acid (LTA) synthase genes, and the inhibition was suppressed by the expression of yfnI. A series of mutation analyses of the sigI promoter revealed that the two WalR binding sites were involved in the increase of PsigI -lacZ activity in the ugtP mutant and decrease of the lacZ activity in the yfnI mutant. Transcription from the SigI recognition sequence was enhanced in the ugtP mutant, whereas yfnI disruption inhibited the transcription from the SigA recognition sequence in the sigI promoter. We found that not only SigI but also WalKR, the essential two-component system, was activated in the ugtP mutant and inhibited in the yfnI mutant. The walK mutants with activated WalR exhibited abnormal morphology, but this phenotype was suppressed by the addition of MgSO4 . We conclude that glucolipids and LTA are key compounds in the maintenance of normal cell surface structure in B. subtilis.

Impairment of the visuospatial working memory in the patients with Parkinson's Disease: an fMRI study.

BACKGROUND: Mild cognitive impairment (MCI) is a common symptom in the patients with Parkinson's disease (PD). The characteristics of cognitive impairment in PD are executive function (including working memory) and visuo-perceptual processing. The visuospatial n-back test has the merit of minimizing the influence of educational biases involved in the verbal n-back test. Furthermore, it can assess both visuospatial recognition and working memory in a single test. METHODS: We aimed to clarify the advantage of the visuospatial n-back test as a tool for detecting impairments of working memory in PD. We enrolled 28 right-handed patients with PD (18 males, 10 females) and 12 age-matched healthy controls (HC; 7 males, 5 females). Thirteen patients were classified as MCI (PD-MCI), and 15 as cognitively normal PD (PD-CN). Using functional MRI (fMRI), we explored the specific brain regions associated with the performance of the n-back test in the PD-MCI, PD-CN, and HC groups. The 0-back test assesses visuospatial recognition, while the 1-back and 2-back tests assess visuospatial working memory. Group comparisons were performed for three loads of this test. RESULTS: Patients with PD performed significantly worse in terms of the correct answer rates of all n-back tests compared with HC. fMRI analyses performed during the 2-back test revealed reduced activation in the bilateral dorsolateral prefrontal cortex, middle frontal gyrus (MFG), and parietal lobule in the PD group compared with the HC group. In contrast, the fMRI result during the 0-back test showed only a marginal difference in the frontal lobe. On comparisons of task performance between the PD-MCI and PD-CN groups, we found that the correct answer rate in the 2-back test was lower in the PD-MCI group than in the PD-CN group. However, scores of the 0-back and 1-back tests were not significantly different between the two groups. The fMRI findings revealed that activations within the middle frontal gyrus (MFG) and inferior parietal lobule (IPL) during the 2-back test were reduced in the patients with PD-MCI when compared to those with PD-CN. CONCLUSIONS: This study reports reduced activation of the MFG and IPL in patients with PD-MCI. These regions may be associated with the pathophysiology of working memory impairment in patients with PD, which involves fronto-striatal network dysfunction.

Long-Term Prognosis of Hyperferritinemia Induced by Intravenous Iron Therapy in Patients Undergoing Maintenance Hemodialysis: A 10-Year, Single-Center Study.

Optimal ferritin level in hemodialysis patients between Japan and other countries is controversial. Long-term side effects of iron supplementation in these patients remain unclear. We aimed to elucidate whether past hyperferritinemia in hemodialysis patients was associated with high risk of death and cerebrovascular and cardiovascular diseases (CCVDs). This small retrospective cohort study included approximately 44 patients unintentionally supplemented with excessive intravenous iron. A significantly higher risk of CCVDs was observed in patients with initial serum ferritin levels ≥1000 ng/mL than in the remaining patients. High ferritin levels slowly decreased to <300 ng/mL in a median of 24.2 (10.5-46.5) months without treatment. However, compared with the remaining patients, only patients whose ferritin levels did not decrease to <300 ng/mL steadily had a significantly higher risk of all-cause death (hazard ratio, 9.6). Long-term hyperferritinemia due to intravenous iron therapy is a risk factor for death in maintenance hemodialysis patients. For a prolonged better prognosis, intravenous iron should be carefully administered so as to avoid hyperferritinemia in patients with hemodialysis.

Accessible Rates to Health Information on the Internet in Elderlies Increased Among Fifteen Years.

Yuzawa Town, located in the Niigata prefecture of Japan, is famous for its hot springs. A citizen-centered health promotion program, Yuzawa family health plan, was initiated in 2002. It has been held for seventeen years. We evaluated changes their accessible rates to health information on the internet between 2002 and 2017 in elderlies. 431 and 435 questionnaires were corrected from elderly people at least 65 years old at 2002 and 2017. The accessible rates to health information on the internet in elderlies increased (p<0.001). Profiles of accessible elderlies to health information on the internet were shown. Son and daughter might give them health information. Elderlies having any health concern or anxiety might be afraid to take health information. Accessible elderlies to health information were able to resolve suffering and breach risks by oneself.

Promoting Healthy Eating Habits for College Students Through Creating Dietary Diaries via a Smartphone App and Social Media Interaction: Online Survey Study.

BACKGROUND: Youth in developed countries face the contradictory health problems of obesity and an excessive desire for weight loss. Developing a better health attitude for college students is essential as this period of life establishes future lifestyle and habits. Online interaction on social media can help to improve eating habits by creating dietary diaries through a smartphone app; however, the effects of such interactions for college students have not been examined to date. OBJECTIVE: The aim of this study was to evaluate the potential effectiveness of social media interactions with the use of dietary diaries on a smartphone app to motivate college students in raising self-awareness of their eating habits. METHODS: Forty-two college students in the greater Tokyo area of Japan participated in the study by creating dietary diaries online through a smartphone app and then followed/interacted with each other using social media for 7 consecutive days in September to November 2017. Online surveys were administered at baseline, immediately after creating the dietary diaries, and at 1-month follow up. Participants rated their degree of interest and self-evaluation of eating habits using 7-point scales, and answered multiple choice questions related to their thoughts in choosing meals/drinks among 10 topics. Free descriptions about their overall experience throughout the project were also collected in the follow-up survey. RESULTS: Data from 38 participants who completed all processes were analyzed. Over time, the mean score for degree of interest in eating habits increased from 4.6 to 6.2 (P<.001), while the self-evaluation score decreased from 4.5 to 3.6 (P<.001); these significant differences remained after 1 month (5.3, P=.002; 4.1, P=0.04, respectively). A weak negative correlation (P=.009) was observed between scores for degree of interest and self-evaluation. Participants with lower scores for degree of interest at baseline tended to increase their interest level by more than 2 points above the average (P<.001). Participants gradually thought more about their eating habits from various perspectives when choosing a meal/drink, particularly with respect to maintaining well-balanced diets and introducing diverse ingredients. Participants evaluated their experiences as interesting/fun and reported familiarity with using the smartphone app and social media as the preferred method to keep track of their eating. All participants welcomed communication with fellow participants on social media and motivated each other, in addition to monitoring their eating habits through online dietary diaries. Some participants experienced difficulty, especially when they were busy or faced a lack of internet access. CONCLUSIONS: Through interactions on social media, college students experienced encouragement and developed an interest and critical thinking with respect to their eating habits. This approach, which embraces peer education and peer support with social media, holds promise for the future of youth health promotion. Further examination will be needed to explore how to sustain this level of heightened awareness.

Population modelling and genetics of a critically endangered Madagascan palm Tahina spectabilis.

Madagascar is home to 208 indigenous palm species, almost all of them endemic and >80% of which are endangered. We undertook complete population census and sampling for genetic analysis of a relatively recently discovered giant fan palm, the Critically Endangered Tahina spectablis in 2008 and 2016. Our 2016 study included newly discovered populations and added to our genetic study. We incorporated these new populations into species distribution niche model (SDM) and projected these onto maps of the region. We developed population matrix models based on observed demographic data to model population change and predict the species vulnerability to extinction by undertaking population viability analysis (PVA). We investigated the potential conservation value of reintroduced planted populations within the species potential suitable habitat. We found that the population studied in 2008 had grown in size due to seedling regeneration but had declined in the number of reproductively mature plants, and we were able to estimate that the species reproduces and dies after approximately 70 years. Our models suggest that if the habitat where it resides continues to be protected the species is unlikely to go extinct due to inherent population decline and that it will likely experience significant population growth after approximately 80 years due to the reproductive and life cycle attributes of the species. The newly discovered populations contain more genetic diversity than the first discovered southern population which is genetically depauperate. The species appears to demonstrate a pattern of dispersal leading to isolated founder plants which may eventually lead to population development depending on local establishment opportunities. The conservation efforts currently put in place including the reintroduction of plants within the species potential suitable habitat if maintained are thought likely to enable the species to sustain itself but it remains vulnerable to anthropogenic impacts.

Stabilizing cardiac ryanodine receptor prevents the development of cardiac dysfunction and lethal arrhythmia in Ca2+/calmodulin-dependent protein kinase IIδc transgenic mice.

AIMS: Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been shown to induce aberrant Ca2+ release from the cardiac ryanodine receptor (RyR2) in various diseased hearts. However, the precise pathogenic mechanism remains to be elucidated. Here, we investigated the effect of dantrolene (DAN): a RyR2 stabilizer on local Ca2+ release, cardiac function, and lethal arrhythmia in CaMKIIδc transgenic (TG) mice. METHODS AND RESULTS: The TG mice showed an increase in left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) with a reduction in LV fractional shortening (LVFS). The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII increased in TG mice. In TG cardiomyocytes, peak cell shortening (CS) decreased, and the frequency of spontaneous Ca2+ transients (sCaTs) increased. Endogenous RyR2-associated calmodulin (CaM) markedly decreased in TG cardiomyocytes. After chronic DAN treatment for 1 month, LVESD (but not LVEDD) decreased with an increase in LVFS. In the chronic DAN-treated cardiomyocytes, CS increased, sCaTs decreased, and the endogenous CaM binding to RyR2 normally restored. The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII remained elevated even after DAN treatment. Moreover, in TG mice, chronic DAN treatment prevented sustained ventricular tachycardia induced by epinephrine. CONCLUSIONS: Defective association of CaM with RyR2 is most likely to be involved in the pathogenesis of CaMKII-mediated cardiac dysfunction and lethal arrhythmia.

G790del mutation in DSC2 alone is insufficient to develop the pathogenesis of ARVC in a mouse model.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease that causes heart failure and/or sudden cardiac death. Several desmosomal genes (DSC2, PKG, PKP2, DSP, and RyR2) are thought to be the causative gene involved in ARVC. Out of them, DSC2 mutations account for 2% of ARVC genetic abnormalities. This study aimed to clarify the effect of G790del mutation in DSC2 on the arrhythmogenic mechanism and cardiac function in a mouse model. RESULT: Neither the heterozygous +/G790del nor homozygous G790del/G790del mice showed structural and functional defects in the right ventricle (RV) or lethal arrhythmia. The homozygous G790del/G790del 6-month-old mice slightly showed left ventricular (LV) dysfunction. Cell shortening decreased with prolongation of intracellular Ca2+ transient in cardiomyocytes isolated from the homozygous G790del/G790del mice, and spontaneous Ca2+ transients were frequently observed in response to isoproterenol. CONCLUSIONS: G790del mutation in DSC2 was not relevant to the pathogenesis of ARVC, but showed a slight contractile dysfunction and Ca2+ dysregulation in the LV.

Reproductive history and risk of cognitive impairment in Japanese women.

OBJECTIVE: While exposure to endogenous estrogen may be associated with better cognitive performance, it is still unclear whether it has an association with mild cognitive impairment (MCI) or dementia. The aim of this study was to clarify the effects of reproductive history, as a surrogate marker of exposure to endogenous estrogen, on the risk of cognitive impairment (MCI or dementia) in women. STUDY DESIGN: A total of 747 women aged 40-59 years in the Saku area (Nagano Prefecture) were followed as part of the Japan Public Health Center-based Prospective (JPHC) Study, which started in 1990. Participants had undergone a mental health examination in 2014-2015. MAIN OUTCOME MEASURES: We used multiple logistic regression to analyze the association between reproductive history, obtained at baseline and 10-year follow-up, with current cognitive impairment diagnosed by a trained psychiatrist, adjusting for various lifestyle factors. RESULTS: Among 670 eligible women, current cognitive impairment was diagnosed in 227, 196 of whom had MCI and 31 dementia. A longer reproductive period had a significantly inverse association with cognitive impairment (P-trend = 0.032). In particular, women with a reproductive period ≥38 years compared with ≤33 years had a significantly lower risk of cognitive impairment (multivariable adjusted odds ratio=0.62, 95% confidence interval=0.40-0.96). CONCLUSIONS: A longer reproductive period was associated with a lower risk of cognitive impairment, which suggests that a longer exposure to endogenous estrogen may have a protective effect against cognitive impairment.

Impaired Motor Skill Acquisition Using Mirror Visual Feedback Improved by Transcranial Direct Current Stimulation (tDCS) in Patients With Parkinson's Disease.

Recent non-invasive brain stimulation techniques in combination with motor training can enhance neuroplasticity and learning. It is reasonable to assume that such neuroplasticity-based interventions constitute a useful rehabilitative tool for patients with Parkinson's Disease (PD). Regarding motor skill training, many kinds of tasks that do not involve real motor movements have been applied to PD patients. The purpose of this study is to elucidate whether motor skill training using mirror visual feedback (MVF) is useful to patients with PD in order to improve untrained hand performance dependent on the time course of training; and whether MVF combined with anodal transcranial direct current stimulation (tDCS) over primary motor cortex (M1) causes an additional effect based on increased motor cortical excitability. Eighteen right-handed patients with PD in the off-medication state and 10 age-matched healthy subjects (HS) performed four sessions of right-hand ball rotation using MVF (intervention) on two separate days, 1 week apart (day 1 and day 2). HS subjects received only sham stimulation. The intervention included four sessions of motor-skill training using MVF for 20 min comprised of four sets of training for 30 s each. PD patients were randomly divided into two intervention groups without or with anodal tDCS over the right M1 contralateral to the untrained hand. As the behavior evaluation, the number of ball rotations of the left hand was counted before (pre) and immediately after (post) intervention on both days (pre day 1, post day 1, pre day 2, and post day 2). Motor evoked potential (MEP), input-output function, and cortical silent period were recorded to evaluate the motor cortical excitatory and inhibitory system in M1 pre day 1 and post day 2. The number of ball rotations of the left hand and the facilitation of MEP by intervention were significantly impaired in patients with PD compared to HS. In contrast, if anodal tDCS was applied to right M1 of patients with PD, the number of ball rotations in accordance with I-O function at 150% intensity was significantly increased after day 1 and retained until day 2. This finding may help provide a new strategy for neurorehabilitation improving task-specific motor memory without real motor movements in PD.

CaMKII-mediated phosphorylation of RyR2 plays a crucial role in aberrant Ca2+ release as an arrhythmogenic substrate in cardiac troponin T-related familial hypertrophic cardiomyopathy.

AIMS: Cardiac Troponin T (TnT) mutation-linked familial hypertrophic cardiomyopathy (FHC) is known to cause sudden cardiac death at a young age. Here, we investigated the role of the Ca2+ release channel of the cardiac sarcoplasmic reticulum (SR), ryanodine receptor (RyR2), in the pathogenic mechanism of lethal arrhythmia in FHC-related TnT-mutated transgenic mice (TG; TnT-delta160E). METHODS AND RESULTS: In TG cardiomyocytes, the Ca2+ spark frequency (SpF) was much higher than that in non-TG cardiomyocytes. These differences were more pronounced in the presence of isoproterenol (ISO; 10 nM). This increase in SpF was largely reversed by a CaMKII inhibitor (KN-93), but not by a protein kinase A inhibitor (H89). CaMKII phosphorylation at Ser2814 in RyR2 was increased significantly in TG. Spontaneous Ca2+ transients (sCaTs) after cessation of a 1-5 Hz pacing, frequently observed in ISO-treated TG cardiomyocytes, were also attenuated by KN-93, but not by H89. The RyR2 stabilizer dantrolene attenuated Ca2+ sparks and sCaTs in ISO-treated TG cardiomyocytes, indicating that the mutation-linked aberrant Ca2+ release is mediated by destabilized RyR2. CONCLUSIONS: In FHC-linked TnT-mutated hearts, RyR2 is susceptible to CaMKII-mediated phosphorylation, presumably because of a mutation-linked increase in diastolic [Ca2+]i, causing aberrant Ca2+ release leading to lethal arrhythmia.

[Suppressive Effects of Extract of Cedar Wood on Heat-induced Expression of Cellular Heat Shock Protein].

In recent years, highly antimicrobial properties of cedar heartwood essential oil against the wood-rotting fungi and pathogenic fungi have been reported in several papers. Antimicrobial properties against oral bacteria by hinokitiol contained in Thujopsis have been also extensively studied. The relation of naturally derived components and human immune system has been studied in some previous papers. In the present study, we focused on Japanese cedar, which has the widest artificial afforestation site in the country among various tree species. Extract oil was obtained from mixture of sapwood and heartwood of about 40-year cedar grown in Oguni, Kumamoto, Japan. We examined the influence of extract components from Japanese cedar woods on the expression of heat shock protein 70 (Hsp70) during heating, and on the micronucleus formation induced by the treatment of bleomycin as a DNA damaging agent. Cell lines used in this study were human fetal glial cells (SVGp12) and human glioma cells (MO54). Remarkable suppression of the Hsp70 expression induced by heating at 43°C was detected by the treatment of cedar extract in both SVGp12 and MO54 cells. We also found that cedar extract had an inhibitory tendency to reduce the micronucleus formation induced by bleomycin. From these results, the extract components from Japanese cedar woods would have an inhibitory effect of the stress response as a suppression of the heat-induced Hsp70 expression, and might have a reductive effect on carcinogenicity.

Reduction of methotrexate and glucocorticoids use after the introduction of biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis in daily practice based on the IORRA cohort.

OBJECTIVES: To evaluate usage patterns for methotrexate (MTX) and/or glucocorticoids in rheumatoid arthritis (RA) patients receiving biological disease-modifying antirheumatic drugs (bDMARDs) in daily practice. METHODS: Data from RA patients who commenced treatment with bDMARDs (infliximab [IFX], etanercept [ETN], tocilizumab [TCZ], or adalimumab [ADA]) from 2008 to 2010 were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. The proportions of patients taking concomitant MTX and glucocorticoids and doses of these medications were evaluated before and 2 years after initiation of each bDMARD. RESULTS: A total of 470 RA patients who had initiated a bDMARD (IFX: n = 98, ETN: n = 181, TCZ: n = 90, and ADA: n = 101) were evaluated. The proportion of patients taking MTX decreased over time among ETN and TCZ users, while it increased among ADA users. The MTX dose decreased over time among IFX, ETN, and TCZ users, but not among ADA users. Although the rate of glucocorticoid use and dose decreased after bDMARD initiation in all four bDMARD groups, approximately 50% of patients continued to receive glucocorticoids 2 years after bDMARD initiation. CONCLUSION: MTX and glucocorticoid use and doses in daily practice were commonly reduced after the initiation of bDMARDs, with the dose adjustment varied depending on the bDMARD.

Exercise-induced acute renal failure in a trainee cyclist without hypouricemia: Successful athletic career post-treatment.

Acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise (ALPE) is exercise-induced acute renal failure that occurs without myoglobinuria. We describe a typical case involving an 18-year-old man. Generally, patients with ALPE are advised to avoid anaerobic exercise due to risk of recurrence, but our patient continued and went on to become a professional cyclist without relapse. About 51% of ALPE cases involve patients with renal hypouricemia. His serum uric acid levels were rather high, at 6.4 mg/dL. He is the first patient with ALPE to succeed as a professional athlete in an anaerobic sport.